WorldWideScience

Sample records for immediate-release oral formulations

  1. Formulation and Dissolution Study of Valsartan Immediate Release Tablets

    Directory of Open Access Journals (Sweden)

    B. Brahmaiah*, K. Sasikanth, Sreekanth Nama , P.Suresh, Patan Adam Khan

    2013-06-01

    Full Text Available In the present study, design of oral immediate release tablets of Valsartan by direct compression techniquewas carried out. The main aim and objective of the work is to formulate immediate release tablets usingdifferent direct compression vehicles (DCV’S in different ratios. The main motive is to compare thedissolution profile of these formulations and conclude the best formulation which release drug at a fasterrate. To determine the best fit dissolution profile for the dosage forms. Valsartan tablets were formulated byusing microcrystalline cellulose (diluents, potato starch, acacia (binder and magnesium stearate(lubricant. The granules were compressed into tablets and were subjected to dissolution studies. Thedissolution profile of the formulation F2 was found to have better dissolution rate compared to others. TheIn-vitro dissolution studies of all the formulations were conducted and the results were obtained, it wasconcluded that formulation F2 was the best with fast release of drug compared to others.

  2. FORMULATION AND EVALUATION OF CANDESARTAN CILEXETIL IMMEDIATE RELEASE TABLETS

    Directory of Open Access Journals (Sweden)

    Jampani Neeharika

    2012-07-01

    Full Text Available Candesartan Cilexetil is an esterified prodrug of Candesartan, a non-peptide angiotensin II type-1(AT1 receptor antagonist used in the treatment of hypertension and congestive heart failure. Candesartan meets the requirement of high potency but it is poorly absorbed when administered orally. Therefore, the prodrug Candesartan Cilexetil is developed. It is soluble in methylene chloride, half life is 5.1 to 10.5hrs and bioavailability is 15%. It is marketed as conventional tablets. In this work, it is formulated as immediate release tablets by changing the concentration of ingredients. For many drug substances, conventional immediate-release formulations provide clinically effective therapy while maintaining the required balance of pharmacokinetic and pharmacodynamic profiles with in acceptable level of safety to the patient. The immediate release formulation of Candesartan Cilexetil is prepared by wet granulation method to provide rapid onset of action. In order to optimize the best formulation, ten different trials are developed. The main ingredients used in the formulation are lactose monohydrate, PEG, calcium CMC and MCC. Weight variation, thickness, friability, disintegration time, in-vitro release, pharmaceutical assay are studied as response variables. The formulation containing 38% of MCC is selected as an optimized product in which the different physical properties and in-vitro release profile showed best comparable results with innovator product.

  3. FORMULATION AND DISSOLUTION STUDY OF DILTIAZEM HYDROCHLORIDE IMMEDIATE RELEASE TABLETS

    Directory of Open Access Journals (Sweden)

    BRAHMAIAH BONTHAGARALA

    2014-08-01

    Full Text Available Objective: The main aim and objective of the work is to formulate immediate release tablets using different direct compression vehicles (DCV’S in different ratios. Methods: In the present study, design of oral immediate release tablets of Diltiazem hydrochloride by direct compression technique was carried out. Results: The main motive is to compare the dissolution profile of these formulations and conclude the best formulation which release drug at a faster rate . To determine the best fit dissolution profile for the dosage forms. Diltiazem hydrochloride tablets were formulated by using microcrystalline cellulose (diluent, potato starch, acacia (binder and magnesium stearate (lubricant. The granules were compressed into tablets and were subjected to dissolution studies. The dissolution profile of the formulation F2 was found to have better dissolution rate compared to others. Conclusion: The Invitro dissolution studies of all the formulations were conducted and the results were obtained, it was concluded that formulation F2 was the best with fast release of drug compared to others.

  4. Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

    Science.gov (United States)

    Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2007-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

  5. Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

    Directory of Open Access Journals (Sweden)

    Kim YH

    2015-07-01

    Full Text Available Yo Han Kim,1 Jong-Lyul Ghim,2 Jin Ah Jung,2 Sang-Heon Cho,3 Sangmin Choe,4 Hee Youn Choi,1 Kyun-Seop Bae,1 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, 2Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, 3Department of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon, 4Clinical Trials Center, Pusan National University Hospital, Busan, Republic of Korea Background: A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR and immediate-release (IR formulations of cilostazol after multiple oral doses in healthy male Korean volunteers.Methods: This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT, the measured peak plasma concentration at steady state (Cmax,ss, and the time to reach Cmax,ss (tmax,ss were analyzed using a noncompartmental method. Results: A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD] AUCT (96–120 hours values for SR and IR were 27,378.0 (10,301.6 ng·h/mL and 27,860.3 (7,152.3 ng·h/mL, respectively. The mean (SD Cmax,ss values were 2,741.4 (836.0 ng/mL and 2,051.0 (433.2 ng/mL, respectively. The median tmax,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals of

  6. Biowaiver monographs for immediate release solid oral dosage forms: prednisone.

    Science.gov (United States)

    Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2007-06-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisone are reviewed. Due to insufficient data prednisone cannot be definitively classified according to the current Biopharmaceutics Classification System (BCS) criteria as both the solubility and the permeability of prednisone are on the borderline of the present criteria of BCS Class I. Prednisone's therapeutic indications and therapeutic index, pharmacokinetics and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

  7. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam.

    Science.gov (United States)

    Petruševska, Marija; Berglez, Sandra; Krisch, Igor; Legen, Igor; Megušar, Klara; Peternel, Luka; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Mehta, Mehul; Polli, James E; Shah, Vinod P; Dressman, Jennifer

    2015-09-01

    Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.

  8. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin.

    Science.gov (United States)

    Goodarzi, Navid; Barazesh Morgani, Ahmadreza; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Mehta, Mehul U; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

    2016-04-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.

  9. Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

    NARCIS (Netherlands)

    Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2007-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongl

  10. Biowaiver monographs for immediate release solid oral dosage forms: metronidazole.

    Science.gov (United States)

    Rediguieri, Camila F; Porta, Valentina; G Nunes, Diana S; Nunes, Taina M; Junginger, Hans E; Kopp, Sabine; Midha, Kamal K; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M

    2011-05-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing metronidazole are reviewed. Metronidazole can be assigned to Biopharmaceutics Classification System Class I. Most BE studies that were identified reported the investigated formulations to be bioequivalent, indicating the risk of bioinequivalence to be low. Formulations showing differences in bioavailability showed dissimilarities in in vitro dissolution profiles. Furthermore, metronidazole has a wide therapeutic index. It is concluded that a biowaiver for solid IR formulations is justified, provided: (a) the test product and its comparator are both rapidly dissolving; (b) meet similarity of the dissolution profiles at pH 1.2, 4.5, and 6.8; (c) the test product contains only excipients present in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form; and (d) if the test product contains sorbitol, sodium laurilsulfate, or propylene glycol, the test product needs to be qualitatively and quantitatively identical to its comparator with respect to these excipients [corrected]..

  11. Biowaiver monographs for immediate release solid oral dosage forms: isoniazid.

    Science.gov (United States)

    Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2007-03-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and permeability are inconclusive, suggesting this API to be on the borderline of BCS Class I and III. For a number of excipients, an interaction with the permeability is extreme unlikely, but lactose and other deoxidizing saccharides can form condensation products with isoniazid, which may be less permeable than the free API. A biowaiver is recommended for IR solid oral drug products containing isoniazid as the sole API, provided that the test product meets the WHO requirements for "very rapidly dissolving" and contains only the excipients commonly used in isoniazid products, as listed in this article. Lactose and/or other deoxidizing saccharides containing formulations should be subjected to an in vivo BE study.

  12. Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

    NARCIS (Netherlands)

    Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M

    2006-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned

  13. Biowaiver monographs for immediate release solid oral dosage forms: levofloxacin.

    Science.gov (United States)

    Koeppe, Marcelle O; Cristofoletti, Rodrigo; Fernandes, Eduardo F; Storpirtis, Silvia; Junginger, Hans E; Kopp, Sabine; Midha, Kamal K; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M

    2011-05-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to Class I. No problems with BE of IR levofloxacin formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. In addition, levofloxacin has a wide therapeutic index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage forms containing levofloxacin as the single API provided that (a) the test product contains only excipients present in IR levofloxacin drug products that have been approved in International Conference on Harmonization (ICH) or associated countries and which have the same dosage form; (b) both the test and comparator dosage form are "very rapidly dissolving" or "rapidly dissolving" with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.

  14. Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

    OpenAIRE

    Vogt, M.; Derendorf, H; Krämer, J.; Junginger, H E; Midha, K.K.; Shah, V. P.; Stavchansky, S; Dressman, J B; Barends, D M

    2007-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into considerat...

  15. Biowaiver monographs for immediate release solid oral dosage forms: piroxicam.

    Science.gov (United States)

    Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B

    2014-02-01

    Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo.

  16. Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

    OpenAIRE

    Jantratid, E; Prakongpan, S.; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K.K.; Barends, D M

    2006-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) pr...

  17. Biowaiver monographs for immediate release solid oral dosage forms: furosemide.

    Science.gov (United States)

    Granero, G E; Longhi, M R; Mora, M J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2010-06-01

    Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.

  18. Biowaiver monographs for immediate release solid oral dosage forms: acetazolamide.

    Science.gov (United States)

    Granero, G E; Longhi, M R; Becker, C; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2008-09-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamide's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.

  19. Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

    Science.gov (United States)

    Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M

    2006-05-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are "rapidly dissolving" as per BCS.

  20. Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.

    Science.gov (United States)

    Potthast, H; Dressman, J B; Junginger, H E; Midha, K K; Oeser, H; Shah, V P; Vogelpoel, H; Barends, D M

    2005-10-01

    Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.

  1. Biowaiver monographs for immediate release solid oral dosage forms: pyrazinamide.

    Science.gov (United States)

    Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2008-09-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing pyrazinamide as the only active pharmaceutical ingredient (API) are reviewed. Pyrazinamide is BCS Class III, with linear absorption over a wide dosing range. The risk of bioinequivalence is estimated to be low. Depending on the definition used, pyrazinamide can be classified as a narrow therapeutic index (NTI) drug, which is usually a caveat to biowaiving but may be deemed acceptable if the Summary of Product Characteristics (SmPCs) of the test product stipulates the need for regular monitoring of liver function. It is concluded that a biowaiver can be recommended for IR solid oral dosage only when the test product (a) contains only excipients present in pyrazinamide IR solid oral drug products approved in ICH or associated countries, (b) these excipients are present in amounts normally used in IR solid oral dosage forms, (c) the test product is very rapidly dissolving, (d) the SmPC of the test product indicates the need for monitoring of the patient's liver function.

  2. Biowaiver monographs for immediate release solid oral dosage forms: rifampicin.

    Science.gov (United States)

    Becker, C; Dressman, J B; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2009-07-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing rifampicin as the only Active Pharmaceutical Ingredient (API) are reviewed. Rifampicin's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and absolute BA data indicate that rifampicin is a BCS Class II drug. Of special concern for biowaiving is that many reports of failure of IR solid oral dosage forms of rifampicin to meet BE have been published and the reasons for these failures are yet insufficiently understood. Moreover, no reports were identified in which in vitro dissolution was shown to be predictive of nonequivalence among products. Therefore, a biowaiver based approval of rifampicin containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.

  3. Biowaiver monographs for immediate release solid oral dosage forms: aciclovir.

    Science.gov (United States)

    Arnal, J; Gonzalez-Alvarez, I; Bermejo, M; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2008-12-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths.

  4. Biowaiver monographs for immediate release solid oral dosage forms: efavirenz.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Nair, Anita; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

    2013-02-01

    Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.

  5. Biowaiver monographs for immediate release solid oral dosage forms: lamivudine.

    Science.gov (United States)

    Strauch, S; Jantratid, E; Dressman, J B; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2011-06-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfills the BCS dissolution criteria for very rapidly dissolving; a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.

  6. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine.

    Science.gov (United States)

    Gajendran, Jayachandar; Krämer, Johannes; Shah, Vinod P; Langguth, Peter; Polli, James; Mehta, Mehul; Groot, D W; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Dressman, Jennifer B

    2015-10-01

    Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.

  7. Biowaiver monographs for immediate release solid oral dosage forms: amitriptyline hydrochloride.

    Science.gov (United States)

    Manzo, R H; Olivera, M E; Amidon, G L; Shah, V P; Dressman, J B; Barends, D M

    2006-05-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.

  8. Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate.

    Science.gov (United States)

    Jantratid, E; Strauch, S; Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2010-04-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for "very rapidly dissolving" or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are "rapidly dissolving.".

  9. Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride.

    Science.gov (United States)

    Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2008-04-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy.

  10. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    Science.gov (United States)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.

  11. Biowaiver monographs for immediate-release solid oral dosage forms: Zidovudine (azidothymidine).

    Science.gov (United States)

    Soares, Kelen C C; Rediguieri, Camila F; Souza, Jacqueline; Serra, Cristina Helena R; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer

    2013-08-01

    Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.

  12. Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

    Science.gov (United States)

    Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

    2014-12-01

    Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8.

  13. Biowaiver monographs for immediate-release solid oral dosage forms: stavudine.

    Science.gov (United States)

    Silva, Arthur L L; Cristofoletti, Rodrigo; Storpirtis, Silvia; Sousa, Varley D; Junginger, Hans E; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M

    2012-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing stavudine (d4T) are reviewed. According to Biopharmaceutics Classification System (BCS), d4T can be assigned to BCS class I. No problems with BE of IR d4T formulations containing different excipients and produced by different manufacturing methods have been reported and, hence, the risk of bioinequivalence caused by these factors appears to be low. Furthermore, d4T has a wide therapeutic index. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing d4T as the single active pharmaceutical ingredient (API) provided that (a) the test product contains only excipients present in the IR d4T drug products that have been approved in a number of countries for the same dosage form, and (b) both test product and its comparator are either "very rapidly dissolving" or "rapidly dissolving" with similarity of dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8.

  14. Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen.

    Science.gov (United States)

    Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B

    2012-10-01

    Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, C(max) ) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of C(max) for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.

  15. Comparative pharmacokinetics of two modified-release oral morphine formulations (Reliadol® and Kapanol®) and an immediate-release morphine tablet (Morfin 'DAK') in healthy volunteers

    DEFF Research Database (Denmark)

    Bochner, F.; Somogyi, A.A.; Danz, C.

    1999-01-01

    , its metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), after ingestion of Reliadol® (2 x 30 mg capsules) compared with Kapanolo (3 x 20 mg) [Glaxo Wellcome Australia Ltd] and an immediate-release morphine tablet (Morfin 'DAK', 30 mg; Nycomed Denmark A/S). Design and Setting...

  16. Biowaiver monographs for immediate-release solid oral dosage forms: quinine sulfate.

    Science.gov (United States)

    Strauch, Stefanie; Dressman, Jennifer B; Shah, Vinod P; Kopp, Sabine; Polli, James E; Barends, Dirk M

    2012-02-01

    The biowaiver approach permits evaluation of bioequivalence (BE) using a set of laboratory tests, obviating the need for expensive and time-consuming pharmacokinetic BE studies provided that both the active pharmaceutical ingredient and the formulations can meet the specified criteria. In the present monograph, the biowaiver-relevant data including solubility and permeability data, therapeutic use and therapeutic index, pharmacokinetic properties, reported excipient interactions, and BE/bioavailability studies of quinine sulfate are itemized and discussed. Quinine sulfate has borderline solubility characteristics and, on the whole, is highly permeable. Thus, depending on the jurisdiction, it is assigned to Biopharmaceutics Classification System class I or II. Although these characteristics would suggest a low risk of bioinequivalence among oral quinine products, a recent pharmacokinetic study showed bioinequivalence of two products. Even though quinine does not, strictly speaking, fit the definition of a narrow therapeutic index drug, it shows dose-related and, in some cases, irreversible side effects and toxicities at concentrations not far above the therapeutic concentration range. Taking all relevant aspects into consideration, a biowaiver cannot be recommended for new quinine immediate-release multisource products or major post-approval changes of already marketed quinine products, and in such cases, BE should be evaluated using an in vivo BE study.

  17. Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride.

    Science.gov (United States)

    Kortejärvi, H; Yliperttula, M; Dressman, J B; Junginger, H E; Midha, K K; Shah, V P; Barends, D M

    2005-08-01

    Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study.

  18. IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods.

    Science.gov (United States)

    Buch, P; Holm, P; Thomassen, J Q; Scherer, D; Kataoka, M; Yamashita, S; Langguth, P

    2010-10-01

    In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.

  19. Biowaiver monographs for immediate release solid oral dosage forms: metoclopramide hydrochloride.

    Science.gov (United States)

    Stosik, A G; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2008-09-01

    Literature data are reviewed relevant to the decision for a biowaiver of immediate release (IR) solid oral dosage forms containing metoclopramide hydrochloride. In addition, new solubility data, obtained under Biopharmaceutics Classification System (BCS) conditions are presented. Metoclopramide HCl is conservatively assigned to BCS Class III. Taken also into consideration excipient interactions reported in metoclopramide drug products, its pharmacokinetic properties and therapeutic use and therapeutic index, a biowaiver can be recommended when: (a) the test product contains only excipients present also in metoclopramide HCl containing IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) in amounts in normal use in IR solid oral dosage forms, and (c) the test product and the comparator both comply with the criteria for very rapidly dissolving.

  20. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine.

    Science.gov (United States)

    Olsson, B; Szamosi, J

    2001-01-01

    To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers. Nonblind, randomised, 2-way crossover trial. 19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping. Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined. 17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated. The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower

  1. Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

    Science.gov (United States)

    Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer

    2017-10-01

    Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  2. Biowaiver monographs for immediate release solid oral dosage forms: ciprofloxacin hydrochloride.

    Science.gov (United States)

    Olivera, M E; Manzo, R H; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2011-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing ciprofloxacin hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ciprofloxacin hydrochloride's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and BA data indicate that ciprofloxacin hydrochloride is a BCS Class IV drug. Therefore, a biowaiver based approval of ciprofloxacin hydrochloride containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.

  3. Biowaiver monographs for immediate release solid oral dosage forms: quinidine sulfate.

    Science.gov (United States)

    Grube, S; Langguth, P; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2009-07-01

    Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products.

  4. Biowaiver monographs for immediate-release solid oral dosage forms: primaquine phosphate.

    Science.gov (United States)

    Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

    2012-03-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing the antimalarial drug primaquine phosphate as the only active pharmaceutical ingredient (API) are reviewed. On the basis of permeability data and solubility studies, primaquine phosphate was found to be "highly soluble" and "highly permeable" API, thus conforming to Class I of the Biopharmaceutical Classification System (BCS). It has a wide therapeutic index. BCS-conform dissolution studies showed the products to be rapidly dissolving. No data pertaining to BE or bioinequivalence of IR primaquine phosphate products could be located in open literature. On the basis of the available data, a biowaiver-procedure-based approval can be recommended for IR solid oral dosage forms of primaquine phosphate, provided the generic product contains excipients present in products already approved by the International Conference on Harmonisation or associated countries in similar amounts and the test and reference products meet the dissolution criteria for "rapidly dissolving" (>85% drug release in 30 min in standard media at pH 1.2, 4.5, and 6.8; similarity factor (f(2)) > 50) or "very rapidly dissolving" products (>85% drug release in 15 min in standard media at pH 1.2, 4.5, and 6.8).

  5. Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium.

    Science.gov (United States)

    Chuasuwan, B; Binjesoh, V; Polli, J E; Zhang, H; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M

    2009-04-01

    Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8.

  6. Biowaiver monographs for immediate-release solid oral dosage forms: codeine phosphate.

    Science.gov (United States)

    Dahan, Arik; Wolk, Omri; Zur, Moran; Amidon, Gordon L; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

    2014-06-01

    The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the "highly soluble" criteria according to World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence (BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies.

  7. Biowaiver monographs for immediate release solid oral dosage forms: mefloquine hydrochloride.

    Science.gov (United States)

    Strauch, S; Jantratid, E; Dressman, J B; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2011-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.

  8. Biowaiver monograph for immediate-release solid oral dosage forms: bisoprolol fumarate.

    Science.gov (United States)

    Charoo, Naseem A; Shamsher, Areeg A A; Lian, Lai Y; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

    2014-02-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol is classified as a Class I API according to the current Biopharmaceutics Classification System (BCS). In addition to the BCS class, its therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability problems are taken into consideration. Qualitative compositions of IR tablet dosage forms of bisoprolol with a marketing authorization (MA) in ICH (International Conference on Harmonisation) countries are tabulated. It was inferred that these tablets had been demonstrated to be bioequivalent to the innovator product. No reports of failure to meet BE standards have been made in the open literature. On the basis of all these pieces of evidence, a biowaiver can currently be recommended for bisoprolol fumarate IR dosage forms if (1) the test product contains only excipients that are well known, and used in normal amounts, for example, those tabulated for products with MA in ICH countries and (2) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  9. Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Yoon S

    2014-01-01

    Full Text Available Seonghae Yoon,1,* Howard Lee,2,* Tae-Eun Kim,1 SeungHwan Lee,1 Dong-Hyun Chee,3 Joo-Youn Cho,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, 3AbbVie Ltd., Seoul, Republic of Korea *These authors contributed equally to this work Background: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER formulation with that of the reference immediate-release (IR formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. Methods: A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22–48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax and area under the plasma concentration versus time curve over 24 hours after dosing (AUC0–24h, were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. Results: A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC0–24h were contained within the conventional bioequivalence range of 0.80–1.25 (0.94 [0.88–1.01], although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC0–24h was not affected. There were no serious adverse events and both formulations were

  10. Piroxicam immediate release formulations: A fasting randomized open-label crossover bioequivalence study in healthy volunteers.

    Science.gov (United States)

    Helmy, Sally A; El-Bedaiwy, Heba M

    2014-11-01

    Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated.

  11. Comparison of single-dose and multiple-dose pharmacokinetics between two formulations of hydrocodone bitartrate/acetaminophen: immediate-release versus biphasic immediate- release/extended release

    Directory of Open Access Journals (Sweden)

    Devarakonda K

    2015-09-01

    Full Text Available Krishna Devarakonda,1 Kenneth Kostenbader,2 Michael J Giuliani,3 Jim L Young4 1Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA; 2Independent Pharmaceuticals Professional, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA; 3Research and Development, 4Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA Objective: This study aimed to compare the single-dose and steady-state pharmacokinetics (PK of biphasic immediate-release (IR/extended-release (ER hydrocodone bitartrate (HB/acetaminophen (APAP and IR HB/APAP. Setting: The study was conducted in a contract research center. Participants: The study included healthy adults. Interventions: In a three-way crossover study, Study 1, participants received the following treatments: (A1 a single dose of IR/ER HB/APAP 7.5/325 mg one tablet, followed by one tablet every 12 hours (q12h; (B1 a single dose of IR/ER HB/APAP 7.5/325 mg two tablets, followed by two tablets q12h; (C1 a single dose of IR HB/APAP 7.5/325 mg two tablets (one tablet at hours 0 and 6, followed by one tablet q6h. In a two-way crossover study, Study 2, participants received the following treatments: (A2 an initial dose of IR/ER HB/APAP 7.5/325 mg three tablets, followed by two tablets q12h; (B2 three doses of IR HB/APAP 7.5/325 mg one tablet q4h, followed by one tablet q6h. Main outcome measures: PK values were compared, and adverse events were assessed. Results: Single-dose and steady-state area under the concentration–time curves for hydrocodone and APAP were similar for IR/ER and IR HB/APAP; the steady-state peak plasma concentrations (Cmax at steady state were also similar, but single-dose Cmax for hydrocodone was lower for IR/ER HB/APAP. For most PK parameters, 90% confidence intervals for geometric least squares mean ratios were not meaningfully different (80%–125%. Steady state was achieved in 2-3 days for IR/ER HB/APAP and in 2 days for IR HB/APAP. Median

  12. Zegerid--immediate-release omeprazole.

    Science.gov (United States)

    2005-04-11

    The FDA has approved marketing of Zegerid powder for oral suspension (Santarus), an immediate-release formulation of the proton-pump inhibitor (PPI) omeprazole (Prilosec, and others). All other oral PPIs are delayed-release, enteric-coated formulations designed to prevent degradation of the drug by gastric acid. Each 20- or 40-mg packet of Zegerid contains 1680 mg sodium bicarbonate, which protects the drug from gastric acid degradation. A dose of Zegerid contains 460 mg of sodium, which may be excessive for some patients. Zegerid is the first oral PPI to be approved by the FDA for reduction of risk of upper GI bleeding in critically ill patients. The drug may be useful for patients who are unable to swallow and have nasogastric (NG) tubes in place. Zegerid cost $70.00 for 14 days' treatment, compared to less than $10 for 14 tablets of Prilosec OTC.

  13. Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology.

    Science.gov (United States)

    Palem, Chinna Reddy; Kumar Battu, Sunil; Maddineni, Sindhuri; Gannu, Ramesh; Repka, Michael A; Yamsani, Madhusudan Rao

    2013-02-01

    The objective of the study was to prepare and characterize the domperidone (DOM) hot-melt extruded (HME) buccal films by both in vitro and in vivo techniques. The HME film formulations contained PEO N10 and/or its combination with HPMC E5 LV or Eudragit RL100 as polymeric carriers, and PEG3350 as a plasticizer. The blends were co-processed at a screw speed of 50 rpm with the barrel temperatures ranging from 120-160°C utilizing a bench top co-rotating twin-screw hot-melt extruder using a transverse-slit die. The HME films were evaluated for drug content, drug excipient interaction, in vitro drug release, mechanical properties, in vivo residence time, in vitro bioadhesion, swelling and erosion, ex vivo permeation from HME films and the selected optimal formulation was subjected for bioavailability studies in healthy human volunteers. The extruded films demonstrated no drug excipient interaction and excellent content uniformity. The selected HME film formulation (DOM2) exhibited a tensile strength (0.72 Kg/mm(2)), elongation at break (28.4% mm(2)), in vivo residence time (120 min), peak detachment force (1.55 N), work of adhesion (1.49 mJ), swelling index (210.2%), erosion (10.5%) and in vitro drug release of 84.8% in 2 h. Bioavailability from the optimized HME buccal films was 1.5 times higher than the oral dosage form and the results showed statistically significant (p < 0.05) difference. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The results indicate that HME is a viable technique for the preparation of DOM buccal-adhesive films with improved bioavailability characteristics.

  14. Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

    Science.gov (United States)

    Dressman, Jennifer B; Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Zimmer, Markus

    2012-08-01

    A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance. Copyright © 2012 Wiley Periodicals, Inc.

  15. Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica

    Directory of Open Access Journals (Sweden)

    Li G

    2012-11-01

    Full Text Available Zhouhua Wang,1,2 Bao Chen,1 Guilan Quan,1 Feng Li,1 Qiaoli Wu,1 Linghui Dian,1 Yixuan Dong,1 Ge Li,2 Chuanbin Wu1,21School of Pharmaceutical Sciences, 2Research and Development Center of Pharmaceutical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaBackground and methods: The aim of this study was to develop an immediate-release pellet formulation with improved drug dissolution and adsorption. Carbamazepine, a poorly water-soluble drug, was adsorbed into mesoporous silica (SBA-15-CBZ via a wetness impregnation method and then processed by extrusion/spheronization into pellets. Physicochemical characterization of the preparation was carried out by scanning electron microscopy, transmission electron microscopy, nitrogen adsorption, small-angle and wide-angle x-ray diffraction, and differential scanning calorimetry. Flowability and wettability of the drug-loaded silica powder were evaluated by bulk and tapped density and by the angle of repose and contact angle, respectively. The drug-loaded silica powder was formulated into pellets to improve flowability.Results: With maximum drug loading in SBA-15 matrices determined to be 20% wt, in vitro release studies demonstrated that the carbamazepine dissolution rate was notably improved from both the SBA-15 powder and the corresponding pellets as compared with the bulk drug. Correspondingly, the oral bioavailability of SBA-15-CBZ pellets was increased considerably by 1.57-fold in dogs (P < 0.05 compared with fast-release commercial carbamazepine tablets.Conclusion: Immediate-release carbamazepine pellets prepared from drug-loaded silica provide a feasible approach for development of a rapidly acting oral formulation for this poorly water-soluble drug and with better absorption.Keywords: ordered mesoporous silica, poorly water-soluble drug, carbamazepine, extrusion, spheronization, pellets, bioavailability

  16. Biowaiver monographs for immediate release solid oral dosage forms: amodiaquine hydrochloride.

    Science.gov (United States)

    Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

    2012-12-01

    The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate release (IR) multisource solid dosage forms containing amodiaquine hydrochloride (ADQ) as the single active pharmaceutical ingredient (API). Both biopharmaceutical and clinical data of ADQ were assessed. Solubility studies revealed that ADQ meets the "highly soluble" criteria according to World Health Organization (WHO) and European Medicines Agency (EMA) but fails to comply with the United States Food and Drug Administration (US FDA) specifications. Although metabolism hints at high permeability, available permeability data are too scanty to classify ADQ inequivocably as a Class I drug substance. According to WHO and EMA guidances, ADQ would be conservatively categorized as a Class III drug, whereas according to the US FDA specifications, it would fall into Class IV. ADQ has a wide therapeutic index. Furthermore, no cases of bioinequivalent products have been reported in the open literature. As risks associated with biowaiving appear minimal and requirements for "highly soluble" API are met in the WHO and EMA jurisdictions, the biowaiver procedure can be recommended for bioequivalence (BE) testing of multisource IR products containing ADQ as the only API, provided the test product contains excipients used in ADQ products approved in International Conference of Harmonisation and associated countries, and in similar amounts. Furthermore, both comparator and test should conform to "very rapidly dissolving" product criteria (≥85% dissolution of the API in 15 min at pH 1.2, 4.5, and 6.8) and the labeling should specify that the product not be coadministered with high-fat meals. If the comparator and/or test product fails to meet these criteria, BE needs to be established by pharmacokinetic studies in humans.

  17. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    OpenAIRE

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K.K.; Shah, V. P.; Stavchansky, S A; Barends, Dirk M.

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increa...

  18. Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica [Erratum

    Directory of Open Access Journals (Sweden)

    Wang Z

    2013-02-01

    Full Text Available Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica Wang Z, Chen B, Quan G, et al. International Journal of Nanomedicine. 2012;7:5807–5818.This paper was published without the Supplementary materials.Read the original article

  19. FORMULATION, OPTIMIZATION AND EVALUATION OF BILAYERED TABLETS OF AMLODIPINE BESILATE AS IMMEDIATE RELEASE AND METOPROLOL SUCCINATE AS SUSTAINED RELEASE

    OpenAIRE

    Arup Ratan Deb; Vivek Keshri; Padmakana Malakar

    2013-01-01

    The purpose of the study was to develop a bilayer tablet of Amlodipine besilate (IR) and Metoprolol succinate (SR) having different release pattern, which is indicated for the management of hypertension. The study was planned in three stages. In the first stage six batches (A1, A2, A3, A4, A5 and A6) of immediate release tables of Amlodipine besilate was prepared by direct compression method using sodium starch glycolate and pre-gelatinised starch as super disintegrant. In the second stage, s...

  20. Report of two cases where sleep related eating behavior occurred with the extended-release formulation but not the immediate-release formulation of a sedative-hypnotic agent.

    Science.gov (United States)

    Chiang, Ambrose; Krystal, Andrew

    2008-04-15

    We report two cases in which amnestic sleep related eating disorder (SRED) occurred with extended-release zolpidem but not with the immediate-release formulation. These cases illustrate how even relatively small differences such as formulation can affect the likelihood of experiencing such events.

  1. [Case of acute exacerbation of neuropathic cancer pain rapidly relieved by simultaneous oral intake of immediate release oxycodone and pregabalin].

    Science.gov (United States)

    Baba, Mika; Gomwo, Ikuo

    2012-10-01

    Cancer pain consists of continuous pain lasting almost all day and transient exacerbation of pain called breakthrough pain. Breakthrough pain is classified as somatic pain and visceral pain, neuropathic pain according to the character of pain. Although the immediate release opioid is used as the first treatment of choice to breakthrough pain, the effect is not enough when it shows the character of neuropathic pain. Pregabalin has become the first medicine for the treatment of neuropathic pain, and it sometimes reveals prompt analgesic effect based on its pharmacological profile. It has also been reported that pregabalin used with oxycodine reveals analgesic effect with smaller dosage than pregabalin alone. We experienced a young patient with lung cancer suffering from sudden exacerbation of symptomatic sciatica, whose pain was markedly reduced within 30 minutes by taking immediate release oxycodone 5 mg and pregabalin 75 mg simultaneously. Conclusions : Pregabalin with immediate release oxycodone simultaneously may be able to improve acute exacerbation of neuropathic cancer pain rapidly.

  2. Extent of use of immediate-release formulations of calcium channel blockers as antihypertensive monotherapy by primary care physicians: multicentric study from Bahrain.

    Directory of Open Access Journals (Sweden)

    Sequeira R

    2002-07-01

    Full Text Available BACKGROUND: The issue of cardiovascular safety of calcium channel blockers (CCBs has been widely debated in view of reflex increase in sympathetic activity induced by immediate release (IR / short acting formulations. It is generally agreed that such CCBs should not be used alone in the management of hypertension. AIMS: We have determined the extent to which primary care physicians prescribe CCBs as monotherapy, especially the immediate release formulations, in the management of uncomplicated hypertension and diabetic hypertension - with an emphasis upon the age of the patients. SETTING, DESIGN AND METHODS: A retrospective prescription-based study was carried out in seven out of 18 Health Centres in Bahrain. The study involved a registered population of 229,300 representing 46% of registered individuals, and 35 physicians representing 43% of all primary care physicians. The data was collected between November 1998 and January 1999 using chronic dispensing cards. RESULTS: In all categories CCBs were the third commonly prescribed antihypertensive as monotherapy, with a prescription rate of 11.1% in uncomplicated hypertension, 18% in diabetic hypertension and 20.1% in elderly patients above 65 years of age. Nifedipine formulations were the most extensively prescribed CCBs. Almost half of the CCB-treated patients were on IR-nifedipine, whereas IR-diltiazem and IR-verapamil, and amlodipine were infrequently prescribed. CONCLUSION: Prescription of IR-formulations of CCBs as monotherapy by primary care physicians does not conform with recommended guidelines. In view of concerns about the safety of such practice, measures to change the prescribing pattern are required.

  3. Evaluation of in vitro release rate and in vivo absorption characteristics of four metoprolol tartrate immediate-release tablet formulations.

    Science.gov (United States)

    Rekhi, G S; Eddington, N D; Fossler, M J; Schwartz, P; Lesko, L J; Augsburger, L L

    1997-02-01

    The purpose of this investigation was to examine the impact of formulation and process changes on dissolution and bioavailability/bioequivalency of metoprolol tartrate tablets manufactured using a high-shear granulation process. A half-factorial (2(4-1), Res IV) design was undertaken to study the selected formulation and processing variables during scale-up. Levels and ranges for excipients and processing changes studied represented level 2 or greater changes as indicated by the SUPAC-IR Guidance. Blend and tableting properties were evaluated. Changes in sodium starch glycolate and magnesium stearate levels, and the order of addition microcrystalline cellulose (intra- vs. extragranular) were significant only in affecting percent drug released (Q) in 5, 10, and 15 min. Statistical analysis of data showed no significant curvature. No interaction effects were found to be statistically significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Subjects received four metoprolol treatments (Lopressor, slow-, medium-, and fast-dissolving formulations) separated by 1 week according to a randomized crossover design. After an overnight fast, subjects were administered one tablet (100 mg), blood samples were collected over 24 hr and plasma samples were analyzed. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that: (i) bioavailability/bioequivalency studies may not be necessary for metoprolol tartrate and perhaps other class 1 drugs after level 2 type changes and (ii) in vitro dissolution tests may be used to show bioequivalence of metoprolol formulations with processing or formulation changes within the specified level 2 ranges for the equipment examined.

  4. Development of In Vitro-In Vivo Correlation/Relationship Modeling Approaches for Immediate Release Formulations Using Compartmental Dynamic Dissolution Data from “Golem”: A Novel Apparatus

    Directory of Open Access Journals (Sweden)

    Martin Čulen

    2015-01-01

    Full Text Available Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. Further evaluation of results was performed using IVIVC/IVIVR development. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data.

  5. Formulation design and evaluation of Cefuroxime axetil 125 mg immediate release tablets using different concentration of sodium lauryl sulphate as solubility enhancer

    Directory of Open Access Journals (Sweden)

    Fozia Israr

    2014-12-01

    Full Text Available Cefuroxime axetil immediate release tablets were formulated by direct compression method with different percentages of sodium lauryl sulphate (SLS such as 0.5, 1.0, 1.5 and also without SLS. Resulting batches of tablets were evaluated by both pharmacopeial and non-pharmacopeial methods to ascertain the physico-mechanical properties. Dissolution test were carried out in different medium like 0.07 M HCl, distilled water, 0.1M HCl of pH 1.2 and phosphate buffers at pH 4.5 and 6.8 to observe the drug release against the respective concentration of SLS used. Later, test formulations were compared by f1(dissimilarity and f2(similarity factors using a reference brand of cefuroxime axetil. Significant differences (p<0.05 in dissolution rate were recorded with the change in concentration of SLS in different media. Test formulation T3 containing 1% SLS was found to be best optimized formulation based on assay, disintegration, dissolution and similarity and dissimilarity factors.

  6. Review of immediate-release omeprazole for the treatment of gastric acid-related disorders.

    Science.gov (United States)

    Castell, Donald

    2005-11-01

    Immediate-release omeprazole (Zegerid, Santarus) is the first immediate-release oral proton pump inhibitor to reach the market. As a powder formulation for oral suspension, it is indicated for the treatment of gastroesophageal reflux disease, erosive oesophagitis, duodenal ulcer and gastric ulcer, and is the only proton pump inhibitor approved for the reduction of risk of upper gastrointestinal bleeding in critically ill patients. Administration of immediate-release omeprazole at bedtime results in a rapid and sustained elevation of gastric pH, and seems to provide better night time control of gastric acidity than that observed with conventional morning dosing of delayed-release proton pump inhibitors. The immediate-release formulation may provide a good treatment option for patients who require flexible dosing, quick onset of action and nocturnal gastric acid control.

  7. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride.

    Science.gov (United States)

    Verbeeck, R K; Junginger, H E; Midha, K K; Shah, V P; Barends, D M

    2005-07-01

    Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

  8. Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology.

    Science.gov (United States)

    Mohammed, Noorullah Naqvi; Majumdar, Soumyajit; Singh, Abhilasha; Deng, Weibin; Murthy, Narasimha S; Pinto, Elanor; Tewari, Divya; Durig, Thomas; Repka, Michael A

    2012-12-01

    The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.

  9. Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

    Science.gov (United States)

    Suarez-Sharp, Sandra; Delvadia, Poonam R; Dorantes, Angelica; Duan, John; Externbrink, Anna; Gao, Zongming; Ghosh, Tapash; Miksinski, Sarah Pope; Seo, Paul

    2016-05-01

    Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.

  10. The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs.

    Science.gov (United States)

    Yu, Lawrence X; Straughn, Arthur B; Faustino, Patrick J; Yang, Yongsheng; Parekh, Ameeta; Ciavarella, Anthony B; Asafu-Adjaye, Ebenezer; Mehta, Mehul U; Conner, Dale P; Lesko, Larry J; Hussain, Ajaz S

    2004-01-01

    The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.

  11. Lornoxicam Immediate-Release Tablets: Formulation and Bioequivalence Study in Healthy Mediterranean Volunteers Using a Validated LC-MS/MS Method.

    Science.gov (United States)

    Zaid, Abdel Naser; Mousa, Ayman; Jaradat, Nidal; Bustami, Rana

    2017-02-08

    This study aimed to demonstrate interchangeability between 2 lornoxicam tablet formulations under fasting conditions among Mediterranean Arabs by using a newly validated high-pressure liquid chromatography-tandem mass spectrometry method. A single-oral solid dosage form (8 mg/tablet), randomized, open-label, 2-way crossover study was conducted on 30 healthy male volunteers. Blood samples were collected prior to dosing and over a 24-hour period, and the washout period was 9 days. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between generic and branded products. The point estimates (ratios of geometric mean %) were 90.91, 96.34, and 94.86 for Cmax, AUC0-last , and AUC0-∞ , respectively. The 90% confidence intervals were within the predefined limits of 80.00%-125.00%, as specified by the international guidelines. This study showed that both formulations met the regulatory criteria for bioequivalence.

  12. Efficacy and safety of a once-daily extended-release formulation of pramipexole switched from an immediate-release formulation in patients with advanced Parkinson's disease: results from an open-label study.

    Science.gov (United States)

    Takanashi, M; Shimo, Y; Hatano, T; Oyama, G; Hattori, N

    2013-12-01

    This study aimed to evaluate the efficacy and safety of an extended-release tablet formulation of pramipexole (PPX-ER) given once daily when switched from an immediate-release tablet formulation (PPX-IR) given 3 times daily. This open-label study included 29 patients with idiopathic Parkinson's disease (PD) who were followed for 8 weeks. Primary endpoints were Unified Parkinson's Disease Rating Scale (UPDRS) part III score, a physician evaluation of motor symptoms; nocturnal and early morning symptoms (NEMS) score, based on the results for 4 items in the Parkinson's Disease Sleep Scale and the Movement Disorder Society - sponsored revision of the UPDRS; and patients' formulation preference, determined through questionnaires. Secondary endpoints were nocturnal sleep disturbance, evaluated using the revised version of the Parkinson's Disease Sleep Scale (PDSS-2); quality of life, evaluated using the 39-item Parkinson's Disease Questionnaire (PDQ-39); Clinical Global Impression-Improvement (CGI-I) score; Patient Global Impression-Improvement (PGI-I) score; and caregiver formulation preference. UPDRS part III score (mean ± SD) was significantly decreased after 4 weeks (13.9 ± 7.3; P=0.030) and 8 weeks (12.2 ± 7.3; P<0.001) from baseline (15.3 ± 7.0). However, no significant change was found in NEMS scale, PDSS-2 or PDQ-39 scores. After 8 weeks, the responder rates based on CGI-I and PGI-I scores were 27.6% and 20.7%, respectively. As a result of the questionnaire, 63.0% of patients and 58.8% of their caregivers preferred PPX-ER. A non-serious drug-related adverse event (diarrhea) was observed in one patient. In conclusion, PPX-ER can be considered as a useful treatment option when PPX-IR needs to be switched to other dopamine agonists.This study is registered with UMIN-CTR (UMIN000006521).

  13. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

    Science.gov (United States)

    Vogelpoel, H; Welink, J; Amidon, G L; Junginger, H E; Midha, K K; Möller, H; Olling, M; Shah, V P; Barends, D M

    2004-08-01

    Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

  14. Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations.

    Science.gov (United States)

    Brvar, Nina; Mateović-Rojnik, Tatjana; Grabnar, Iztok

    2014-10-01

    This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation.

  15. Developing Quantitative In Vitro-In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method.

    Science.gov (United States)

    Xu, Hao; Shi, Yi; Vela, Socrates; Marroum, Patrick; Gao, Ping

    2017-06-27

    This study is to evaluate 3 fenofibrate (FEN) formulations including Fournier® 200 mg capsule, Lipidil® 145 mg tablet, and a clinical HME 160 mg tablet by an in vitro biphasic method. Key experimental parameters were evaluated including the selection of biorelevant media, the United States Pharmacopeia IV flow rate, and the United States Pharmacopeia paddle speed. Varying the hydrodynamic condition resulted in a significant impact on FEN concentration time profiles in both aqueous and octanol phases for these formulations. In vivo pharmacokinetic profiles of the HME tablet, the Lipidil tablet, and Fournier capsule under the fasting and low-fat fed states are reported. Their corresponding absorption-time profiles were obtained through deconvolution by the Wagner-Nelson method. When fed state simulated intestinal fluid version 2 was used, the partitioned FEN amount-time profiles in octanol from the 3 formulations under an appropriate hydrodynamic condition exhibited a good agreement with their in vivo absorbed amount-time profiles, permitting a quantitative in vitro-in vivo correlation. When fasted state simulated intestinal fluid version 2 was used, partitioned FEN amounts into octanol from these formulations are significantly lower than those from in vivo data. Although no food effect was observed for both HME and Lipidil tablets, the positive food effect of the Fournier capsules significantly overestimated by the biphasic test. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. In vitro dissolution of generic immediate-release solid oral dosage forms containing BCS class I drugs: comparative assessment of metronidazole, zidovudine, and amoxicillin versus relevant comparator pharmaceutical products in South Africa and India.

    Science.gov (United States)

    Reddy, Nallagundla H S; Patnala, Srinivas; Löbenberg, Raimar; Kanfer, Isadore

    2014-10-01

    Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f 2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.

  17. Necessity of rethinking oral pediatric formulations

    DEFF Research Database (Denmark)

    Bar-Shalom, Daniel

    2014-01-01

    This commentary reviews the difficulties in formulating oral products for children. The significance of the fragmentation of the pediatric population in terms of development and ability to ingest different dosage formulations is examined. It is postulated that a flexible formulation, acceptable...

  18. Necessity of rethinking oral pediatric formulations.

    Science.gov (United States)

    Bar-Shalom, Daniel

    2014-02-01

    This commentary reviews the difficulties in formulating oral products for children. The significance of the fragmentation of the pediatric population in terms of development and ability to ingest different dosage formulations is examined. It is postulated that a flexible formulation, acceptable by all patient groups, is needed, and an automated compounding concept is proposed. The finishing of the formulation is done at the dispensing pharmacy using an automated process. The individual components (pudding-like carrier, microencapsulated drug, and the dispensing robot and its software) are reviewed. The involvement of different stakeholders is considered because new regulatory, clinical, and marketing thinking is required. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

  19. Review article: immediate-release proton-pump inhibitor therapy--potential advantages.

    Science.gov (United States)

    Howden, C W

    2005-12-01

    The absorption of most oral proton-pump inhibitors is delayed by the enteric coating required to protect the acid-labile proton-pump inhibitor from degradation in the stomach and, as a result, antisecretory effect is also delayed. This article provides an overview of the pharmacokinetics and pharmacodynamics of a new immediate-release omeprazole [(IR-OME) Zegerid power for oral suspension; Santarus Inc., San Diego, CA, USA] and its potential advantages over delayed-release proton-pump inhibitors. Immediate-release omeprazole has a higher mean peak plasma omeprazole concentration (C(max)) and a significantly shorter mean time to reach C(max) (t(max)) than delayed-release omeprazole. Immediate-release omeprazole 40 mg has a prolonged antisecretory effect with median intragastric pH above 4.0 for 18.6 h/day at steady-state, after 7 days of once daily dosing. The sodium bicarbonate in immediate-release omeprazole protects the uncoated omeprazole from degradation by gastric acid. The accelerated antisecretory action of immediate-release omeprazole compared with delayed-release omeprazole may be due to the activation of proton pumps by the rapid neutralization of intragastric acid by the sodium bicarbonate. The faster onset of action seen with immediate-release omeprazole is not achieved by using an antacid with a delayed-release proton-pump inhibitor, because administering antacids with conventional delayed-release proton-pump inhibitors does not significantly enhance absorption of the proton-pump inhibitor. In conclusion, immediate-release omeprazole is associated with rapid absorption of omeprazole and rapid onset of antisecretory effect, without compromising the duration of acid suppression.

  20. Microbiological quality of pediatric oral liquid formulations

    Directory of Open Access Journals (Sweden)

    Maria Josep Cabañas Poy

    2016-09-01

    Full Text Available The oral administration of drugs to the pediatric population involves the extemporaneous preparation of liquid formulations. These formulations have studies on their physicochemical stability, but they often lack microbiological studies. The objective of this study is to check the microbiological quality of five oral liquid formulations prepared with different excipients, which represent five major combinations, in two conditions: kept unopened until the day of the test, and in a multi-dose vial opened daily. The formulations were prepared according to standard operating procedures. Half of each batch was packaged in vials that remained closed until the day of testing, and the other half in a single container which was opened daily. Both the vials and the containers had been previously sterilized. Microbiological tests were performed weekly during the first month of the study, and then every two weeks, until the expiration date. The microbiological quality of oral liquid formulations is determined by the Royal Spanish Pharmacopoeia. The conclusion was that none of the formulations prepared that were packaged in sterilized containers became contaminated, either in unopened vials or in multi-dose containers when they were opened daily

  1. Assessment of pharmacokinetics and pharmacodynamic effects related to abuse potential of a unique oral osmotic-controlled extended-release methylphenidate formulation in humans.

    Science.gov (United States)

    Parasrampuria, Dolly A; Schoedel, Kerri A; Schuller, Reinhard; Gu, Joan; Ciccone, Patrick; Silber, Steven A; Sellers, Edward M

    2007-12-01

    This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with

  2. Treatment-Continuity of ADHD Compared Using Immediate-Release and Extended-Release MPH

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-07-01

    Full Text Available The continuity of methylphenidate (MPH therapy for ADHD in young Medicaid beneficiaries (ages 6 to 17 years treated with immediate-release (IR or extended-release (ER MPH formulations was compared in an analysis of statewide California Medicaid claims (2000-2003 conducted at Columbia University, New York; University of Pennsylvania, Philadelphia; and McNeil Pharmaceuticals, Fort Washington, PA.

  3. Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data.

    Science.gov (United States)

    Lukacova, Viera; Woltosz, Walter S; Bolger, Michael B

    2009-06-01

    The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlus (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration-time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs' bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

  4. Quality by design I: Application of failure mode effect analysis (FMEA) and Plackett-Burman design of experiments in the identification of "main factors" in the formulation and process design space for roller-compacted ciprofloxacin hydrochloride immediate-release tablets.

    Science.gov (United States)

    Fahmy, Raafat; Kona, Ravikanth; Dandu, Ramesh; Xie, Walter; Claycamp, Gregg; Hoag, Stephen W

    2012-12-01

    As outlined in the ICH Q8(R2) guidance, identifying the critical quality attributes (CQA) is a crucial part of dosage form development; however, the number of possible formulation and processing factors that could influence the manufacturing of a pharmaceutical dosage form is enormous obviating formal study of all possible parameters and their interactions. Thus, the objective of this study is to examine how quality risk management can be used to prioritize the number of experiments needed to identify the CQA, while still maintaining an acceptable product risk profile. To conduct the study, immediate-release ciprofloxacin tablets manufactured via roller compaction were used as a prototype system. Granules were manufactured using an Alexanderwerk WP120 roller compactor and tablets were compressed on a Stokes B2 tablet press. In the early stages of development, prior knowledge was systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA). The factors identified using FMEA were then followed by a quantitative assessed using a Plackett-Burman screening design. Results show that by using prior experience, literature data, and preformulation data the number of experiments could be reduced to an acceptable level, and the use of FMEA and screening designs such as the Plackett Burman can rationally guide the process of reducing the number experiments to a manageable level.

  5. Oral pulsatile delivery: rationale and chronopharmaceutical formulations.

    Science.gov (United States)

    Maroni, Alessandra; Zema, Lucia; Del Curto, Maria Dorly; Loreti, Giulia; Gazzaniga, Andrea

    2010-10-15

    Oral pulsatile/delayed delivery systems are designed to elicit programmable lag phases preceding a prompt and quantitative, repeated or prolonged release of drugs. Accordingly, they draw increasing interest because of the inherent suitability for accomplishing chronotherapeutic goals, which have recently been highlighted in connection with a number of widespread chronic diseases with typical night or early-morning recurrence of symptoms (e.g. bronchial asthma, cardiovascular disease, rheumatoid arthritis, early-morning awakening). In addition, time-based colonic release can be attained when pulsatile delivery systems are properly adapted to overcome unpredictable gastric emptying and provide delay phases that would approximately match the small intestinal transit time. Oral pulsatile delivery is pursued by means of a variety of release platforms, namely reservoir, capsular and osmotic devices. The aim of the present review is to outline the rationale and main formulation strategies behind delayed-release dosage forms intended for the pharmacological treatment of chronopathologies.

  6. Formulation of nimodipine nanocrystals for oral administration.

    Science.gov (United States)

    Li, Jianwen; Fu, Qiang; Liu, Xiaohong; Li, Mo; Wang, Yongjun

    2016-02-01

    The aim of this paper is to optimize nimodipine (NMD) nanocrystals (NCs) for oral administration. The effects of independent process variables (microprecipitation temperature, shearing speed, shearing time, homogenization pressure and number of cycles) on the particle size have been studied. Experiments were conducted to optimize the formulation composition. A single factor exploration was used to screen the primary stabilizers. Then, the selected polymers/surfactants were further optimized using an L9 (3(4)) orthogonal design. The optimal formulation was composed of NMD (0.7 %, w/v), F127 (0.4 %, w/v), HPMC-E5 (0.1 %, w/v), and sodium deoxycholate (0.05 %, w/v) and was rod-shaped as shown by SEM observations, and it had a particle size of 833.3 ± 20.6 nm, determined by laser diffraction. These aqueous NCs were physically stable for 15 days. To further improve the stability, the NCs were freeze-dried. The powder obtained exhibited acceptable flowability and was physically stable for at least 24 months. Additionally, the NMD NCs displayed much higher dissolution profiles than the bulk drug. The pharmacokinetic results showed that the relative bioavailability was 397 % in comparison with Nimotop(®), suggesting that NCs are an efficient strategy for improving the oral bioavailability of poorly water-soluble drugs.

  7. Solubilizing excipients in oral and injectable formulations.

    Science.gov (United States)

    Strickley, Robert G

    2004-02-01

    A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.

  8. A Randomized, Single-Blind, Substitution Study of OROS Methylphenidate (Concerta) in ADHD Adults Receiving Immediate Release Methylphenidate

    Science.gov (United States)

    Spencer, Thomas J.; Mick, Eric; Surman, Craig B. H.; Hammerness, Paul; Doyle, Robert; Aleardi, Megan; Kotarski, Meghan; Williams, Courtney G.; Biederman, Joseph

    2011-01-01

    Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants…

  9. Formulation and Characterization of Acetaminophen Nanoparticles in Orally Disintegrating Films

    Science.gov (United States)

    AI-Nemrawi, Nusaiba K.

    not extracted before analysis. The amount of drug in extracted and non-extracted samples was different which indicated that the NPs diffused through the membrane. The primary screening showed that films with 6% of HPMC E15, 2% PVA 80% and 5% PEG 400 had good properties; 1018.5 N/m2, 750 N and 37 s for TS, FB and DT, respectively. Therefore, these film ingredients were used in later steps to prepare nanoparticles in films. The nanoparticles physical properties and drug release from the nanoparticles showed a high sensitivity to the materials used and methods of preparation. The prepared NPs size ranged from 180 to 645 nm. The particle size was not changed as the addition rate increases till we get to 2.0 drop/s. In other words, as the hydrolyzation increases the particle size increases. The particle size did not show a pattern that's related to PLGA polymerization. Both the agitation rate and the ratio of PLGA to PVA had a negative effect on the particles size. In general, all NPs have negative zeta potential ranged between -7.07 and -0.98. Zeta potential was found to decrease (become more negative) when PLGA polymerization increases, PVA hydrolyzation increases or the ratio of PLGA to PVA decreases. EE was almost constant and not affected by formulation variables and recorded high values (above 90%). EE recorded a huge drop when acetaminophen was dissolved in the aqueous phase rather than being dissolved in the acetone phase. All films disintegrated in less than one minute, but acetaminophen was not free in the dissolution media, even after 6 days. These results indicate that although the nanoparticles immediately released from the films when impressed in solution, the drug is retained in the nanoparticles for a longer time. The release from the NPs was related to PVA hydrolyzation, PLGA polymerization and the PLGA to PVA ratio. Finally, from the results we got ex-vivo, and by comparing the extracted and non-extracted samples we were able to estimate the amount of NPs

  10. A single-dose, 3-way crossover pharmacokinetic comparison between immediate-release oxycodone hydrochloride with aversion technology (IRO-A, Oxecta), IRO-a with Niacin, and Oxycodone Hydrochloride (Roxicodone) in healthy adults under fasting conditions.

    Science.gov (United States)

    Leibowitz, Mark T; Zamora, Cynthia A; Brzeczko, Albert W; Stark, Jeffrey G

    2014-01-01

    Snorting and intravenous use are common routes of administration for advanced opioid abusers. A tablet form of immediate-release oxycodone (IRO) developed using Aversion Technology combines immediate release (IR) oxycodone HCl with inactive functional excipients that are intended to discourage tampering associated with intranasal and intravenous abuse (IRO-A; Oxecta, Pfizer). The purpose of this single-dose, open-label, randomized, 3-period, 3-treatment crossover study was to evaluate the bioequivalence of IRO-A to the marketed immediate-release oxycodone HCl (IRO; Roxicodone, Xanodyne Pharmaceuticals Inc., Newport, KY). IRO-A was also compared with IRO-A with niacin, a product previously developed containing the same functional excipients plus niacin as an aversive agent to discourage oral overconsumption. Healthy adults (N = 40) aged 18-55 years received single 15-mg doses of IRO-A, IRO-A with niacin (60 mg), or IRO after fasting overnight. Naltrexone was administered to diminish opioid effects. Doses were separated by a ≥7-day washout. Plasma samples taken at designated time points were analyzed using liquid chromatography with tandem mass spectrometry. Geometric mean ratios for ln-transformed parameters for IRO-A and IRO were 92%, 104%, and 104% for Cmax, AUClast (AUC is area under the concentration-time curve), and AUCinf; 90% confidence intervals were within the accepted 80%-125% range. IRO-A was also bioequivalent to IRO-A with niacin. Adverse events were mild to moderate in intensity and typical of opioid therapy (nausea, headache, vomiting). Flushing only occurred when the subjects received the IRO-A with niacin treatment (9/37 subjects). The results demonstrated that IRO-A is bioequivalent to IRO and IRO-A with niacin. With features designed to discourage tampering associated with common forms of abuse, IRO-A may provide an alternative to conventional immediate-release oxycodone formulations.

  11. FORMULATION AND DEVELOPMENT OF ORAL DISSOLVING FILMS OF BUMETANIDE

    OpenAIRE

    Dr.A.Yasodha

    2016-01-01

    Objective: Formulation and Development of oral dissolving Films of Bumetanide. Materials and methods: BUMETANIDE, HPMC E-50, HPMC E-5, HPMC E-3, PE, 4000 (Flakes) and Aspartame. Citric Acid could be formulated with low viscosity film formers viz. HPMC E50 in combination with HPMC E5, E15. Bumetanide could be successfully incorporated in FDFs with of the above polymers and polyethylene glycol 4000 is used as a plasticizer. PEG 4000 itself has a solubulizing affect and result in faster dissolut...

  12. Immediate release pellets with lipid binders obtained by solvent-free cold extrusion.

    Science.gov (United States)

    Krause, Julia; Thommes, Markus; Breitkreutz, Jörg

    2009-01-01

    Lipid-based drug delivery systems have spread in their use in pharmaceutical drug development. This work focuses on the use of lipid binders as alternative non-toxic extrusion aid for pellet formulations. The preparation of immediate release pellets with solid lipid binders through a solvent-free cold extrusion/spheronisation process was investigated in this study. Various binary, ternary and quaternary mixtures of powdered lipids and the model drug sodium benzoate were investigated and compared to well-known wet extrusion binders like microcrystalline cellulose and kappa-carrageenan. The cold lipid extrusion process offers multiple advantages as it is suitable for thermal sensitive as well as for hygroscopic drugs, furthermore no drying process to evaporate the solvent is needed and the process is feasible for different extruder types. Some of the developed pellets showed favourable properties like spherical shape, narrow size distribution, a high drug load of 80% sodium benzoate and a drug release of more than 90% within 40 min. The stability of drug release, which can be problematic when using lipid excipients, was sufficient for some mixtures, as storage under elevated temperatures changed the release profiles only slightly and no formulation released less than 80% within the first 60 min. A formulation with a mixture of hard fat, glycerol distearate and glycerol trimyristate showed the best results, as pellets with a low aspect ratio, narrow size distribution and complete drug release were obtained. Using appropriate mixtures of acylglycerides it becomes possible to produce pharmaceutical pellets with immediate release characteristics by cold extrusion and subsequent spheronisation. Thus, lipids are very promising alternatives to commonly used extrusion/spheronisation binders.

  13. Methodology of oral formulation selection in the pharmaceutical industry.

    Science.gov (United States)

    Kuentz, Martin; Holm, René; Elder, David P

    2016-05-25

    Pharmaceutical formulations have to fulfil various requirements with respect to their intended use, either in the development phase or as a commercial product. New drug candidates with their specific properties confront the formulation scientist with industrial challenges for which a strategy is needed to cope with limited resources, stretched timelines as well as regulatory requirements. This paper aims at reviewing different methodologies to select a suitable formulation approach for oral delivery. Exclusively small-molecular drugs are considered and the review is written from an industrial perspective. Specific cases are discussed starting with an emphasis on poorly soluble compounds, then the topics of chemically labile drugs, low-dose compounds, and modified release are reviewed. Due to the broad scope of this work, a primary focus is on explaining basic concepts as well as recent trends. Different strategies are discussed to approach industrial formulation selection, which includes a structured product development. Examples for such structured development aim to provide guidance to formulators and finally, the recent topic of a manufacturing classification system is presented. It can be concluded that the field of oral formulation selection is particularly complex due to both multiple challenges as well as opportunities so that industrial scientists have to employ tailored approaches to design formulations successfully.

  14. Triple antioxidant SNEDDS formulation with enhanced oral bioavailability

    DEFF Research Database (Denmark)

    Tripathi, Shailja; Kushwah, Varun; Thanki, Kaushik;

    2016-01-01

    .3, respectively. DPPH scavenging assay showed comparable antioxidant activity of antioxidant loaded SNEDDS to free antioxidants combination. Furthermore, coumarin-6 loaded SNEDDS formulation showed rapid internalization within 1h of incubation by Caco-2 cells. Moreover, the pharmacokinetic studies in rats......The present study aimed to develop quercetin, resveratrol and genistein loaded self-nanoemulsifying drug delivery system (SNEDDS) by QbD approach in order to improve their oral bioavailability and antioxidant potential. The size and PDI of the optimized formulation were found to be ... for the optimized formulation and free antioxidant suspension were performed. SNEDDS have significantly increased the Cmax and area under curve (AUC) of all three antioxidants. The SNEDDS demonstrated ~4.27 fold enhancement in oral bioavailability of quercetin, ~1.5 fold in case of resveratrol and ~2.8 fold in case...

  15. In vitro and in vivo evaluation of an oral multiple-unit formulation for colonic delivery of insulin.

    Science.gov (United States)

    Maroni, Alessandra; Del Curto, Maria Dorly; Salmaso, Stefano; Zema, Lucia; Melocchi, Alice; Caliceti, Paolo; Gazzaniga, Andrea

    2016-11-01

    A multiple-unit formulation for time-dependent colonic release of insulin was obtained by coating insulin and sodium glycocholate immediate-release minitablets with: (i) Methocel® E50, a low-viscosity hydroxypropyl methylcellulose (inner coating), (ii) 5:1 w/w Eudragit® NE/Explotab® V17, a mixture of a neutral polymethacrylate with a pore-forming superdisintegrant (intermediate coating), and (iii) Aqoat® AS, enteric-soluble hydroxypropyl methylcellulose acetate succinate (outer coating). Sodium glycocholate was added as a permeation enhancer while the inner, intermediate and outer coatings were aimed, respectively, at delaying the onset of release through swelling/erosion processes, extending the duration of the lag phase by slowing down water penetration into the underlying functional layer, and overcoming variable gastric residence time. In vitro studies showed that neither insulin nor sodium glycocholate were released from the three-layer system during 2h of testing in 0.1N HCl, while complete release of the protein and of the enhancer occurred in phosphate buffer, pH 6.8, after consistent lag phases. No significant changes were noticed in the release profiles following twelve-month storage at 4°C. Oral administration of the novel formulation to diabetic rats elicited a peak in the plasma insulin concentration after 6h, which was associated with a sharp decrease in the glycemic levels. The relative bioavailability and pharmacological availability of such a formulation, as determined vs. the uncoated tablets, were 2.2 and 10.3, respectively. Based on these results, the three-layer system presented was considered a potentially interesting tool for oral colonic delivery of insulin and adjuvant compounds.

  16. 基于流化床包衣工艺的伊曲康唑速释微丸的制备和评价研究%Formulation and Characterization of Immediate-Release Itraconazole-Loaded Pellets Prepared by Fluidized Bed Spray Coating

    Institute of Scientific and Technical Information of China (English)

    单利; 史焱; 王玉丽; 赵琳琳; 杨美燕; 蒋庆宇; 高春生

    2013-01-01

    目的 采用流化床包衣工艺制备速释型伊曲康唑固体分散体载药微丸.方法 以常见的亲水性辅料为载体材料,溶剂法制备水不溶性药伊曲康唑的固体分散溶液,然后将其喷雾干燥共沉淀于流化床底喷锅内的蔗糖丸芯表面上,直接形成速释型伊曲康唑固体分散体载药微丸,并对其药物溶出度、晶型表征、外观性状、以及溶剂残留等进行系统评价.结果 制备的伊曲康唑载药微丸外观光洁美观,药物以无定形或分子态存在于载药层中,符合固体分散体结构特征.HPMC ES/伊曲康唑(1.5∶1,w/w)固体分散体载药微丸的药物溶出迅速,15 min可达80%以上.为保证溶剂残留在药典规定的限度内,制备的伊曲康唑载药微丸需要在真空80℃干燥6h以上.结论 采用流化床底喷上药包衣技术制备速释型伊曲康唑固体分散体载药微丸,质量可控,工艺可行.%OBJECTIVE To develop immediate-released itraconazole-loaded pellets prepared by fluidized bed spray coating. METHODS With common hydrophilic excipients( HPMC E5, PVP K30, PEG6000, and Poloxamer 188) as the carrier material, solid dispersion solution(dichloromethane-ethanol, 1:1, V/V)containing water-insoluble itraconazole was prepared, and then was sprayed on the surface of the sugar cores in fluidized bed to directly form immediate-reaease drug-loaded pellets containing itraconazole solid dispersion. Subsequently, its drug dissolution, crystal characterization, appearance, and residual solvent were evaluated. RESULTS The obtained pellets are clean and beautiful appearance. And itraconazole in the drug-loaded layer exists in amorphous or molecular state, meets with the solid dispersion structure. It was interesting that, the pellets containing HPMC E5/itraconazole( 1.5: 1 , w/w)solid dispersion were of rapid drug dissolution( 15 min up to 80% ). To ensure that residual solvent within the limits, it was necessary that the obtained pellets were

  17. Itraconazole nanosuspension for oral delivery: Formulation, characterization and in vitro comparison with marketed formulation

    Directory of Open Access Journals (Sweden)

    M Nakarani

    2010-06-01

    Full Text Available "n Background and the purpose of the study:Itraconazole is a poorly water soluble drug which results in its insufficient bioavailability. The purpose of the present study was to formulate Itraconazole in a nanosuspension to increase the aqueous solubility and to improve its formulation related parameters, dissolution and hence oral bioavailability. "nMethods:Itraconazole nanosuspension was prepared by pearl milling technique using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and glycerol as a wetting agent. Effects of various process parameters like, stirring time and the ratio of the beads were optimized by keeping drug:surfactant:milling media (1:3.0:50 as a constant initially and then optimized process parameters were used to optimize formulation parameters by 32 factorial designs. The optimized nanosuspension was lyophilized using mannitol (1:1 ratio as a cryoprotectant. Nanosuspension was characterized by particle size and size distribution, drug content, scanning electron microscopy, differential scanning colorimetry and X-ray diffraction techniques. "nResults:Optimized nanosuspension showed spherical shape with surface oriented surfactant molecules and a mean particle diameter of 294 nm. There was no significant change in crystalline nature after formulation and it was found to be chemically stable with high drug content. Conclusion:The in vitro dissolution profile of the optimized formulation compared to the pure drug and marketed formulation (Canditral Capsule by using 0.1N Hydrochloric acid as release medium showed higher drug release.

  18. Development, Formulation and Evaluation of Atomoxetine Oral Films

    Directory of Open Access Journals (Sweden)

    Mamatha Tirunagari

    2014-03-01

    Full Text Available Fast-dissolving drug delivery system offers solution for the problems related to patient compliance especially in the case of geriatric and paediatric population. Atomoxetine is a selective nor epinephrine re-uptake inhibitor. It is used for the treatment of attention-deficit hyperactivity disorder (ADHD. The objective of formulating atomoxetine oral films is to provide rapid dissolution of drug and absorption which may produce the rapid onset of action and also to improve the bioavailability of the drug. Oral films were developed and prepared by solvent evaporation method. The film forming agent used was hydroxypropyl methylcellulose (HPMC and propylene glycol as a plasticizer. A standard calibration curve was established with the maximum absorption at 269 nm. Further the evaluation of the film was done through a series of tests like thickness, weight variation, in vitro dispersion time and pH, drug content determination and drug – excipient compatibility by FT-IR. The mechanical properties of the developed films (tensile strength, % elongation, folding endurance were also found to be in acceptable limits. Hence, atomoxetine oral dispersing film was formulated and evaluated which results in the development of the product with higher efficacy and bio availability.

  19. Opioid Treatment Patterns Following Prescription of Immediate-Release Hydrocodone.

    Science.gov (United States)

    Ben-Joseph, Rami; Bell, Jill A; Brixner, Diana; Kansal, Anuraag; Paramore, Clark; Chitnis, Abhishek; Holly, Pamela; S Burgoyne, Douglas

    2016-04-01

    Immediate-release (IR) hydrocodone is the most widely prescribed opioid in the United States; however, little is known about the utilization patterns and duration of opioid use among patients prescribed IR hydrocodone. A better understanding of the use of IR hydrocodone would result in more appropriate prescribing patterns of extended-release opioids. To assess downstream length of opioid therapy and utilization patterns of extended-release/long-acting (ER/LA) opioids among patients on IR hydrocodone to provide a better understanding of how IR and ER/LA opioids are used to manage pain. Retrospective analysis using health care claims from the Truven MarketScan Commercial, Medicare Supplemental, and Medicaid databases was performed. Patients prescribed IR hydrocodone during the 6-month baseline period (July 2011-December 2011) and with continuous enrollment for a 12-month follow-up period (2012) post-index date (January 1, 2012) were selected. Downstream length of therapy, defined as number of days supplied with opioids, and downstream use of ER/LA opioids during follow-up were examined by average pills per month (≤ 60 vs. > 60 pills per month) and days supply ( 60 pills per month than with ≤ 60 pills per month (7.8% vs. 1.2%, respectively, P 60 pills per month than with ≤ 60 pills per month. All results were consistent when examined by levels of days supply. A majority of the population prescribed IR hydrocodone was not prescribed opioid therapy beyond 2 months on average in the 1-year follow-up period. Only a small subset of patients with increased pills per month or days supply of IR hydrocodone in the baseline period continued to be high utilizers in the following year, averaging nearly 8 months of prescribed opioid use. A limited proportion of patients prescribed IR hydrocodone converted to ER/LA opioids. This knowledge can assist policymakers and physicians, providing an opportunity to identify small subsets of patients to improve ER/LA opioid prescribing

  20. Preparation of fenofibrate immediate-release tablets involving wet grinding for improved bioavailability.

    Science.gov (United States)

    Zhang, Lili; Chai, Guihong; Zeng, Xueping; He, Haibing; Xu, Hui; Tang, Xing

    2010-09-01

    The purpose of this study was to investigate the dissolution and oral bioavailability of an immediate-release tablet involving wet grinding of a poorly water-soluble drug, fenofibrate. The milled suspension was prepared using a Basket Dispersing Mill in the presence of a hydrophilic polymer solution and then granulated with common excipients, and compressed into an immediate-release tablet with blank microcrystalline cellulose granules. Compared with unmilled tablets (56% within 30 minutes), the dissolution of wet-milled tablets (about 98% in 30 minutes) was markedly enhanced. No significant decrease in the dissolution rate (96% in 30 minutes) of the wet-milled tablet was observed after 3 months under 40 degrees C and 75% relative humidity storage. In addition, the oral bioavailability of the wet-milled tablets (test) and Lipanthyl supra-bioavailability tablets (reference) was determined in beagle dogs after a single dose (160 mg fenofibrate) in a randomized crossover, own-control study. The results suggested that both the area under the plasma concentration-time curve (AUC((0-t)) = 46.83 +/- 11.09 microg/mL h) and the mean peak concentration of the test (C(max) = 4.63 +/- 1.71 microg/mL) were higher than the reference (AUC((0-t)) = 35.12 +/- 10.97 microg/mL h, C(max) = 2.11 +/- 0.08 microg/mL). The relative bioavailability of the wet-milled tablet was approximately 1.3-fold higher. Furthermore, the apparent rate of absorption of fenofibrate from the wet-milled tablet (T(max) = 2.63 hours) was faster than that from Lipanthyl (T(max) = 3.75 hours). These results indicated that the dissolution and the bioavailability of fenofibrate were significantly enhanced by wet-grinding process. So, this shows that wet grinding is a powerful technique to improve the bioavailability for poorly water-soluble drugs, especially for Biopharmaceutics Classification System Class II compounds.

  1. Development of nanosuspension formulation for oral delivery of quercetin.

    Science.gov (United States)

    Sun, Min; Gao, Yan; Pei, Yan; Guo, Chenyu; Li, Houli; Cao, Fengliang; Yu, Aihua; Zhai, Guangxi

    2010-08-01

    With the aim to enhance dissolution rate and oral bioavailability of quercetin, a poorly water-soluble drug, quercetin loaded nanosuspension (QT-NS) was fabricated by a tandem of nano-precipitation (NP) and high pressure homogenization (HPH) method. The formulation of nanosuspension was optimized by screening different stabilizers. Characterization of the original QT powder and QT-NS was carried out by transmission electron microscopy and scanning electron microscopy, X-ray diffraction (XRD) and dissolution tests. QT-NS presented a sphere-like shape under transmission electron microscopy with an average diameter of 393.5 nm and the zeta potential of -35.75 mV. XRD study suggested that QT was maintained in the state of crystalline during the fabrication process. The solubility of QT in nanosuspension was about 70-fold that of crude QT, and the dissolution of QT from QT-NS was increased as compared to that of the original QT powder. In plasma, QT-NS exhibited a significant reduction of clearance rate (2 +/- 0.1 mL/min vs. 15 +/- 4 mL/min) and increase of AUC(0-infinity), (53995 +/- 4126 microg/mL x min versus 3470 +/- 110.1 microg/mL x min) compared with the control suspension. Our results showed that the developed nanosuspension formulation had a great potential as a possible formulation of the poorly water-soluble QT to enhance the bioavailability.

  2. The role of lipid-based nano delivery systems on oral bioavailability enhancement of fenofibrate, a BCS II drug: comparison with fast-release formulations.

    Science.gov (United States)

    Weng, Tengfei; Qi, Jianping; Lu, Yi; Wang, Kai; Tian, Zhiqiang; Hu, Kaili; Yin, Zongning; Wu, Wei

    2014-09-24

    The aim of this study was to compare various formulations solid dispersion pellets (SDP), nanostructured lipid carriers (NLCs) and a self-microemulsifying drug delivery system (SMEDDS) generally accepted to be the most efficient drug delivery systems for BCS II drugs using fenofibrate (FNB) as a model drug. The size and morphology of NLCs and SMEDDS was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Their release behaviors were investigated in medium with or without pancreatic lipase. The oral bioavailability of the various formulations was compared in beagle dogs using commercial Lipanthyl® capsules (micronized formulation) as a reference. The release of FNB from SDP was much faster than that from NLCs and SMEDDS in medium without lipase, whereas the release rate from NLCs and SMEDDS was increased after adding pancreatic lipase into the release medium. However, NLCs and SMEDDS increased the bioavailability of FNB to 705.11% and 809.10%, respectively, in comparison with Lipanthyl® capsules, although the relative bioavailability of FNB was only 366.05% after administration of SDPs. Thus, lipid-based drug delivery systems (such as NLCs and SMEDDS) may have more advantages than immediate release systems (such as SDPs and Lipanthyl® capsules).

  3. Review article: putting immediate-release proton-pump inhibitors into clinical practice--improving nocturnal acid control and avoiding the possible complications of excessive acid exposure.

    Science.gov (United States)

    Katz, P O

    2005-12-01

    Nocturnal gastro-oesphageal reflux is an under-appreciated clinical challenge. This condition may cause symptoms such as nocturnal heartburn, or it may be asymptomatic. In addition, patients may experience sleep disturbances that can potentially lead to complications such as erosive oesophagitis and Barrett's oesophagus, and may be a risk factor for development of oesophageal adenocarcinoma. Delayed-release proton-pump inhibitors (PPIs) have traditionally been effective in treating both daytime and night-time reflux symptoms, but are limited in control of nocturnal acidity by their pharmacodynamic characteristics. This narrative review addresses the prevalence, impact and pharmacologic approaches used to control nocturnal acidity. Methods to optimize nocturnal acid control include careful attention to dosing schedule, using higher doses of PPIs, adding an histamine H2-receptor antagonist at bedtime to once or twice daily delayed-release PPI, or using immediate-release omeprazole (Zegerid powder for oral suspension; Santarus, Inc., San Diego, CA, USA). This new formulation appears to provide sustained control of intragastric pH at steady state, and when dosed at bedtime, and may be effective in improving control of nocturnal pH and treating night-time GERD.

  4. Process Optimization of a Novel Immediate Release Film Coating System using QbD Principles

    National Research Council Canada - National Science Library

    Teckoe, Jason; Mascaro, Tracey; Farrell, Thomas P; Rajabi-Siahboomi, Ali R

    2013-01-01

    This work describes a quality-by-design (QbD) approach to determine the optimal coating process conditions and robust process operating space for an immediate release aqueous film coating system (Opadry® 200...

  5. A simple and sensitive high-performance liquid chromatography method for determination of ciprofloxacin in bioavailability studies of conventional and gastroretentive prolonged-release formulations

    Directory of Open Access Journals (Sweden)

    Jaber Emami

    2016-01-01

    Conclusion: This validated HPLC method was successfully used for the determination of ciprofloxacin in human plasma following oral administration of controlled release formulation, conventional immediate-release tablets and when administered concomitantly with divalent and trivalent cations such as aluminum-, magnesium-, or calcium-containing products under which the bioavailability of ciprofloxacin is significantly reduced.

  6. 77 FR 40060 - Renewal of Declaration Regarding Emergency Use of All Oral Formulations of Doxycycline...

    Science.gov (United States)

    2012-07-06

    ... HUMAN SERVICES Renewal of Declaration Regarding Emergency Use of All Oral Formulations of Doxycycline... the authorization of emergency use of all oral formulations of doxycycline accompanied by emergency..., Michael O. Leavitt, declared an emergency justifying the emergency use of doxycycline hyclate...

  7. 77 FR 39708 - Renewal of Declaration Regarding Emergency Use of All Oral Formulations of Doxycycline...

    Science.gov (United States)

    2012-07-05

    ... Emergency Use of All Oral Formulations of Doxycycline Accompanied by Emergency Use Information AGENCY... oral formulations of doxycycline accompanied by emergency use information subject to the terms of any... emergency use of doxycycline hyclate tablets accompanied by emergency use information subject to the...

  8. Construction of Pseudoternary Phase Diagram and its Evaluation: Development of Self-dispersible Oral Formulation

    Directory of Open Access Journals (Sweden)

    Javed Ahmad

    2013-06-01

    Full Text Available The purpose of this study is to give an insight into the significance of pseudoternary phase diagram construction and its evaluation, as an important tool for the development of lipid based selfdispersible oral formulation. This formulation was designed in order to improve the oral efficacy of hydrophobic drug, which display dissolution rate limited absorption. Construction of pseudoternary phase diagram is an important tool for screening of self-dispersible formulation components and to assess the effect of different component on in-vitro performance of formulation. Spontaneity of formulation to convert into nano drug carrier and robustness to dilution inside gastrointestinal lumen is an important aspect of such lipid based formulation to predict its in-vivo performance. Thus our study provides an important tool for designing of lipid based formulation for improved oral delivery of low bioavailable drug.

  9. Stability of an alternative extemporaneous captopril fast-dispersing tablet formulation versus an extemporaneous oral liquid formulation.

    Science.gov (United States)

    Pabari, Ritesh M; McDermott, Claire; Barlow, James; Ramtoola, Zebunnissa

    2012-11-01

    Administration of medications to pediatric patients is challenging because many drugs are not commercially available in appropriate dosage formulations and/or strengths. Consequently, these drugs are prepared extemporaneously as oral liquid (OL) formulations using marketed tablets or capsules. In many cases, the stability of these extemporaneous preparations, which may affect their tolerability, has not been documented. An alternative extemporaneous solid formulation, such as a fast-dispersing tablet (FDT), may offer enhanced stability as well as dosing flexibility because it may be administered as an orodispersible tablet or as a reconstituted suspension/solution. Although FDTs are available increasingly as patient-friendly oral dosage formulations, and their simple method of manufacture can be applied to extemporaneous formulations, such applications have not been explored to date. The use of extemporaneous captopril OL formulations in hospitals in Ireland was surveyed, and the stability of the most commonly used captopril formulation (reference) was investigated and compared with that of a newly available extemporaneous FDT formulation. The survey was carried out in 120 hospitals in the Republic of Ireland. The 56-day stability of the most commonly used formulation was compared with that of a newly available extemporaneous captopril FDT preparation. The captopril content of the formulations was measured by high-performance liquid chromatography analysis. Formulations were also monitored for changes in appearance, including color; odor; and pH (OLs only). The survey showed that extemporaneously prepared captopril OLs were extensively used, particularly in specialist children's hospitals. The most commonly used preparation was a xanthan gum-based oral suspension. Analysis of these OL preparations showed the OLs to have been stable up to day 7, but that the captopril concentration decreased to 72% to 84% at day 14 and to 59% to 68% at day 56; this decrease was

  10. Immediate-Release Methylphenidate for ADHD in Children with Comorbid Chronic Multiple Tic Disorder

    Science.gov (United States)

    Gadow, Kenneth D.; Sverd, Jeffrey; Nolan, Edith E.; Sprafkin, Joyce; Schneider, Jayne

    2007-01-01

    Objective: To examine the safety and efficacy of immediate-release methylphenidate (MPH-IR) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (ages 6-12 years) with Tourette's syndrome (96%) or chronic motor tic disorder (4%). Method: Two cohorts of prepubertal children (N = 71) received placebo and three doses of…

  11. Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

    Directory of Open Access Journals (Sweden)

    Jurjen van der Schans

    Full Text Available Attention-Deficit/Hyperactivity Disorder (ADHD is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH formulation may improve drug response and economic efficiency.To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated.A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1 optimal response, (2 sub-optimal response, (3 discontinued treatment, and (4 natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs. Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios.Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations.This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.

  12. Efficacy of natural antimicrobials in toothpaste formulations against oral biofilms in vitro

    NARCIS (Netherlands)

    Verkaik, M.J.; Busscher, H.J.; Jager, D.; Slomp, A.M.; Abbas, F.; Mei, H.C. van der

    2011-01-01

    Objectives: To evaluate the antimicrobial efficacies of two toothpaste formulations containing natural antimicrobials (herbal extracts and chitosan) against oral biofilms of different composition and maturational status. Methods: Bacteria from a buffer suspension or fresh saliva were adhered for 2 h

  13. Efficacy of natural antimicrobials in toothpaste formulations against oral biofilms in vitro

    NARCIS (Netherlands)

    Verkaik, M.J.; Busscher, H.J.; Jager, D.; Slomp, A.M.; Abbas, F.; Mei, H.C. van der

    Objectives: To evaluate the antimicrobial efficacies of two toothpaste formulations containing natural antimicrobials (herbal extracts and chitosan) against oral biofilms of different composition and maturational status. Methods: Bacteria from a buffer suspension or fresh saliva were adhered for 2 h

  14. Properties and formulation of oral drug delivery systems of protein and peptides

    Directory of Open Access Journals (Sweden)

    Semalty A

    2007-01-01

    Full Text Available Although most protein pharmaceuticals are usually formulated as a solution or suspension and delivered by invasive routes such as subcutaneous injections, major efforts in both academic and industrial laboratories have been directed towards developing effective oral formulations and increasing the oral absorption of intact protein through the use of formulations that protect the macromolecule and/or enhance it′s uptake into the intestinal mucosa. However, in spite of these major attempts, relatively little progress has been made. For the efficient delivery of peptides and proteins by non-parenteral route, in particular via the gastrointestinal tract, novel concepts are needed to overcome significant enzymatic and diffusion barriers. The properties of protein and peptides, which are of major interest in oral delivery, are highlighted in the article. This article reviews the various problems associated and novel approaches for formulation and development of oral protein and peptide drug delivery systems.

  15. The use of formulation technology to assess regional gastrointestinal drug absorption in humans.

    Science.gov (United States)

    Basit, Abdul W; Podczeck, Fridrun; Newton, J Michael; Waddington, Wendy A; Ell, Peter J; Lacey, Larry F

    2004-02-01

    The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.

  16. In vitro-in vivo relationships of several "immediate" release tablets containing a low permeability drug.

    Science.gov (United States)

    Polli, J E

    1997-01-01

    The objective of this work was to gain insight into the biopharmaceutical performance of four different but bioequivalent ranitidine hydrochloride tablet formulations. This analysis employed a recently described method1 to relate in vitro and in vivo data and aimed to facilitate an understanding of oral drug product performance. For each ranitidine formulation, dissolution was performed using the USP procedure. A four-way, single dose bioequivalence study (n = 14) was performed. The fraction of the total amount of dose absorbed at each plasma sample time was determined by the Wagner-Nelson method. Equation 1 (see below) was fitted to the in vitro vs. in vivo data. For all four formulations, this analysis suggests absorption was permeation-rate limited, where ranitidine exhibited a low permeation rate constant of 0.01/min.

  17. Formulation Optimization and In-vitro Evaluation of Oral Floating ...

    African Journals Online (AJOL)

    forming agents for formulating controlled release floating tablets of captopril. FTIR and DSC spectra showed ..... correspond to the stretching vibrations of C–H bond and carboxyl .... barrier which produces upward motion and as a result tablets ...

  18. FORMULATION DEVELOPMENT AND EVALUATION OF QUICK DISSOLVING ORAL STRIPs CONTAINING SUMATRIPTAN SUCCINATE

    OpenAIRE

    Pandit Mihir; Gandhi Nirvi; Bonde Smita; Pandya Sudhir

    2012-01-01

    The present study was aimed to formulate and evaluate quick dissolving oral strips (QDOS) of Sumatriptan succinate for the treatment of migraine headaches. Sumatriptan succinate is 5-HT1D agonist which is antimigraine. Hydroxyl propyl methyl cellulose is used as film forming agent. Quick dissolving oral strips are meant to be dissolved in saliva and remain in oral cavity until swallowed. Hence, taste masking becomes critically important. The strips were prepared by solvent casting method and ...

  19. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery.

    Science.gov (United States)

    Das, Surajit; Chaudhury, Anumita

    2011-03-01

    Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed. © 2010 American Association of Pharmaceutical Scientists

  20. Similar risk reduction of death of extended-release metoprolol once daily and immediate-release metoprolol twice daily during 5 years after myocardial infarction.

    Science.gov (United States)

    Herlitz, J; Dellborg, M; Karlson, B W; Lindqvist, J; Sandèn, W; Svensson, H; Sjölin, M; Wedel, H

    1999-04-01

    The pooled results from five placebo-controlled postinfarction studies with metoprolol have shown a significant reduction in total mortality. All five studies used immediate-release metoprolol twice daily. An extended-release formulation of metoprolol for once-daily use has since been developed. The aim of the present study was to compare the two different forms of metoprolol with regard to the risk reduction of death for 5 years postinfarction and to analyze whether treatment with the beta-blocker metoprolol is associated with a reduced mortality after the introduction of modern therapies such as thrombolysis, aspirin, and ACE inhibitors. All patients discharged after an acute myocardial infarction (AMI) from Sahlgrenska University Hospital (SU) during 1986-1987 (n = 740, Period I) and during 1990-1991 (n = 1446, Period II) from both SU and Ostra Hospital, Göteborg, Sweden, were included in the study. During Period I, 56% were prescribed immediate-release metoprolol compared with 61% prescribed extended-release metoprolol during Period II. Immediate-release metoprolol was not available for outpatient use during Period II. In a multivariate analysis, all variables significantly associated with either increased or decreased postinfarction mortality during Periods I and II (univariate analysis of patient characteristics, medical history, complications during the AMI medication at discharge) studied were with Cox's proportional hazards model. Treatment with immediate-release metoprolol was significantly associated with reduced mortality over 5 years during Period I (relative risk reduction for total mortality, -34%, P = 0.003; 95% CI for RR, 0.51-0.87), and treatment with extended-release metoprolol was significantly associated with reduced mortality during Period II (-34%, P metoprolol given once daily was associated with a similar risk reduction of death over 5 years as immediate-release metoprolol given twice daily. The data, furthermore, indicate that the beta

  1. Clinical studies with oral lipid based formulations of poorly soluble compounds

    DEFF Research Database (Denmark)

    Fatouros, Dimitrios; Karpf, Ditte M; Nielsen, Flemming S

    2007-01-01

    of these properties on the in vivo performance of the formulation. Equally important is the effect of concurrent food intake on the bioavailability of poorly soluble compounds. The effect of food on the bioavailability of compounds formulated in lipid and surfactant based formulations is also reviewed.......This work is an attempt to give an overview of the clinical data available on lipid based formulations. Lipid and surfactant based formulations are recognized as a feasible approach to improve bioavailability of poorly soluble compounds. However not many clinical studies have been published so far....... Several drug products intended for oral administration have been marketed utilizing lipid and surfactant based formulations. Sandimmune((R)) and Sandimmune Neoral((R)) (cyclosporin A, Novartis), Norvir((R)) (ritonavir), and Fortovase((R)) (saquinavir) have been formulated in self-emulsifying drug delivery...

  2. An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen.

    Science.gov (United States)

    Vergote, G J; Vervaet, C; Van Driessche, I; Hoste, S; De Smedt, S; Demeester, J; Jain, R A; Ruddy, S; Remon, J P

    2001-05-21

    A controlled release pellet formulation using a NanoCrystal colloidal dispersion of ketoprofen was developed. In order to be able to process the aqueous NanoCrystal colloidal dispersion into a hydrophobic solid dosage form a spray drying procedure was used. The in vitro dissolution profiles of wax based pellets loaded with nanocrystalline ketoprofen are compared with the profiles of wax based pellets loaded with microcrystalline ketoprofen and of a commercial sustained release ketoprofen formulation. Pellets were produced using a melt pelletisation technique. All pellet formulations were composed of a mixture of microcrystalline wax and starch derivatives. The starch derivatives used were waxy maltodextrin and drum dried corn starch. Varying the concentration of drum dried corn starch increased the release rate of ketoprofen but the ketoprofen recovery remained problematic. To increase the dissolution yield surfactants were utilised. The surfactants were either added during the production process of the NanoCrystal colloidal dispersion (sodium laurylsulphate) or during the pellet manufacturing process (Cremophor RH 40). Both methods resulted in a sustained but complete release of nanocrystalline ketoprofen from the matrix pellet formulations.

  3. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

    Science.gov (United States)

    Epstein, Tamir; Patsopoulos, Nikolaos A; Weiser, Mark

    2014-09-18

    Symptoms of attention deficit hyperactivity disorder (ADHD), diagnosed mainly in children, often persist into adulthood. Adults in this group have a high rate of other psychiatric problems and functional difficulties in a number of key areas such as academic achievement, interpersonal relationships, and employment. Although the usefulness of immediate-release methylphenidate in children has been extensively studied, studies in adults, which are few, demonstrate varying results. To evaluate the efficacy and tolerability of immediate-release methylphenidate versus placebo in the treatment of adults with ADHD. We searched the following databases in November 2013: CENTRAL, Ovid MEDLINE, EMBASE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), and two trials registers. Biosis was searched in December 2013. We inspected references of all relevant papers to identify more studies and contacted authors of recently published trials. We included all randomized trials comparing immediate-release methylphenidate versus placebo in participants aged 18 years or older with ADHD. We excluded trials conducted on subpopulations of adults with ADHD such as adults with both ADHD and substance dependence. Two review authors independently selected trials, extracted data, and assessed trial risk of bias. We contacted authors of trials to ask for additional and missing data. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous outcomes, we calculated mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. Results from the 11 randomized controlled trials (474 participants, counting participants from cross-over studies as a single arm, and counting both arms from parallel studies) included in the review demonstrated improvement in core clinical ADHD symptoms of hyperactivity, impulsivity, and inattentiveness, and overall improvement. We were able to pool results from 10 studies, which included 466

  4. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    NARCIS (Netherlands)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absor

  5. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    NARCIS (Netherlands)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absor

  6. IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system.

    Science.gov (United States)

    Buch, Philipp; Langguth, Peter; Kataoka, Makoto; Yamashita, Shinji

    2009-06-01

    The usefulness of a dissolution/permeation (D/P) system to predict the in vivo performance of solid dosage forms containing the poorly soluble drug, fenofibrate, was studied. Biorelevant dissolution media simulating the fasted and fed state conditions of the human gastrointestinal tract were used in order to simulate the effect of food on the absorption of fenofibrate. Moreover, the results obtained from the D/P system were correlated with pharmacokinetic parameters obtained following in vivo studies in rats. The in vitro parameter (amount permeated in the D/P system) reflected well the in vivo performance in rats in terms of AUC and C(max) of fenofibric acid. This study thus demonstrates the potential of the D/P system as valuable tool for absorption screening of dosage forms for poorly soluble drugs. (c) 2008 Wiley-Liss, Inc.

  7. 77 FR 40069 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

    Science.gov (United States)

    2012-07-06

    ... implementation, or to review product names, to avoid look-alike and sound-alike names that may lead to medication... medication errors may have been due to the visual similarity of the container labels and carton labeling of... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND...

  8. Formulation, optimization and evaluation of levocetirizine dihyrochloride oral thin strip

    Directory of Open Access Journals (Sweden)

    J Gunjan Patel

    2012-01-01

    Full Text Available The aim of present research was to develop a fast releasing oral polymeric film, with good mechanical properties, instant disintegration and dissolution, producing an acceptable taste when placed on tongue. Solvent casting method was used to prepare oral films. Levocetirizine dihydrochloride, an antihistaminic was incorporated to relieve the symptoms of allergic rhinitis. The polymers selected were HPMC E 15 and PVA. Propylene glycol was the plasticizers used. Nine batches of films with drug were prepared using different combinations of polymers and plasticizer concentration. The resultant films were evaluated for weight variation, content uniformity, folding endurance, thickness, surface pH, in vitro disintegration and in vitro dissolution. The optimized films which disintegrated in less than 30 sec, releasing 85-98% of drug within 2 minutes. The percentage release was varying with concentration of plasticizer and polymer. The films made with HPMC: PVA (1:2 released 96% of drug in 1 min, which was the best release amongst all.

  9. Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155 compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen

    Directory of Open Access Journals (Sweden)

    Devarakonda K

    2015-09-01

    Full Text Available Krishna Devarakonda,1 Kenneth Kostenbader,2 Michael J Giuliani,3 Jim L Young41Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, 2Mallinckrodt Pharmaceuticals, 3Research and Development, Mallinckrodt Pharmaceuticals, 4Department of Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USAObjective: To characterize the single-dose and steady-state pharmacokinetics (PK of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP, IR HB/ibuprofen, and IR tramadol HCl/APAP.Methods: In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1 a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose on day 1, followed by two tablets every 12 hours (q12h beginning on day 3; 2 a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6, followed by one tablet every 6 hours (q6h beginning on day 3; 3 a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6, followed by one tablet q6h beginning on day 3; and 4 a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored.Results: The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures

  10. Development of Maltodextrin-Based Immediate-Release Tablets Using an Integrated Twin-Screw Hot-Melt Extrusion and Injection-Molding Continuous Manufacturing Process.

    Science.gov (United States)

    Puri, Vibha; Brancazio, Dave; Desai, Parind M; Jensen, Keith D; Chun, Jung-Hoon; Myerson, Allan S; Trout, Bernhardt L

    2017-07-04

    The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach. The present study develops maltodextrin (MDX)-based extrusion-molded immediate-release tablets for a crystalline drug (griseofulvin) using an integrated twin-screw HME-IM continuous process. At 10% w/w drug loading, MDX was selected as the tablet matrix former based on a preliminary screen. Furthermore, liquid and solid polyols were evaluated for melt processing of MDX and for impact on tablet performance. Smooth-surfaced tablets, comprising crystalline griseofulvin solid suspension in the amorphous MDX-xylitol matrix, were produced by a continuous process on a twin-screw extruder coupled to a horizontally opening IM machine. Real-time HME process profiles were used to develop automated HME-IM cycles. Formulation adjustments overcame process challenges and improved tablet strength. The developed MDX tablets exhibited adequate strength and a fast-dissolving matrix (85% drug release in 20 min), and maintained performance on accelerated stability conditions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Development and validation of a dissolution test for diltiazem hydrochloride in immediate release capsules

    Directory of Open Access Journals (Sweden)

    Taciane Ferreira Mendonça

    2011-01-01

    Full Text Available This work describes the development and validation of a dissolution test for 60 mg of diltiazem hydrochloride in immediate release capsules. The best dissolution in vitro profile was achieved using potassium phosphate buffer at pH 6.8 as the dissolution medium and paddle as the apparatus at 50 rpm. The drug concentrations in the dissolution media were determined by UV spectrophotometry and HPLC and a statistical analysis revealed that there were significant differences between HPLC and spectrophotometry. This study illustrates the importance of an official method for the dissolution test, since there is no official monograph for diltiazem hydrochloride in capsules.

  12. Evaluation of USP apparatus 3 for dissolution testing of immediate-release products

    OpenAIRE

    Yu, Lawrence X.; Wang, Jin T.; Hussain, Ajaz S.

    2002-01-01

    We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution pr...

  13. Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects.

    Science.gov (United States)

    Castelli, M Cristina; Wong, Diane F; Friedman, Kristen; Riley, M Gary I

    2011-07-01

    Vitamin B12 (cobalamin) deficiency may be caused by inadequate dietary intake of B12 or by conditions that result in malabsorption of the vitamin. Crystalline vitamin B12, usually in the form of cyanocobalamin, is administered parenterally (ie, intramuscularly) or orally for treating deficiency states. Intramuscular administration is widely accepted as a treatment method. Oral B12 supplementation is also used, but it is considered to be less reliable. This study was conducted to compare the pharmacokinetics and tolerability of 2 oral formulations of cyanocobalamin-a marketed cyanocobalamin tablet (immediate-release B12 5 mg) and cyanocobalamin formulated with a proprietary carrier, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)-to establish the feasibility of using an absorption enhancer with B12 to improve uptake of the vitamin. This was the first clinical study conducted with the cyanocobalamin/SNAC coformulation. An open-label, randomized, single-dose, parallel-group study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 4 treatment groups: Treatment A subjects (n = 4) received 2 tablets of 5-mg cyanocobalamin formulated with 100-mg SNAC as part of a dose range-finding arm included to determine a dose to provide a measurable concentration of vitamin B12 at all time points when tested with the available vitamin B12 assay; treatment B subjects (n = 6) received 1 tablet of 5-mg cyanocobalamin formulated with 100-mg SNAC; treatment C subjects (n = 6) received 1 commercially available 5-mg cyanocobalamin tablet; and treatment D subjects (n = 4) received commercially available 1-mg cyanocobalamin IV. Treatment A was completed 3 weeks before treatments B, C, and D were studied. Human serum B12 was analyzed by chemiluminescence assay method. Validation procedures established that samples could be diluted up to 100 times without any effects on accuracy and precision. The pharmacokinetic properties of vitamin B12 were characterized by

  14. In vitro and in vivo evaluation of a novel oral insulin formulation

    Institute of Scientific and Technical Information of China (English)

    Er-li MA; Hong MA; Zheng LIU; Chang-xue ZHENG; Ming-xing DUAN

    2006-01-01

    Aim: To develop a stable self-emulsifying formulation for oral delivery of insulin. Methods: Caco-2 cell line and diabetic beagles were used as in vitro and in vivo models to study the absorption mechanism and the hypoglycemic efficacy of the formulation. In addition, various physicochemical parameters of the formulation such as droplet size, insulin encapsulation efficiency and stability were evaluated. Results: This formulation enabled changes in barrier properties of Caco-2 monolayers, as referred by transepithelial electrical resistance (TEER) and apparent permeability coefficients (Papp) of the paracellular marker ranitidine (20-fold greater than control) but not transcellular marker propranolol, suggesting that the opening of tight junctions was involved. In diabetic beagle dogs, the bioavailability of this formulation was up to 15.2% at a dose of 2.5 IU/kg in comparison with the hypoglycemic effect of native insulin (0.5 IU/kg) delivered by subcutaneous injection. Conclusion: This formulation, recently approved by the China State Food and Drug Administration to enter clinical trials, was stable, degradation-protected and absorption-enhanced, and provided a promising formulation for oral insulin delivery.

  15. The role of citric acid in oral peptide and protein formulations

    DEFF Research Database (Denmark)

    Welling, Søren H; Hubálek, František; Jacobsen, Jette;

    2014-01-01

    The excipient citric acid (CA) has been reported to improve oral absorption of peptides by different mechanisms. The balance between its related properties of calcium chelation and permeation enhancement compared to a proteolysis inhibition was examined. A predictive model of CA's calcium chelation...... not occur significantly at the acidic pH values where it effectively inhibits proteolysis, which is its dominant action in oral peptide formulations. On account of insulin's low basal permeability, inclusion of alternative permeation enhancers is likely to be necessary to achieve sufficient oral...

  16. Powdered self-emulsified lipid formulations of meloxicam as solid dosage forms for oral administration.

    Science.gov (United States)

    Agarwal, Vikas; Alayoubi, Alaadin; Siddiqui, Akhtar; Nazzal, Sami

    2013-11-01

    The objectives of this study were to prepare a powdered self-emulsified (SEDDS) formulation of meloxicam and to compare its oral bioavailability against commercial Mobic tablets. The SEDDS formulation was prepared by in situ salt formation of meloxicam in a blend of lipid excipients and aqueous tris (hydroxymethyl) aminomethane solution. The liquid SEDDS was subsequently adsorbed on silica powder and was tested for size, flow, and crystal growth. The flowability index of the powdered SEDDS was borderline acceptable. Absence of crystal growth with storage was confirmed by DSC and PXRD studies. Dissolution of meloxicam from the powdered SEDDS was >90% vs. meloxicam and meloxicam SEDDS formulation showed a 1.3-fold increase in AUC vs. commercial Mobic® tablets. Overall, this study described a novel SEDDS formulation of meloxicam and outlined a systematic approach to adsorbing and testing the flow and stability behavior of powdered SEDDS formulations.

  17. Stability of benzocaine formulated in commercial oral disintegrating tablet platforms.

    Science.gov (United States)

    Köllmer, Melanie; Popescu, Carmen; Manda, Prashanth; Zhou, Leon; Gemeinhart, Richard A

    2013-12-01

    Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography-mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions.

  18. Evaluation of an oral insulin formulation in normal and diabetic rats

    Directory of Open Access Journals (Sweden)

    Hossein Najafzadeh

    2012-01-01

    Full Text Available Aim: As injection is not an ideal means for insulin delivery, various attempts have been made to administer insulin orally until now. The development of an oral dosage form of insulin would help diabetic patients and make the treatment more convenient. The aim of the present study is to evaluate the effectiveness of an oral insulin formulation containing polar and non-polar ingredients. Materials and Methods: New excipient for oral insulin administration in normal and diabetic rats was evaluated by measuring blood glucose concentrations in two groups (10 rats each of normal and streptozotocin-induced diabetic rats. Oral insulin was administrated and blood glucose was measured by glucometer at 0, 1, 2, 3 and 4 h post-feeding. The data was compared by Student′s t test. Results: Oral insulin formulation significantly (P<0.05 reduced blood glucose from 100 mg/dl to 33.73 mg/dl and 451.66 mg/dl to 200.83 mg/dl at 4 h in normal and diabetic rats, respectively. Conclusion: The novel excipient used could protect insulin from gastric and pancreatic enzymes and reduce blood glucose concentration in both healthy and diabetic rats suggesting that oral delivery of insulin is feasible in a near future.

  19. Relative bioavailability and bioquivalence of three different oral formulations of Eslicarbazepine Acetate

    OpenAIRE

    Nunes, Teresa; Falcão, Amílcar; Almeida, Luís; Lima, Ricardo; Tavares, Susana; Neta, Carla; Fontes-Ribeiro, Carlos; Macedo, Tice; Soares-da-Silva, Patricio

    2005-01-01

    AES Proceedings of the Annual Meeting of the American Epilepsy Society To investigate the bioavailability and bioequivalence of three formulations of eslicarbazepine acetate: 50 mg/mL oral suspension (Test 1), 200 mg tablets (Test 2) and 800 mg tablets (Reference)

  20. 76 FR 47197 - Authorization of Emergency Use of Oral Formulations of Doxycycline; Availability

    Science.gov (United States)

    2011-08-04

    ... Doxycycline; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and... Authorization) for oral formulations of doxycycline for the post-exposure prophylaxis of inhalational anthrax..., conditions on the emergency use of the authorized doxycycline products. The Authorization follows...

  1. Formulation development and evaluation of orally disintegrating tablets of doxazosin mesylate

    Directory of Open Access Journals (Sweden)

    Shilpa P Chaudhari

    2012-01-01

    Full Text Available Doxazosin mesylate has some of the ideal characteristics required for an orally disintegrating tablet. There were some challenges faced during this formulation development. The aims of the present research were to mask the bitter taste of Doxazosin mesylate and to formulate orally disintegrating tablets of taste masked drug. Taste masking was performed by coating Doxazosin Mesylate with suitable polymer Eudragit powdered E-100 using spray drying technique. The resultant microspheres were then evaluated for thermal analysis, yield, particle size, entrapment efficiency and in vitro taste masking. The tablets were formulated by mixing the taste masked microspheres with different types and concentration of super-disintegrants and granulated Mannitol was selected as diluent and compressed using direct compression method. The tablets prepared were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release and compared with marketed IR tablet of Doxazosin mesylate.

  2. Characterisation of commercial Perna canaliculus samples and development of extemporaneous oral veterinary paste formulations containing Perna.

    Science.gov (United States)

    Juliano, Claudia; Manconi, Paola; Cossu, Massimo

    2016-09-01

    Perna canaliculus is a nutritional supplement recently studied and highly recommended for its anti-inflammatory effects in both animals and humans. In this study, the physicochemical properties, the microbiological quality, the total lipid content and fatty acids composition of three commercial samples of Perna powder were determined. Subsequently, three simple formulations of extemporaneous oral pastes containing Perna were prepared and designed for veterinary use. Their microbiological stability was assessed after 1-month storage at either room temperature or 35 °C. The results demonstrated that commercial Perna samples lack homogeneity, in regard to some technological properties and fatty acid composition; therefore, a preliminary characterisation of commercial Perna samples is recommended to assure the quality of formulations containing this nutritional supplement. Oral paste formulations are easy and simple to prepare and show good physical and microbiological stability, suggesting their large-scale production.

  3. Design and physicochemical stability studies of paediatric oral formulations of sildenafil.

    Science.gov (United States)

    Provenza, N; Calpena, A C; Mallandrich, M; Halbaut, L; Clares, B

    2014-01-02

    Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process.

  4. Press-coating of immediate release powders onto coated controlled release tablets with adhesives.

    Science.gov (United States)

    Waterman, Kenneth C; Fergione, Michael B

    2003-05-20

    A novel adhesive coating was developed that allows even small quantities of immediate-release (IR) powders to be press-coated onto controlled-release (CR), coated dosage forms without damaging the CR coating. The process was exemplified using a pseudoephedrine osmotic tablet (asymmetric membrane technology, AMT) where a powder weighing less than 25% of the core was pressed onto the osmotic tablet providing a final combination tablet with low friability. The dosage form with the adhesive plus the press-coated powder showed comparable sustained drug release rates to the untreated dosage form after an initial 2-h lag. The adhesive layer consisted of an approximately 100- microm coating of Eudragit RL, polyethylene glycol (PEG) and triethyl citrate (TEC) at a ratio of 5:3:1.2. This coating provides a practical balance between handleability before press-coating and good adhesion.

  5. Microencapsulation techniques to develop formulations of insulin for oral delivery: a review.

    Science.gov (United States)

    Cárdenas-Bailón, Fernando; Osorio-Revilla, Guillermo; Gallardo-Velázquez, Tzayhrí

    2013-01-01

    Oral insulin delivery represents one of the most challenging goals for pharmaceutical industry. In general, it is accepted that oral administration of insulin would be more accepted by patients and insulin would be delivered in a more physiological way than the parenteral route. From all strategies to deliverer insulin orally, microencapsulation or nanoencapsulation of insulin are the most promising approaches because these techniques protect insulin from enzymatic degradation in stomach, show a good release profile at intestine pH values, maintain biological activity during formulation and enhance intestinal permeation at certain extent. From different microencapsulation techniques, it seems that complex coacervation, multiple emulsion and internal gelation are the most appropriate techniques to encapsulate insulin due to their relative ease of preparation. Besides that, the use of organic solvents is not required and can be scaled up at low cost; however, relative oral bioavailability still needs to be improved.

  6. Characterization of organogel as a novel oral controlled release formulation for lipophilic compounds.

    Science.gov (United States)

    Iwanaga, Kazunori; Sumizawa, Toru; Miyazaki, Makoto; Kakemi, Masawo

    2010-03-30

    A low molecular mass gelator can form soft solids in a variety of organic liquids and vegetable oils. These soft solids are generally called organogels. In this study, we prepared organogel using 12-hydroxystearic acid (12-HSA) as a gelator for soybean oil and investigated its characteristics as a controlled release formulation for lipophilic compounds. The release rate of ibuprofen, a model lipophilic compound, from organogel decreased with the increase of 12-HSA concentration in the formulation; however, the difference in the concentration of 12-HSA in the formulation did not affect the diffusivity of ibuprofen in the organogel. The erosion constant of organogel in the intestinal tract was examined by using simulated gastric fluid and intestinal fluid. Regardless of 12-HSA concentration in the formulation, organogel is very stable in the simulated gastric fluid. On the other hand, the erosion constant of organogel in the simulated intestinal fluid increased with the decreasing concentration of 12-HSA. Therefore, it is speculated that the difference in the release rate of ibuprofen among organogels with various concentrations of 12-HSA was mainly caused by the difference in the erosion rate. To characterize the organogel effect in vivo, ibuprofen was orally administered to rats in an aqueous suspension or organogel. Ibuprofen concentration in plasma rapidly increased after administration with an aqueous suspension, whereas organogel suppressed the rapid absorption. In conclusion, organogel is clearly useful as an oral controlled release formulation for lipophilic compounds.

  7. Oral Liquid Formulation of Levothyroxine Is Stable in Breakfast Beverages and May Improve Thyroid Patient Compliance

    Directory of Open Access Journals (Sweden)

    Alberto Bernareggi

    2013-12-01

    Full Text Available Patients on treatment with levothyroxine (T4 are informed to take this drug in the morning, at least 30 min before having breakfast. A significant decrease of T4 absorption was reported, in fact, when T4 solid formulations are taken with food or coffee. According to preliminary clinical study reports, administration of T4 oral solution appears to be less sensitive to the effect of breakfast beverages on oral bioavailability. In the present study, stability of T4 oral solution added to breakfast beverages was investigated. A 1 mL ampoule of single-dose Tirosint® oral solution (IBSA Farmaceutici Italia, Lodi, Italy was poured into defined volumes of milk, tea, coffee, and coffee with milk warmed at 50 °C, as well as in orange juice at room temperature. Samples were sequentially collected up to 20 min and analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS methods. The results of the study demonstrated that T4 is stable in all beverages after 20 min incubation. Demonstration of T4 stability is a prerequisite for a thorough evaluation of the effect of breakfast beverages on the bioavailability of T4 given as oral solution and for a better understanding of the reasons underlying a decreased T4 bioavailability administered as solid formulations.

  8. A novel approach to establishing the design space for the oral formulation manufacturing process.

    Science.gov (United States)

    Norioka, Tadashi; Hayashi, Yoshihiro; Onuki, Yoshinori; Andou, Hirotaka; Tsunashima, Daisuke; Yamashita, Kazunari; Takayama, Kozo

    2013-01-01

    A novel approach to establishing the design space for the oral formulation manufacturing process was investigated. A response surface method incorporating multivariate spline interpolation was applied to overcome the nonlinear problem, which is always problematic in pharmaceutical development studies, and a bootstrap resampling technique, polynomial approximation technique, and 95% confidence intervals based on a nonparametric approach were applied to estimate the reliability of the established design space derived from the nonlinear response surface model. The critical quality attributes (CQAs) of intermediate material rather than the critical process parameters (CPPs) were chosen as the causal factors for the response variables, which were CQAs of the final product to avoid scale-gap and equipment-gap. This enabled the effective use of data sets accumulated during all pharmaceutical development studies. It was confirmed that a conservative border as well as an optimistic border of the design space for practical use was obtained considering the variability of the border of the design spaces on nonlinear response surfaces. Furthermore, the nonlinear response surface model using CQAs of intermediate material derived from data sets of a laboratory scale study and pilot scale studies could predict the CQA of the final product (2.5 h dissolution of commercial-scale study) with high accuracy. Consequently, the proposed novel approach overcame all of the difficulties for the manufacturing process development of oral formulations and this is the first study to demonstrate the effectiveness of the design space using CQA of intermediate material for the oral formulation manufacturing process.

  9. Enhanced oral bioavailability and in vivo antioxidant activity of chlorogenic acid via liposomal formulation.

    Science.gov (United States)

    Feng, Yingshu; Sun, Congyong; Yuan, Yangyang; Zhu, Yuan; Wan, Jinyi; Firempong, Caleb Kesse; Omari-Siaw, Emmanuel; Xu, Yang; Pu, Zunqin; Yu, Jiangnan; Xu, Ximing

    2016-03-30

    In the present study, a formulation system consisting of cholesterol and phosphatidyl choline was used to prepare an effective chlorogenic acid-loaded liposome (CAL) with an improved oral bioavailability and an increased antioxidant activity. The developed liposomal formulation produced regular, spherical and multilamellar-shaped distribution nanoparticles. The pharmacokinetic analysis of CAL compared with chlorogenic acid (CA), showed a higher value of Cmax(6.42 ± 1.49 min versus 3.97 ± 0.39 min) and a delayed Tmax(15 min versus 10 min), with 1.29-fold increase in relative oral bioavailability. The tissue distribution in mice also demonstrated that CAL predominantly accumulated in the liver which indicated hepatic targeting potential of the drug. The increased activities of antioxidant enzymes (Total Superoxide Dismutase (T-SOD) and Glutathione Peroxidase (GSH-Px)) and total antioxidant capacity (T-AOC), in addition to decreased level of malondialdehyde (MDA) in CCl4-induced hepatotoxicity study further revealed that CAL exhibited significant hepatoprotective and antioxidant effects. Collectively, these findings present a liposomal formulation with significantly improved oral bioavailability and an increased in vivo antioxidant activity of CA.

  10. Ferrous versus Ferric Oral Iron Formulations for the Treatment of Iron Deficiency: A Clinical Overview

    Directory of Open Access Journals (Sweden)

    Palacios Santiago

    2012-01-01

    Full Text Available Iron deficiency anaemia represents a major public health problem, particularly in infants, young children, pregnant women, and females with heavy menses. Oral iron supplementation is a cheap, safe, and effective means of increasing haemoglobin levels and restoring iron stores to prevent and correct iron deficiency. Many preparations are available, varying widely in dosage, formulation (quick or prolonged release, and chemical state (ferrous or ferric form. The debate over the advantages of ferrous versus ferric formulations is ongoing. In this literature review, the tolerability and efficacy of ferrous versus ferric iron formulations are evaluated. We focused on studies comparing ferrous sulphate preparations with ferric iron polymaltose complex preparations, the two predominant forms of iron used. Current data show that slow-release ferrous sulphate preparations remain the established and standard treatment of iron deficiency, irrespective of the indication, given their good bioavailability, efficacy, and acceptable tolerability demonstrated in several large clinical studies.

  11. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview.

    Science.gov (United States)

    Santiago, Palacios

    2012-01-01

    Iron deficiency anaemia represents a major public health problem, particularly in infants, young children, pregnant women, and females with heavy menses. Oral iron supplementation is a cheap, safe, and effective means of increasing haemoglobin levels and restoring iron stores to prevent and correct iron deficiency. Many preparations are available, varying widely in dosage, formulation (quick or prolonged release), and chemical state (ferrous or ferric form). The debate over the advantages of ferrous versus ferric formulations is ongoing. In this literature review, the tolerability and efficacy of ferrous versus ferric iron formulations are evaluated. We focused on studies comparing ferrous sulphate preparations with ferric iron polymaltose complex preparations, the two predominant forms of iron used. Current data show that slow-release ferrous sulphate preparations remain the established and standard treatment of iron deficiency, irrespective of the indication, given their good bioavailability, efficacy, and acceptable tolerability demonstrated in several large clinical studies.

  12. Development and characterization of an atorvastatin solid dispersion formulation using skimmed milk for improved oral bioavailability

    Directory of Open Access Journals (Sweden)

    Ankush Choudhary

    2012-08-01

    Full Text Available Atorvastatin has low aqueous solubility resulting in low oral bioavailability (12% and thus presents a challenge in formulating a suitable dosage form. To improve the aqueous solubility, a solid dispersion formulation of atorvastatin was prepared by lyophilization utilising skimmed milk as a carrier. Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared. The formation of a solid dispersion formulation was confirmed by differential scanning calorimetry and X-ray diffraction studies. The optimum drug-to-carrier ratio of 1:9 enhanced solubility nearly 33-fold as compared to pure drug. In vitro drug release studies exhibited a cumulative release of 83.69% as compared to 22.7% for the pure drug. Additionally, scanning electron microscopy studies suggested the conversion of crystalline atorvastatin to an amorphous form. In a Triton-induced hyperlipidemia model, a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug. These results suggest that solid dispersion of atorvastatin using skimmed milk as carrier is a promising approach for oral delivery of atorvastatin.

  13. Lichenoid Drug Eruptionfollowing Intravenous Applicationof Orally Formulated Diamorphine, a Semisynthetic Heroin

    Directory of Open Access Journals (Sweden)

    I. Kolm

    2013-06-01

    Full Text Available Background: Lichen planus is a common skin disorder of unknown etiology. Most cases are idiopathic, but substances such as gold, antimalarials, penicillamine, thiazide diuretics, β-blockers, arsenic and nonsteroidal anti-inflammatory drugs have been implicated as trigger factors. Case Presentation: We report the case of a lichenoid eruption in a male drug addict who administered oral heroin (diamorphine intravenously. Diamorphine was stopped immediately. Following topical steroids, phototherapy and oral acitretin, the lesions gradually disappeared. A lymphocyte transformation test was negative for pure morphine and codeine. Discussion: A coincidental association between the intravenous application of orally formulated semisynthetic heroin and the lichenoid eruption cannot be completely ruled out. However, the diagnosis of a lichenoid drug eruption is favoured over idiopathic lichen planus because of the clear chronological correlation between drug use and appearance as well as drug withdrawal and disappearance of the skin lesions, and because of a flare-up following repeated intravenous application of diamorphine.

  14. Process optimization of a novel immediate release film coating system using QbD principles.

    Science.gov (United States)

    Teckoe, Jason; Mascaro, Tracey; Farrell, Thomas P; Rajabi-Siahboomi, Ali R

    2013-06-01

    This work describes a quality-by-design (QbD) approach to determine the optimal coating process conditions and robust process operating space for an immediate release aqueous film coating system (Opadry® 200). Critical quality attributes (CQAs) or associated performance indicators of the coated tablets were measured while coating process parameters such as percent solids of the coating dispersion, coating spray rate, inlet air temperature, airflow rate and pan speed were varied, using a design of experiment protocol. The optimized process parameters were then confirmed by independent coating trials. Disintegration time of coated tablets was not affected by the coating process conditions used in this study, while tablet appearance, as determined by measurement of tablet color, coating defects and gloss was determined to be a CQA. Tablet gloss increased when low spray rate and low percent solids were used, as well as with increased coating pan speed. The study used QbD principles and experimental design models to provide a basis to identify ranges of coating process conditions which afford acceptable product quality. High productivity, color uniformity, and very low defect levels were obtained with Opadry 200 even when using a broad range of coating process conditions.

  15. A novel electrostatic dry powder coating process for pharmaceutical dosage forms: immediate release coatings for tablets.

    Science.gov (United States)

    Qiao, Mingxi; Zhang, Liqiang; Ma, Yingliang; Zhu, Jesse; Chow, Kwok

    2010-10-01

    An electrostatic dry powder coating process for pharmaceutical solid dosage forms was developed for the first time by electrostatic dry powder coating in a pan coater system. Two immediate release coating compositions with Opadry® AMB and Eudragit® EPO were successfully applied using this process. A liquid plasticizer was sprayed onto the surface of the tablet cores to increase the conductivity of tablet cores to enhance particle deposition, electrical resistivity reduced from greater than 1×10(13)Ωm to less than 1×10(9)Ωm, and to lower the glass transition temperature (T(g)) of the coating polymer for film forming in the pan coater. The application of liquid plasticizer was followed by spraying charged coating particles using an electrostatic charging gun to enhance the uniform deposition on tablet surface. The coating particles were coalesced into a thin film by curing at an acceptable processing temperature as formation was confirmed by SEM micrographs. The results also show that the optimized dry powder coating process produces tablets with smooth surface, good coating uniformity and release profile that are comparable to that of the tablet cores. The data also suggest that this novel electrostatic dry powder coating technique is an alternative to aqueous- or solvent-based coating process for pharmaceutical products. Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.

  16. Biopharmaceutical constants for carbamazepine immediate release tablets in simplifying bioequivalence studies

    Directory of Open Access Journals (Sweden)

    Nanayakkara Mangala

    2006-01-01

    Full Text Available Current study was undertaken in order to determine model biopharmaceutical constants for carbamazepine immediate release tablets (200 mg from documented data of plasma concentration vs time curves. The constants and the proposed methodology simplify bioequivalence determinations to blood sampling restricted only to two time points. Twelve volunteer drug plasma concentration (Cp determinations from a crossover design bioequivalence study were fitted into equations containing two rate processes. The optimized rate constants were used to generate the Cp vs time curves (generated curves. Generated curves were then differentiated (dCp/dt to obtain the first derivative curve for each volunteer from which times for highest rate of absorption (TAmaxn and highest rate of elimination (TEmaxn were determined. The corresponding highest rate of absorption and the highest rate of elimination for each individual were then obtained from the generated curve and named as Amaxn and Emaxn. Individual Amaxn and Emaxn values were then averaged to obtain the mean Amax and Emax. Out of the 24 determinations, a total of 13 Amaxn and 20 Emaxn values fell within ±20% of the overall mean. Final Amax and Emax values ware arrived at by averaging each set of individual 13 values and 20 values respectively. From these two mean coordinates, the corresponding constants, plasma drug concentration at the point of highest rate of absorption (CpAmax and corresponding time TAmax, as well as the plasma drug concentration at the point of highest rate of elimination (CpEmax and the corresponding time TEmax, were determined.

  17. Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study.

    Science.gov (United States)

    Venables, Rebecca; Batchelor, Hannah; Stirling, Heather; Marriott, John

    2016-01-30

    There is a paucity of research exploring barriers to non-oral medicines administration in paediatric patients; however, these undoubtedly influence medicines adherence. Studies conducted with healthcare professionals have identified various issues with the administration and acceptance of non-oral medicines and devices (Venables et al., 2012; Walsh et al., 2015). EMA (2014) guidelines specify that formulation teams should demonstrate 'acceptability' of paediatric formulations when developing pharmaceutical formulations. Semi-structured interviews exploring barriers to administering non-oral medicines were conducted with young persons and the parents/legal guardians of children (0-17 years) with chronic conditions at the University Hospital of Coventry and Warwickshire, UK. 90 children prescribed a total of 148 non-oral medicines were recruited to the study; 88 barriers to administering non-oral medicines were reported. The most commonly reported barriers were: poor acceptance of face mask/difficulties with spacer for inhaled formulations (38% of reports); disliking parenteral/preferring alternative formulations (38% of reports); greasy texture of topical preparations; difficulty with administering an ocular ointment and the large dose volume of a nasal preparation. Formulation teams should consider the use of child-friendly, age-appropriate designs to improve usability and acceptance, thus medicines adherence. These findings should be used to inform future development of non-oral formulations and devices, suitable in terms of safety, efficacy and acceptability to paediatric patients.

  18. Simvastatin-loaded PLGA nanoparticles for improved oral bioavailability and sustained release: Effect of formulation variables

    Directory of Open Access Journals (Sweden)

    Aman Soni

    2011-01-01

    Full Text Available The objective of this study was to prepare a nanoparticulate formulation of simvastatin (SV for improving oral bioavailability and sustaining the drug release while investigating the effect of various formulation parameters on characteristics of nanoparticles. Nanoparticles containing SV were prepared by a modified emulsification solvent evaporation technique using a biodegradable polymer, poly(d,l-lactide-coglycolide (PLGA as a sustained release carrier. The effect of various formulation parameters such as drug polymer ratios (SV:PLGA, 1:4 to 1:1, organic solvents (methanol/dichloromethane, and surfactants (PVA/polysorbate-80 in a fixed concentration (0.5%, w/v were studied for particle size, drug loading, and entrapment efficiency. Nanoparticles were characterized by differential scanning calorimetry (DSC and their shapes were observed by scanning electron microscopy (SEM. An aqueous solubility study indicated that the dissolution rates were remarkably increased for nanoparticles compared with the drug alone. The in vitro drug release study of the nanoparticles showed a biphasic release pattern: one initial burst release of 40.56% in the first 4 h which can be helpful to improve the penetration of drug followed by a second slow-release phase (extended release consistent with a Higuchi diffusion mechanism. The hypolipidemic activity of nanoparticles was determined in comparison with SV in male Wistar rats for changes in total cholesterol (CH and triglyceride (TG levels in blood. Nanoparticles showed a significantly better in vivo performance than SV in reducing total CH and TG levels which is primarily attributed to the improved solubility and dissolution of nanoparticles. Together, these results indicate that nanoparticulate formulations are ideal carriers for oral administration of SV having great potential to improve the oral bioavailability and sustain the drug release, thereby minimizing the dose-dependent adverse effects and maximizing

  19. Formulation and evaluation of orally disintegrating tablet of Rizatriptan using natural superdisintegrant

    Directory of Open Access Journals (Sweden)

    Tabbakhian Majid

    2014-01-01

    Full Text Available Introduction: Rizatriptan benzoate is a potent and selective 5-HT1B/1D receptor agonist and is effective for the treatment of acute migraine. Difficulty in swallowing is common among all age groups, especially elderly and pediatrics. Orally disintegrating tablets may constitute an innovative dosage form that overcome the problem of swallowing and provides a quick onset of action. This study was aimed to formulate and evaluate an Orally Disintegrating Tablet (ODT containing Rizatriptan while using semi-synthetic and natural superdisintegrants. Methods: Orodispersible tablets were prepared by direct compression using natural superdisntegrant (Plantago ovata mucilage and semi-synthetic superdisntegrant (crospovidone. The prepared tablets were evaluated for hardness, friability, thickness, drug content uniformity, water absorption and wetting time. A 32 factorial design was used to investigate the effect of independent variables (amount of crospovidone and Plantago ovata mucilage on dependent variables [disintegration time, wetting time and Q5 (cumulative amount of drug release after 5 minutes]. A counter plot was also presented to graphically represent the effect of independent variable on the disintegration time, wetting time and Q5. The check point batch was also prepared to prove the validity of the evolved mathematical model. The systematic formulation approach helped in understanding the effect of formulation processing variable. Results: According to the results of optimized batches, the best concentration of superdisintegrant were as follows: 9.4 mg Psyllium mucilage and 8.32 mg crospovidone gave rapid disintegration in 35sec and showed 99% drug release within 5 minutes. Conclusion: Plantago ovata mucilage, a natural superdisintegrant, gives a rapid disintegration and high release when used with synthetic superdisntegrant in formulation of orally disintegrating tablet of Rizatriptan.

  20. BIOEQUIVALENCE STUDY OF TWO ORAL FORMULATIONS OF METAMIZOLE 500 MG IN HEALTHY VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    Dhaneshwar Shep *, Rakesh Ojha , Rajeshwari Rathod , Sweta Patel , Manish Nivsarkar , Sanjay Maroo and Harish Padh

    2012-06-01

    Full Text Available Background: Metamizole (Dipyrone is widely used and has effective analgesic, antipyretic, and antispasmodic properties. After oral or intravenous administration, dipyrone is rapidly hydrolyzed to the active moiety 4-methylaminoantipyrine. Aim: The aim of this study was to assess the bioequivalence of 2 oral formulations of Metamizole 500 mg. Methods: This double blind, randomized, single-dose, 2-period crossover study in healthy Indian adult volunteers was conducted at PERD Centre, Ahmedabad. Subjects received Metamizole 500 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 24 hours. Plasma concentration of 4-methylaminoantipyrine was measured by pre-validated LC-MS method. Pharmacokinetic (PK parameters Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and kel, were determined for test and reference formulations. The formulations were to be considered bioequivalent if the log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence range of 80% to 125%. Results: A total of 14 subjects were enrolled. No significant differences were found based on analysis of variance, with mean values and 90% confidence intervals of test/reference ratios for these parameters as follows: Cmax, 18.24 versus 18.44 μg/mL (92.68 - 106.61; AUC0-t, 92.97 Versus 91.37 μg.hr/mL (89.49 - 113.09; and AUC0-∞, 96.64 Versus 94.65 μg.hr/mL (92.31 - 111.63. Conclusion: Since the 90% confidence intervals for Cmax, AUC0-t, and AUC0−∞ were within the interval of 80-125%, it was concluded that both formulations were bioequivalent, according to both the rate and extent of absorption.

  1. Formulation of cyclodextrin inclusion complex-based orally disintegrating tablet of eslicarbazepine acetate for improved oral bioavailability

    Energy Technology Data Exchange (ETDEWEB)

    Desai, Samixa; Poddar, Aditi; Sawant, Krutika, E-mail: dr_krutikasawant@yahoo.co.in

    2016-01-01

    The present investigation was aimed towards developing a beta-cyclodextrin (β-CD) solid dispersion (SD) based orally disintegrating tablet (ODT) of eslicarbazepine acetate (ESL), for improving the dissolution and providing fast onset of anti-epileptic action. Optimum ratio of ESL and β-CD was determined by Job's plot. Thereafter, solid dispersions were prepared by solvent evaporation method and evaluated for yield, assay, Differential scanning calorimetry (DSC), Fourier transform infra red spectroscopy (FTIR), X-ray diffraction (XRD), and in vitro dissolution. Optimized SD was compressed into ODT by direct compression using super disintegrants and evaluated for wetting time, drug content, in vitro drug release and in vivo studies. The results of DSC, FTIR and XRD analysis supported the formation of inclusion complex. An improved dissolution with 99.95 ± 2.80% drug release in 60 min was observed in comparison to 24.85 ± 2.96% release from a plain drug suspension. Tablets with crosspovidone as a super disintegrant showed the least disintegration time of 24.66 ± 1.52 s and higher in vitro drug release against marketed tablets. In vivo studies indicated that the formulated tablets had 2 times higher bioavailability than marketed tablets. Thus, the developed β-CD–ESL SD-ODT could provide faster onset of action and higher bioavailability, which would be beneficial in case of epileptic seizures. - Highlights: • β-cyclodextrin–eslicarbazepine acetate complex developed with enhanced solubility. • Formulated Orally disintegrating tablets (ODT) disintegrated within 30 s. • Bioavailability from ODT was 2 times higher than marketed tablets. • Onset of action for ODT was also faster than marketed tablets. • Formulated ODT would aid epileptic patients incapable of swallowing tablets.

  2. Solid-Nanoemulsion Preconcentrate for Oral Delivery of Paclitaxel: Formulation Design, Biodistribution, and γ Scintigraphy Imaging

    Directory of Open Access Journals (Sweden)

    Javed Ahmad

    2014-01-01

    Full Text Available Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC using oil [propylene glycol monocaprylate/glycerol monooleate, 4 : 1 w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1 : 1 w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1 : 1 w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM, differential scanning calorimetry (DSC, X-ray diffraction (XRD, and Fourier transform infrared spectroscopy (FTIR were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel, respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in γ scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC.

  3. FORMULATION AND EVALUATION OF DENTAL GEL CONTAINING ESSENTIAL OIL OF CORIANDER AGAINST ORAL PATHOGENS

    Directory of Open Access Journals (Sweden)

    Pawar Vinita A

    2013-10-01

    Full Text Available The objective of this study was to investigate the antimicrobial potency of essential oil of Coriander against clinical samples isolated from the oral cavity of various patients and to formulate a suitable topical preparation containing Coriander oil. A total of 41 swabs were obtained from patients (age between 20 - 50 years which were diagnosed with oral infections like periodontal abscess, periapical abscess, chronic periodontities, periapical granuloma, dental caries, root caries and plaque samples. These samples were inoculated on Blood agar, Mac-conkeys agar and MRS Lactobacilli MRS agar, Mutans Sanguis agar, KF Streptococcal agar at 37°C for 24 – 48 h aerobically except for KF Streptococcal agar and Mutans Sanguis agar, which was incubated anaerobically at 37°C for 24 – 48 h. The isolates were identified by standard microbiological procedures. The samples had positive cultures of Streptococcus faecalis, Streptococcus sanguis, Streptococcus oralis, Streptococcus mutans, Streptococcus salivarius, Lactobacilli, CONS. The susceptibility of these isolates was determined using agar disc diffusion method for zone of inhibition. The evaluation of antimicrobial potency was studied prior to gel formulation to compare the changes in activity after incorporation in polymer gel. The topical formulations were developed using different concentrations of polymers and evaluated for various physicochemical parameters like pH, color, clarity, viscosity, consistency, homogeneity, spread ability. The activity of oil was not much affected by incorporation in gel. The gel showed promising antimicrobial activity against the strains used for the study.

  4. Continuous multimechanistic postoperative analgesia: a rationale for transitioning from intravenous acetaminophen and opioids to oral formulations.

    Science.gov (United States)

    Pergolizzi, Joseph V; Raffa, Robert B; Tallarida, Ronald; Taylor, Robert; Labhsetwar, Sumedha A

    2012-02-01

    Good surgical outcomes depend in part on good pain relief, allowing for early mobilization, optimal recovery, and patient satisfaction. Postsurgical pain has multiple mechanisms, and multimechanistic approaches to postoperative analgesia are recommended and may be associated with improved pain relief, lowered opioid doses, and sometimes a lower rate of opioid-associated side effects. Acetaminophen (paracetamol) is a familiar agent for treating many types of pain, including postsurgical pain. Oral acetaminophen has been shown to be safe and effective in a variety of acute pain models. Combination products using a fixed-dose of acetaminophen and an opioid have also been effective in treating postsurgical pain. Combination products with acetaminophen have demonstrated an opioid-sparing effect, which inconsistently results in a reduced rate of opioid-associated side effects. Intravenous (IV) acetaminophen and an opioid analgesic administered in the perioperative period may be followed by an oral acetaminophen and opioid combination in the postoperative period. Transitioning from an IV acetaminophen and opioid formulation to a similar but oral formulation of the same drugs appears to be a reasonable step in that both analgesic therapies are known to be safe and effective. For postsurgical analgesia with any acetaminophen product, patient education is necessary to be sure that the patient does not concurrently take any over-the-counter products containing acetaminophen and accidentally exceed dose limits.

  5. Tapentadol immediate release: a new treatment option for acute pain management

    Directory of Open Access Journals (Sweden)

    Marc Afilalo

    2010-02-01

    Full Text Available Marc Afilalo1, Jens-Ulrich Stegmann2, David Upmalis31Sir Mortimer B. Davis Jewish General Hospital, Montréal, Canada; 2Global Drug Safety, Grünenthal GmbH, Aachen, Germany; 3Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey, USAAbstract: The undertreatment of acute pain is common in many health care settings. Insufficient management of acute pain may lead to poor patient outcomes and potentially life-threatening complications. Opioids provide relief of moderate to severe acute pain; however, therapy with pure µ-opioid agonists is often limited by the prevalence of side effects, particularly opioid-induced nausea and vomiting. Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, µ-opioid receptor agonism and norepinephrine reuptake inhibition. The analgesic effects of tapentadol are independent of metabolic activation and tapentadol has no active metabolites; therefore, in theory, tapentadol may be associated with a low potential for interindividual efficacy variations and drug–drug interactions. Previous phase 3 trials in patients with various types of moderate to severe acute pain have shown that tapentadol immediate release (IR; 50 to 100 mg every 4 to 6 hours provides analgesia comparable to that provided by the pure µ-opioid agonist comparator, oxycodone HCl IR (10 or 15 mg every 4 to 6 hours, with a lower incidence of nausea, vomiting, and constipation. Findings suggest tapentadol may represent an improved treatment option for acute pain.Keywords: tapentadol IR, acute pain, opioid, gastrointestinal tolerability

  6. IDENTIFICATION OF PHARMACEUTICAL EXCIPIENT BEHAVIOR OF CHICKPEA (CICER ARIETINUM) STARCH IN GLICLAZIDE IMMEDIATE RELEASE TABLETS.

    Science.gov (United States)

    Meka, Venkata Srikanth; Yee, Phung; Sheshala, Ravi

    2016-01-01

    In the past few years, there are number of researchers carrying out their research on the excipients derived from polysaccharides and some of these researches show that natural excipients are comparable and can serve as an alternative to the synthetic excipients. Hence, the objectives of this research are to characterize the naturally sourced chickpea starch powder and to study the pharmaceutical excipient behavior of chickpea starch in gliclazide immediate release (IR) tablets. In this research, the binding properties of chickpea starch were compared to that of povidone, whereas the disintegrant properties of chickpea starch were compared to those of crospovidone, croscarmellose sodium and sodium starch glycolate. Flow property of chickpea starch was assessed with the measurement of bulk density, tapped density, compressibility index and angle of repose. Calibration curve for gliclazide in phosphate buffer pH 7.4 was developed. Gliclazide IR tablets were then produced with direct compression method. Physicochemical characteristics of the tablets, including thickness, tablet weight uniformity, hardness, disintegration time and friability were evaluated. Then, in vitro dissolution studies were performed by following United States Pharmacopeia (USP) dissolution method. The dissolution results were analyzed and compared with t30, t50, dissolution efficiency (DE). Lastly, drug-excipient compatibility studies, including Fourier transform infrared (FTIR) spectroscopic analysis and differential scanning calorimetric (DSC) analysis were carried out. Fair flow property was observed in the chickpea starch powder. Furthermore, the tablets produced passed all the tests in physicochemical characteristics evaluation except hardness and disintegration test. Additionally, in vitro dissolution studies show that chickpea starch acted as a disintegrant instead of a binder in gliclazide IR tablets and its disintegrant properties were comparable to those of crospovidone, croscarmellose

  7. Evaluation of USP apparatus 3 for dissolution testing of immediate-release products.

    Science.gov (United States)

    Yu, Lawrence X; Wang, Jin T; Hussain, Ajaz S

    2002-01-01

    We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f(2) similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.

  8. Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug

    NARCIS (Netherlands)

    A.C. Van Der Vossen (Anna C.); I. Van Der Velde (Iris); O. Smeets (Oscar); Postma, D.J.; Eckhardt, M.; A. Vermes (Andras); B.C.P. Koch (Birgit C. P.); A.G. Vulto (Arnold); L.M. Hanff (Lidwien)

    2017-01-01

    textabstractIntroduction Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of admini

  9. Quality-by-design III: application of near-infrared spectroscopy to monitor roller compaction in-process and product quality attributes of immediate release tablets.

    Science.gov (United States)

    Kona, Ravikanth; Fahmy, Raafat M; Claycamp, Gregg; Polli, James E; Martinez, Marilyn; Hoag, Stephen W

    2015-02-01

    The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development.

  10. Formulation and evaluation of in situ gels containing clotrimazole for oral candidiasis

    Directory of Open Access Journals (Sweden)

    Harish N

    2009-01-01

    Full Text Available Gel dosage forms are successfully used as drug delivery systems to control drug release and protect the medicaments from a hostile environment. The main objective is to formulate and evaluate in situ oral topical gels of clotrimazole based on the concept of pH triggered and ion activated systems. The system utilizes polymers that exhibit sol-to-gel phase transition due to change in specific physico-chemical parameters. A pH triggered system consisting of carbopol 934P (0.2-1.4% w/v and ion triggered system using gellan gum (0.1-0.75% w/v along with hydroxylpropylmethylcelluose E50LV was used to prolong the release of clotrimazole (0.1% w/v. Formulations were evaluated for gelling capacity, viscosity, gel strength, bioadhesive force, spreadability, microbiological studies and in vitro release. The use of carbopol as in situ gel forming system was substantiated by the property to transform into stiff gels when the pH was raised, whereas in gellan gum this transformation occurred in the presence of monovalent/divalent cations. Effect of calcium carbonate and other process parameters optimized and found that increase in calcium ions produced stronger gels. The drug content, clarity, and pH of the formulation were found to be satisfactory. The viscosity was found to be in the range 5 to 85 centipoise for the sol, whereas for the gels it was up to 16000 centipoise. The formulation showed pseudoplastic flow with thixotrophy. The maximum gel strength (using texture analyzer and bioadhesion was found to be up to 6.5 g and 4 g, respectively. The optimized formulations were able to release the drug up to 6 h. The formulation containing gellan gum showed better sustained release compared to carbopol based gels.

  11. On the bioavailability of oral chondroitin sulfate formulations: proposed criteria for bioequivalence studies.

    Science.gov (United States)

    Vergés, Josep; Castañeda-Hernández, Gilberto

    2004-01-01

    Chondroitin sulfate (CS) is a symptomatic slow-acting drug for osteoarthritis (SYSADOA). It should be noted, however, that there is a CS formulation approved as a drug in Europe, with evidenced efficacy and safety demonstrated by clinical trials in osteoarthritic patients. This formulation should therefore be considered as the reference product. This CS is manufactured by Bioibérica (Spain), commercialized in Europe by IBSA (Switzerland) and Bioibérica, and in the United States by Nutramax. Hence, all other CS formulations must demonstrate their bioequivalence with the reference product. Pharmacokinetic studies have shown that oral exogenous CS is absorbed as several metabolites, and the active moiety has not yet been identified. It is thus difficult to establish bioequivalence from plasma concentration against time curves. However, the FDA permits bioequivalence studies comparing the time course of the pharmacological response with two formulations of the same compound. It has been reported that the time course of CS response can be fitted to a modified Hill equation, as follows: E-E0=[(Emax x Ty )/(T50y+Ty)]. Where E is the effect at time T, E0 is the basal effect, Emax is the maximal effect, T50 is the time required to achieve 50% of the maximal effect and y is the sigmoid slope factor. Hence, it is proposed that a generic CS can be compared to the reference product using the Emax, T50, and y values derived by non-linear regression fitting to the modified Hill equation. The reference/test formulation ratio with the 90% confidence intervals (CI) can thus be estimated. If CI for each parameter ratio lies within 0.8-1.2, both CS formulations can be considered as bioequivalent. In the absence of such bioequivalence studies, physicians and patients are advised to use the reference product to obtain the maximal benefit in terms of efficacy and safety.

  12. Translation of an experimental oral vaccine formulation into a commercial product.

    Science.gov (United States)

    Carter, K C; Ferro, V A; Alexander, J; Mullen, A B

    2006-02-01

    An effective experimental vaccine may fail to become a therapeutic reality for a number of scientific, regulatory or commercial reasons. In this review, we share some of our personal experiences as University-based researchers and provide an account of some of the problems that we have encountered during preliminary scale-up and assessment of an oral influenza vaccine formulation. Many of the problems we have faced have been non-scientific and related to identifying project-funding sources, finding suitable contract manufacturing companies that are GMP compliant, and protecting intellectual property generated from the scientific studies. The review is intended as a practical guide that will allow other researchers to adopt effective strategies to permit the translation of an effective experimental formulation to a viable commercial product.

  13. Palatability evaluation study of a new oral formulation of marbofloxacin in cats.

    Science.gov (United States)

    Cron, M; Zemirline, C; Beranger, J; Privat, V

    2014-07-26

    At a time when antimicrobial resistance is a global concern in human and animal health, it is of primary importance to draw attention to the problem of compliance with antibiotic therapy in animals hard to medicate such as cats. Resistance may develop because of poor patient compliance with the prescribed course of antibiotic therapy. Increasing palatability might enhance administration compliance. We assessed the acceptability of EFEX tablets, a new oral marbofloxacin formulation for cats. The objective of this study was to compare EFEX to two commercial formulations of marbofloxacin: MARBOCYL P palatable tablets and MARBOCYL Vet tablets. Acceptance tests were run in experimental conditions in 24 cats to compare the spontaneous intake and full consumption of the three pharmaceutical products. The results indicated that EFEX was more palatable than MARBOCYL Vet (0.001

  14. FORMULATION AND EVALUATION OF ORAL CONTROLLED RELEASE DOSAGE FORM OF ANTI-HYPERTENSIVE AGENT

    Directory of Open Access Journals (Sweden)

    Lakshmi Parvathi A

    2012-12-01

    Full Text Available The aim of present investigation is preparation, characterization and evaluation of oral controlled release matrix tablets of Propranolol HCl in order to improve efficacy and to reduce the side effects. Tablets were prepared by direct compression method using different polymers like Guar gum, HPMC K4M, PVP and MCC used as the directly compressible vehicle. The granules were evaluated for pre-formulation characteristics and the tablets were subjected to post compression parameters, drug content and in-vitro dissolution release studies. In-vitro dissolution studies were carried out for 12 hrs and the results showed that among the nine formulations F8 and F9 showed good dissolution profile to control the drug release respectively. The drug release follows first order kinetics and the mechanism was found to be diffusion controlled for all the formulations (except F-9. The mechanism of drug release from F-9 was diffusion coupled with erosion. The Stability studies were carried out according to ICH guideline which indicates that the selected formulations (F8 and F9 were stable. In conclusion the results suggest that the developed matrix tablets of Propranolol HCl could perform therapeutically better than conventional dosage form, leading to improved efficacy and better patient compliance.

  15. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

    Science.gov (United States)

    Moes, Johannes; Koolen, Stijn; Huitema, Alwin; Schellens, Jan; Beijnen, Jos; Nuijen, Bastiaan

    2013-01-01

    For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190±63.1ng/mLh for vs. 247±100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel.

  16. Relative bioavailability of oral low dose methotrexate. A comparison of 2 different formulations.

    Science.gov (United States)

    Fosså, S D; Tveit, K; Börmer, O; Moxnes, A; Jørgensen, N P; Orjaseter, H; Kristoffersen, D T

    1988-01-01

    In 39 patients the bioavailability of methotrexate from the two tablets Emthexat 2.5 mg and Methotrexate 2.5 mg was assessed in a double-blind study after a single oral dose of 30 mg/m2 Methotrexate. There was a considerable inter-individual variation of the serum pharmacokinetics in regard to Cmax and tmax, independent on the MTX formulation. Emthexat 2.5 mg tablets and Methotrexate 2.5 mg tablets were bioequivalent according to the definition (AUCE greater than or equal to AUCM X 80%).

  17. Formulation and evaluation of controlled porosity osmotic pump for oral delivery of ketorolac.

    Science.gov (United States)

    Dasankoppa, Fatima Sanjeri; Ningangowdar, Mahesh; Sholapur, Hasanpasha

    2012-12-01

    The osmotic drug delivery systems suitable for oral administration typically consist of a compressed tablet core that is coated with a semipermeable membrane that has an orifice drilled on it by means of a laser beam or mechanical drill. Ketorolac is a nonsteroidal agent with powerful analgesic. Oral bioavailability of ketorolac was reported to be 90% with very low hepatic first-pass elimination; the biological half-life of 4-6 hours requires frequent administration to maintain the therapeutic effect. The aim of the current study was to design a controlled porosity osmotic pump (CPOP)based drug delivery system for controlled release of an NSAID agent, ketorolac tromethamine, which is expected to improve patient compliance due to reduced frequency; it also eliminates the need for complicated and expensive laser drilling and maintain continuous therapeutic concentration. The CPOP was designed containing pore-forming water-soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a micro porous structure. The effect of different formulation variables, namely level of pore former (PVP), plasticizer (dibutyl phthalate) in the membrane, and membrane weight gain were studied. Drug release was inversely proportional to the membrane weight but directly related to the initial concentration of pore former (PVP) in the membrane. Drug release was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Based on the in vitro dissolution profile, formulation F3C1 (containing 0.5 g PVP and 1 g dibutyl phthalate in coating membrane) exhibited Peppas kinetic with Fickian diffusion-controlled release mechanism with a drug release of 93.67% in 12 hours and hence it was selected as optimized formulation. SEM studies showed the formation of pores in the membrane. The formulations were stable after 3 months of accelerated stability studies. CPOP was designed for

  18. Improved oral therapeutic potential of nanoencapsulated cryptdin formulation against Salmonella infection.

    Science.gov (United States)

    Rishi, Praveen; Bhogal, Akanksha; Arora, Sumeha; Pandey, Satish K; Verma, Indu; Kaur, Indu Pal

    2015-05-25

    An encapsulated system for cryptdin-2 (a Paneth cell antimicrobial peptide) was developed, with a view to help it sustain adverse gut conditions and to ensure its bioavailability on oral administration. The formulation was characterized on the basis of particle size, zeta potential and polydispersity index. Cryptdin-2 loaded nanoparticles of size 105±7 nm, formulated by ionotropic gelation method using chitosan: tripolyphosphate (5:2), revealed 60% drug entrapment efficiency with 65% in vitro release in 4.5 h. Developed system was evaluated for its therapeutic application against Salmonella Typhimurium infection in mice, on the basis of survivability of animals, bacterial load in tissues, histo-architecture and oxidative damage markers. Infected mice when treated with the encapsulated peptide showed 83% survivability and approximately 2 log unit reductions in the bacterial load in the tissues versus 100% mortality observed with the free peptide. The encapsulated cryptdin-2 also achieved a decrease in the level of oxidants, particularly nitrite by 3.25 folds and increased the level of antioxidant catalase by 2 folds when compared to the levels exhibited by the free peptide. The bacteriological and biochemical alterations illustrated by encapsulated peptide co-related well with the histo-architectural studies. The study is a first pre-clinical report on the oral effectiveness of cryptdin-2 by its suitable encapsulation and has potential for future clinical applications.

  19. Formulation strategy and evaluation of nanocrystal piroxicam orally disintegrating tablets manufacturing by freeze-drying.

    Science.gov (United States)

    Lai, Francesco; Pini, Elena; Corrias, Francesco; Perricci, Jacopo; Manconi, Maria; Fadda, Anna Maria; Sinico, Chiara

    2014-06-05

    Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poor water solubility and consequently by a low oral bioavailability. In this work, different nanocrystal orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution rate and saturation solubility. PRX nanocrystals were prepared by means of high pressure homogenization technique using poloxamer 188 as stabilizer. Three different ODTs were prepared with the same nanosuspension using different excipients in order to study their effect on the PRX dissolution properties. PRX nanocrystal size and zeta potential were determined by photon correlation spectroscopy. Additional characterization of PRX nanocrystal ODT was carried out by infrared spectroscopy, X-ray powder diffractometry, differential scanning calorimetry. Dissolution study was performed in distilled water (pH 5.5) and compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a PRX commercial ODT. All PRX nanocrystal ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystal ODT prepared using gelatin or croscarmellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and ODT prepared using xanthan gum. Overall results confirmed that improved PRX dissolution rate is due to the increased surface-to-volume ratio due to the nanosized drug particle but also revealed the important role of different excipients used.

  20. Florfenicol - pharmacodynamic, pharmacokinetics and clinical efficacy of oral formulations in domestic animals: A systematic review

    Directory of Open Access Journals (Sweden)

    Ščuka Leon

    2005-01-01

    Full Text Available Porcine respiratory disease complex (PRDC is a major economic problem for swine producers world-wide. Pharmacodynamic, pharmacokinetics and clinical efficacy of florfenicol oral formulations in domestic animals were evaluated. For this purpose the systematic review and meta-analysis were done. In vitro efficacy of florfenicol showed that this drug is highly effective against most important respiratory pathogens. All these facts are shown in our survey. Three studies in pigs were relevant to include in the meta-analysis, which showed that results in the florfenicol group were better than in comparative control groups in all observed parameters: clinical signs, lung lesions and resolution of Actinobacillus pleuropneumoniae (P<0,001. A second meta-analysis with 7 studies showed that the usage of florfenicol reduces mortality in pig herds with PRDC (P<0.05. Other field trials in pigs using florfenicol oral forms where reviewed. After treatment with florfenicol oral solution there was a significant drop of mortality in both groups of pigs (P<0.01; eg. one using florfenicol oral solution in treating PRDC (n=85 and another mixed pneumoenteric infection (n=54. Analysis of data when using premix in pigs (n=118 also suggests that a medicated premix has a favorable anti-infectious effect on pigs, irrespective of the group of animals or the evolution stage of the disease. Finally, favorable effect of florfenicol in treating swine ileitis was also presented. Regarding their pharmacokinetics, in vitro and clinical efficacy of florfenicol oral forms, they should be considered as a powerful tool for combating complex infections that are frequently met in intensive animal production.

  1. A new formulation for orally disintegrating tablets using a suspension spray-coating method.

    Science.gov (United States)

    Okuda, Y; Irisawa, Y; Okimoto, K; Osawa, T; Yamashita, S

    2009-12-01

    The aim of this study was to design a new orally disintegrating tablet (ODT) that has high tablet hardness and a fast oral disintegration rate using a new preparation method. To obtain rapid disintegration granules (RDGs), a saccharide, such as trehalose, mannitol, or lactose, was spray-coated with a suspension of corn starch using a fluidized-bed granulator (suspension method). As an additional disintegrant, crospovidone, light anhydrous silicic acid, or hydroxypropyl starch was also included in the suspension. The RDGs obtained possessed extremely large surface areas, narrow particle size distribution, and numerous micro-pores. When tabletting these RDGs, it was found that the RDGs increased tablet hardness by decreasing plastic deformation and increasing the contact frequency between granules. In all tablets, a linear relationship was observed between tablet hardness and oral disintegration time. From each linear correlation line, a slope (D/H value) and an intercept (D/H(0) value) were calculated. Tablets with small D/H and D/H(0) values could disintegrate immediately in the oral cavity regardless of the tablet hardness and were considered to be appropriate for ODTs. Therefore, these values were used as key parameters to select better ODTs. Of all the RDGs prepared in this study, mannitol spray-coated with a suspension of corn starch and crospovidone (2.5:1 w/w ratio) showed most appropriate properties for ODTs; fast in vivo oral disintegration time, and high tablet hardness. In conclusion, this simple method to prepare superior formulations for new ODTs was established by spray-coating mannitol with a suspension of appropriate disintegrants.

  2. Pharmacokinetics of Ginkgolide B after Oral Administration of Three Different Ginkgolide B Formulations in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Jie Zhao

    2015-11-01

    Full Text Available Ginkgolide B (GB, an important active constituent of Ginkgo biloba extract, has been used in clinical applications for the treatment of dementia, cerebral insufficiency or related cognitive decline. To investigate the main pharmacokinetic characteristics of three different GB formulations in beagle dogs, a simple, specific and sensitive LC-MS/MS method was established and validated. The separation of the analytes was achieved on an Agilent Eclipse Plus C18 column (1.8 μm, 2.1 × 50 mm with a mobile phase consisting of water and acetonitrile. The flow rate was set at 0.4 mL/min. Quantitation was performed using multiple reaction monitoring (MRM in negative ion mode, with the transitions at m/z (Q1/Q3 423.1/367.1 for GB and m/z 269.3/170.0 for IS. The linear calibration curve of GB was obtained over the concentration range of 2–200 ng/mL. The intra- and inter-day precisions were <15% and the accuracies were within ±12.7%. The validated method was applied to compare the pharmacokinetic characteristics of GB in healthy beagle dogs after oral administration of three formulations (HME08, GB capsule prepared by hot-melt extrusion technology; LL06, GB pellet prepared by liquid layer technology; conventional GB tablet. The Cmax values of GB from different formulations in beagle dog plasma were 309.2, 192.4 and 66.6 µg/L, and the AUC values were 606.7, 419.1 and 236.2 µg/L·h, respectively. The data suggested that the exposure level of GB from HME08 and LL06 in beagle dog plasma was greatly improved compared with conventional tablets. This study should be helpful for the design and development of oral GB preparations.

  3. Pharmacokinetics of Ginkgolide B after Oral Administration of Three Different Ginkgolide B Formulations in Beagle Dogs.

    Science.gov (United States)

    Zhao, Jie; Geng, Ting; Wang, Qi; Si, Haihong; Sun, Xiaoping; Guo, Qingming; Li, Yanjing; Huang, Wenzhe; Ding, Gang; Xiao, Wei

    2015-11-06

    Ginkgolide B (GB), an important active constituent of Ginkgo biloba extract, has been used in clinical applications for the treatment of dementia, cerebral insufficiency or related cognitive decline. To investigate the main pharmacokinetic characteristics of three different GB formulations in beagle dogs, a simple, specific and sensitive LC-MS/MS method was established and validated. The separation of the analytes was achieved on an Agilent Eclipse Plus C18 column (1.8 μm, 2.1×50 mm) with a mobile phase consisting of water and acetonitrile. The flow rate was set at 0.4 mL/min. Quantitation was performed using multiple reaction monitoring (MRM) in negative ion mode, with the transitions at m/z (Q1/Q3) 423.1/367.1 for GB and m/z 269.3/170.0 for IS. The linear calibration curve of GB was obtained over the concentration range of 2-200 ng/mL. The intra- and inter-day precisions were beagle dogs after oral administration of three formulations (HME08, GB capsule prepared by hot-melt extrusion technology; LL06, GB pellet prepared by liquid layer technology; conventional GB tablet). The Cmax values of GB from different formulations in beagle dog plasma were 309.2, 192.4 and 66.6 µg/L, and the AUC values were 606.7, 419.1 and 236.2 µg/L·h, respectively. The data suggested that the exposure level of GB from HME08 and LL06 in beagle dog plasma was greatly improved compared with conventional tablets. This study should be helpful for the design and development of oral GB preparations.

  4. FORMULATION AND EVALUATION OF TASTE MASKED ORALLY DISINTEGRATING TABLETS OF SITAGLIPTIN PHOSPHATE MONOHYDRATE

    Directory of Open Access Journals (Sweden)

    Abbaraju Prasanna Lakshmi

    2012-09-01

    Full Text Available The purpose of the work is to mask the unpleasant taste of sitagliptin phosphate monohydrate with mannitol by co-grinding method and to formulate it as an oral disintegrating tablet by direct compression method. Drug-mannitol complexes were taken in 1:1, 1:1.5 and 1:2 ratios and tested for in vitro and in vivo bitter masking capacity of mannitol, drug content and molecular property. Different super-disintegrants like croscaramellose, sodium starch glycolate and crospovidone was used as disintegrating agents. The prepared tablets were characterized for tensile strength, wetting time, water absorption ratio, and In vitro and in vivo disintegration time. In addition, aspartame is used as sweetening agent which gives more pleasant taste in the mouth. Among all the formulations F1 to F6, Formulation F6 has good taste masking capacity and fast disintegration within 40sec. Furthermore, 96.7% of the drug has been released in 15min.The results disclosed that the productivity of taste masking of the drug has been done effectively with mannitol and 40mg of crosscarmellose sodium is efficient for rapid disintegrating of tablet.

  5. New perspective to develop memantine orally disintegrating tablet formulations: SeDeM expert system.

    Science.gov (United States)

    Gülbağ, Sıla; Yılmaz Usta, Duygu; Gültekin, Hazal E; Oktay, Ayşe N; Demirtaş, Özden; Karaküçük, Alptuğ; Çelebi, Nevin

    2017-07-18

    Nowadays pharmaceutical industries and regulatory authorities suggest new approaches such as Quality by Design principles to reduce experiments of formulation studies, improve product quality, save cost and time. SeDeM Expert System is a predictive approach for the preformulation studies and it provides information about suitability of API for direct compression by evaluating 12 parameters. The system also allows selecting appropriate excipients by determining same parameters to improve compressibility of API. The objective of this study was to develop direct compressed memantine orally disintegrating tablets using SeDeM Expert System. Memantine was found to have poor flow and compressibility properties. Three different direct compressibility and super disintegrating agents (Ludiflash(®), Ludipress(®) and Parteck(®)) were used to improve compressibility of memantine and according to SeDeM diagrams, Parteck(®) was selected for final formulation. Memantine direct compressed tablets showed proper friability, hardness and thickness. The disintegration time of the tables were found below 15 s which was suitable for ODTs. It was found that SeDeM Expert System was easy to use and application of this method provided to develop memantine direct compressed ODT formulation was successful.

  6. Stabilization challenges and formulation strategies associated with oral biologic drug delivery systems.

    Science.gov (United States)

    Truong-Le, Vu; Lovalenti, Phillip M; Abdul-Fattah, Ahmad M

    2015-10-01

    Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems.

  7. Bioequivalence studies of 2 oral cefaclor capsule formulations in chinese healthy subjects.

    Science.gov (United States)

    Chen, J; Jiang, B; Lou, H; Yu, L; Ruan, Z

    2012-03-01

    An open-label, single-dose, randomized, crossover study was carried out in 20 Chinese healthy male subjects to compare the pharmacokinetics of 2 cefaclor (CAS 53994-73-3) formulations after administration of a single 250 mg dose of each drug with a 1-week wash-out period. Blood samples were collected before and with 6 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detector. 2 formulations were evaluated using the following pharmacokinetic parameters: AUC0-t, Cmax and tmax was analyzed nonparametrically. The 90% confidence interval (CI) of the ratios (teat/reference) of log-transformed AUC0-t and Cmax fell within the bioequivalence acceptance range of 80-125%. The results showed that the 90% CI of the ratios of AUC0-t and Cmax were 105.1% (101.0-109.4%) and 92.4% (82.5-103.4%), respectively, which therefore could conclude 2 oral cefaclor capsule formulations of cefaclor are bioequivalent. Both treatments showed similar tolerability and safety.

  8. Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers.

    Science.gov (United States)

    Tofoli, Giovana Radomille; Cereda, Cíntia M S; Araújo, Daniele Ribeiro; Franz-Montan, Michelle; Groppo, Francisco Carlos; Quaglio, Daiane; Pedrazzoli Junior, Jose; Calafatti, Silvana Aparecida; Barros, Fabio Alessandro Proença; de Paula, Eneida

    2012-03-01

    The pharmacokinetics of commercial and liposome-encapsulated mepivacaine (MVC) injected intra-orally in healthy volunteers was studied. In this double blind, randomized cross-over study, 15 volunteers received, at four different sessions, 1.8 ml of the following formulations: 2% MVC with 1 : 100 000 epinephrine (MVC(2%EPI) ), 3% MVC (MVC(3%) ), 2% and 3% liposome-encapsulated MVC (MVC(2%LUV) and MVC(3%LUV) ). Blood samples were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after injections. Liquid chromatography-tandem mass spectrometry was used to quantify plasma MVC concentrations. Pharmacokinetic analysis showed that the maximum plasma concentration (Cmax) and the areas under the curves (AUC(0-360) and AUC(0-∞)) after MVC(2%LUV) and MVC(2%EPI) injections were smaller (P 0.05). Cmax, AUC(0-360) and AUC(0-∞) after injection of the 2% formulations (MVC(2%LUV) and MVC(2%EPI) ) did not exhibit statistically significant differences (P > 0.05). The pharmacokinetics of MVC(2%LUV) were comparable to the pharmacokinetics of MVC(2%EPI). The liposomal formulation of 2% MVC exhibits similar systemic absorption to the local anesthetic with vasoconstrictor. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  9. Liposomes as a carrier for oral administration of insulin: effect of formulation factors.

    Science.gov (United States)

    Choudhari, K B; Labhasetwar, V; Dorle, A K

    1994-01-01

    The present work was undertaken to study the effect of liposome formulation factors on its efficiency as a carrier for oral administration of insulin. The insulin-liposomes were prepared by two methods: solvent evaporation hydration and solvent spherule evaporation, with various variables such as concentration of insulin (I), lecithin (L), cholesterol (C), and Tween-80 (T). It was found that the insulin-liposomes when administered orally could produce hypoglycaemia. Variation in liposome composition was found to affect the efficiency of liposome as a carrier for oral administration of insulin. A liposome system containing L, 100 mg; C, 20 mg; I, 150 units; T, 1 per cent v/v, and prepared by the solvent spherule evaporation method was found to be most effective. The effect of insulin-liposome had prolonged action in diabetes-induced rabbits compared with that in normal rabbits. The results of the insulin-liposome system were comparable with the action of 1 unit of insulin/kg administered subcutaneously.

  10. Formulation development and evaluation of zolmitriptan oral soluble films using 22 factorial designs

    Science.gov (United States)

    Koteswari, Poluri; Sravanthi, G. Puja; Mounika, M.; Mohammed Rafi, S. K.; Nirosha, K.

    2016-01-01

    Objective: The present investigation involves the development of zolmitriptan oral soluble film (OSF) formulations and optimization with quality by design (QBD) using natural polymers and evaluation. Materials and Methods: Initially, various natural polymers such as sodium alginate, pectin, and gelatin were screened by casting films using solvent casting technique and the prepared films were evaluated. Based on the physical and mechanical properties, sodium alginate was selected as best film former and zolmitriptan-loaded films were casted. The formulation was optimized with the help of 22 factorial experimental designs (QBD) in which sodium alginate concentration and plasticizer concentrations were used as factors and at two levels. The drug-loaded films were evaluated for various mechanical, physicochemical properties, and in vitro drug release properties. Factor effects were interpreted by calculating the main factor effects and by plotting the interaction plots. Results: Thickness of the films, disintegration time, and percent drug loading efficiency were in the range of 0.698 ± 0.13–1.318 ± 0.22 mm, 175 ± 3.1–280 ± 1.7 s, and 68.34 ± 0.5–94.70 ± 0.7% w/v, respectively. Cumulative percent drug released was 61.8 ± 2.6–94.7 ± 4.1% after 30 min. Polymer concentration at two levels of plasticizer had statistically significant effect on drug loading efficiency and in vitro drug release rate. X2 formulation was found to be excellent in drug loading efficiency and in vitro drug release profiles; hence, drug excipient compatibility studies using Fourier transform infrared spectroscopy and stability studies for 60 days were carried out for X2 formulation and found to be stable. Conclusion: Sodium alginate OSFs containing zolmitriptan was successfully prepared, optimized, and evaluated. PMID:28123989

  11. Bioequivalence study of two losartan formulations administered orally in healthy male volunteers.

    Science.gov (United States)

    Bienert, Agnieszka; Brzezińiski, Rafał; Szałek, Edyta; Dubai, Vitali; Grześkowiak, Edmund; Dyderski, Stanisław; Drobnik, Leon; Wolc, Anna; Olejniczak-Rabinek, Magdalena

    2006-01-01

    The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.

  12. Development of enteric submicron particle formulation of papain for oral delivery

    Directory of Open Access Journals (Sweden)

    Sharma M

    2011-09-01

    Full Text Available Manu Sharma1, Vinay Sharma2, Amulya K Panda3, Dipak K Majumdar41Department of Pharmacy, Banasthali Vidhyapith, Banasthali, India; 2Department of Bioscience and Biotechnology, Banasthali Vidhyapith, Banasthali, India; 3National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India; 4Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, University of Delhi, New Delhi, IndiaBackground: Particulate systems have received increasing attention for oral delivery of biomolecules. The objective of the present study was to prepare submicron particulate formulations of papain for pH-dependent site-specific release using pH-sensitive polymers.Methods: Enteric submicron particle formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP, Eudragit L100, and Eudragit S100, to avoid gastric inactivation of papain.Results: Smaller internal and external aqueous phase volumes provided maximum encapsulation efficiency (75.58%–82.35%, the smallest particle size (665.6–692.4 nm, and 25%–30% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastroresistance of the formulations. The anionic submicron particles aggregated in 0.1 N HCl (ie, gastric pH 1.2 due to protonation of carboxylic groups in the enteric polymer. Aggregates < 500 µm size would not impede gastric emptying. However, at pH > 5.0 (duodenal pH, the submicron particles showed deaggregation due to restoration of surface charge. HPMCP submicron particles facilitated almost complete release of papain within 30 minutes at pH 6.0, while Eudragit L100 and Eudragit S100 particles released 88.82% and 53.00% of papain at pH 6.8 and pH 7.4, respectively, according to the Korsmeyer–Peppas equation. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorescence spectroscopy confirmed that the structural integrity of the enzyme was maintained during encapsulation. Fourier

  13. Comparative Pharmacokinetic Study of Mangiferin After Oral Administration of Pure Mangiferin and US Patented Polyherbal Formulation to Rats

    OpenAIRE

    Kammalla, Ananth Kumar; Ramasamy, Mohan Kumar; Inampudi, Jyothi; Dubey, Govind Prasad; Agrawal, Aruna; Kaliappan, Ilango

    2014-01-01

    The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg...

  14. Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product.

    Science.gov (United States)

    Lees, P; Cheng, Z; Keefe, T J; Weich, E; Bryd, J; Cedergren, R; Cozzi, E

    2013-02-01

    A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two-period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max)) and area under plasma concentration-time curve to last sampling time (AUC(last)) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam.

  15. Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation.

    Science.gov (United States)

    Stepensky, D; Friedman, M; Srour, W; Raz, I; Hoffman, A

    2001-03-12

    We examined the pharmacokinetic (PK) and pharmacodynamic (PD) rationales to develop controlled release (CR) formulations of metformin. Unrestrained diabetic rats received the drug as intravenous bolus (i.v.), oral solution (p.o.), intra-duodenal bolus, 4-h infusion, or intra-colonic bolus. In addition, we developed two CR-gastroretentive dosage forms (CR-GRDF) that released the drug over 3 or 6 h (in vitro), and retained in the rats' stomach for 8-10 h. Metformin exhibited flip-flop PK. The colonic absorption was low but sustained and was associated with highly variable glucose-lowering effects, thus providing a PK rationale to develop CR-GRDF. In addition, the glucose-lowering effect was greater following p.o. vs. i.v. administration, despite equivalent AUC, indicating a first pass PD effect, thus, adding a PD rationale to develop metformin CR-GRDF. When administered to the diabetic rats, CR-GRDFs produced bioavailability and extent of glucose-lowering effects that were similar to those of the duodenal infusion and p.o. metformin administration. These findings are attributed to the adsorption of metformin to the intestine that yields slow and prolonged absorption even following p.o. administration of drug solution. The data indicates that unless the CR formulation could significantly extend the absorption period, it is not likely to improve glucose-lowering efficacy.

  16. Formulation and evaluation of acyclovir nanosuspension for enhancement of oral bioavailability

    Directory of Open Access Journals (Sweden)

    Mangesh Ramesh Bhalekar

    2014-01-01

    Full Text Available Acyclovir, an antiviral drug used against herpes simplex virus and varicella zoster virus. The dose ranges between 200 and 800 mg and the oral bioavailability is 10-20%, which decreases as the dose is increased. The aim of this research work was to formulate and characterize nanosuspensions of acyclovir with an intention to increase the oral bioavailability. Nanosuspensions were prepared by the precipitation-ultra sonication method and the effects of important process parameters i.e., precipitation temperature, stirring speed, end point temperature of probe sonicator, energy input and sonication time were investigated systematically, the optimal nanosuspension (particle size 274 nm was obtained at values of 4°C, 10,000 rpm, 30°C, 600 Watt and 20 min, respectively. The nanosuspension was lyophilized using different matrix formers and sucrose (100% w/w to drug was found to prevent agglomeration and particle size upon reconstitution was found to be 353 nm. The lyophilized nanocrystals appeared flaky in scanning electron microscopy images, the X-ray powder diffraction and differential scanning calorimetry analysis showed the nanoparticles to be in the crystalline state. Ex vivo permeation study for calculating absorption rate and in vivo bioavailability area under the curve both showed three-fold increase over marketed suspension.

  17. Pharmacokinetics and bioequivalence of 2 meloxicam oral dosage formulations in healthy adult horses.

    Science.gov (United States)

    Vivancos, Melanie; Barker, Jessica; Engbers, Sarah; Fischer, Carrie; Frederick, Jami; Friedt, Heather; Rybicka, Joanna M; Stastny, Tereza; Banse, Heidi; Cribb, Alastair E

    2015-07-01

    Meloxicam, a non-steroidal anti-inflammatory drug, is approved for use in horses in several countries, but an equine formulation is not available in North America. However, meloxicam is being used in an extra-label manner in horses in Canada. The purpose of this study, therefore, was to assess the bioequivalence of an approved oral meloxicam suspension (Metacam 15 mg/mL for horses; Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany) from the European Union with human meloxicam tablets (Meloxicam 15 mg tablets; TEVA Canada, Toronto, Ontario) compounded with molasses to improve palatability and administration. The geometric mean ratios (GMR test/reference) and the 90% confidence intervals of the pivotal pharmacokinetic parameters (area under the curve and maximum concentration) were within the defined limits of 80% to 125% generally accepted for products to be considered bioequivalent. Therefore, use of human meloxicam tablets compounded with molasses would be expected to produce a similar clinical response in horses as the approved oral product from the European Union.

  18. Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults.

    Science.gov (United States)

    Fey, Constanze; Thyroff-Friesinger, Ursula; Jones, Spencer

    2014-01-01

    Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair(®) mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18-55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration-time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00-125.00%: 92.2% (90% CI: 87.42-97.30%) for Cmax, 98.1% (90% CI: 94.49-101.81%) for AUC0-t and 97.6% (90% CI: 94.14-101.27%) for AUC0-∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair(®) 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice.

  19. Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms.

    Science.gov (United States)

    Speroff, Leon; Haney, Arthur F; Gilbert, Richard D; Ellman, Herman

    2006-01-01

    To determine the efficacy of three doses of a new, oral formulation of estradiol acetate (EA) for alleviation of vasomotor and urogenital symptoms in postmenopausal women. Two separate 12-week studies were undertaken in postmenopausal women with moderate to severe vasomotor symptoms. In the first study, women were randomly assigned to EA 0.9 mg/day, EA 1.8 mg/day, or placebo (study 1; N = 293), and in the second study to oral EA 0.45 mg/day or placebo (study 2; N = 259). Women recorded the frequency and severity of vasomotor symptoms daily and urogenital symptoms weekly on diary cards. Investigators assessed signs of vaginal atrophy. Frequency of moderate to severe vasomotor symptoms decreased significantly versus placebo, starting at week 2 in the EA 1.8-mg group (P = 0.005), week 3 in the EA 0.9-mg group (P = 0.003), and week 6 in the EA 0.45-mg group (P < 0.05). At week 12, mean percent reduction from baseline in vasomotor-symptom frequency was 91%, 78%, and 61%, respectively. Vasomotor-symptom severity decreased significantly versus placebo, starting at weeks 2 and 3 with EA 1.8 mg and 0.9 mg, respectively, and at week 5 with EA 0.45 mg. Vaginal pH and maturation index improved significantly in all EA groups versus placebo, and some signs and symptoms of vaginal atrophy improved at the EA 0.9- and 1.8-mg doses. Side effects were mild to moderate and consistent with estrogen therapy. Oral EA at all doses was well tolerated and significantly reduced the frequency and severity of postmenopause symptoms versus placebo.

  20. An orally active formulation of angiotensin-(1-7 produces an antithrombotic effect

    Directory of Open Access Journals (Sweden)

    Rodrigo Araujo Fraga-Silva

    2011-01-01

    Full Text Available INTRODUCTION AND OBJECTIVE: The heptapeptide angiotensin-(1-7 is a component of the renin-angiotensin system, which promotes many beneficial cardiovascular effects, including antithrombotic activity. We have recently shown that the antithrombotic effect of angiotensin-(1-7 involves receptor Mas-mediated NO-release from platelets. Here, we describe an orally active formulation based on angiotensin-(1-7 inclusion in cyclodextrin [Ang-(1-7- CyD] as an antithrombotic agent. Cyclodextrins are pharmaceutical tools that are used to enhance drug stability, absorption across biological barriers and gastric protection. METHOD: To test the antithrombotic effect of Ang-(1-7-CyD, thrombus formation was induced in the abdominal vena cava of spontaneously hypertensive rats that were pretreated either acutely or chronically with Ang-(1-7-CyD. Male Mas-knockout and wild-type mice were used to verify the role of the Mas receptor on the effect of Ang-(1-7-CyD. RESULTS: Acute or chronic oral treatment with Ang-(1-7-CyD promoted an antithrombotic effect (measured by thrombus weight; all values are, respectively, untreated vs. treated animals in spontaneously hypertensive rats (acute: 2.86 + 0.43 mg vs. 1.14 + 0.40 mg; chronic: 4.27 + 1.03 mg vs. 1.39 + 0.68 mg. This effect was abolished in Mas-knockout mice (thrombus weight in Mas wild-type: 0.76 + 0.10 mg vs. 0.37 + 0.02 mg; thrombus weight in Mas-knockout: 0.96 + 0.11 mg vs. 0.87 + 0.14 mg. Furthermore, the antithrombotic effect of Ang-(1-7-CyD was associated with an increase in the plasma level of Angiotensin-(1-7. CONCLUSION: These results show for the first time that the oral formulation Ang-(1-7-CyD has biological activity and produces a Mas-dependent antithrombotic effect.

  1. A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets.

    Science.gov (United States)

    Okwuosa, Tochukwu C; Stefaniak, Dominika; Arafat, Basel; Isreb, Abdullah; Wan, Ka-Wai; Alhnan, Mohamed A

    2016-11-01

    The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing. Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus. Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern. Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

  2. Comparative study on the in vitro performance of blister molded and conventional lornoxicam immediate release liquitablets: accelerated stability study and anti-inflammatory and ulcerogenic effects.

    Science.gov (United States)

    El-Setouhy, Doaa Ahmed; Gamiel, Alaa Abdel-Rahman; Badawi, Alia Abd El-Latif; Osman, Afaf Sayed; Labib, Dina Ahmed

    2017-03-01

    Lornoxicam is a potent non-steroidal anti-inflammatory drug (NSAID). It shows limited solubility in the gastric pH, delayed bioavailability and pharmacodynamic effects with aggravated gastric side effects (due to longer residence in the stomach wall). To enhance dissolution of lornoxicam in the gastric fluid and expectedly absorption and pharmacological action, with less ulcerogenic effects. Formulation of immediate release (IR) lornoxicam liquitablets containing both liquid and solid release modulators (wetting agent, solubilizers and microenvironmental pH modifiers). Beside the traditional direct compression technique employed for the preparation of liquitablets a new technique, blister molding, was also used. The effect of the two different manufacturing methods on the fast release characteristics (rapid disintegration and dissolution) was studied. Stability and pharmacological activity of the optimum formula were also explored. Similarity factor pointed out the superiority of molding technique in enhancing dissolution of lornoxicam owing to significant crystallinity reduction (XRD). Optimum formula showed negligible change in drug content and dissolution profiles over 12 weeks, significantly improved anti-inflammatory activity and significantly reduced gastric ulcerative effect over pure lornoxicam and commercial formula. Blister molded lornoxicam liquitablet of improved dissolution and pharmacological activity and less gastric erosion was successfully prepared.

  3. 50years of oral lipid-based formulations: Provenance, progress and future perspectives.

    Science.gov (United States)

    Feeney, Orlagh M; Crum, Matthew F; McEvoy, Claire L; Trevaskis, Natalie L; Williams, Hywel D; Pouton, Colin W; Charman, William N; Bergström, Christel A S; Porter, Christopher J H

    2016-06-01

    Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and presystemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification, and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained ongoing solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with ongoing solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but

  4. Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel

    NARCIS (Netherlands)

    Sawicki, Emilia; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2016-01-01

    Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorph

  5. Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

    Science.gov (United States)

    Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

    2017-04-01

    Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

  6. Preparation and stability of extemporaneous oral liquid formulations of oseltamivir using commercially available capsules.

    Science.gov (United States)

    Winiarski, Aleksander P; Infeld, Martin H; Tscherne, Ronald; Bachynsky, Maria; Rucki, Richard; Nagano-Mate, Kathy

    2007-01-01

    To develop a simple, standardized method for the extemporaneous compounding of an oral liquid form of oseltamivir from commercially available Tamiflu 75 mg capsules (Roche Pharmaceuticals) and to determine the stability of oseltamivir in this preparation. Chemical and microbial stability study. Laboratory. None. Extemporaneous oral liquid formulations of oseltamivir (15 mg/mL) were prepared in Cherry Syrup (Humco) and Ora-Sweet SF (Paddock Laboratories) using methods consistent with current compounding practice in a pharmacy setting. Preparations were stored in amber glass and amber polyethyleneterephthalate bottles at 5 degrees C +/- 2 degrees C (41 degrees F +/- 4 degrees F) and 25 degrees C +/- 2 degrees C (77 degrees F +/- 4 degrees F) at 60% +/- 5% relative humidity (RH) for 35 days and 30 degrees C +/- 2 degrees C (86 degrees F +/- 4 degrees F) at 65% +/- 5% RH for 13 days. Samples were monitored for appearance, pH, assay, degradation products, and microbiologic stability. The Cherry Syrup preparation, in either bottle type, was stable for up to 35 days under refrigeration (5 degrees C) and up to 5 days at room temperature (25 degrees C). It was not stable when stored at 30 degrees C for 5 days. The Ora-Sweet SF preparation was stable for up to 35 days at 5 degrees C or 25 degrees C and for up to 13 days at 30 degrees C in either bottle type. Both preparations maintained microbiologic stability for 35 days. Both preparations are stable under the described conditions and may provide an option in situations where the marketed suspension is unavailable.

  7. Pharmacokinetic and bioequivalence studies of immediate release diclofenac potassium tablets (50mg) in healthy volunteers.

    Science.gov (United States)

    Ali, Huma; Shoaib, Muhammad Harris; Zafar, Farya; Hanif, Muhammad; Bushra, Rabia; Naz, Asia; Khursheed, Raheela

    2016-09-01

    This study was conducted with the aim to determine the pharmacokinetic and bioequivalence of diclofenac potassium 50 mg test (F4) tablet formulation with reference product (Caflam). Present study was single dose, randomized, two phase cross over design, conducted in 12 healthy Pakistani volunteers and planned in accordance with FDA guidelines. In this study a simple, selective, sensitive and reproducible HPLC procedure was developed and validated for the estimation of diclofenac potassium in plasma. The process was validated in the range of 50 - 0.05 µg.mL-1 and used in bioequivalence trial of two products. Multiple blood samples were collected at various time points (0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 14 hr after treating volunteers with test (F4) and marketed reference brand. Plasma separation and deproteination were carried out with acetonitrile; samples (20µL) were injected using the validated HPLC method. Various pharmacokinetic parameters (compartmental and noncompartmental) were estimated using KineticaTM 4.4.1 (Thermo Electron Corp. USA). Bioequivalence among the products was established by calculating the 90% CI with log and non log transformed data for Cmaxcalc, Tmaxcalc, AUC0-∞, AUCtot and AUClast using two way ANOVA and Schirmann's Two one sided t- test. No significant difference was found between log and non-log data. The 90% confidence interval values using log transformed data for AUC0-∞ (0.997-1.024), AUCtot (1.004-1.031), AUClast (0.997 -1.024), Cmaxcalc (0.994-1.007) and Tmaxcalc (0.996-1.013) for the trial and reference products were found within the FDA acceptable limits of 0.8-1.25. Results were further verified by the Schirmann's one-sided t test. Results showed the bioequivalence of test and reference formulations. Both the products were well tolerated.

  8. A novel in situ gel formulation of ranitidine for oral sustained delivery.

    Science.gov (United States)

    Xu, Haoping; Shi, Min; Liu, Ying; Jiang, Jinling; Ma, Tao

    2014-02-01

    The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing (99m)Tc tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement.

  9. Reproducibility of neutron activated Sm-153 oral dose formulations intended for human administration

    Energy Technology Data Exchange (ETDEWEB)

    Yeong, C.H. [Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Blackshaw, P.E. [Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH (United Kingdom); Ng, K.H.; Abdullah, B.J.J. [Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Blaauw, M. [Reactor Institute Delft, Faculty of Applied Sciences, Delft University of Technology, 2628 CJ Delft (Netherlands); Dansereau, R.J. [Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Rd, Mason (United States); Perkins, A.C., E-mail: alan.perkins@nottingham.ac.uk [Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH (United Kingdom); Radiological and Imaging Sciences and Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham NG7 2UH (United Kingdom)

    2011-09-15

    Neutron activation of Sm-152 offers a method of radiolabeling for the in vivo study of oral dose formulations by gamma scintigraphy. Reproducibility measurements are needed to ensure the robustness of clinical studies. 204 enteric-coated guaifenesin core tablets (10 mg of Sm{sub 2}O{sub 3}) were irradiated by thermal neutrons to achieve 1 MBq at 48 h. Administered activities were 0.86{+-}0.03 MBq. Good reproducibility (CV=3.5%) was observed over 24 weeks ensuring that volunteer doses were within the dose reference level of 0.8 mSv. - Highlights: > 204 enteric-coated guaifenesin core tablets were irradiated by thermal neutrons. > Activity measured at 48 h after irradiation was 1.01{+-}0.03 MBq. > Activity administered per subject was 0.88{+-}0.03 MBq. > Good reproducibility (CV=3.5%) of Sm-153 radioactivity was obtained. > Effective doses to volunteers were within dose reference level of 0.8 mSv.

  10. Endodontics pastes formulated with copaiba oil: action on oral microbiota and dentin bridge formation in dogs

    Directory of Open Access Journals (Sweden)

    Fernanda Gosuen Gonçalves Dias

    2015-06-01

    Full Text Available This study analysed the effect of pastes formulated with calcium hydroxide P.A. and different vehicles (saline solution - paste A and Copaifera langsdorffii Desfon oil - paste B on oral microorganisms and dentin bridge formation in dogs. The antimicrobial action of the pastes and their components was analysed by the minimum inhibitory concentration in agar gel technique. The components were diluted and tested on fifteen standard strains of microorganisms associated with endodontic diseases. The microorganisms were cultivated and after incubation data was analysed using One-Way ANOVA and Turkey's test (P≤0.05. Four superior incisors of ten animals were used to evaluate dentin bridge formation. Two incisors were capped with paste A (GA and two with paste B (GB. After 90 days, the teeth were extracted for histological analysis and the degree of dentin bridge formation evaluated. Data was analysed by the Kruskal-Wallis test (P<0.05. The pastes and their components were classified in the following decreasing order of antimicrobial action: calcium hydroxide P.A., paste A, paste B and Copaifera langsdorffii Desfon oil. Calcium hydroxide P.A. showed significantly higher antimicrobial action than the pastes or their vehicles. No significant difference was observed between the two pastes in dentin bridge formation. Based on the microorganisms studied, it can be concluded that the pastes analysed showed similar antimicrobial potential but differed significantly from their individual components. No significant difference was observed in dentin bridge formation between the different pastes tested.

  11. Difficulties in administration of oral medication formulations to pet cats: an e-survey of cat owners.

    Science.gov (United States)

    Sivén, M; Savolainen, S; Räntilä, S; Männikkö, S; Vainionpää, M; Airaksinen, S; Raekallio, M; Vainio, O; Juppo, A M

    2017-03-11

    The purpose here was to determine the problems cat owners encounter in medicating their cats with orally administered drugs at home. The study was carried out as an open e-questionnaire survey addressed to cat owners in which the authors focused on the oral administration route. A total of 46 completed questionnaires were included in the survey. In the study, 46 cats received 67 orally administered drugs. Approximately half of the drugs were registered for use in cats by the European Medicines Agency (54 per cent), and there were also off-label drugs registered for human (36 per cent) and canine medication (7.4 per cent) and an ex tempore drug (3.0 per cent). The owners were unable to give the doses as prescribed for their cats for one-fourth of the medications (16/67). Drugs that were registered for feline medication were significantly more palatable than drugs registered for other species (odds ratio (OR) 4.9), and liquid formulations were significantly more palatable than solid formulations (OR 4.8). However, most of the owners (22/38) preferred a solid dosage form, while few (4/38) chose a liquid formulation. The results indicate that there is still a need for more palatable and easily administered oral drugs for cats.

  12. Formulation and physiological and biopharmaceutical issues in the development of oral lipid-based drug delivery systems.

    Science.gov (United States)

    Wasan, K M

    2001-04-01

    The rapidly increasing availability of drug receptor structural characteristics has permitted the receptor-guided synthesis of potential new drug molecules. This synthesis strategy frequently results in the creation of polycyclic and highly hydrophobic compounds, with attendant poor oral bioavailability resulting from low solubility and slow dissolution rate in the primarily aqueous contents of the gastrointestinal (GI) tract. In an attempt to improve the solubility-limited bioavailabiliy associated with these compounds, formulators have turned to the use of lipid excipients in which the compounds can be solubilized prior to oral administration. This new class of excipients presents the pharmaceutical scientist with a number of new challenges at all stages of the formulation development process, beginning with the excipient selection and stability assessment of the prototype formulation, up to and including scale-up and mass production of the final market-image product. The interaction of lipid-based formulations with the gastrointestinal system and associated digestive processes presents additional challenges and opportunities that will be understood more fully as we begin to unravel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wall mediated by p-glycoprotein (PGP). And, it is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formulation development and scale-up issues and the physiological and biopharmaceutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form.

  13. Assessment of novel oral lipid-based formulations of amphotericin B using an in vitro lipolysis model.

    Science.gov (United States)

    Ibrahim, Fady; Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Wasan, Kishor M

    2012-08-15

    The purpose of this study was to investigate the intraluminal processing of novel oral lipid-based formulations of amphotericin B using an in vitro lipolysis model. Amphotericin B (AmB) was formulated in three lipid-based formulations consisting of different lipid components: iCo-009, iCo-010 and iCo-011. Various lipid loads (0.25, 0.5, 1 and 2 g) were digested using the lipolysis model to assess AmB distribution among the lipolysis phases. The duration of lipolysis was comparable among the three formulations except for 2 g load of iCo-009 which had a significantly longer lipolysis than iCo-010 and iCo-011. The lipid components of iCo-009 experienced lower extent of lipolysis as compared to other formulations. Amphotericin B concentration in the aqueous phases was the highest with iCo-010 which also had the lowest sediment recovery. Amphotericin B levels in the undigested lipid layers were comparable between iCo-009 and iCo-010 and were higher than with iCo-011. Given the observation that iCo-010 had the highest aqueous micellar solubilization and the lowest sediment recovery of AmB among the tested formulations, these results could potentially be used to interpret and predict the in vivo performance of AmB- SEDDS formulations in future studies. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  14. Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets.

    Science.gov (United States)

    Sadia, Muzna; Sośnicka, Agata; Arafat, Basel; Isreb, Abdullah; Ahmed, Waqar; Kelarakis, Antonios; Alhnan, Mohamed A

    2016-11-20

    This work aims to employ fused deposition modelling 3D printing to fabricate immediate release pharmaceutical tablets with several model drugs. It investigates the addition of non-melting filler to methacrylic matrix to facilitate FDM 3D printing and explore the impact of (i) the nature of filler, (ii) compatibility with the gears of the 3D printer and iii) polymer: filler ratio on the 3D printing process. Amongst the investigated fillers in this work, directly compressible lactose, spray-dried lactose and microcrystalline cellulose showed a level of degradation at 135°C whilst talc and TCP allowed consistent flow of the filament and a successful 3D printing of the tablet. A specially developed universal filament based on pharmaceutically approved methacrylic polymer (Eudragit EPO) and thermally stable filler, TCP (tribasic calcium phosphate) was optimised. Four model drugs with different physicochemical properties were included into ready-to-use mechanically stable tablets with immediate release properties. Following the two thermal processes (hot melt extrusion (HME) and fused deposition modelling (FDM) 3D printing), drug contents were 94.22%, 88.53%, 96.51% and 93.04% for 5-ASA, captopril, theophylline and prednisolone respectively. XRPD indicated that a fraction of 5-ASA, theophylline and prednisolone remained crystalline whilst captopril was in amorphous form. By combining the advantages of thermally stable pharmaceutically approved polymers and fillers, this unique approach provides a low cost production method for on demand manufacturing of individualised dosage forms. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Bioequivalence of two oral formulations of triflusal capsules in healthy volunteers.

    Science.gov (United States)

    Quetglas, Emilio García; Campanero, Miguel Angel; Sádaba, Belén; Escolar, Manuel; Azanza, Jose Ramón

    2008-01-01

    Triflusal (CAS 322-79-2) is an antiplatelet agent related to salicylates used in several European and Latin American countries in the treatment of cardiovascular diseases. The aim of this paper was to evaluate the bioequivalence of triflusal derived from two preparations using both parent drug and metabolite pharmacokinetic data. The bioavailabolity was measured in 24 healthy male Caucasian volunteers following a single oral dose (600 mg) of the test or reference products in the fasting state. Blood samples were collected for 120 h. Plasma concentrations of triflusal and its metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) were analyzed by high-performance liquid chromatography with UV and fluorescence detection, respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax, AUC0-t and AUC0-infinity were tested for bioequivalence using ANOVA and Schuirmann's two-one sided t-test. Tmax was analyzed by nonparametric pharmacokinetic parameters of triflusal and HTB derived from the two formulations were nearly consistent with previous observations. Triflusal parameters derived from the test and reference drug were as follows: Cmax (16.85 +/- 11.41 vs 14.48 +/- 7.22 mg/l), AUC0-t (18.43 +/- 10.91 vs 16.22 +/- 7.58 mg/l per hour), Tmax (1 range 0.25-2h vs 0.875 range 0.25-1.5 h), and t(1/2) (0.49 +/- 00.27 vs 0.76 +/- 0.64). HTB parameters after test and reference formulation administration were as follows: Cmax (68.13 +/- 23.05 vs 65.51 +/- 19.44 mg/l), AUC0-t (2748.18 +/- 971.91 vs 2877.97 +/- 881.2 h x mg/l), AUC0-infinity (3350.15 +/- 1182.62 vs 3372.49 +/- 1110.35 h x mg/l), Tmax (2 range 1-10 h vs 2 range 0.75-12 h), and t(1/2) (42.19 +/- 7.82 vs 43.13 +/- 6.56 h). 90% of confidence intervals for the test/reference ratio of Cmax AUC0-t and AUC0-infinity derived from both triflusal and HTB were found within the range of 80%-125% acceptable for bioequivalence. No significant difference was found between the Tmax values

  16. Nanoparticle formulation by Büchi B-90 Nano Spray Dryer for oral mucoadhesion

    Directory of Open Access Journals (Sweden)

    Harsha SN

    2015-01-01

    Full Text Available Sree N Harsha,1 Bander E Aldhubiab,1 Anroop B Nair,1 Ibrahim Abdulrahman Alhaider,1 Mahesh Attimarad,1 Katharigatta N Venugopala,1  Saminathan Srinivasan,2 Nagesh Gangadhar,2 Afzal Haq Asif3 1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; 2Department of Pharmaceutics, East Point College of Pharmacy, Bangalore, India; 3Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia Abstract: Diabetes is considered one of the main threats to global public health in this era. It is increasing rapidly in every part of the world; the prevalence of the disease will grow to the point where 366 million people will be affected by 2030. The prevalence of diabetes mellitus (DM in the Saudi population is high, and the majority of patients suffer from type 2 DM. Marketed oral antidiabetic drugs have indicated poor tolerability during chronic treatments, and this contributes to the moderately large proportion of type 2 DM patients that remain inadequately managed. Vildagliptin nanospheres were prepared with aminated gelatin using a spray-drying method; narrow particle-size distribution was seen at 445 nm. The angle of repose was found to be θ <33.5°. The nanospheres appeared to be spherical with a smooth surface. The drug content and percentage yield of the nanospheres were found to be 76.2%±4.6% and 83%±2%, respectively. The nanosphere-swell profile was found to be 165%±7%. The pure drug was 100% dissolved in 30 minutes, and the nanosphere formulation took 12 hours to dissolve (97.5%±2%, and followed a Korsmeyer–Peppas kinetic model with an R2 of 0.9838. The wash-off test of nanospheres found that they exhibited an excellent mucoadhesive property at 86.7% for 8 hours. The stability-study data showed no changes in the physicochemical properties of the nanospheres, and suggested that the nanospheres be stored below room

  17. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

    Science.gov (United States)

    Teo, S K; Colburn, W A; Thomas, S D

    1999-11-01

    Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly

  18. Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs.

    Science.gov (United States)

    Carrière, Frédéric

    2016-06-01

    Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids, …) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilization/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility.

  19. Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats.

    Science.gov (United States)

    Kammalla, Ananth Kumar; Ramasamy, Mohan Kumar; Inampudi, Jyothi; Dubey, Govind Prasad; Agrawal, Aruna; Kaliappan, Ilango

    2015-04-01

    The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg mangiferin and its distribution among the major tissue in Wistar rats. Plasma samples were collected at different time points (15, 30, 60, 120, 180, 240, 360, 480, 600, 1,440, 2,160, and 2880 min) and subsequently analyzed using a validated simple and rapid LC-MS method. Plasma concentration versus time profiles were explored by non-compartmental analysis. Mangiferin plasma exposure was significantly increased when administered from formulation compared to the standard mangiferin. Mangiferin resided significantly longer in the body (last mean residence time (MRTlast)) when given in the form of the formulation (3.65 h). Cmax values of formulation (44.16 μg/mL) administration were elevated when compared to equivalent dose of the pure mangiferin (15.23 μg/mL). Tissue distribution study of mangiferin from polyherbal formulation was also studied. In conclusion, the exposure of mangiferin is enhanced after formulation and administration and could result in superior efficacy of polyherbal formulation when compared to an equivalent dose of mangiferin. The results indicate that the reason which delays the elimination of mangiferin and enhances its bioavailability might the interactions of the some other constituents present in the polyherbal formulation. Distribution study results indicate that mangiferin was extensively bound to the various tissues like the small intestine, heart, kidney, spleen, and liver except brain tissue.

  20. Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults : a randomized, open-label, two-period crossover, single-centre study.

    Science.gov (United States)

    Darwish, Mona; Hellriegel, Edward T; Xie, Fang

    2008-01-01

    Cyclobenzaprine immediate release (CIR) has shown efficacy in the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. An extended-release formulation of cyclobenzaprine (CER) has been developed to provide effective muscle spasm relief with once-daily dosing. The objective of this study was to compare the pharmacokinetics of CER and CIR. This was a single-centre study of 18 healthy young adults (aged 18-45 years). Healthy volunteers were assigned to receive either a single dose of CER 30 mg or three doses of CIR 10 mg on days 1 and 15 (separated by a 14-day washout) in an open-label, two-period crossover study. Pharmacokinetic parameters were monitored through 168 hours after the last dose in each dose period; adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Cyclobenzaprine was administered as a single oral 30 mg dose of CER or three 10 mg oral doses of CIR given every 8 hours over 24 hours. Statistical tests were conducted against a two-sided alternative hypothesis at a 0.05 level of significance with equivalence limits of 80% and 125%. Measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours and infinity, maximum plasma cyclobenzaprine concentration (C(max)), and time to observed C(max) (t(max)). Eighteen subjects were randomized and 17 completed both periods of the study. CER exhibited a consistent concentration-time profile with a single peak, in contrast to the pharmacokinetic profile for CIR, which displayed multiple peaks and troughs over the 24-hour period. The pharmacokinetic profile of CER 30 mg was characterized by an absorption phase with a median t(max) of approximately 6 hours, compared with the initial peak of CIR (following the first dose) of about 4 hours. Mean plasma concentrations at 4 hours were comparable (12.1 ng/mL for CER; 12.4 ng/mL for CIR). Systemic cyclobenzaprine exposure (AUC and C(max)) was similar

  1. Alendronate sodium hydrate (oral jelly for the treatment of osteoporosis: review of a novel, easy to swallow formulation

    Directory of Open Access Journals (Sweden)

    Imai K

    2013-06-01

    Full Text Available Kazuhiro Imai Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan Abstract: Osteoporosis is a skeletal disorder characterized by loss of bone mass, decreased bone strength, and an increased risk of bone fracture. The disease progresses with age, especially in postmenopausal women. Japan is one of the most rapidly aging societies worldwide. Japanese individuals over 65 years of age constituted 23.0% of the population in 2010 and 25.1% to 25.2% as of 2013. The estimated number of people with osteoporosis in Japan is currently 13 million. Bisphosphonates increase bone mineral density by inhibiting osteoclast-mediated bone resorption, thereby reducing the risk of fractures. Alendronate sodium hydrate (alendronate is a bisphosphonate that potently inhibits bone resorption and is used to treat osteoporosis. Sufficient water is required to take an alendronate oral tablet; insufficient water could result in digestive system diseases, such as esophageal ulceration. Elderly patients with swallowing difficulty may choke on the tablet. Taking a tablet with oral jelly is a method to prevent digestive system disease and reduce the choking hazard. Once-weekly alendronate oral jelly was approved in 2012 by the Ministry of Health, Labour, and Welfare of Japan as the world's first drug for osteoporosis in a jelly formulation. It consists of a jelly portion and an air portion. The jelly formulation is smoothly discharged by pushing the air portion. Therefore, elderly patients with physical disabilities are able to easily take all of the jelly formulation from the package. In this review, this new formulation of alendronate sodium hydrate (oral jelly is introduced and discussed in terms of osteoporosis treatment. This new formulation provides an alternative so that patients may select a method of dosing tailored to their preferences. Management of osteoporosis involves assessing fracture risk and preventing

  2. Cytotoxic effects of oxytetracycline residues in the bones of broiler chickens following therapeutic oral administration of a water formulation

    OpenAIRE

    ODORE, R; De Marco, M.; Gasco, L.; Rotolo, L.; Meucci, V.; Palatucci, A. T.; Rubino, V.; Ruggiero, G.; Canello, S.; Guidetti, G; Centenaro, S.; A. Quarantelli; Terrazzano, G.; A. Schiavone

    2015-01-01

    Tetracyclines, which represent one of the most commonly used antibiotics for poultry, are known to be deposited in bones, where they can remain, despite the observation of appropriate withdrawal times. The aim of the study was to determine the concentration of oxytretracycline (OTC) residues in the bone and muscle of chickens, following the oral administration of a commercially available liquid formulation, and to test their cytotoxic effects on an in vitro cell culture model. Seventy-two 1-d...

  3. Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation.

    Science.gov (United States)

    Teramura, T; Watanabe, T; Higuchi, S; Hashimoto, K

    1997-02-01

    1. The metabolism and pharmacokinetics of barnidipine hydrochloride, a 1, 4-dihydropyridine calcium antagonist were evaluated following single oral administration of a sustained release formulation (SR) capsule comprising of quick and slow release pellets to healthy male volunteers. 2. Various metabolites were identified and quantitated by newly established GC-MS analytical methods. Major metabolites were the hydrolyzed product of the benzyl-pyrrolidinyl ester (M-3) in plasma and its oxidized pyridine product (M-4) in plasma and urine. The pyridine form of unchanged barnidipine and the N-debenzylated product were observed as minor metabolites. Therefore, the primary metabolic pathways in man are (a) hydrolysis of the benzylpyrrolidine ester, (b) N-debenzylation, and (c) oxidation of the dihydropyridine ring. 3. When the SR and normal capsules were administered at a dose of 10 mg to six subjects in a crossover design, AUC 0-infinity of unchanged drug, M-3 and 4 in each subject receiving the SR were 97 +/- 15, 85 +/- 31 and 76 +/- 21% respectively of those subjects receiving the normal formulation. The sum of the excretion of urinary metabolites for the SR formulation was 65 +/- 6% of that for the normal formulation. These data suggest that the absorption of the SR formulation is slightly reduced but that its bioavailability is comparable to that of the normal formulation.

  4. Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-II: Oral soft gel

    Directory of Open Access Journals (Sweden)

    Mohapatra Ashutosh

    2008-01-01

    Full Text Available Dionvenience of administration and patient compliance are gaining significant importance in the design of dosage forms. Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2 diabetes mellitus. Difficulty in swallowing (dysphagia is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. Persons suffering from dysphagia may get choked when they consume liquid formulation, thus to alleviate such problem liquid formulation of high viscosity was prepared. Formulation of oral soft gel batches of metformin was carried out using hydrophilic polymer gellan gum at concentrations ranging from 0.2-0.4% w/v and sodium citrate at two different concentrations (0.3% and 0.5%. The prepared batches were evaluated for appearance, viscosity, pH, drug content, syneresis, in vitro drug release, and taste masking. The batch with 0.4% w/v gellan gum and 0.5% sodium citrate not only showed 85% drug release at 15 min, but all the desired organoleptic properties. The taste masking was carried out using nonnutritive sugar and flavors. The optimized batch showed substantial stability when subjected to short term stability study (0-8°C and Room temperature. The problem of dose measurement by patients was outweighed as oral medicated gels are to be packed in unit dose container.

  5. The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2010-08-02

    The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns

  6. Formulation development and evaluation of novel oral jellies of carbamazepine using pectin, guar gum, and gellan gum

    Directory of Open Access Journals (Sweden)

    Katakam Prakash

    2014-01-01

    Full Text Available Medicated jelly formulations are more suitable for pediatric, geriatric and dysphagic patients, which offer rapid dissolution and absorption of drugs thereby early onset of action. The aim was to develop and evaluate oral jelly formulations of carbamazepine (CBZ. Carbamazepine oral jellies were prepared to employ pectin, guar gum and gellan gum alone and pectin-guar gum combination. Preformulation studies, organoleptic, physical characteristics, drug content, pH, spreadability, rheological properties, syneresis, taste masking, in vitro dissolution testing, drug release kinetics and stability studies were conducted. The Fourier transform infrared and differential scanning calorimeter studies showed that there was no interaction between drug and excipients. The pH of all the formulations was found between pH 6.37 ± 0.03 and 6.83 ± 0.04. The concentration of gelling agents influenced the spreadability. Syneresis was observed in jellies made from guar gum alone, whereas those made from pectin and guar gum it was absent. The optimized formulations (F3, F11 and F15 masked the bitter taste of CBZ and demonstrated acceptable flavor and mouth feel. All formulations showed more than 50% drug release in 15 min except those made of gellan gum alone. The formulations F3, F11 and F15, were found stable for 90 days as per International Conference on Harmonization stability protocol. Carbamazepine jellies made from pectin (F3, 1.2%, gellan gum (F11, 1.5% and pectin-guar gum (F15, 1:0.4% were found more successful and could be employed to improve the palatability and acceptability by pediatric, geriatric and dysphagic patients. The jellies could be useful to overcome the problems of poorly soluble CBZ.

  7. Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs

    Directory of Open Access Journals (Sweden)

    Bin Yang

    2017-01-01

    Full Text Available The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax, and the time (Tmax to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE limits (0.80–1.25. However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.

  8. Design, Formulation and Evaluation of an Oral Gel from Punica Granatum Flower Extract for the Treatment of Recurrent Aphthous Stomatitis

    Science.gov (United States)

    Aslani, Abolfazl; Zolfaghari, Behzad; Davoodvandi, Fatemeh

    2016-01-01

    Purpose: Recurrent aphthous stomatitis is a disease with unknown etiology that’s mostly treated symptomatically and has no definite cure. Pomegranate (Punica granatum) flowers have been used as medicinal herb that due to its antimicrobial, antioxidant, anti-inflammatory, analgesic and healing effects, has been useful in treatment of oral aphthous. Therefore, we decided to formulate a mucoadhesive gel with pomegranate flower extract to reduce the need for corticosteroid therapy in patients. Methods: Pomegranate flowers are extracted by percolation method. Several formulations with different amounts of carbomer 934, sodium carboxymethylcellulose (SCMC) and hydroxypropyl methylcellulose K4M were prepared and the condensed extract was dispersed in polyethyleneglycol (PEG) 400 and added to gel bases. Then the formulations underwent macroscopic and microscopic studies. The formulations that passed these tests successfully were studied through assay tests using spectrophotometry in 765 nm, drug release from mucoadhesive gel using cell diffusion method, viscosity test, mucoadhesion test and accelerated stability test. Results: The phenolic content of pomegranate flower dried extract was found to be 212.3±1.4 mg/g in dried extract. The F4–F6 formulations contains carbomer 934, SCMC, pomegranate flower extract, PEG 400, potassium sorbate and purified water passed all above tests. Conclusion: The F4 formulation had higher viscosity and mucoadhesion values due to its higher carbomer 934 and SCMC content. Since F4, F5 and F6 had no significant variation in drug release, the F4 formulation was chosen as the superior formulation because of proper appearance and uniformity, acceptable viscosity, mucoadhesion and stability in different temperatures. PMID:27766223

  9. Design, Formulation and Evaluation of an Oral Gel from Punica Granatum Flower Extract for the Treatment of Recurrent Aphthous Stomatitis

    Directory of Open Access Journals (Sweden)

    Abolfazl Aslani

    2016-09-01

    Full Text Available Purpose: Recurrent aphthous stomatitis is a disease with unknown etiology that’s mostly treated symptomatically and has no definite cure. Pomegranate (Punica granatum flowers have been used as medicinal herb that due to its antimicrobial, antioxidant, anti-inflammatory, analgesic and healing effects, has been useful in treatment of oral aphthous. Therefore, we decided to formulate a mucoadhesive gel with pomegranate flower extract to reduce the need for corticosteroid therapy in patients. Methods: Pomegranate flowers are extracted by percolation method. Several formulations with different amounts of carbomer 934, sodium carboxymethylcellulose (SCMC and hydroxypropyl methylcellulose K4M were prepared and the condensed extract was dispersed in polyethyleneglycol (PEG 400 and added to gel bases. Then the formulations underwent macroscopic and microscopic studies. The formulations that passed these tests successfully were studied through assay tests using spectrophotometry in 765 nm, drug release from mucoadhesive gel using cell diffusion method, viscosity test, mucoadhesion test and accelerated stability test. Results: The phenolic content of pomegranate flower dried extract was found to be 212.3±1.4 mg/g in dried extract. The F4–F6 formulations contains carbomer 934, SCMC, pomegranate flower extract, PEG 400, potassium sorbate and purified water passed all above tests. Conclusion: The F4 formulation had higher viscosity and mucoadhesion values due to its higher carbomer 934 and SCMC content. Since F4, F5 and F6 had no significant variation in drug release, the F4 formulation was chosen as the superior formulation because of proper appearance and uniformity, acceptable viscosity, mucoadhesion and stability in different temperatures.

  10. Pharmacokinetics and bioavailability study of two ondansetron oral soluble film formulations in fasting healthy male Chinese volunteers

    Directory of Open Access Journals (Sweden)

    Zhu YB

    2015-08-01

    Full Text Available Yubing Zhu,1 Qian Zhang,1 Jianjun Zou,2 Meng Wan,1 Zheng Zhao,1 Junrong Zhu1 1Department of Pharmacy, 2Laboratory of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China Background: Ondansetron oral soluble film is designed to be applied on top of the tongue without requiring water to aid dissolution or swallowing, which is especially fitting for nausea and vomiting patients.Purpose: This study was conducted to compare the bioavailability of two 8 mg ondansetron oral soluble film formulations.Patients and methods: This randomized, open-label, two-period crossover study was performed under fasting conditions. A total of ten eligible subjects were randomly assigned at a 1:1 ratio to receive a single 8 mg dose of the test and reference ondansetron oral soluble film formulations, followed by a 1-week washout period and administration of the alternate formulation. The concentrations of ondansetron were assayed using an liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS method. For analysis of pharmacokinetic properties, including the peak concentration of Tmax (Cmax, AUC from time 0 (baseline to t hours (AUC0–t, and AUC from baseline to infinity (AUC0–∞, blood samples were obtained at intervals over the 24-hour period after studying drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis and by questioning subjects about adverse events.Results: The mean (standard derivation [SD] relative bioavailability was 96.5 (23.7%. The 90% confidence intervals (CIs for the log-transformed ratios of Cmax and AUC0–t were 84.71%–103.28% and 91.38%–108.60%, respectively (P>0.05. Similar results were found for the data without log-transformation. No statistically significant differences were found based on analysis of variance. No significant adverse events occurred

  11. A pilot human pharmacokinetic study and influence of formulation factors on orodispersible tablet incorporating meloxicam solid dispersion using factorial design.

    Science.gov (United States)

    Aboelwafa, Ahmed A; Fahmy, Rania H

    2012-01-01

    Meloxicam (MLX) suffers from poor aqueous solubility leading to slow absorption following oral administration; hence, immediate release MLX tablet is unsuitable in the treatment of acute pain. This study aims to overcome such a drawback by increasing MLX solubility and dissolution using PEG solid dispersion (SD), then, to investigate the feasibility of incorporating the SD into orodispersible tablets (ODTs). A 2(3) full factorial design was employed to investigate the influence of three formulation variables on MLX ODTs. The selected factors: camphor (X(1)) as pore-forming material, and croscarmellose sodium (X(2)) as superdisintegrant, showed significant positive influence, while PEG content (X(3)) was proved to negatively affect both disintegration and wetting times. In addition, isomalt increased disintegration and wetting times when compared to mannitol as diluents. The pharmacokinetic assessment of the optimum ODT formulation in healthy human subjects proved that the faster MLX dissolution by using PEG solid dispersion at pH 6.8 resulted in more rapid absorption of MLX. The rate of absorption of MLX from ODT was significantly faster (p = 0.030) with a significantly higher peak plasma concentration (P = 0.037) when compared to the marketed immediate release MLX tablet with a mean oral disintegration time of 17 ± 3 s.

  12. Proliposomes containing a bile salt for oral delivery of Ginkgo biloba extract: Formulation optimization, characterization, oral bioavailability and tissue distribution in rats.

    Science.gov (United States)

    Zheng, Bin; Teng, Lirong; Xing, Gaoyang; Bi, Ye; Yang, Shuang; Hao, Fei; Yan, Guodong; Wang, Xinmei; Lee, Robert J; Teng, Lesheng; Xie, Jing

    2015-09-18

    Proliposomes containing a bile salt were developed to improve the oral bioavailability of Ginkgo biloba extract (GbE). GbE loaded proliposomes (P-GbE) were successfully prepared by spray drying method. The formulation was optimized using the response surface methodology. FE-SEM, DSC, and FT-IR were used to study the surface morphology and molecular state of proliposomes, and demonstrated key interactions between the formulation ingredients. In vitro studies showed delayed release and enhanced dissolution of Ginkgo flavonoids and terpene lactones from GbE proliposomes. Proliposomes significantly enhanced GbE absorption in the gastrointestinal tract and decreased its elimination. The bioavailabilities of quercetin, kaempferol, isorhmnetin, ginkgolide A, ginkgolide B and ginkgolide C from proliposomes relative to the control were 245%, 211%, 264%, 203%, 333%, and 294%, respectively. Proliposomes were shown to selectively deliver GbE to critical target tissues. In conclusion, development of proliposomes formulation for GbE solved the problem of its poor oral bioavailability, prolonged its duration of action, and increased drug distribution in critical tissues, especially in the brain, therefore, warrant further investigation.

  13. Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy.

    Science.gov (United States)

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

    2017-01-01

    This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. (153)Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region.

  14. Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy

    Science.gov (United States)

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

    2017-01-01

    This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region. PMID:28031701

  15. Once daily baclofen sustained release or gastro-retentive system are acceptable alternatives to thrice daily baclofen immediate release at same daily dosage in patients

    Directory of Open Access Journals (Sweden)

    Sampat Nitin

    2009-01-01

    Full Text Available Background: Baclofen, a GABA-agonist, is currently available as an immediate release (IR formulation for relieving neurogenic spasticity in a variety of disorders. Baclofen IR requires to be administered three times a day which inadvertently increases the chances of medication noncompliance among patients and is also associated with side effects such as drowsiness and muscle weakness. Aim: To overcome the shortcomings of baclofen IR, two modified formulations, baclofen sustained release (SR and gastric retentive system (GRS, have been proposed to be equivalent in efficacy to baclofen IR with the administration of a single daily dose. Materials and Methods: Ninety patients with chronic neurogenic muscular spasticity were enrolled requiring 10-20 mg of baclofen IR every eight hours. The patients were randomized to two treatment arms: SR (n = 46 or GRS (n = 44 at the same once-daily dose for four weeks. Efficacy was measured by Ashworth score for muscle tone, spasm score, reflex score, 30-item functional independence score, and patient′s diary score for three most affected activities of daily life. Results: The mean Ashworth score changed significantly (P = 0.00 for patients in the SR group from 3.03-2.69 (-0.35 and 3.07-2.70 (-0.37 for patients in the GRS group. There was no significant difference (P = 0.87 between baseline-adjusted Ashworth score reductions on SR (-0.35 and GRS (-0.37. Similar results were obtained for spasm, reflex, and functional independence scores. The mean baseline-adjusted patient-diary scores did not differ significantly between 8 am, 12 pm, 4 pm, and 8 pm (P = 0.96, either on SR (-5.3 to -6.1 or GRS (-7.3 to -8.1, indicating a uniform effect round-the-day on both. Further, sedation scores (mean ± SEM decreased significantly (P < 0.05 on both SR (10.36 ± 1.37 to 6.18 ± 0.92 and GRS (8.14 ± 1.57 to 5.33 ± 1.11, suggesting better toleration. Conclusion: Once-daily baclofen SR and GRS are efficacious, convenient, and

  16. Kozeny-Carman permeability relationship with disintegration process predicted from early dissolution profiles of immediate release tablets.

    Science.gov (United States)

    Kumari, Parveen; Rathi, Pooja; Kumar, Virender; Lal, Jatin; Kaur, Harmeet; Singh, Jasbir

    2017-07-01

    This study was oriented toward the disintegration profiling of the diclofenac sodium (DS) immediate-release (IR) tablets and development of its relationship with medium permeability kperm based on Kozeny-Carman equation. Batches (L1-L9) of DS IR tablets with different porosities and specific surface area were prepared at different compression forces and evaluated for porosity, in vitro dissolution and particle-size analysis of the disintegrated mass. The kperm was calculated from porosities and specific surface area, and disintegration profiles were predicted from the dissolution profiles of IR tablets by stripping/residual method. The disintegration profiles were subjected to exponential regression to find out the respective disintegration equations and rate constants kd. Batches L1 and L2 showed the fastest disintegration rates as evident from their bi-exponential equations while the rest of the batches L3-L9 exhibited the first order or mono-exponential disintegration kinetics. The 95% confidence interval (CI95%) revealed significant differences between kd values of different batches except L4 and L6. Similar results were also spotted for dissolution profiles of IR tablets by similarity (f2) test. The final relationship between kd and kperm was found to be hyperbolic, signifying the initial effect of kperm on the disintegration rate. The results showed that disintegration profiling is possible because a relationship exists between kd and kperm. The later being relatable with porosity and specific surface area can be determined by nondestructive tests.

  17. Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls.

    Science.gov (United States)

    Kesisoglou, Filippos; Hermans, Andre; Neu, Colleen; Yee, Ka Lai; Palcza, John; Miller, Jessica

    2015-09-01

    Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its application to establishing dissolution specifications and in-process controls. Four different 40 mg batches were manufactured at different tablet hardnesses to produce distinct dissolution profiles. These batches were evaluated in a relative bioavailability clinical study in healthy volunteers. Although no differences were observed for the total exposure (AUC) of the different batches, a clear relationship between dissolution and Cmax was observed. A validated Multiple Level C IVIVC against Cmax was developed for the 10, 15, 20, 30, and 45 min dissolution time points and the tablet disintegration time. The relationship established between tablet tensile strength and dissolution was subsequently used to inform suitable tablet hardness ranges within acceptable Cmax limits. This is the first published report for a validated Multiple Level C IVIVC for an IR solid dispersion formulation demonstrating how this approach can facilitate Quality by Design in formulation development and help toward clinically relevant specifications and in-process controls. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  18. Population pharmacokinetic modeling and noncompartmental analysis demonstrated bioequivalence between metformin component of metformin/vildagliptin fixed-dose combination products and metformin immediate-release tablet sourced from various countries.

    Science.gov (United States)

    Chitnis, Shripad D; Han, Yi; Yamaguchi, Masayuki; Mita, Sachiko; Zhao, Rong; Sunkara, Gangadhar; Kulmatycki, Kenneth

    2016-01-01

    Metformin is the first-line pharmacotherapy choice for treating type-2 diabetes mellitus, alone or in combination with other antidiabetic drugs. During the development of immediate-release (IR) metformin containing novel fixed-dose combination (FDC) products, several health-authorities require sponsors to demonstrate bioequivalence between FDC products and the country-sourced metformin for market approval. Eight bioequivalence studies that compared metformin/vildagliptin FDC product (test) to metformin IR tablet sourced from various countries (reference) were conducted. A population pharmacokinetic (PPK) analysis of pooled metformin concentration-time data was performed to evaluate whether country-sourced metformin is a significant covariate. The PPK analysis demonstrated that there was no clinically relevant effect of metformin source or race/ethnicity on metformin pharmacokinetics. Also, noncompartmental analysis conducted showed that 90%CI of geometric mean ratios of test to reference metformin formulations, calculated for maximum-concentration and exposure parameters, were within the 80%-125% criteria, indicating comparable metformin exposure regardless of the country-sourced metformin IR formulation. These results are consistent with the biopharmaceutics properties of metformin and provide scientific evidence that after assessing in vitro dissolution of novel FDC formulation, additional bioequivalence studies with multiple countries' reference products may not be required once bioequivalence is established with 1 country-sourced IR metformin formulation.

  19. Cost-Effectiveness of Extended-Release Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder Sub-Optimally Treated with Immediate Release Methylphenidate

    NARCIS (Netherlands)

    van der Schans, Jurjen; Kotsopoulos, Niko; Hoekstra, Pieter J.; Hak, Eelko; Postma, Maarten J.

    2015-01-01

    BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at

  20. Formulation optimization of hydrodynamically balanced oral controlled release bioadhesive tablets of tramadol hydrochloride.

    Science.gov (United States)

    Singh, Bhupinder; Rani, Ashu; Babita; Ahuja, Naveen; Kapil, Rishi

    2010-01-01

    The directly compressible floating-bioadhesive tablets of tramadol were formulated using varying amounts Carbopol 971P (CP) and hydroxy-propylmethyl cellulose (HPMC), along with other requisite excipients. In vitro drug release profile, floatational characteristics and ex vivo bioadhesive strength using texture analyzer were determined, and systematically optimized using a 3(2) central composite design (CCD). The studies indicated successful formulation of gastroretentive compressed matrices with excellent controlled release, mucoadhesion and hydrodynamic balance. Comparison of the dissolution profiles of the optimized formulation, with optimal composition of CP:HPMC :: 80.0:125.0, with that of the marketed controlled release formulation other indicated analogy of drug release performance with each other. Validation of optimization study using eight confirmatory experimental runs indicated very high degree of prognostic ability of CCD with mean  SEM of â0.06%  0.37. Further, the study successfully unravels the effect of the polymers on the selected response variables.

  1. Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy

    Directory of Open Access Journals (Sweden)

    Razavi M

    2016-12-01

    Full Text Available Mahboubeh Razavi,1 Hamed Karimian,1 Chai Hong Yeong,2 Mehran Fadaeinasab,3 Si Lay Khaing,4 Lip Yong Chung,1 Didi Erwandi B Mohamad Haron,5 Mohamed Ibrahim Noordin1,6 1Department of Pharmacy, 2University Malaya Research Imaging Centre and Department of Biomedical Imaging, Faculty of Medicine, 3Center for Natural Product Research and Drug Discovery (CENAR, 4Department of Obstetrics & Gynaecology, 5Shimadzu-UMMC Centre for Xenobiotics Studies, Pharmacology Department, Faculty of Medicine, University of Malaya, 6Malaysian Institute of Pharmaceuticals and Nutraceuticals (IPharm, National Institutes of Biotechnology Malaysia, Ministry of Science, Technology and Innovation, Penang, Malayasia Abstract: This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl, using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP:xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP,3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax at which the maximum concentration of metformin HCl

  2. Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care.

    Science.gov (United States)

    Guglielmi, Valeria; Bellia, Alfonso; Bianchini, Elisa; Medea, Gerardo; Cricelli, Iacopo; Sbraccia, Paolo; Lauro, Davide; Cricelli, Claudio; Lapi, Francesco

    2017-09-14

    Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug-drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations. By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design. Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77-0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64-0.85). In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.

  3. Core-shell hybrid nanocapsules for oral delivery of camptothecin: formulation development, in vitro and in vivo evaluation

    Science.gov (United States)

    Ünal, Hale; d'Angelo, Ivana; Pagano, Ester; Borrelli, Francesca; Izzo, Angelo; Ungaro, Francesca; Quaglia, Fabiana; Bilensoy, Erem

    2015-01-01

    The objective of this study was to design and in vitro-in vivo evaluate oral nanocapsules prepared from amphiphilic cyclodextrins (CDs) or poly-ɛ-caprolactone (PCL) for the effective oral delivery of an anticancer agent, camptothecin (CPT). CPT-loaded anionic and Chitosan (CS)-coated cationic nanocapsules were prepared and characterized in vitro. Morphological analysis was performed by scanning electron microscope (SEM). CPT release profile was evaluated using dialysis method under sink conditions. To determine the protective effect and drug stability provided by nanocapsules, all the formulations were incubated in simulated gastrointestinal media. Measurement of mucoadhesive tendency of CPT-loaded nanocapsules was realized by turbidimetric method. Penetration of nanocapsules was performed through an artificial mucus model. The permeability of CPT in solution form and bound to nanocapsule formulations were demonstrated across Caco-2 cell line. Finally, the intestinal uptake of nanocapsules was evaluated in vivo, in a mouse model. Both anionic and cationic formulations were in the range of 180-220 nm with a narrow size distribution and desired zeta potential values. CPT-loaded nanocapsules were found to be stable in simulated gastrointestinal media. Turbidimetric measurements confirmed the interaction between nanoparticles and mucin. Penetration of CPT through an artificial mucus gel layer was higher with CS-coated nanocapsules in accordance with the results obtained from permeability studies across Caco-2 cell line. In vivo animal studies confirmed that the intestinal uptake of nanocapsules was significantly higher with cationic nanocapsules. CPT-loaded positively charged CD nanocapsules might be an attractive and promising treatment for oral chemotherapy.

  4. Core–shell hybrid nanocapsules for oral delivery of camptothecin: formulation development, in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Ünal, Hale, E-mail: unalhale@gmail.com [Hacettepe University, Division of Nanotechnology and Nanomedicine, Institute of Pure and Applied Science (Turkey); D’Angelo, Ivana [Second University of Napoli, Di.S.T.A.Bi.F. (Italy); Pagano, Ester; Borrelli, Francesca; Izzo, Angelo; Ungaro, Francesca; Quaglia, Fabiana [University of Naples Federico II, Department of Pharmacy (Italy); Bilensoy, Erem [Hacettepe University, Division of Nanotechnology and Nanomedicine, Institute of Pure and Applied Science (Turkey)

    2015-01-15

    The objective of this study was to design and in vitro–in vivo evaluate oral nanocapsules prepared from amphiphilic cyclodextrins (CDs) or poly-ε-caprolactone (PCL) for the effective oral delivery of an anticancer agent, camptothecin (CPT). CPT-loaded anionic and Chitosan (CS)-coated cationic nanocapsules were prepared and characterized in vitro. Morphological analysis was performed by scanning electron microscope (SEM). CPT release profile was evaluated using dialysis method under sink conditions. To determine the protective effect and drug stability provided by nanocapsules, all the formulations were incubated in simulated gastrointestinal media. Measurement of mucoadhesive tendency of CPT-loaded nanocapsules was realized by turbidimetric method. Penetration of nanocapsules was performed through an artificial mucus model. The permeability of CPT in solution form and bound to nanocapsule formulations were demonstrated across Caco-2 cell line. Finally, the intestinal uptake of nanocapsules was evaluated in vivo, in a mouse model. Both anionic and cationic formulations were in the range of 180–220 nm with a narrow size distribution and desired zeta potential values. CPT-loaded nanocapsules were found to be stable in simulated gastrointestinal media. Turbidimetric measurements confirmed the interaction between nanoparticles and mucin. Penetration of CPT through an artificial mucus gel layer was higher with CS-coated nanocapsules in accordance with the results obtained from permeability studies across Caco-2 cell line. In vivo animal studies confirmed that the intestinal uptake of nanocapsules was significantly higher with cationic nanocapsules. CPT-loaded positively charged CD nanocapsules might be an attractive and promising treatment for oral chemotherapy.

  5. Oral probiotic microcapsule formulation ameliorates non-alcoholic fatty liver disease in Bio F1B Golden Syrian hamsters.

    Directory of Open Access Journals (Sweden)

    Jasmine Bhathena

    Full Text Available The beneficial effect of a microencapsulated feruloyl esterase producing Lactobacillus fermentum ATCC 11976 formulation for use in non-alcoholic fatty liver disease (NAFLD was investigated. For which Bio F1B Golden Syrian hamsters were fed a methionine deficient/choline devoid diet to induce non-alcoholic fatty liver disease. Results, for the first time, show significant clinical benefits in experimental animals. Examination of lipids show that concentrations of hepatic free cholesterol, esterified cholesterol, triglycerides and phospholipids were significantly lowered in treated animals. In addition, serum total cholesterol, triglycerides, uric acid and insulin resistance were found to decrease in treated animals. Liver histology evaluations showed reduced fat deposits. Western blot analysis shows significant differences in expression levels of key liver enzymes in treated animals. In conclusion, these findings suggest the excellent potential of using an oral probiotic formulation to ameliorate NAFLD.

  6. Clinical trial of a monophasic estroprogestin oral formulation containing 20 micrograms ethinyl estradiol and 75 micrograms gestodene.

    Science.gov (United States)

    Lello, S; Monterubbianesi, M; Guardianelli, F; Bianchi, C; Simonelli, C

    2001-08-01

    The attempt to decrease the hormonal components of combined estrogen/progestin-containing oral formulations has led to use of low-dose formulations. The monophasic formulation containing ethinyl estradiol 20 micrograms (EE20) plus gestodene 75 micrograms (GSD75) was studied in an open, non-comparative, multicenter, clinical trial investigating its efficacy, safety, effects on body weight, blood pressure and sexual function. To evaluate the impact on sexual function, the Golombok Rust Questionnaire on Sexual Satisfaction (GRISS) was used. The study population comprised 216 women treated for 1 year. The EE20/GSD75 formulation did not show any significant effect on blood pressure, hematological parameters, body weight or sexual function. The treatment was well tolerated with a high compliance rate by the patients, with a low rate of estrogen-dependent symptoms. Moreover, there was no overall effect on sexual function, with no disturbance of sexual behavior or activity. In conclusion, our data show that the EE20/GSD75 has a very good tolerability profile, without any significant side-effects.

  7. Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films.

    Science.gov (United States)

    Mazumder, Sonal; Pavurala, Naresh; Manda, Prashanth; Xu, Xiaoming; Cruz, Celia N; Krishnaiah, Yellela S R

    2017-07-15

    The present investigation was carried out to understand the impact of formulation and process variables on the quality of oral disintegrating films (ODF) using Quality by Design (QbD) approach. Lamotrigine (LMT) was used as a model drug. Formulation variable was plasticizer to film former ratio and process variables were drying temperature, air flow rate in the drying chamber, drying time and wet coat thickness of the film. A Definitive Screening Design of Experiments (DoE) was used to identify and classify the critical formulation and process variables impacting critical quality attributes (CQA). A total of 14 laboratory-scale DoE formulations were prepared and evaluated for mechanical properties (%elongation at break, yield stress, Young's modulus, folding endurance) and other CQA (dry thickness, disintegration time, dissolution rate, moisture content, moisture uptake, drug assay and drug content uniformity). The main factors affecting mechanical properties were plasticizer to film former ratio and drying temperature. Dissolution rate was found to be sensitive to air flow rate during drying and plasticizer to film former ratio. Data were analyzed for elucidating interactions between different variables, rank ordering the critical materials attributes (CMA) and critical process parameters (CPP), and for providing a predictive model for the process. Results suggested that plasticizer to film former ratio and process controls on drying are critical to manufacture LMT ODF with the desired CQA. Published by Elsevier B.V.

  8. Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen

    DEFF Research Database (Denmark)

    Jain, Amit K; Thanki, Kaushik; Jain, Sanyog

    2014-01-01

    PURPOSE: The present work reports rationalized development and characterization of solidified self-nanoemulsifying drug delivery system for oral delivery of combinatorial (tamoxifen and quercetin) therapeutic regimen. METHODS: Suitable oil for the preparation of liquid SNEDDS was selected based o...

  9. Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

    Science.gov (United States)

    Darwish, Mona; Ma, Yuju; Tracewell, William; Robertson, Philmore; Webster, Lynn R.

    2017-01-01

    Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated. PMID:27330154

  10. Formulation, optimization, and in vitro/in vivo evaluation of furosemide nanosuspension for enhancement of its oral bioavailability

    Science.gov (United States)

    Sahu, Bhanu P.; Das, Malay K.

    2014-04-01

    Furosemide is a poorly soluble diuretic used for treatment of hypertension and edema. It has very poor or variable oral bioavailability due to its reduced solubility in gastric fluid and reduced permeability in intestinal fluid. The aim of this study was to prepare nanosuspension of furosemide to enhance its oral bioavailability by increasing its dissolution in stomach where it has better permeability. Full factorial design was used for a systematic approach of formulation and optimization. The nanosuspensions were prepared by precipitation with ultrasonication method. Polyvinyl acetate was used for sterically stabilizing the nanosuspensions. The diffusing drug concentration and stabilizer were used as the factors and the particle size, polydispersity index, and drug release were selected as dependent variables and characterized. The effect of nanoprecipitation on enhancement of oral bioavailability of furosemide nanosuspension was studied by in vitro dissolution and in vivo absorption studies in rats and compared to pure drug. Quality by design using full factorial design provided a systematic approach in optimizing nanosuspensions to produce products with desired quality. Stable nanosuspension were obtained with average size range of the precipitated nanoparticles between 150 and 300 nm and were found to be homogenous showing a narrow polydispersity index of 0.3 ± 0.1. The in vivo studies on rats revealed a significant increase in the oral absorbtion of furosemide in the nanosuspension compared to pure drug. The AUC0→24 and C max values of nanosuspension were approximately 1.38- and 1.68-fold greater than that of pure drug, respectively. Furosemide nanosuspension showed 20.06 ± 0.02 % decrease in systolic blood pressure compared to 13.37 + 0.02 % in plain furosemide suspension, respectively. The improved oral bioavailability and pharmacodynamic effect of furosemide may be due to the improved dissolution of furosemide in simulated gastric fluid which results

  11. Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats.

    Science.gov (United States)

    Ibrahim, Fady; Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Wasan, Kishor M

    2013-09-01

    The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10 mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63 h followed by iCo-009 then iCo-011 (36 and 27 h). The AUC(0-24h) of iCo-009 and iCo-010 was 1.5-2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.

  12. A new oral formulation for the release of sodium butyrate in the ileo-cecal region and colon

    Institute of Scientific and Technical Information of China (English)

    Aldo Roda; Patrizia Simoni; Maria Magliulo; Paolo Nanni; Mario Baraldini; Giulia Roda; Enrico Roda

    2007-01-01

    AIM:To develop a new formulation with hydroxy propyl methyl cellulose and Shellac coating for extended and selective delivery of butyrate in the ileo-caecal region and colon.METHODS:One-gram sodium butyrate coated tablets containing 13C-butyrate were orally administered to 12 healthy subjects and 12 Crohn's disease patients and the rate of 13C-butyrate absorption was evaluated by 13CO2 breath test analysis for eight hours.Tauroursodeoxycholic acid(500 mg)was co-administered as a biomarker of oro-ileal transit time to determine also the site of release and absorption of butyrate by the time of its serum maximum concentration.RESULTS:The coated formulation delayed the 13C-butyrate release by 2-3 h with respect to the uncoated tablets.Sodium butyrate was delivered in the intestine of all subjects and a more variable transit time was found in Crohn's disease patients than in healthy subjects.The variability of the peak 13CO2 in the kinetic release of butyrate was explained by the inter-subject variability in transit time.However,the coating chosen ensured an efficient release of the active compound even in patients with a short transit time.CONCLUSION:Simultaneous evaluation of breath 13CO2 and tauroursodeoxycholic acid concentrationtime curves has shown that the new oral formulation consistently releases sodium butyrate in the ileo-cecal region and colon both in healthy subjects and Crohn's disease patients with variable intestinal transit time.This formulation may be of therapeutic value in inflammatory bowel disease patients due to the appropriate release of the active compound.

  13. Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model.

    Science.gov (United States)

    Sivak, Olena; Gershkovich, Pavel; Lin, Molly; Wasan, Ellen K; Zhao, Jinying; Owen, David; Clement, John G; Wasan, Kishor M

    2011-08-08

    The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

  14. Tropically stable novel oral lipid formulation of amphotericin B (iCo-010: biodistribution and toxicity in a mouse model

    Directory of Open Access Journals (Sweden)

    Owen David

    2011-08-01

    Full Text Available Abstract Background The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010. Methods BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone® 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. Results The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone® resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone® treatment induced necrotic changes in hepatic and kidney tissues. Conclusions Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

  15. Bioequivalence of oral and intravenous carbamazepine formulations in adult patients with epilepsy.

    Science.gov (United States)

    Tolbert, Dwain; Cloyd, James; Biton, Victor; Bekersky, Ihor; Walzer, Mark; Wesche, David; Drummond, Rebecca; Lee, Deborah

    2015-06-01

    To evaluate the safety, tolerability, and comparative pharmacokinetics (PK) of intravenous and oral carbamazepine. In this phase 1, open-label study, adult patients with epilepsy on a stable oral carbamazepine dosage (400-2,000 mg/day) were converted to intravenous carbamazepine (administered at 70% of the oral dosage). A 28-day outpatient period preceded an up to 10-day inpatient period and a 30-day follow-up period. Intravenous carbamazepine was administered over 15 or 30 min every 6 h on days 1-7; some patients in the 15-min group were eligible to receive four 2- to 5-min (rapid) infusions on day 8. Patients underwent blood sampling to determine the area under the concentration-time curve (AUC) for carbamazepine and metabolite carbamazepine-10,11-epoxide following oral (day 0) and intravenous carbamazepine administration (days 1, 7, and 8). Bioequivalence was evaluated in patients with normal renal function (creatinine clearance >80 ml/min). Safety assessments were conducted through day 38. Ninety-eight patients enrolled and 77 completed the PK component. The mean daily oral and intravenous carbamazepine dosage for 64 PK-evaluable patients with normal renal function was 962.5 and 675.1 mg (70% of oral dosage), respectively. Steady-state minimum concentration (C(min)) and overall exposure (AUC0-24) for intravenous carbamazepine infused over 30, 15, or 2-5 min were similar to oral carbamazepine. The 90% confidence intervals (CIs) for the ratios of the adjusted means for AUC0-24, maximum concentration (Cmax), and C(min) were within the 80%-125% bioequivalence range for 30-min intravenous infusions versus oral administration, but exceeded the upper limit for Cmax for the 15-min and rapid infusions. All intravenous carbamazepine infusions were well tolerated. Intravenous carbamazepine infusions (70% of oral daily dose) of 30-, 15-, and 2- to 5-min duration, given every 6 h, maintained patients' plasma carbamazepine concentrations. Intravenous carbamazepine 30-min

  16. Evaluation of the tamper-resistant properties of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    Science.gov (United States)

    Eisenhauer, Tiffani D; Matchett, Mike; Heasley, Ralph; Morton, Terri; Devarakonda, Krishna; Giuliani, Michael; Young, Jim L; Barrett, Thomas

    2016-01-01

    Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release. To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets. IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet. IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol. IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets. IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.

  17. Formulation development and evaluation of controlled porosity osmotic pump delivery system for oral delivery of atenolol

    Directory of Open Access Journals (Sweden)

    Garvendra S Rathore

    2012-01-01

    Full Text Available In the present study, we developed and evaluated the controlled porosity osmotic pump (CPOP based drug delivery system of sparingly water soluble drug atenolol (ATL. We selected target release profile and optimized different variables to help us achieve this. Formulation variables, such as, the levels of solubility enhancer (0-15% w/w of drug, ratio of the drug to the osmogents, coat thickness of the semipermeable membrane (SPM and level of pore former (0-20% w/w of polymer were found to effect the drug release from the developed formulations. Cellulose acetate (CA 398-10 was used as the semipermeable membrane containing polyethylene glycol 400 as the Cplasticizer. ATL release was directly proportional to the level of the solubility enhancer, osmotic pressure generated by osmotic agent and level of pore former; however, was inversely proportional to the coat thickness of SPM. Drug release from developed formulations was independent of the pH and agitation intensities of release media. Burst strength of the exhausted shells decreased with increase in the level of pore former. The optimized formulations were subjected to stability studies as per International Conference on Harmonisation (ICH guidelines, and formulations were found to be stable after 3 months study. Steady-state plasma levels of drug were predicted by the method of superposition.

  18. In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation.

    Science.gov (United States)

    McCarthy, Carol A; Faisal, Waleed; O'Shea, Joseph P; Murphy, Colm; Ahern, Robert J; Ryan, Katie B; Griffin, Brendan T; Crean, Abina M

    2017-03-28

    Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships, was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Beneficial Effects of Long-Term Administration of an Oral Formulation of Angiotensin-(1–7 in Infarcted Rats

    Directory of Open Access Journals (Sweden)

    Fúlvia D. Marques

    2012-01-01

    Full Text Available In this study was evaluated the chronic cardiac effects of a formulation developed by including angiotensin(Ang-(1–7 in hydroxypropyl β-cyclodextrin (HPβCD, in infarcted rats. Myocardial infarction (MI was induced by left coronary artery occlusion. HPβCD/Ang-(1–7 was administered for 60 days (76 μg/Kg/once a day/gavage starting immediately before infarction. Echocardiography was utilized to evaluate usual cardiac parameters, and radial strain method was used to analyze the velocity and displacement of myocardial fibers at initial time and 15, 30, and 50 days after surgery. Real-time PCR was utilized to evaluate the fibrotic signaling involved in the remodeling process. Once-a-day oral HPβCD/Ang-(1–7 administration improved the cardiac function and reduced the deleterious effects induced by MI on TGF-β and collagen type I expression, as well as on the velocity and displacement of myocardial fibers. These findings confirm cardioprotective effects of Ang-(1–7 and indicate HPβCD/Ang-(1–7 as a feasible formulation for long-term oral administration of this heptapeptide.

  20. Lipid-based formulations for oral administration of poorly water-soluble drugs

    DEFF Research Database (Denmark)

    Mu, Huiling; Holm, René; Müllertz, Anette

    2013-01-01

    Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving....../dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect...

  1. Comparative bioavailability of two oral formulations of bromazepam in healthy volunteers.

    Science.gov (United States)

    Lerner, F E; Schere, D; Batafarano, N; Casas, F; Glancszpigel, R

    2001-01-01

    The aim of this study was to assess the pharmacokinetic profile of two bromazepam (CAS 1812-30-2) formulations in 24 healthy volunteers. An open, randomised clinical trial designed as two-period crossover with 14-day washout between doses was employed. Plasma samples for assessments of their bromazepam concentration by HPLC-UV were obtained over 96 h after administration. No adverse effect was reported for any of the formulations administered. The following pharmacokinetics parameters were calculated: AUC(0-96 h), AUCinf, Cmax, Tmax, Ke and T1/2. The 90% confidence intervals (CI) for the mean test/reference individual ratios were 81-109 for AUC and 84-116 for Cmax. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the Food and Drug Administration, it is concluded that the new bromazepam slow-release formulation is therapeutic equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.

  2. Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen

    DEFF Research Database (Denmark)

    Jain, Amit K; Thanki, Kaushik; Jain, Sanyog

    2014-01-01

    PURPOSE: The present work focuses on the in vivo evaluation of tamoxifen and quercetin combination loaded into solid self-nanoemulsifying drug delivery system (s-Tmx-QT-SNEDDS). METHODS: Lyophilization was employed to prepare s-Tmx-QT-SNEDDS using Aerosil 200 as carrier. The developed formulation...

  3. Bioequivalence study of two oral formulations of irbesartan 300 mg in healthy volunteers.

    Science.gov (United States)

    Cánovas, M; Cabré, F; Polonio, F

    2014-01-01

    A bioequivalence study of 2 irbesartan (CAS 138402-11-6) film-coated tablet formulations was carried out in 40 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 96 h following drug administration. Plasma concentrations of irbesartan were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t (98.06-109.48%, point estimator 103.61%) and Cmax (88.93-100.87%, point estimator 94.72%) were within the bioequivalence acceptance range of 80-125%. According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that test formulation of irbesartan 300 mg film-coated tablet is bioequivalent to the reference formulation. Overall, it was judged that the study was conducted with a good tolerance of the subjects to both study drugs.

  4. Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders

    Directory of Open Access Journals (Sweden)

    Sajatovic M

    2013-05-01

    Full Text Available Martha Sajatovic,1 Thomas R Thompson,2 Kevin Nanry,3 Suzanne Edwards,2 Ranjani Manjunath21Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH, 2GlaxoSmithKline, Research Triangle Park, NC; 3Quintiles, Durham, NC, USABackground: Lamotrigine is an anticonvulsant drug indicated for the maintenance treatment of bipolar I disorder and for various types of epilepsy. An orally disintegrating tablet (ODT of lamotrigine was developed to provide a formulation option that might increase patient convenience and satisfaction.Methods: Subjects with mood disorders who reported difficulty swallowing currently prescribed lamotrigine immediate-release medication (baseline were enrolled and treated with lamotrigine ODT for three weeks (end of treatment. Subject satisfaction and convenience were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM. Also measured were global psychopathology using the Clinical Global Impression severity index (CGI-S and depressive symptoms using the Beck Depression Inventory (BDI-II.Results: Lamotrigine ODT was found to be significantly more convenient to use than lamotrigine immediate-release (change in baseline TSQM convenience score: 23.3, n = 97, P < 0.001. The mean TSQM global satisfaction score was similar at baseline (76.3 and after treatment with lamotrigine ODT (76.0. There were no significant changes on CGI-S and BDI-II.Conclusion: Subjects reported that lamotrigine ODT was significantly more convenient than lamotrigine immediate-release, while both formulations were associated with good satisfaction. Lamotrigine ODT may be a treatment option for patients who have difficulty swallowing medication.Keywords: lamotrigine, epilepsy, antiepileptic drug, bipolar disorder, mood disorder

  5. Pharmacokinetics of guaifenesin, pseudoephedrine and hydrocodone in a combination oral liquid formulation, administered as single and multiple doses in healthy Chinese volunteers, and comparison with data for individual compounds formulated as Antuss®.

    Science.gov (United States)

    Deng, Shuhua; Huang, Wencan; Ni, Xiaojia; Zhang, Ming; Lu, Haoyang; Wang, Zhanzhang; Hu, Jinqing; Zhu, Xiuqing; Qiu, Chang; Shang, Dewei; Zhang, Yuefeng; Xiong, Linghui; Wen, Yuguan

    2017-10-01

    1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.

  6. Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers.

    Science.gov (United States)

    Viganò, G; Garagiola, U; Gaspari, F

    1991-01-01

    A single-blind, randomized, crossover pharmacokinetic study was carried out to investigate the bioavailability of a new oral buffered 325 mg acetylsalicylic acid (ASA) formulation (ASPIRINA 03) in comparison with a 325 mg plain tablet. Twelve healthy volunteers of both sexes, aged between 20 and 37 years, received buffered or plain ASA on two separate occasions with a wash-out interval of at least two weeks. ASA and salicylic acid (SA) plasma levels were determined by a chromatographic method. The results showed no difference between the area under concentration time curve (AUC0-infinity) ASA values of both formulations (p = 0.19), and buffered ASA relative bioavailability was 102.49% (= bioequivalence). A significant difference was found between the AUC0-30 min ASA values: 90.5 micrograms. min/ml with buffered and 67.7 micrograms. min/ml with the plain tablet (p less than 0.05). The buffered ASA time of maximum concentration was shorter (28 +/- 8 min) than the plain one (38 +/- 19 min, p less than 0.05). The plasma concentrations and pharmacokinetic parameters of SA were not significantly different after the administration of the two ASA formulations. The plain ASA tablet had a significantly lower (p less than 0.05) dissolution rate than buffered ASA tablet. Moreover, the buffered ASA tablet significantly (p less than 0.01) increased the pH by 0.5 units. In conclusion, the bioavailability of the new oral buffered ASA was equivalent to that of plain ASA, but the plasma concentration peak was reached in a shorter time.

  7. Physicochemical characterisation of fluids and soft foods frequently mixed with oral drug formulations prior to administration to children.

    Science.gov (United States)

    Kersten, E; Barry, A; Klein, S

    2016-03-01

    Oral drug administration to children poses specific pharmaceutical challenges that are often not seen to the same extent in adults, and whose occurrence may also be age dependent. When an age-appropriate dosage form is not available, manipulation of adult dosage forms (e.g., splitting and crushing of tablets or opening of capsules) has been reported as a means to facilitate administration to children. To enhance swallowability and/or mask an unpleasant taste of the dosage form to be administered, crushed/split tablets or the contents of capsules are often mixed with food or drinks or suspended in a vehicle prior to administration. However, it seems that the risks and benefits of an approach whereby the dosage form is modified prior to administration in this manner are everything but clear. The aim of the present study was to gain an overview of the physicochemical properties of a number of fluids, soft foods and suspension vehicles that are commonly reported to be mixed with oral medications before administration to children to improve patient acceptability. For this purpose, physicochemical parameters of 15 different fluids, soft foods and suspension vehicles were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Results of the study clearly show the differences in physicochemical properties of the test candidates. It is thus obvious that the type of fluid/food mixed with a drug product before administration may have a significant impact on bioavailability of the drug administered. Therefore, a risk-based assessment of such practices considering API properties, formulation features and physicochemical properties of the fluids and foods intended to be co-administered with the dosage form, in conjunction with the anatomical and physiological maturity of the gastro-intestinal tract in the intended paediatric population, should be an essential part of paediatric oral formulation development.

  8. Formulation,Optimization and Evaluation of Orally Disintegrating Tablet of Non-Steroidal Anti-inflammatory Drug

    Directory of Open Access Journals (Sweden)

    Patel Minal Arvindbhai

    2012-05-01

    Full Text Available Piroxicam is a non steroidal anti-inflammatory drug with analgesic properties. The purpose of this studywas to develop a taste masked orally disintegrating tablet of poorly soluble Piroxicam by directcompression technique with β-cyclodextrin (ß-CD complexes using various superdisintegrants likesodium starch glycolate, crospovidone XL and croscarmellose sodium. Complex was characterizedusing infrared spectroscopy, differential scanning calorimetry, % drug release study, gustatoryevaluation for taste masking. A 32 full factorial design was applied to systematically optimize the drugdisintegration time. The concentration of Crospovidone (X1 and concentration of Croscarmellose (X2were selected as independent variables. The Disintegration time (Y1 and Wetting time (Y2 wereselected as dependent variables. The prepared tablets were evaluated for hardness, friability,disintegration time, wetting time and In-vitro drug release. FT-IR studies and physical compatibilitystudy were conducted for drug, and drug excipient mixture for interactions if any. The differentformulations showed disintegration time between 12 to 58 sec. The results indicated that concentrationof Crospovidone (X1 and concentration of Croscarmellose (X2 significantly affected theDisintegration time (Y1 and Wetting time (Y2. Regression analysis and numerical optimization wereperformed to identify the best formulation. Formulation F10 prepared with croscarmellose (4.23% &crospovidone (6.74% was found to be the best formulation with disintegration time 16 sec, wetting time21 sec and % drug release in 10 min 94.23%.

  9. The role of citric acid in oral peptide and protein formulations: relationship between calcium chelation and proteolysis inhibition.

    Science.gov (United States)

    Welling, Søren H; Hubálek, František; Jacobsen, Jette; Brayden, David J; Rahbek, Ulrik L; Buckley, Stephen T

    2014-04-01

    The excipient citric acid (CA) has been reported to improve oral absorption of peptides by different mechanisms. The balance between its related properties of calcium chelation and permeation enhancement compared to a proteolysis inhibition was examined. A predictive model of CA's calcium chelation activity was developed and verified experimentally using an ion-selective electrode. The effects of CA, its salt (citrate, Cit) and the established permeation enhancer, lauroyl carnitine chloride (LCC) were compared by measuring transepithelial electrical resistance (TEER) and permeability of insulin and FD4 across Caco-2 monolayers and rat small intestinal mucosae mounted in Ussing chambers. Proteolytic degradation of insulin was determined in rat luminal extracts across a range of pH values in the presence of CA. CA's capacity to chelate calcium decreased ~10-fold for each pH unit moving from pH 6 to pH 3. CA was an inferior weak permeation enhancer compared to LCC in both in vitro models using physiological buffers. At pH 4.5 however, degradation of insulin in rat luminal extracts was significantly inhibited in the presence of 10mM CA. The capacity of CA to chelate luminal calcium does not occur significantly at the acidic pH values where it effectively inhibits proteolysis, which is its dominant action in oral peptide formulations. On account of insulin's low basal permeability, inclusion of alternative permeation enhancers is likely to be necessary to achieve sufficient oral bioavailability since this is a weak property of CA.

  10. Oral toxicity, formulation effects, and field performance of flufenoxuron against the German cockroach (Dictyoptera: Blattellidae).

    Science.gov (United States)

    Reid, B L; Appel, A G; Demark, J J; Bennett, G W

    1992-08-01

    Laboratory and field studies on the benzoylphenyl urea (BPU) chitin synthetase inhibitor flufenoxuron (DPX EY-059) showed great potential for its use in suppressing infestations of German cockroach, Blattella germanica (L.). When fed continuously to fifth (last) instars, the LC50 of flufenoxuron was estimated at 0.82 ppm (95% FL, 0.76-0.87 ppm). A rating scale specific for BPU effects was developed and shown to be positively correlated with the insect's exposure to concentration of flufenoxuron. Manipulating the particle size of wettable powder formulations of flufenoxuron significantly altered their activity in contact bioassays. Larger particles (volume mean diameter, 12.2 mu; range, 10-20 mu) were more active. Field trials in multifamily housing with this wettable powder formulation at 0.033 and 0.066% (AI) achieved high level (greater than 80%) population suppression within 8 wk of treatment. The potential for the use of flufenoxuron in B. germanica management programs is discussed.

  11. Development and Validation of a Discriminating In Vitro Dissolution Method for Oral Formulations Containing Satranidazole

    Directory of Open Access Journals (Sweden)

    Harshal Ashok Pawar

    2014-01-01

    Full Text Available The development of a meaningful dissolution procedure for drug products with limited water solubility has been a challenge to the pharmaceutical industry. Satranidazole (BCS Class II drug is a new nitroimidazole derivative with potent antiamoebic action. There is no official dissolution medium available in the literature. In the present study, parameters such as saturation solubility in different pH medium, dissolution behavior of formulations, influence of sink conditions, stability, and discriminatory effect of dissolution testing were studied for the selection of a proper dissolution medium. Results of solubility data revealed that solubility of Satranidazole decreases with an increase in pH. Satranidazole showed better sink condition in 0.1 N HCl as compared to other media. The drug and marketed formulations were stable in the dissolution media used. An agitation speed of 75 rpm showed a more discriminating drug release profile than 50 rpm. Using optimized dissolution parameters (paddle at 75 rpm, 900 mL 0.1 N HCl greater than 80% of the label amount is released over 60 minutes. UV-spectroscopic method used was validated for the specificity, linearity, precision, robustness, and solution stability. The method was successfully applied to granular formulations and also to marketed tablets containing 300 mg Satranidazole.

  12. Will novel oral formulations change the management of inflammatory bowel disease?

    DEFF Research Database (Denmark)

    Nielsen, Ole Haagen; Seidelin, Jakob Benedict; Ainsworth, Mark;

    2016-01-01

    INTRODUCTION: The traditional management of inflammatory bowel disease (IBD) with sulphasalazine/5-aminosalicylic acid, glucocorticoids and immunomodulators (i.e., thiopurines and methotrexate) was nearly two decades ago extended with intravenously or subcutaneously administered biologics (i......334, and amiselimod), as well as anti-sense therapy (mongersen) targeting SMAD7, drugs which directly target intracellular pathways of relevance for intestinal inflammation. EXPERT OPINION: A new avenue using easily administered oral therapies for the management of IBD is being introduced. While...

  13. Formulation of 20(S)-protopanaxadiol nanocrystals to improve oral bioavailability and brain delivery.

    Science.gov (United States)

    Chen, Chen; Wang, Lisha; Cao, Fangrui; Miao, Xiaoqing; Chen, Tongkai; Chang, Qi; Zheng, Ying

    2016-01-30

    The aim of this study was to fabricate 20(S)-protopanaxadiol (PPD) nanocrystals to improve PPD's oral bioavailability and brain delivery. PPD nanocrystals were fabricated using an anti-solvent precipitation approach where d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was optimized as the stabilizer. The fabricated nanocrystals were nearly spherical with a particle size and drug loading of 90.44 ± 1.45 nm and 76.92%, respectively. They are in the crystalline state and stable at 4°C for at least 1 month. More than 90% of the PPD could be rapidly released from the nanocrystals, which was much faster than the physical mixture and PPD powder. PPD nanocrystals demonstrated comparable permeability to solution at 2.52 ± 0.44×10(-5)cm/s on MDCK monolayers. After oral administration of PPD nanocrystals to rats, PPD was absorbed quickly into the plasma and brain with significantly higher Cmax and AUC0-t compared to those of the physical mixture. However, no brain targeting was observed, as the ratios of the plasma AUC0-t to brain AUC0-t for the two groups were similar. In summary, PPD nanocrystals are a potential oral delivery system to improve PPD's poor bioavailability and its delivery into the brain for neurodegenerative disease and intracranial tumor therapies in the future.

  14. Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations

    Directory of Open Access Journals (Sweden)

    Spinks CB

    2017-02-01

    Full Text Available Crystal B Spinks,1 Ahmed S Zidan,2,3 Mansoor A Khan,4 Muhammad J Habib,1 Patrick J Faustino2 1Department of Pharmaceutical Sciences, School of Pharmacy, Howard University, Washington, DC, 2Division of Product Quality Research, Office of Pharmaceutical Quality, Food and Drug Administration, Silver Spring, MD, USA; 3Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; 4Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX, USA Abstract: Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/acetonitrile pH 7.4 (95:5 v/v. The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 µL with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that

  15. Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations.

    Science.gov (United States)

    Spinks, Crystal B; Zidan, Ahmed S; Khan, Mansoor A; Habib, Muhammad J; Faustino, Patrick J

    2017-01-01

    Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/acetonitrile pH 7.4 (95:5 v/v). The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 µL with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that calibration curves were linear with r(2) > 0.9995 over the analytical range of 1-10 µg/mL. Inter- and intraday accuracy and precision values ranged from 95% to 101% and 0.3% to 2.6%, respectively. The method was determined to be specific and robust. Regarding the potential of the prepared vectors to potentiate tenofovir permeability through the Caco-2 model, a 10-fold increase in tenofovir apparent permeability was observed compared to its oral solution. In conclusion, this novel and validated method was

  16. Suppression of Tumorigenesis: Modulation of Inflammatory Cytokines by Oral Administration of Microencapsulated Probiotic Yogurt Formulation

    Directory of Open Access Journals (Sweden)

    Aleksandra Malgorzata Urbanska

    2010-01-01

    Full Text Available The objective of this study was to examine the ability of a novel microencapsulated probiotic yogurt formulation to suppress the intestinal inflammation. We assessed its anticancer activity by screening interleukin-1, 6, and 12 (IL-1, 6, 12, secretory levels of tumor necrosis factor-alpha (TNF-α, interferon-gamma (IFN-γ, prostaglandin E2  (PGE2, and thromboxane B2 in the digesta obtained from the duodenum, jejunum, proximal, and distal segments of the ileum of C57BL/6J-ApcMin/J mice. Formulation-receiving animals showed consistently lower proinflammatory cytokines' levels when compared to control group animals receiving empty alginate-poly-L-lysine-alginate (APA microcapsules suspended in saline. The concentrations of IL-12 found in serum in control and treatment group animals were significant: 46.58±16.96 pg/mL and 158.58±28.56 pg/mL for control and treatment animals, respectively. We determined a significant change in plasma C-reactive protein: 81.04±23.73 ng/mL in control group and 64.21±16.64 ng/mL in treatment group. Western blots showed a 71% downregulation of cyclooxygenase-2 (COX-2 protein in treatment group animals compared to control. These results point to the possibility of using this yogurt formulation in anticancer therapies, in addition to chronic gut diseases such as Crohn's disease, irritable bowel syndrome (IBS, and inflammatory bowel disease (IBD thanks to its inflammation lowering properties.

  17. A Novel In Situ Gel Formulation of Ranitidine for Oral Sustained Delivery

    OpenAIRE

    Xu, Haoping; Shi, Min; Liu, Ying; Jiang, Jinling; Ma, Tao

    2014-01-01

    The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was ch...

  18. Monitoring of threo-methylphenidate enantiomers in oral fluid by capillary electrophoresis with head-column field-amplified sample injection.

    Science.gov (United States)

    Theurillat, Regula; Thormann, Wolfgang

    2014-04-01

    Threo-methylphenidate is a chiral psychostimulant drug widely prescribed to treat attention-deficit hyperactivity disorder in children and adolescents. An enantioselective CE-based assay with head-column field-amplified sample stacking for analysis of threo-methylphenidate enantiomers in liquid/liquid extracts of oral fluid is described. Analytes are electrokinetically injected across a short water plug placed at the capillary inlet and become stacked at the interface between plug and buffer. Enantiomeric separation occurs within a few minutes in a pH 3.0 phosphate/triethanolamine buffer containing 20 mg/mL (2-hydroxypropyl)-β-CD as chiral selector. The assay with six point multilevel internal calibration provides a linear response for each enantiomer in the 10-200 ng/mL concentration range, is simple, inexpensive, and reproducible, and has an LOQ of 5 ng/mL. It was applied to oral fluid patient samples that were collected up to 12 h after intake of an immediate release tablet and two different extended release formulations with racemic methylphenidate. Drug profiles could thereby be assessed in a stereoselective way. Almost no levorotary threo-methylphenidate enantiomer was detected after intake of the two extended release formulations, whereas this enantiomer was detected during the first 2.5 h after intake of the immediate release preparation. The noninvasive collection of oral fluid is an attractive alternative to plasma for the monitoring of methylphenidate exposure in the pediatric community.

  19. A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis

    DEFF Research Database (Denmark)

    Lottmann, H; Froeling, F; Alloussi, S

    2007-01-01

    AIMS: Desmopressin is a useful treatment for primary nocturnal enuresis (PNE), a common childhood condition that can persist into adolescence. This open-label, randomised, cross-over study evaluated the preference of children and adolescents with PNE for sublingual desmopressin oral lyophilisate....../MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets identical with 120/240 microg MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded...... for the MELT, and a statistically significant preference for desmopressin MELT in children aged 5-11 years. Desmopressin MELT had similar levels of efficacy and safety at lower dosing levels than the tablet, and therefore facilitates early initiation of PNE treatment in children aged 5-6 years. Udgivelsesdato...

  20. Bioequivalence study with lapatinib powder for oral suspension and the original tablet formulation in cancer patients.

    Science.gov (United States)

    Koch, Kevin M; Ferron-Brady, Geraldine; Lemmon, Colleen; Cartee, Leanne; Hollyfield, Hedy; D'Amelio, Anthony M; Piepszak, Alexandra; Swaby, Ramona F; Curran, David; Arya, Niki

    2015-01-01

    Lapatinib is approved for use in various therapeutic combinations for treating metastatic breast cancers that over-express HER2. To deliver the approved doses, up to six large tablets need to be ingested with the current 250-mg tablets. For ease of ingestion, a powder for oral suspension was developed. This study was an open-label, randomized, adaptive design, two-period crossover bioequivalence study of the powder for suspension relative to the commercial tablet at steady state following once daily dosing for 7 days in patients with advanced cancer. To minimize the number of cancer patients required for a pivotal bioequivalence study (144 in this case), a four-stage adaptive group sequential design with interim analyses after every 36 subjects was implemented to allow for early termination. Bioequivalence for the oral suspension relative to the commercial tablet was demonstrated in both the first (and only) interim analysis and the final analysis, as the 90% confidence intervals for the treatment comparison ratios for both AUC0-24 and Cmax were contained within the acceptance criteria (0.80, 1.25). Additionally, there was no statistical difference in tlag or tmax , suggesting no difference in the absorption rate between treatments. There were no unexpected safety findings during this study.

  1. A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets

    Directory of Open Access Journals (Sweden)

    Li FQ

    2011-04-01

    Full Text Available Feng-Qian Li1, Cheng Yan2, Juan Bi1, Wei-Lin Lv3, Rui-Rui Ji3, Xu Chen1, Jia-Can Su3, Jin-Hong Hu31Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Pharmacy, Bethune International Peace Hospital, Shijiazhuang, People’s Republic of China; 3Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of ChinaAbstract: Scopolamine hydrobromide (SH-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w and loading capacity of 20% (w/w were achieved for the microparticles, which ranged from 2 µm to 8 µm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH’s intrinsic characteristics.Keywords: scopolamine hydrobromide, chitosan, nanoparticles-in-microparticles system, spray-drying, orally disintegrating tablets

  2. A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets.

    Science.gov (United States)

    Li, Feng-Qian; Yan, Cheng; Bi, Juan; Lv, Wei-Lin; Ji, Rui-Rui; Chen, Xu; Su, Jia-Can; Hu, Jin-Hong

    2011-01-01

    Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH's intrinsic characteristics.

  3. Solvent-free melting techniques for the preparation of lipid-based solid oral formulations.

    Science.gov (United States)

    Becker, Karin; Salar-Behzadi, Sharareh; Zimmer, Andreas

    2015-05-01

    Lipid excipients are applied for numerous purposes such as taste masking, controlled release, improvement of swallowability and moisture protection. Several melting techniques have evolved in the last decades. Common examples are melt coating, melt granulation and melt extrusion. The required equipment ranges from ordinary glass beakers for lab scale up to large machines such as fluid bed coaters, spray dryers or extruders. This allows for upscaling to pilot or production scale. Solvent free melt processing provides a cost-effective, time-saving and eco-friendly method for the food and pharmaceutical industries. This review intends to give a critical overview of the published literature on experiences, formulations and challenges and to show possibilities for future developments in this promising field. Moreover, it should serve as a guide for selecting the best excipients and manufacturing techniques for the development of a product with specific properties using solvent free melt processing.

  4. Cannabinoid derivate-loaded PLGA nanocarriers for oral administration: formulation, characterization, and cytotoxicity studies

    Directory of Open Access Journals (Sweden)

    Prados J

    2012-11-01

    Full Text Available Lucía Martín-Banderas,1 Josefa Álvarez-Fuentes,1 Matilde Durán-Lobato,1 José Prados,2 Consolación Melguizo,2 Mercedes Fernández-Arévalo,1 Mª Ángeles Holgado11Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain; 2Institute of Biopathology and Regenerative Medicine (IBIMER, School of Medicine, University of Granada, Granada, SpainAbstract: CB13 (1-Naphthalenyl[4-(pentyloxy-1-naphthalenyl]methanone-loaded poly(lactic-co-glycolic acid nanoparticles (NPs were produced by nanoprecipitation and tested for their in vitro release behavior and in vitro cytotoxicity assays. The effects of several formulation parameters such as polymer type, surfactant concentration, and initial drug amount were studied. NPs had a particle size 90–300 nm in diameter. Results obtained show that the main influence on particle size was the type of polymer employed during the particle production: the greater the hydrophobicity, the smaller the particle size. In terms of encapsulation efficiency (%, high values were achieved (~68%–90% for all formulations prepared due to the poor solubility of CB13 in the external aqueous phase. Moreover, an inverse relationship between release rate and NP size was found. On the other hand, low molecular weight and low lactide content resulted in a less hydrophobic polymer with increased rates of water absorption, hydrolysis, and erosion. NPs showed no cytotoxicity and may be considered to be appropriate for drug-delivery purposes.Keywords: neuropathic pain, CB13, nanoprecipitation

  5. Effect of a high-fat meal on the pharmacokinetics of 300-milligram posaconazole in a solid oral tablet formulation.

    Science.gov (United States)

    Kersemaekers, Wendy M; Dogterom, Peter; Xu, Jialin; Marcantonio, Eugene E; de Greef, Rik; Waskin, Hetty; van Iersel, Marlou L P S

    2015-01-01

    Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets × 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC0-72) and maximum concentration in plasma (Cmax) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to Cmax (Tmax) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ∼1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal.

  6. Polymeric nanoparticles for oral delivery of 5-fluorouracil: Formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study.

    Science.gov (United States)

    Mattos, Ana Cristina de; Altmeyer, Clescila; Tominaga, Tania Toyomi; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

    2016-03-10

    Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU.

  7. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

    Directory of Open Access Journals (Sweden)

    Lindsay R Ancelet

    Full Text Available Oral delivery of BCG in a lipid formulation (Liporale™-BCG targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4(+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4(+ T cell response, evident by the detection of effector CD4(+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4(+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4(+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4(+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.

  8. FORMULATION OF ORAL MUCOADHESIVE TABLETS OF TERBUTALINE SULPHATE USING SOME NATURAL MATERIALS AND IN VITRO-IN VIVO EVALUATION

    Directory of Open Access Journals (Sweden)

    RANABIR CHANDA,AMITAVA GHOSH, SANTONU BISWAS,SANTANU ROY CHOWDHURY

    2013-09-01

    Full Text Available Mucoadhesive polymers that bind to the gastric mucin or epithelial cell surface are useful in drug delivery for the purpose of increasing the intimacy and duration of contact of drug with the absorbing membrane. Several synthetic polymers are in use for this purpose. Since the biodegradability of the synthetic polymers are questionable, in this investigation an oral mucoadhesive controlled delivery system has been developed for terbutaline sulphate (TS using natural mucoadhesive materials extracted from the edible fruits like Zizyphus mauritiana (ZM and Aegle marmelos (Linn. Cor. (AM that have better mucoadhesive property than synthetic polymer hydroxypropylmethylcellulose K4M (HPMC K4M. The in vitro adhesive and mucoadhesive strength of mucoadhesive materials extracted from the fruits of ZM and AM were evaluated and compared with HPMCK4M using both Share Stress and Wilhelmy Plate. Different formulations of oral mucoadhesive coated TS tablets were prepared using these natural materials and compared with tablets prepared with HPMCK4M and hardness, thickness, friability, weight variation and drug content of tablets were tested. The in vitro release of TS was studied in buffer pH 7.2 at 370C 0.50C. Tablets were orally administered to rabbits and blood plasma concentration of TS was determined using HPLC. It was found that mucoadhesive materials extracted from the fruits of ZM and AM exhibited better adhesiveness and mucoadhesiveness as compared with the HPMC- K4M. The in vitro study of TS exhibited showed greater drug release profile for tablets prepared with natural materials than synthetic polymers and confirmed with in vivo study. In vitro and in vivo correlation showed the same release profile.

  9. Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany.

    Science.gov (United States)

    Laux, Gerd; Heeg, Bart; van Hout, Ben A; Mehnert, Angelika

    2005-01-01

    Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security 'Sozialversicherung'). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and

  10. Pharmacokinetics of menthol and carvone after administration of an enteric coated formulation containing peppermint oil and caraway oil.

    Science.gov (United States)

    Mascher, H; Kikuta, C; Schiel, H

    2001-01-01

    Enteric coating of peppermint oil/caraway oil capsules avoids subjective discomfort to the patient caused by gastroesophageal reflux. In order to confirm bioequivalence of an enteric coated formulation containing peppermint oil and caraway oil (CAS 277309-55-4, Enteroplant) and an immediate release formulation of both oils, the pharmacokinetics of menthol and carvone after oral administration of the two formulations were studied in a randomized, two-period cross-over study in 16 healthy male volunteers. The subjects received 180 mg peppermint oil and 100 mg caraway oil, once as 2 enteric coated capsules of the fixed enteric coated combination preparation containing 90 mg peppermint oil (WS 1340) and 50 mg caraway oil (WS 1520) each (test) and once in the form of 5 capsules of an immediate release formulation (reference) containing 36 mg peppermint (WS 1340) oil and 20 mg caraway oil (WS 1520) each. The capsules were taken with 250 ml water after a 10 h fast. Both substances were determined in plasma by GC/MS after extraction. The limit of quantification was 10 ng/ml for menthol and 0.5 ng/ml for carvone. The mean maximum plasma levels for menthol were 1196 ng/ml after administration of the test medication and 1492 ng/ml after administration of the reference medication. The bioavailability with respect to the AUC was comparable after administration of test and reference preparation, the 90% confidence interval was 97 to 105%. As expected, there were considerable differences for Tmax. After application of the enteric coated form the maximum concentration was reached significantly later (3.0 h vs. 1.7 h) compared to the immediate release capsule. Corresponding data were also calculated for carvone. After application of the test medication the maxima of 14 ng/ml for both formulations were reached later (2.5 h vs. 1.3 h). The 90% confidence interval of the AUC for carvone was 79 to 119% and therefore slightly outside the acceptable range for bioequivalence of 80 to 125

  11. Halitosis in cystinosis patients after administration of immediate-release cysteamine bitartrate compared to delayed-release cysteamine bitartrate

    NARCIS (Netherlands)

    Besouw, Martine; Tangerman, Albert; Cornelissen, Elisabeth; Rioux, Patrice; Levtchenko, Elena

    2012-01-01

    Halitosis due to dimethylsulfide (DMS) generation is a major side effect of cysteamine in the treatment of cystinosis. Recently, an enteric coated formulation of cysteamine bitartrate (RP103) administered twice daily was demonstrated to be non-inferior for lowering WBC cystine levels compared to the

  12. Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation.

    Science.gov (United States)

    Fabio, Karine; Curley, Kieran; Guarneri, Joseph; Adamo, Benoit; Laurenzi, Brendan; Grant, Marshall; Offord, Robin; Kraft, Kelly; Leone-Bay, Andrea

    2015-12-01

    In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).

  13. Formulation for Oral Delivery of Lactoferrin Based on Bovine Serum Albumin and Tannic Acid Multilayer Microcapsules

    Science.gov (United States)

    Kilic, Ece; Novoselova, Marina V.; Lim, Su Hui; Pyataev, Nikolay A.; Pinyaev, Sergey I.; Kulikov, Oleg A.; Sindeeva, Olga A.; Mayorova, Oksana A.; Murney, Regan; Antipina, Maria N.; Haigh, Brendan; Sukhorukov, Gleb B.; Kiryukhin, Maxim V.

    2017-03-01

    Lactoferrin (Lf) has considerable potential as a functional ingredient in food, cosmetic and pharmaceutical applications. However, the bioavailability of Lf is limited as it is susceptible to digestive enzymes in gastrointestinal tract. The shells comprising alternate layers of bovine serum albumin (BSA) and tannic acid (TA) were tested as Lf encapsulation system for oral administration. Lf absorption by freshly prepared porous 3 μm CaCO3 particles followed by Layer-by-Layer assembly of the BSA-TA shells and dissolution of the CaCO3 cores was suggested as the most efficient and harmless Lf loading method. The microcapsules showed high stability in gastric conditions and effectively protected encapsulated proteins from digestion. Protective efficiency was found to be 76 ± 6% and 85 ± 2%, for (BSA-TA)4 and (BSA-TA)8 shells, respectively. The transit of Lf along the gastrointestinal tract (GIT) of mice was followed in vivo and ex vivo using NIR luminescence. We have demonstrated that microcapsules released Lf in small intestine allowing 6.5 times higher concentration than in control group dosed with the same amount of free Lf. Significant amounts of Lf released from microcapsules were then absorbed into bloodstream and accumulated in liver. Suggested encapsulation system has a great potential for functional foods providing lactoferrin.

  14. Formulation and evaluation of gastroretentive microballoons containing baclofen for a floating oral controlled drug delivery system.

    Science.gov (United States)

    Dube, T S; Ranpise, N S; Ranade, A N

    2014-01-01

    The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

  15. Formulation and evaluation of bilayer tablet by using melt granulation technique for treatment of diabetes mellitus.

    Science.gov (United States)

    Patel, Dhruvita; Patel, Ankita; Solanki, Trupti

    2012-03-01

    The objective of present study was to prepare and characterize Bilayer tablet formulation containing Metformin HCl in extended release matrix form and Pioglitazone HCl in immediate release form for the treatment of diabetes mellitus. Different formulations containing Metformin HCl were manufactured using 3(2) factorial designs. Influence of hydrophilic carrier, hydrophobic polymer on drug release was studied. Immediate release layer of Pioglitazone was optimized using different super disintegrants. All formulations were evaluated for percentage drug release. Optimization results indicated that release rate of Metformin is directly proportional to the levels of Eudragit S 100 and PEG 6000. Results confirmed that Bilayer tablet formulation containing extended release of Metformin HCl and immediate release of Pioglitazone HCl could be developed by using melt granulation technique.

  16. Oral medication delivery in impaired swallowing: thickening liquid medications for safe swallowing alters dissolution characteristics.

    Science.gov (United States)

    Manrique, Yady J; Sparkes, Arron M; Cichero, Julie A Y; Stokes, Jason R; Nissen, Lisa M; Steadman, Kathryn J

    2016-09-01

    Acetaminophen (paracetamol) is available in a wide range of oral formulations designed to meet the needs of the population across the age-spectrum, but for people with impaired swallowing, i.e. dysphagia, both solid and liquid medications can be difficult to swallow without modification. The effect of a commercial polysaccharide thickener, designed to be added to fluids to promote safe swallowing by dysphagic patients, on rheology and acetaminophen dissolution was tested using crushed immediate-release tablets in water, effervescent tablets in water, elixir and suspension. The inclusion of the thickener, comprised of xanthan gum and maltodextrin, had a considerable impact on dissolution; acetaminophen release from modified medications reached 12-50% in 30 min, which did not reflect the pharmacopeia specification for immediate release preparations. Flow curves reflect the high zero-shear viscosity and the apparent yield stress of the thickened products. The weak gel nature, in combination with high G' values compared to G'' (viscoelasticity) and high apparent yield stress, impact drug release. The restriction on drug release from these formulations is not influenced by the theoretical state of the drug (dissolved or dispersed), and the approach typically used in clinical practice (mixing crushed tablets into pre-prepared thickened fluid) cannot be improved by altering the order of incorporation or mixing method.

  17. A novel tropically stable oral amphotericin B formulation (iCo-010) exhibits efficacy against visceral Leishmaniasis in a murine model.

    Science.gov (United States)

    Wasan, Ellen K; Gershkovich, Pavel; Zhao, Jinying; Zhu, Xiaohua; Werbovetz, Karl; Tidwell, Richard R; Clement, John G; Thornton, Sheila J; Wasan, Kishor M

    2010-12-07

    To develop an oral formulation of amphotericin B (AmB) that is stable at the temperatures of WHO Climatic Zones 3 and 4 (30-43 °C) and to evaluate its efficacy in a murine model of visceral leishmaniasis (VL). The stability testing of four novel oral lipid AmB formulations composed of mono- and di-glycerides and pegylated esters (iCo-010 to iCo-013) was performed over 60 d and analyzed by HPLC-UV. In addition, the four formulations were incubated 4 h in fasted-state simulated intestinal fluid. AmB concentration was measured spectrophotometrically and emulsion droplet diameter was assessed by dynamic light scattering. Antileishmanial activity of iCo-010 was evaluated at increasing oral doses (2.5 to 10 mg/kg) in a murine model of VL. AmB stability in the lipid formulation (iCo-010) was >75% over 60 days. After 4 h in fasted-state simulated intestinal fluid, AmB concentration was >95%. iCo-010 demonstrated significant efficacy when orally administered to VL-infected mice bid for five days (inhibition of 99%, 98%, and 83% at 10, 5 and 2.5 mg/kg compared to the vehicle control). In addition, the qd dose of 20 mg/kg provided 96% inhibition compared to the vehicle control. The oral AmB formulation iCo-010 is stable at the temperatures of WHO Climatic Zones 3 and 4 (30-43 °C). iCo-010 showed excellent antileishmanial activity at both 10 mg/kg po bid for 5 days (<99% reduction in parasitic infection) and 20 mg/kg po qd for 5 days (95% inhibition when compared to control).

  18. A comparison of oral controlled-release morphine and oxycodone with transdermal formulations of buprenorphine and fentanyl in the treatment of severe pain in cancer patients

    Directory of Open Access Journals (Sweden)

    Nosek K

    2017-08-01

    Full Text Available Krzysztof Nosek,1 Wojciech Leppert,2,3 Hanna Nosek,4 Jerzy Wordliczek,5 Dariusz Onichimowski6 1Non–public Saint Lazarius Health Care Unit, Biskupiec, 2Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznań, 3Department of Quality of life Research, Gdańsk Medical University, Gdańsk, 4Department of Paediatrics, Regional Children Specialized Hospital, Olsztyn, 5Department of Interdisciplinary Intensive Care, Jagiellonian University College of Medicine, Kraków, 6Department of Intensive Care, Regional Hospital, Olsztyn, Poland Aim of the study: To compare analgesia and adverse effects during oral morphine and oxycodone and transdermal fentanyl and buprenorphine administration in cancer patients with pain. Patients and methods: Cancer patients treated at home and in outpatient clinics with severe pain (numerical rating scale score 6–10 fail to respond to non-opioids and/or weak opioids. All patients were randomized to either morphine, oxycodone, fentanyl or buprenorphine and divided into subgroups with predominant neuropathic and nociceptive pain component. Doses of opioids were titrated to satisfactory analgesia and acceptable adverse effects intensity. Patients were assessed at baseline and followed for 28 days. In all patient groups, immediate-release oral morphine was the rescue analgesic and lactulose 10 mL twice daily was the prophylaxis of constipation; no antiemetics were used as prophylaxis. Results: A total of 62 patients participated and 53 patients completed the study. Good analgesia was obtained for all 4 opioids, for both nociceptive and neuropathic pain. The use of co-analgesics was greater in patients with neuropathic pain. Morphine treatment was associated with less negative impact of pain on ability to walk, work and activity (trend according to Brief Pain Inventory-Short Form scores and less consumption of rescue morphine. The most common adverse effects included nausea and drowsiness

  19. From edible clay to a clay-containing formulation for optimization of oral delivery of some trace elements: a review.

    Science.gov (United States)

    Kikouama, Odilon Jean Richard; Balde, Lamine

    2010-12-01

    The present review describes the double beneficial effect of using clays for purposes of health and human nutrition: first, their chemical composition, which can enable the release of trace elements; and second, their mineralogical composition, which allows them to be used in the treatment of digestive diseases. The last part of the review is devoted to the release of trace elements contained in clay: clay-containing pellets designed for oral delivery of the trace elements iron and zinc. This multiple-unit pellet system is designed to be retained by flotation in the stomach cavity for a few hours (5 h), with simultaneous control of the release of the trace elements in order to optimize their gastrointestinal absorption. Finally, it is shown that the total amount of ions released from the clay was increased when the formulations were added, in comparison with raw clay, respectively as follows: Zn(2+) (60% versus 40%), Fe(3+) (70% versus 30%) and Fe(2+) (95% versus 40%).

  20. Design of pediatric oral formulations with a low proportion of methadone or phenobarbital for the treatment of neonatal abstinence syndrome.

    Science.gov (United States)

    Provenza, Nora; Calpena, Ana C; Mallandrich, Mireia; Pueyo, Blanca; Clares, Beatriz

    2016-09-01

    Elaboration of oral liquid formulations is the best alternative when no marketed forms are available for pediatrics. The development, characterization and stability evaluation of methadone (MI, MII, MIII) and phenobarbital (PI, PII) can be used for the treatment of neonatal abstinence syndrome (NAS). A standard operating procedure was established and parameters such as appearance, pH, rheological behavior and drug content were evaluated at three temperatures for 90 days. Changes in color of phenobarbital made necessary the storage below 25 °C. pH did not change in methadone solutions and was able to maintain phenobarbital solubilized. Degradation data at 4 °C fitted to Plateau equation followed by one phase decay. MI was stable for 60 days at the three temperatures; MII for 90 days at 4 and 25 °C and 60 days at 40 °C; MIII for 60 days at 4 °C, 15 days at 25 °C and 7 days at 4 °C. PI was stable for 60 days at 4 °C and 30 days at 25 °C. PII was stable for 7 days at 4 and 25 °C. All solutions met microbial specifications. A correct dosage for the treatment of NAS was guaranteed.

  1. Novel oral amphotericin B formulation (iCo-010) remains highly effective against murine systemic candidiasis following exposure to tropical temperature.

    Science.gov (United States)

    Wasan, Kishor M; Sivak, Olena; Bartlett, Karen; Wasan, Ellen K; Gershkovich, Pavel

    2015-01-01

    To evaluate the antifungal activity of amphotericin B (AmB) in a mouse model of systemic candidiasis following administration of a novel oral AmB formulation (iCo-010) that has been pre-exposed to tropical temperatures. Amphotericin B (AmB) was prepared as a 5 mg/mL dispersion in a mixture of Peceol, Gelucire 44/14 and VitE-TPGS 2,3 (iCo-010). The formulation was protected from light and incubated in a sealed container at 43 °C for 60 days. Mice infected with Candida albicans were treated with either iCo-010 formulation pre-incubated at 43 °C for 60 days or freshly prepared iCo-010 formulation at doses of 5, 10 and 20 mg/kg once daily for five consecutive days. Single intravenous 5 mg/kg dose of AmBisome® was used as a positive control group. Seven days following the last dose, the kidney, liver, spleen, lung, heart and brain were removed and the number of colony forming units (CFUs) was determined as a measure of tissue fungal load. In addition, the concentration of AmB within each tissue was determined using high performance liquid chromatography (HPLC). There were no significant differences in the reduction of CFUs and the concentration of AmB recovered in all organs at all iCo-010 doses tested between the freshly prepared iCo-010 formulation compared to the formulation that was incubated at 43 °C for 60 days. A novel oral AmB formulation, iCo-010, incubated at 43 °C for 60 days to simulate the exposure of the formulation to tropical temperatures remained highly effective against murine systemic candidiasis.

  2. Acidic oral moisturizers with pH below 6.7 may be harmful to teeth depending on formulation: a short report

    Directory of Open Access Journals (Sweden)

    Delgado AJ

    2017-08-01

    Full Text Available Alex J Delgado,1 Vilhelm G Olafsson2,3 1Department of Restorative Dental Sciences, University of Florida, Gainesville, FL, USA; 2Department of Operative Dentistry, Faculty of Odontology, University of Iceland and Private Practice, Reykjavic, Iceland; 3Department of Operative Dentistry, School of Dentistry at the University of North Carolina, Chapel Hill, NC, USA Abstract: Xerostomia affects 30% of the population and manifests as a side effect of medications, systemic diseases, or cancer therapy. Oral moisturizers are prescribed to overcome the ailments of dry mouth and its symptoms. It is imperative that these products help to restore hyposalivation and that they do not present any secondary effect that can harm oral health. It has been shown in the literature that some oral moisturizers may have an erosive potential due to their acidic pH, which is below the critical pH of dentin and enamel. The purpose of this paper was to make clinicians aware of the erosive potential of these products and make recommendations to manufactures for future formulations avoiding acidic pH. For this reason, care should be taken to formulate these products with safe pH values for both enamel and root dentin which, based on specific formulation should be around 6.7 or higher. Keywords: oral moisturizers, pH, erosion, caries, xerostomia, dry mouth

  3. A pilot study on the feasibility of training nurses to formulate multicomponent oral health interventions in a residential aged care facility.

    Science.gov (United States)

    Deutsch, Alan; Siegel, Emma; Cations, Monica; Wright, Clive; Naganathan, Vasi; Brodaty, Henry

    2017-08-23

    This 10 weeks feasibility study investigated whether residential care nurses with 12 hours advanced oral health training in assessments and saliva testing could formulate, implement and monitor individualised oral care plans of early dementia residents. Four trained lead advocate nurses using SXI-D, OHIP14, oral health assessment tool (OHAT) assessments and a modified saliva test formulated nurse scheduled comprehensive oral care plans (NSCOCPs) by selecting and scheduling preventive products and procedures multiple times throughout the day to alkalise the mouth of 8 residents as an adjunct to assisted brushing and high-fluoride toothpaste. Nurse assessments, saliva tests and care plans were validated against oral health therapist (OHT) findings. Care plan agreement between Nurse and OHT intervention selection and scheduling was high (75%-88%). Untrained nurse compliance was very high, 86%-99% for the 4930 scheduled interventions. Untrained nurses delivered multiple scheduled interventions by following NSCOCPs despite initially not understanding the reason for each of 9 interventions categories. NSCOCPs could track and monitor whether a recommended intervention had been completed by general nursing staff over 3 nursing shifts. The role of nurses may have to be expanded beyond traditional roles to meet the growth and changes in oral health needs in residential facilities. Intensive training of a few lead advocate nurses to assess risk and formulate individualised NSCOCPs provides a method to transfer knowledge to untrained staff and deliver multicomponent preventive interventions soon after entry into residential care where timely visits by dental professionals to examine residents and prescribe preventive interventions are infrequent or unlikely. © 2017 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.

  4. Development of long-acting bioadhesive vaginal gels of oxybutynin: formulation, in vitro and in vivo evaluations.

    Science.gov (United States)

    Tuğcu-Demiröz, Fatmanur; Acartürk, Füsun; Erdoğan, Deniz

    2013-11-30

    Overactive bladder (OAB) and vaginal dryness are common problems after menopause. Oxybutynin (OXY) is an antimuscarinic agent that has been available for more than 30 years in the treatment of OAB patients. The aim of the work reported in this paper was to develop long acting mucoadhesive gel formulations of OXY and to investigate their effects on blood levels compared to those of oral OXY immediate release tablets, in rabbits. Mucoadhesive gels were prepared with chitosan, hydroxypropyl methylcellulose (HPMC K100M) and Poloxamer 407 (Pluronic F 127). The physicopharmaceutical properties of gels were evaluated. The gel formulation which was prepared with HPMC K100M, exhibited the highest viscosity, the greatest adhesiveness, cohesiveness and mucoadhesion values. The formulation which was prepared from HPMC K100M showed suitable permeation characteristics across the vaginal mucosa. Comparative bioavailability studies were carried out on rabbits with vaginal HPMC gel, vaginal chitosan gel, vaginal OXY solution and commercially available oral Üropan tablets. It was concluded that the highest AUC and relative bioavailability values were obtained for the bioadhesive vaginal gel formulation prepared with HPMC K100M. Therefore, the mucoadhesive vaginal gels of OXY can be a promising and innovative alternative therapeutic system for the treatment of OAB. It can be safely used in cases of overactive bladder and as well as vaginal dryness after menopause.

  5. Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

    Science.gov (United States)

    Olivares-Morales, Andrés; Ghosh, Avijit; Aarons, Leon; Rostami-Hodjegan, Amin

    2016-11-01

    A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

  6. Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women.

    Science.gov (United States)

    Teo, S K; Scheffler, M R; Kook, K A; Tracewell, W G; Colburn, W A; Stirling, D I; Thomas, S D

    2000-01-01

    The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.

  7. Differential in vitro effects of intravenous versus oral formulations of silibinin on the HCV life cycle and inflammation.

    Directory of Open Access Journals (Sweden)

    Jessica Wagoner

    Full Text Available Silymarin prevents liver disease in many experimental rodent models, and is the most popular botanical medicine consumed by patients with hepatitis C. Silibinin is a major component of silymarin, consisting of the flavonolignans silybin A and silybin B, which are insoluble in aqueous solution. A chemically modified and soluble version of silibinin, SIL, has been shown to potently reduce hepatitis C virus (HCV RNA levels in vivo when administered intravenously. Silymarin and silibinin inhibit HCV infection in cell culture by targeting multiple steps in the virus lifecycle. We tested the hepatoprotective profiles of SIL and silibinin in assays that measure antiviral and anti-inflammatory functions. Both mixtures inhibited fusion of HCV pseudoparticles (HCVpp with fluorescent liposomes in a dose-dependent fashion. SIL inhibited 5 clinical genotype 1b isolates of NS5B RNA dependent RNA polymerase (RdRp activity better than silibinin, with IC50 values of 40-85 µM. The enhanced activity of SIL may have been in part due to inhibition of NS5B binding to RNA templates. However, inhibition of the RdRps by both mixtures plateaued at 43-73%, suggesting that the products are poor overall inhibitors of RdRp. Silibinin did not inhibit HCV replication in subgenomic genotype 1b or 2a replicon cell lines, but it did inhibit JFH-1 infection. In contrast, SIL inhibited 1b but not 2a subgenomic replicons and also inhibited JFH-1 infection. Both mixtures inhibited production of progeny virus particles. Silibinin but not SIL inhibited NF-κB- and IFN-B-dependent transcription in Huh7 cells. However, both mixtures inhibited T cell proliferation to similar degrees. These data underscore the differences and similarities between the intravenous and oral formulations of silibinin, which could influence the clinical effects of this mixture on patients with chronic liver diseases.

  8. Novel formulation strategies for enhancing oral delivery of methoxyflavones in Kaempferia parviflora by SMEDDS or complexation with 2-hydroxypropyl-β-cyclodextrin.

    Science.gov (United States)

    Mekjaruskul, Catheleeya; Yang, Yu-Tsai; Leed, Marina G D; Sadgrove, Matthew P; Jay, Michael; Sripanidkulchai, Bungorn

    2013-03-10

    The Kaempferia parviflora (KP) plant contains several methoxyflavones including 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF). Ethanolic extracts of KP have shown various pharmacological effects and have been used as an aphrodisiac, a antimicrobial agent and for the treatment of inflammation, and peptic ulcers. Given its poor water solubility and low oral bioavailability (1-4%), there are limitations to the utilization of KP. Accordingly, self-microemulsifying drug delivery system (SMEDDS) and cyclodextrin (CD) complex formulations were developed to improve the oral absorption of methoxyflavones. Polyoxyethylene castor oil (53.3%), propylene glycol (26.7%), and triglyceride of coconut oil (20%) were combined to form KP-SMEDDS. A complex of 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) and KP was prepared by lyophilization. The developed formulations were then evaluated for their physicochemical properties, in vitro dissolution tests, permeability through Caco-2 cells, and in vivo oral absorption in rats by using PMF, TMF, and DMF as the markers for quantitation. The results showed that KP-SMEDDS and KP-2-HP-β-CD complex improved the dissolution rate of methoxyflavones in both 0.1N HCl and 0.2M PBS pH 6.8 compared to KP dissolved in a solution of propylene glycol, PEG 400, ethanol, and water. KP-SMEDDS and KP-2-HP-β-CD formulations showed about 10- and 3.5-fold greater Papp values of methoxyflavones in Caco-2 cells. The oral bioavailability values of KP-SMEDDS formulations were higher than those of KP (25.38-, 42.00-, and 26.01-fold for PMF, TMF, and DMF, respectively). For the KP-2-HP-β-CD complex, oral bioavailability values were 21.63-, 34.20-, and 22.90-fold greater than those of KP, respectively. Therefore, these two novel formulations, KP-SMEDDS and KP-2-HP-β-CD, were successfully developed to improve the dissolution rate, drug permeability through Caco-2 cells and oral bioavailability of

  9. Preparation of fenofibrate solid dispersion using electrospray deposition and improvement in oral absorption by instantaneous post-heating of the formulation.

    Science.gov (United States)

    Kawakami, Kohsaku; Zhang, Shaoling; Chauhan, Rohit Singh; Ishizuka, Narimoto; Yamamoto, Marina; Masaoka, Yoshie; Kataoka, Makoto; Yamashita, Shinji; Sakuma, Shinji

    2013-06-25

    A coaxial electrospray technique was applied to a poorly soluble drug, fenofibrate (FEN), to increase its bioavailability. A particulate core-shell solid dispersion was designed using poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100) as a shell material and poly(vinyl pyrrolidone) K12-17 as a dispersant for FEN in the core phase. Although 58% of FEN remained in the crystalline state in the electrosprayed formulation, the dissolution behavior was significantly improved due to decrease in particle size, decrease in crystallinity, and increase in dispersion efficiency. The formulation was subjected to post-heating at 100 °C for 30 s to transform the remaining crystals into the amorphous state to further improve the dissolution behavior. Oral bioavailability was also on the order of: heated formulation>intact formulation>crystalline FEN. Instantaneous heating significantly improved the performance of the formulation despite its simple procedure, and thus can be a powerful step to be incorporated in the formulation manufacturing process. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir.

    Science.gov (United States)

    Janković, Jovana; Djekic, Ljiljana; Dobričić, Vladimir; Primorac, Marija

    2016-01-30

    The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol(®), polysorbate 20, or Kolliphor(®) RH40), cosurfactant (Plurol(®) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18-31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave≤100nm, PdIdrug release rates of 0.325 mg cm(-2)min(-1) and 0.323 mg cm(-2)min(-1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent.

  11. Probabilistic markov model estimating cost effectiveness of methylphenidate osmotic-release oral system versus immediate-release methylphenidate in children and adolescents: Which information is needed?

    NARCIS (Netherlands)

    S.J. Schawo (Saskia); A. van der Kolk (Annemarie); C.A.M. Bouwmans-Frijters (Clazien); L. Annemans (Lieven); M.J. Postma (Maarten); J.K. Buitelaar (Jan); M. van Agthoven (Michel); L. van Hakkaart-van Roijen (Leona)

    2015-01-01

    textabstractBackground: Incidence of attention deficit hyperactivity disorder (ADHD) in children and adolescents has been increasing. The disorder results in high societal costs. Policymakers increasingly use health economic evaluations to inform decisions on competing treatments of ADHD. Yet,

  12. Preparation and characterization of solid oral dosage forms containing soy isoflavones

    Directory of Open Access Journals (Sweden)

    Stela R. de Oliveira

    2013-02-01

    Full Text Available Soy isoflavones have been extensively used for menopausal symptoms and prevention of hormone-related cancer, osteoporosis and cardiovascular diseases. Commercially available forms of isoflavones include supplements, capsules and tablets. However, the non-standardization of soy isoflavones extracts and different dissolution profiles of these solid dosage forms highlight the need of additional studies on the development of well characterized pharmaceutical dosage forms of isoflavones. In this work, immediate release oral tablets of soy isoflavones were obtained and evaluated. Genistein and daidzein, were the main constituents of the dried soy extract. Preparation of the tables was accomplished in a rotary tableting machine following either a dry mixture for direct compression or wet granulation with different excipients. Powder, granules and tablets were evaluated for several parameters, including flow properties, Carr and Hausner indexes, hardness, friability, disintegration time and drug release profile. Also, a fast and validated HPLC analytical method for both genistein and daidzein was developed. Formulations containing sodium croscarmellose and sodium dodecyl sulfate resulted in better flowability as indicated by the flow rate and angle of repose, faster disintegration time and immediate release dissolution profile.

  13. Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach.

    Science.gov (United States)

    Fei, Yang; Kostewicz, Edmund S; Sheu, Ming-Thau; Dressman, Jennifer B

    2013-11-01

    Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C(max) and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption

  14. Enhanced oral bioavailability of a sterol-loaded microemulsion formulation of Flammulina velutipes, a potential antitumor drug

    Directory of Open Access Journals (Sweden)

    Yi C

    2012-09-01

    Full Text Available Chengxue Yi,* Hui Zhong,* Shanshan Tong,* Xia Cao,* Caleb K Firempong, Hongfei Liu, Min Fu, Yan Yang, Yingshu Feng, Huiyun Zhang, Ximing Xu, Jiangnan Yu Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, People's Republic of China*These authors contributed equally to this workPurpose: To investigate the growth inhibition activity of Flammulina velutipes sterol (FVS against certain human cancer cell lines (gastric SGC and colon LoVo and to evaluate the optimum microemulsion prescription, as well as the pharmacokinetics of encapsulated FVS.Methods: Molecules present in the FVS isolate were identified by gas chromatography/mass spectrometry analysis. The cell viability of FVS was assessed with methyl thiazolyl tetrazolium (MTT bioassay. Based on the solubility study, phase diagram and stability tests, the optimum prescription of F. velutipes sterol microemulsions (FVSMs were determined, followed by FVSMs characterization, and its in vivo pharmacokinetic study in rats.Results: The chemical composition of FVS was mainly ergosterol (54.8% and 22,23-dihydroergosterol (27.9%. After 72 hours of treatment, both the FVS (half-maximal inhibitory concentration [IC50] = 11.99 µg • mL-1 and the standard anticancer drug, 5-fluorouracil (IC50 = 0.88 µg • mL-1 exhibited strong in vitro antiproliferative activity against SGC cells, with IC50 > 30.0 µg • mL-1; but the FVS performed poorly against LoVo cells (IC50 > 40.0 µg • mL-1. The optimal FVSMs prescription consisted of 3.0% medium chain triglycerides, 5.0% ethanol, 21.0% Cremophor EL and 71.0% water (w/w with associated solubility of FVS being 0.680 mg • mL-1 as compared to free FVS (0.67 µg • mL-1. The relative oral bioavailability (area-under-the-curve values of ergosterol and 22,23-dihydroergosterol showed a 2.56-fold and 4.50-fold increase, respectively of FVSMs (mean diameter ~ 22.9 nm as against free

  15. Cytotoxic effects of oxytetracycline residues in the bones of broiler chickens following therapeutic oral administration of a water formulation.

    Science.gov (United States)

    Odore, R; De Marco, M; Gasco, L; Rotolo, L; Meucci, V; Palatucci, A T; Rubino, V; Ruggiero, G; Canello, S; Guidetti, G; Centenaro, S; Quarantelli, A; Terrazzano, G; Schiavone, A

    2015-08-01

    Tetracyclines, which represent one of the most commonly used antibiotics for poultry, are known to be deposited in bones, where they can remain, despite the observation of appropriate withdrawal times. The aim of the study was to determine the concentration of oxytretracycline (OTC) residues in the bone and muscle of chickens, following the oral administration of a commercially available liquid formulation, and to test their cytotoxic effects on an in vitro cell culture model. Seventy-two 1-day-old broiler chickens were randomly allotted into 2 groups (control and treated animals). OTC (40 mg/kg BW) was administered via drinking water during the 1 to 5 and 20 to 25 days of life periods. At the end of the trial, the birds were slaughtered and the OTC residues in the target tissues were measured by means of liquid chromatography (LC) - tandem mass spectrometry (MS/MS). Cytotoxicity was assessed by evaluating the pro-apoptotic effect of the bone residues on the K562 erythroleukemic line and on the peripheral blood mononuclear cells (PBMC). In all the animals, the OTC residues in the muscle were far below the established MRL of 100 μg/kg. The OTC levels in the bones of the treated animals were instead found in the parts per million (ppm) range. Cell cytotoxicity was assessed by evaluating the pro-apoptotic effect of OTC bone residues on the haematopoietic cell system. This in vitro system has revealed a significant pro-apoptotic effect on both the K562 cell line and PBMC cultures. This result suggests potential human and animal health risks due to the entry of tetracycline residues contained in the bones of treated livestock into the food-chain. This could be of concern, particularly for canine and feline diets, as meat, bone meal, and poultry by-products represent some of the main ingredients of pet foods, especially in the case of dry pet food. Further studies are needed to define the underlying mechanisms of cytotoxicity and to evaluate the in vivo toxicological

  16. Oral controlled release formulation for highly water-soluble drugs: drug--sodium alginate--xanthan gum--zinc acetate matrix.

    Science.gov (United States)

    Zeng, W M

    2004-05-01

    An oral controlled release formulation matrix for highly water-soluble drugs was designed and developed to achieve a 24-hour release profile. Using ranitidine HCl as a model drug, sodium alginate formulation matrices containing xanthan gum or zinc acetate or both were investigated. The caplets for these formulations were prepared by direct compression and the in vitro release tests were carried out in simulated intestinal fluid (SIF, pH 7.5) and simulated gastric fluid (SGF, pH 1.2). The release of the drug in the sodium alginate formulation containing only xanthan gum completed within 12 hours in the SIF, while the drug release in the sodium alginate formulation containing only zinc acetate finished almost within 2 hours in the same medium. Only the sodium alginate formulation containing both xanthan gum and zinc acetate achieved a 24-hour release profile, either in the SIF or in the pH change medium. In the latter case, the caplet released in the SGF for 2 hours was immediately transferred into the SIF to continue the release test. The results showed that the presence of both xanthan gum and zinc acetate in sodium alginate matrix played a key role in controlling the drug release for 24 hours. The helical structure and high viscosity of xanthan gum might prevent zinc ions from diffusing out of the ranitidine HCl--sodium alginate--xanthan gum--zinc acetate matrix so that zinc ions could react with sodium alginate to form zinc alginate precipitate with a cross-linking structure. The cross-linking structure might control a highly water-soluble drug to release for 24 hours. Evaluation of the release data showed the release mechanism for the novel formulation might be attributed to the diffusion of the drug.

  17. The efficacy and plasma profiles of abamectin plus levamisole combination anthelmintics administered as oral and pour-on formulations to cattle.

    Science.gov (United States)

    Leathwick, D M; Miller, C M; Sauermann, C W; Candy, P M; Ganesh, S; Fraser, K; Waghorn, T S

    2016-08-30

    In phase I, faecal egg count reduction tests (FECRT) were conducted on six commercial cattle farms to compare the performance of two pour-on and one oral combination anthelmintic. Groups of 12-15 calves were sampled for faecal nematode egg count (FEC) before treatment with either abamectin oral, levamisole oral, an abamectin+levamisole oral combination or one of two abamectin+levamisole combination pour-ons. Samples were collected again 14days after treatment to calculate the percentage reduction in FEC. The proportions of infective stage larvae (L3) in faecal cultures were used to apportion egg counts to, and calculate efficacy against, the main parasite genera. Abamectin oral was effective against Ostertagia except on one farm where resistance was indicated, but had reduced efficacy against Cooperia on four farms. Levamisole oral was effective against Cooperia on all farms, but had variable efficacy against Ostertagia. The abamectin+levamisole oral was effective against both species on all farms. The abamectin+levamisole pour-ons were effective on some farms but not on others. In particular, pour-on 2 failed to achieve 95% efficacy in 45% of evaluations, 4/6 against Cooperia and 1/5 against Ostertagia. On some farms the combination pour-ons were less effective than their constituent actives administered alone as orals. In phase II, 8 groups of 6 calves, grazing parasite-free pasture, were infected with putatively ML-resistant isolates of Cooperia oncophora and Ostertagia ostertagi. Once infections were patent groups were treated with oral or pour-on formulations of abamectin alone, levamisole alone, abamectin+levamisole (two pour-ons) or remained untreated. Blood samples were collected for analysis and after 8days all calves were euthanized and abomasa and intestines recovered for worm counts. All treatments were effective against O. ostertagi and all treatments containing levamisole were effective against C. oncophora. Animals treated with the oral combination

  18. CONTEMPORARY APPROACHES FOR BI-LAYER TECHNOLOGY OF DRUGS THROUGH ORAL ROUTE: AN OVERVIEW

    Directory of Open Access Journals (Sweden)

    Rishikesh*, M. A. Bhuiyan, S. M. Ashraful Islam, I. Dewan, Md. A. Islam and Md. S.- Ul H. Miah

    2013-04-01

    Full Text Available ABSTRACT: Bi-layer tablet technology for bimodal release of drug and co-administration of drugs via oral route has been engaged a significant place in the field of drug delivery technology. At present, several pharmaceutical companies are developing bilayer tablet for co-administration of drugs to improve the therapeutic efficacy as well as to reduce the chances of drug-drug interaction. This review indicates the different aspects of drug release mechanism, different strategies of drug release, various techniques for bilayer tablet, and the influence of different process and formulation parameters must be considered during the development of bilayer tablet. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose.

  19. Influence of surfactants in self-microemulsifying formulations on enhancing oral bioavailability of oxyresveratrol: Studies in Caco-2 cells and in vivo.

    Science.gov (United States)

    Sangsen, Yaowaporn; Wiwattanawongsa, Kamonthip; Likhitwitayawuid, Kittisak; Sritularak, Boonchoo; Graidist, Potchanapond; Wiwattanapatapee, Ruedeekorn

    2016-02-10

    Self-microemulsifying drug delivery systems (SMEDDS) containing two types (Tween80 and Labrasol) and two levels (low; 5% and high; 15%) of co-surfactants were formulated to evaluate the impact of surfactant phase on physical properties and oral absorption of oxyresveratrol (OXY). All formulations showed a very rapid release in the simulated gastric fluid (SGF) pH 1.2. After dilution with different media, the microemulsion droplet sizes of the Tween80-based (∼26 to 36 nm) were smaller than that of the Labrasol-based systems (∼34 to 45 nm). Both systems with high levels of surfactant increased the Caco-2 cells permeability of OXY compared to those with low levels of surfactant (1.4-1.7 folds) and the unformulated OXY (1.9-2.0 folds). It was of interest, that there was a reduction (4.4-5.3 folds) in the efflux transport of OXY from both systems compared to the unformulated OXY. The results were in good agreement with the in vivo absorption studies of such OXY-formulations in rats. Significantly greater values of Cmax and AUC(0-10h) (psurfactant in the SMEDDS to enhance oral drug bioavailability.

  20. Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing.

    Science.gov (United States)

    Elander, Mikael; Boll, Jette B; Hojman, Anne S; Rasmussen, Allan D

    2016-11-01

    The selection of a vehicle for oral formulations of compounds to be used in non-clinical safety studies is a challenge for poorly soluble compounds. Typically a compromise between solubility and tolerability has to be reached. Vehicle tolerability data are not readily available for a number of vehicles, and a series of oral tolerability studies were, therefore, conducted with Gelucire and Gelucire:PEG400 formulations in rats, dogs and minipigs in order to determine tolerable daily dose volumes in these species. Gelucire and Gelucire:PEG400 formulations were assessed in studies for up to 5 days in minipigs, 7 days in rats and up to 39 weeks in dogs. Gastrointestinal side effects in terms of soft and/or liquid faeces were noted in all species, but the sensitivity to these effects differed between species with the dog being the most sensitive. It was concluded that Gelucire:PEG400 (90:10) was tolerated in Beagle dogs when administered at 1 ml kg(-1) once daily for 39 weeks, and 100% Gelucire was tolerated in the rat and the minipig when administered once daily at 5 ml kg(-1) for 5 days. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Concentrated protein body product derived from rice endosperm as an oral tolerogen for allergen-specific immunotherapy--a new mucosal vaccine formulation against Japanese cedar pollen allergy.

    Directory of Open Access Journals (Sweden)

    Yuhya Wakasa

    Full Text Available The endoplasmic reticulum-derived type-I protein body (PB-I from rice endosperm cells is an ideal candidate formulation for the oral delivery of bioencapsulated peptides as tolerogens for allergen-specific immunotherapy. In the present study, PBs containing the deconstructed Japanese cedar pollen allergens Cryptomeria japonica 1 (Cry j 1 and Cry j 2 were concentrated by treatment with thermostable α-amylase at 90°C to remove the starch from milled rice powder, which resulted in a 12.5-fold reduction of dry weight compared to the starting material. The modified Cry j 1 and Cry j 2 antigens in this concentrated PB product were more resistant to enzymatic digestion than those in the milled seed powder despite the absence of intact cell wall and starch, and remained stable for at least 10 months at room temperature without detectable loss or degradation. The high resistance of these allergens could be attributed to changes in protein physicochemical properties induced by the high temperature concentration process, as suggested by the decreased solubility of the antigens and seed proteins in PBs in step-wise-extraction experiments. Confocal microscopy showed that the morphology of antigen-containing PB-Is was preserved in the concentrated PB product. The concentrated PB product induced specific immune tolerance against Cry j 1 and Cry j 2 in mice when orally administered, supporting its potential use as a novel oral tolerogen formulation.

  2. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states.

    Science.gov (United States)

    Abuhelwa, Ahmad Y; Foster, David J R; Mudge, Stuart; Hayes, David; Upton, Richard N

    2015-09-01

    Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.

  3. 吡罗昔康口崩片处方和工艺研究%Formulation and Preparation Technology of Piroxicam Orally Disintegrating Tablets

    Institute of Scientific and Technical Information of China (English)

    徐知; 彭红; 陈文杰

    2011-01-01

    制备了吡罗昔康口腔崩解片,并评价其质量.采用直接粉末压片法制备口腔崩片解,以片剂可压性、崩解时限、口感为指标.在先进行预试验的基础上,进行了最佳处方的筛选,并对其溶出度进行检测.结果采用最佳处方及制备工艺的吡罗昔康口崩片口感良好,与市售普通片比较,口腔崩解片具有明显速释效果.说明吡罗昔康口腔崩处方设计合理、制备工艺可行、产品质量可控.%To make Piroxicam orally disintegrating tablets and investigate its quality, the tablets were pre-pared using the direct compression method. The formulation was optimized with compressibility, disintegration time and taste as reference parameters, earlier on the basis of pre-test, the best prescription was screened and their dis-solutionwere examined. It is resulted the orally disintegrating tablets with the best formulation and preparation taste good, the orally disintegrating tablets had better fast release effect than marketed tablets. It is conclused that formu-lation design is reasonable, the process of preparation is feasible and the quality can be controlled.

  4. Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-I: Orally disintegrating tablets

    OpenAIRE

    Mohapatra Ashutosh; Parikh Rajesh; Gohel Mukesh

    2008-01-01

    Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. In this study, orally disintegrating tablets were prepared using direct compression and wet granulation method. First, the ta...

  5. Field Trial of Attenuated Salmonella Typhi Live Oral Vaccine TY21A in Liquid and Enteric-Coated Formulations and Epidemiological Survey for Incidence of Diarrhea due to Shigella Species

    Science.gov (United States)

    1989-03-01

    AD-A248 309 till AD FIELD TRIAL OF ATTENUATED SALMONELLA TYPHI LIVE ORAL VACCINE TY21A IN LIQUID AND ENTERIC-COATED FORMULATIONS AND EPIDEMIOLOGICAL...024 11- TITLE WL-* .S-wrYCIAo40 (U) Field Trial of Attenuated Salmonella typhi Live Oral Vaccine Ty2la in Liquid and Enteric-Coated Formulations and...Clements ML, Lanata C, Rooney J, Germanier R, Chilean Typhoid Cormmittee. The efficacy of attenuated Salmonella typhi oral vaccine strain Ty2la evaluated in

  6. Efficacy of oral, injectable and pour-on formulations of moxidectin against gastrointestinal nematodes in cattle in New Zealand.

    Science.gov (United States)

    Leathwick, D M; Miller, C M

    2013-01-31

    The efficacy of moxidectin administered by different routes, against naturally acquired infections of gastrointestinal nematode parasites of cattle, was compared using faecal egg count reduction tests on 14 commercial farms throughout New Zealand. On each farm, groups of 15 calves were sampled for faecal nematode egg count and then treated with ivermectin administered orally, or with moxidectin administered either by the oral, subcutaneous injection or topical (pour-on) route. Samples were again collected 14 days after treatment and efficacy was calculated as the percentage reduction in-group mean egg count between the pre- and post-treatment samples. In addition, efficacy was calculated for individual animals, in order to compare the variability of the different treatments. On four farms untreated control groups were run and five animals from each of the control and all of the moxidectin-treated groups were bled over time to estimate plasma-moxidectin concentrations. Averaged across all tests, the reduction in faecal egg count was significantly greater after treatment with moxidectin oral (91.1%) than following treatment with moxidectin injection (55.5%) or with moxidectin pour-on (51.3%). Low efficacies were invariably against Cooperia oncophora. The oral treatments were significantly less variable in efficacy than the injection and pour-on treatments. Moxidectin concentrations in plasma were highest following subcutaneous injection and lowest following pour-on administration. Plasma levels following oral administration were intermediate, being significantly lower than post-injection and significantly higher than post-pour-on. There was no evidence of transfer of moxidectin to untreated animals through licking. Based on these results, along with those of other studies, it is proposed that oral administration of macrocyclic lactone anthelmintics results in higher concentrations of active reaching the target worms in the gastrointestinal tract than following either

  7. [Comparison of the bioavailability of beta-aescin after single oral administration of two different drug formulations containing an extract of horse-chestnut seeds].

    Science.gov (United States)

    Schrader, E; Schwankl, W; Sieder, C; Christoffel, V

    1995-09-01

    The relative oral bioavailability of beta-escine (CAS 11072-93-8) from a sugar-coated tablet formulation was compared to a reference preparation available in capsule form in 18 healthy, male volunteers over a 48 h period. The study design was randomized, single-blind and cross-over. Both the test and the reference preparation contained 50 mg standardized horse chestnut seed extract; beta-escine was taken as the reference substance. By means of a newly developed, validated radioimmunosorbent assay (RIA), beta-escine in plasma was determined (blind samples) after oral intake of a single dose of each drug formulation. The confidence limits calculated for the AUC, Cmax and Tmax of the test preparation exceed the upper limit of the specified equivalence range of 80%--125%, but do never fall below the lower limit. Therefore, bioin-equivalence cannot be rejected statistically. All the bioavailability data for the test preparation--measured with the newly developed RIA--exceed the corresponding values for the reference preparation. As the rate of absorption of aesculetinic triterpene glycosides is low, the higher bioavailability of the test preparation is desirable from a therapeutical point of view. Since the reference preparation is classified as being clinically effective, the test preparation must also be estimated as being clinically effective. Adverse drug effects were not observed with either the test preparation or the reference preparation.

  8. Age-appropriate and acceptable paediatric dosage forms: Insights into end-user perceptions, preferences and practices from the Children's Acceptability of Oral Formulations (CALF) Study.

    Science.gov (United States)

    Ranmal, Sejal R; Cram, Anne; Tuleu, Catherine

    2016-11-30

    A lack of evidence to guide the design of age-appropriate and acceptable dosage forms has been a longstanding knowledge gap in paediatric formulation development. The Children's Acceptability of Oral Formulations (CALF) study captured end-user perceptions and practices with a focus on solid oral dosage forms, namely tablets, capsules, chewables, orodispersibles, multiparticulates (administered with food) and mini-tablets (administered directly into the mouth). A rigorous development and testing phase produced age-adapted questionnaires as measurement tools with strong evidence of validity and reliability. Overall, 590 school children and adolescents, and 428 adult caregivers were surveyed across hospitals and various community settings. Attitudes towards dosage forms primarily differed based on age and prior use. Positive attitudes to tablets and capsules increased with age until around 14 years. Preference was seen for chewable and orodispersible preparations across ages, while multiparticulates were seemingly less favourable. Overall, 59.6% of school children reported willingness to take 10mm diameter tablets, although only 32.1% of caregivers perceived this size to be suitable. While not to be taken as prescriptive guidance, the results of this study provide some evidence towards rational dosage form design, as well as methodological approaches to help design tools for further evaluation of acceptability within paediatric studies.

  9. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection.

    Science.gov (United States)

    Ribichini, Danilo; Fiorini, Giulia; Repaci, Andrea; Castelli, Valentina; Gatta, Luigi; Vaira, Dino; Pasquali, Renato

    2016-11-15

    To compare the clinical efficacy of tablet and oral liquid L-thyroxine (LT4) formulation in naïve hypothyroid subjects with Helicobacter pylori infection. Forty-seven adult naïve hypothyroid subjects with dyspeptic symptoms were investigated with upper endoscopy and divided into: 28 patients with Helicobacter pylori infection (Group A); 15 patients without gastric alterations (group B); 4 patients with autoimmune gastritis were excluded from the study. Subjects were randomly treated with a same dose of LT4 tablet (TAB) or oral liquid formulation (SOL), for 9 months on group A and 6 months on group B. Helicobacter pylori infection was eradicated after 3 months of LT4 treatment. On group A, after 3 months (before Helicobacter pylori eradication), subjects treated with SOL showed a greater thyroid-stimulating hormone reduction (ΔTSH3-0: TAB = -4.1 ± 4.6 mU/L; SOL = -7.7 ± 2.5 mU/L; p = 0.029) and a greater homogeneity in the thyroid-stimulating hormone values (TSH3mo: TAB = 5.7 ± 4.9 mU/L; SOL = 4.1 ± 2.0 mU/L; p = 0.025), compared to LT4 tablet. At 9 months (after 6 months of Helicobacter pylori eradication) mean thyroid-stimulating hormone values were lower in subjects treated with LT4 tablet (TSH9mo: TAB = 1.8 ± 1.2 mU/L; SOL = 3.2 ± 1.7 mU/L; p = 0.006). On group B no difference were observed, at each time point, in the mean thyroid-stimulating hormone values and thyroid-stimulating hormone variations between two LT4 formulations. LT4 liquid formulation may produce a better clinical response compared to the tablet formulation in hypothyroid subjects with Helicobacter pylori infection.

  10. Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability

    Directory of Open Access Journals (Sweden)

    Guo S

    2016-04-01

    Full Text Available Shujie Guo,1 Kevin Pham,2 Diana Li,2 Scott R Penzak,3 Xiaowei Dong2 1State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pharmaceutical Sciences, 3Department of Pharmacotherapy, University of North Texas Health Science Center, Fort Worth, TX, USA Purpose: The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability. Materials and methods: In one method, we prepared ritonavir (RTV nanoparticles (NPs by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs. We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules. Results: RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability

  11. Effect of food on the pharmacokinetics of canagliflozin/metformin (150/1,000 mg) immediate-release fixed-dose combination tablet in healthy participants.

    Science.gov (United States)

    Murphy, Joseph; Wang, Shean-Sheng; Stieltjes, Hans; Wajs, Ewa; Devineni, Damayanthi

    2015-03-01

    To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. A randomized, open-label, singlecenter, single-dose, 2-period, 2-sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10-14 day washout between treatments PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUC∞, and Cmax were within the bioequivalence limits of 80-125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin.

  12. Switch from Immediate-release Pramipexole to Extended-release Pramipexole: The Safety and Efficacy Characteristics of Sixty-eight Patients

    Directory of Open Access Journals (Sweden)

    Müge Kuzu

    2016-09-01

    Full Text Available Objective: To evaluate the safety and efficacy of switching from immediate-release pramipexole (pex to extended-release pramipexole (pex-ER. Materials and Methods: Pex-ER became available in Turkey about a year ago, since then we documented satisfactory information on patients (26 women; 38% who were switched from pex to pex-ER. We recorded pre- and post-switch pex and levodopa, equivalent doses of other anti-parkinsonian medication, and analyzed the frequency and nature of reported adverse effects. Results: The mean age of the patients was 63.3 years (range, 44-88 years, and the mean disease duration was 7.1 years (range, 1-27 years. The other drugs were levodopa (57 patients, 82.6%, entacapone (24 patients, 34.58%, rasagiline (20 patients, 29%, amantadine (18 patients, 26.1%, and apomorphine (six patients, 8.7%. Switch from pex to pex-ER was uneventful in 62 (91.2% patients. Adverse events were reported in six (8.8% patients: ankle swelling (two patients, nausea (one patient, dyskinesia (one patient, hypersexuality (one patient, and psychosis (one patient. Problems resolved with further medication change in two patients. Four patients preferred to return to pex. Conclusion: The great majority of patients (91.2% switched from three times daily pex to once daily pex-ER uneventfully. A slight increase in pex daily dose, which was tailored according to patients’ symptomatic needs, resulted in an increase in post-switch levodopa equivalent doses. Our experience is compatible with previously reported studies.

  13. A randomized, crossover pharmacodynamic study of immediate-release omeprazole/sodium bicarbonate and delayed-release lansoprazole in healthy adult volunteers.

    Science.gov (United States)

    Pratha, Vijayalakshmi S; McGraw, Thomas; Tobin, William

    2016-06-01

    Proton pump inhibitors (PPIs) effectively block gastric acid secretion and are the treatment of choice for heartburn. PPIs differ, however, in onset of action and bioavailability. In this single-center, open-label, three-way crossover study, onset of action of immediate-release omeprazole 20 mg/sodium bicarbonate 1100 mg (IR-OME) and delayed-release (DR) lansoprazole 15 mg was evaluated in 63 healthy fasting adults. Subjects were randomized to once daily IR-OME, or DR-lansoprazole, or no treatment for 7 days. The primary efficacy endpoint was the earliest time where a statistically significant difference was observed between IR-OME and DR-lansoprazole in median intragastric pH scores for three consecutive 5-min intervals on day 7. Secondary endpoints compared effects of active treatments on days 1 and 7 (e.g., time to sustained inhibition, percentage of time with pH >4). A significant difference in median intragastric pH favoring IR-OME was observed on day 7 starting at the 10- to 15-min interval postdosing (P = 0.024) and sustaining through the 115- to 120-min interval (P = 0.017). On day 1, IR-OME achieved sustained inhibition of intragastric acidity significantly faster than DR-lansoprazole. IR-OME maintained pH >4 significantly longer than DR-lansoprazole over a 24-h period (P = 0.007) on day 7. Overall, results of this study demonstrate IR-OME is safe and well tolerated and that treatment with IR-OME results in significantly faster onset of action and better gastric acid suppression at steady state than DR-lansoprazole.

  14. Efficacy of a moxidectin/triclabendazole oral formulation against mixed infections of Fasciola hepatica and gastrointestinal nematodes in sheep.

    Science.gov (United States)

    Martínez-Valladares, M; Cordero-Pérez, C; Castañón-Ordóñez, L; Famularo, M R; Fernández-Pato, N; Rojo-Vázquez, F A

    2010-11-24

    We have evaluated the efficacy in sheep of a combination drench formulation at the recommended dose rate of 0.2 mg moxidectin/kg bodyweight and 10 mg triclabendazole/kg bodyweight against an experimental infection with Fasciola hepatica and a natural infection with gastrointestinal nematodes. We confirmed that the efficacy of reducing fecal egg output was 98.3% for trichostrongyle eggs and 100% for F. hepatica eggs. Based on adult worm and fluke recovery, the efficacy varied according to the target species. A reduction was found in the number of Teladorsagia circumcincta, Trichostrongylus spp., Nematodirus spp., and Trichuris spp. greater than 95%, but the efficacy for Oesophagostomum spp. varied, with values below 90%. The reduction in F. hepatica was higher than 95% for all stages. The effectiveness of the formulation was also confirmed by an increase in total proteins and albumin following treatment.

  15. Taste Masked Orally Disintegrating Pellets of Antihistaminic and Mucolytic Drug: Formulation, Characterization, and In Vivo Studies in Human

    OpenAIRE

    Taj, Yasmeen; Pai, Roopa S.; V. Kusum Devi; Singh, Gurinder

    2014-01-01

    The main aim of the present study was to evaluate the potential of orally disintegrating pellets (ODPs) as an approach for taste masking of bitter drugs, namely, Ambroxol hydrochloride (A-HCl) and Cetirizine dihydrochloride (C-DHCl). Pellets were prepared by extrusion/spheronization with Eudragit EPO, kyron T-134, Kyron T-314, mannitol, sorbitol, MCC (Avicel PH-101), sucralose, chocolate flavor, and 5% xanthum gum. The prepared pellets were characterized for percentage yield, drug content, pa...

  16. Taste Masked Orally Disintegrating Pellets of Antihistaminic and Mucolytic Drug: Formulation, Characterization, and In Vivo Studies in Human

    OpenAIRE

    Taj, Yasmeen; Pai,Roopa S.; V Kusum Devi; Singh,Gurinder

    2014-01-01

    The main aim of the present study was to evaluate the potential of orally disintegrating pellets (ODPs) as an approach for taste masking of bitter drugs, namely, Ambroxol hydrochloride (A-HCl) and Cetirizine dihydrochloride (C-DHCl). Pellets were prepared by extrusion/spheronization with Eudragit EPO, kyron T-134, Kyron T-314, mannitol, sorbitol, MCC (Avicel PH-101), sucralose, chocolate flavor, and 5% xanthum gum. The prepared pellets were characterized for percentage yield, drug content, pa...

  17. Formulation Development of Mouth Dissolving Film of Etoricoxib for Pain Management

    Directory of Open Access Journals (Sweden)

    K. Senthilkumar

    2015-01-01

    Full Text Available Etoricoxib is a potent, orally active, and highly selective COX-2 inhibitor that exhibits anti-inflammatory, analgesic, and antipyretic activities. The present research was undertaken to develop mouth dissolving films of etoricoxib to have rapid onset of action. Mouth dissolving film (MDF is a better alternate to oral disintegrating tablets due to its novelty, ease of use, and the consequent patient compliance. Solubility enhancement and taste masking of etoricoxib were the two challenges solved by formulating drug-inclusion complex with beta-cyclodextrin (BCD. MDF prepared by solvent casting etoricoxib-BCD complex along with HPMC as film forming polymer was found to possess desirable physicomechanical properties. In vitro release of etoricoxib from MDF in simulated salivary fluid and 0.1 N HCl was more than 95% within 2 minutes. Taste masking and in vivo disintegration were in acceptable range as assessed by human volunteers. Etoricoxib MDF was further characterized by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. The index of analgesia shown by etoricoxib MDF was comparable to that of immediate release tablets (100% activity within 40 minutes in animal studies. Conclusively, the present study documents the development of a commercially viable formula for an MDF of etoricoxib with rapidity in pain management.

  18. Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

    Science.gov (United States)

    Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Magil, Alex B; Owen, David; Clement, John G; Wasan, Kishor M

    2010-12-01

    The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

  19. Efficacy of an oral and tropically stable lipid-based formulation of Amphotericin B (iCo-010) in an experimental mouse model of systemic candidiasis.

    Science.gov (United States)

    Ibrahim, Fady; Sivak, Olena; Wasan, Ellen K; Bartlett, Karen; Wasan, Kishor M

    2013-10-29

    An oral lipid based formulation that exhibits tropical stability (iCo-010) was developed to enhance the absorption of orally administered amphotericin B (AmB). iCo-010 has previously shown high efficacy in an acute model of systemic candidiasis in rats, directing the focus of this study to be its efficacy in a chronic model of systemic candidiasis in mice. Mice were infected with 0.6 to 1×108 CFUs of Candida albicans ATCC 18804 strain by tail vein injection and were left for three days to develop the infection after which time treatment was initiated. The infected animals were assigned to the following treatment groups: no treatment (control) or iCo-010 at 5, 10 and 20 mg/kg administered by oral gavage once daily (QD) for 5 consecutive days. The animals were sacrificed 7 days after the last dose and the concentration of AmB and the fungal burden were assessed within the liver, kidneys, heart, lungs, spleen and brain. Although the infection was relatively low (~ 60-100 CFUs/ 1 ml tissue homogenate) in the liver, lungs and heart, the infection level was very high (70 000 CFUs / 1 ml tissue homogenate) in the kidney tissues for the control group. The highest concentrations of AmB were recovered in the kidneys and the spleen. The fungal burden in the tissues was lowered by 69-96% in the treatment groups when compared to the control group. Oral iCo-010 is an effective treatment of systemic candidiasis in the mouse model.

  20. Dissolution efficiency and bioequivalence study using urine data from healthy volunteers: a comparison between two tablet formulations of cephalexin

    Directory of Open Access Journals (Sweden)

    Cristina Helena dos Reis Serra

    2015-06-01

    Full Text Available The aim of the present study was to assess the bioequivalence of two cephalexin tablet formulations available in the Brazilian market (product A as reference formulation and product B as test formulation. Dissolution efficiency (DE% was calculated for both formulations to evaluate their in vitrobiopharmaceutical features. The oral bioequivalence study was performed in twenty-four healthy volunteers in a crossover design. Single oral dose (tablet containing 500 mg of cephalexin of each product was administered with two weeks of washout period. Urinary concentrations of cephalexin were measured by high-performance liquid chromatography (HPLC method and pharmacokinetics parameters were estimated by urinary excretion data. The bioequivalence was determined by the following parameters: the cumulative amount of cephalexin excreted in the urine, the total amount of cephalexin excreted in the urine and the maximum urinary excretion rate of cephalexin. DE values of immediate-release cephalexin tablets (500 mg were 68.69±4.18% for product A and 71.03±6.63% for product B. Regarding the dissolution test of the two brands (A and B analysed, both were in compliance with the official pharmacopeial specifications, since the dissolution of both formulations was superior to 80% of the amount declared in the label after 45 minutes of test (A=92.09%±1.84; B=92.84%±1.08. The results obtained indicated that the products A and B are pharmaceutical equivalents. Confidence intervals for the pharmacokinetic parameters were in compliance with the international standards, indicating that products A and B can be considered bioequivalents and, therefore, interchangeable.

  1. Formulation development of ambroxol hydrochloride soft gel with application of statistical experimental design and response surface methodology.

    Science.gov (United States)

    Dabhi, Mahesh; Gohel, Mukesh; Parikh, Rajesh; Sheth, Navin; Nagori, Stavan

    2011-01-01

    The purpose of present work was to develop ambroxol hydrochloride soft gel formulation with the application of statistical experimental design and response surface methodology (RSM). A two-factor, three-level (3(2)) full factorial design of experiment with RSM was run to evaluate the main and interaction effect of two independent formulation variables that included the amount of low-acetylated gellan gum and sodium citrate. The dependent variables included viscosity (Y(1)), amount of drug release at 10 min (Y(2)) and 30 min (Y(3)), and gelation time (Y(4)). In order to obtain a formulation having the maximum amount of drug release at 10 min and minimum gelation time, RSM optimization was used. The prepared formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. All the formulations showed a gelation time in the range of 6 to 48 min. The drug content in all the formulations was within limit (99.6 ± 1.56%). The viscosity of all the formulations was found in the range of 1872-12,182 cP. Dissolution studies of the formulations showed drug release in the range of 40.56-72.46% within 10 min and 80.2-100.5% within 30 min. Human evaluation tests revealed that all the gels possessed acceptable characteristics. This study showed that the soft gel formulation GA5, containing 0.3% of gellan gum and 0.4% of sodium citrate, has potential use as an immediate release soft gel for oral drug delivery. The objective of this investigation was to develop a new, immediate-release, soft gel dosage form for ambroxol hydrochloride, an oral expectorant and mucolytic agent. This novel soft gel dosage form needs to be suitable for pediatric and geriatric patients as well as patients with dysphagia. A statistical technique was used for optimization of the gel formulation. The methodology, called a design of experiment with response surface methodology, evaluated several independent formulation variables

  2. Anthelmintic efficacy of an oral formulation of Aurixazol against gastrointestinal nematodes of naturally and experimentally infected sheep.

    Science.gov (United States)

    Sakamoto, Claudio Alessandro M; Lopes, Welber Daniel Zanetti; Buzzulini, Carolina; Cruz, Breno Cayeiro; Felippelli, Gustavo; de Lima, Roberto Cesar Araújo; dos Santos, Thais Rabelo; Santana, Luis Fernando; de Mendonça, Rafael Paranhos; Soares, Vando Edésio; Henrique, Carlos Henrique; da Costa, Alvimar José

    2013-12-06

    As a result of the need to develop new active principles for the control of endoparasites in ruminants, the present in vivo study evaluated a formulation containing 24% Aurixazol (48 mg/kg), a parasiticide molecule based on disophenolate of levamisole. Two experiments were conducted: one evaluating the anthelmintic efficacy of 24% Aurixazol (48 mg/kg) against gastrointestinal nematodes in naturally infected sheep, compared to an association of ivermectin (0.2mg/kg)+albendazole (5.0mg/kg)+levamisole (7.5mg/kg) (IAL), and a second one which evaluated the persistent efficacy of the same formulation against immature stages (L4) and adults of Haemonchus contortus in experimentally infected animals. In experiment I, against H. contortus, the formulation of Aurixazol and the IAL association reached efficacies (arithmetic means) of 99.32% and 96.11%, respectively. For Trichostrongylus colubriformis, the efficacy values were 88.92% and 98.08% for Aurixazol and the IAL association, respectively. Both formulations were totally effective against Oesophagostomum columbianum (100%). The results of the statistical analysis demonstrated that the mean parasitic burden of treated animals was significantly different (P ≤ 0.05) compared to the average number of helminths diagnosed in animals from the control group for H. contortus, T. colubriformis and O. columbianum. Comparing only the treated groups, it was possible to verify that the average number of H. contortus recovered from animals treated with Aurixazol was different (P ≤ 0.05) when compared to the mean amount recovered from sheep treated with the IAL association. When evaluating the prevention of H. contortus infection in experiment II, Aurixazol did not present preventive efficacy. Up until 21 days after treatment the groups treated with Aurixazol contained less adults and L4 of H. contortus (P ≤ 0.05) when compared to the non-medicated control group. However, future studies will be necessary to assess the

  3. Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin.

    Science.gov (United States)

    Ünal, Hale; Öztürk, Naile; Bilensoy, Erem

    2015-01-01

    The aim of this study was to design and evaluate hybrid cyclodextrin (CD) nanocapsules intended for the oral delivery of the anticancer agent camptothecin (CPT) in order to maintain drug stability in the body and to improve its eventual bioavailability. For this reason, an amphiphilic cyclodextrin (CD) derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes through positive surface charge. Nanocapsules were evaluated for their in vitro characteristics such as particle size, zeta potential, drug loading and release profiles followed by cell culture studies with the MCF-7 and Caco-2 cell line evaluating their anticancer efficacy and permeability. The CD nanocapsules were imaged by scanning electron microscopy (SEM). The concentration of CPT entrapped in nanocapsules was determined by reversed phase HPLC. The in vitro release study of CPT was performed with a dialysis bag method under sink conditions mimicking the gastric and intestinal pH. The hydrolytic stability of CPT in nanocapsules was investigated in simulated gastric and intestinal fluids (SGF, SIF). The mean particle sizes of both anionic and cationic CPT-loaded nanocapsules were in the range of 180-200 nm with polydispersity indices lower than 0.400 indicating monodisperse size distribution of nanocapsules with favourable potential for intracellular drug delivery to tumour cells. Surface charges of anionic and cationic nanocapsules were demonstrated as -21 mV and +18 mV, respectively. The stability of CPT in simulated release media, SGF and SIF were maintained suggesting the improved protection of the drug molecule from rapid hydrolysis degradation or gastrointestinal pH in nanocapsule oily core. Furthermore CD nanocapsules showed higher anticancer efficacy than CPT solution against the MCF

  4. Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin

    Directory of Open Access Journals (Sweden)

    Hale Ünal

    2015-02-01

    Full Text Available Background: The aim of this study was to design and evaluate hybrid cyclodextrin (CD nanocapsules intended for the oral delivery of the anticancer agent camptothecin (CPT in order to maintain drug stability in the body and to improve its eventual bioavailability. For this reason, an amphiphilic cyclodextrin (CD derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes through positive surface charge. Nanocapsules were evaluated for their in vitro characteristics such as particle size, zeta potential, drug loading and release profiles followed by cell culture studies with the MCF-7 and Caco-2 cell line evaluating their anticancer efficacy and permeability. The CD nanocapsules were imaged by scanning electron microscopy (SEM. The concentration of CPT entrapped in nanocapsules was determined by reversed phase HPLC. The in vitro release study of CPT was performed with a dialysis bag method under sink conditions mimicking the gastric and intestinal pH. The hydrolytic stability of CPT in nanocapsules was investigated in simulated gastric and intestinal fluids (SGF, SIF.Results: The mean particle sizes of both anionic and cationic CPT-loaded nanocapsules were in the range of 180–200 nm with polydispersity indices lower than 0.400 indicating monodisperse size distribution of nanocapsules with favourable potential for intracellular drug delivery to tumour cells. Surface charges of anionic and cationic nanocapsules were demonstrated as −21 mV and +18 mV, respectively. The stability of CPT in simulated release media, SGF and SIF were maintained suggesting the improved protection of the drug molecule from rapid hydrolysis degradation or gastrointestinal pH in nanocapsule oily core. Furthermore CD nanocapsules showed higher anticancer

  5. Development and validation of an in vitro–in vivo correlation (IVIVC model for propranolol hydrochloride extended-release matrix formulations

    Directory of Open Access Journals (Sweden)

    Chinhwa Cheng

    2014-06-01

    Full Text Available The objective of this study was to develop an in vitro–in vivo correlation (IVIVC model for hydrophilic matrix extended-release (ER propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid.

  6. A comparison between use of spray and freeze drying techniques for preparation of solid self-microemulsifying formulation of valsartan and in vitro and in vivo evaluation.

    Science.gov (United States)

    Singh, Sanjay Kumar; Vuddanda, Parameswara Rao; Singh, Sanjay; Srivastava, Anand Kumar

    2013-01-01

    The objective of the present study was to develop self micro emulsifying formulation (SMEF) of valsartan to improve its oral bioavailability. The formulations were screened on the basis of solubility, stability, emulsification efficiency, particle size and zeta potential. The optimized liquid SMEF contains valsartan (20% w/w), Capmul MCM C8 (16% w/w), Tween 80 (42.66% w/w) and PEG 400 (21.33% w/w) as drug, oil, surfactant and co-surfactant, respectively. Further, Liquid SMEF was adsorbed on Aerosol 200 by spray and freeze drying methods in the ratio of 2 : 1 and transformed into free flowing powder. Both the optimized liquid and solid SMEF had the particle size drying methods are equally capable for producing stable solid SMEF and immediate release of drug in in vitro and in vivo conditions. However, the solid SMEF produced by spray drying method showed high flowability and compressibility. The solid state characterization employing the FTIR, DSC and XRD studies indicated insignificant interaction of drug with lipid and adsorbed excipient. The relative bioavailability of solid SMEF was approximately 1.5 to 3.0 folds higher than marketed formulation and pure drug. Thus, the developed solid SMEF illustrates an alternative delivery of valsartan as compared to existing formulations with improved bioavailability.

  7. Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-I: Orally disintegrating tablets

    Directory of Open Access Journals (Sweden)

    Mohapatra Ashutosh

    2008-01-01

    Full Text Available Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2 diabetes mellitus. Difficulty in swallowing (dysphagia is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. In this study, orally disintegrating tablets were prepared using direct compression and wet granulation method. First, the tablets of metformin were prepared using starch RX1500 and microcrystalline cellulose by direct compression. The tablets showed erosion behavior rather than disintegration. Then lactose was incorporated which created pores to cause burst release of drug. But these tablets did not give good mouth feel. Thus, Pearlitol SD 200 (spray dried mannitol was used to prepare tablets by wet granulation (10% polyvinylpyrrolidone in Isopropyl alcohol as binder. The optimized batches of tablets (LMCT3 and MP13 not only exhibited desired mouth feel but also disintegration time, in vitro dispersion time, water absorption ratio, and in vitro drug release. All the batches contained 15% starch 1500 and 4% of croscarmellose sodium. The optimized batches prepared by direct compression and wet granulation showed 85% drug release at 4 min and 8 min, respectively. The strong saline and slight bitter taste of the drug was masked using nonnutritive sweetener and flavor.

  8. Evaluation of the Influence of Formulation and Process Variables on Mechanical Properties of Oral Mucoadhesive Films Using Multivariate Data Analysis

    Directory of Open Access Journals (Sweden)

    Hana Landová

    2014-01-01

    Full Text Available Oral mucosa is an attractive region for the local and systemic application of many drugs. Oral mucoadhesive films are preferred for their prolonged time of residence, the improved bioavailability of the drug they contain, their painless application, their protection against lesions, and their nonirritating properties. This work was focused on preparation of nonmedicated carmellose-based films using both solvent casting and impregnation methods, respectively. Moreover, a modern approach to evaluation of mucoadhesive films applying analysis of texture and subsequent multivariate data analysis was used. In this experiment, puncture strength strongly correlated with tensile strength and could be used to obtain necessary information about the mechanical film characteristics in films prepared using both methods. Puncture work and tensile work were not correlated in films prepared using the solvent casting method, as increasing the amount of glycerol led to an increase in the puncture work in thinner films. All measured texture parameters in films prepared by impregnation were significantly smaller compared to films prepared by solvent casting. Moreover, a relationship between the amount of glycerol and film thickness was observed, and a greater recalculated tensile/puncture strength was needed for an increased thickness in films prepared by impregnation.

  9. Taste Masked Orally Disintegrating Pellets of Antihistaminic and Mucolytic Drug: Formulation, Characterization, and In Vivo Studies in Human.

    Science.gov (United States)

    Taj, Yasmeen; Pai, Roopa S; Kusum Devi, V; Singh, Gurinder

    2014-01-01

    The main aim of the present study was to evaluate the potential of orally disintegrating pellets (ODPs) as an approach for taste masking of bitter drugs, namely, Ambroxol hydrochloride (A-HCl) and Cetirizine dihydrochloride (C-DHCl). Pellets were prepared by extrusion/spheronization with Eudragit EPO, kyron T-134, Kyron T-314, mannitol, sorbitol, MCC (Avicel PH-101), sucralose, chocolate flavor, and 5% xanthum gum. The prepared pellets were characterized for percentage yield, drug content, particle size, in vitro drug release, and in vivo evaluation on humans for taste, mouth feel, and in vivo disintegration time. The results revealed that the average size of pellets was influenced greatly by the percentage of binder and extrusion speed. The optimized ODPs disintegrated in less than 20 s and showed more than 98% of drugs in ODPs dissolved within 15 min. Taste perception study was carried out on human volunteers to evaluate the taste masking ability of ODPs for taste, mouth feel, and in vivo disintegration time. Crystalline state evaluation of drugs in the optimized ODPs was conducted for X-ray powder diffraction. In conclusion, the study confirmed that ODPs can be utilized as an alternative approach for effective taste masking and rapid disintegration in the oral cavity.

  10. Taste Masked Orally Disintegrating Pellets of Antihistaminic and Mucolytic Drug: Formulation, Characterization, and In Vivo Studies in Human

    Science.gov (United States)

    Taj, Yasmeen; Pai, Roopa S.; Kusum Devi, V.; Singh, Gurinder

    2014-01-01

    The main aim of the present study was to evaluate the potential of orally disintegrating pellets (ODPs) as an approach for taste masking of bitter drugs, namely, Ambroxol hydrochloride (A-HCl) and Cetirizine dihydrochloride (C-DHCl). Pellets were prepared by extrusion/spheronization with Eudragit EPO, kyron T-134, Kyron T-314, mannitol, sorbitol, MCC (Avicel PH-101), sucralose, chocolate flavor, and 5% xanthum gum. The prepared pellets were characterized for percentage yield, drug content, particle size, in vitro drug release, and in vivo evaluation on humans for taste, mouth feel, and in vivo disintegration time. The results revealed that the average size of pellets was influenced greatly by the percentage of binder and extrusion speed. The optimized ODPs disintegrated in less than 20 s and showed more than 98% of drugs in ODPs dissolved within 15 min. Taste perception study was carried out on human volunteers to evaluate the taste masking ability of ODPs for taste, mouth feel, and in vivo disintegration time. Crystalline state evaluation of drugs in the optimized ODPs was conducted for X-ray powder diffraction. In conclusion, the study confirmed that ODPs can be utilized as an alternative approach for effective taste masking and rapid disintegration in the oral cavity. PMID:27379290

  11. Comparative Effect of Divided Doses of Adult Solid and Liquid Oral Formulations of Antiepileptic Drugs in the Management of Pediatric Epilepsy.

    Science.gov (United States)

    Nidanapu, Ravi Prasad; Tamijarassy, Bascarane; Mahadevan, Subramanian; Gitanjali, Batmanabane

    2017-01-01

    To compare the differences in the efficacy and safety of the commonly prescribed AEDs in the management of epilepsy in children when using divided doses of adult solid oral formulations (DDSF) with the liquid oral formulations (LFs). Patients who had one or more seizures per month and prescribed with DDSF were recruited. Initially the patients were continued on DDSF for 4 months following which they were switched over to LF for the subsequent 4 months. Seizure frequencies and adverse drug effects (ADRs) were recorded every month for 8 months and plasma AED levels were estimated at the end of 4(th) and 8(th) months. A total of 200 patients completed the study protocol. The median seizure frequencies per month with DDSF and LF were: partial seizures (20.5, 9.0; P < 0.001), generalized tonic-clonic seizures (6.5, 2.0; P < 0.001), myoclonic seizures (58.5, 29.0; P < 0.001). Mean plasma drug levels ± SD (μg/ml) with DDSF and LF were: sodium valproate (48.2 ± 13.7, 69.1 ± 16.3; P < 0.001), phenytoin sodium (5.0 ± 2.4, 12.8 ± 3.8; P < 0.001), carbamazepine (4.5 ± 2.0, 11.5 ± 4.8; P < 0.001) and phenobarbitone (14.1 ± 5.2, 25.4 ± 12.3, P < 0.001). The incidence of treatment emergent ADRs was poor scholastic performance (25.5%), behavioral problems and dizziness/sedation (21.0%), somnolence/sleep disorders (19.5%). Patients treated with LF had better seizure control and optimal therapeutic drug levels and less adverse effects when compared to DDSF.

  12. The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership

    Directory of Open Access Journals (Sweden)

    Gaudin Karen

    2011-05-01

    Full Text Available Abstract Background Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries. Methods Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal within a larger Public Private partnership (the FACT project, set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DNDi. Results The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi. Conclusions Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public

  13. An integrated, quality by design (QbD) approach for design, development and optimization of orally disintegrating tablet formulation of carbamazepine.

    Science.gov (United States)

    Mishra, Saurabh M; Rohera, Bhagwan D

    2016-06-27

    The objective of the present study was to design and develop a formulation for orally disintegrating tablets (ODTs) of carbamazepine using quality by design principles. The target product profile (TPP) and quality target product profile (QTPP) of ODTs were identified. Risk assessment was carried out by leveraging prior knowledge and experience to define the criticality of factors based on their impact by Ishikawa fishbone diagram and preliminary hazard analysis tool. Box-Behnken response surface methodology was used to study the effect of critical factors on various attributes of ODTs. The independent factors selected were compression pressure (X1), concentration of sublimating agent (volatile material) (X2), disintegrant concentration (X3) and the responses were tablet crushing strength, tablet porosity, disintegration time, water absorption time, tablet friability and drug dissolution. ANOVA and lack of fit test illustrated that selected independent variables had significant effect on the response variables, and excellent correlation was observed between actual and predicted values. Optimization by desirability function indicated that compression pressure, X1 (1534 lbs), ammonium bicarbonate concentration, X2 (7.68%) and Kollidon(®) CL-SF concentration, X3 (6%) were optimum to prepare ODT formulation of carbamazepine of desired attributes complying with QTPP. Thus, in the present study, a high level of assurance was established for ODT product quality and performance.

  14. Two Different Approaches for Oral Administration of Voriconazole Loaded Formulations: Electrospun Fibers versus β-Cyclodextrin Complexes

    Directory of Open Access Journals (Sweden)

    Panoraia I. Siafaka

    2016-02-01

    Full Text Available In this work, a comparison between two different preparation methods for the improvement of dissolution rate of an antifungal agent is presented. Poly(ε-caprolactone (PCL electrospun fibers and β-cyclodextrin (β-CD complexes, which were produced via an electrospinning process and an inclusion complexation method, respectively, were addressed for the treatment of fungal infections. Voriconazole (VRCZ drug was selected as a model drug. PCL nanofibers were characterized on the basis of morphology while phase solubility studies for β-CDs complexes were performed. Various concentrations (5, 10, 15 and 20 wt % of VRCZ were loaded to PCL fibers and β-CD inclusions to study the in vitro release profile as well as in vitro antifungal activity. The results clearly indicated that all formulations showed an improved VRCZ solubility and can inhibit fungi proliferation.

  15. Two Different Approaches for Oral Administration of Voriconazole Loaded Formulations: Electrospun Fibers versus β-Cyclodextrin Complexes.

    Science.gov (United States)

    Siafaka, Panoraia I; Üstündağ Okur, Neslihan; Mone, Mariza; Giannakopoulou, Spyridoula; Er, Sevda; Pavlidou, Eleni; Karavas, Evangelos; Bikiaris, Dimitrios N

    2016-02-25

    In this work, a comparison between two different preparation methods for the improvement of dissolution rate of an antifungal agent is presented. Poly(ε-caprolactone) (PCL) electrospun fibers and β-cyclodextrin (β-CD) complexes, which were produced via an electrospinning process and an inclusion complexation method, respectively, were addressed for the treatment of fungal infections. Voriconazole (VRCZ) drug was selected as a model drug. PCL nanofibers were characterized on the basis of morphology while phase solubility studies for β-CDs complexes were performed. Various concentrations (5, 10, 15 and 20 wt %) of VRCZ were loaded to PCL fibers and β-CD inclusions to study the in vitro release profile as well as in vitro antifungal activity. The results clearly indicated that all formulations showed an improved VRCZ solubility and can inhibit fungi proliferation.

  16. Development of flexible and dispersible oral formulations containing praziquantel for potential schistosomiasis treatment of pre-school age children.

    Science.gov (United States)

    Trastullo, Ramona; Dolci, Luisa Stella; Passerini, Nadia; Albertini, Beatrice

    2015-11-10

    Praziquantel (PZQ), an anthelmintic drug used in developing countries for the treatment of schistosome infections, was processed using the fluid bed wet granulation technology to prepare fast dispersible granules, as an appropriate and flexible dosage form for pre-school-aged children. Granulation experiments were performed incorporating PZQ either in the powder mixture, according to the traditional way, or in the liquid phase containing wetting agents. In the powder mixture several excipients were tested: Flowlac 100 as filler, Galeniq 721 (isomalt) and Neosorb P 100 T (D-sorbitol) as sweeteners and PVP K30 as binder; while in the liquid phase Lutrol F68, Cremophor RH 40 or Tween 80 as surfactants were investigated. Different formulations loaded with 10% w/w (batches 1-8) and 20% w/w of PZQ (batches 9-13) were produced The majority of granules displayed good flow properties and uniform drug content. X-ray powder diffraction showed that PZQ remained in its original crystalline state, while differential scanning calorimetry and Fourier transform-infrared analysis evidenced the formation of chemical interactions among the ingredients. The solubilisation test performed in non-sink condition to reproduce the actual condition in which a child of 4 years takes the medicine revealed that granules quickly formed a very fine suspension in water (dV90=39.9 μm). Although after the granulation process the solubility of raw PZQ was not increased, adding the aqueous suspension to 500 ml of buffer solution of pH 1.5, simulating the fasted state of a child, 50% of the drug was dissolved after 30 min. After granule manipulation with milk and fruit juices, no PZQ degradation was observed during time. Finally, the selected granule formulation provided evidence to be stable even at hot and very humid climate (30°C/75% RH), at least for the examined time.

  17. Testing a Low Molecular Mass Fraction of a Mushroom (Lentinus edodes Extract Formulated as an Oral Rinse in a Cohort of Volunteers

    Directory of Open Access Journals (Sweden)

    Caterina Signoretto

    2011-01-01

    Full Text Available Although foods are considered enhancing factors for dental caries and periodontitis, laboratory researches indicate that several foods and beverages contain components endowed with antimicrobial and antiplaque activities. A low molecular mass (LMM fraction of an aqueous mushroom extract has been found to exert these activities in in vitro experiments against potential oral pathogens. We therefore conducted a clinical trial in which we tested an LMM fraction of shiitake mushroom extract formulated in a mouthrinse in 30 young volunteers, comparing the results with those obtained in two identical cohorts, one of which received water (placebo and the other Listerine. Plaque index, gingival index and bacterial counts in plaque samples were determined in all volunteers over the 11 days of the clinical trial. Statistically significant differences (P<0.05 were obtained for the plaque index on day 12 in subjects treated with mushroom versus placebo, while for the gingival index significant differences were found for both mushroom versus placebo and mushroom versus Listerine. Decreases in total bacterial counts and in counts of specific oral pathogens were observed for both mushroom extract and Listerine in comparison with placebo. The data suggest that a mushroom extract may prove beneficial in controlling dental caries and/or gingivitis/periodontitis.

  18. Formulation development of fast releasing oral thin films of levocetrizine dihydrochloride with Eudragit® Epo and optimization through Taguchi orthogonal experimental design

    Directory of Open Access Journals (Sweden)

    P K Lakshmi

    2011-01-01

    Full Text Available The aim of this study was to develop a fast releasing oral polymeric film, prepared using the solvent casting method, with good mechanical properties, instant disintegration and dissolution, an acceptable taste in the oral cavity. Levocetirizine dihydrochloride, an antihistamine, was incorporated to relieve the symptoms of allergic rhinitis. Four batches of films with drug were prepared using different combinations of polymers and plasticizers Eudragit; EPO, HPMC E 5 LV, and PVA were the selected polymers. Glycerin, dibutyl phthalate, propylene glycol, and PEG 400 were the selected plasticizers. The resultant films were evaluated for weight variation, assay, content uniformity, folding endurance, thickness, tensile strength, percent elongation, surface pH, in vitro disintegration and in vitro dissolution. The formulations from the preliminary trial were analyzed using Taguchi OA experimental design, which was applied to optimize the type of polymers, concentration of polymers, plasticizer, and sweetener based on their disintegration data at three different levels. The optimized films disintegrated in less than 30s, releasing 70-90% of drug within 2 mins. The percentage release varied with the type of polymer and concentration of polymer. The films made with EPO released 96% of drug in 2 mins, which was the best release among all.

  19. A novel gradient HPLC method for simultaneous determination of ranitidine, methylparaben and propylparaben in oral liquid pharmaceutical formulation.

    Science.gov (United States)

    Kokoletsi, Magdalene Xenou; Kafkala, Stella; Tsiaganis, Michael

    2005-07-15

    A selective and accurate high-performance liquid chromatographic method has been developed and validated for the simultaneous determination of ranitidine, methylparaben (MP) and propylparaben (PP) in oral liquids. Samples were purified by solid-phase extraction (SPE) using a copolymeric [poly(divinylbenzene-co-N-vinylpyrrolidone)] sorbent. The chromatographic separation was achieved by HPLC using a mixture of ammonium acetate solution (0.5 M), acetonitrile and methanol as the mobile phase with gradient elution, a Nucleosil C18 column and UV detection at 254 nm. The method was validated with respect to linearity, precision, accuracy, selectivity, and robustness. All the parameters examined met the current recommendations for bioanalytical method validation. The method was found to be applicable to routine analysis (assays and stability tests) of active compound (ranitidine) and preservatives (MP and PP).

  20. Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment.

    Science.gov (United States)

    Neupane, Yub Raj; Srivastava, Manish; Ahmad, Nafees; Kumar, Neeraj; Bhatnagar, Aseem; Kohli, Kanchan

    2014-12-30

    The aim of this study was to design and fabricate nanostructured lipid carrier (NLC) for the potential oral delivery of decitabine (DCB). NLC was prepared by cold homogenization technique and optimized by the Box-Behnken experimental design. It was further characterized by particle size, zeta potential, transmission electron microscopy (TEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro release study, and stability study. Moreover, ex vivo and in vivo efficacy of the NLC was assessed by gut permeation study, γ scintigraphy imaging, and MTT assay. NLC was found to have particle size (116.64 ± 6.67 nm), zeta potential (-31.8 ± 0.96 mV) and sustained drug release (80.23 ± 4.67%) up to 24h. TEM and AFM proved that the particles were spherical in shape and smooth surface. DSC and XRD studies had demonstrated the reduced crystallinity and stability enhancing effect of the NLC. Stability studies revealed the changes in the observed parameters up to 45 days were not significantly differences (p>0.05). Ex vivo gut permeation study showed 4-folds increment in the permeation of drug compared with the plain drug solution. γ Scintigraphy imaging and MTT assay results inferred that DCB loaded NLC possesses excellent cytotoxic activity against cancer cells. Thus, NLC holds high potential for the oral delivery of DCB to treat cancer cells and future prospects for the industrial purpose. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Pilot study of oral administration of a curcumin-phospholipid formulation for treatment of central serous chorioretinopathy

    Directory of Open Access Journals (Sweden)

    Mazzolani F

    2012-05-01

    Full Text Available Fabio MazzolaniPrivate Practice, Milan, ItalyBackground: The purpose of this open-label study was to investigate the effect of a curcumin-phospholipid (lecithin, Meriva® formulation (Norflo® tablet on visual acuity and retinal thickness in patients with acute or chronic central serous chorioretinopathy.Methods: Visual acuity was assessed by ophthalmologic evaluation, and optical coherence tomography was used to measure retinal thickness. Norflo tablets were administered twice a day to patients affected by central serous chorioretinopathy. The study included 18 eyes from 12 patients who completed a 6-month follow-up period. Visual acuity before and after Norflo treatment was the primary endpoint. The secondary endpoints were neuroretinal or pigment epithelial detachment, as measured by optical coherence tomography.Results: After 6 months of therapy, 0% of eyes showed reduction in visual acuity, 39% showed stabilization, and 61% showed improvement. The improvement was statistically significant (P = 0.08. After 6 months of therapy, 78% of eyes showed reduction of neuroretinal or retinal pigment epithelium detachment, 11% showed stabilization, and 11% showed an increase.Conclusion: Our results, albeit preliminary, show that curcumin administered as Norflo tablets is efficacious for the management of central serous chorioretinopathy, a relapsing eye disease, and suggest that bioavailable curcumin is worth considering as a therapeutic agent for the management of inflammatory and degenerative eye conditions, including those that activate the retinal microglia.Keywords: curcumin, central serous chorioretinopathy, retinal pigment epithelium detachment, Norflo®, Meriva®

  2. Effects of an orabase formulation with ethanolic extract of Malva sylvestris L. in oral wound healing in rats.

    Science.gov (United States)

    Kovalik, Ana Cristina; Bisetto, Paula; Pochapski, Márcia Thaís; Campagnoli, Eduardo Baulm; Pilatti, Gibson Luiz; Santos, Fábio André

    2014-05-01

    Malva sylvestris L. is widely used in medicine for treatment of inflammatory processes. The plant has anti-inflammatory properties due to substances such as mucilage, flavonoids, and tannins. A mouthwash with leaves from the plant can be used for the treatment of wounds in the oral mucosa. The aim of this study was to assess the wound healing effect of Malva sylvestris L. on a palate mucosa wound in rats. After intraperitoneal anesthesia, a 4-mm-diameter excisional wound was made in the center of the palatal mucosa of 136 rats, using a punch-out biopsy tool. Eight animals were used as baseline wound. The remaining rats were divided into four groups: CO, control; OB, orabase vehicle; CX, 2% chlorhexidine; and MA, 20% Malva in orabase. At 24 h postoperatively, the animals were immobilized without anesthetic to apply 25 mg of each substance twice a day, totaling 50 mg daily. The wound areas were measured photographically and the reepithelialization rates were determined histologically (%) after 0, 3, 7, 15, and 21 days. The data were analyzed by ANOVA and Tukey post hoc test. Similar healing pattern was observed among the groups (P>.05; ANOVA). According to the methodology, Malva sylvestris L. extract had no effect on wound healing in the palatal mucosa of rats.

  3. Combined Atomistic Molecular Calculations and Experimental Investigations for the Architecture, Screening, Optimization, and Characterization of Pyrazinamide Containing Oral Film Formulations for Tuberculosis Management.

    Science.gov (United States)

    Adeleke, Oluwatoyin A; Monama, Nkwe O; Tsai, Pei-Chin; Sithole, Happy M; Michniak-Kohn, Bozena B

    2016-02-01

    To date, effective treatment, prophylaxis, and control of tuberculosis (TB) infection is mainly dependent on the use of drugs. However, patient noncompliance with prescribed anti-TB treatment schemes remains a major problem confronting successful pharmacotherapeutic outcomes. Thus, the development of alternative delivery systems that can improve adherence for the existing anti-TB bioactives has been intensified in recent times. The aim of this investigation was to engineer an optimal, thermodynamically stable oral film (OF) formulation containing a key anti-TB agent, pyrazinamide (PYZ), employing molecular modeling and experimental tools. Four PYZ-loaded film variants (OF 1, OF 2, OF 3, OF 4) were constructed in silico and then prepared in vitro using the Accelrys Materials Studio software and solvent casting method, respectively. Screening and selection of the optimal OF was based on the computation of the total interaction energy (ET), kinetic energy (EK), solubility parameter (S), and cohesive energy density (CED) as well as determining mass, thickness, dissolution and disintegration times, dissolution pH, drug loading capacity, and surface morphology in vitro. OF 2 was selected as the optimal formulation as it displayed the lowest ET (-8006.28 kcal/mol), dissolution time (9.96 min), disintegration time (56.49 s), and weight (39.33 mg); moderate EK (1052.98 kcal/mol); highest S (44.55 (J/cm(3))(0.5)) and CED (1.99 × 10(9) J/m(3)), slim dimension (166 μm), good and unvarying drug loading capacity (98.04%), acceptable dissolution pH (6.70), and well-layered surface topography. The drug release behavior of the optimal OF 2 was best elucidated with the zero order (R(2) = 0.97) and Korsmeyer-Peppas (R(2) = 0.99) models. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) analyses showed that OF 2 was made of physically mixed multiple component polymeric and nonpolymeric compounds. OF 2 was

  4. Effect of mouth-rinse formulations on oral malodour processes in tongue-derived perfusion biofilm model.

    Science.gov (United States)

    Saad, S; Hewett, K; Greenman, J

    2012-03-01

    An in vitro matrix biofilm perfusion model of tongue-derived microcosms for studying volatile sulfur compound (VSC) biogenesis has been previously described. The model was modified in order to monitor H(2)S in situ by use of a specialized electrode assembly based on microbial fuel cell technology. This system was designed to give real-time measurements expressed as electrode power output, which were proportional to H(2)S levels, measured by other means. In addition to the model modifications, the aim of this study was to demonstrate the biofilm responses following single or multiple exposure to biocidal, biostatic or VSC-inhibiting active compounds used in products. Tongue-derived biofilms (n = 6 per experiment) were perfused with one-fifth strength BHI at 20 ml h(-1) pH 7.2 and pulsed with putative treatment agent, placebo and controls including Zn(2+) ions and chlorhexidine (CHX). Compared with their pre-treatment conditions, all biofilms responded to the treatments in terms of reductions in hydrogen sulfide generation (as detected by the biofilm-electrode response) and other microbial volatile organic compounds (VOCs) as detected using a selected ion flow tube mass spectrometry analyser. The microbiological analysis of the treated and control biofilms show that test products (formulations with active agents) all gave reduced cell populations compared to the control biofilm. An order of effects (magnitude and duration) suggests that both the test agent and CHX produced the strongest reductions, distinct from the responses obtained for the placebo and water controls, which were largely similar. It is concluded that the in vitro perfusion model may be used to replicate many of the activities and reactions believed to be occurring by the tongue biofilm microflora within a real mouth, including H(2)S and VOC biogenesis and their inhibition by exposure to active agents.

  5. Influence of Drug Properties and Formulation on In Vitro Drug Release and Biowaiver Regulation of Oral Extended Release Dosage Forms.

    Science.gov (United States)

    Lin, Zhongqiang; Zhou, Deliang; Hoag, Stephen; Qiu, Yihong

    2016-03-01

    Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory

  6. Ability of an oral formulation of afoxolaner to protect dogs from Borrelia burgdorferi infection transmitted by wild Ixodes scapularis ticks.

    Science.gov (United States)

    Baker, C F; McCall, J W; McCall, S D; Drag, M D; Mitchell, E B; Chester, S T; Larsen, D

    2016-12-01

    A randomized, blinded, negative controlled study was conducted to determine whether treatment with afoxolaner (NexGard(®), Merial, Inc.) would prevent the transmission of Borrelia burgdorferi to dogs by wild caught Ixodes scapularis ticks. Twenty healthy dogs were randomly assigned to two groups of ten dogs each. Ten dogs were treated orally on Day 0 at a dose near the minimum recommended dose of afoxolaner of 2.5mg/kg (actual doses 2.5-3.1mg/kg) and ten control dogs were not treated. On Day 28, each dog was infested with approximately 50 adult unfed wild caught I. scapularis that had a 67% B. burgdorferi infection rate (determined by polymerase chain reaction). On Day 33, live ticks were counted and removed. No ticks were found on treated dogs while control dogs had an average of 21.4 ticks. To detect infection, the B. burgdorferi-specific C6 antibody SNAP(®) 4Dx(®) test (IDEXX) was performed on serum collected before infestation (all dogs seronegative on Days -6 and 27) and on Days 48, 63, 77 and 92. The ten treated dogs remained seronegative through the end of the study (Day 92), while nine out of the ten control dogs were infected, as demonstrated by their seroconversion to being positive for the presence of the B. burgdorferi-specific C6 antibody starting on Day 48. In this study, all dogs treated with NexGard(®) 28days prior to challenge with wild caught I. scapularis ticks were protected from B. burgdorferi infection, while nine out of the ten untreated control dogs were infected.

  7. Decorporation of systemically distributed americium by a novel orally administered diethylenetriaminepentaacetic acid (DTPA) formulation in beagle dogs.

    Science.gov (United States)

    Wilson, James P; Cobb, Ronald R; Dungan, Nathanael W; Matthews, Laura L; Eppler, Bärbel; Aiello, Kenneth V; Curtis, Shiro; Boger, Teannetta; Guilmette, Raymond A; Weber, Waylon; Doyle-Eisele, Melanie; Talton, James D

    2015-03-01

    Novel decorporation agents are being developed to protect against radiological accidents and terrorists attacks. Radioactive americium is a significant component of nuclear fallout. Removal of large radioactive materials, such as 241Am, from exposed persons is a subject of significant interest due to the hazards they pose. The objective of this study was to evaluate the dose-related efficacy of daily doses of NanoDTPA™ Capsules for decorporating Am administered intravenously as a soluble citrate complex to male and female beagle dogs. In addition, the efficacy of the NanoDTPA™ Capsules for decorporating 241Am was directly compared to intravenously administered saline and DTPA. Animals received a single IV administration of 241Am(III)-citrate on Day 0. One day after radionuclide administration, one of four different doses of NanoDTPA™ Capsules [1, 2, or 6 capsules d(-1) (30 mg, 60 mg, or 180 mg DTPA) or 2 capsules BID], IV Zn-DTPA (5 mg kg(-1) pentetate zinc trisodium) as a positive control, or IV saline as a placebo were administered. NanoDTPA™ Capsules, IV Zn-DTPA, or IV saline was administered on study days 1-14. Animals were euthanized on day 21. A full necropsy was conducted, and liver, spleen, kidneys, lungs and trachea, tracheobronchial lymph nodes (TBLN), muscle samples (right and left quadriceps), gastrointestinal (GI) tract (stomach plus esophagus, upper and lower intestine), gonads, two femurs, lumbar vertebrae (L1-L4), and all other soft tissue remains were collected. Urinary and fecal excretion profiles were increased approximately 10-fold compared to those for untreated animals. Tissue contents were decreased compared to untreated controls. In particular, liver content was decreased by approximately eightfold compared to untreated animals. The results from this study further demonstrate that oral NanoDTPA™ Capsules are equally efficient compared to IV Zn-DTPA in decorporation of actinides.

  8. Determination of the effective dose of a novel oral formulation of sarolaner (Simparica™) for the treatment and month-long control of fleas and ticks on dogs.

    Science.gov (United States)

    McTier, Tom L; Six, Robert H; Fourie, Josephus J; Pullins, Aleah; Hedges, Laura; Mahabir, Sean P; Myers, Melanie R

    2016-05-30

    Three laboratory studies were conducted to determine the appropriate dose of sarolaner, a novel isoxazoline, for the treatment and month-long control of infestations of fleas and ticks on dogs. In the first study, dogs were treated orally with sarolaner suspension formulations at 1.25, 2.5 or 5.0mg/kg, and infested with Dermacentor reticulatus, Rhipicephalus sanguineus ticks and with Ctenocephalides felis felis (cat flea) prior to treatment and then weekly for up to 8 weeks. Fleas and ticks were counted 48h after treatment and after each subsequent infestation at 24h for fleas and 48h for ticks. The lowest dose of sarolaner (1.25mg/kg) provided 100% efficacy against fleas from treatment through Day 35 and 98.4% at Day 56. This dose of sarolaner resulted in 99.7-100% control of both species of ticks through Day 28. In Study 2, dogs were dosed orally with placebo or sarolaner suspension formulations at 0.625, 1.25 or 2.5mg/kg and infested with Ixodes scapularis prior to treatment and weekly for 6 weeks, Amblyomma americanum (pretreatment and Day 26), Dermacentor variabilis (Day 33) and A. maculatum (Day 41). Ixodes scapularis was the most susceptible; the lowest dose (0.625mg/kg) providing>95% efficacy through Day 43. Efficacy against D. variabilis on Day 35 was>95% at 1.25 and 2.5mg/kg, whereas the 0.625mg/kg dose gave only 61.4% efficacy. Amblyomma spp. were the least susceptible ticks; efficacy of the 1.25mg/kg dose at Day 28 for A. americanum was markedly lower (88.5%) than achieved for D. reticulatus (100%) at Day 28 and also lower than for D. variabilis at Day 35 (96.2%). In Study 3, dogs were dosed orally with placebo or sarolaner in the proposed commercial tablet (Simparica™) at 1.0, 2.0 or 4.0mg/kg, and infested with A. maculatum, one of the ticks determined to be dose limiting, prior to treatment and then weekly for 5 weeks. All doses gave 100% control of the existing infestation. The two highest dosages resulted in >93% control of subsequent challenges

  9. Lipid-formulated bcg as an oral-bait vaccine for tuberculosis: vaccine stability, efficacy, and palatability to brushtail possums (Trichosurus vulpecula) in New Zealand.

    Science.gov (United States)

    Cross, Martin L; Henderson, Ray J; Lambeth, Matthew R; Buddle, Bryce M; Aldwell, Frank E

    2009-07-01

    Bovine tuberculosis (Tb), due to infection with virulent Mycobacterium bovis, represents a threat to New Zealand agriculture due to vectorial transmission from wildlife reservoir species, principally the introduced Australian brushtail possum (Trichosurus vulpecula). An oral-delivery wildlife vaccine has been developed to immunize possums against Tb, based on formulation of the human Tb vaccine (M. bovis BCG) in edible lipid matrices. Here BCG bacilli were shown to be stable in lipid matrix formulation for over 8 mo in freezer storage, for 7 wk under room temperature conditions, and for 3-5 wk under field conditions in a forest/pasture margin habitat (when maintained in weatherproof bait-delivery sachets). Samples of the lipid matrix were flavored and offered to captive possums in a bait-preference study: a combination of 10% chocolate powder with anise oil was identified as the most effective attractant/palatability combination. In a replicated field study, 85-100% of wild possums were shown to access chocolate-flavored lipid pellets, when baits were applied to areas holding approximately 600-800 possums/km(2). Finally, in a controlled vaccination/challenge study, chocolate-flavored lipid vaccine samples containing 10(8) BCG bacilli were fed to captive possums, which were subsequently challenged via aerosol exposure to virulent M. bovis: vaccine immunogenicity was confirmed, and protection was identified by significantly reduced postchallenge weight loss in vaccinated animals compared to nonvaccinated controls. These studies indicate that, appropriately flavored, lipid delivery matrices may form effective bait vaccines for the control of Tb in wildlife.

  10. Assessment of different formulations of oral Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine in rodent models for immunogenicity and protection against aerosol challenge with M. bovis.

    Science.gov (United States)

    Clark, Simon; Cross, Martin L; Smith, Alan; Court, Pinar; Vipond, Julia; Nadian, Allan; Hewinson, R Glyn; Batchelor, Hannah K; Perrie, Yvonne; Williams, Ann; Aldwell, Frank E; Chambers, Mark A

    2008-10-29

    Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Meles meles) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guérin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery

  11. Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Farr SJ

    2015-01-01

    Full Text Available Stephen J Farr,1 Cynthia Y Robinson,1 Christopher M Rubino2,3 1Zogenix, Inc., Emeryville, CA, 2Institute for Clinical Pharmacodynamics, Latham, NY, 3School of Pharmacy and Pharmaceutical Sciences, The State University of New York, University at Buffalo, Buffalo, NY, USA Background: The purpose of this study was to evaluate the pharmacokinetics, bioavailability, and safety of oral extended-release hydrocodone (HC-ER when administered with food or alcohol. Methods: Two single-center, open-label, randomized, crossover studies were conducted in healthy volunteers. In a two-period food-interaction study, 12 subjects received HC-ER 20 mg after an overnight fast and a high-fat meal. In a three-period alcohol-interaction study, 30 naltrexone-blocked subjects received HC-ER 50 mg with a 0%, 20%, or 40% alcohol/orange juice solution after an overnight fast. Pharmacokinetic parameters were derived from plasma concentrations of hydrocodone and its metabolites. Results: Exposure to hydrocodone after HC-ER 20 mg was similar in the fed and fasted states, as assessed by area under the plasma concentration versus time curve from time of dosing to time of last detectable concentration (AUC0–t; 316.14 versus 311.94 ng · h/mL; relative bioavailability (Frel was 101.74%. Differences (fed versus fasted in hydrocodone mean maximum plasma concentration (Cmax; 28.86 versus 22.74 ng/mL and median time to Cmax (tmax; 6 versus 8 hours were not clinically significant. Administration of 20% alcohol with HC-ER 50 mg did not increase systemic exposure relative to 0% alcohol (AUC0–t 878 versus 832 ng · h/mL; Frel 105% or result in clinically meaningful changes in Cmax (51.8 versus 46.3 ng/mL or tmax (5.44 versus 6.16 hours. Administration with 40% alcohol increased AUC0–t (1,008 ng · h/mL versus 832 ng · h/mL; Frel 120% and Cmax (109 versus 46.3 ng/mL, and shortened tmax (2.43 versus 6.16 hours. Adverse events occurred in 10.0%, 24.1%, and 66.7% of subjects after 0

  12. Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

    Directory of Open Access Journals (Sweden)

    Eunice Kazue Kano

    2015-03-01

    Full Text Available Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product and Levaquin(c (Janssen-Cilag Farmacêutica Ltda, Brazil, test product was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c and Levaquin(c are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

  13. 鹿茸氨基酸口服液基础配方开发%Development of Based Formulation of Cervus elaphus Amino Acid Oral Liquid

    Institute of Scientific and Technical Information of China (English)

    胡朝奇; 陈新; 徐会丹

    2013-01-01

    目的:开发氨基酸口服液的基础配方.方法:选取同一产地的两份鹿茸细粉,按提取方法不同分为仿生组和超声组,比较各组样品中氨基酸含量,并使用SIMCA-P软件进行主成分分析.结果:两组样本间存在显著性差异,其中蛋氨酸、脯氨酸、精氨酸、苏氨酸、异亮氨酸、苯丙氨酸、缬氨酸差异最为明显;获得核心氨基酸组群配方为蛋氨酸0.96%,脯氨酸11.50%,精氨酸8.29%,苏氨酸2.64%,异亮氨酸1.71%,苯丙氨酸2.62%,缬氨酸3.46%;基础氨基酸组群为天门冬氨酸7.39%,丝氨酸4.07%,谷氨酸13.31%,甘氨酸21.72%,丙氨酸10.30%,亮氨酸4.64%,酪氨酸0.97%,赖氨酸5.07%,组氨酸1.36%.结论:鹿茸经人体消化后氨基酸配比与之自然状态下存在一定区别.以鹿茸消化后氨基酸配比为基础,开发的鹿茸氨基酸口服液可更好地发挥鹿茸的补益功效.%Objective:To develop based formulation of Cervus elaphus amino acid oral liquid.Method:Selected two C.elaphus powder from the same origin,divided into the biomimetic group and the ultrasound group according to different extraction methods.The content of amino acid of different groups was compared,and SIMCA-P statistical software was adopted to do principal component analysis.Result:There was a significant difference between samples from two groups,especially methionine,proline,arginine,threonine,isoleucine,phenylalanine and valine.Formulation of core amino acids group was as following:methionine 0.96%,proline 11.50%,arginine 8.29%,threonine 2.64%,isoleucine 1.71%,phenylalanine 2.62% and valine 3.46% ; Formulation of based amino acids group was aspartic acid 7.39%,serine 4.07%,glutamic acid 13.31%,glycine 21.72%,alanine 10.30%,leucine 4.64%,tyrosine 0.97%,lysine 5.07%,histidine 1.36%.Conclusion:There are some differences in amino acid proportion between the natural state and the digestion state.With amino acids

  14. Development of an oral dosage form of capecitabine with modified release characteristics

    NARCIS (Netherlands)

    Meulenaar, J

    2013-01-01

    Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of a.o. metastatic breast, gastric and colorectal cancer and is commercially available as an immediate release tablet (Xeloda®, Roche). Capecitabine is a pre-pro-drug that is enzymatically converted into 5-fluorourac

  15. Diseño de una formulación de ciclosporina A solución oral con alto grado de dispersión Design of a formulation of highly dispersed cyclosporine A oral solution

    Directory of Open Access Journals (Sweden)

    Suslebys Salomón Izquierdo

    2013-03-01

    properties, is used in the transplantation of solid organs, bone marrow, and in some stages of certain autoimmune diseases. In Cuba, the Cyclosporine A oral solution causes gastrointestinal absorption problems. Objectives: to achieve a pre-concentrated micro-emulsion containing highly dispersed cyclosporine A that may be equal to or higher than the one in the commercial formulation. Methods: study of percentages of emulsifiers and of hydrophilic lipophilic balance (HLB, at some intervals that allow obtaining self-emulsifying systems through a multilevel factorial design. The percent transmittance was used as the response variable in determining the formulation dispersion degree. The evaluation of the organoleptic characteristics of the selected formulation, the rheological study, the microbial count and the antimicrobial effectiveness estimation were all performed. Results: the studied factors have a significant influence on the transmittance percentage, the formulation with the highest degree of dispersion was achieved when using 60% of emulsifiers and an HLB of 11.5, being transmittance values of 95.03%, which were significantly higher than those of the leading product in the form of soft capsules, equal to 84.6%. Organoleptically speaking, the product meets the characteristics of a clear brilliant fluid without suspended particles and Newtonian behavior from the rheological point of view. The bacteria and fungi count met requirements of U.S. Pharmacopoeia for oral solutions. Conclusions: a pre-concentrate highly dispersed CsA microemulsion was achieved in a drinkable solution meeting the physical requirements and microbiological criteria established for this type of dosage form.

  16. Therapeutic efficacy of milbemycin oxime/praziquantel oral formulation (Milbemax® against Thelazia callipaeda in naturally infested dogs and cats

    Directory of Open Access Journals (Sweden)

    Motta Bruna

    2012-05-01

    Full Text Available Abstract Background Over the last few decades, canine and feline thelaziosis caused by Thelazia callipaeda eye worms has gained the attention of the veterinary community due to the spread of this ocular infestation in geographical areas previously regarded as non endemic. The therapeutic efficacy of milbemycin oxime/praziquantel tablets (Milbemax® against T. callipaeda was tested in naturally infested dogs and cats. Methods From January 2009 to July 2011 a placebo controlled and randomized field study was conducted in T. callipaeda endemic areas of Switzerland (CH and Italy (ITA involving client-owned animals. Dogs (n = 56 and cats (n = 31 were physically examined at enrolment Day 0 (D0 and twice afterwards (D7 and D14. Infested animals were orally treated with Milbemax® or with placebo tablets on D0 and, if an animal was found still infested with T. callipaeda, also on D7. On D14 nematodes were flushed from the conjunctiva, identified and counted. Results Out of 56 dogs, 43 were included in the statistical analysis, whereas 13 were excluded because the products under investigation were not administered with food, as required by the label. On D7 and D14, 72.7% and 90.9% of treated dogs were eye worm free, whereas in the placebo group 95.2% and 76.2% still harbored nematodes, resulting in a mean percentage worm count reduction for the Milbemax® group of 86.1% and 96.8%, respectively. Both results were significantly higher (p = 0.0001 than the placebo group. Out of the 31 cats included in the study at D7 and D14, 53.3% and 73.3% treated with Milbemax® were free of T. callipaeda, while 81.3% and 73.3 in the placebo group were still harbouring eye worms, resulting in a mean percentage worm count reduction for the treated group of 62.2% and 80.0%, respectively. Both results were significantly higher (p = 0.0106 and p = 0.0043 than the placebo group. Conclusions The commercial formulation of milbemycin oxime at the minimal dose

  17. Development of a Physiologically Relevant Population Pharmacokinetic in Vitro-in Vivo Correlation Approach for Designing Extended-Release Oral Dosage Formulation.

    Science.gov (United States)

    Kim, Tae Hwan; Shin, Soyoung; Bulitta, Jürgen B; Youn, Yu Seok; Yoo, Sun Dong; Shin, Beom Soo

    2017-01-03

    Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying Vmax, and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (Vmax(0)in vivo) was highly correlated (r(2) > 0

  18. FORMULATION DEVELOPMENT AND IN VITRO – IN VIVO CHARACTERIZATION OF ORAL FAST DISINTEGRATING FILMS OF A DRUG MEANT FOR CHRONIC DISEASE

    Directory of Open Access Journals (Sweden)

    P. Vijayalakshmi*, E. Surender , B. Pragna , Md. Zia Askary , Lohidasu Borubhadra , A.J. Balamurugan and Hemant Joshi

    2013-01-01

    Full Text Available The objective of the work was to design oral FDFs of a drug meant for management of chronic disease like type-2 diabetes mellitus which affects mostly elderly population. Glimepiride was the drug of choice because of its low dose. Since in vitro dissolution rate is the rate limiting step in drug absorption for class II drugs, in the present work, it was also proposed to make a complex of the drug with hydroxypropyl betacyclodextrin (HPBCD to improve the physicochemical-pharmacokinetic characters of the drug. Various batches of FDFs were developed by the solvent casting method using water soluble polymers HPMC-E5 and Maltodextrin as film formers; Glycerol and PEG-600 as plasticizers; Sodium starch glycollate as super disintegrating/channeling agent; Sodium lauryl sulphate, polaxamer 407 and Tween-80 as surfactants; aspartame as a sweetener and brilliant blue as coloring agent. The drug was complexed with HPBCD by kneading method in the ratio of 1:1 and was incorporated in the film in the place of plain drug. Poloxamer containing films gave better physico-chemical characters than the other tested surfactants and addition of HPBCD complexed drug further improved the characters of the films. The formulation containing drug- HPBCD complex and polaxamer 407 as the surfactant gave lowest disintegration time, more uniform and faster dissolution profile, had better taste, highter Cmax and lower tmax values during in vivo studies. It can therefore be concluded that the drug in its most soluble form gives better physicochemical and pharmacokinetic characters which results in better management of the disease as patient compliance improves.

  19. Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.

    Science.gov (United States)

    Zhu, Wanyi; Schmehl, Daniel R; Mullin, Christopher A; Frazier, James L

    2014-01-01

    Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.

  20. Adverse drug reaction labelling for atomoxetine, methylphenidate and modafinil: comparison of product information for oral formulations in Australia, Denmark and the United States.

    Science.gov (United States)

    Aagaard, Lise; Hansen, Ebba Holme

    2013-07-01

    Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted information about study design (clinical trials, spontaneous report). Discrepancies in ADR labelling for the medications were found across the three countries. A total of 75 ADR categories were listed for atomoxetine and 80% of these were listed in all three countries. For methylphenidate, totally 101 ADR categories and for modafinil 115 ADR categories were listed. For both substances approximately 60% of listed ADRs were found in all three countries. Discrepancies were primarily detected for ADRs information based on clinical trials. For methylphenidate, many ADRs labelled in Australia and Denmark were not mentioned in PIs issued in the United States. In conclusion, information about possible ADRs associated with the use of a specific product should be made available worldwide, as the prescriber information about medicines' safety profile should not depend on the country in which the medication is licensed.

  1. Four Common Pesticides, Their Mixtures and a Formulation Solvent in the Hive Environment Have High Oral Toxicity to Honey Bee Larvae

    Science.gov (United States)

    Zhu, Wanyi; Schmehl, Daniel R.; Mullin, Christopher A.; Frazier, James L.

    2014-01-01

    Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax - fluvalinate, coumaphos, chlorothalonil, and chloropyrifos - tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common ‘inert’ ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated. PMID:24416121

  2. Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations.

    Science.gov (United States)

    Patel, Mit J; Badmanaban, R; Patel, C N

    2011-04-01

    A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min(1) with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 - 21 μg ml for TOLP μg / ml and 8 - 56 μg / ml for ETD. The detection limit of the proposed method was 0.16 μg / ml and 0.58 μg / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 μg / ml and 1.7 μg / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 - 101.15 for TOLP and 98.63 - 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form.

  3. Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.

    Directory of Open Access Journals (Sweden)

    Wanyi Zhu

    Full Text Available Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L. health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.

  4. The influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine

    OpenAIRE

    Stout, Stephen M.; Nielsen, Jace; Welage, Lynda S; Shea, Michael; Brook, Robert; Kerber, Kevin; Bleske, Barry E

    2010-01-01

    Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used β-adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open-label, randomized, 4 phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate release (IR) tartrate and extende...

  5. 流化床混悬液上药法制备非诺贝特速释微丸的工艺研究%Formulation Study of Fenofibrate Immediate-release Pellets by Suspension layering

    Institute of Scientific and Technical Information of China (English)

    舒欣; 王明浩; 杨晖; 黄春玉; 谢俊; 周建平

    2015-01-01

    目的:采用流化床混悬液上药法制备非诺贝特速释微丸.方法:以上药效率、脆碎度、粘连率为评价指标,考察并优化混悬液上药法制备非诺贝特速释微丸的处方.结果:确定FNBT/HPMC-E5/SDS=160:20:1.6为最佳配比处方,选定固含量为20%,上药效率为95%,溶出度为15 min达90%.结论:流化床混悬液上药法制备非诺贝特微丸,上药效率高,方法简便可靠,溶出迅速.

  6. Dissolution Model Development: Formulation Effects and Filter Complications

    DEFF Research Database (Denmark)

    Berthelsen, Ragna; Holm, Rene; Jacobsen, Jette

    2016-01-01

    This study describes various complications related to sample preparation (filtration) during development of a dissolution method intended to discriminate among different fenofibrate immediate-release formulations. Several dissolution apparatus and sample preparation techniques were tested. The flow......-through cell apparatus (USP 4) was found unfit for dissolution testing of fenofibrate MeltDose formulations due to clogging of filters and varying flow rates. A mini paddle dissolution setup produced dissolution profiles of the tested formulations that correlated well with clinical data. The work towards...... the mini paddle dissolution method demonstrates that sample preparation influenced the results. The investigations show that excipients from the formulations directly affected the drug–filter interaction, thereby affecting the dissolution profiles and the ability to predict the in vivo data...

  7. Novel Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Oral Delivery of Olmesartan Medoxomil: Design, Formulation, Pharmacokinetic and Bioavailability Evaluation.

    Science.gov (United States)

    Nasr, Ali; Gardouh, Ahmed; Ghorab, Mamdouh

    2016-06-27

    The main purpose of this study was to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of Olmesartan (OLM) for enhancement of its solubility and dissolution rate. In this study, liquid SNEDDS containing Olmesartan was formulated and further developed into a solid form by the spray drying technique using Aerosil 200 as a solid carrier. Based on the preliminary screening of different unloaded SNEDDS formulae, eight formulae of OLM loaded SNEEDS were prepared using Capryol 90, Cremophor RH40 and Transcutol HP as oil, surfactant and cosurfactant, respectively. Results showed that the mean droplet size of all reconstituted SNEDDS was found to be in the nanometric range (14.91-22.97 nm) with optimum PDI values (0.036-0.241). All formulae also showed rapid emulsification time (15.46 ± 1.34-24.17 ± 1.47 s), good optical clarity (98.33% ± 0.16%-99.87% ± 0.31%) and high drug loading efficiency (96.41% ± 1.20%-99.65% ± 1.11%). TEM analysis revealed the formation of spherical and homogeneous droplets with a size smaller than 50 nm. In vitro release of OLM from SNEDDS formulae showed that more than 90% of OLM released in approximately 90 min. Optimized SNEDDS formulae were selected to be developed into S-SNEDDS using the spray drying technique. The prepared S-SNEDDS formulae were evaluated for flow properties, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), reconstitution properties, drug content and in vitro dissolution study. It was found that S-SNEDDS formulae showed good flow properties and high drug content. Reconstitution properties of S-SNEDDS showed spontaneous self-nanoemulsification and no sign of phase separation. DSC thermograms revealed that OLM was in solubilized form and FTIR supported these findings. SEM photographs showed smooth uniform surface of S-SNEDDS with less aggregation. Results of the in vitro drug release showed that there was great enhancement in the dissolution rate of OLM. To clarify the

  8. Novel Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS for Oral Delivery of Olmesartan Medoxomil: Design, Formulation, Pharmacokinetic and Bioavailability Evaluation

    Directory of Open Access Journals (Sweden)

    Ali Nasr

    2016-06-01

    Full Text Available The main purpose of this study was to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS of Olmesartan (OLM for enhancement of its solubility and dissolution rate. In this study, liquid SNEDDS containing Olmesartan was formulated and further developed into a solid form by the spray drying technique using Aerosil 200 as a solid carrier. Based on the preliminary screening of different unloaded SNEDDS formulae, eight formulae of OLM loaded SNEEDS were prepared using Capryol 90, Cremophor RH40 and Transcutol HP as oil, surfactant and cosurfactant, respectively. Results showed that the mean droplet size of all reconstituted SNEDDS was found to be in the nanometric range (14.91–22.97 nm with optimum PDI values (0.036–0.241. All formulae also showed rapid emulsification time (15.46 ± 1.34–24.17 ± 1.47 s, good optical clarity (98.33% ± 0.16%–99.87% ± 0.31% and high drug loading efficiency (96.41% ± 1.20%–99.65% ± 1.11%. TEM analysis revealed the formation of spherical and homogeneous droplets with a size smaller than 50 nm. In vitro release of OLM from SNEDDS formulae showed that more than 90% of OLM released in approximately 90 min. Optimized SNEDDS formulae were selected to be developed into S-SNEDDS using the spray drying technique. The prepared S-SNEDDS formulae were evaluated for flow properties, differential scanning calorimetry (DSC, scanning electron microscopy (SEM, reconstitution properties, drug content and in vitro dissolution study. It was found that S-SNEDDS formulae showed good flow properties and high drug content. Reconstitution properties of S-SNEDDS showed spontaneous self-nanoemulsification and no sign of phase separation. DSC thermograms revealed that OLM was in solubilized form and FTIR supported these findings. SEM photographs showed smooth uniform surface of S-SNEDDS with less aggregation. Results of the in vitro drug release showed that there was great enhancement in the dissolution rate of OLM

  9. Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir.

    Science.gov (United States)

    Garg, Babita; Katare, O P; Beg, Sarwar; Lohan, Shikha; Singh, Bhupinder

    2016-05-01

    The present studies entail the development of the systematically optimized solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the systemic bioavailability of lopinavir and targeting the same to the sanctuary site, i.e., lymphatic system for complete HIV inhibition. The patient-centric quality target product profile (QTPP) was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through failure mode and effect critically analysis (FMECA), helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. As per the preliminary studies, viz solubility and phase titration studies, and factor screening studies, Maisine (i.e., lipid), Tween 80 (emulgent), Transcutol HP (i.e., cosolvent) were selected as the critical material attributes (CMAs) of the liquid SNEOFs (L-SNEOFs). D-optimal mixture design was employed for the optimization of aforesaid CMAs and evaluated for in vitro dissolution, globule size, ex vivo permeation studies as the critical quality attributes (CQAs). Optimal composition of CMAs, was embarked through numerical optimization and desirability function, exhibited excellent permeation and drug release characteristics besides possessing globule size in nano range, i.e., 53.16 nm. Further to increase the stability and drug loading, the OPT-L-SNEOFs were then adsorbed onto the porous carrier, i.e., Aeroperl, to prepare the OPT-SNEOF tablets which were finally compressed into the tablet employing MCC as the filler. The performance evaluation through in situ SPIP studies ascribed the significant enhancement in absorptivity parameters of both the SNEOFs vis-à-vis the pure drug. Also, chylomicron flow block SPIP studies revealed lymphatic uptake of lopinavir from the SNEOFs. Overall, in vivo pharmacokinetic studies in rats revealed significant improvement in the rate and extent of oral bioavailability of the SNEOFs compared to the pure drug. These studies

  10. Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy?: a pharmacokinetic study with two oral formulations (Luminal(®) vet, Phenoleptil(®)) in dogs.

    Science.gov (United States)

    Bankstahl, Marion; Bankstahl, Jens P; Löscher, Wolfgang

    2013-10-09

    In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal(®) or the veterinary products Luminal(®) vet and the generic formulation Phenoleptil(®). Luminal(®) and Luminal(®) vet are identical 100 mg tablet formulations, while Phenoleptil(®) is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil(®) for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal(®) (human tablets) to Phenoleptil(®) in epileptic dogs, which were controlled by treatment with Luminal(®), induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal(®) vet vs. Phenoleptil(®) with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Peak plasma concentrations (Cmax) following Luminal(®) vet vs. Phenoleptil(®) were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil(®) vs. Luminal(®) vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil(®) vs. Luminal(®) vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability. Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to recurrence of

  11. Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy?: a pharmacokinetic study with two oral formulations (Luminal® vet, Phenoleptil®) in dogs

    Science.gov (United States)

    2013-01-01

    Background In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal® or the veterinary products Luminal® vet and the generic formulation Phenoleptil®. Luminal® and Luminal® vet are identical 100 mg tablet formulations, while Phenoleptil® is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil® for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal® (human tablets) to Phenoleptil® in epileptic dogs, which were controlled by treatment with Luminal®, induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal® vet vs. Phenoleptil® with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Results Peak plasma concentrations (Cmax) following Luminal® vet vs. Phenoleptil® were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil® vs. Luminal® vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil® vs. Luminal® vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability. Conclusions Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to

  12. Omeprazole/antacid-powder suspension--Santarus: Acitrel, Rapinex Powder for oral suspension, SAN 05.

    Science.gov (United States)

    2004-01-01

    Santarus Inc., is developing an immediate-release formulation of omeprazole in combination with an antacid (sodium bicarbonate) as a powder for suspension, known as Acitrel [SAN 05], and also as Rapinex powder for oral suspension. Acitrel is based on technology licensed from the University of Missouri. Santarus have also licensed technology from Tulane and North Carolina Universities relating to potential treatments for GI diseases. Santarus have licensed exclusive, worldwide rights to patent applications covering specific combination-formulations of proton pump inhibitors and antacids for treating various upper GI diseases and disorders. Santarus plans to license development, distribution and marketing rights of Rapinex Powder for oral suspension 20mg outside the US, to one or more well established pharmaceutical companies. The US FDA has requested that Santarus pursue a name other than Rapinex for the product. Santarus is currently discussing potential alternative names for the product with the FDA. Santarus announced positive results, in August 2003, from a phase III trial comparing oral Acitrel (Rapinex 40mg) to intravenous cimetidine in preventing upper GI bleeding in 359 critically ill adult patients. Santarus has also completed an open-label clinical trial in 243 patients, including 97 patients with gastric ulcers, evaluating the safety of Rapinex 40mg for an 8-week period. In connection with the NDA for Rapinex 40mg, Santarus provided notice to the NDA holder for Prilosec delayed-release capsules and related patent owners that Rapinex 40mg does not infringe currently listed patents for Prilosec or that those patents are invalid.

  13. IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

    Science.gov (United States)

    Margolskee, Alison; Darwich, Adam S; Pepin, Xavier; Pathak, Shriram M; Bolger, Michael B; Aarons, Leon; Rostami-Hodjegan, Amin; Angstenberger, Jonas; Graf, Franziska; Laplanche, Loic; Müller, Thomas; Carlert, Sara; Daga, Pankaj; Murphy, Dónal; Tannergren, Christer; Yasin, Mohammed; Greschat-Schade, Susanne; Mück, Wolfgang; Muenster, Uwe; van der Mey, Dorina; Frank, Kerstin Julia; Lloyd, Richard; Adriaenssen, Lieve; Bevernage, Jan; De Zwart, Loeckie; Swerts, Dominique; Tistaert, Christophe; Van Den Bergh, An; Van Peer, Achiel; Beato, Stefania; Nguyen-Trung, Anh-Thu; Bennett, Joanne; McAllister, Mark; Wong, Mei; Zane, Patricia; Ollier, Céline; Vicat, Pascale; Kolhmann, Markus; Marker, Alexander; Brun, Priscilla; Mazuir, Florent; Beilles, Stéphane; Venczel, Marta; Boulenc, Xavier; Loos, Petra; Lennernäs, Hans; Abrahamsson, Bertil

    2017-01-01

    Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

  14. Efficacy of a combined oral formulation of derquantel-abamectin against the adult and larval stages of nematodes in sheep, including anthelmintic-resistant strains.

    Science.gov (United States)

    Little, Peter R; Hodge, Andrew; Maeder, Steven J; Wirtherle, Nicole C; Nicholas, David R; Cox, George G; Conder, George A

    2011-09-27

    Derquantel (DQL), a semi-synthetic member of a novel anthelmintic class, the spiroindoles, in combination with abamectin (ABA) [as the combination product STARTECT(®)] is a new entry for the treatment and control of parasites in sheep. The 19 studies reported herein were conducted in Australia, New Zealand, South Africa and the United Kingdom to demonstrate the efficacy of derquantel-abamectin (DQL-ABA) against a broad spectrum of gastrointestinal and respiratory nematodes of sheep, and to support registration of the combination product. Eleven studies were conducted using natural or experimental parasite infections with unknown or unconfirmed resistance, while eight studies utilised isolates/strains with confirmed or well characterised resistance to one or more currently available anthelmintics, including macrocyclic lactones. All studies included DQL-ABA and negative control groups, and in selected studies one or more reference anthelmintic groups were included. In all studies the commercial formulation of DQL-ABA was administered orally at 2mg/kg DQL and 0.2mg/kg ABA; placebo was administered in the same volume as DQL-ABA; and reference anthelmintics were administered as per label recommendations, except in one instance where levamisole was administered at twice the label dose. Infection, necropsy, worm collection and worm counting procedures were performed using standard techniques. Efficacy was calculated based on the percentage reduction in geometric mean worm count relative to negative control for each nematode species and lifecycle stage targeted. Twenty-two isolates/strains used in the eight studies targeting resistant worms had proven resistance: three to one anthelmintic class, eleven to two classes and eight to three or more classes; of these resistant strains, 16 demonstrated resistance to a macrocyclic lactone anthelmintic. Regardless of resistance status in the 19 studies, DQL-ABA controlled a broad range of economically important gastrointestinal

  15. Comparative bioavailability of two oral formulations of clopidogrel: Determination of clopidogrel and its carboxylic acid metabolite (SR26334 under fasting and fed conditions in healthy subjects

    Directory of Open Access Journals (Sweden)

    Brvar Nina

    2014-03-01

    Full Text Available Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka’s formulation to the innovator’s formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC0-t, AUC0-inf and Cmax of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.

  16. Field Trial of Attentuated Salmonella Typhi Live Oral Vaccine Ty21a in Liquid and Enteric-Coated Formulations and Epidemiological Survey for Incidence of Diarrhea due to Shigella Species

    Science.gov (United States)

    1988-05-18

    rx F’~ ~ 3ostAvailable COPY S~AD o FIELD TRIAL OF ATTENTUATED SALMONELLA TYPHI LIVE ORAL VACCINE Ty2la IN LIQUID AND ENTERIC-COATED FORMULATIONS AND...rampant, for example, among U.S. troops in Cuba during the Spanish-American War (1). Inactivated vaccines consisting of killed whole Salmonella typhi organisms...typhoid vaccines. Amer J Hyg 1964; 79:196-206. 10. Germanier R, Furer E. Isolation and characterization of gal E mutant Ty2la of Salmonella typhi : a

  17. Bacteriophage formulated into a range of semisolid and solid dosage forms maintain lytic capacity against isolated cutaneous and opportunistic oral bacteria.

    Science.gov (United States)

    Brown, Teagan L; Thomas, Tereen; Odgers, Jessica; Petrovski, Steve; Spark, Marion Joy; Tucci, Joseph

    2017-03-01

    Resistance of bacteria to antimicrobial agents is of grave concern. Further research into the development of bacteriophage as therapeutic agents against bacterial infections may help alleviate this problem. To formulate bacteriophage into a range of semisolid and solid dosage forms and investigate the capacity of these preparations to kill bacteria under laboratory conditions. Bacteriophage suspensions were incorporated into dosage forms such as creams, ointments, pastes, pessaries and troches. These were applied to bacterial lawns in order to ascertain lytic capacity. Stability of these formulations containing phage was tested under various storage conditions. A range of creams and ointments were able to support phage lytic activity against Propionibacterium acnes. Assessment of the stability of these formulations showed that storage at 4 °C in light-protected containers resulted in optimal phage viability after 90 days. Pessaries/suppositories and troches were able to support phage lytic activity against Rhodococcus equi. We report here the in-vitro testing of semisolid and solid formulations of bacteriophage lytic against a range of bacteria known to contribute to infections of the epithelia. This study provides a basis for the future formulation of diverse phage against a range of bacteria that infect epithelial tissues. © 2016 Royal Pharmaceutical Society.

  18. Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications.

    Science.gov (United States)

    Hartman, N R; Yarchoan, R; Pluda, J M; Thomas, R V; Wyvill, K M; Flora, K P; Broder, S; Johns, D G

    1991-09-01

    2',3'-Dideoxyinosine (ddI) has shown activity against human immunodeficiency virus in phase I clinical trials. The drug is rapidly degraded by acid, however, thus raising questions as to the efficiency and reproducibility of its absorption after oral administration. This investigation studies the bioavailability of several oral dosage forms of ddI. When ddI was given to fasting patients as an oral solution with antacid, the bioavailability was 41% +/- 7% (mean +/- SEM). However, when given as buffered tablets, the bioavailability was considerably less (25% +/- 5%). The bioavailability increased slightly when the tablets were given with supplemental antacid (36% +/- 6%). Two enteric-coated preparations had reasonable bioavailability (36% +/- 5% and 26% +/- 5%), but the peak plasma level was much lower and occurred at a much later time than with the oral solution. When ddI was given as a premeasured powder containing sucrose and buffer to be reconstituted by the patient (the "sachet" preparation), the bioavailability was 29% +/- 6%. This was similar to that of the oral solution for this particular group of patients (30% +/- 7%). However, the bioavailability of the sachet was only 17% +/- 4% when administered with food. When the sachet was given to patients receiving ranitidine, no consistent change in bioavailability was noted. Also, no change in ddI pharmacokinetics was noted in patients receiving ganciclovir.

  19. 基于生物药剂学分类系统的口服固体速释制剂生物豁免%Biowaiver for immediate-release solid oral dosage forms based on biopharmaceutics classification system

    Institute of Scientific and Technical Information of China (English)

    刘曼; 张文萍; 张丽娜; 刘会臣

    2016-01-01

    生物药剂学分类系统将药物按溶解度和渗透性分为4类,在指导新药研发和剂型设计、预测药物体内体外相关性、进行生物豁免研究等方面发挥了非常重要的作用.本文综述了基于生物药剂学分类系统的口服固体速释制剂生物豁免所需溶解度、渗透性和溶出度的接受标准和测定方法,并分类描述了进行过生物豁免研究的药物及其有关资料;建议我国尽快开展和接受生物豁免.

  20. Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: effect of Vitamin E TPGS and nanocrystal particle size on oral absorption.

    Science.gov (United States)

    Ghosh, Indrajit; Schenck, Daniel; Bose, Sonali; Ruegger, Colleen

    2012-11-20

    The purpose of this study was to develop nanosuspension formulations of a poorly soluble drug using a wet media milling technique. The milling process was optimized by studying the effects of critical process parameters on the size of nanoparticles using a factorial design approach. During the design of experiments (DOEs) study, different concentrations of Vitamin E TPGS in the suspensions were used to evaluate its influence on the stabilization of a nanosuspension. Once the final formulation was optimized, a pharmacokinetic study was performed in beagle dogs to investigate the effect of different ranges of particle size of nanocrystals on the plasma profile. A significant increase in AUC and C(max) was observed when the drug substance was converted into nanocrystals, likely due to the increase in dissolution rate. Results also revealed that the nanosuspension formulation (consists of nanocrystals with narrow size distribution, having a mean particle size<300 nm) produced less variability with regards to the individual plasma concentrations in the dogs when compared an alternate nanocrystal formulation (consists of nanocrystals with broad size distribution having a mean particle size<750 nm). This type of observation can be explained due to the Ostwald ripening phenomena between the nanocrystals when the particle size distribution was very broad (higher poly dispersity index). Surprisingly, the un-micronized suspension containing Vitamin E TPGS did not show any significant impact on pharmacokinetic parameters.

  1. Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users.

    Science.gov (United States)

    Parasrampuria, Dolly A; Schoedel, Kerri A; Schuller, Reinhard; Silber, Steven A; Ciccone, Patrick E; Gu, Joan; Sellers, Edward M

    2007-10-01

    The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.

  2. Impact of methylphenidate formulation on treatment patterns and hospitalizations: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Lage Maureen J

    2006-04-01

    Full Text Available Abstract Background While stimulant therapy has been shown to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD, there is less information concerning differences between alternative stimulant medications. The purpose of this study is to examine how different formulations of methylphenidate (MPH affect treatment patterns and hospitalizations. Methods From a large claims database we retrospectively identified individuals age 6 or older who were diagnosed with ADHD and who received either once daily, extended-release oral system methylphenidate (OROS® MPH (e.g., Concerta® or three-times daily immediate-release generic methylphenidate (TID MPH. There were 5,939 individuals included in the analysis – 4,785 who initiated therapy with OROS MPH and 1,154 who initiated therapy with TID MPH. We used Analyses of Covariance (ANCOVAs to examine differences in treatment patterns between individuals who initiated therapy on OROS MPH and those who initiated therapy on TID MPH. We used logistic and negative binomial multivariate regressions to examine the probability of being hospitalized and the hospital length of stay. Results Controlling for demographic characteristics, patient general health status, and comorbid diagnoses, significantly fewer individuals who initiated therapy with OROS MPH had a 15-day gap in therapy (85% vs. 97%, p Conclusion Results demonstrate that among individuals diagnosed with ADHD who receive either OROS MPH or TID MPH, the use of OROS MPH is associated with fewer gaps in medication, less switches in medication, and more days on intent-to-treat therapy. In addition, use of OROS MPH compared to TID MPH was associated with improved outcomes, as measured by the reduced use of hospitalizations.

  3. Immediate efficacy and persistent speed of kill of a novel oral formulation of afoxolaner (NexGardTM) against induced infestations with Ixodes ricinus ticks

    OpenAIRE

    Halos, Lénaïg; Lebon, Wilfried; Chalvet-Monfray, Karine; Larsen, Diane; Beugnet, Frederic

    2014-01-01

    Background Ticks are hematophageous arthropods that transmit a wide spectrum of pathogens to human and animals. The ability of an acaricidal product to kill ticks quickly provides an important added benefit, especially as protecting dogs from tick bites remains the best preventive measure against tick-borne diseases. The speed of kill of afoxolaner in a novel soft chewable formulation (NexGardTM) against induced infestations with Ixodes ricinus adult ticks was evaluated during a full-month ne...

  4. Clinical pharmacology of novel anticancer drug formulations

    OpenAIRE

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The majority of new anti-cancer drugs are oral pharmaceutical formulations, consisting of new chemical entities, like molecular targeted agents and novel variants of existing drugs. The development of oral ...

  5. Preliminary investigations of the colonisation of upper respiratory tract tissues of infants using a paediatric formulation of the oral probiotic Streptococcus salivarius K12.

    Science.gov (United States)

    Power, D A; Burton, J P; Chilcott, C N; Dawes, P J; Tagg, J R

    2008-12-01

    A powder preparation of the oral probiotic Streptococcus salivarius K12 has been given to 19 young otitis media-prone children following a 3-day course of amoxicillin administered as a preliminary to ventilation tube placement. In two subjects, the use of strain K12 appeared to effect the expansion of an indigenous population of inhibitory S. salivarius. In other children, strain K12 colonisation extended beyond the oral cavity to also include the nasopharynx or adenoid tissue. The relatively low proportion (33%) of subjects that colonised was attributed to failure of the amoxicillin pre-treatment to sufficiently reduce the indigenous S. salivarius populations prior to dosing with strain K12 powder.

  6. New chitosan salt in gastro-resistant oral formulation could interfere with enteric bile salts emulsification of diet fats: preliminary laboratory observations and physiologic rationale.

    Science.gov (United States)

    Fratter, Andrea; Frare, Carmen; Uras, Giovanni; Bonini, Mauro; Casari Bariani, Enrico; Ragazzo, Barbara; Gaballo, Paolo; Longobardi, Pasquale; Codemo, Carlo; Paoli, Antonio

    2014-06-01

    Chitosan (CH) is a polymer of glucosamine that is extracted from the shells of several sea fruits. It is well recognized as a nutritional supplement that is used to reduce body weight and blood lipid levels, but its clinical efficacy has not been clearly demonstrated. The true mechanism of action and physiological processes involved in these properties of CH are not yet understood or explained. The most accepted theories assume that CH reduces dietary fat absorption by trapping the fat in the gastric lumen. The very low pH of the gastric lumen induces CH jellification and, therefore, entrapment of the fats. This article describes the most plausible mechanism by which CH interferes with fat absorption in the first part of the enteric tract while interacting with cholic acids. We emphasize the weak points of the classic CH-containing formulations, which are unable to prove this theory. We also report preliminary experimental data of a new CH salt-containing formulation that is capable of effectively interfering with bile salt emulsification processes and, as a result, reducing dietary fat absorption.

  7. HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHOD VALIDATION OF α-MANGOSTIN ASSAY IN MANGOSTEEN (Garcinia mangostana L. FRUIT RIND EXTRACT FORMULATED IN ORAL SOLUTION

    Directory of Open Access Journals (Sweden)

    Liliek Nurhidayati

    2015-12-01

    Full Text Available Mangosteen fruit rind extract contain a lot of antioxidants. α-Mangostin is a component in mangosteen fruit rind that has highest antioxidant effect. The oral solution containing mangosteen fruit rind extract is required an assay method for quality assessment. Determination of a very low concentration of analyte in sample with very complex matrix, such as α-mangostin in oral solution, needs a selective and sensitive method, such as high performance liquid chromatography (HPLC. In this study, α-mangostin assay was performed by reverse phase HPLC system using octadecylsilane (C18 as stationary phase, methanol-water (90:10 as mobile phase, the flow rate is 1.0 mL/min, and the UV detector at 316 nm. The retention time of α-mangostin was 9.622 minutes. Peak of α-mangostin was well separated with resolution of 1.725. Linearity was in the range of 1.67-5.01 ppm with correlation coefficient of 0.9986. The relative standard deviation (RSD was 1.30 %, the recovery was in the range of 95.80-100.76.

  8. Oral Doxycycline in the Management of Acne Vulgaris: Current Perspectives on Clinical Use and Recent Findings with a New Double-scored Small Tablet Formulation.

    Science.gov (United States)

    Del Rosso, James Q

    2015-05-01

    Oral antibiotics have been used for the treatment of acne vulgaris for six decades. Among dermatologists, tetracyclines represent at least three-fourths of the oral antibiotics prescribed in clinical practice. Unlike other specialties, antibiotic use in dermatology is predominantly for the treatment of noninfectious disorders, such as acne vulgaris and rosacea, which usually involves prolonged therapy over several weeks to months as compared to short courses used to treat cutaneous infections. At the present time, doxycycline and minocycline are the most commonly prescribed tetracyclines in dermatology, used primarily for treatment of acne vulgaris with a long overall favorable track record of effectiveness and safety. Although both are commonly used, doxycycline may be chosen by clinicians more readily as there is a lower risk of rare yet potentially serious adverse reactions, although doxycycline does warrant preventative measures to reduce the risks of esophagitis and phototoxicity reactions. This article reviews data with a new double-scored small 150mg tablet of doxycycline hyclate that has proven functional scoring, exhibits bioavailability similar to enteric-coated doxycycline, and has been shown to be associated with a low potential for gastrointestinal adverse reactions very comparable to what is achieved with enteric-coated tablets.

  9. Bilayer Tablet Formulation of Metformin HCl and Acarbose: A Novel Approach To Control Diabetes.

    Science.gov (United States)

    Tiwari, Ruchi; Gupta, Ankita; Joshi, Meenakshi; Tiwari, Gaurav

    2014-01-01

    The present investigation studied a novel bilayer tablet having an extended release system of metformin HCl with Eudragit RS 100 and RL 100 and an immediate release system of acarbose with polyvinylpyrrolidone K30 (PVP K30) and polyethylene glycol 6000 (PEG 6000) in different ratios using solvent evaporation and cogrinding techniques. Solid dispersions (SDs) were characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), scanning electron microscopy (SEM), as well as by content uniformity, in vitro dissolution studies, and release kinetics. The selected SD system was subjected to bilayer tablet preparation by direct compression. Compressed tablets were evaluated for drug content, weight variation, friability, hardness, and thickness, and they underwent in vitro dissolution studies. The progressive disappearance of IR, x-ray, and thermotropic drug signals in SDs and physical mixtures were related to increasing amount of polymer. SEM studies suggested the homogenous dispersion of drug in polymers. FT-IR studies confirmed the formation of hydrogen bonding between drug and polymer. All tablet formulations showed compliance with pharmacopoeial standards. The formulations gave an initial burst effect to provide the loading dose of the drug followed by extended release for 12 h (Higuchi model via a non-Fickian diffusion controlled release mechanism). Stability studies conducted for the optimized formulation did not show any change in physical properties, drug content, or in vitro drug release. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of elevated blood glucose levels. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting

  10. Analgesic efficacy of an oral transmucosal spray formulation of meloxicam alone or in combination with tramadol in cats with naturally occurring osteoarthritis.

    Science.gov (United States)

    Monteiro, Beatriz P; Klinck, Mary P; Moreau, Maxim; Guillot, Martin; Steagall, Paulo Vm; Edge, Daniel K; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Gauvin, Dominique; Del Castillo, Jérôme Re; Troncy, Eric

    2016-11-01

    To evaluate the analgesic efficacy of meloxicam oral transmucosal spray (OTMS) alone and with tramadol in cats with osteoarthritis (OA). Randomized, blinded study. Fifteen geriatric cats weighing 4.5 ± 1.0 kg. Healthy cats with OA were randomly administered a placebo (every 12 hours orally) and meloxicam OTMS (approximately 0.05 mg kg(-1) every 24 hours) (group M, n = 7), or tramadol (3 mg kg(-1) every 12 hours orally) and meloxicam OTMS (group TM, n = 8) for 25 days. Evaluations performed before treatment (D0) and at week 3 (W3) consisted of peak vertical force, motor activity and response to mechanical temporal summation of pain (RMTS). Data were analyzed with mixed models and Fisher's exact test. Mean ± standard deviation peak vertical force (percentage of body weight) increased significantly in both groups (p = 0.02), from 47.7 ± 6.5% to 60.5 ± 9.4% in group M, and from 51.8 ± 5.0% to 64.1 ± 6.5% in group TM, with no difference between groups. Motor activity increased in M (from 43 ± 12 to 56 ± 13; p = 0.02), but not in TM. The number of stimulations from RMTS increased in TM only. Cut-off values were reached in a larger number of cats (n = 5) in TM than M (n = 1) (p tramadol-meloxicam combination provided no evident benefit over meloxicam alone, except for central hypersensitivity (assessed with RMTS). Further assessment of the potential toxicity of the combination is required prior to clinical use. Gingival administration was well accepted overall. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  11. Validated HPLC method for the pharmacokinetic study of oral extended-release cefpodoxime proxetil chitosan-alginate beads in rabbits.

    Science.gov (United States)

    Mujtaba, Ali; Kohli, Kanchan

    2017-05-01

    The aim of this study is to develop a simple and applicable HPLC method for the detection of cefpodoxime acid (CFA) in rabbit plasma after oral administration of cefpodoxime proxetil (CFP) loaded chitosan-alginate (CH-ALG) beads formulation. CFP is a prodrug that is deesterified in vivo to its active metabolite CFA to exhibit antibiotic activity. Chromatographic separation of CFA and internal standard (IS) was achieved by a RP18(C18), Phenomenax®100, (250×4.6mm) with the mobile phase consisting of (0.02mol/l (20mM) ammonium acetate solution and acetonitrile (92:8, v/v, pH=4.6) at a flow rate of 1.0ml/min. The method was validated according to the requirements of US-FDA guidelines for bioanalytical method validation. The linear regression analysis for the calibration plots showed good linear relationship (R(2)=0.9905) in the working concentration range of 0.5-50μg/ml. The limits of detection and quantification (S/N=3) were 0.069 and 0.136μg/ml. Plasma CFA levels were successfully determined in rabbit with satisfactory precision and accuracy. The analyte was found to be stable after a number of stability studies. The proposed HPLC method was successfully applied to pharmacokinetic study in rabbits for CFP loaded CH-ALG beads and marketed immediate release (IR) tablets. All pharmacokinetic parameters were assessed.

  12. Pharmacological and clinical evidence of nevirapine immediate- and extended-release formulations

    Directory of Open Access Journals (Sweden)

    Ena J

    2012-11-01

    Full Text Available Javier Ena, Concepción Amador, Conxa Benito, Francisco PasquauHIV Unit, Hospital Marina Baixa, Villajoyosa, SpainAbstract: We reviewed the current information available on nevirapine immediate- and extended-release formulations and its role in single-dose and combination antiretroviral therapy. Nevirapine was approved in 1996 and was the first non-nucleoside reverse-transcriptase inhibitor available for the treatment of HIV-1 infection. Nevirapine has demonstrated good efficacy and a well-characterized safety profile. A major drawback is the low genetic barrier, allowing the emergence of resistance in the presence of single mutations in the reverse-transcriptase gene. This shortcoming is particularly relevant when nevirapine is administered in a single dose to prevent mother-to-child transmission of HIV-1 infection, compromising the efficacy of future non-nucleoside reverse transcriptase–inhibitor regimens. Studies published recently have probed the noninferiority of nevirapine compared to ritonavir-boosted atazanavir with both tenofovir disoproxil fumarate and emtricitabine in antiretroviral treatment–naïve patients. In 2011, a new formulation of nevirapine (nevirapine extended release that allowed once-daily dosing was approved by the Food and Drug Administration and by the European Medicines Agency. VERxVe, a study comparing nevirapine extended release with nevirapine immediate release in antiretroviral treatment–naïve patients, and TRANxITION, a study carried out in antiretroviral treatment–experienced patients who switched therapy from nevirapine immediate release to nevirapine extended release, provided data on the noninferiority of the new formulation of nevirapine compared with nevirapine immediate release in terms of efficacy and safety. Nevirapine extended release will further increase the durability and persistence of nevirapine-containing antiretroviral therapy, allowing once-daily dosing regimens.Keywords: nevirapine

  13. Lanthanum carbonate for the control of hyperphosphatemia in chronic renal failure patients: a new oral powder formulation - safety, efficacy, and patient adherence.

    Science.gov (United States)

    Lloret, M Jesús; Ruiz-García, César; Dasilva, Iara; Furlano, Mónica; Barreiro, Yaima; Ballarín, José; Bover, Jordi

    2013-11-06

    Chronic kidney disease (CKD) is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P) and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients.

  14. The Acute Oral Toxicity of 300 Formulated Pesticides to Apis mellifera%300个农药制剂对蜜蜂的急性经口毒性

    Institute of Scientific and Technical Information of China (English)

    赵帅; 袁善奎; 才冰; 姜辉; 王晓军; 林荣华; 瞿唯钢; 张招荣

    2011-01-01

    [Aims] Honey bee is one of the most important insects for plant pollination, but the honey bees are underlying the phenomenon of colony collapse disorder (CCD), one of the factors causing this problem is the much use of pesticides in agricultural production. Totally 300 pesticides were tested for their acute omi toxicity to honey bee (Apis mellifera) by dietary method in the paper, the objective of this study is to understand the status of toxicity of common used pesticides.[Restults] The results indicated that the pesticides with very high toxicity, high toxicity, moderate toxicity and low toxicity pesticides accounted for 14.7, 35.6, 10.7, 39% respectively, the high toxic and very high toxic pesticide covered more than 50%, and these pesticides were mainly the insecticides, while the fungicides and herbicides with relative low toxicity.The toxicity of different pesticide formulations with the same active ingredients (AI) to zebra fish maybe varied for the difference in AI content, formulation type and processing technique. Regarding to the biological pesticides, some of them still have high toxicity to honeybee. [Conclusions] These results suggested that the pesticides with high toxicity to honey bee covered a large proportion of common used pesticides in China, therefore, some precautions should be involved as we used the pesticides, particularly for insecticides to reduce or avoid the side effects on honey bee.%[目的]蜜蜂是一种重要的传粉昆虫,近年来世界各地出现了严重的种群衰退现象,原因之一是农业生产过程中使用了大量农药.采用摄入法测定f300个农药制剂对蜜蜂的急性经口毒性,旨在了解我国常用农药对蜜蜂的毒风险情况.[结果]结果表明:对蜜蜂的急性经口毒性表现剧毒、高毒、中毒、低毒的农药制剂分别占14.7%、35.6%、10.7%、39%,高毒和剧毒农药产品达50%以上,但这些制剂主要为杀虫剂,占整个杀虫剂的74.1%,杀菌剂和除草剂

  15. Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Sateesh Kumar Vemula

    2013-01-01

    Full Text Available The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4 showed almost complete drug release in the colon (99.86% within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period. The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The Cmax of colon targeted tablets was 11956.15 ng/mL at Tmax of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

  16. Colon targeted guar gum compression coated tablets of flurbiprofen: formulation, development, and pharmacokinetics.

    Science.gov (United States)

    Vemula, Sateesh Kumar; Bontha, Vijaya Kumar

    2013-01-01

    The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C(max) of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

  17. Lanthanum carbonate for the control of hyperphosphatemia in chronic renal failure patients: a new oral powder formulation – safety, efficacy, and patient adherence

    Directory of Open Access Journals (Sweden)

    Lloret MJ

    2013-11-01

    Full Text Available MªJesús Lloret, César Ruiz-García, Iara DaSilva, Mónica Furlano, Yaima Barreiro, José Ballarín, Jordi Bover Nephrology Department, Fundació Puigvert, IIB Sant Pau, Barcelona, Spain; REDinREN, Instituto de Investigación Carlos III, Madrid, Spain Abstract: Chronic kidney disease (CKD is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients. Keywords: chronic kidney disease, phosphate, phosphate binder

  18. Formulation and Evaluation of Multilayered Tablets of Pioglitazone Hydrochloride and Metformin Hydrochloride

    Directory of Open Access Journals (Sweden)

    Y. Ankamma Chowdary

    2014-01-01

    Full Text Available In the treatment of type 2 diabetes mellitus a continuous therapy is required which is a more complex one. As in these patients there may be a defect in both insulin secretion and insulin action exists. Hence, the treatment depends on the pathophysiology and the disease state. In the present study, multilayered tablets of pioglitazone hydrochloride 15 mg and metformin hydrochloride 500 mg were prepared in an attempt for combination therapy for the treatment of type 2 diabetes mellitus. Pioglitazone HCl was formulated as immediate release layer to show immediate action by direct compression method using combination of superdisintegrants, namely, crospovidone and avicel PH 102. Crospovidone at 20% concentration showed good drug release profile at 2 hrs. Metformin HCl was formulated as controlled release layer to prolong the drug action by incorporating hydrophilic polymers such as HPMC K4M by direct compression method and guar gum by wet granulation method in order to sustain the drug release from the tablets and maintain its integrity so as to provide a suitable formulation. The multilayered tablets were prepared after carrying out the optimization of immediate release layer and were evaluated for various precompression and postcompression parameters. Formulation F13 showed 99.97% of pioglitazone release at 2 hrs in 0.1 N HCl and metformin showed 98.81% drug release at 10 hrs of dissolution in 6.8 pH phosphate buffer. The developed formulation is equivalent to innovator product in view of in vitro drug release profile. The results of all these evaluation tests are within the standards. The procedure followed for the formulation of these tablets was found to be reproducible and all the formulations were stable after accelerated stability studies. Hence, multilayered tablets of pioglitazone HCl and metformin HCl can be a better alternative way to conventional dosage forms.

  19. Pharmacokinetic considerations of formulation: extended-release metoprolol succinate in the treatment of heart failure.

    Science.gov (United States)

    Wikstrand, John; Andersson, Bert; Kendall, Martin J; Stanbrook, Hilary; Klibaner, Michael

    2003-02-01

    Extended-release (ER) metoprolol succinate is a controlled-release formulation designed to deliver metoprolol succinate at a near constant rate for approximately 20 h, independent of food intake and gastrointestinal pH. Once-daily dosing of ER metoprolol succinate 12.5-200 mg produces even plasma concentrations over a 24-h period, without the marked peaks and troughs characteristically observed with the immediate-release (IR) formulation. This leads to consistent beta1-blockade over 24 h, while maintaining cardioselectivity at doses up to 200 mg daily. Pharmacokinetic studies have also been performed in heart failure patients and have demonstrated that ER metoprolol succinate is associated with a more pronounced and even beta1-blockade over a 24-h period than the IR formulation. The efficacy and good tolerability of ER metoprolol succinate in heart failure patients has now been demonstrated in a large-scale clinical trial.

  20. Oral steroid contraception.

    Science.gov (United States)

    Sech, Laura A; Mishell, Daniel R

    2015-11-01

    Oral steroid contraception is a popular method of family planning worldwide. Over the past several decades, this method of contraception has changed significantly by decreasing the estrogen dose, changing the progestin component, and reducing the hormone free interval. Despite the popularity of oral steroid contraception, there has been much criticism regarding the associated risks of venous thromboembolism and stroke. Despite these established, yet uncommon risks, oral steroid contraception has many important health benefits. This review highlights the available formulations of oral contraceptives along with their evidence-based associated risks and benefits. Highlights regarding future directions for development of novel oral contraceptives are also addressed.

  1. Influence of Solid Drug Delivery System Formulation on Poorly Water-Soluble Drug Dissolution and Permeability

    Directory of Open Access Journals (Sweden)

    Marko Krstić

    2015-08-01

    Full Text Available The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD, solid self-microemulsifying drug delivery systems (S-SMEDDS and solid self-nanoemulsifying drug delivery systems (S-SNEDDS were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin® UFL2 was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin® UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6 were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine.

  2. pH-triggered drug release from biodegradable microwells for oral drug delivery

    DEFF Research Database (Denmark)

    Nielsen, Line Hagner; Nagstrup, Johan; Gordon, Sarah;

    2015-01-01

    Microwells fabricated from poly-L-lactic acid (PLLA) were evaluated for their application as an oral drug delivery system using the amorphous sodium salt of furosemide (ASSF) as a model drug. Hot embossing of PLLA resulted in fabrication of microwells with an inner diameter of 240 μm and a height...... of microwell cavities with an Eudragit® layer prevented drug release in biorelevant gastric medium. An immediate release of the ASSF from coated microwells was observed in the intestinal medium. This pH-triggered release behavior demonstrates the future potential of PLLA microwells as a site-specific oral drug...

  3. Niosomal Formulation Of Orlistat: Formulation And In-Vitro Evaluation

    Directory of Open Access Journals (Sweden)

    SAMYUKTHA RANI. B

    2011-06-01

    Full Text Available The purpose of the research was to prepare Orlistat niosomes from proniosome to improve its poor and variable oral bioavailability. The non-ionic surfactant vesicles are prepared by the reverse phase evaporation technique (slurry method. The slurry of - Cyclodextrin and Span 60 was dried to form a free flowing powder in rotary flash evaporator which could be rehydrated by addition of buffer (0.5% NaCl with 3% SLS at pH 6.0. The lipid mixture consisted of cholesterol, Span 60 and - Cyclodextrin carrier in molar ratios of (0.1:0.9:1 to 0.9:0.1:1 respectively. The niosomal formulations were evaluated for particle size, entrapment efficiency, in-vitro drug release, release kinetics, Interactions and compatibility (FT-IR, surface morphology (SEM, stability studies, conductivity and sedimentation rate, pH density, viscosity. The formulation OT9 which showed higher entrapment efficiency of 44.09% and invitro releases of 94.59% at the end of 12hrs was found to be best among all the 9 formulations. Release was best fitted with Hixson kinetics and it shows that the drug release may follow diffusion mechanism. FT-IR data revealed that, compatible and there were no interactions between the drug and excipients added in the formulation. SEM images of niosomes with various magnifications revealed the mean size of the niosomes were 100 nm with smooth surface. Niosome formulation has showed appropriate stability for 90 days by storing the formulation at room temperature. Thus the niosomal formulations could be a promising delivery system for Orlistat with improved oral bioavailability, stability and for sustained drug release.

  4. Oral calcitonin

    Directory of Open Access Journals (Sweden)

    Hamdy RC

    2012-09-01

    Full Text Available Ronald C Hamdy,1,2 Dane N Daley11Osteoporosis Center, College of Medicine, East Tennessee State University, 2Veterans Affairs Medical Center, Johnson City, TN, USAAbstract: Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl-amino-caprylic acid (5-CNAC (Emisphere Technologies, Cedar Knolls, NJ. Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis failed to

  5. Toothpaste formulation efficacy in reducing oral flora

    African Journals Online (AJOL)

    Erah

    Purpose: To assess the microbial quality as well as the effectiveness of seven brands of toothpaste ... ingredient to achieve the effect the consumer desires ... health. Triclosan is usually used in gum. It is a constituent used to avert gum disease.

  6. Oral supplementation with a nutraceutical formulation containing omega-3 fatty acids, vitamins, minerals, and antioxidants in a large series of patients with dry eye symptoms: results of a prospective study

    Directory of Open Access Journals (Sweden)

    Gatell-Tortajada J

    2016-05-01

    Full Text Available Jordi Gatell-TortajadaOn behalf of the Large Dry Eye Clinical Study Group (LDECSGCornea and Ocular Surface Department, Institut Català de Retina, Barcelona, SpainPurpose: To assess the benefits and tolerability of a dietary supplement based on omega-3 fatty acids to relieve dry eye symptoms.Methods: A total of 1,419 patients (74.3% women, mean age 58.9 years with dry eye syndrome using artificial tears participated in a 12-week prospective study. Patients were instructed to take 3 capsules/day of the nutraceutical formulation (Brudysec® 1.5 g. Study variables were dry eye symptoms (scratchy and stinging sensation, eye redness, grittiness, painful and tired eyes, grating sensation, and blurry vision, conjunctival hyperemia, tear breakup time (TBUT, Schrimer I test, and Oxford grading scheme.Results: At 12 weeks, each dry eye symptom improved significantly (P<0.001, and the use of artificial tears decreased significantly from 3.77 (standard deviation [SD] =2.08 at baseline to 3.45 (SD =1.72 (P<0.01. In addition, the Schirmer test scores and the TBUT increased significantly, and there was an increase in patients grading 0–I in the Oxford scale and a decrease of those grading IV–V. Significant differences in improvements of dry eye symptoms were also found in compliant versus noncompliant patients as well as in those with moderate/severe versus none/mild conjunctival hyperemia.Conclusion: Oral ω-3 fatty acids supplementation was an effective treatment for dry eye symptoms.Keywords: dry eye symptoms, artificial tears, omega-3 polyunsaturated fatty acids, nutraceutical supplement, ocular inflammation, eye discomfort

  7. Quantification of strontium in human serum by ICP-MS using alternate analyte-free matrix and its application to a pilot bioequivalence study of two strontium ranelate oral formulations in healthy Chinese subjects.

    Science.gov (United States)

    Zhang, Dan; Wang, Xiaolin; Liu, Man; Zhang, Lina; Deng, Ming; Liu, Huichen

    2015-01-01

    A rapid, sensitive and accurate ICP-MS method using alternate analyte-free matrix for calibration standards preparation and a rapid direct dilution procedure for sample preparation was developed and validated for the quantification of exogenous strontium (Sr) from the drug in human serum. Serum was prepared by direct dilution (1:29, v/v) in an acidic solution consisting of nitric acid (0.1%) and germanium (Ge) added as internal standard (IS), to obtain simple and high-throughput preparation procedure with minimized matrix effect, and good repeatability. ICP-MS analysis was performed using collision cell technology (CCT) mode. Alternate matrix method by using distilled water as an alternate analyte-free matrix for the preparation of calibration standards (CS) was used to avoid the influence of endogenous Sr in serum on the quantification. The method was validated in terms of selectivity, carry-over, matrix effects, lower limit of quantification (LLOQ), linearity, precision and accuracy, and stability. Instrumental linearity was verified in the range of 1.00-500ng/mL, corresponding to a concentration range of 0.0300-15.0μg/mL in 50μL sample of serum matrix and alternate matrix. Intra- and inter-day precision as relative standard deviation (RSD) were less than 8.0% and accuracy as relative error (RE) was within ±3.0%. The method allowed a high sample throughput, and was sensitive and accurate enough for a pilot bioequivalence study in healthy male Chinese subjects following single oral administration of two strontium ranelate formulations containing 2g strontium ranelate.

  8. Olaparib tablet formulation

    DEFF Research Database (Denmark)

    Plummer, Ruth; Swaisland, Helen; Leunen, Karin

    2015-01-01

    BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet...... formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part...... exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption....

  9. A new formulation of fenofibrate: suprabioavailable tablets.

    Science.gov (United States)

    Guichard, J P; Blouquin, P; Qing, Y

    2000-01-01

    The rationale for, and development of, a new suprabioavailable fenofibrate tablet formulation is described. The new suprabioavailable tablet formulation combines well-established micronisation technology with a new micro-coating process. The new formulation provides more predictable and reliable drug absorption. Owing to the strong relationship between the fenofibrate dissolution performance and its oral bioavailability, equivalent plasma levels of active principal are achieved at a lower dose, with less inter-subject variability and a reduced food effect. The new suprabioavailable tablet may, therefore, be a more efficient and better tolerated formulation.

  10. Formulations of Amlodipine: A Review

    Directory of Open Access Journals (Sweden)

    Muhammad Ali Sheraz

    2016-01-01

    Full Text Available Amlodipine (AD is a calcium channel blocker that is mainly used in the treatment of hypertension and angina. However, latest findings have revealed that its efficacy is not only limited to the treatment of cardiovascular diseases as it has shown to possess antioxidant activity and plays an important role in apoptosis. Therefore, it is also employed in the treatment of cerebrovascular stroke, neurodegenerative diseases, leukemia, breast cancer, and so forth either alone or in combination with other drugs. AD is a photosensitive drug and requires protection from light. A number of workers have tried to formulate various conventional and nonconventional dosage forms of AD. This review highlights all the formulations that have been developed to achieve maximum stability with the desired therapeutic action for the delivery of AD such as fast dissolving tablets, floating tablets, layered tablets, single-pill combinations, capsules, oral and transdermal films, suspensions, emulsions, mucoadhesive microspheres, gels, transdermal patches, and liposomal formulations.

  11. Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies

    Science.gov (United States)

    2013-01-01

    Background The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed. The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. Methods A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Results Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Conclusions Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy

  12. Crystallization Formulation Lab

    Data.gov (United States)

    Federal Laboratory Consortium — The Crystallization Formulation Lab fills a critical need in the process development and optimization of current and new explosives and energetic formulations. The...

  13. Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

    Science.gov (United States)

    Sugihara, Masahisa; Takeuchi, Susumu; Sugita, Masaru; Higaki, Kazutaka; Kataoka, Makoto; Yamashita, Shinji

    2015-12-07

    In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are

  14. Inherent formulation issues of kinase inhibitors.

    Science.gov (United States)

    Herbrink, M; Schellens, J H M; Beijnen, J H; Nuijen, B

    2016-10-10

    The small molecular Kinase Inhibitor (smKI) drug class is very promising and rapidly expanding. All of these drugs are administered orally. The clear relationship between structure and function has led to drugs with a general low intrinsic solubility. The majority of the commercial pharmaceutical formulations of the smKIs are physical mixtures that are limited by the low drug solubility of a salt form. This class of drugs is therefore characterized by an impaired and variable bioavailability rendering them costly and their therapies suboptimal. New formulations are sparingly being reported in literature and patents. The presented data suggests that continued research into formulation design can help to develop more efficient and cost-effective smKI formulation. Moreover, it may also be of help in the future design of the formulations of new smKIs.

  15. In vitro models for the prediction of in vivo performance of oral dosage forms

    DEFF Research Database (Denmark)

    Kostewicz, Edmund S; Abrahamsson, Bertil; Brewster, Marcus

    2014-01-01

    Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connectio...

  16. Development of a controlled release formulation by continuous twin screw granulation: Influence of process and formulation parameters.

    Science.gov (United States)

    Vanhoorne, V; Vanbillemont, B; Vercruysse, J; De Leersnyder, F; Gomes, P; Beer, T De; Remon, J P; Vervaet, C

    2016-05-30

    The aim of this study was to evaluate the potential of twin screw granulation for the continuous production of controlled release formulations with hydroxypropylmethylcellulose as hydrophilic matrix former. Metoprolol tartrate was included in the formulation as very water soluble model drug. A premix of metoprolol tartrate, hydroxypropylmethylcellulose and filler (ratio 20/20/60, w/w) was granulated with demineralized water via twin screw granulation. After oven drying and milling, tablets were produced on a rotary Modul™ P tablet press. A D-optimal design (29 experiments) was used to assess the influence of process (screw speed, throughput, barrel temperature and screw design) and formulation parameters (starch content of the filler) on the process (torque), granule (size distribution, shape, friability, density) and tablet (hardness, friability and dissolution) critical quality attributes. The torque was dominated by the number of kneading elements and throughput, whereas screw speed and filling degree only showed a minor influence on torque. Addition of screw mixing elements after a block of kneading elements improved the yield of the process before milling as it resulted in less oversized granules and also after milling as less fines were present. Temperature was also an important parameter to optimize as a higher temperature yielded less fines and positively influenced the aspect ratio. The shape of hydroxypropylmethylcellulose granules was comparable to that of immediate release formulations. Tensile strength and friability of tablets were not dependent on the process parameters. The use of starch as filler was not beneficial with regard to granule and tablet properties. Complete drug release was obtained after 16-20h and was independent of the design's parameters.

  17. CombiCap: A novel drug formulation for the basel phenotyping cocktail.

    Science.gov (United States)

    Camblin, Marine; Berger, Benjamin; Haschke, Manuel; Krähenbühl, Stephan; Huwyler, Jörg; Puchkov, Maxim

    2016-10-15

    Phenotyping of cytochrome P450 isoenzymes is used for metabolic profiling. Phenotyping cocktails are usually administered as individual marketed products, which are not designed for diagnostic applications. Therefore, a formulation strategy was developed, which can be applied to any phenotyping cocktail. The formulation was validated in vitro and in vivo in human volunteers using caffeine, efavirenz, flurbiprofen, metoprolol, midazolam, and omeprazole (Basel Cocktail). Spray dried di-calcium phosphate particles (Fujicalin) were used as an inert drug carrier for probe drugs. All drugs were successfully loaded into Fujicalin by a solvent evaporation method. Mini-tablets were produced and demonstrated good physical characteristics, expected drug content and immediate release profiles for all drug formulations. Mini-tablets were introduced into a capsule (CombiCap) and used for a pilot study in human volunteers. Plasma samples were collected and analyzed by liquid chromatography and mass spectrometry. Plasma concentration ratios between the parent drugs and the respective metabolites were equivalent for the novel CombiCap formulation and individually dosed Basel Cocktail drugs. We conclude that the CombiCap formulation platform can be easily adopted for different types of phenotyping cocktails due to its scalable and modular design, which allows a simple and convenient combination of variable doses of different probe drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Clinical pharmacology of novel anticancer drug formulations

    NARCIS (Netherlands)

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The

  19. Clinical pharmacology of novel anticancer drug formulations

    NARCIS (Netherlands)

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The major

  20. In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010 against Candida albicans, human monocytic and kidney cell lines

    Directory of Open Access Journals (Sweden)

    Clement John G

    2011-08-01

    Full Text Available Abstract Background Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B and azoles. Amphotericin B (AmpB presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation. The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010 against Candida albicans, human kidney (293T cells and monocytic (THP1 cells. Methods Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation. Results None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 μg/L (n = 4-10, p The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 ± 2.9 for iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (μg of AmpB/L, n = 6-12, p Conclusions The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizone™ and Ambisome™, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model. The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.

  1. In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010) against Candida albicans, human monocytic and kidney cell lines.

    Science.gov (United States)

    Leon, Carlos G; Lee, Jinkyung; Bartlett, Karen; Gershkovich, Pavel; Wasan, Ellen K; Zhao, Jinying; Clement, John G; Wasan, Kishor M

    2011-08-20

    Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation. The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells. Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation. None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 μg/L (n = 4-10, p iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (μg of AmpB/L, n = 6-12, p iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.

  2. IT Supporting Strategy Formulation

    NARCIS (Netherlands)

    Achterbergh, J.M.I.M.

    2005-01-01

    This overview approaches information and communication technology (ICT) for competitive intelligence from the perspective of strategy formulation. It provides an ICT architecture for supporting the knowledge processes producing relevant knowledge for strategy formulation. To determine what this arch

  3. IT Supporting Strategy Formulation

    NARCIS (Netherlands)

    Achterbergh, J.M.I.M.

    2005-01-01

    This overview approaches information and communication technology (ICT) for competitive intelligence from the perspective of strategy formulation. It provides an ICT architecture for supporting the knowledge processes producing relevant knowledge for strategy formulation. To determine what this arch

  4. Torsion formulation of gravity

    Energy Technology Data Exchange (ETDEWEB)

    Lledo, M A; Sommovigo, L, E-mail: Maria.Lledo@ific.uv.e, E-mail: Luca.Sommovigo@mfn.unipmn.i [Departament de Fisica Teorica, Universitat de Valencia, and IFIC (Centro mixto CSIC-UVEG) C/Dr Moliner, 50, E-46100 Burjassot (Valencia) (Spain)

    2010-03-21

    We explain precisely what it means to have a connection with torsion as a solution of the Einstein equations. While locally the theory remains the same, the new formulation allows for topologies that would have been excluded in the standard formulation of gravity. In this formulation it is possible to couple arbitrary torsion to gauge fields without breaking the gauge invariance.

  5. Research design strategies to evaluate the impact of formulations on abuse liability.

    Science.gov (United States)

    McColl, Shelley; Sellers, Edward M

    2006-06-01

    Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective.

  6. Formulation and evaluation of floating tablets of niacin for sustained release

    Directory of Open Access Journals (Sweden)

    Haripriya Puthoori

    2012-01-01

    Full Text Available Niacin or nicotinic acid (NA is used in the treatment of hyperlipidemia. NA immediate release formulation shows undesirable effects like flushing of the face and neck parts. In the present study, NA floating sustained release dosage form was developed to prolong the drug release, to retain the drug delivery system above the site of absorption for the desired period of time, and to reduce the drug release rate compared to conventional formulations in order to minimize the side effects. The preformulation parameters such as flow properties and drug-excipient compatibility studies were performed. The drug excipient compatibility studies were performed using the FTIR study and the results showed that all the polymers used in the study are compatible with the pure drug. The floating sustained release tablets of niacin were prepared by the wet granulation method and the granules were evaluated for various micromeritic properties like bulk density, tapped density, Carr′s Index, Hausner′s ratio, and angle of repose. The tablets were evaluated for post-compressional parameters like average weight, thickness, hardness, friability, swelling index, floating lag time and total floating time, and in vitro drug release studies. All the formulations showed total floating time >20 hr. The concentration of the effervescent agent and the concentration and type of polymer showed an effect on the floating behavior and drug release. The formulation containing 13% sodium bicarbonate, HPMC (33% and Eudragit RS PO (4% showed required drug release up to 20 hr.

  7. Formulation and evaluation of press coated tablets of salbutamol sulphate for time controlled release

    Directory of Open Access Journals (Sweden)

    M D Wasimul Hasan

    2014-01-01

    Full Text Available The objective of the present study was to formulate and evaluate a press coated pulsatile drug delivery system of salbutamol sulphate in order to attain a time controlled release for treatment of nocturnal asthma. The core was prepared by direct compression, while press coating technique was used in coating the outer layer there by preparing a press coated tablet. The immediate release core formulations comprised of salbutamol sulphate and disintegrants like crospovidone, croscarmellose sodium and sodium starch glycolate in different ratios with the drug. The outer coat formulations were prepared using a hydrophilic (HPMC and hydrophobic (EC polymer of similar viscosity. The polymers were reviewed individually for their influence on lag time further obtaining the lag time using polymer combinations were assessed by employing central composite design. All the preliminary trials were evaluated for various post compression parameters along with the dissolution study that was performed using USP paddle method at 50 rpm in 0.1 N HCl and phosphate buffer pH 6.8. The formulation containing 300 mg of EC N50 and 75-100 mg of HPMC E50 may be regarded as the minimum quantity required in outer press coat so as to attain a predetermined lag time of 6 h.

  8. Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine.

    Science.gov (United States)

    Stout, Stephen M; Nielsen, Jace; Welage, Lynda S; Shea, Michael; Brook, Robert; Kerber, Kevin; Bleske, Barry E

    2011-03-01

    Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used beta-adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open-label, randomized, 4-phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate-release (IR) tartrate and extended-release (ER) succinate metoprolol formulations. Ten healthy participants received metoprolol IR (50 mg) and ER (100 mg) with and without paroxetine coadministration. Blood samples were collected over 24 hours for determination of metoprolol plasma enantiomer concentrations. Paroxetine coadministration significantly increased S and R metoprolol area under the plasma concentration-time curve from time 0 to the 24-hour blood draw (AUC(0-24h)) by 4- and 5-fold, respectively for IR, and 3- and 4-fold, respectively, for ER. S/R AUC ratios significantly decreased. These results demonstrate a pharmacokinetic interaction between paroxetine and both formulations of metoprolol. The interaction is greater with R metoprolol, and stereoselective metabolism is lost. This could theoretically result in greater beta-blockade and lost cardioselectivity. The magnitude of the interaction was similar between metoprolol formulations, which may be attributable to low doses/drug input rates employed.

  9. Formulation development and comparative in vitro study of metoprolol tartrate (IR) tablets.

    Science.gov (United States)

    Husain, Tazeen; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Maboos, Madiha; Khan, Madeeha; Bashir, Lubna; Naz, Shazia

    2016-05-01

    The objective of the present work was to develop Immediate Release (IR) tablets of Metoprolol Tartrate (MT) and to compare trial formulations to a reference product. Six formulations (F1-F6) were designed using central composite method and compared to a reference brand (A). Two marketed products (brands B and C) were also evaluated. F1-F6 were prepared with Avicel PH101 (filler), Crospovidone (disintegrant) and Magnesium Stearate (lubricant) by direct compression. Pharmacopoeial and non-pharmacopoeial methods were used to assess their quality. Furthermore, drug profiles were characterized using model dependent and independent (f(2)) approaches. Brands B and C and F5 and F6 did not qualify the tests for content uniformity. Moreover, brand B did not meet weight variation criteria and brand C did not satisfy requirements for single point dissolution test. Of the trial formulations, F2 failed the test for uniformity in thickness while F4 did not disintegrate within time limit. Only F1 and F3 met all quality parameters and were subjected to accelerated stability testing without significant alterations in their physicochemical characteristics. Based on AIC and r(2)(adjusted) values obtained by applying various kinetic models, drug release was determined to most closely follow Hixson-Crowell cube root law. F1 was determined to be the optimized formulation.

  10. Lyophilized Oral Sustained Release Polymeric Nanoparticles of Nateglinide

    National Research Council Canada - National Science Library

    Kaleemuddin, Mohammad; Srinivas, Prathima

    2013-01-01

    The objective of this study is to formulate lyophilized oral sustained release polymeric nanoparticles of nateglinide in order to decrease dosing frequency, minimize side effects, and increase bioavailability...

  11. Immediate release niacin effect at stratified lipid levels

    Directory of Open Access Journals (Sweden)

    Elise Vo

    2015-12-01

    If initial LDL-C was  =130, LDL-C decreased 35% in MTG vs. 32% decrease in CTG. If initial HDL-C  150, there was a 48% decrease in MTG vs. 54% decrease in CTG. Lpa decreased 49% for all patients with initially elevated Lpa. Data except for LDL-C  130, but not significantly when LDL-C < 130. Patients in AIM-HIGH and HPS-2-THIRVE received statin therapy causing very low initial LDL-C. Our results may explain why adding niacin to statin therapy failed in AIM-HIGH and HPS-2-THRIVE since niacin did not further lower LDL-C.