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Sample records for release solid oral

  1. 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

  2. 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

  3. 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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  4. 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. © 2013 Wiley Periodicals, Inc. and the

  5. 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. Copyright © 2016 American Pharmacists Association®. All rights reserved.

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

    NARCIS (Netherlands)

    Verbeeck, Roger K; Kanfer, Isadore; Löbenberg, Raimar; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Polli, James E; Parr, Alan; Shah, Vinod P; Mehta, Mehul; Dressman, Jennifer B

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active

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

    NARCIS (Netherlands)

    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

    2017-01-01

    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

  8. Individual Oral Therapy with Immediate Release and Effervescent Formulations Delivered by the Solid Dosage Pen

    Science.gov (United States)

    Wening, Klaus; Laukamp, Eva Julia; Thommes, Markus; Breitkreutz, Jörg

    2012-01-01

    New devices enabling freely selectable dosing of solid oral medications are urgently needed for personalized medicine. One approach is the use of the recently published Solid Dosage Pen, allowing flexible dosing of tablet-like sustained release slices from drug loaded extruded strands. Slices were suitable for oral single dosed application. The aim of the present study was the development of immediate release dosage forms for applications of the device, especially for young children. Using two model drugs, two different concepts were investigated and evaluated. Effervescent formulations were manufactured by an organic wet-extrusion process and immediate release formulations by a melt-extrusion process. Dissolution experiments were performed for both formulations to ensure the immediate release behavior. Extruded strands were individually dosed by the Solid Dosage Pen. Various doses of the two formulations were analyzed regarding uniformity of mass and content according to pharmacopoeial specifications. Proof of concept was demonstrated in both approaches as results comply with the regulatory requirements. Furthermore, storing stress tests were performed and drug formulations were characterized after storing. The results show that suitable packaging material has been selected and storage stability is probable. PMID:25562361

  9. Solid lipid particles for oral delivery of peptide and protein drugs I - Elucidating the release mechanism of lysozyme during lipolysis

    DEFF Research Database (Denmark)

    Christophersen, Philip Carsten B; Zhang, L.; Yang, M

    2013-01-01

    The mechanism of protein release from solid lipid particles was investigated by a new lipolysis model in a biorelevant medium containing both bile salts and phospholipids. Lysozyme, a model protein, was formulated into solid lipid particles using four different types of lipids, two triglycerides ...... the drug release mechanism from solid lipid particles and can potentially be used in rational selection of lipid excipients for oral delivery of peptide/protein drugs....

  10. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

    Science.gov (United States)

    Hofsäss, Martin A; Souza, Jacqueline de; Silva-Barcellos, Neila M; Bellavinha, Karime R; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Parr, Alan; Langguth, Peter; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Mehta, Mehul U; Dressman, Jennifer B

    2017-08-24

    This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  11. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

    Science.gov (United States)

    Verbeeck, Roger K; Kanfer, Isadore; Löbenberg, Raimar; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Polli, James E; Parr, Alan; Shah, Vinod P; Mehta, Mehul; Dressman, Jennifer B

    2017-08-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  12. 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  13. Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms.

    Science.gov (United States)

    Hermans, Andre; Abend, Andreas M; Kesisoglou, Filippos; Flanagan, Talia; Cohen, Michael J; Diaz, Dorys A; Mao, Y; Zhang, Limin; Webster, Gregory K; Lin, Yiqing; Hahn, David A; Coutant, Carrie A; Grady, Haiyan

    2017-11-01

    This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.

  14. 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.

  15. 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  16. Use of the ninhydrin assay to measure the release of chitosan from oral solid dosage forms.

    Science.gov (United States)

    Leane, M M; Nankervis, R; Smith, A; Illum, L

    2004-03-01

    This study evaluated and optimised the ninhydrin assay as a tool for measuring the in vitro release and dissolution of chitosan from solid dosage forms. The precision and accuracy of the assay for the type of chitosan used in the study were examined by measuring the inter- and intra-sample variation and found to be within acceptable limits. The assay was applied practically to construct a pH/solubility profile for chitosan and subsequently to measure the release and dissolution of chitosan from dosage forms in the presence and absence of a model drug, sodium salicylate. Assay performance was found to be satisfactory over a wide range of physiologically relevant pH values. It is concluded that the ninhydrin assay is an essential aid in the design and testing of solid dosage forms with different chitosan-drug release profiles.

  17. 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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  18. Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

    Directory of Open Access Journals (Sweden)

    Praveen Kumar Gaur

    2014-01-01

    Full Text Available Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5±3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75±5% relative humidity (RH for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (Cmax⁡ and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES.

  19. 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. Copyright © 2011 Wiley Periodicals, Inc.

  20. Development of Houttuynia cordata Extract-Loaded Solid Lipid Nanoparticles for Oral Delivery: High Drug Loading Efficiency and Controlled Release

    Directory of Open Access Journals (Sweden)

    Ju-Heon Kim

    2017-12-01

    Full Text Available Houttuynia cordata (H. cordata has been used for diuresis and detoxification in folk medicine as well as a herbal medicine with antiviral and antibacterial activities. H. cordata extract-loaded solid lipid nanoparticles (H-SLNs were prepared with various concentration of poloxamer 188 or poloxamer 407 by a hot homogenization and ultrasonication method. H-SLNs dispersion was freeze-dried with or without trehalose as a cryoprotectant. The physicochemical characteristics of H-SLNs were evaluated by dynamic laser scattering (DLS, differential scanning calorimetry (DSC, Fourier transform infrared spectroscopy (FT-IR, and scanning electron microscopy (SEM. Additionally, the in vitro release and in vitro cytotoxicity of H-SLNs were measured. Encapsulation efficiencies of H-SLNs (as quercitrin were 92.9–95.9%. The SEM images of H-SLNs showed that H-SLNs have a spherical morphology. DSC and FT-IR showed that there were no interactions between ingredients. The increased extent of particle size of freeze-dried H-SLNs with trehalose was significantly lower than that of H-SLNs without trehalose. H-SLNs provided sustained release of quercitrin from H. cordata extracts. Cell viability of Caco-2 cells was over 70% according to the concentration of various formulation. Therefore, it was suggested that SLNs could be good carrier for administering H. cordata extracts.

  1. The Use of Hibiscus esculentus (Okra) Gum in Sustaining the Release of Propranolol Hydrochloride in a Solid Oral Dosage Form

    Science.gov (United States)

    Noordin, Mohamed Ibrahim; Kadivar, Ali

    2014-01-01

    The effectiveness of Okra gum in sustaining the release of propranolol hydrochloride in a tablet was studied. Okra gum was extracted from the pods of Hibiscus esculentus using acetone as a drying agent. Dried Okra gum was made into powder form and its physical and chemical characteristics such as solubility, pH, moisture content, viscosity, morphology study using SEM, infrared study using FTIR, crystallinity study using XRD, and thermal study using DSC and TGA were carried out. The powder was used in the preparation of tablet using granulation and compression methods. Propranolol hydrochloride was used as a model drug and the activity of Okra gum as a binder was compared by preparing tablets using a synthetic and a semisynthetic binder which are hydroxylmethylpropyl cellulose (HPMC) and sodium alginate, respectively. Evaluation of drug release kinetics that was attained from dissolution studies showed that Okra gum retarded the release up to 24 hours and exhibited the longest release as compared to HPMC and sodium alginate. The tensile and crushing strength of tablets was also evaluated by conducting hardness and friability tests. Okra gum was observed to produce tablets with the highest hardness value and lowest friability. Hence, Okra gum was testified as an effective adjuvant to produce favourable sustained release tablets with strong tensile and crushing strength. PMID:24678512

  2. The use of Hibiscus esculentus (Okra) gum in sustaining the release of propranolol hydrochloride in a solid oral dosage form.

    Science.gov (United States)

    Zaharuddin, Nurul Dhania; Noordin, Mohamed Ibrahim; Kadivar, Ali

    2014-01-01

    The effectiveness of Okra gum in sustaining the release of propranolol hydrochloride in a tablet was studied. Okra gum was extracted from the pods of Hibiscus esculentus using acetone as a drying agent. Dried Okra gum was made into powder form and its physical and chemical characteristics such as solubility, pH, moisture content, viscosity, morphology study using SEM, infrared study using FTIR, crystallinity study using XRD, and thermal study using DSC and TGA were carried out. The powder was used in the preparation of tablet using granulation and compression methods. Propranolol hydrochloride was used as a model drug and the activity of Okra gum as a binder was compared by preparing tablets using a synthetic and a semisynthetic binder which are hydroxylmethylpropyl cellulose (HPMC) and sodium alginate, respectively. Evaluation of drug release kinetics that was attained from dissolution studies showed that Okra gum retarded the release up to 24 hours and exhibited the longest release as compared to HPMC and sodium alginate. The tensile and crushing strength of tablets was also evaluated by conducting hardness and friability tests. Okra gum was observed to produce tablets with the highest hardness value and lowest friability. Hence, Okra gum was testified as an effective adjuvant to produce favourable sustained release tablets with strong tensile and crushing strength.

  3. Oral hydromorphone extended-release.

    Science.gov (United States)

    Guay, David R P

    2010-12-01

    To review the chemistry, pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of the Osmotic-controlled Release Oral delivery System (OROS) hydromorphone extended-release (ER) tablets. A MEDLINE/PUBMED search (1986-August 2010) was conducted to identify studies in the English language, with additional references being obtained from their bibliographies. All studies of hydromorphone ER were reviewed. This is the second long-acting hydromorphone formulation to receive approval by the Food and Drug Administration (a twice-daily formulation was approved in September 2004, but was subsequently withdrawn in July 2005). Hydromorphone is a semi-synthetic mu-opioid receptor agonist structurally similar to morphine, hydrocodone, and oxymorphone. OROS ER technology allows once-daily dosing. Clinical trials have focused on the convertibility of (an) other opioid(s) to hydromorphone ER in chronic malignant and nonmalignant pain. This product displays the expected opioid side effects, being comparable to oxycodone controlled-release. Coadministration with ethanol does not produce the degree of "dose-dumping" seen with the former hydromorphone twice-daily product or oxymorphone ER. Hydromorphone ER is indicated for the management of moderate-to-severe pain in opioidtolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time. Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B) and moderate renal impairment (creatinine clearance of 30-60 mL/min). Hydromorphone ER is the newest oral opioid to enter a crowded marketplace now totaling 15 different Schedule 2 opioids (including tapentadol), and tramadol, available in oral, parenteral, rectal, transdermal, transmucosal, and intranasal formulations. It does not appear to have any unique assets or liabilities and should be considered as one of many oral opioids available for the management of persistent pain of moderate

  4. Solid lipid particles for oral delivery of peptide and protein drugs III - the effect of fed state conditions on the in vitro release and degradation of desmopressin

    DEFF Research Database (Denmark)

    Christophersen, Philip C; Vaghela, Dimple; Müllertz, Anette

    2014-01-01

    The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles...... and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows...... that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract....

  5. Controlled release of acidic drugs in compendial and physiological hydrogen carbonate buffer from polymer blend-coated oral solid dosage forms.

    Science.gov (United States)

    Wulff, R; Rappen, G-M; Koziolek, M; Garbacz, G; Leopold, C S

    2015-09-18

    The objective of this study was to investigate the suitability of "Eudragit® RL/Eudragit® L55" (RL/L55) blend coatings for a pH-independent release of acidic drugs. A coating for ketoprofen and naproxen mini tablets was developed showing constant drug release rate under pharmacopeial two-stage test conditions for at least 300 min. To simulate drug release from the mini tablets coated with RL/L55 blends in the gastrointestinal (GI) tract, drug release profiles in Hanks buffer pH 6.8 were recorded and compared with drug release profiles in compendial media. RL/L55 blend coatings showed increased drug permeability in Hanks buffer pH 6.8 compared to phosphate buffer pH 6.8 due to its higher ion concentration. However, drug release rates of acidic drugs were lower in Hanks buffer pH 6.8 because of the lower buffer capacity resulting in reduced drug solubility. Further dissolution tests were performed in Hanks buffer using pH sequences simulating the physiological pH conditions in the GI tract. Drug release from mini tablets coated with an RL/L55 blend (8:1) was insensitive to pH changes of the medium within the pH range of 5.8-7.5. It was concluded that coatings of RL/L55 blends show a high potential for application in coated oral drug delivery systems with a special focus on pH-independent release of acidic drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Development of sustained release tablets containing solid ...

    African Journals Online (AJOL)

    Sustained release tablets containing solid dispersions granules of a poorly water soluble drug were prepared to investigate the controlled release of the drug. Baclofen was chosen because of its poor water solubility and short elimination half-life. Poloxamer 188 and PEG 6000 were used as solid dispersion carrier.

  7. New oral solid dosage form for furosemide oral administration.

    Science.gov (United States)

    Perioli, Luana; D'Alba, Giuseppina; Pagano, Cinzia

    2012-04-01

    Furosemide (FURO) is a drug labeled in class IV of the Biopharmaceutics Classification System (BCS) as it is both poor soluble and poor permeable. The aim of this work was to improve FURO biopharmaceutical properties by its formulation in a new solid oral dosage form. It consists in the realization of the composite MgAl-HTlc-FURO, obtained by FURO intercalation into the inorganic matrix hydrotalcite (MgAl-HTlc), and its successive formulation in tablets intended to be swallowed whole and to disintegrate rapidly in the stomach. These formulations were prepared by direct compression of a simple powder mixture constituted by MgAl-HTlc-FURO, a super disintegrant (Explotab, PolyplasdoneXL, PolyplasdoneXL-10, PolyplasdoneINF 10 or L-HPCLH-21) and a filler. The prepared formulations were submitted to disintegration time tests, and only those displaying the lowest disintegration time in gastric medium were submitted to in vitro release studies. Drug dissolution profiles from MgAl-HTlc-FURO tablets were compared with those containing crystalline FURO alone or physically mixed to MgAl-HTlc instead of MgAl-HTlc-FURO. The results revealed that tablets containing MgAl-HTlc-FURO give the best dissolution profile and that L-HPCLH-21 is able to promote the highest drug release in gastric medium, resulting in the most suitable super disintegrant in comparison with the other tested. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Trismus release in oral cancer patients.

    Science.gov (United States)

    Lee, Yao-Chou; Wong, Tung-Yiu; Shieh, Shyh-Jou; Lee, Jing-Wei

    2012-12-01

    Trismus is a common problem among oral cancer patients. This report aimed to study the inciting factors of trismus and to find out the rationale of trismus release. Between 1996 and 2008, 61 oral cancer patients with retrievable records of interincisor distance (IID) were analyzed by retrospective chart review. The IID decreased from 31.4 (12.4) to 24.9 (12.0) mm in 36 patients undergoing cancer ablation only (P = 0.001). Other variables prompting trismus include buccal cancer (P = 0.017), radiotherapy (P = 0.008), and recurrence (P = 0.001). In contrast, the IID improved from 11.7 (7.1) to 22.7 (11.9) mm in 25 patients receiving cancer ablative and trismus releasing surgeries (P = 0.000). The improvement fared better in individuals with IID less than 15 mm than the others (P = 0.037). In conclusion, involvement of buccal region, ablative surgery, radiotherapy, and recurrence are provocative factors of trismus. Patients with IID less than 15 mm will benefit from releasing surgery significantly. Others may better be handled with conservative managements firstly, and enrolled as candidates of surgical release only until the patients entertained a 28-month period of disease-free interval, by which time the risk of recurrence would be markedly reduced.

  9. DEVELOPMENT OF SUSTAINED RELEASE TABLETS CONTAINING SOLID DISPERSIONS OF BACLOFEN

    Directory of Open Access Journals (Sweden)

    K. H. Janardhana

    2015-07-01

    Full Text Available Sustained release tablets containing solid dispersions granules of a poorly water soluble drug were prepared to investigate the controlled release of the drug. Baclofen was chosen because of its poor water solubility and short elimination half-life. Poloxamer 188 and PEG 6000 were used as solid dispersion carrier. Free flowing solid dispersion granules were prepared by adsorbing the melt of the drug and carriers onto the surface of an adsorbent, Carbopol 934P followed by direct compression with HPMC K4M and HPMC K100 to obtain an solid dispersion loaded sustained release tablets. FTIR studies confirmed that the compatibility of drug and carriers. Differential scanning calorimetry (DSC and X-ray diffraction (XRD revealed partially amorphous structures of the drug in solid dispersion granules. The solid dispersion granules dissolved completely within 30 min, which was much faster than that of pure drug baclofen. The sustained release of baclofen from the solid dispersion containing tablet was achieved for 2 h in gastric fluid (pH 1.2 and for up to 10 h in intestinal fluid (pH 6.8. A combination of solid dispersion techniques using adsorption and sustained release concepts is a promising approach to control the release rate of poorly water-soluble drugs.

  10. Fabrication, Characterization, and In Vivo Evaluation of Famotidine Loaded Solid Lipid Nanoparticles for Boosting Oral Bioavailability

    Directory of Open Access Journals (Sweden)

    Muhammad Shafique

    2017-01-01

    Full Text Available Famotidine as H2 receptor has antagonistic effects on gastric secretion. Unfortunately, its hydrophobic nature contributes to its variable and poor oral bioavailability. In the current study efforts are being made to fabricate famotidine loaded solid lipid nanoparticles with narrow size distribution. Prepared nanoformulations were pharmaceutically evaluated to confirm the desired boosted oral bioavailability. Famotidine loaded nanoformulation (FFSe-4 showed particle size 111.9±1.3 nm, polydispersity index 0.464±0.03, zeta potential −33.46±2 mV, entrapment efficiency 84±2.7%, and drug loading capacity 2.709±0.13%. Drug-excipients compatibility was confirmed by Fourier transformed infrared spectroscopy. Scanning electron microscopy confirmed spherical shaped, nanosized particles. Differential scanning calorimetry and powder X-ray diffractometry confirmed the change in crystalline nature. Prepared nanoformulation was more stable at refrigerated temperature. In vitro study showed that drug release time is proportional to drug pay load and followed zero order kinetics. Release exponent (n>0.5 confirmed non-Fickian-diffusion mechanism for drug release. In vivo pharmacokinetic studies showed 2.06-fold increase in oral bioavailability of famotidine dispersed in solid lipid nanoparticles compared to commercial product. These results authenticate solid lipid nanoparticles as drug delivery system and propose prolonged release with improved oral bioavailability for famotidine.

  11. Sulfur Release from Cement Raw Materials during Solid Fuel Combustion

    DEFF Research Database (Denmark)

    Nielsen, Anders Rooma; Larsen, Morten B.; Glarborg, Peter

    2011-01-01

    During combustion of solid fuels in the material inlet end of cement rotary kilns, local reducing conditions can occur and cause decomposition of sulfates from cement raw materials. Decomposition of sulfates is problematic because it increases the gas-phase SO2 concentration, which may cause...... deposit formation in the kiln system. SO2 release from cement raw materials during combustion of solid fuels has been studied experimentally in a high temperature rotary drum. The fuels were tire rubber, pine wood, petcoke, sewage sludge, and polypropylene. The SO2 release from the raw materials...

  12. Lyophilized Oral Sustained Release Polymeric Nanoparticles of Nateglinide

    OpenAIRE

    Kaleemuddin, Mohammad; Srinivas, Prathima

    2012-01-01

    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. Nateglinide-loaded poly Ɛ-caprolactone nanoparticles were prepared by emulsion solvent evaporation with ultrasonication technique and subjected to various studies for characterization including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, photon correlati...

  13. Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro methods.

    Science.gov (United States)

    Pescina, Silvia; Macaluso, Claudio; Gioia, Gloria Antonia; Padula, Cristina; Santi, Patrizia; Nicoli, Sara

    2017-09-01

    The aim of the present paper was the development of semi-solid (hydrogels) and solid (film) ophthalmic formulations for the controlled release of two mydriatics: phenylephrine and tropicamide. The formulations - based on polyvinylalcohol and hyaluronic acid - were characterized, and release studies were performed with three different in vitro set-ups, i.e. Franz-type diffusion cell, vial method and inclined plane; for comparison, a solution and a commercial insert, both clinically used to induce mydriasis, were evaluated. Both gels and film allowed for a controlled release of drugs, appearing a useful alternative for mydriatics administration. However, the release kinetic was significantly influenced by the method used, highlighting the need for optimization and standardization of in vitro models for the evaluation of drug release from ophthalmic dosage forms.

  14. Polyvinylpyrrolidone oral films of enrofloxacin: film characterization and drug release.

    Science.gov (United States)

    Kumar, G Prem; Phani, A R; Prasad, R G S V; Sanganal, Jagadeesh S; Manali, N; Gupta, R; Rashmi, N; Prabhakara, G S; Salins, C Paul; Sandeep, K; Raju, D B

    2014-08-25

    Enrofloxacin is a fluoroquinolone derivative used for treating urinary tract, respiratory and skin infections in animals. However, low solubility and low bioavailability prevented it from using on humans. Polyvinylpyrrolidone (PVP) is an inert, non toxic polymer with excellent hydrophilic properties, besides it can enhance bioavailability by forming drug polymer conjugates. With the aim of increasing solubility and bioavailability, enrofloxacin thin films were prepared using PVP as a polymer matrix. The obtained oral thin films exhibited excellent uniformity and mechanical properties. Swelling properties of the oral thin films revealed that the water uptake was enhanced by 21%. The surface pH has been found to be 6.8±0.1 indicating that these films will not cause any irritation to oral mucosa. FTIR data of the oral thin films indicated physical interaction between drug and polymer. SEM analysis revealed uniform distribution of drug in polymer matrix. In vitro drug release profiles showed enhanced release profiles (which are also pH dependant) for thin films compared to pure drug. Antibacterial activity was found to be dose dependent and maximum susceptibility was found on Klebsiella pneumonia making this preparation more suitable for respiratory infections. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Absorption Study of Genistein Using Solid Lipid Microparticles and Nanoparticles: Control of Oral Bioavailability by Particle Sizes.

    Science.gov (United States)

    Kim, Jeong Tae; Barua, Sonia; Kim, Hyeongmin; Hong, Seong-Chul; Yoo, Seung-Yup; Jeon, Hyojin; Cho, Yeongjin; Gil, Sangwon; Oh, Kyungsoo; Lee, Jaehwi

    2017-07-01

    In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

  16. Dissolution Failure of Solid Oral Drug Products in Field Alert Reports.

    Science.gov (United States)

    Sun, Dajun; Hu, Meng; Browning, Mark; Friedman, Rick L; Jiang, Wenlei; Zhao, Liang; Wen, Hong

    2017-05-01

    From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator. Published by Elsevier Inc.

  17. Solid dispersion in the development of a nimodipine delayed-release tablet formulation

    Directory of Open Access Journals (Sweden)

    Yang Zhao

    2014-02-01

    Full Text Available Nimodipine (NMD is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological disorders and other cerebrovascular disorders, such as stroke which is associated with biological rhythm. This study was mainly designed to solve the drawback of conventional NMD solid dosage form, low bioavailability and limited clinical efficacy, by preparing enteric solid dispersion (SD and the SD was prepared via melting method. The physical state of the dispersed NMD in the polymer matrix was characterized by differential scanning calorimetry (DSC, powder X-ray diffraction (PXRD and dissolution studies. Compared with pure drug and physical mixture, the dissolution of NMD-SD was enhanced dramatically (about 80%. Furthermore, in consideration of the biological rhythm of stroke, we first obtained a delayed-release tablet containing NMD-SD by a direct powder compression method. As shown in the dissolution studies, the tablet released less than 10% in the artificial gastric acid in the initial 2 h and released 32.1%, 75%, more than 90% at 4, 10 and 14 h respectively in the artificial intestinal fluid. This investigation has solved the problems of oral solid dosage forms of NMD, and it has the good industry prospect.

  18. Lyophilized oral sustained release polymeric nanoparticles of nateglinide.

    Science.gov (United States)

    Kaleemuddin, Mohammad; Srinivas, Prathima

    2013-03-01

    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. Nateglinide-loaded poly Ɛ-caprolactone nanoparticles were prepared by emulsion solvent evaporation with ultrasonication technique and subjected to various studies for characterization including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, photon correlation spectroscopy and evaluated for in vitro drug release and pharmacodynamic studies. The influence of increase in polymer concentration, ultrasonication time, and solvent evaporation rate on nanoparticle properties was investigated. The formulations were optimized based on the above characterization, and the formulation using 5% polymer, 3-min sonication time, and rota-evaporated was found to have the best drug entrapment efficiency of 64.09±4.27% and size of 310.40±11.42 nm. Based on SEM, nanoparticles were found to be spherical with a smooth surface. In vitro drug release data showed that nanoparticles sustained the nateglinide release for over 12 h compared to conventional tablets (Glinate 60 mg), and drug release was found to follow Fickian mechanism. In vivo studies showed that nanoparticles prolonged the antidiabetic activity of nateglinide in rats significantly (p≤0.05) compared to the conventional tablets (Glinate 60 mg) over a period of 12 h. Accelerated stability data indicated that there was minimal to no change in drug entrapment efficiency.

  19. Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms.

    Science.gov (United States)

    Debotton, Nir; Dahan, Arik

    2017-01-01

    Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products. © 2016 Wiley Periodicals, Inc.

  20. 21 CFR 330.3 - Imprinting of solid oral dosage form drug products.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form drug...

  1. Ingested (oral) thyrotropin releasing factor (TRH) inhibits EAE.

    Science.gov (United States)

    Brod, Staley A; Bauer, Victoria

    2013-01-01

    Ingested immunoactive proteins type I IFN, SIRS peptide 1-21, α-MSH, ACTH, SST inhibit clinical attacks and inflammation in acute EAE by decreasing Th1-like cytokines, increasing Th2-like cytokines or increasing T(reg) cell frequencies. We examined whether another protein, thyrotropin releasing factor (TRH), would have similar anti-inflammatory effects in EAE after oral administration. B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TRH during ongoing disease. Splenocytes from mock fed or TRH fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Ingested (oral) TRH inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TRH fed donors protected against actively induced disease and decreased inflammation. In actively fed mice, oral TRH decreased IL-17 and TNF-α cytokines in both the spleen and the CNS. In recipients of donor cells from TRH fed mice there was a reduction of Th1 and Th17 and induction of Th2-like IL-13 cytokines in both the spleen and CNS. Oral TRH decreased clinical score and decreased inflammatory foci in both actively fed and recipients of actively fed mice. There was no significant increase in T(reg) cell frequencies in actively fed or recipients of TRH fed donor cells. Ingested (orally administered) TRH can inhibit clinical disease, inhibit CNS inflammation by decreasing Th1-like, Th17 and TNF-α cytokines and increasing Th2-like cytokines (IL-13) in the CNS. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. 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.

  3. AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration.

    Science.gov (United States)

    Patel, Pratikkumar A; Patravale, Vandana B

    2011-10-01

    Amphotericin B is the most effective gold standard drug against various fungal infections, especially in second line treatment of leishmaniasis. However, its usefulness is limited due to severe nephrotoxicity, which may lead to kidney failure. Due to its poor oral bioavailability, it is often administered parenterally to patients suffering from systemic fungal infection or visceral leishmaniasis (kala azar). In this investigation, solid lipid nanoparticles were formulated for oral administration of Amphotericin B. For this purpose, novel microemulsion based nanoprecipitation technique was employed. The influence of process variables such as sonication and dialysis time was studied. The optimized formulation was characterized for parameters such as particle size, polydispersity index, zeta potential, drug content and entrapment efficiency. The pH stability of the developed Amphotericin B solid lipid nanoparticles (AmbiOnp) at pH 1.2, 4, 6.8 values demonstrated enhanced protection of entrapped Amphotericin B. Further, single dose acute toxicity study established the safety of AmbiOnp for oral administration. In vivo pharmacokinetic studies revealed increase in % relative bioavailability of AmbiOnp in comparison to the plain drug. Additionally, the t1/2 of encapsulated Amphotericin B was significantly greater than that of plain drug, indicating the controlled release of Amphotericin B from AmbiOnp. Overall, the developed formulation; AmbiOnp was found to be successful in oral delivery of Amphotericin B.

  4. 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.

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

    Science.gov (United States)

    Ahmad, Javed; Mir, Showkat R.; Kohli, Kanchan; Chuttani, Krishna; Mishra, Anil K.; Panda, A. K.

    2014-01-01

    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. PMID:25114933

  6. Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

    Science.gov (United States)

    Claeys, Bart; Vervaeck, Anouk; Hillewaere, Xander K D; Possemiers, Sam; Hansen, Laurent; De Beer, Thomas; Remon, Jean Paul; Vervaet, Chris

    2015-02-01

    This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations

    NARCIS (Netherlands)

    Gohler, K.; Brett, M.; Smit, J.W.A.; Rengelshausen, J.; Terlinden, R.

    2013-01-01

    OBJECTIVE: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). METHODS: Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2

  8. 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics.

    Science.gov (United States)

    Goyanes, Alvaro; Wang, Jie; Buanz, Asma; Martínez-Pacheco, Ramón; Telford, Richard; Gaisford, Simon; Basit, Abdul W

    2015-11-02

    Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design

  9. A dual strategy to improve psychotic patients’ compliance using sustained release quetiapine oral disintegrating tablets

    Directory of Open Access Journals (Sweden)

    Refaat Ahmed

    2016-12-01

    Full Text Available Quetiapine (QT is a short acting atypical antipsychotic drug effective in schizophrenia and bipolar disorder. This study aims at designing a novel dosage form of sustained release taste-masked QT orally disintegrating tablets (ODTs based on solid lipid micro-pellets (SLMPs. QT SLMPs were prepared using the hot melt extrusion technique and utilizing three lipid carriers: Compritol, Precirol and white beeswax either alone or in mixtures. They showed sustained QT release and a taste masking effect. The selected QT SLMP was further blended with an aqueous solution containing polyvinylpyrollidone (2.5 %, croscarmellose sodium (2 % and mannitol (50 %; it was then lyophilized into ODT in a mass ratio of 1:2, respectively. ODTs containing QT SLMPs showed: average wetting time (40.92 s, average oral disintegration time (21.49 s, average hardness (16.85 N and also imparted suitable viscosity to suspend pellets during the lyophilization process. In conclusion, lyophilization is a promising technique for the formulation of multiparticulate systems into ODTs.

  10. A dual strategy to improve psychotic patients' compliance using sustained release quetiapine oral disintegrating tablets.

    Science.gov (United States)

    Refaat, Ahmed; Sokar, Magda; Ismail, Fatma; Boraei, Nabila

    2016-12-01

    Quetiapine (QT) is a short acting atypical antipsychotic drug effective in schizophrenia and bipolar disorder. This study aims at designing a novel dosage form of sustained release taste-masked QT orally disintegrating tablets (ODTs) based on solid lipid micro-pellets (SLMPs). QT SLMPs were prepared using the hot melt extrusion technique and utilizing three lipid carriers: Compritol, Precirol and white beeswax either alone or in mixtures. They showed sustained QT release and a taste masking effect. The selected QT SLMP was further blended with an aqueous solution containing polyvinylpyrollidone (2.5 %), croscarmellose sodium (2 %) and mannitol (50 %); it was then lyophilized into ODT in a mass ratio of 1:2, respectively. ODTs containing QT SLMPs showed: average wetting time (40.92 s), average oral disintegration time (21.49 s), average hardness (16.85 N) and also imparted suitable viscosity to suspend pellets during the lyophilization process. In conclusion, lyophilization is a promising technique for the formulation of multiparticulate systems into ODTs.

  11. Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications.

    Science.gov (United States)

    De Jaeghere, W; De Beer, T; Van Bocxlaer, J; Remon, J P; Vervaet, C

    2015-08-15

    The primary purpose of this study was to process partially hydrolyzed PVOH grades (degree of hydroxylation (DH): 33-88%) via HME and to evaluate them as carrier for oral immediate release dosage forms in order to improve the release rate of poorly water soluble drugs (i.e., HCT and CEL) via the formulation of solid dispersions. PVOH grades (DH >70%) were able to solubilize HCT and CEL up to 15%, but required higher extrusion temperature, due to the crystalline nature of PVOH. The highest drug release rate was observed from hot-melt extruded PVOH samples with a high DH. While drug release from extrudates consisting of PVOH with a low DH was affected by ionic strength, there was no influence of pH and ionic strength on HCT release from PVOH samples with a higher DH. However, PVOH (DH >70%) required higher extrusion temperatures, which could hamper its application for thermosensitive drugs. Therefore, the secondary purpose was to investigate the effect of sorbitol, a water-soluble plasticizer, on the thermal properties of hot-melt extruded PVOH (DH >70%). The melting of PVOH/sorbitol mixture was required to establish molecular interactions between PVOH and sorbitol. These molecular interactions were reflected in the HME behavior: whereas an extrusion temperature of 180 °C was necessary to process physical mixtures of PVOH (DH >70%) and sorbitol, only 140 °C was necessary during re-extrusion (after quench cooling and cryomilling) of the PVOH/sorbitol mixture. In addition, the in vitro and in vivo dug release of plasticized PVOH was examined; whereas the CEL/PVO/sorbitol system was able to maintain supersaturation during in vitro dissolution (0.1N HCl) compared to Celebrex(®), the in vivo pharmacokinetic parameters (AUC0-24h, Cmax and Tmax) were highly comparable. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Stereolithographic (SLA) 3D printing of oral modified-release dosage forms.

    Science.gov (United States)

    Wang, Jie; Goyanes, Alvaro; Gaisford, Simon; Basit, Abdul W

    2016-04-30

    The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs

    DEFF Research Database (Denmark)

    Fong, Sophia Yui Kau; Martins, Susana A. M.; Brandl, Martin

    2016-01-01

    Celecoxib (CXB) is a Biopharmaceutical Classification System class II drug in which its oral bioavailability is limited by poor aqueous solubility. Although a range of formulations aiming to increase the solubility of CXB have been developed, it is not completely understood, whether (1) an increase...... in CXB solubility leads to a subsequent increase in permeability across intestinal barrier and (2) the presence of bile salts affects the solubility and permeability behavior of CXB formulations. By formulating CXB solid phospholipid (PL) dispersions with various PL-to-drug ratios using freeze drying......, the present study illustrated that the enhancement of CXB solubility was not proportionally translated into enhanced permeability; both parameters were highly dependent on the PL-to-drug ratios as well as the dispersion media (i.e., the presence of 3-mM sodium taurocholate). This study highlights...

  14. SILYMARIN FOOD SUPPLEMENTS – ORAL SOLID DOSAGE FORMS

    Directory of Open Access Journals (Sweden)

    FELICIA G. GLIGOR

    2016-12-01

    Full Text Available Several tablet formulations containing silymarin were developed, in order to meet the requirements of different markets. Milk thistle - Silybum marianum (L. Gaertn – standardized extracts have proven their positive effect on liver functionality plus other health benefits. Lactose is a widely used excipient for the production of oral solid dosage forms. One important inconvenient of lactose is related to the lactose intolerant potential customers. Cellulose, isomalt and dicalcium phosphate have been selected as alternative possible tablet binders and diluents. Laboratory and pilot batches were studied for each excipient. The pharmacotechnical properties and silybin content of the tablets were measured and recorded in accordance to the European Pharmacopoeia. All pilot batches had results in the desired range of values in order to permit large scale compacting and blistering of the tablets. Currently the formulations containing isomalt and dicalcium phosphate that made the subject of this study are being produced on industrial scale.

  15. Evaluation of oral bioavailability and anticancer potential of raloxifene solid lipid nanoparticles.

    Science.gov (United States)

    Battani, Somashekhar; Pawar, Harish; Suresh, Sarasija

    2014-08-01

    The objective of the present investigation was formulation of raloxifene loaded solid lipid nanoparticles (R-SLN) for oral administration and evaluation of its anticancer potential in 7,12- dimethylbenzanthracene (DMBA)-induced breast cancer in Sprague-Dawley rats. Optimized R-SLN formulation prepared by modified micro-emulsion method resulted in R-SLN of 288.0±28.5 nm size and 95.56% entrapment efficiency. R-SLN exhibited in vitro prolonged release of raloxifene for 72 h in phosphate buffered saline. R-SLN was stable in simulated gastro-intestinal (GIT) fluids consisting of pH 1.2, pH 7.4, simulated gastric fluid and simulated intestinal fluid. A two-fold increase was observed in raloxifene oral bioavailability from R-SLN. R-SLN exhibited enhanced efficacy and chemopreventive activity over pure raloxifene as indicated by evaluation of tumor burden (P raloxifene solid lipid nanoparticles in optimizing chemoprevention of breast cancer by R-SLN.

  16. ORAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM: AN OVERVIEW

    OpenAIRE

    Modi Kushal; Modi Monali; Mishra Durgavati; Panchal Mittal; Sorathiya Umesh; Shelat Pragna

    2013-01-01

    Oral drug delivery is the most preferred and convenient option as the oral route provides maximum active surface area among all drug delivery system for administration of various drugs. The attractiveness of these dosage forms is due to awareness to toxicity and ineffectiveness of drugs when administered by oral conventional method in the form of tablets and capsules. Usually conventional dosage form produces wide range of fluctuation in drug concentration in the bloodstream and tissues with ...

  17. [Effect of EUDRAGIT® RS on the release behaviour of theophylline solid dispersions].

    Science.gov (United States)

    Orugun, Oluwaseun; Oyi, Avosuahi; Olowosulu, Adeniji; Apeji, Yonni; Olayemi, Olubunmi

    The purpose of this study was to extend the release of theophylline using Eudragit® RS 100 and Eudragit® RSPO as carriers. Solid dispersions of theophylline were prepared by the solvent evaporation technique using Eudragit® RS 100, Eudragit® RSPO and their blend in various drug : polymer ratios. The prepared solid dispersions were characterized with respect to entrapment efficiency, solubility and recovery yield. In vitro drug release of theophylline from the solid dispersions was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Solubility studies demonstrated a decrease in the solubility of the drug from the solid dispersions. The solubilities of pure drug and solid dispersions were lowered in SGF compared to SIF. Solid dispersions prepared with Eudragit® RS 100 entrapped a greater amount of theophylline in comparison to those with Eudragit® RSPO or the polymer blends and were able to extend the release of theophylline over 24 hrs. Formulation SD4 released 95.52% of the drug in SIF and 93.56% in SGF. Hence, it was selected as the optimized formulation because it was able to extend the release of theophylline over 24 hrs.Key words: solid dispersion extended release Eudragit® drug release.

  18. 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.

  19. Oral floating extended release stavudine hydrophilic matrix tablets ...

    African Journals Online (AJOL)

    Formulation of extended-release (ER) d4T improves patient compliance and minimizes dose related side effects. This study, therefore, aims at formulating once-a-day floating d4T ER hydrophilic matrix tablets using hydroxypropyl methylcellulose (HPMC) as a release-modifying polymer. NaHCO3 and microcrystalline ...

  20. New oral system for timing-release of drugs.

    Science.gov (United States)

    Conte, U; Maggi, L; Giunchedi, P; La Manna, A

    1992-05-01

    Polymeric barriers applied by compression have already been used to control drug release rate from matrix tablets. In this paper, polymeric barrier layers, used to prepare and develop a new device able to release the drug after a programmable period of time, are described. Some matrix core formulations, containing Trapidil or Sodium Diclofenac as a model drug, were dry-coated using either a swellable or an erodible shell. This coating prevents drug release from the core until the polymeric layer is not completely eroded or swollen. The time-lag can be modified by changing the barrier formulation and/or the coating thickness. Also drug release profiles (release rate and kinetics), can be widely modified changing the barrier layer characteristics.

  1. Sustained-release drug delivery of antimicrobials in controlling of supragingival oral biofilms.

    Science.gov (United States)

    Steinberg, Doron; Friedman, Michael

    2017-04-01

    Dental caries, a bacterial biofilm-associated disease, is a prevalent oral health problem. It is a bacterial biofilm-associated disease. Conventional means of combating this disease involves oral hygiene, mostly tooth brushing. Supplementary means of prevention and treatment is often necessary. The use of sustained-release delivery systems, locally applied to the oral cavity appears to be one of the most acceptable avenues for the delivery of antimicrobial agents. Area covered: The development and current approaches of local sustained delivery technologies applied to the oral cavity for treatment and prevention of dental caries is discussed. The use of polymeric drug delivery systems, varnishes, liposomes and nanoparticles is presented. Expert opinion: The use of local sustained-release delivery systems applied to the oral cavity has numerous clinical, pharmacological and toxicological advantages over conventional means. Various sustained-release technologies have been suggested over the course of several years. The current research on oral diseases concentrates predominantly on improving the drug delivery. With progress in pharmaceutical technology, sophisticated controlled-release platforms are being developed. The sustained release concept is innovative and there are few products available for the benefit of all populations. Harmonizing academic research with the dental industry will surely expedite the development and commercialization of more products of such pharmacological nature.

  2. Bioavailability and Bioequivalence Aspects of Oral Modified-Release Drug Products.

    Science.gov (United States)

    Wang, Rong; Conner, Dale P; Li, Bing V

    2017-03-01

    Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products.

  3. Formulation of Fast-Release Gastroretentive Solid Dispersion of ...

    African Journals Online (AJOL)

    transform infrared spectroscopy FTIR, bouyancy as well as by in vitro release and in vivo studies. Further aging studies were carried out for the samples. Results: PXRD showed that ..... Lee JW, Park JH, Robinson JP, Bioadhesive based dosage forms, the next generation, J. Pharm. Sci. 2000; 89: 850-866. 3. Bardonnet PL ...

  4. Determination of solid state characteristics of spray-congealed Ibuprofen solid lipid microparticles and their impact on sustaining drug release.

    Science.gov (United States)

    Wong, Priscilla Chui Hong; Heng, Paul Wan Sia; Chan, Lai Wah

    2015-05-04

    This study was used to find solid state characteristics of ibuprofen loaded spray-congealed solid lipid microparticles (SLMs) by employing simple lipids as matrices, with or without polymeric additives, and the impact of solid drug-matrix miscibility on sustaining drug release. Solid miscibility of ibuprofen with two lipids, cetyl alcohol (CA) and stearic acid (SA), were investigated using differential scanning calorimetry (DSC). SLMs containing 20% w/w ibuprofen with or without polymeric additives, PVP/VA and EC, were produced by spray congealing, and the resultant microparticles were subjected to visual examination by scanning electron microscopy (SEM), thermal analysis using DSC, and hot-stage microscopy. Intermolecular interactions between lipids and drug as well as additives were investigated by Fourier-transformed infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). X-ray diffractometry (XRD) was utilized to study polymorphic changes of drug and matrix over the course of a year. Ibuprofen was found to depress the melting points of CA and SA in a colligative manner, reaching maximum solubility at 10% w/w and 30% w/w for CA and SA, respectively. Drug encapsulation efficiencies and yields of spray-congealed SLMs containing 20% w/w ibuprofen were consistently high for both lipid matrices. CA and SA were found to adopt their stable γ- and β-polymorphs, respectively, immediately after spray congealing. The spray congealing process resulted in ibuprofen adopting an amorphous or poorly crystalline state, with no further changes over the course of a year. SEM, DSC, and hot stage microscope studies on the SLMs confirmed the formation of a solid dispersion between ibuprofen and CA and a solid solution between ibuprofen and SA. SA was found to sustain the release of ibuprofen significantly better than CA. PVP/VA and EC showed some interactions with CA, which led to an expansion of unit cell dimensions of CA upon spray congealing, whereas they

  5. Sustained Release Oral Nanoformulated Green Tea for Prostate Cancer

    Science.gov (United States)

    2011-05-01

    of chemopreventive agents. However, many agents have low bioavailability because of their poor biopharmaceutical and/or pharmacokinetic profile. As a...cases high oral dose leads to adverse effects. Various drug delivery systems, each one having its own limitations, have been developed to overcome the...hurdles of bioavailability and toxicity. Polymeric nanoparticles offer a great promise for drug delivery and in line with this fact we have

  6. Development of oral solid self-emulsifying lipid formulations of risperidone with improved in vitro dissolution and digestion.

    Science.gov (United States)

    Kazi, Mohsin; Al-Qarni, Hassan; Alanazi, Fars K

    2017-05-01

    Liquid adsorption on solid adsorbent carriers is an emerging technique for oral lipid-based drug delivery systems. The purpose of the current study is to convert liquid into solid self-emulsifying lipid formulations (SELFs) using an inorganic adsorbent Neusilin® grade US2 (NUS2) and investigate in vitro dissolution and digestion performance of the model antipsychotic compound risperidone. The liquid SELFs were designed using various oils, nonionic surfactants and converted into solid at various SELF: NUS2 (%m/m) mixing ratios. The characterization of solid SELF powder was performed by using SEM, XRD, FT-IR & DSC to investigate the physical nature of the drug. The in vitro dissolution experiments were conducted to compare the representative formulations with marketed product risperdal®. In vitro digestion experiments were performed using a pH-stat at pH 6.8 for 30mins to predict the fate of risperidone in the GI tract after exposure of the solid SELF to pancreatic enzymes and bile. The results from the characterization studies showed that NUS2 with SELF at 1:1 (%m/m) yield superior flowability of the powder. The SEM revealed that pure risperidone was in irregular crystal shape whereas the drug loaded solid SELFs were in smooth regular shape. The XRD and DSC analyses of pure risperidone also confirmed the intense peaks due to the native crystalline form of the drug. However, the absence of sharp peaks in solid SELFs indicated the amorphous form of the drug. From the dissolution studies it was found that solid SELFs provided significant release profiles (>95%) compared to marketed product risperdal®. The digestion experiments suggested that risperidone was in a supersaturated state which could be maintained in the presence of mixed bile salt micelles. Solid SELF of risperidone with improved dissolution and digestion profile was successfully prepared using Neusilin® US2 as an adsorbent carrier. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Response surface based co-optimization of release kinetics and mucoadhesive strength for an oral mucoadhesive tablet of cefixime trihydrate

    Directory of Open Access Journals (Sweden)

    Jagdish Manwar

    2016-12-01

    Conclusion: Cefixime trihydrate can be effectively formulated as an oral controlled release mucoadhesive tablet using RSM, and it is possible to achieve adequate mucoadhesive strength and the desired release profile with the optimum combination of polymers.

  8. Artificial Neural Networks in Evaluation and Optimization of Modified Release Solid Dosage Forms

    Directory of Open Access Journals (Sweden)

    Zorica Djurić

    2012-10-01

    Full Text Available Implementation of the Quality by Design (QbD approach in pharmaceutical development has compelled researchers in the pharmaceutical industry to employ Design of Experiments (DoE as a statistical tool, in product development. Among all DoE techniques, response surface methodology (RSM is the one most frequently used. Progress of computer science has had an impact on pharmaceutical development as well. Simultaneous with the implementation of statistical methods, machine learning tools took an important place in drug formulation. Twenty years ago, the first papers describing application of artificial neural networks in optimization of modified release products appeared. Since then, a lot of work has been done towards implementation of new techniques, especially Artificial Neural Networks (ANN in modeling of production, drug release and drug stability of modified release solid dosage forms. The aim of this paper is to review artificial neural networks in evaluation and optimization of modified release solid dosage forms.

  9. Oral controlled release formulation of diclofenac sodium by microencapsulation with ethyl cellulose.

    Science.gov (United States)

    Sajeev, C; Vinay, G; Archna, R; Saha, R N

    2002-01-01

    The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of diclofenac sodium (DFS) using different proportions of ethyl cellulose (EC) as the retardant material to extend the release. The formulated microcapsules were then compressed into tablets to obtain controlled release oral formulations. Phase separation-coacervation technique was employed to prepare microcapsules of DFS using different proportions of EC in cyclohexane. Physical characteristics of microcapsules and their tablets, in vitro release pattern of the designed microcapsules and their tablets prepared from them were studied using USP dissolution apparatus (USP 2000) type 2 (paddle method) in triple distilled water. The prepared microcapsules were white, free flowing and spherical in shape, with the particle size varying from 49.94-52.72 microm. The duration of DFS release from microcapsules was found to be directly proportional to the proportion of EC and, thus, coat thickness. All tablets were of good quality with respect to appearance, drug content uniformity, hardness, weight variation, friability and thickness uniformity. In vitro release study of the tabletted microcapsules in triple distilled water showed a zero order release kinetics and extended release beyond 24 h. A good correlation was obtained between drug release (t(60)) and proportion of EC in the microcapsules. In the case of tabletted microcapsules, very good correlation could be established between t(60), proportion of EC, weight of the tablets and between release rate constant (K) and proportion of EC. All the formulations were highly stable and possessed reproducible release kinetics across the batches.

  10. Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent wetting technique.

    Science.gov (United States)

    Jang, Sun Woo; Kang, Myung Joo

    2014-10-01

    The aim of this study was to improve the physicochemical properties and oral absorption of poorly water-soluble everolimus via preparation of a solid dispersion (SD) system using a solvent wetting (SW) technique. The physicochemical properties, drug release profile, and bioavailability of SD prepared by SW process were also compared to SD prepared by the conventional co-precipitation method. Solid state characterizations using scanning electron microscopy, particle size analysis and X-ray powder diffraction indicated that drug homogeneously dispersed and existed in an amorphous state within the intact polymeric carrier. Whereas, a film-like mass was obtained by a co-precipitation method and further pulverization step was needed for tabletization. The drug release from the SD tablet prepared by SW process at a ratio of drug to hydroxypropyl methylcellulose of 1:15 was markedly higher than the drug alone and equivalent to the marketed product (Afinitor(®), Novartis Pharmaceuticals), a SD tablet prepared by co-precipitation method, archiving over 75% the drug release after 30 min. At the accelerated (40°C/75% R.H.) and stress (80°C) stability tests, the novel formula was more stable than drug powder and provided comparable drug stability with the commercially available product, which contains a potentially risky antioxidant, butylated hydroxyl toluene. The pharmacokinetic parameters after single oral administration in beagles showed no significant difference (P>0.01) between the novel SD-based tablet and the marketed product. The results of this study, therefore, suggest that the novel SD system prepared by the solvent wetting process may be a promising approach for improving the physicochemical stability and oral absorption of the sirolimus derivatives. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. 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

  12. Environmentally Regulated Abiotic Release of Volatile Pheromones from the Sugar-based Oral Secretions of Caribflies

    Science.gov (United States)

    We report an abiotic mechanism for the emission of volatile insect pheromones that is controlled by environmentally-induced change in the physicochemical properties of the sugar-based release matrix. Male Anastrepha suspensa [Loew] (caribflies) mark mating sites on leaf surfaces by depositing oral ...

  13. Hybrid polymeric matrices for oral modified release of Desvenlafaxine succinate tablets

    Directory of Open Access Journals (Sweden)

    Wael Samy

    2017-07-01

    Full Text Available Purpose: Desvenlafaxine succinate (DSV is a water soluble anti-depressant drug, which is rapidly absorbed after oral administration exaggerating its side effects. The current work aimed to prepare controllable release DSV matrix to reduce DSV side effects related to its initial burst. Methods: Fifteen DSV matrix formulations were prepared using different polymers, polymer/drug ratios and matrix excipients and characterized using Differential Scanning Calorimetry (DSC, infrared (IR spectroscopy, water uptake and in vitro DSV release. The release kinetics were calculated to determine the drug release mechanism. Ex-vivo DSV absorption via rat intestinal mucosal cells and the calculation of the apparent permeability coefficient (Papp were performed using everted sac technique. Results: Maltodextrin was the best matrix excipient (F7 and F10 showing acceptable decrease in the initial burst compared to the innovator. The addition of negatively charged polymers sodium carboxy methyl cellulose (SCMC or sodium alginate resulted in an interaction that was proved by DSC and IR findings. This interaction slowed DSV release. F10 showed an excellent absorption of more than 80% of DSV after 4 h and the highest similarity factor with the innovator (84.7. Conclusion: A controllable release pattern of DSV was achieved using Methocel, Maltodextrin and SCMC. The obtained results could be used as a platform to control the release of cationic water soluble drugs that suffer from side effects associated with their initial burst after oral administration.

  14. Pharmaceutically active ionic liquids with solids handling, enhanced thermal stability, and fast release

    DEFF Research Database (Denmark)

    Bica, Katharina; Rodríguez, Héctor; Gurau, Gabriela

    2012-01-01

    Pharmaceutically active compounds in ionic liquid form immobilized onto mesoporous silica are stable, easily handled solids, with fast and complete release from the carrier material when placed into an aqueous environment. Depending on specific ion-surface interactions, they may also exhibit...

  15. The improvement of the dissolution rate of ziprasidone free base from solid oral formulations.

    Science.gov (United States)

    Zakowiecki, Daniel; Cal, Krzysztof; Kaminski, Kamil; Adrjanowicz, Karolina; Swinder, Lech; Kaminska, Ewa; Garbacz, Grzegorz

    2015-08-01

    This work aims at increasing solubility and dissolution rate of ziprasidone free base-Biopharmaceutics Classifaction System (BCS) class II compound. The authors describe a practical approach to amorphization and highlight problems that may occur during the development of formulations containing amorphous ziprasidone, which was obtained by grinding in high-energy planetary ball mills or cryogenic mills. The release of ziprasidone free base from the developed formulations was compared to the reference drug product containing crystalline ziprasidone hydrochloride-Zeldox® hard gelatin capsules. All preparations were investigated using compendial tests (USP apparatuses II and IV) as well as novel, biorelevant dissolution tests. The novel test methods simulate additional elements of mechanical and hydrodynamic stresses, which have an impact on solid oral dosage forms, especially during gastric emptying. This step may prove to be particularly important for many formulations of BCS class II drugs that are often characterized by narrow absorption window, such as ziprasidone. The dissolution rate of the developed ziprasidone free base preparations was found to be comparable or even higher than in the case of the reference formulation containing ziprasidone hydrochloride, whose water solubility is about 400 times higher than its free base.

  16. Floating solid cellulose nanofibre nanofoams for sustained release of the poorly soluble model drug furosemide

    DEFF Research Database (Denmark)

    Svagan, Anna Justina; Müllertz, Anette; Löbmann, Korbinian

    2017-01-01

    OBJECTIVES: This study aimed to prepare a furosemide-loaded sustained release cellulose nanofibre (CNF)-based nanofoams with buoyancy. METHODS: Dry foams consisting of CNF and the model drug furosemide at concentrations of 21% and 50% (w/w) have been prepared by simply foaming a CNF-drug suspension...... followed by drying. The resulting foams were characterized towards their morphology, solid state properties and dissolution kinetics. KEY FINDINGS: Solid state analysis of the resulting drug-loaded foams revealed that the drug was present as an amorphous sodium furosemide salt and in form of furosemide...... form I crystals embedded in the CNF foam cell walls. The foams could easily be shaped and were flexible, and during the drug release study, the foam pieces remained intact and were floating on the surface due to their positive buoyancy. Both foams showed a sustained furosemide release compared...

  17. Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study.

    Science.gov (United States)

    Blaesi, Aron H; Saka, Nannaji

    2017-11-01

    In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin-walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, both minimally-porous solid and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and analyzed. Microstructures of the solid forms and the cell walls range from single-phase solid solutions of the excipient and a small amount of drug molecules to two-phase composites of the excipient and tightly packed drug particles. Results of dissolution experiments show that the minimally-porous solid forms disintegrate and release drug by slow surface erosion. The erosion rate decreases as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration time is independent of drug weight fraction. Drug release models suggest that the solid forms erode by convective mass transfer of the faster-eroding excipient if the drug volume fraction is small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite. Conversely, the disintegration rate of the cellular forms is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, and the particles are enveloped by the excipient during melt-processing, the drug particles cannot hinder diffusion through the excipient across the walls. Thus the disintegration time of the cellular forms is mostly unaffected by the volume fraction of drug

  18. Rational use of antioxidants in solid oral pharmaceutical preparations

    Directory of Open Access Journals (Sweden)

    Maísa Teodoro Celestino

    2012-09-01

    Full Text Available Antioxidants are currently used as efficient excipients that delay or inhibit the oxidation process of molecules. Excipients are often associated with adverse reactions. Stability studies can guide the search for solutions that minimize or delay the processes of degradation. The ability to predict oxidation reactions in different drugs is important. Methods: This study was conducted to assess the rational use of butylated hydroxyanisole (BHA, butylated hydroxytoluene (BHT, sodium metabisulfite (SMB, propyl gallate (PG and cysteine (CYS in tablet formulations of simvastatin and ketoconazole. These antioxidants were evaluated according to stability parameters and the relationship between efficiency of the antioxidant and chemical structure of the drugs. Results were compared with DPPH tests and computational simulations. BHT was most efficient regarding simvastatin stability, and the most effective BHT concentrations for maintaining stability were 0.5 and 0.1%. In relation to ketoconazole, SMB was most efficient for maintaining content and dissolution profile. The evaluation by DPPH showed that the largest percentage of absorbance reduction was observed for PG, while SMB proved most efficient and had lower consumption of DPPH. The same pattern was observed, albeit with lower efficiency, for the other lipophilic antioxidants such as BHT and BHA. The results of the molecular modeling study demonstrated that electronic properties obtained were correlated with antioxidant activity in solution, being useful for the rational development of liquid pharmaceutical formulations but not for solid oral formulations. This study demonstrated the importance of considering stability parameters and molecular modeling to elucidate the chemical phenomena involved in antioxidant activity, being useful for the rational use of antioxidants in the development of pharmaceutical formulations.Atualmente, antioxidantes são usados como excipientes eficientes, que retardam

  19. Intra-oral adsorption and release of aroma compounds following in-mouth wine exposure.

    Science.gov (United States)

    Esteban-Fernández, Adelaida; Rocha-Alcubilla, Nuria; Muñoz-González, Carolina; Moreno-Arribas, María Victoria; Pozo-Bayón, María Ángeles

    2016-08-15

    Wine "after-odour" defined as the long lasting aroma perception that remains after wine swallowing is an outstanding characteristic in terms of wine quality but a relatively unstudied phenomenon. Among the different parameters that might affect wine after-odour, the adsorption of odorants by the oral mucosa could be important but has been little explored. In this work, the impact of the chemical characteristics of aroma compounds on intra-oral adsorption was assessed by an in vivo approach that determined the amounts of odorants remaining in expectorated wine samples. In addition, the subsequent aroma release after in-mouth wine exposure was studied by means of intra-oral SPME/GC-MS using three different panellists. Oral adsorption of the aroma compounds added to the wines ranged from 6% to 43%, depending on their physicochemical characteristics. A progressive intra-oral aroma decrease at different decay rates depending on compound type and panellist was also found. The strength of the aroma-oral mucosa interactions seems to explain these results more than the amount of compound adsorbed by the oral mucosa. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. A biorelevant in vitro release/permeation system for oral transmucosal dosage forms.

    Science.gov (United States)

    Delvadia, Poonam R; Barr, William H; Karnes, H Thomas

    2012-07-01

    This research describes the development and validation of a biorelevant in vitro release/permeation system to predict the in vivo performance of oral transmucosal dosage forms. The system is a biorelevant bidirectional transmucosal apparatus which allows better simulation of oral cavity physiological variables in comparison to compendial dissolution apparatuses and therefore may be a better predictor of in vivo behavior. The feasibility of the bidirectional apparatus was studied using smokeless tobacco (snus) as a model oral transmucosal product. In this research, nicotine release and permeation was investigated from commercially available snus using a modified USP IV flow-through apparatus, a commercially available vertical diffusion cell and a fabricated novel bidirectional transmucosal apparatus. The percent nicotine released/permeated was utilized as an input function for the prediction of in vivo plasma nicotine profiles by back calculation based on the Wagner-Nelson method. The prediction errors in C(max) and AUC(0-∞) with the USP IV flow-through device, vertical diffusion cell and novel apparatus were 4.03, 22.85 and 1.59 and -5.85, 5.85 and -9.27% respectively. This work demonstrated the suitability of the novel bidirectional transmucosal apparatus for predicting the in vivo behavior of oral transmucosal products. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib

    OpenAIRE

    Truong, Duy Hieu; Tran, Tuan Hiep; Ramasamy, Thiruganesh; Choi, Ju Yeon; Lee, Hee Hyun; Moon, Cheol; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2015-01-01

    To improve the solubility and oral bioavailability of erlotinib, a poorly water-soluble anticancer drug, solid self-emulsifying drug delivery system (SEDDS) was developed using solid inert carriers such as dextran 40 and Aerosil® 200 (colloidal silica). The preliminary solubility of erlotinib in various oils, surfactants, and co-surfactants was determined. Labrafil M2125CS, Labrasol, and Transcutol HP were chosen as the oil, surfactant, and co-surfactant, respectively, for preparation of the ...

  2. Methylphenidate extended-release oral suspension for the treatment of attention-deficit/hyperactivity disorder: a practical guide for pharmacists

    Directory of Open Access Journals (Sweden)

    Caballero J

    2017-10-01

    Full Text Available Joshua Caballero,1 Edress H Darsey,2 Faith Walters,2 Heidi W Belden2 1Department of Clinical and Administrative Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL, 2Pfizer Inc, New York, NY, USA Abstract: Attention-deficit/hyperactivity disorder (ADHD is a neurodevelopmental condition that affects children, adolescents, and adults worldwide. The purpose of this review was to inform pharmacists of the numerous options to treat ADHD, with a focus on one of the more recently approved formulations, methylphenidate extended-release oral suspension (MEROS. Symptoms of ADHD can negatively impact an individual’s health and quality of life and impair function in multiple settings. Psychostimulants such as methylphenidate- and amphetamine-based agents are first-line pharmacologic treatments for ADHD. However, there are multiple formulations, including immediate release (administered two to three times/day, solid extended release (ER, or transdermal patch. MEROS is a once daily, long-acting liquid preparation that has demonstrated favorable safety and efficacy in patients with ADHD. MEROS may improve treatment adherence in patients who cannot tolerate or have difficulties administering pill or transdermal patch formulations. Keywords: drug formulation, administration, adherence

  3. Physical solid-state properties and dissolution of sustained-release matrices of polyvinylacetate.

    Science.gov (United States)

    Gonzalez Novoa, Gelsys Ananay; Heinämäki, Jyrki; Mirza, Sabir; Antikainen, Osmo; Colarte, Antonio Iraizoz; Paz, Alberto Suzarte; Yliruusi, Jouko

    2005-02-01

    Solid-state compatibility and in vitro dissolution of direct-compressed sustained-release matrices of polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP) containing ibuprofen as a model drug were studied. Polyvinylalcohol (PVA) was used as an alternative water-soluble polymer to PVP. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) were used for characterizing solid-state polymer-polymer and drug-polymer interactions. The mechanical treatment for preparing physical mixtures of polyvinyl polymers and the drug (i.e. simple blending or stressed cogrinding) was shown not to affect the physical state of the drug and the polymers. With the drug-polymer mixtures the endothermic effect due to drug melting was always evident, but a considerable modification of the melting point of the drug in physical binary mixtures (drug:PVP) was observed, suggesting some interaction between the two. On the other hand, the lack of a significant shift of the melting endothermic peak of the drug in physical tertiary drug-polymer mixtures revealed no evidence of solid-state interaction between the drug and the present polymers. Sustained-release dissolution profiles were achieved from the direct-compressed matrices made from powder mixtures of the drug and PVAc combined with PVP, and the proportion of PVAc in the mixture clearly altered the drug release profiles in vitro. The drug release from the present matrix systems is controlled by both diffusion of the drug through the hydrate matrix and the erosion of the matrix itself.

  4. A review and perspective of existing research on the release of nanomaterials from solid nanocomposites.

    Science.gov (United States)

    Froggett, Stephan J; Clancy, Shaun F; Boverhof, Darrell R; Canady, Richard A

    2014-04-07

    Advances in adding nanomaterials to various matrices have occurred in tandem with the identification of potential hazards associated with exposure to pure forms of nanomaterials. We searched multiple research publication databases and found that, relative to data generated on potential nanomaterial hazards or exposures, very little attention has focused on understanding the potential and conditions for release of nanomaterials from nanocomposites. However, as a prerequisite to exposure studying release is necessary to inform risk assessments. We identified fifty-four studies that specifically investigated the release of nanomaterials, and review them in the following release scenario groupings: machining, weathering, washing, contact and incineration. While all of the identified studies provided useful information, only half were controlled experiments. Based on these data, the debris released from solid, non-food nanocomposites contains in varying frequencies, a mixture of four types of debris. Most frequently identified are (1) particles of matrix alone, and slightly less often, the (2) matrix particles exhibit the nanomaterial partially or fully embedded; far less frequently is (3) the added nanomaterial entirely dissociated from the matrix identified: and most rare are (4) dissolved ionic forms of the added nanomaterial. The occurrence of specific debris types appeared to be dependent on the specific release scenario and environment. These data highlight that release from nanocomposites can take multiple forms and that additional research and guidance would be beneficial, allowing for more consistent characterization of the release potential of nanomaterials. In addition, these data support calls for method validation and standardization, as well as understanding how laboratory release scenarios relate to real-world conditions. Importantly, as risk is considered to be a function of the inherent hazards of a substance and the actual potential for exposure, data

  5. Instrumental and sensory quantification of oral coatings retained after swallowing semi-solid foods

    NARCIS (Netherlands)

    Prinz, J.F.; Huntjens, L.; Wijk, de R.A.

    2006-01-01

    After a mouthful of food has been swallowed, some food material is always retained in the mouth. With semi-solid foods this is in the form of a coating that adheres to the oral mucosa. The amount and location of this material may play an important role in food sensations. In this study two

  6. Miniaturized approach for excipient selection during the development of oral solid dosage form

    DEFF Research Database (Denmark)

    Raijada, Dharaben Kaushikkumar; Müllertz, Anette; Cornett, Claus

    2014-01-01

    The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed...

  7. Solid dispersions in oncology: a solution to solubility-limited oral drug absorption

    NARCIS (Netherlands)

    Sawicki, Emilia

    2017-01-01

    This thesis discusses the formulation method solid dispersion and how it works to resolve solubility-limited absorption of orally dosed anticancer drugs. Dissolution in water is essential for drug absorption because only dissolved drug molecules are absorbed. The problem is that half of the arsenal

  8. Understanding aroma release from model cheeses by a statistical multiblock approach on oral processing.

    Directory of Open Access Journals (Sweden)

    Gilles Feron

    Full Text Available For human beings, the mouth is the first organ to perceive food and the different signalling events associated to food breakdown. These events are very complex and as such, their description necessitates combining different data sets. This study proposed an integrated approach to understand the relative contribution of main food oral processing events involved in aroma release during cheese consumption. In vivo aroma release was monitored on forty eight subjects who were asked to eat four different model cheeses varying in fat content and firmness and flavoured with ethyl propanoate and nonan-2-one. A multiblock partial least square regression was performed to explain aroma release from the different physiological data sets (masticatory behaviour, bolus rheology, saliva composition and flux, mouth coating and bolus moistening. This statistical approach was relevant to point out that aroma release was mostly explained by masticatory behaviour whatever the cheese and the aroma, with a specific influence of mean amplitude on aroma release after swallowing. Aroma release from the firmer cheeses was explained mainly by bolus rheology. The persistence of hydrophobic compounds in the breath was mainly explained by bolus spreadability, in close relation with bolus moistening. Resting saliva poorly contributed to the analysis whereas the composition of stimulated saliva was negatively correlated with aroma release and mostly for soft cheeses, when significant.

  9. Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA/PLA nanoparticles.

    Science.gov (United States)

    Panyam, Jayanth; Williams, Deborah; Dash, Alekha; Leslie-Pelecky, Diandra; Labhasetwar, Vinod

    2004-07-01

    Biodegradable nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid-state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug-polymer phase separation was developed to determine the solid-state drug-polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion-solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid-state drug-polymer solubility depends on the polymer composition, molecular weight, and end-functional groups (ester or carboxyl) in polymer chains. Higher solid-state drug-polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid-state drug-polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter. Copyright 2004 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 93:1804-1814, 2004

  10. Structural modifications of polymethacrylates: impact on thermal behavior and release characteristics of glassy solid solutions.

    Science.gov (United States)

    Claeys, Bart; De Coen, Ruben; De Geest, Bruno G; de la Rosa, Victor R; Hoogenboom, Richard; Carleer, Robert; Adriaensens, Peter; Remon, Jean Paul; Vervaet, Chris

    2013-11-01

    Polymethacrylates such as Eudragit® polymers are well established as drug delivery matrix. Here, we synthesize several Eudragit E PO (n-butyl-, dimethylaminoethyl-, methyl-methacrylate-terpolymer) analogues via free radical polymerization. These polymers are processed via hot melt extrusion, followed by injection molding and evaluated as carriers to produce immediate release solid solution tablets. Three chemical modifications increased the glass transition temperature of the polymer: (a) substitution of n-butyl by t-butyl groups, (b) reduction of the dimethylaminoethyl methacrylate (DMAEMA) content, and (c) incorporation of a bulky isobornyl repeating unit. These structural modifications revealed the possibility to increase the mechanical stability of the tablets via altering the polymer Tg without influencing the drug release characteristics and glassy solid solution forming properties. The presence of DMAEMA units proved to be crucial with respect to API/polymer interaction (essential in creating glassy solid solutions) and drug release characteristics. Moreover, these chemical modifications accentuate the need for a more rational design of (methacrylate) polymer matrix excipients for drug formulation via hot melt extrusion and injection molding. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Stereolithographic (SLA) 3D printing of oral modified-release dosage forms.

    OpenAIRE

    Wang, J.; Goyanes, A.; Gaisford, S.; Basit, A. W.

    2016-01-01

    The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets...

  12. Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form.

    Science.gov (United States)

    Haznar-Garbacz, Dorota; Kaminska, Ewa; Zakowiecki, Daniel; Lachmann, Marek; Kaminski, Kamil; Garbacz, Grzegorz; Dorożyński, Przemysław; Kulinowski, Piotr

    2018-02-01

    The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.

  13. Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application.

    Science.gov (United States)

    Nudelman, Zakhar; Findler, Mordechai; Barasch, Dinorah; Nemirovski, Alina; Pikovsky, Anna; Kirmayer, David; Basheer, Maamoun; Gutkind, J Silvio; Friedman, Michael; Czerninski, Rakefet

    2015-05-01

    Sirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system. Sirolimus sustained-release varnish drug delivery system containing a total of 0.5 mg of the drug was applied to nine healthy male volunteers. Saliva and blood levels were determined utilizing mass spectrometry and chemiluminescent microparticle immunoassay, respectively. The prolonged release profile and safety were evaluated for the oral topical delivery system. After the application of the drug delivery system, a sustained-release profile was observed in the oral cavity. We have measured moderate sirolimus levels for up to 12 h. The safety was confirmed, and systemic sirolimus blood levels were negligible. After an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs.

  14. Solid lipid particles for oral delivery of peptide and protein drugs II--the digestion of trilaurin protects desmopressin from proteolytic degradation.

    Science.gov (United States)

    Christophersen, Philip Carsten; Zhang, Long; Müllertz, Anette; Nielsen, Hanne Mørck; Yang, Mingshi; Mu, Huiling

    2014-09-01

    To investigate the in vitro release and degradation of desmopressin from saturated triglyceride microparticles under both lipolytic and proteolytic conditions. The release of desmopressin from different solid lipid microparticles in the absence and presence of a microbial lipase and protease was determined. Trilaurin (TG12), trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18) were used as lipid excipients to produce solid lipid microparticles. In the presence of lipase, the rate of drug release from different lipid particles was in the order of TG14 > TG16 > TG18, which is the same rank order as the lipid degradation rate. A reverse rank order was found for the protection of desmopressin from enzymatic degradation due to spatial separation of desmopressin from the protease. TG12 accelerated the release of desmopressin from all lipid particles when added as either drug-free microparticles to the lipolysis medium or incorporated in TG16 particles. Additionally, TG12 particles protected desmopressin from degradation when present in the lipolysis medium with the other lipid microparticles. TG12 is a very interesting lipid for oral lipid formulations containing peptides and proteins as it alters release and degradation of the incorporated desmopressin. The present study demonstrates the possibility of bio-relevant in vitro evaluation of lipid-based solid particles.

  15. Integrity of the Oral Tissues in Patients with Solid-Organ Transplants

    Directory of Open Access Journals (Sweden)

    Gonzalo Rojas

    2012-01-01

    Full Text Available The relationship between the use of immunosuppressants in solid-organ transplant patients and oral tissue abnormalities has been recognized. The objective of this study was to determine the state of oral tissue integrity in renal, heart, and liver transplant patients who are on continuous medical and dental control. Forty patients of both sexes were clinically evaluated at the Clinical Hospital of the University of Chile to identify pathologies of oral mucosa, gingival enlargement (GE, decayed, missing, filled teeth (DMFT index, and salivary flow. The average age of the transplant subjects was 49.4 years, and the age range was 19 to 69 years. Most subjects maintained a good level of oral hygiene, and the rate mean of DMFT was 14.7. The degree of involvement of the oral mucosa and GE was low (10%. Unlike other studies, the frequency of oral mucosal diseases and GE was low despite the fact that these patients were immunosuppressed. Care and continuous monitoring seem to be of vital importance in maintaining the oral health of transplant patients.

  16. High- and Low-Dose Oral Delayed-Release Mesalamine in Children With Mild-to-Moderately Active Ulcerative Colitis

    National Research Council Canada - National Science Library

    Winter, Harland S; Krzeski, Piotr; Heyman, Melvin B; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kolaček, Sanja; Osuntokun, Bankole; Quiros, J Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M

    2014-01-01

    OBJECTIVE:The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild...

  17. An oral multi-particulate, modified release, hydrocortisone replacement therapy that provides physiological cortisol exposure

    Science.gov (United States)

    Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J.

    2013-01-01

    Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multi-particulate technology. Design and Measurements Screening by in-vitro dissolution profiles, pharmacokinetic testing in dexamethasone suppressed dogs and humans, and comparison to a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed-release) design configuration with an extended (sustained-release) dissolution profile. In-vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained release functionality. Pharmacokinetic characterisation of DIURF-006 showed that, despite absence of a sustained release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n=16) receiving a twice daily ‘toothbrush’ regimen (20mg at 23:00h and 10mg at 07:00h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 hr*nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8.5h vs clock time 08:12 hours for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89% and cortisol levels increased linearly with doses between 5 and 30mg. Conclusion A multi-particulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure. PMID:23980724

  18. An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure.

    Science.gov (United States)

    Whitaker, Martin; Debono, Miguel; Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J

    2014-04-01

    It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Field laboratories and clinical research facility. Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure. © 2013 John Wiley & Sons Ltd.

  19. Effects of NOM properties on copper release from model solid phases.

    Science.gov (United States)

    Gao, Yuan; Korshin, Gregory

    2013-09-15

    This study examined impacts of concentrations and properties of natural organic matter (NOM) on copper release from characteristic copper solid model phases such as tenorite CuO and malachite Cu2(OH)2CO3. Unaltered Aldrich humic acid (AHA) and standard Suwannee River fulvic acid (SRFA) strongly increased copper release from the model phases but NOM alteration by chlorination or ozonation gradually suppressed or, at higher oxidant doses, eliminated these effects. The nature of NOM changes induced by chlorination and ozonation was examined using differential absorbance spectroscopy (DAS) and high-performance size-exclusion chromatography (HPSEC). The data of these methods show that NOM molecules with higher apparent molecular weight (AMW), higher aromaticities and contributions of protonation-active phenolic and carboxylic groups play a key role in adsorption and colloidal dispersion of the model solids. The data also show that metal release from model phases was well correlated with a number of spectroscopic parameters characterizing NOM properties, notably SUVA254, spectral slopes of NOM absorbance, and differential absorbance at wavelength of 280 nm and 350 nm that is indicative of the contributions of carboxylic and phenolic functional groups. Changes of ζ-potential of the model solid phases were the strongest predictor of the enhancement of copper release especially in the system controlled by malachite. While effects of NOM on the ζ-potential of tenorite and malachite were prominent for unaltered NOM, its oxidation by chlorine and ozone was accompanied by a gradual decrease and ultimately disappearance of its surface activity. Published by Elsevier Ltd.

  20. Controlling the Uptake and Regulating the Release of Nitric Oxide in Microporous Solids.

    Science.gov (United States)

    Haikal, Rana R; Hua, Carol; Perry, John J; O'Nolan, Daniel; Syed, Imran; Kumar, Amrit; Chester, Adrian H; Zaworotko, Michael J; Yacoub, Magdi H; Alkordi, Mohamed H

    2017-12-20

    Representative compounds from three classes of microporous solids, namely, metal-organic frameworks (MOFs), hybrid ultra-microporous materials (HUMs), and porous-organic polymers (POPs), were investigated for their nitric oxide gas uptake and release behavior. Low-pressure sorption studies indicated strong chemisorption of NO on the free amine groups decorating the MOF UiO-66-NH2 when compared to its non-amine-functionalized parent. The HUMs demonstrated reversible physisorption within the low-pressure regime, but interestingly in one case there was evidence for chemisorption following pressurization with NO at 10 bar. Significant release of chemisorbed NO from the UiO-66-NH2 and one of the HUMs was triggered by addition of acid to the medium, a pH change from 7.4 to 5.4 being sufficient to trigger NO release. An imidazole-based POP exhibited chemisorption of NO at high pressure wherein the ring basicity facilitated both NO uptake and spontaneous release upon contact with the aqueous release medium.

  1. An oral controlled release system for ambroxol hydrochloride containing a wax and a water insoluble polymer.

    Science.gov (United States)

    Chi, Na; Guo, Ju Hong; Zhang, Yu; Zhang, Wei; Tang, Xing

    2010-01-01

    This study was carried out to develop and optimize oral sustained-release formulations for Ambroxol hydrochloride matrix pellets using a combination of wax and water-insoluble polymer, glyceryl behenate (Compritol 888 ATO) and Ethylcellulose (EC(7 FP)). It involved three factors: the content of Compritol 888 ATO (X(1)), EC(7 FP) (X(2)), and the matrix formation methods (X(3)), as independent variables. The drug release percentages at 1, 2 and 4 h were the target responses and were restricted to 15-45% (Y(1)), 45-80% (Y(2)) and 80-100% (Y(3)), respectively. The final blend formulation prepared by extrusion spheronization, was achieved with 27.00% (w/w) Ambroxol hydrochloride, 48.70% (w/w) Compritol 888 ATO, and 24.30% (w/w) EC(7 Fp) with 40 degrees C for 12 h. Comparing the single matrix materials consisting of just the wax or water-insoluble in the complex matrix system containing wax and water-insoluble polymer, the release of the drug can be far more retarded, when the formulations have undergone the process of heat treatment. Furthermore, the combination of the two polymers, with flexible matrix formation methods, will offer a very promising way of producing matrix pellets instead of coated controlled-release pellets to meet various demands of drug release.

  2. Optimizing Prednisolone Loading into Distiller's Dried Grain Kafirin Microparticles, and In vitro Release for Oral Delivery.

    Science.gov (United States)

    Lau, Esther T L; Johnson, Stuart K; Williams, Barbara A; Mikkelsen, Deirdre; McCourt, Elizabeth; Stanley, Roger A; Mereddy, Ram; Halley, Peter J; Steadman, Kathryn J

    2017-05-19

    Kafirin microparticles have potential as colon-targeted delivery systems because of their ability to protect encapsulated material from digestive processes of the upper gastrointestinal tract (GIT). The aim was to optimize prednisolone loading into kafirin microparticles, and investigate their potential as an oral delivery system. Response surface methodology (RSM) was used to predict the optimal formulation of prednisolone loaded microparticles. Prednisolone release from the microparticles was measured in simulated conditions of the GIT. The RSM models were inadequate for predicting the relationship between starting quantities of kafirin and prednisolone, and prednisolone loading into microparticles. Compared to prednisolone released in the simulated gastric and small intestinal conditions, no additional drug release was observed in simulated colonic conditions. Hence, more insight into factors affecting drug loading into kafirin microparticles is required to improve the robustness of the RSM model. This present method of formulating prednisolone-loaded kafirin microparticles is unlikely to offer clinical benefits over commercially available dosage forms. Nevertheless, the overall amount of prednisolone released from the kafirin microparticles in conditions simulating the human GIT demonstrates their ability to prevent the release of entrapped core material. Further work developing the formulation methods may result in a delivery system that targets the lower GIT.

  3. Drug release from extruded solid lipid matrices: theoretical predictions and independent experiments.

    Science.gov (United States)

    Güres, Sinan; Siepmann, Florence; Siepmann, Juergen; Kleinebudde, Peter

    2012-01-01

    The aim of this study was to use a mechanistically realistic mathematical model based on Fick's second law to quantitatively predict the release profiles from solid lipid extrudates consisting of a ternary matrix. Diprophylline was studied as a freely water-soluble model drug, glycerol tristearate as a matrix former and polyethylene glycol or crospovidone as a pore former (blend ratio: 50:45:5%w/w/w). The choice of these ratios is based on former studies. Strains with a diameter of 0.6, 1, 1.5, 2.7 and 3.5mm were prepared using a twin-screw extruder at 65 °C and cut into cylinders of varying lengths. Drug release in demineralised water was measured using the USP 32 basket apparatus. Based on SEM pictures of extrudates before and after exposure to the release medium as well as on DSC measurements and visual observations, an analytical solution of Fick's second law of diffusion was identified in order to quantify the resulting diprophylline release kinetics from the systems. Fitting the model to one set of experimentally determined diprophylline release kinetics from PEG containing extrudates allowed determining the apparent diffusion coefficient of this drug (or water) in this lipid matrix. Knowing this value, the impact of the dimensions of the cylinders on drug release could be quantitatively predicted. Importantly, these theoretical predictions could be confirmed by independent experimental results. Thus, diffusion is the dominant mass transport mechanism controlling drug release in this type of advanced drug delivery systems. In contrast, theoretical predictions of the impact of the device dimensions in the case of crospovidone containing extrudates significantly underestimated the real diprophylline release rates. This could be attributed to the disintegration of this type of dosage forms when exceeding a specific minimal device diameter. Thus, mathematical modelling can potentially significantly speed up the development of solid lipid extrudates, but care has

  4. Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique.

    Science.gov (United States)

    Tran, Tuan Hiep; Poudel, Bijay Kumar; Marasini, Nirmal; Woo, Jong Soo; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2013-01-01

    The purpose of this study was to develop a raloxifene-loaded solid dispersion with enhanced dissolution rate and bioavailability via spray-drying technique. Solid dispersions of raloxifene (RXF) were prepared with PVP K30 at weight ratios of 1:4, 1:6 and 1:8 using a spray-drying method, and characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and solubility and dissolution tests. The bioavailability of the solid dispersion in rats was also evaluated compared to those of RXF powder and commercial product. Results showed that the RXF-loaded solid dispersion was in amorphous form with increased solubility and dissolution rate. The absorption of RXF from solid dispersion resulted in approximately 2.6-fold enhanced bioavailability compared to pure drug. Moreover, RXF-loaded solid dispersion gave similar AUC, C(max) and T(max) values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. These findings suggest that an amorphous solid dispersion of RXF could be a viable option for enhancing the oral bioavailability of RXF.

  5. Mice with Deletion of Neuromedin B Receptor Exhibit Decreased Oral Glucose-Stimulated Insulin Release.

    Science.gov (United States)

    Paula, G S M; Souza, L L; Bressane, N O S; Maravalhas, R; Wilieman, M; Bento-Bernardes, T; Silva, K R; Mendonca, L S; Oliveira, K J; Pazos-Moura, C C

    2016-12-01

    Neuromedin B (NB) and gastrin-releasing peptide (GRP) are bombesin-like peptides, found in the gastrointestinal tube and pancreas, among other tissues. Consistent data proposed that GRP stimulates insulin secretion, acting directly in pancreatic cells or in the release of gastrointestinal hormones that are incretins. However, the role of NB remains unclear. We examined the glucose homeostasis in mice with deletion of NB receptor (NBR-KO). Female NBR-KO exhibited similar fasting basal glucose with lower insulinemia (48.4%) and lower homeostasis model assessment of insulin resistance index (50.5%) than wild type (WT). Additionally, they were more tolerant to oral glucose, demonstrated by a decrease in the area under the glucose curve (18%). In addition, 15 min after an oral glucose load, female and male NBR-KO showed lower insulin serum levels (45.6 and 26.8%, respectively) than WT, even though blood glucose rose to similar levels in both groups. Single injection of NB, one hour before the oral glucose administration, tended to induce higher serum insulin in WT (28.9%, p=0.3), however the same did not occur in NBR-KO. They showed no changes in fasting insulin content in pancreatic islets by immunohistochemistry, however, the fasting serum levels of glucagon-like peptide, a potent incretin, exhibited a strong trend to reduction (40%, p=0.07). Collectively, mice with deletion of NB receptor have lower insulinemia, especially in response to oral glucose, and females also exhibited a better glucose tolerance, suggesting the involvement of NB and its receptor in regulation of insulin secretion induced by incretins, and also, in insulin sensitivity. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Bioequivalence study designs for generic solid oral anticancer drug products: scientific and regulatory considerations.

    Science.gov (United States)

    Kaur, Paramjeet; Chaurasia, Chandra S; Davit, Barbara M; Conner, Dale P

    2013-12-01

    The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples. © 2013, The American College of Clinical Pharmacology.

  7. Carboxymethyl chitosan/phospholipid bilayer-capped mesoporous carbon nanoparticles with pH-responsive and prolonged release properties for oral delivery of the antitumor drug, Docetaxel.

    Science.gov (United States)

    Zhang, Yanzhuo; Zhu, Wufu; Zhang, Heran; Han, Jin; Zhang, Lihua; Lin, Qisi; Ai, Fengwei

    2017-10-30

    In this article, a new type of carboxymethyl chitosan/phospholipid bilayer-capped mesoporous carbon nanomatrix (CCS/PL/MC) was fabricated as a potential nano-drug delivery system. In this drug delivery system, a mesoporous carbon nanomatrix (MC) acts as the support for loading drug molecules, a positively charged phospholipid (PL) layer works as the inner shell for prolonged drug release and a negatively charged carboxymethyl chitosan (CCS) layer serves as the outer shell for pH-responsive drug release. Docetaxel (DTX) was selected as a model drug. The drug-loaded CCS/PL/MC was synthesized via a combination approach of double emulsion/solvent evaporation followed by lyophilization. The drug-loaded nanoparticles were characterized for their particle size, structure, morphology, zeta (ζ)-potential, specific surface area, porosity, drug loading and solid state. In vitro drug release tests showed that the drug-loaded CCS/PL/MC nanoparticles possess a good pH-sensitivity and prolonged releasing ability with negligible release in gastric media and controlled release in intestinal media. Compared with MC and PL-capped MC, CCS/PL/MC had a greater mucoadhesiveness. Moreover, cellular uptake study indicated that CCS/PL/MC might improve intracellular drug delivery. These results suggest that this hybrid nanocarrier, combining the beneficial features of CCS, PL and MC, is a promising drug delivery system able to improve the oral absorption of antitumor drugs. Copyright © 2017. Published by Elsevier B.V.

  8. Collecting peptide release from the brain using porous polymer monolith-based solid phase extraction capillaries

    Science.gov (United States)

    Iannacone, Jamie M.; Ren, Shifang; Hatcher, Nathan G.; Sweedler, Jonathan V.

    2010-01-01

    Porous polymer monolithic (PPM) columns are employed to collect and concentrate neuronal release from invertebrate and vertebrate model systems, prior to their characterization with mass spectrometry. The monoliths are fabricated in fused silica capillaries from lauryl methacrylate (LMA) and ethylene glycol dimethacrylate (EDMA). The binding capacities for fluorescein and for fluorescently labeled peptides are on the order of nanomoles per millimeter length of monolith material for a 200 μm inner diameter capillary. To evaluate this strategy for collecting peptides from physiological solutions, angiotensin I and insulin in artificial seawater are loaded onto, and then released from the monoliths after a desalination rinse, resulting in femtomole limits of detection via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Positioned in the extracellular media near Aplysia californica bag cell neurons, upon electrical stimulation, these LMA-EDMA monoliths are also used to collect and concentrate peptide release, with egg laying hormone and acidic peptide detected. In addition, the collection of several known peptides secreted from chemically stimulated mouse brain slices demonstrates their ability to collect releasates from a variety of neuronal tissues. When compared to collection approaches using individual beads placed on brain slices, the PPM capillaries offer greater binding capacity. Moreover, they maintain higher spatial resolution as compared to the larger-volume, solid phase extraction collection strategies. PMID:19485405

  9. Amorphous Solid Dispersion of Epigallocatechin Gallate for Enhanced Physical Stability and Controlled Release

    Directory of Open Access Journals (Sweden)

    Yizheng Cao

    2017-11-01

    Full Text Available Epigallocatechin gallate (EGCG has been recognized as the most prominent green tea extract due to its healthy influences. The high instability and low bioavailability, however, strongly limit its utilization in food and drug industries. This work, for the first time, develops amorphous solid dispersion of EGCG to enhance its bioavailability and physical stability. Four commonly used polymeric excipients are found to be compatible with EGCG in water-dioxane mixtures via a stepwise mixing method aided by vigorous mechanical interference. The dispersions are successfully generated by lyophilization. The physical stability of the dispersions is significantly improved compared to pure amorphous EGCG in stress condition (elevated temperature and relative humidity and simulated gastrointestinal tract environment. From the drug release tests, one of the dispersions, EGCG-Soluplus® 50:50 (w/w shows a dissolution profile that only 50% EGCG is released in the first 20 min, and the remains are slowly released in 24 h. This sustained release profile may open up new possibilities to increase EGCG bioavailability via extending its elimination time in plasma.

  10. Geochemistry, mineralogy, solid-phase fractionation and oral bioaccessibility of lead in urban soils of Lisbon.

    Science.gov (United States)

    Reis, A P; Patinha, C; Wragg, J; Dias, A C; Cave, M; Sousa, A J; Costa, C; Cachada, A; Ferreira da Silva, E; Rocha, F; Duarte, A

    2014-10-01

    An urban survey of Lisbon, the largest city in Portugal, was carried out to investigate its environmental burden, emphasizing metallic elements and their public health impacts. This paper examines the geochemistry of lead (Pb) and its influence on human health data. A total of 51 soil samples were collected from urban recreational areas used by children to play outdoors. The semi-quantitative analysis of Pb was carried out by inductively coupled plasma mass spectrometry after an acid digestion. X-ray diffraction was used to characterize the soil mineralogy. The solid-phase distribution of Pb in the urban soils was investigated on a subset of 7 soils, out of a total of 51 samples, using a non-specific sequential extraction method coupled with chemometric analysis. Oral bioaccessibility measurements were obtained using the Unified BARGE Method developed by the Bioaccessibility Research Group of Europe. The objectives of the study are as follows: (1) investigation of Pb solid-phase distribution; (2) interpretation of Pb oral bioaccessibility measurements; (3) integration of metal geochemistry with human health data; and (4) understanding the influence of geochemistry and mineralogy on oral bioaccessibility. The results show that the bioaccessible fraction of Pb is lower when major metal fractions are associated with less soluble soil phases such as Fe oxyhydroxides, and more increased when the metal is in the highly soluble carbonate phase. However, there is some evidence that the proportion of carbonates in the soil environment is also a key control over the oral bioaccessibility of Pb, irrespective of its solid-phase fractionation.

  11. Semi-solid dosage form of clonazepam for rapid oral mucosal absorption.

    Science.gov (United States)

    Sakata, Osamu; Machida, Yoshiharu; Onishi, Hiraku

    2011-07-01

    In order to obtain an alternative to the intravenous (i.v.) dosage form of clonazepam (CZ), an oral droplet formulation of CZ was developed previously; however, the droplet was physically unstable. Therefore, in the present study, it was attempted to develop an easily-handled dosage form, which was more physically stable and allowed rapid drug absorption from oral mucosa. A semi-solid dosage form, composed of polyethylene glycol 1500 (PEG), CZ, and oleic acid (OA) at 37/1/2 (w/w) and named PEG/CZ/OA, and a semi-solid dosage form containing PEG and CZ at 39/1 (w/w), called PEG/CZ, were prepared. Their physical stability in air at room temperature and oral mucosal absorption in rats were investigated. The semi-solid dosage forms were much more stable physically than the droplet, that is, no recrystallization of CZ was observed for at least 8 days. The effective concentration for humans and rats (20 ng/mL or more) was achieved within 30 min after buccal administration for both PEG/CZ/OA and PEG/CZ. The plasma concentration increased gradually and less varied at each time point for PEG/CZ/OA. PEG/CZ/OA was found to show more rapid and higher absorption of CZ in buccal administration than in sublingual administration. Buccal administration with the semi-solid dosage PEG/CZ with or without OA was suggested to be a possibly useful novel dosage form as an alternative to i.v. injection.

  12. Probucol release from novel multicompartmental microcapsules for the oral targeted delivery in type 2 diabetes.

    Science.gov (United States)

    Mooranian, Armin; Negrulj, Rebecca; Al-Sallami, Hesham S; Fang, Zhongxiang; Mikov, Momir; Golocorbin-Kon, Svetlana; Fakhoury, Marc; Watts, Gerald F; Matthews, Vance; Arfuso, Frank; Lambros, Amanda; Al-Salami, Hani

    2015-02-01

    In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of -66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules.

  13. Metabolism, excretion, and pharmacokinetics of oral brivanib in patients with advanced or metastatic solid tumors.

    Science.gov (United States)

    Mekhail, Tarek; Masson, Eric; Fischer, Bruce S; Gong, Jiachang; Iyer, Ramaswamy; Gan, Jinping; Pursley, Janice; Patricia, Daniel; Williams, Daphne; Ganapathi, Ram

    2010-11-01

    The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of (14)C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [(14)C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non-small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [(14)C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.

  14. Polymeric and Solid Lipid Nanoparticles for Sustained Release of Carbendazim and Tebuconazole in Agricultural Applications

    Science.gov (United States)

    Campos, Estefânia Vangelie Ramos; Oliveira, Jhones Luiz De; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P. C.; Fernandes Fraceto, Leonardo

    2015-09-01

    Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.

  15. Members of the Oral Microbiota Are Associated with IL-8 Release by Gingival Epithelial Cells in Healthy Individuals.

    Science.gov (United States)

    Schueller, Katharina; Riva, Alessandra; Pfeiffer, Stefanie; Berry, David; Somoza, Veronika

    2017-01-01

    The triggers for the onset of oral diseases are still poorly understood. The aim of this study was to characterize the oral bacterial community in healthy humans and its association with nutrition, oral hygiene habits, and the release of the inflammatory marker IL-8 from gingival epithelial cells (GECs) with and without stimulation by bacterial endotoxins to identify possible indicator operational taxonomic units (OTUs) associated with inflammatory marker status. GECs from 21 healthy participants (13 females, 8 males) were incubated with or without addition of bacterial lipopolysaccharides (LPSs), and the oral microbiota was profiled using 16S rRNA gene-targeted sequencing. The basal IL-8 release after 6 h was between 9.9 and 98.2 pg/ml, and bacterial communities were characteristic for healthy oral microbiota. The composition of the oral microbiota was associated with basal IL-8 levels, the intake of meat, tea, white wine, sweets and the use of chewing gum, as well as flossing habits, allergies, gender and body mass index. Additionally, eight OTUs were associated with high basal levels of IL-8 and GEC response to LPS, with high basal levels of IL-8, and 1 with low basal levels of IL8. The identification of indicator bacteria in healthy subjects with high levels of IL-8 release is of importance as they may be promising early warning indicators for the possible onset of oral diseases.

  16. Mesoporous silicon microparticles for oral drug delivery: loading and release of five model drugs.

    Science.gov (United States)

    Salonen, J; Laitinen, L; Kaukonen, A M; Tuura, J; Björkqvist, M; Heikkilä, T; Vähä-Heikkilä, K; Hirvonen, J; Lehto, V-P

    2005-11-28

    Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

  17. Preparation of calcium chloride-loaded solid lipid particles and heat-triggered calcium ion release

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Huangying; Kim, Jin-Chul [Kangwon National University, Chunchon (Korea, Republic of)

    2015-08-15

    CaCl{sub 2}-loaded solid lipid particles (SLPs) were prepared by a melt/emulsification/solidification method. CaCl{sub 2} microparticles (1-5 μm) could be obtained in a mortar with aid of the dispersant (Tween 80/Span80 (35/65, w/w)) when the ratio of CaCl{sub 2} to dispersant was 2 : 0.1 (w/w). SLP was prepared by dispersing 0.42 g of micronized CaCl{sub 2} particles in 2 g of molten PBSA, emulsifying the mixture at 85 .deg. C in 40 ml of Tween 20 solution (0.5% w/v), and quenching the emulsion in an ice bath. The diameter of CaCl{sub 2}-loaded SLP was 10-150 μm. The unenveloped CaCl{sub 2} could be removed by dialysis and the specific loading of CaCl{sub 2} in SLP was 0.036mg/mg. An EDS spectrum of CaCl{sub 2}-loaded SLP, which was dialyzed, showed that the unenveloped CaCl{sub 2} was completely removed. Any excipients (dispersant, Tween 20, CaCl{sub 2}) had little effect on the melting point of SLPs. No appreciable amount of Ca2+ was released in 20-50 .deg. C for 22 h. But the release degree at 60 .deg. C was significant (about 2.3%) during the same period. The matrix of the lipid particle was in a liquid state at 60 .deg. C, so CaCl{sub 2} particles could move freely and contact the surrounding water, leading to the release. At 70 .deg. C, the release degree at a given time was a few times higher than that obtained at 60 .deg. C.

  18. Preparation and characterization of loperamide-loaded Dynasan 114 solid lipid nanoparticles for increased oral absorption in the treatment of diarrhea

    Directory of Open Access Journals (Sweden)

    Lili Wei

    2016-09-01

    Full Text Available The aim of the project was to assemble two optimum solid lipid nanoparticle (SLN formulations for oral delivery of loperamide (LPM to treat different types of diarrhea, and to evaluate their release profiles in vitro and pharmacokinetic properties in vivo. In this work, glyceryl trimyristate (Dynasan 114 nanoparticles containing the drug LPM and sodium cholate as a stabilizer were prepared using a modified solvent evaporation technique. Two LPM-loaded SLNs, namely LPM-SLN-1 (LPM-SLN with a high ratio rate of lipid to drug and LPM-SLN-2 (LPM-SLN with a low ratio rate of lipid to drug, were prepared by the solvent evaporation method. A change in the lipid concentration affects the characteristics of LPM-SLNs. The average sizes of the LPM-SLNs were 303 ± 18 nm and 519 ± 36 nm, separately, as analyzed by dynamic light scattering (DLS. The LPM-SLNs were found to be round with a smooth surface, as observed using a transmission electron microscope (TEM and a scanning electron microscope (SEM. The average encapsulation efficiencies were 87 ± 3.78% w/w and 84 ± 5.17%, accordingly. In the in vitro release experiments, LPM-SLNs showed a continuous release profile of LPM without any burst release. The oral bioavailability of LPM-SLNs was analyzed using Wistar rats. The relative bioavailabilities of LPM-SLNs were 227% and 153%, respectively, as compared that of the LPM tablet. There was no difference in the Tmax between LPM-SLN-2 and the LPM tablet. In conclusion, LPM-SLN-1 significantly improved the oral bioavailability of LPM, while LPM-SLN-2 having the same swift action as the LPM tablet. These results demonstrate the potential of LPM-SLNs in the oral delivery of LPM to treat different types of diarrhea.

  19. Development and characterization of solid lipid nanoparticles for enhancement of oral bioavailability of Raloxifene

    Directory of Open Access Journals (Sweden)

    B Divyakant Patel

    2012-01-01

    Full Text Available The objective of this study was to increase the oral bioavailability of Raloxifene having an absolute bioavailability only 2% due to extensive first pass hepatic metabolism by incorporating it in Solid Lipid Nanoparticles (SLNs. The optimized RSLNs prepared by Ultrasonic Emulsification and Low Temperature Solidification method showed the mean particle size, zeta potential and percentage drug entrapment of 101.4±3.5 nm, 19.4±0.279 mv, 97.67±1.02% respectively. The in-vitro intestinal permeability study indicated significantly higher permeation of the RSLNs than the marketed preparation. The in-vivo studies showed that pharmacokinetic parameters for the RSLNs were 3.5 times higher than the marketed preparation indicating significant increase in the oral bioavailability of the Raloxifene.

  20. Development and characterization of solid dispersion-microsphere controlled release system for poorly water-soluble drug.

    Science.gov (United States)

    Malipeddi, Venkata Ramana; Dua, Kamal; Awasthi, Rajendra

    2016-10-01

    The present study aimed to improve solubility and prolong the release duration of a poorly soluble drug using a combination of two different types of formulations (solid dispersion and microspheres). The solid dispersions were prepared by fusion method using urea and mannitol as hydrophilic carriers. Microspheres were prepared by solvent evaporation method using Eudragit L-100 (EL100) and Eudragit RS PO (ERS) as rate-controlling polymers. Flurbiprofen (FBP)-urea (1:2) solid dispersion and microspheres of FBP-EL-100-ERS (1:0.25:0.75) were used for the development of controlled release formulation by mixing them in different proportions. The FBP-containing formulations were evaluated for percentage yield, drug content, morphology, in vitro release, and in vivo anti-inflammatory activity. The best selected formulation was further evaluated for the controlled and improved effects. SEM photomicrograph confirmed the spherical shape of microspheres and with particle size in the range of 73.5-85.4 μm. In vitro release of FBP from controlled release formulations indicated that the formulation containing solid dispersion:microspheres (1:0.5) yielded prolonged effect up to 10 h. The release kinetics followed zero-order, and the mechanism of drug release was found to be diffusion rate controlled. This formulation had shown better inhibition of edema of rat paw up to 16 h and identified as a suitable product for controlled delivery of FBP. In conclusion, the concept of using a binary mixture of solid dispersion and microspheres can be used for other drugs that exhibit a poor solubility in stomach pH and a faster release in intestinal pH.

  1. Descriptive analysis of primary package labels from commercially available prescription solid oral dosage form drugs.

    Science.gov (United States)

    Chermak, Todd E; Lambert, Bruce L

    2009-01-01

    To describe formats used by manufacturers to display drug names on primary package labels for prescription solid oral dosage forms. Cross-sectional study. Independent community pharmacy in rural Indiana. The images were collected in February 2006. Not applicable. High-resolution digital photos were taken of 918 primary package labels (422 brand name and 496 generic) from all solid oral dosage forms stocked in an independent community pharmacy. We coded the images for the presence or absence of specific typographical characteristics used to distinguish the name of the drug. We also coded for the presence or absence of an image of the product on the label. Frequency of various typographical characteristics used to display the drug name(s) on a primary package label. Manufacturers use a wide variety of techniques to increase the distinctiveness of drug names on primary package labels, including color, boldface, underlining, italics, capitalization, highlighting, use of abbreviations, and use of parentheses to differentiate the generic name of the drug, as well as use of images of the drug product. The frequency of use of the different techniques varied substantially (e.g., boldface fonts used in nearly 98% of brand-name labels, underlining used in only 0.2% of brand-name labels). The frequency of use of the techniques differed across brand and generic products. The lack of standardization in the typographical presentation of drug names on primary package labels of solid oral dosage forms in the United States appears to reflect underlying uncertainty about the relative effectiveness of the different techniques. Given the frequency and severity of wrong drug errors caused, at least in part, by the inability of clinicians to distinguish between similar labels, research is urgently needed to determine which technique or combination of techniques will minimize the risk of confusion.

  2. Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations.

    Science.gov (United States)

    Göhler, Karin; Brett, Martin; Smit, Johan W; Rengelshausen, Jens; Terlinden, Rolf

    2013-04-01

    To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (IV) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non-compartmental analysis and relative bioavailability using dose-adjusted, log-transformed analysis of variance models for maximum concentration (Cmax) and areas under the serum concentration-time curve (AUC0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4 - 34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0 - 35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8 - 104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of about 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolonged-release characteristics of tapentadol PR 86 mg were evident with a lower Cmax (22.5 ng/ml vs. 64.2 ng/ml), a longer time to Cmax (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed

  3. Effect of directly compressible excipient and treated agar on drug release of clopidogrel oral disintegrating tablets.

    Science.gov (United States)

    Venkateswarlu, Kambham; Nirosha, Manyam; Kumar Reddy, Budideti Kishore; Sai Kiran, Badithala Siva

    2017-07-01

    In the present investigation, oral dissolving/dispersible/disintegrating tablets (ODTs) of clopidogrel were designed with a view to enhance the bioavailability and patient compliance by two different methods, namely, direct compression and effervescent methods using directly compressible excipient and treated agar (TAG). In the direct compression method, TAG was used as a disintegrant and another method used a mixture of sodium bicarbonate and tartaric acid along with TAG as disintegrants. Among the directly compressed tablets, treated agar formulation 3 and among the effervescent tablets, treated agar and effervescent formulation 4 was found to be promising. Treated agar formulation 3 prepared by direct compression method emerged as an overall best formulation based on the in vitro drug release characteristics.

  4. Comparative study of sustained-release lipid microparticles and solid dispersions containing ibuprofen

    Directory of Open Access Journals (Sweden)

    Hugo Almeida

    2012-09-01

    Full Text Available Ibuprofen is one of the most important non-steroidal anti-inflammatory drugs used in the treatment of inflammatory diseases. In its pure state, ibuprofen presents poor physical and mechanical characteristics and its use in solid dosage forms needs the addition of excipients that improve these properties. The selection of the best excipients and the most suitable pharmaceutical dosage form to carry ibuprofen is very important for the industrial success of this drug. Given these factors, lipid microparticles and solid dispersions of ibuprofen with cetyl alcohol, stearic acid, and hydrogenated castor oil were prepared. These formulations were intended to improve the physical and mechanical characteristics and to sustain the release of this drug. Physical mixtures were also prepared with the same ingredients in similar proportions. The solid dispersions of ibuprofen/stearic acid and ibuprofen/hydrogenated castor oil showed the best flow characteristics compared with pure ibuprofen. Further, gelatin capsules filled with lipid microparticles and solid dispersions were submitted to dissolution tests in order to study the influence of the prepared systems in the release profiles of ibuprofen. Prolonged release of ibuprofen was achieved with the lipid microparticles and solid dispersions prepared with the different types of excipients.O ibuprofeno é um dos antiinflamatórios não esteróides mais utilizados no tratamento de patologias associadas a processos inflamatórios. Este fármaco, quando no seu estado puro, apresenta características físicas e mecânicas pouco satisfatórias e a sua utilização em formas sólidas só é possível se forem adicionados excipientes que permitam melhorar estas propriedades. A seleção dos excipientes ideais e da forma farmacêutica mais adequada para veicular o ibuprofeno é fundamental para o sucesso industrial deste fármaco. Tendo em conta estes fatores, prepararam-se micropartículas lipídicas e dispersões s

  5. A two-step strategy to design high bioavailable controlled-release nimodipine tablets: the push-pull osmotic pump in combination with the micronization/solid dispersion techniques.

    Science.gov (United States)

    Liu, Xiaohong; Wang, Shang; Chai, Liqing; Zhang, Dong; Sun, Yinghua; Xu, Lu; Sun, Jin

    2014-01-30

    In order to decrease the fluctuation of blood concentration and to increase the oral bioavailability of nimodipine (NMD), a two-step strategy including the push-pull osmotic pump (PPOP) method in combination with micronization and solid dispersion techniques, was used to prepare the controlled-release high-bioavailability solid dosages. The optimization of formulation and process was conducted by comparing effects of different solubilization methods on release behavior of NMD. The in vitro dissolution studies indicated that both the two strategies were able to deliver NMD in the predetermined zero-order manner from 2 to 12h, regardless of effects of release media and agitation rates. Although the Cmax values of two PPOP tablets were lower than that of the reference formulation, both the Tmax values were prolonged, demonstrating the prominent controlled release performance. In comparison with the commercial reference tables, the relative bioavailability of the two formulations was 67.0% and 121.1%, respectively, indicating the solid dispersion technique was more efficient than the micronization technique in terms of solubilization capability and absorption enhancement. In summary, the two-step strategy, combining the push-pull osmotic pump method with the solid dispersion technique, is a very effective method to prepare high bioavailable controlled-release formulations of the poorly soluble drugs, i.e. NMD, taking into account the therapeutical efficiency and safety. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Combatting pain after orthopedic/trauma surgery- perioperative oral extended-release tapentadol vs. extended-release oxycodone/naloxone.

    Science.gov (United States)

    Haeseler, Gertrud; Schaefers, Dirk; Prison, Natalie; Ahrens, Jörg; Liu, Xiaofei; Karch, Annika

    2017-07-11

    High post-operative pain scores after "minor" orthopedic/trauma surgery are in part attributed to inadequate prescription of opioid analgesics. Novel concepts aiming to achieve sufficient analgesia while minimizing opioid-related side effects by avoiding fluctuating plasma levels are based on perioperative oral administration of extended-release opioids beginning with the first dose pre-operatively. This is the first study to evaluate analgesic efficacy and side effect rates of extended-release tapentadol compared to oxycodone/naloxone following orthopedic/trauma surgery. This randomized, observer-blinded, active-controlled prospective clinical trial had 2 co-primary endpoints: (1) Analgesic efficacy: Mean pain level on a numeric rating scale (NRS) from 0 to 10 during exercise over 5 days. (2) Safety: Side effect sum score of the following events: Nausea, vomiting, constipation, sedation, vertigo, somnolence. The study was powered to detect superiority of tapentadol for at least one endpoint pending statistical proof of non-inferiority for both endpoints in a first step. Two hundred sixty-six trauma patients were randomized to receive either tapentadol (n = 133) or oxycodone/naloxone (n = 133). Analgesic efficacy: Mean (±SD) daily pain levels in the first five post-operative days were 2.8 ± 1.3 in both groups. Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 (oxycodone/naloxone). Statistically tapentadol was non-inferior but not superior to oxycodone/naloxone. Vomiting on day 1 occurred in 11%, constipation in 35% of the tapentadol patients and in 16% and 30% of the oxycodone/naloxone patients (p = 0.60 and 0.33), respectively. The incidence of sedation/ vertigo was  0.3, respectively). The sum score of side effect events was 51% in the tapentadol vs. 49% in the oxycodone/naloxone group; risk difference 3% [95% CI, -8 to 14%]; p = 0.6). Non-inferiority of

  7. A (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-dispersed sustained-release tablet for imperialine to simultaneously prolong the drug release and improve the oral bioavailability.

    Science.gov (United States)

    Lin, Qing; Fu, Yu; Li, Jia; Qu, Mengke; Deng, Li; Gong, Tao; Zhang, Zhirong

    2015-11-15

    Imperialine, extracted from Bulbus Fritillariae Cirrhosae, is an efficient antitussive and expectorant medicine. However, its short half-life and stomach degradation limited imperialine from further clinical use. The current study was conducted to develop a sustained-release tablet for imperialine both to prolong absorption time and to improve the oral bioavailability of the drug. The tablets were prepared by a direct compression method formulated on optimized solid dispersion (SD) for imperialine based on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) with imperialine/Soluplus(®) ratio of 1:8 (w/w). In order to obtain the optimized formulation, factors that affected the drug release were investigated by in vitro dissolution studies in the media of pH1.2, 5.8, 7.0 and 7.4. Powder X-ray diffraction and scanning electron microscope confirmed that the imperialine in SD was amorphous instead of crystalline, and still stayed amorphous even after the direct compression. And besides, pharmacokinetic study in Beagle dogs was performed to inspect the in vivo sustained release. Plasma concentration-time curves and pharmacokinetic parameters were gained. As a result, the Cmax of imperialine was one-fold reduced and Tmax was two-fold prolonged, and the mean AUC0-24 was expressed as 89.581±21.243μgh/L, which showed that the oral bioavailability of imperialine was 2.46-fold improved. Moreover, the in vitro-in vivo correlation was recommended to carry out, demonstrating the percentages of drug release in vitro were well-correlated with the absorptive fraction in vivo with the correlation coefficients above 0.9900. By mathematically modeling and moment imaging of the drug release, Peppas equation was selected as the most fitted model for the sustained-release tablets with the diffusional coefficient in the range of 0.59-0.62, indicating the release of imperialine from the sustained-release tablets was an anomalous process involving

  8. Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

    Science.gov (United States)

    Stuurman, F E; Voest, E E; Awada, A; Witteveen, P O; Bergeland, T; Hals, P-A; Rasch, W; Schellens, J H M; Hendlisz, A

    2013-08-01

    CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

  9. Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib.

    Science.gov (United States)

    Truong, Duy Hieu; Tran, Tuan Hiep; Ramasamy, Thiruganesh; Choi, Ju Yeon; Lee, Hee Hyun; Moon, Cheol; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-04-01

    To improve the solubility and oral bioavailability of erlotinib, a poorly water-soluble anticancer drug, solid self-emulsifying drug delivery system (SEDDS) was developed using solid inert carriers such as dextran 40 and Aerosil® 200 (colloidal silica). The preliminary solubility of erlotinib in various oils, surfactants, and co-surfactants was determined. Labrafil M2125CS, Labrasol, and Transcutol HP were chosen as the oil, surfactant, and co-surfactant, respectively, for preparation of the SEDDS formulations. The ternary phase diagram was evaluated to show the self-emulsifying area. The formulations were optimized using the droplet size and polydispersity index (PDI) of the resultant emulsions. Then, the optimized formulation containing 5% Labrafil M2125CS, 65% Labrasol, and 30% Transcutol was spray dried with dextran or Aerosil® and characterized for surface morphology, crystallinity, and pharmacokinetics in rats. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) exhibited the amorphous form or molecular dispersion of erlotinib in the formulations. The pharmacokinetic parameters of the optimized formulations showed that the maximum concentration (C max) and area under the curve (AUC) of erlotinib were significantly increased, compared to erlotinib powder (p < 0.05). Thus, this SEDDS could be a promising method for enhancing the oral bioavailability of erlotinib.

  10. Miniaturized approach for excipient selection during the development of oral solid dosage form.

    Science.gov (United States)

    Raijada, Dhara; Müllertz, Anette; Cornett, Claus; Munk, Tommy; Sonnergaard, Jørn; Rantanen, Jukka

    2014-03-01

    The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed by sieving, drying, and compaction of the agglomerated material. The mini-compacts were subjected to stability studies at 25°C/5% relative humidity (RH), 25°C/60% RH and 40°C/75% RH for 3 months. The physical stability of the drug was affected by the storage condition and by the characteristics of the excipients, whereas all the samples were chemically stable. Force-distance curves obtained during the compression of agglomerated material were used for the comparison of compressibility of different drug-excipient mixtures. The agglomerated drug-excipient mixtures were also subjected to studies of the dissolution trend under sequential pH conditions to simulate pH environment of gastrointestinal tract. Major factors affecting the dissolution behavior were the diffusion layer pH of the binary mixtures and the ability of the excipients to alter the diffusion layer thickness. The proposed approach can be used for excipient selection and for early-stage performance testing of active pharmaceutical ingredient intended for oral solid dosage form. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  11. Consumer Preferences and Perceptions towards the use Colored Oral Solid Dosage Forms in Baghdad

    Directory of Open Access Journals (Sweden)

    Inas Rifaat Ibrahim,*, Mohamed Izham M.I & Mahmoud Al-Haddad

    2010-10-01

    Full Text Available Objective: The main aims of this study were to determine consumers’ preferences and perceptions in Baghdad towards the color of Oral Solid Dosage Form.Materials and Methods: A cross sectional study was conducted using a self–administered questionnaire. A convenient sampling method was adopted to approach the consumers visiting the community pharmacies in Baghdad.The data collected was analyzed using SPSS version 16 ®. Anon-parametric statistics i.e [Chi-square, Mann-Whitney and Kruskal-Wallis tests] were used to evaluate the association of demographic variables with respondents perceptions toward physical characteristics of Oral Solid Dosage Form.Results: Colored OSDF was preferred by 76.4% of consumers.Significant differences in this preference were found among genders (P=0.029; age (P<0.001; educational level (P=0.001;and monthly income level (0.007. Further, consumers perceived that color of OSDF is related with the therapeutic activity of medicine. Significant differences in this perception were found to be influenced by gender (P=0.016; age group(P<0.001; and educational level (P<0.001.Conclusion: In a conclusion, color was the most preferred characteristic of OSDF by Baghdadi consumers with the perceptions that color is related to therapeutic activity of medicines. Gender, age, educational level, and monthly income are important factors that are associated with the preferences and perceptions toward colored OSDF.

  12. The Use of Animated Videos to Illustrate Oral Solid Dosage Form Manufacturing in a Pharmaceutics Course.

    Science.gov (United States)

    Yellepeddi, Venkata Kashyap; Roberson, Charles

    2016-10-25

    Objective. To evaluate the impact of animated videos of oral solid dosage form manufacturing as visual instructional aids on pharmacy students' perception and learning. Design. Data were obtained using a validated, paper-based survey instrument designed to evaluate the effectiveness, appeal, and efficiency of the animated videos in a pharmaceutics course offered in spring 2014 and 2015. Basic demographic data were also collected and analyzed. Assessment data at the end of pharmaceutics course was collected for 2013 and compared with assessment data from 2014, and 2015. Assessment. Seventy-six percent of the respondents supported the idea of incorporating animated videos as instructional aids for teaching pharmaceutics. Students' performance on the formative assessment in 2014 and 2015 improved significantly compared to the performance of students in 2013 whose lectures did not include animated videos as instructional aids. Conclusions. Implementing animated videos of oral solid dosage form manufacturing as instructional aids resulted in improved student learning and favorable student perceptions about the instructional approach. Therefore, use of animated videos can be incorporated in pharmaceutics teaching to enhance visual learning.

  13. The Use of Animated Videos to Illustrate Oral Solid Dosage Form Manufacturing in a Pharmaceutics Course

    Science.gov (United States)

    Roberson, Charles

    2016-01-01

    Objective. To evaluate the impact of animated videos of oral solid dosage form manufacturing as visual instructional aids on pharmacy students’ perception and learning. Design. Data were obtained using a validated, paper-based survey instrument designed to evaluate the effectiveness, appeal, and efficiency of the animated videos in a pharmaceutics course offered in spring 2014 and 2015. Basic demographic data were also collected and analyzed. Assessment data at the end of pharmaceutics course was collected for 2013 and compared with assessment data from 2014, and 2015. Assessment. Seventy-six percent of the respondents supported the idea of incorporating animated videos as instructional aids for teaching pharmaceutics. Students’ performance on the formative assessment in 2014 and 2015 improved significantly compared to the performance of students in 2013 whose lectures did not include animated videos as instructional aids. Conclusions. Implementing animated videos of oral solid dosage form manufacturing as instructional aids resulted in improved student learning and favorable student perceptions about the instructional approach. Therefore, use of animated videos can be incorporated in pharmaceutics teaching to enhance visual learning. PMID:27899837

  14. Oral administration of insulin in solid form to nondiabetic and diabetic dogs.

    Science.gov (United States)

    Ziv, E; Kidron, M; Raz, I; Krausz, M; Blatt, Y; Rotman, A; Bar-On, H

    1994-06-01

    It was previously demonstrated that a biologically active insulin could cross the mucosal membrane in the gut by using surface active substances. In this report we describe studies in which insulin administered orally, in a solid formulation, was effectively absorbed in the canine model. The insulin was mixed with cholate and soybean trypsin inhibitor. It was delivered orally, as enterocoated microtablets, to nondiabetic and diabetic (pancreatectomized) dogs in a fasting state. The time interval between the administration of the drug and the beginning of a decrease in the plasma glucose levels was 60-140 min. This decrease reached a minimum level of 20-40 % of the initial values and lasted for more than 90 min following administration of the drug. In this model a pronounced increment in plasma insulin levels was shown prior to the drop of plasma glucose concentrations. It is concluded that with this novel oral insulin formulation a beneficial biological effect can be achieved in the treatment of diabetes.

  15. Cardiovascular safety of the oral controlled absorption system (OCAS) formulation of tamsulosin compared to the modified release (MR) formulation

    NARCIS (Netherlands)

    Michel, M. C.; Korstanje, C.; Klauwinkel, W.; Shear, M.; Davies, J.; Quartel, A.

    2005-01-01

    Objective: The potential to interfere with efferent adrenergic drive in the cardiovascular system was tested in elderly healthy subjects for the new oral controlled absorption system (OCAS) 0.4 mg tablet formulation of tamsulosin compared to the modified release (MR) 0.4 mg capsule formulation of

  16. Comparison of vascular alpha(1)-adrenoceptor antagonism of tamsulosin in oral controlled absorption system (OCAS) and modified release (MR) formulations

    NARCIS (Netherlands)

    Michel, M. C.; Korstanje, C.; Krauwinkel, W.; Shear, M.; Davies, J.; Quartel, A.

    2005-01-01

    Objective: The cardiovascular a-l-adrenoceptor (AR) antagonism of the new oral controlled absorption system (OCAS) 0.4 mg tablet formulation of tamsulosin was compared with that of the modified release (MR) 0.4 mg capsule formulation in healthy male volunteers after a single dose in the fasted

  17. Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients.

    Directory of Open Access Journals (Sweden)

    Yutaka Fujiwara

    Full Text Available PURPOSE: Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR oxycodone. METHOD: This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning. The steady-state trough concentrations (Css were measured from day 1 to day 3. RESULTS: Aprepitant increased the area under the plasma concentration-time curve (AUC0-8 of oxycodone by 25% (p<0.001 and of oxymorphone by 34% (p<0.001, as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001. Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001 and of oxymorphone by 36% (p<0.001 and decreased Css of noroxycodone by 24% (p = 0.02 at day 3 compared to day 1. CONCLUSIONS: The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose. TRIAL REGISTRATION: UMIN.ac.jp UMIN000003580.

  18. Formulation development and evaluation of the anti-malaria properties of sustained release artesunate-loaded solid lipid microparticles based on phytolipids.

    Science.gov (United States)

    Chinaeke, E E; Chime, S A; Onyishi, V I; Attama, A A; Okore, V C

    2015-01-01

    CONTEXTS: Artemisinins and its derivatives are considered the basis in the treatment of Plasmodium falciparum malaria due to their high potency and rapid action. However, they have short half life, low solubility, and poor oral bioavailability, hence the need to formulate sustained release lipid particulate dosage form of these drugs. To formulate and evaluate artesunate-loaded solid lipid microparticles (SLMs) based on structured lipid matrices consisting of soybean oil and dika wax. The lipid matrices were characterized by differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD), and wide-angle X-ray diffraction (WAXD). The SLMs were prepared by hot melt-homogenization. Time-dependent particle size analysis, time-dependent pH stability studies, encapsulation efficiency (EE%), and in vitro drug release were carried out on the SLMs. In vivo anti-malarial studies were performed using a modified Peter's 4-day suppressive protocol using Plasmodium berghei infected mice. Thermograms of the lipid matrices showed modifications in the microstructure of dika wax as a result of inclusion of soybean oil. SAXD and WAXD diffractograms showed that the lipid matrices were found to be non-lamellar. Particle size of SLM increased with time, while the pH was almost constant. The SLMs had maximum EE% of 80.6% and sustained the release of artesunate more than the reference tablet. In vivo pharmacodynamic studies showed that the SLMs had significant (p daily in the treatment of malaria.

  19. Injection-molded capsular device for oral pulsatile release: development of a novel mold.

    Science.gov (United States)

    Zema, Lucia; Loreti, Giulia; Macchi, Elena; Foppoli, Anastasia; Maroni, Alessandra; Gazzaniga, Andrea

    2013-02-01

    The development of a purposely devised mold and a newly set up injection molding (IM) manufacturing process was undertaken to prepare swellable/erodible hydroxypropyl cellulose-based capsular containers. When orally administered, such devices would be intended to achieve pulsatile and/or colonic time-dependent delivery of drugs. An in-depth evaluation of thermal, rheological, and mechanical characteristics of melt formulations/molded items made of the selected polymer (Klucel® LF) with increasing amounts of plasticizer (polyethylene glycol 1500, 5%-15% by weight) was preliminarily carried out. On the basis of the results obtained, a new mold was designed that allowed, through an automatic manufacturing cycle of 5 s duration, matching cap and body items to be prepared. These were subsequently filled and coupled to give a closed device of constant 600 μm thickness. As compared with previous IM systems having the same composition, such capsules showed improved closure mechanism, technological properties, especially in terms of reproducibility of the shell thickness, and release performance. Moreover, the ability of the capsular container to impart a constant lag phase before the liberation of the contents was demonstrated irrespective of the conveyed formulation. Copyright © 2012 Wiley Periodicals, Inc.

  20. Hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

    Science.gov (United States)

    Verstraete, G; Van Renterghem, J; Van Bockstal, P J; Kasmi, S; De Geest, B G; De Beer, T; Remon, J P; Vervaet, C

    2016-06-15

    Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. (1)H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Solid lipid nanoparticles as oral delivery systems of phenolic compounds: Overcoming pharmacokinetic limitations for nutraceutical applications.

    Science.gov (United States)

    Nunes, Sara; Madureira, Ana Raquel; Campos, Débora; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Manuela; Reis, Flávio

    2017-06-13

    Drug delivery systems, accompanied by nanoparticle technology, have recently emerged as prominent solutions to improve the pharmacokinetic properties, namely bioavailability, of therapeutic and nutraceutical agents. Solid lipid nanoparticles (SLNs) have received much attention from researchers due to their potential to protect or improve drug properties. SLNs have been reported to be an alternative system to traditional carriers, such as emulsions, liposomes, and polymeric nanoparticles. Phenolic compounds are widespread in plant-derived foodstuffs and therefore abundant in our diet. Over the last decades, phenolic compounds have received considerable attention due to several health promoting properties, mostly related to their antioxidant activity, which can have important implications for health. However, most of these compounds have been associated with poor bioavailability being poorly absorbed, rapidly metabolized and eliminated, which compromises its biological and pharmacological benefits. This paper provides a systematic review of the use of SLNs as oral delivery systems of phenolic compounds, in order to overcome pharmacokinetic limitations of these compounds and improved nutraceutical potential. In vitro studies, as well as works describing topical and oral treatments will be revisited and discussed. The classification, synthesis, and clinical application of these nanomaterials will be also considered in this review article.

  2. Development and characterization of solid oral dosage form incorporating candesartan nanoparticles.

    Science.gov (United States)

    Nekkanti, Vijaykumar; Pillai, Raviraj; Venkateshwarlu, Vobalaboina; Harisudhan, T

    2009-01-01

    Sparingly water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop a tablet dosage form of candesartan cilexetil incorporating drug nanoparticles to increase its saturation solubility and dissolution rate for enhancing bioavailability while reducing variability in systemic exposure. The bioavailability of candesartan cilexetil is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of candesartan cilexetil was developed. Candesartan cilexetil nanoparticles were prepared using a wet bead milling technique. The milled nanosuspension was converted into solid intermediate using a spray drying process. The nanosuspensions were characterized for particle size before and after spray drying. The spray dried nanoparticles were blended with excipients for tableting. The saturation solubility and dissolution characteristics of the nanoparticle formulation were investigated and compared with commercial candesartan cilexetil formulation. The drug nanoparticles were evaluated for solid-state transitions before and after milling. This study demonstrated that tablet formulation incorporating drug nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared to commercially available tablet formulation. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption.

  3. The effect of oral and product temperature on the perception of flavor and texture attributes of semi-solids

    NARCIS (Netherlands)

    Engelen, L.; Wijk, R.A.de; Prinz, J.F.; Janssen, A.M.; Weenen, H.; Bosman, F.

    2003-01-01

    This study examined the effect of oral and product temperature on the perception of texture and flavor attributes. A trained panel assessed 21 texture and flavor attributes in one high-fat and one low-fat product of two semi-solids: custard dessert and mayonnaise. The products were evaluated at 10,

  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

  5. Kinetics study of solid ammonia borane hydrogen release--modeling and experimental validation for chemical hydrogen storage.

    Science.gov (United States)

    Choi, Young Joon; Rönnebro, Ewa C E; Rassat, Scot; Karkamkar, Abhi; Maupin, Gary; Holladay, Jamie; Simmons, Kevin; Brooks, Kriston

    2014-05-07

    Ammonia borane (AB), NH3BH3, is a promising material for chemical hydrogen storage with 19.6 wt% gravimetric hydrogen capacity of which maximum 16.2 wt% hydrogen can be released via an exothermic thermal decomposition below 200 °C. We have investigated the kinetics of hydrogen release from AB and from an AB-methyl cellulose (AB/MC) composite at temperatures of 160-300 °C using both experiments and modeling. The hydrogen release rate at 300 °C is twice as fast as at 160 °C. The purpose of our study was to show safe hydrogen release without thermal runaway effects and to validate system model kinetics. AB/MC released hydrogen at ∼20 °C lower than neat AB and at a faster release rate in that temperature range. Based on the experimental results, the kinetics equations were revised to better represent the growth and nucleation process during decomposition of AB. We explored two different reactor concepts; auger and fixed bed. The current auger reactor concept turned out to not be appropriate, however, we demonstrated safe self-propagation of the hydrogen release reaction of solid AB/MC in a fixed bed reactor.

  6. [Impact of slow-release oral morphine on drug abusing habits in Austria].

    Science.gov (United States)

    Beer, Beate; Rabl, Walter; Libiseller, Kathrin; Giacomuzzi, Salvatore; Riemer, Yvonne; Pavlic, Marion

    2010-01-01

    A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is

  7. 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.

  8. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs.

    Science.gov (United States)

    Lee, Kathy W Y; Nguyen, Tri-Hung; Hanley, Tracey; Boyd, Ben J

    2009-01-05

    Nanostructured lipid-based liquid crystalline systems have been proposed as sustained oral drug delivery systems, but the interplay between their intrinsic release rates, susceptibility to digestive processes, and the manner in which these effects impact on their application in vivo, are not well understood. In this study, two different bicontinuous cubic phases, prepared from glyceryl monooleate and phytantriol, and a reversed hexagonal phase formed by addition of a small amount of vitamin E to phytantriol (Q(II GMO), Q(II PHYT) and H(II PHYT+VitEA), respectively) were prepared. The release kinetics for a number of model hydrophilic drugs with increasing molecular weights (glucose, Allura Red and FITC-dextrans) was determined in in vitro release experiments. Diffusion-controlled release was observed in all cases as anticipated from previous studies with liquid crystalline systems, and it was discovered that the release rates of each drug decreased as the matrix was changed from Q(II GMO) to Q(II PHYT) to H(II PHYT+VitEA). Formulations containing (14)C-glucose, utilized as a rapidly absorbed marker of drug release, were then orally administered to rats to determine the relative in vivo absorption rates from the different formulations. The results showed a trend by which the rate of absorption of (14)C-glucose followed that observed in the corresponding in vitro release studies, providing the first indication that the nanostructure of these materials may provide the ability to tailor the absorption kinetics of hydrophilic drugs in vivo, and hence form the basis of a new drug delivery system.

  9. High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately active ulcerative colitis.

    Science.gov (United States)

    Winter, Harland S; Krzeski, Piotr; Heyman, Melvin B; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kolaček, Sanja; Osuntokun, Bankole; Quiros, J Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M

    2014-12-01

    The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥ 10 to ≤ 55 and a truncated Mayo Score of ≥ 1 for both rectal bleeding and stool frequency, were enrolled. They received body weight-dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27-71 mg · g(-1) · day(-1)) or high-dose group (53-118 mg · g(-1) · day(-1)). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score mesalamine low- and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose.

  10. Enhanced Supersaturation and Oral Absorption of Sirolimus Using an Amorphous Solid Dispersion Based on Eudragit® E

    Directory of Open Access Journals (Sweden)

    Youngseok Cho

    2015-05-01

    Full Text Available The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD on the degradation of sirolimus in simulated gastric fluid (pH 1.2 and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1 solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1 solid dispersion in simulated gastric fluid (pH 1.2, owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1 solid dispersion, the sirolimus/E-SD/TPGS (1/8/1 solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC. Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.

  11. Improved oral absorption profile of itraconazole in hypochlorhydria by self-micellizing solid dispersion approach.

    Science.gov (United States)

    Kojo, Yoshiki; Matsunaga, Saori; Suzuki, Hiroki; Sato, Hideyuki; Seto, Yoshiki; Onoue, Satomi

    2017-01-15

    The present study was aimed to evaluate the applicability of a self-micellizing solid dispersion (SMSD) system of itraconazole (ITZ) with the use of Soluplus® to achieve improved dissolution and stable oral absorption of ITZ under hypochlorhydric conditions. The SMSD of ITZ (SMSD/ITZ) was prepared by the freeze-drying method. Physicochemical properties of SMSD/ITZ were assessed in terms of morphology, crystallinity, particle size, thermal behavior, dissolution profile, and stability. The pharmacokinetic profile of SMSD/ITZ was evaluated in both normal rats and omeprazole-treated rats as a hypochlorhydric model. From the crystallinity assessment, ITZ in SMSD/ITZ might exist in an amorphous state. The dissolution behavior of SMSD/ITZ was markedly improved under both acidic and neutral conditions through the formation of nano-micelles with a diameter of 127nm. The degradation of ITZ in SMSD/ITZ was negligible after storage under accelerated conditions at 40°C or 40°C/75%RH for 4weeks. Under light exposure, ca. 33% of ITZ in SMSD/ITZ was degraded, suggesting the need for protection from light. Although the oral absorption of crystalline ITZ was negligible, SMSD/ITZ showed an improved pharmacokinetic profile in normal rats, with an absolute bioavailability (BA) of 2.9%, and even 6.3% in the hypochlorhydric model. From these findings, SMSD technology could be beneficial for improving the absorption profiles of weak basic drugs, even in hypochlorhydric patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Alternative antiretroviral therapy formulations for patients unable to swallow solid oral dosage forms.

    Science.gov (United States)

    Duggan, Joan M; Akpanudo, Barbara; Shukla, Vipul; Gutterson, Glen; Eitniear, Lindsey; Sahloff, Eric G

    2015-09-15

    Evidence-based guidance is presented to assist clinicians in selecting alternative formulations of antiretroviral (ARV) agents for patients with human immunodeficiency virus (HIV) infection who are unable to swallow tablets or capsules. The inability to take medications in standard oral dosage forms can be associated with nonadherence or the use of alternative administration strategies such as capsule or tablet breaking, crushing, or chewing. Patients with HIV infection require long-term ARV therapy to maintain viral suppression; ARV agents are predominately available as tablets and capsules that may pose swallowing difficulties for some patients. Using a variety of sources (the primary literature, pharmaceutical package inserts, and requests for unpublished data from drug manufacturers), available evidence on the bioavailability of ARV medications after disruption of the capsule or tablet matrix was reviewed; information on alternative formulations of ARV agents was also assessed. With several ARV agents, disruption of the solid oral dosage form by crushing, chewing, or breaking tablets or opening capsules prior to ingestion has been shown to result in altered bioavailability or pharmacokinetics and thus the potential for incomplete virological suppression, increased adverse effects, and suboptimal health outcomes. Of the 33 single-agent ARV medications and combination ARV products in five classes available at the time of review, approximately half exist as powders, liquids, injectables, or chewable or dissolvable tablets. If alternative ARV formulations or administration methods are used, close monitoring for achievement of virological and immunologic success and potential toxicities is recommended. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  13. Application of Physiologically Based Absorption Modeling to Characterize the Pharmacokinetic Profiles of Oral Extended Release Methylphenidate Products in Adults

    Science.gov (United States)

    Yang, Xiaoxia; Duan, John; Fisher, Jeffrey

    2016-01-01

    A previously presented physiologically-based pharmacokinetic model for immediate release (IR) methylphenidate (MPH) was extended to characterize the pharmacokinetic behaviors of oral extended release (ER) MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI) tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations. A variety of mathematical functions can be utilized to account for the engineered release/dissolution technologies to achieve better model performance. The physiological absorption model tracked well the plasma concentration profiles in adults receiving a multilayer-release MPH formulation or Metadate CD, while some degree of discrepancy was observed between predicted and observed plasma concentration profiles for Ritalin LA and Medikinet Retard. A local sensitivity analysis demonstrated that model parameters associated with the GI tract significantly influenced model predicted plasma MPH concentrations, albeit to varying degrees, suggesting the importance of better understanding the GI tract physiology, along with the intestinal non-specific loss of MPH. The model provides a quantitative tool to predict the biphasic plasma time course data for ER MPH, helping elucidate factors responsible for the diverse plasma MPH concentration profiles following oral dosing of different ER formulations. PMID:27723791

  14. Influence of drug polarity upon the solid-state structure and release properties of self-emulsifying drug delivery systems in relation with water affinity.

    Science.gov (United States)

    Chambin, O; Karbowiak, T; Djebili, L; Jannin, V; Champion, D; Pourcelot, Y; Cayot, P

    2009-06-01

    To overcome low oral bioavailability of poorly water-soluble drugs, self-emulsifying drug delivery systems (SEDDS) have been noted as a promising strategy. However, incorporation of drugs into SEDDS composed of Gelucire44/14 could induce interactions not yet well understood. The aim of this study was to investigate the influence of drug polarity upon the solid-state structure of SEDDS formulation, particularly in terms of wettability, thermal behaviour and microscopic aspects and their effect upon the release properties of the SEDDS. Model drugs were naproxen and sodium naproxen (10% w/w), two drugs with similar chemical structure but different water solubilities. Both drugs had an effect on the structure and behaviour of SEDDS: sodium naproxen mainly increased surface wettability while naproxen modified its thermal behaviour. Moreover, influence of Gelucire44/14 as self-emulsifying matrix was very marked for naproxen with a huge increase of naproxen release, the less water-soluble drug in condition where the solubility was the limiting parameter (at pH 1.2). Study of SEDDS structure and its physico-chemical properties using different techniques brought novel findings about the behaviour of SEDDS with different kinds of drugs (various water solubilities) and could be linked to their performances during in vitro dissolution.

  15. 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

  16. Steric effects in release of amides from linkers in solid-phase synthesis. Molecular mechanics modeling of key step in peptide and combinatorial chemistry

    DEFF Research Database (Denmark)

    Norrby, Per-Ola; Jensen, Knud Jørgen

    2006-01-01

    Acidolytic release of an amide from a solid support by C-N bond cleavage is all ubiquitous and crucial step in many solid-phase syntheses. We have used molecular modeling of a pseudo-equilibrium to explore substituent and steric effects in the release of peptides. The high acid-lability of the ba......Acidolytic release of an amide from a solid support by C-N bond cleavage is all ubiquitous and crucial step in many solid-phase syntheses. We have used molecular modeling of a pseudo-equilibrium to explore substituent and steric effects in the release of peptides. The high acid...... of the lability of a linkage. In addition, predictions indicated that steric effects from the C-alpha-substituent in a BAL anchored amino acid residue should accelerate the acidolytic release. The finding that steric crowding leads to increased acid-lability will be important for further development and use...

  17. In vivo gastrointestinal drug-release monitoring through second near-infrared window fluorescent bioimaging with orally delivered microcarriers

    Science.gov (United States)

    Wang, Rui; Zhou, Lei; Wang, Wenxing; Li, Xiaomin; Zhang, Fan

    2017-03-01

    Non-invasive monitoring of gastrointestinal drug release in vivo is extremely challenging because of the limited spatial resolution and long scanning time of existing bioimaging modalities, such as X-ray radiation and magnetic resonance. Here, we report a novel microcarrier that can retain drugs and withstand the harsh conditions of gastrointestinal tract. Significantly, we can track the microcarrier fate and semi-quantitatively monitor the content of drug released in vivo in real time by measuring the fluorescence signals in the second near-infrared window of lanthanide-based downconversion nanoparticles with an absorption competition-induced emission bioimaging system. The microcarriers show a prolonged residence time of up to 72 h in the gastrointestinal tract, releasing up to 62% of their content. Moreover, minimal deposition of the microcarriers is found in non-target organs, such as the liver, spleen and kidney. These findings provide novel insights for the development of therapeutic and bioimaging strategies of orally administered drugs.

  18. Type of oral solid medication packaging and medication preparation time in nursing homes: A direct observation study.

    Science.gov (United States)

    Cready, C M; Hudson, C; Dreyer, K

    2017-12-01

    Medication administration is a substantial portion of the workday in nursing homes, with the medication preparation step being the most time-consuming. However, little is known about how medication preparation time is affected by the type of packaging used for oral solid medications (ie, tablets/capsules). We examined the effects of two types of packaging. As fewer steps are associated with strip packaging compared to bingo card packaging, we hypothesized that the increase in medication preparation seconds per resident with each additional oral solid medication would be smaller when strip packaging was used. A total of 430 medication preparations conducted by eight nurses during the regularly scheduled morning medication administration period in two nursing homes-using strip packaging and bingo card packaging, respectively-were observed. Each medication preparation observation was matched to its corresponding medication administration record and observations averaged across resident. Using the resident sample (N=149), we estimated three regression models (adjusting the standard errors for the clustering of resident by nurse). The first model regressed medication preparation seconds on the number of oral solid medications. The second model added the type of packaging used and the control variables (type of unit [long-term care, post-acute care], the number of one-half pills and the dosage form diversity in the preparation). To test our hypothesis, the third model added an interaction term between the number of oral solid medications and the type of packaging used. As hypothesized, all else equal, the number of oral solid medications tended to increase medication preparation time per resident in both nursing homes, but the increase was smaller in the strip packaging nursing home (P<.05). Each additional oral solid medication in the bingo card packaging nursing home increased medication preparation by an average of 13 seconds (b=13.077), whereas each oral solid

  19. Instrumental and sensory quantification of oral coatings retained after swallowing semi-solid foods.

    Science.gov (United States)

    Prinz, J F; Huntjens, L; de Wijk, R A

    2006-12-01

    After a mouthful of food has been swallowed, some food material is always retained in the mouth. With semi-solid foods this is in the form of a coating that adheres to the oral mucosa. The amount and location of this material may play an important role in food sensations. In this study two quantitative methods of describing the coatings, generated by a set of 16 model custards varying in degree of lubrication (fat content) and degree of viscosity (starch concentration) are investigated. In the first method, a trained quantitative descriptive analysis panel (N=8) was instructed to take single mouthfuls of semi-solid foods, swallow and then rinse twice for 5s with water and spit out. The turbidity of the rinse water was then measured. During the same session, sensory assessments of the products were obtained. In the second method the thickness of the coating on the anterior and middle one-thirds of the tongue was quantified using a pair of opto-electronic reflectance sensors mounted on a probe which was placed on the tongue, one sensor measuring the anterior part of the tongue the other the posterior (middle third) of the tongue. Turbidity of the first rinse related strongly to the food's viscosity, as well as to sensory attributes associated with the food's fat content and viscosity, such as perceived thickness, creaminess and fattiness. Turbidity of subsequent rinses related primarily to fat content. These results indicate that turbidity of rinse water is a useful tool in fundamental (e.g., food texture research) as well as applied research (e.g., product development and quality assurance in food industry). Reflectance varied primarily with fat content and did not relate well to sensory attributes.

  20. Chemical imaging of Oral Solid Dosage Forms and Changes upon Dissolution Using Coherent Anti-Stokes Raman Scattering Microscopy

    NARCIS (Netherlands)

    Windbergs, Maike; Jurna, M.; Offerhaus, Herman L.; Herek, Jennifer Lynn; Kleinebudde, Peter; Strachan, Clare J.

    2009-01-01

    Dissolution testing is a crucial part of pharmaceutical dosage form investigations and is generally performed by analyzing the concentration of the released drug in a defined volume of flowing dissolution medium. As solid-state properties of the components affect dissolution behavior to a large and

  1. Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Pugliese SC

    2016-01-01

    Full Text Available Steven C Pugliese,1 Todd M Bull1,2 1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, 2UCD Pulmonary Vascular Disease Center, Division of Pulmonary Sciences and Critical Care Medicine and Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Abstract: The development of parenteral prostacyclin therapy marked a dramatic breakthrough in the treatment of pulmonary arterial hypertension (PAH. Intravenous (IV epoprostenol was the first PAH specific therapy and to date, remains the only treatment to demonstrate a mortality benefit. Because of the inherent complexities and risks of treating patients with continuous infusion IV therapy, there is great interest in the development of an oral prostacyclin analog that could mimic the benefits of IV therapy. Herein, we highlight the development of oral prostacyclin therapy, focusing on oral treprostinil, the only US Food and Drug Administration approved oral prostacyclin. Recent Phase III clinical trials have shown the drug to improve exercise tolerance in treatment-naïve PAH patients, but not patients on background oral therapy. Oral treprostinil appears to be most efficacious at higher doses, but its side effect profile and complexities with dosing complicate its use. While oral treprostinil’s current therapeutic role in PAH remains unclear, ongoing studies of this class of medication should help clarify their role in the treatment of PAH. Keywords: oral treprostinil, pulmonary arterial hypertension, selexipag

  2. The release of soluble forms of TRAIL and DR5 by neutrophils of oral cavity cancer patients.

    Directory of Open Access Journals (Sweden)

    Magdalena Marcinczyk

    2008-06-01

    Full Text Available In the present study we examined the release of the soluble form of TRAIL by neutrophils (PMN derived from patients with oral cavity cancer. Simultaneously, we estimated the ability of PMNs of these patients to release the soluble form of DR5 receptor, a natural regulatory protein of TRAIL. The obtained results were confronted with the serum levels of sTRAIL and sDR5. The cells were isolated from 21 patients with squamous cell carcinoma of oral cavity at diagnosis and three weeks after surgery treatment. For comparative purposes we performed similar examinations in autologous peripheral blood mononuclear cells (PBMC. Cytoplasmic protein fractions of the cells were analyzed for the presence of TRAIL and DR5 by western blotting. Soluble TRAIL and soluble DR5 concentrations in the culture supernatants of cells were confronted with their serum levels using ELISA kit. PMN and PBMC of the whole cancer patient group expressed decreased TRAIL protein and unchanged expression of DR5 receptor in comparison with the control group. Unchanged release of sTRAIL by PMNs of patients in Stage II was accompanying the decrease of the ability of PBMC to secrete this protein. In patients in Stage IV the secretion of sTRAIL by PMNs and PBMC was impaired. In contrast to changes in sTRAIL secretion by PMN and PBMC of oral cavity cancer patients, the secretion of sDR5 by these cells was unchanged. The serum levels of sTRAIL were increased in patients in Stage II before treatment and decreased in the same patients after treatment. The altered ability of PMN of PBMC to secrete sTRAIL may have different implications for the immune response of patients with oral cavity cancer cells at different stages of disease.

  3. Recent advances in oral delivery of drugs and bioactive natural products using solid lipid nanoparticles as the carriers

    Directory of Open Access Journals (Sweden)

    Chih-Hung Lin

    2017-04-01

    Full Text Available Chemical and enzymatic barriers in the gastrointestinal (GI tract hamper the oral delivery of many labile drugs. The GI epithelium also contributes to poor permeability for numerous drugs. Drugs with poor aqueous solubility have difficulty dissolving in the GI tract, resulting in low bioavailability. Nanomedicine provides an opportunity to improve the delivery efficiency of orally administered drugs. Solid lipid nanoparticles (SLNs are categorized as a new generation of lipid nanoparticles consisting of a complete solid lipid matrix. SLNs used for oral administration offer several benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. The nontoxic excipients and sophisticated material engineering of SLNs tailor the controllable physicochemical properties of the nanoparticles for GI penetration via mucosal or lymphatic transport. In this review, we highlight the recent progress in the development of SLNs for disease treatment. Recent application of oral SLNs includes therapies for cancers, central nervous system-related disorders, cardiovascular-related diseases, infection, diabetes, and osteoporosis. In addition to drugs that may be active cargos in SLNs, some natural compounds with pharmacological activity are also suitable for SLN encapsulation to enhance oral bioavailability. In this article, we systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for drug- and natural compound-loaded SLNs.

  4. Vagally mediated inhibition of acoustic stress-induced cortisol release by orally administered kappa-opioid substances in dogs.

    Science.gov (United States)

    Bueno, L; Gue, M; Fargeas, M J; Alvinerie, M; Junien, J L; Fioramonti, J

    1989-04-01

    The effects of oral vs. iv administration of kappa- and mu-opioid agonists on plasma cortisol release induced by acoustic stress (AS) were evaluated in fasted dogs with an implanted jugular catheter. AS was induced by 1 h of music (less than or equal to 86 decibels) played through earphones and was accompanied by a 382% maximal rise in plasma cortisol after 15-30 min. Administered orally 30 min before the AS session, both U-50488 (0.1 mg/kg) and PD 117-302 (0.05 mg/kg) significantly (P less than or equal to 0.01) decreased (by 71.2% and 80.9%, respectively) the maximal increase in plasma cortisol induced by AS, while bremazocine, morphine, as well as iv administration of U-50488 at similar doses were ineffective. The effects of U-50488 and PD 117-302 orally administered (0.1 mg/kg) on the hypercortisolemia induced by AS were abolished by pretreatment with iv naloxone (0.1 mg/kg) or MR 2266 (0.1 mg/kg). Naloxone given alone significantly (P less than 0.01) increased basal plasma cortisol, without affecting cortisol increase induced by AS. Vagotomy abolished the effects of orally administered U-50488 on the AS-induced increase in plasma cortisol. Neither U-50488 nor PD 117302 (0.1 mg/kg, orally) reduced the increase in plasma cortisol induced by intracerebroventricular administration of ovine CRF (100 ng/kg). It is concluded that kappa- but not mu-opioid agonists are able to inhibit the stimulation of the hypothalamo-pituitary-adrenocortical axis induced by AS by acting selectively on peripheral kappa-receptors located in the wall of the proximal gut. This action is neurally mediated through afferent vagal fibers affecting central nervous system release of CRF induced by a centrally acting stressor.

  5. Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension.

    Science.gov (United States)

    Durani, Urshila; Tosh, Pritish K; Barreto, Jason N; Estes, Lynn L; Jannetto, Paul J; Tande, Aaron J

    2015-08-01

    While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  6. Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery.

    Science.gov (United States)

    Kawakami, Kohsaku

    2017-06-01

    Amorphous solid dispersions (ASDs) are one of the key formulation technologies that aid the development of poorly soluble candidates. However, their dynamic behaviors, including dissolution and crystallization processes, are still full of mystery. Further understanding of these processes should enhance their wider use. Areas covered: The first part of this review describes the current understanding of the dissolution of ASDs, where phase separation behavior is frequently involved and attempts to develop appropriate dissolution tests to achieve an in vitro-in vivo correlation are examined. The second part of this review discusses crystallization of the drug molecule with the eventual aim of establishing an accelerated testing protocol for predicting its physical stability. Expert opinion: The phase separation behavior from the supersaturated state during the dissolution test must be understood, and its relevance to the oral absorption behavior needs to be clarified. Research efforts should focus on the differences between the phase behavior in in vitro and in vivo situations. Initiation time of the crystallization was shown to be predicted only from storage and glass transition temperatures. This finding should encourage the establishment of testing protocol of the physical stability of ASDs.

  7. Slow heat release - solid fuel stove with acetat-trihydrate heat storage sodium; Slow heat release - Braendeovn med salthydratvarmelager

    Energy Technology Data Exchange (ETDEWEB)

    Zielke, U.; Bjerrum, M.; Noergaard, T. (Teknologisk Institut, Aarhus (Denmark))

    2012-07-01

    Of the 700,000 solid fuel stoves in Denmark, 600,000 are installed in permanent residences, and 100,000 are installed in summer cottages. Recent examinations have shown that in the heating season, these stoves contribute with a not negligible share of air pollution in the cities. The reason is often inexpedient firing and an inappropriate performance of the stove. In many cases the thermal output of the stove exceeds the heating demand of a modern residence; and the user typically reduces the stove's combustion air supply with the purpose of lowering the temperature of the accommodation space. The result is a sooting combustion followed by undesired and environmentally damaging emissions. In worst case the user fires throughout the night reducing the air to an absolutely minimum. In these situations the fuel smoulders all night, and the stove emits large amounts of undesirable and unhealthy emissions. By constructing the stove with a heat storage that can accumulate the heat from the stove and emit the heat later (when not firing), the problem with the unhealthy ''night firings'' should be eliminated. The project started with a pre-examination regarding suitable materials for a heat storage and a literature study of the subject. By using an OGC material, in this case sodiumacetat-trihydrat, the weight of the stove, in spite of the heat storage, could be held within reasonable frames, since 130 kg PCM can contain the same heat amount as 1,200 kg stone. The great challenge was to compensate for PCM's poor heat conductivities, to distribute the heat in the whole heat storage, making it melt regularly without generating local boiling. This problem was solved by construction measures. The system with sodiumacetat-trihydrat, which melts by 58 deg. C, came to function satisfactorily. 14 hours after the last firing, the temperature of the heat storage was 30 deg. C. The tests with PCM were followed by an extensive emission measuring program

  8. Burning rate of solid wood measured in a heat release rate calorimeter

    Science.gov (United States)

    H. C. Tran; R. H. White

    1992-01-01

    Burning rate is a key factor in modeling fire growth and fire endurance of wood structures. This study investigated the burning rate of selected wood materials as determined by heat release, mass loss and charring rates. Thick samples of redwood, southern pine, red oak and basswood were tested in a heat release rate calorimeter. Results on ignitability and average beat...

  9. Preparation and investigation of controlled-release glipizide novel oral device with three-dimensional printing.

    Science.gov (United States)

    Li, Qijun; Wen, Haoyang; Jia, Danyang; Guan, Xiaoying; Pan, Hao; Yang, Yue; Yu, Shihui; Zhu, Zhihong; Xiang, Rongwu; Pan, Weisan

    2017-06-15

    The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol (PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in vitro dissolution condition, and we found the release profile fit Korsmeyer-Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module.

    Science.gov (United States)

    Chaudhari, Manisha B; Desai, Preshita P; Patel, Pratikkumar A; Patravale, Vandana B

    2016-08-01

    Amphotericin B, a gold standard broad spectrum antibiotic used in treatment of systemic fungal infections and visceral leishmaniasis, though is effective parenterally offers severe nephrotoxicity whereas the oral delivery is reported to give very meager oral bioavailability. Thus, to alleviate the toxicity and to improve oral bioavailability, an effective oral delivery approach in the form of solid lipid nanoparticles of amphotericin B (AmbiOnp) was reported earlier by our group. In this investigation, we report the predominant formation of nontoxic superaggregated form of amphotericin B, resulting from the probe sonication-assisted nanoprecipitation technique. The developed formulation was further confirmed to retain this nontoxic form and was found to be stable over the varied gastrointestinal conditions. Further, in vitro antifungal activity of AmbiOnp against Candida albicans showed minimum inhibitory concentration value of 7.812 μg/mL attributed to controlled release of drug from nanoparticulate matrix. In vivo pharmacokinetic studies revealed a relative bioavailability of AmbiOnp to be 1.05-fold with a Cmax of 1109.31 ± 104.79 ng/mL at the end of 24 h which was comparable to Cmax of 1417.49 ± 85.52 ng/mL achieved with that of marketed formulation (Fungizone®) given intravenously establishing efficacy of AmbiOnp. In vivo biodistribution studies indicated very low levels of Amphotericin B in kidneys when given as AmbiOnp as compared to that of marketed formulation proving its safety and was further corroborated by renal toxicity studies. Further, the formulations were found to be stable under refrigeration condition over a period of 3 months.

  11. Nanoemulsion for Solubilization, Stabilization, and In Vitro Release of Pterostilbene for Oral Delivery

    National Research Council Canada - National Science Library

    Zhang, Yue; Shang, Zhenhua; Gao, Chunhui; Du, Man; Xu, Shixia; Song, Haiwen; Liu, Tingting

    2014-01-01

    .... But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using low-energy emulsification method...

  12. Comparison of drug release from liquid crystalline monoolein dispersions and solid lipid nanoparticles using a flow cytometric technique

    Directory of Open Access Journals (Sweden)

    Mohamed Z. Dawoud

    2016-03-01

    Full Text Available Colloidal lipid particles such as solid lipid nanoparticles and liquid crystalline nanoparticles have great opportunities as drug carriers especially for lipophilic drugs intended for intravenous administration. In order to evaluate drug release from these nanoparticles and determine their behavior after administration, emulsion droplets were used as a lipophilic compartment to which the transfer of a model drug was measured. The detection of the model drug transferred from monoolein cubic particles and trimyristin solid lipid nanoparticles into emulsion droplets was performed using a flow cytometric technique. A higher rate and amount of porphyrin transfer from the solid lipid nanoparticles compared to the monoolein cubic particles was observed. This difference might be attributed to the formation of a highly ordered particle which leads to the expulsion of drug to the surface of the crystalline particle. Furthermore, the sponge-like structure of the monoolein cubic particles decreases the rate and amount of drug transferred. In conclusion, the flow cytometric technique is a suitable technique to study drug transfer from these carriers to large lipophilic acceptors. Monoolein cubic particles with their unique structure can be used successfully as a drug carrier with slow drug release compared with trimyristin nanoparticles.

  13. Development of megestrol acetate solid dispersion nanoparticles for enhanced oral delivery by using a supercritical antisolvent process

    Directory of Open Access Journals (Sweden)

    Ha ES

    2015-08-01

    Full Text Available Eun-Sol Ha,1 Jeong-Soo Kim,2 In-hwan Baek,3 Jin-Wook Yoo,1 Yunjin Jung,1 Hyung Ryong Moon,1 Min-Soo Kim1 1College of Pharmacy, Pusan National University, 2Dong-A ST Co Ltd, Yongin, 3College of Pharmacy, Kyungsung University, Busan, South Korea Abstract: In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was <500 nm. Powder X-ray diffraction and differential scanning calorimetry measurements showed that megestrol acetate was present in an amorphous or molecular dispersion state within the solid dispersion nanoparticles. Hydroxypropylmethyl cellulose (HPMC solid dispersion nanoparticles significantly increased the maximum dissolution when compared with polyvinylpyrrolidone K30 solid dispersion nanoparticles. The extent and rate of dissolution of megestrol acetate increased after the addition of a surfactant into the HPMC solid dispersion nanoparticles. The most effective surfactant was Ryoto sugar ester L1695, followed by d-a-tocopheryl polyethylene glycol 1000 succinate. In this study, the solid dispersion nanoparticles with a drug:HPMC:Ryoto sugar ester L1695 ratio of 1:2:1 showed >95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0–24 hours and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol

  14. Oral processing characteristics of solid savoury meal components, and relationship with food composition, sensory attributes and expected satiation.

    Science.gov (United States)

    Forde, C G; van Kuijk, N; Thaler, T; de Graaf, C; Martin, N

    2013-01-01

    The modern food supply is often dominated by a large variety of energy dense, softly textured foods that can be eaten quickly. Previous studies suggest that particular oral processing characteristics such as large bite size and lack of chewing activity contribute to the low satiating efficiency of these foods. To better design meals that promote greater feelings of satiation, we need an accurate picture of the oral processing characteristics of a range of solid food items that could be used to replace softer textures during a normal hot meal. The primary aim of this study was to establish an accurate picture of the oral processing characteristics of a set of solid savoury meal components. The secondary aim was to determine the associations between oral processing characteristics, food composition, sensory properties, and expected satiation. In a within subjects design, 15 subjects consumed 50 g of 35 different savoury food items over 5 sessions. The 35 foods represented various staples, vegetables and protein rich foods such a meat and fish. Subjects were video-recorded during consumption and measures included observed number of bites, number of chews, number of swallows and derived measures such as chewing rate, eating rate, bite size, and oral exposure time. Subjects rated expected satiation for a standard 200 g portion of each food using a 100mm and the sensory differences between foods were quantified using descriptive analysis with a trained sensory panel. Statistical analysis focussed on the oral processing characteristics and associations between nutritional, sensory and expected satiation parameters of each food. Average number of chews for 50 g of food varied from 27 for mashed potatoes to 488 for tortilla chips. Oral exposure time was highly correlated with the total number of chews, and varied from 27 s for canned tomatoes to 350 s for tortilla chips. Chewing rate was relatively constant with an overall average chewing rate of approximately 1 chew

  15. Abnormal release of incretins and cortisol after oral glucose in subjects with insulin-resistant myotonic dystrophy

    DEFF Research Database (Denmark)

    Johansson, Asa; Olsson, Tommy; Cederquist, Kristina

    2002-01-01

    patients and controls, although long CTG repeat expansions were associated with a more pronounced GIP response. Interestingly, the GLP-1 response to oral glucose correlated with the insulin response in patients but not in controls whereas, in controls, the insulin response closely correlated with the GIP...... response. Furthermore, cortisol and ACTH levels increased paradoxically in patients after glucose; this was more pronounced in patients with long CTG repeat expansions. CONCLUSIONS: This study showed that the GLP-1 and ACTH/cortisol responses to oral glucose are abnormal in insulin-resistant DM1 patients...... and that CTG triplet repeats are linked to GIP release. These abnormalities may contribute both to the severe insulin resistance and hyperinsulinemia in DM1 and to the preservation of adequate islet function, enabling glucose tolerance to be normal in spite of this marked insulin resistance in DM1....

  16. Oral fat exposure increases the first phase triacylglycerol concentration due to release of stored lipid in humans.

    Science.gov (United States)

    Mattes, Richard D

    2002-12-01

    Oral exposure to dietary fat (through modified sham feeding, which entails mastication and expectoration of foods) augments the postprandial triacylglycerol (TAG) concentration, in part, though augmented lipid absorption. This study was designed to characterize early events in this process. At 2200 h, 25 healthy adults (13 men, 12 women) consumed 80 g of almonds (high oleic acid content) and fasted until approximately 0700 h. After placement of a catheter in a hand vein and 4 blood draws at 10-min intervals, 50 1-g safflower oil (high linoleic acid content) capsules were consumed. After another blood draw, modified sham feeding was initiated with a cracker only or cracker with cream cheese in random order with 1 wk between trials. Oral exposures occurred at 5-min intervals for 60 min then at 15-min intervals from min 60 to 120. Additional blood draws occurred at 2, 4, 6, 8, 10, 12, 14, 30, 60, 120, 240, 360 and 480 min. Oral stimulation, especially by fat, prompted the rapid (mean approximately 23 min) release of lipid stored from the previous meal (almonds) in all participants. This resulted in multimodal postprandial triacylglycerol (TAG) peaks generally occurring at 0-30 min, 60-120 min and 240-480 min after loading and initiation of oral stimulation. TAG magnitudes during these times were correlated (r = 0.40-0.89, P absorption of meal lipid; this in turn supplements a later peak associated with release of endogenously synthesized TAG because lipid from all three sources competed for a common clearance mechanism. If substantiated, additional understanding of the behavioral factors (e.g., eating patterns) that initiate this cascade will be warranted.

  17. Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

    Science.gov (United States)

    Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas

    2015-04-01

    To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

  18. High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately active ulcerative colitis

    OpenAIRE

    Heyman, Melvin; Winter, HS; Krzeski, P; Heyman, MB; Ibarguen-Secchia, E; Iwanczak, B; Kaczmarski, M; Kierkus, J.; Kolaček, S; Osuntokun, B; Quiros, JA

    2014-01-01

    ABSTRACT Objective: The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Methods: Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥10 to ≤55 and a truncated Mayo Score of ≥1 for both rectal bleeding and stool frequency, were enrolled. They received body weight–dependent d...

  19. Long-standing oral mucosal lesions in solid organ-transplanted children-a novel clinical entity.

    Science.gov (United States)

    Saalman, Robert; Sundell, Sten; Kullberg-Lindh, Carola; Lövsund-Johannesson, Eva; Jontell, Mats

    2010-03-15

    Acute oral angioedema is well documented in young pediatric liver-transplanted patients. This is a report of an identified novel entity of long-standing oral mucosal lesions (OML) in children who had undergone solid organ transplantation. In conjunction with routine medical follow-ups, all solid organ-transplanted children were examined annually for OML. Eight children developed a novel entity of long-standing OML after solid organ transplantation. Seven of the eight children had undergone liver transplantation whereas one child was kidney transplanted. The children received tacrolimus immunosuppression after transplantation. All recipients presented with multiple spherical nodules on the dorsum of the tongue, which later on displayed a fissured appearance. Most patients also presented with mucosal tags or ridges and swollen lips similar to those found in patients with orofacial granulomatosis. In addition, most patients had a clinical history of immediate-onset food-induced allergic reactions, including transient angioedema, after transplantation, but this clinical manifestation appeared separately from the long-standing lesions. A novel entity of long-standing OML that share some features with orofacial granulomatosis has been identified in children after solid organ transplantation.

  20. Pharmacokinetics of 2 Novel Formulations of Modified-Release Oral Testosterone Alone and With Finasteride in Normal Men With Experimental Hypogonadism

    Science.gov (United States)

    Snyder, Christin N.; Clark, Richard V.; Caricofe, Ralph B.; Bush, Mark A.; Roth, Mara Y.; Page, Stephanie T.; Bremner, William J.; Amory, John K.

    2011-01-01

    Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current “immediate-release” formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency. PMID:20378927

  1. Formulation of novel sustained release rifampicin-loaded solid lipid microparticles based on structured lipid matrices from Moringa oleifera.

    Science.gov (United States)

    Onyishi, Ikechukwu V; Chime, Salome A; Ogudiegwu, Echezona O

    2015-01-01

    To formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G). Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized in terms of particle morphology and size, percentage drug content (PDC), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats. Rifampicin-loaded SLMs had particle size range of 32.50 ± 2.10 to 34.0 ± 8.40 μm, highest PDC of 87.6% and showed stable pH. SLMs had good sustained release properties with about 77.1% release at 12 h in phosphate buffer (pH 6.8) and 80.3% drug release at 12 h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51% degradation of rifampicin in SGF at 3 h, while rifampicin pure sample had 95.5% degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5 μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p < 0.05). Rifampicin-loaded SLMs could be used once daily for the treatment tuberculosis.

  2. Kinetics Study of Solid Ammonia Borane Hydrogen Release – Modeling and Experimental Validation for Chemical Hydrogen Storage

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yong-Joon; Ronnebro, Ewa; Rassat, Scot D.; Karkamkar, Abhijeet J.; Maupin, Gary D.; Holladay, Jamelyn D.; Simmons, Kevin L.; Brooks, Kriston P.

    2014-02-24

    Ammonia borane (AB), NH3BH3, is a promising material for chemical hydrogen storage with 19.6 wt% gravimetric hydrogen capacity of which 16.2 wt% hydrogen can be utilized below 200°C. We have investigated the kinetics of hydrogen release from AB and from an AB-methyl cellulose (AB/MC) composite at temperatures of 160-300°C using both experiments and modeling. The purpose of our study was to show safe hydrogen release without thermal runaway effects and to validate system model kinetics. AB/MC released hydrogen at ~20°C lower than neat AB and at a rate that is two times faster. Based on the experimental results, the kinetics equations were revised to better represent the growth and nucleation process during decomposition of AB. We explored two different reactor concepts; Auger and fixed bed. The current Auger reactor concept turned out to not be appropriate, however, we demonstrated safe self-propagation of the hydrogen release reaction of solid AB/MC in a fixed bed reactor.

  3. Preparation and in vitro characterization of solid dispersion floating tablet by effervescent control release technique with improved floating capabilities.

    Science.gov (United States)

    Singhal, Peeush; Kaushik, Rajneesh Dutt; Kumar, Vijay Jyoti; Verma, Anurag; Gupta, Pranav

    2016-09-01

    In this Research, an effort has been done for the development of effervescent controlled release floating tablet (ECRFT) from solid dispersions (SDs) of diclofenac sodium (DS) for upsurge the solubility and dissolution rate. ECRFT of DS was prepared by using SDs of DS and its SDs prepared with PEG as carrier using thermal method (Simple fusion). SDs of DS were formulated in many ratio (1:1, 1:2, 1:3 and 1:4). Prepared SDs was optimized for its solubility, % drug content and % dissolution studies. Tablets were formulated by using optimized SDs products and all formulation was evaluated for various parameters. A clear rise in dissolution rate was detected with entirely SD, amid that the optimized SD (SD4) was considered for ECRFT. Among all the tablet formulations, its F3 formulation was better in all the terms of pre compression and post compression parameters. It had all the qualities of a good ECRFT, based on this F3 formulation was selected as the best formulation. Data of in vitro release was fitted in several kinetics models to explain release mechanism. The F3 formulation shows zero order release. From this study we can concluded that ECRFT containing SDs of DS can be successfully used for achieving better therapeutic objective.

  4. 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.

  5. A Comparison of the Pharmacokinetics of Methylphenidate Extended-Release Orally Disintegrating Tablets With a Reference Extended-Release Formulation of Methylphenidate in Healthy Adults.

    Science.gov (United States)

    Childress, Ann; Stark, Jeffrey G; McMahen, Russ; Engelking, Dorothy; Sikes, Carolyn

    2018-02-01

    Extended-release (ER) methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. This was a randomized, open-label, 3-period, 3-treatment study comparing the bioavailability and absorption of 2 MPH XR-ODT formulations with an MPH ER reference medication. Here we report the 2 treatments comparing the commercial MPH XR-ODT formulation and reference medication. Following a ≥10-hour fast, 42 healthy adults received 60 mg of reference medication or MPH XR-ODT (2 × 30 mg). The following pharmacokinetic (PK) parameters were calculated for total methylphenidate (d + l): maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), terminal half-life (T 1/2 ), and areas under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC last ), and from time zero extrapolated to infinity (AUC inf ). Secondary PK end points included partial AUCs. Safety was also assessed. Overall systemic exposure to methylphenidate after MPH XR-ODT administration was similar to that of the reference product, and the concentration-time profiles for MPH XR-ODT and the reference drug were similar, although the C max was 25% higher for MPH XR-ODT. The most common treatment-emergent adverse events were nausea (6) and anxiety (4), which were similar across treatments. © 2017, The American College of Clinical Pharmacology.

  6. Determining the Release of Radionuclides from Tank 18F Waste Residual Solids: FY2016 Report

    Energy Technology Data Exchange (ETDEWEB)

    King, William D. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Hobbs, David T. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2016-08-12

    Pore water leaching studies were conducted on actual Savannah River Site (SRS) Tank 18F residual waste solids to support Liquid Waste tank closure efforts. A test methodology was developed during previous simulant testing to produce slurries of tank residual solids and grout-representative solids in grout pore water solutions (based on SRS groundwater compositions) with pH and Eh values expected during the aging of the closed waste tank. The target conditions are provided below where the initial pore water has a reducing potential and a relatively high pH (Reducing Region II). The pore water is expected to become increasingly oxidizing with time (Oxidizing Region II) and during the latter stages of aging (Oxidizing Region III) the pH is expected to decrease. For the reducing case, tests were conducted with both unwashed and washed Tank 18F residual solids. For the oxidizing cases (Oxidizing Regions II and III), all samples were washed with simulated grout pore water solutions prior to testing, since it is expected that these conditions will occur after considerable pore water solution has passed through the system. For the reducing case, separate tests were conducted with representative ground grout solids and with calcium carbonate reagent, which is the grout phase believed to be controlling the pH. Ferrous sulfide (FeS) solids were also added to the reducing samples to lower the slurry Eh value. Calcium carbonate solids were used as the grout-representative solid phase for each of the oxidizing cases. Air purge-gas with and without CO2 removed was transferred through the oxidizing test samples and nitrogen purge-gas was transferred through the reducing test samples during leach testing. The target pH values were achieved to within 0.5 pH units for all samples. Leaching studies were conducted over an Eh range of approximately 0.7 V. However, the highest and lowest Eh values achieved of ~+0.5 V and ~-0.2 V were

  7. BUDGET IMPACT ANALYSIS OF USING OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION IN REPLACE OF INTRAVENOUS PANTOPRAZOLE IN CRITICALLY ILL PATIENTS.

    Science.gov (United States)

    Foroutan, Naghmeh; Fahimi, Fanak; Dabiri, Yasamin; Foroutan, Arash; Habibi, Maryam; Salamzadeh, Jamshid

    2015-12-31

    The aim of the present study was to estimate the financial consequence of using omeprazole immediate-release (IR) oral suspension versus pantoprazole intravenous infusion for preventing stress-related upper gastrointestinal bleeding in critically ill patients from the perspective of the health care system. An Excel-based model was developed to compare the cost of prevention of upper gastrointestinal bleeding early after intensive care admission using the current intravenous (IV) pantoprazole formulation versus omeprazole IR oral suspension. Total costs included the cost of acid suppressive drugs and related clinical outcomes. Inputs were obtained from a local clinical trial, the Ministry of Health database, insurance organizations, hospital and pharmacy registries, the relevant literature, and expert opinion. The robustness of the input data was investigated by one-way sensitivity analysis. The model was developed based on the results of a randomized control trial (RCT), in which experimental and control groups received omeprazole and pantoprazole, respectively. According to the proposed model, the cost of gastrointestinal (GI) bleeding prevention using pantoprazole IV was US$ 950,000 while US$ 750,000 was spent on receiving omeprazole oral suspension. These costs led to the annual cost-saving of almost US$ 200,000 (US$4 per member, per month) for the health care system. In the present study, a budget impact analysis was performed to assess the financial consequences of using omeprazole IR oral suspension in place of pantoprazole IV for prevention of upper gastrointestinal bleeding. The better preventive effect of omeprazole IR oral suspension when compared with conventional therapy using pantoprazole IV was the major reason for the final comparative budgetary savings.

  8. Mucoadhesive Gels Designed for the Controlled Release of Chlorhexidine in the Oral Cavity

    Directory of Open Access Journals (Sweden)

    Adamo Fini

    2011-09-01

    Full Text Available This study describes the in vitro/ex vivo buccal release of chlorhexidine (CHX from nine mucoadhesive aqueous gels, as well as their physicochemical and mucoadhesive properties: CHX was present at a constant 1% w/v concentration in the chemical form of digluconate salt. The mucoadhesive/gel forming materials were carboxymethyl- (CMC, hydroxypropylmethyl- (HPMC and hydroxypropyl- (HPC cellulose, alone (3% w/w or in binary mixtures (5% w/w; gels were tested for their mucoadhesion using the mucin method at 1, 2 and 3% w/w concentrations. CHX release from different formulations was assessed using a USP method and newly developed apparatus, combining release/permeation process in which porcine mucosa was placed in a Franz cell. The combination of HPMC or HPC with CMC showed slower drug release when compared to each of the individual polymers. All the systems proved suitable for CHX buccal delivery, being able to guarantee both prolonged release and reduced transmucosal permeation. Gels were compared for the release of previously studied tablets that contained Carbopol and HPMC, alone or in mixture. An accurate selection and combination of the materials allow the design of different pharmaceutical forms suitable for different purposes, by simply modifying the formulation compositions.

  9. Analytical model for release calculations in solid thin-foils ISOL targets

    Energy Technology Data Exchange (ETDEWEB)

    Egoriti, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Politecnico di Milano, Department of Energy, CeSNEF-Nuclear Engineering Division, Via Ponzio, 34/3, 20133 Milano (Italy); Boeckx, S. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); ICTEAM Inst., Univ. Catholique de Louvain, Louvain-la-Neuve (Belgium); Ghys, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Houngbo, D., E-mail: donald.houngbo@sckcen.be [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Department of Flow, Heat and Combustion Mechanics, Gent University (UGent), St.-Pietersnieuwstraat 41, B-9000 Gent (Belgium); Popescu, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium)

    2016-10-01

    A detailed analytical model has been developed to simulate isotope-release curves from thin-foils ISOL targets. It involves the separate modeling of diffusion and effusion inside the target. The former has been modeled using both first and second Fick's law. The latter, effusion from the surface of the target material to the end of the ionizer, was simulated with the Monte Carlo code MolFlow+. The calculated delay-time distribution for this process was then fitted using a double-exponential function. The release curve obtained from the convolution of diffusion and effusion shows good agreement with experimental data from two different target geometries used at ISOLDE. Moreover, the experimental yields are well reproduced when combining the release fraction with calculated in-target production.

  10. Determining the release of radionuclides from tank waste residual solids. FY2015 report

    Energy Technology Data Exchange (ETDEWEB)

    King, William D. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Hobbs, David T. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2015-09-11

    Methodology development for pore water leaching studies has been continued to support Savannah River Site High Level Waste tank closure efforts. For FY2015, the primary goal of this testing was the achievement of target pH and Eh values for pore water solutions representative of local groundwater in the presence of grout or grout-representative (CaCO3 or FeS) solids as well as waste surrogate solids representative of residual solids expected to be present in a closed tank. For oxidizing conditions representative of a closed tank after aging, a focus was placed on using solid phases believed to be controlling pH and Eh at equilibrium conditions. For three pore water conditions (shown below), the target pH values were achieved to within 0.5 pH units. Tank 18 residual surrogate solids leaching studies were conducted over an Eh range of approximately 630 mV. Significantly higher Eh values were achieved for the oxidizing conditions (ORII and ORIII) than were previously observed. For the ORII condition, the target Eh value was nearly achieved (within 50 mV). However, Eh values observed for the ORIII condition were approximately 160 mV less positive than the target. Eh values observed for the RRII condition were approximately 370 mV less negative than the target. Achievement of more positive and more negative Eh values is believed to require the addition of non-representative oxidants and reductants, respectively. Plutonium and uranium concentrations measured during Tank 18 residual surrogate solids leaching studies under these conditions (shown below) followed the general trends predicted for plutonium and uranium oxide phases, assuming equilibrium with dissolved oxygen. The highest plutonium and uranium concentrations were observed for the ORIII condition and the lowest concentrations were observed for the RRII condition. Based on these results, it is recommended that these test methodologies be used to

  11. 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...

  12. Release of nanomaterials from solid nanocomposites and consumer exposure assessment - a forward-looking review

    DEFF Research Database (Denmark)

    Mackevica, Aiga; Hansen, Steffen Foss

    2016-01-01

    identify and discuss the key data needs and provide recommendations for consumer exposure assessment of nanomaterials. In total, we identified 76 studies of relevance. Most studies have analyzed the release of Ag and TiO2 from textiles and paints, and CNT and SiO2 from nanocomposites. Less than half...

  13. Approaches to evaluating weathering effects on release of engineered nanomaterials from solid matrices

    Science.gov (United States)

    Increased production and use of engineered nanomaterials (ENMs) over the past decade has increased the potential for the transport and release of these materials into the environment. Here we present results of two separate studies designed to simulate the effects of weathering o...

  14. Second Order Kinetic Modeling of Headspace Solid Phase Microextraction of Flavors Released from Selected Food Model Systems

    Directory of Open Access Journals (Sweden)

    Jiyuan Zhang

    2014-09-01

    Full Text Available The application of headspace-solid phase microextraction (HS-SPME has been widely used in various fields as a simple and versatile method, yet challenging in quantification. In order to improve the reproducibility in quantification, a mathematical model with its root in psychological modeling and chemical reactor modeling was developed, describing the kinetic behavior of aroma active compounds extracted by SPME from two different food model systems, i.e., a semi-solid food and a liquid food. The model accounted for both adsorption and release of the analytes from SPME fiber, which occurred simultaneously but were counter-directed. The model had four parameters and their estimated values were found to be more reproducible than the direct measurement of the compounds themselves by instrumental analysis. With the relative standard deviations (RSD of each parameter less than 5% and root mean square error (RMSE less than 0.15, the model was proved to be a robust one in estimating the release of a wide range of low molecular weight acetates at three environmental temperatures i.e., 30, 40 and 60 °C. More insights of SPME behavior regarding the small molecule analytes were also obtained through the kinetic parameters and the model itself.

  15. Spectroscopic-Based Chemometric Models for Quantifying Low Levels of Solid-State Transitions in Extended Release Theophylline Formulations.

    Science.gov (United States)

    Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval A; Khan, Mansoor A

    2016-01-01

    Variations in the solid state form of a pharmaceutical solid have profound impact on the product quality and clinical performance. Quantitative models that allow rapid and accurate determination of polymorphic changes in pharmaceutical products are essential in ensuring product quality throughout its lifecycle. This study reports the development and validation of chemometric models of Raman and near infrared spectroscopy (NIR) for quantifying the extent of pseudopolymorphic transitions of theophylline in extended release formulations. The chemometric models were developed using sample matrices consisting of the commonly used excipients and at the ratios in commercially available products. A combination of scatter removal (multiplicative signal correction and standard normal variate) and derivatization (Savitzky-Golay second derivative) algorithm were used for data pretreatment. Partial least squares and principal component regression models were developed and their performance assessed. Diagnostic statistics such as the root mean square error, correlation coefficient, bias and Q(2) were used as parameters to test the model fit and performance. The models developed had a good fit and performance as shown by the values of the diagnostic statistics. The model diagnostic statistics were similar for MSC-SG and SNV-SG treated spectra. Similarly, PLSR and PCR models had comparable performance. Raman chemometric models were slightly better than their corresponding NIR model. The Raman and NIR chemometric models developed had good accuracy and precision as demonstrated by closeness of the predicted values for the independent observations to the actual TMO content hence the developed models can serve as useful tools in quantifying and controlling solid state transitions in extended release theophylline products. Copyright © 2016. Published by Elsevier Inc.

  16. Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations.

    Science.gov (United States)

    Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval; Mohammad, Adil; Wu, Suyang; Siddiqui, Akhtar; Khan, Mansoor A

    2016-02-29

    Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug

  17. 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

  18. Cognitive Improvement of Attention and Inhibition in the Late Afternoon in Children With Attention-Deficit Hyperactivity Disorder (ADHD) Treated With Osmotic-Release Oral System Methylphenidate.

    Science.gov (United States)

    Slama, Hichem; Fery, Patrick; Verheulpen, Denis; Vanzeveren, Nathalie; Van Bogaert, Patrick

    2015-07-01

    Long-acting medications have been developed and approved for use in the treatment of attention-deficit hyperactivity disorder (ADHD). These compounds are intended to optimize and maintain symptoms control throughout the day. We tested prolonged effects of osmotic-release oral system methylphenidate on both attention and inhibition, in the late afternoon. A double-blind, randomized, placebo-controlled study was conducted in 36 boys (7-12 years) with ADHD and 40 typically developing children. The ADHD children received an individualized dose of placebo or osmotic-release oral system methylphenidate. They were tested about 8 hours after taking with 2 continuous performance tests (continuous performance test-X [CPT-X] and continuous performance test-AX [CPT-AX]) and a counting Stroop. A positive effect of osmotic-release oral system methylphenidate was present in CPT-AX with faster and less variable reaction times under osmotic-release oral system methylphenidate than under placebo, and no difference with typically developing children. In the counting Stroop, we found a decreased interference with osmotic-release oral system methylphenidate but no difference between children with ADHD under placebo and typically developing children. © The Author(s) 2014.

  19. [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

    Science.gov (United States)

    Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

    2014-03-01

    To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

  20. Design of prolonged release tablets using new solid acrylic excipients for direct compression.

    Science.gov (United States)

    Villanova, J C O; Ayres, E; Oréfice, R L

    2011-11-01

    The design of new excipients that extend the release of drugs from tablets over prolonged periods is essential in reaching enhanced therapeutic performances. In this sense, the objective of this study was to develop new excipients, based on acrylic monomers (ethyl acrylate, methyl methacrylate, and butyl methacrylate) for use in direct compression (DC). The polymeric excipients were prepared by suspension and emulsion polymerization reactions and were characterized by FTIR to confirm the polymerization reaction. For the success of direct compression, excipients must present good flow and compactability properties. Therefore, excipients were submitted to analysis of morphology (SEM), particle size and size distribution by laser diffraction, and powder density (bulk density and tapped density). The Carr index, Hausner ratio, flow ratio, and cotangent of the angle α were determined. Thereafter, the polymeric excipients were used to prepare inert matrices by DC using propranolol hydrochloride (PHCl) as a model drug. The tablets were evaluated for average weight, breaking force, and friability tests. The release profiles were determined, and the dissolution kinetics was studied. The results indicated that matrices prepared from excipients obtained by suspension polymerization (NWCB and PECB) presented a release of PHCl for a period exceeding 12h, most likely due to the higher micromeritic properties. The results suggested that the increase in the percentage of polymers, as well as in the compression time, resulted in a higher hardness of the matrix with a reduced rate release of the PHCl. Finally, in vitro preliminary tests showed that the polymeric excipients produced were non-toxic for the gingival fibroblasts. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging.

    Science.gov (United States)

    Ewing, Andrew V; Clarke, Graham S; Kazarian, Sergei G

    2014-08-18

    This work presents the use of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and spectroscopic imaging to study the stability and dissolution behaviour of amorphous solid dispersions (ASDs). ASDs are employed to improve the bioavailability of drugs which are poorly soluble in aqueous solutions. Selecting the appropriate polymeric excipients for use in pharmaceutical tablets is crucial to control drug stability and subsequent release. In this study, indomethacin was used as a model poorly-aqueous soluble drug since the amorphous-form has improved dissolution properties over its crystalline forms. ASDs of indomethacin/polyethylene glycol (PEG) and indomethacin/hydroxypropyl methylcellulose (HPMC) in a 1:3 wt ratio were compared. Firstly, ATR-FTIR spectroscopy was employed to monitor the stability of indomethacin in the ASDs over 96 h. While the indomethacin/HPMC ASD showed the ability to maintain the amorphous indomethacin form for longer periods of time, ATR-FTIR spectra revealed that indomethacin in the drug/PEG ASD crystallised to the stable γ-form, via the α-form. Secondly, ATR-FTIR spectroscopic imaging was used to study the dissolution of ASD tablets in a phosphate buffer (pH 7.5). Crystallisation of amorphous indomethacin was characterised in the spectra collected during the dissolution of the indomethacin/PEG ASD which consequently hindered release into the surrounding solution. In contrast, release of amorphous indomethacin was more effective from HPMC. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. In vitro dissolution study of acetylsalicylic acid solid dispersions. Tunable drug release allowed by the choice of polymer matrix.

    Science.gov (United States)

    Policianova, Olivia; Brus, Jiri; Hruby, Martin; Urbanova, Martina

    2014-07-22

    Abstract Due to their high versatility and diverse excipient options, solid dispersions (SDs) are an elegant choice for the formulation of active pharmaceutical ingredients with inconvenient solubility. Four distinct types of polymers with different physicochemical properties [polyvinylpyrrolidone, poly[N-(2-hydroxypropyl)-metacrylamide], poly(2-ethyl-2-oxazoline), and polyethylene glycol] and variable molecular weights were compared to investigate the influence of the polymer matrix on drug release. To probe the extent of intercomponent interactions, acetylsalicylic acid (ASA) was used as a model active substance. Controlled drug release was demonstrated for all four types of polymer-ASA SDs created by the freeze-drying method. While the polyethylene glycol-ASA SD exhibited an increased dissolution rate, the other polymer-ASA systems exhibited significantly reduced drug dissolution kinetics compared to free ASA. Furthermore, in contrast to physical mixtures, the prepared SDs all exhibited zero-order dissolution kinetics for ASA. The dissolution rate was strongly dependent on the molecular weight of the polymer. These results demonstrate that the type of SD may be controlled by the chemical constitutions of the polymers and that appropriate selection of the molecular weight of the polymer matrix enables finely tuned drug release over a wide range of dissolution rates.

  3. High-Amylose Sodium Carboxymethyl Starch Matrices: Development and Characterization of Tramadol Hydrochloride Sustained-Release Tablets for Oral Administration

    Science.gov (United States)

    Nabais, Teresa; Leclair, Grégoire

    2014-01-01

    Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol. PMID:25006518

  4. An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing.

    Science.gov (United States)

    Alhijjaj, Muqdad; Belton, Peter; Qi, Sheng

    2016-11-01

    FDM 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds. This study explored the use of polymer blends as a formulation strategy to overcome this processability issue and to provide adjustable drug release rates from the printed dispersions. Solid dispersions of felodipine, the model drug, were successfully fabricated using FDM 3D printing with polymer blends of PEG, PEO and Tween 80 with either Eudragit E PO or Soluplus. As PVA is one of most widely used polymers in FDM 3D printing, a PVA based solid dispersion was used as a benchmark to compare the polymer blend systems to in terms of processability. The polymer blends exhibited excellent printability and were suitable for processing using a commercially available FDM 3D printer. With 10% drug loading, all characterization data indicated that the model drug was molecularly dispersed in the matrices. During in vitro dissolution testing, it was clear that the disintegration behavior of the formulations significantly influenced the rates of drug release. Eudragit EPO based blend dispersions showed bulk disintegration; whereas the Soluplus based blends showed the 'peeling' style disintegration of strip-by-strip. The results indicated that interplay of the miscibility between excipients in the blends, the solubility of the materials in the dissolution media and the degree of fusion between the printed strips during FDM process can be used to manipulate the drug release rate of the dispersions. This brings new insight into the design principles of controlled release formulations using FDM 3D printing. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. oral

    African Journals Online (AJOL)

    association between oral candidosis and. AIDS; the first documented patient with. AIDS had oral candidosis.3 A sub- stantial amount of data now emphasise its high prevalence in HIV-infected individuals. The manifestations of candidal infection in HIV-infected persons are restricted to superficial mucosal lesions of varying ...

  6. Release of peppermint flavour compounds from chewing gum: effect of oral functions

    DEFF Research Database (Denmark)

    Haahr, Anne-Mette; Bardow, A.; Thomsen, C.E.

    2004-01-01

    masseter muscle activity (MMA), chewing force (CFO), and saliva flow rate (SFR), may also play a role. In 10 healthy young males, the retronasal expired air of menthol and menthone from peppermint-flavoured (2%) chewing gum was determined as functions of CF, SFR, MMA, and CFO. The experimental setup......, the concentration of flavour compounds in the expired air depended primarily on MMA and CF, becoming higher with increased MMA and CF. The concentration of flavour compounds in saliva depended primarily on SFR and the duration of the chewing task, becoming lower with high SFR and prolonged chewing duration....... An increased volume of saliva in the mouth seemed to keep more flavour compounds in the aqueous phase, thereby diminishing the release via the retronasal route. In conclusion, flavour release to the retronasal compartment was dependent on MMA and CF and influenced by the volume of saliva present in the mouth....

  7. Tailoring controlled-release oral dosage forms by combining inkjet and flexographic printing techniques

    DEFF Research Database (Denmark)

    Genina, Natalja; Fors, Daniela; Vakili, Hossein

    2012-01-01

    We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper...... substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer....... The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced...

  8. Determination of amphetamine-type stimulants in oral fluid by solid-phase microextraction and gas chromatography-mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Daniele Z., E-mail: daniele.dzs@dpf.gov.br [Setor Tecnico-Cientifico, Superintendencia Regional do Departamento de Policia Federal no Rio Grande do Sul, 1365 Ipiranga Avenue, Azenha, Zip Code 90160-093 Porto Alegre, Rio Grande do Sul (Brazil); Programa de Pos-Graduacao em Ciencias Farmaceuticas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, 2752 Ipiranga Avenue, Santana, Zip Code 90610-000 Porto Alegre, Rio Grande do Sul (Brazil); Boehl, Paula O.; Comiran, Eloisa; Mariotti, Kristiane C. [Programa de Pos-Graduacao em Ciencias Farmaceuticas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, 2752 Ipiranga Avenue, Santana, Zip Code 90610-000 Porto Alegre, Rio Grande do Sul (Brazil); Pechansky, Flavio [Centro de Pesquisa em Alcool e Drogas (CPAD), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350, Ramiro Barcelos Street, Zip Code 90035-903 Porto Alegre, Rio Grande do Sul (Brazil); Duarte, Paulina C.A.V. [Secretaria Nacional de Politicas sobre Drogas (SENAD), Esplanada dos Ministerios, Block ' A' , 5th floor, Zip Code 70050-907 Brasilia, Distrito Federal (Brazil); De Boni, Raquel [Centro de Pesquisa em Alcool e Drogas (CPAD), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350, Ramiro Barcelos Street, Zip Code 90035-903 Porto Alegre, Rio Grande do Sul (Brazil); Froehlich, Pedro E.; Limberger, Renata P. [Programa de Pos-Graduacao em Ciencias Farmaceuticas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, 2752 Ipiranga Avenue, Santana, Zip Code 90610-000 Porto Alegre, Rio Grande do Sul (Brazil)

    2011-06-24

    Graphical abstract: Highlights: > Propylchloroformate derivatization of amphetamine-type stimulants in oral fluid. > Direct immersion solid-phase microextraction/gas chromatography-mass spectrometry. > Linear range 2(4)-256 ng mL{sup -1}, detection limits 0.5-2 ng mL{sup -1}. > Accuracy 98-112%, precision <15% of RSD, recovery 77-112%. > Importance of residual evaluation in checking model goodness-of-fit. - Abstract: A method for the simultaneous identification and quantification of amphetamine (AMP), methamphetamine (MET), fenproporex (FEN), diethylpropion (DIE) and methylphenidate (MPH) in oral fluid collected with Quantisal{sup TM} device has been developed and validated. Thereunto, in-matrix propylchloroformate derivatization followed by direct immersion solid-phase microextraction and gas chromatography-mass spectrometry were employed. Deuterium labeled AMP was used as internal standard for all the stimulants and analysis was performed using the selected ion monitoring mode. The detector response was linear for the studied drugs in the concentration range of 2-256 ng mL{sup -1} (neat oral fluid), except for FEN, whereas the linear range was 4-256 ng mL{sup -1}. The detection limits were 0.5 ng mL{sup -1} (MET), 1 ng mL{sup -1} (MPH) and 2 ng mL{sup -1} (DIE, AMP, FEN), respectively. Accuracy of quality control samples remained within 98.2-111.9% of the target concentrations, while precision has not exceeded 15% of the relative standard deviation. Recoveries with Quantisal{sup TM} device ranged from 77.2% to 112.1%. Also, the goodness-of-fit concerning the ordinary least squares model in the statistical inference of data has been tested through residual plotting and ANOVA. The validated method can be easily automated and then used for screening and confirmation of amphetamine-type stimulants in drivers' oral fluid.

  9. Technical Note: Determination of Cholecalciferol (Vitamin D₃) in Standard Reference Material 3532 Calcium-Containing Solid Oral Dosage Form.

    Science.gov (United States)

    Burdette, Carolyn Q

    2017-09-01

    Vitamin D is an important nutrient for many areas of human health and well-being, including improved bone strength, muscle movement, cognitive function, and immune health. The National Institute of Standards and Technology, in collaboration with the National Institutes of Health Office of Dietary Supplements, has developed SRM 3532 Calcium-Containing Solid Oral Dosage Form to help address the analytical challenges seen by the dietary supplement communities for the determination of vitamin D3 (cholecalciferol) and elements. Described here is the process to assess the homogeneity and stability of the material, as well as the value assignment of the vitamin D3 levels.

  10. Base Release and Modification in Solid-Phase DNA Exposed to Low-Energy Electrons.

    Science.gov (United States)

    Choofong, Surakarn; Cloutier, Pierre; Sanche, Léon; Wagner, J Richard

    2016-11-01

    Ionization generates a large number of secondary low-energy electrons (LEEs) with a most probable energy of approximately 10 eV, which can break DNA bonds by dissociative electron attachment (DEA) and lead to DNA damage. In this study, we investigated radiation damage to dry DNA induced by X rays (1.5 keV) alone on a glass substrate or X rays combined with extra LEEs (average energy of 5.8 eV) emitted from a tantalum (Ta) substrate under an atmosphere of N2 and standard ambient conditions of temperature and pressure. The targets included calf-thymus DNA and double-stranded synthetic oligonucleotides. We developed analytical methods to measure the release of non-modified DNA bases from DNA and the formation of several base modifications by LC-MS/MS with isotopic dilution for precise quantification. The results show that the yield of non-modified bases as well as base modifications increase by 20-30% when DNA is deposited on a Ta substrate compared to that on a glass substrate. The order of base release (Gua > Ade > Thy ∼ Cyt) agrees well with several theoretical studies indicating that Gua is the most susceptible site toward sugar-phosphate cleavage. The formation of DNA damage by LEEs is explained by DEA leading to the release of non-modified bases involving the initial cleavage of N1-C1', C3'-O3' or C5'-O5' bonds. The yield of base modifications was lower than the release of non-modified bases. The main LEE-induced base modifications include 5,6-dihydrothymine (5,6-dHT), 5,6-dihydrouracil (5-dHU), 5-hydroxymethyluracil (5-HmU) and 5-formyluracil (5-ForU). The formation of base modifications by LEEs can be explained by DEA and cleavage of the C-H bond of the methyl group of Thy (giving 5-HmU and 5-ForU) and by secondary reactions of H atoms and hydride anions that are generated by primary LEE reactions followed by subsequent reaction with Cyt and Thy (giving 5,6-dHU and 5,6-dHT).

  11. The role of risk communication planning in the release of the oral rabies vaccine in New Jersey: An evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Pflugh, K.K. [New Jersey Department of Environmental Protection, Trenton, NJ (United States)

    1995-12-01

    Communicating health risk information is a complicated task. Citizen reaction to such information is difficult to predict, which makes it hard to plan an appropriate response. Research indicates that the way citizens respond to risk information often depends on whether the risk is familiar or unfamiliar, whether it is seen as imposed on them, whether it is man made or natural, or whether they have control over the risk. Potentially controversial cases that deal with delivering risk information have a special need for a well planned communication effort. Natural resource issues with an impact on public health are no exception. In New Jersey, a proposal to release an experimental bioengineered oral rabies vaccine for raccoons to test the effectiveness of the vaccine in halting the spread of rabies into an as yet unaffected area met with widespread public support and approval due in large part to the use of a unique risk communication planning process. This paper will describe the risk communication planning process used to gain public support and approval for release of oral rabies raccoon vaccine while focusing on the evaluation component of the process. The seven step process includes setting goals, profiling the issue or information gathering, audience identification and assessment, message development, method selection, implementation of the strategy and evaluation and follow-up. The goal of the evaluation component was to determine the effectiveness of the public information campaign on citizen`s knowledge of the field trial nearly three years after the initial announcement. In addition, it sought to learn citizen interest in maintaining the rabies free barrier that was created by the field trial using funds from local taxes. This evaluation includes the results of a mailed survey to 280 citizens, local officials and professional organizations. Finally, this paper will discuss the implications for future outreach efforts dealing complicated technical issues.

  12. Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain.

    Science.gov (United States)

    Tassain, V; Attal, N; Fletcher, D; Brasseur, L; Dégieux, P; Chauvin, M; Bouhassira, D

    2003-07-01

    Morphine is increasingly used in patients with chronic non-cancer pain, but a major concern associated with chronic use relates to possible cognitive side-effects. The aim of this long-term prospective study was to evaluate the cognitive impact of oral sustained release morphine in patients with non-cancer pain. A battery of neuropsychological tests to explore attention, psychomotor speed and memory was administered. The effects of morphine on pain, quality of life, mood, subjective memory impairment and side-effects were also investigated. Evaluations were performed at baseline in patients free from opioids and then after 3, 6 and 12 months. Twenty-eight patients were included: 18 received oral sustained morphine (range 40-140 mg/day), ten patients stopped morphine prematurely because of side-effects or insufficient pain relief and were followed as a control group. There was no impairment of any neuropsychological variable over time in the morphine treated patients in comparison with the control group. Two measures of information processing speed - the Stroop interference score and the digit symbol test were improved at 6 and 12 months and there were significant correlations with the pain relief and improvement of mood. Self-reported memory impairment improved notably in responders to morphine. Morphine induced persisting effects on pain, and to a lesser extent on quality of life and mood. The visual analog scale score for side-effects increased at 12 months and essentially consisted of gastrointestinal disorders. This study demonstrates that 12 months treatment with oral morphine does not disrupt cognitive functioning in patients with chronic non-cancer pain and instead results in moderate improvement of some aspects of cognitive functioning, as a consequence of the pain relief and concomitant improvement of well-being and mood.

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

    OpenAIRE

    Darwish, Mona; Bond, Mary; 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 ...

  14. Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology.

    Science.gov (United States)

    Bonhoeffer, Bastian; Kwade, Arno; Juhnke, Michael

    2017-11-16

    Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  15. Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

    Science.gov (United States)

    Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

    2017-11-01

    Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

  16. Organic matter-solid phase interactions are critical for predicting arsenic release and plant uptake in Bangladesh paddy soils.

    Science.gov (United States)

    Williams, Paul N; Zhang, Hao; Davison, William; Meharg, Andrew A; Hossain, Mahmud; Norton, Gareth J; Brammer, Hugh; Islam, M Rafiqul

    2011-07-15

    Agroecological zones within Bangladesh with low levels of arsenic in groundwater and soils produce rice that is high in arsenic with respect to other producing regions of the globe. Little is known about arsenic cycling in these soils and the labile fractions relevant for plant uptake when flooded. Soil porewater dynamics of field soils (n = 39) were recreated under standardized laboratory conditions to investigate the mobility and interplay of arsenic, Fe, Si, C, and other elements, in relation to rice grain element composition, using the dynamic sampling technique diffusive gradients in thin films (DGT). Based on a simple model using only labile DGT measured arsenic and dissolved organic carbon (DOC), concentrations of arsenic in Aman (Monsoon season) rice grain were predicted reliably. DOC was the strongest determinant of arsenic solid-solution phase partitioning, while arsenic release to the soil porewater was shown to be decoupled from that of Fe. This study demonstrates the dual importance of organic matter (OM), in terms of enhancing arsenic release from soils, while reducing bioavailability by sequestering arsenic in solution.

  17. Volatile trace compounds released from municipal solid waste at the transfer stage: Evaluation of environmental impacts and odour pollution.

    Science.gov (United States)

    Zhao, Yan; Lu, Wenjing; Wang, Hongtao

    2015-12-30

    Odour pollution caused by municipal solid waste is a public concern. This study quantitatively evaluated the concentration, environmental impacts, and olfaction of volatile trace compounds released from a waste transfer station. Seventy-six compounds were detected, and ethanol presented the highest releasing rate and ratio of 14.76 kg/d and 12.30 g/t of waste, respectively. Life cycle assessment showed that trichlorofluoromethane and dichlorodifluoromethane accounted for more than 99% of impact potentials to global warming and approximately 70% to human toxicity (non-carcinogenic). The major contributor for both photochemical ozone formation and ecotoxicity was ethanol. A detection threshold method was also used to evaluate odour pollution. Five compounds including methane thiol, hydrogen sulphide, ethanol, dimethyl disulphide, and dimethyl sulphide, with dilution multiples above one, were considered the critical compounds. Methane thiol showed the highest contribution to odour pollution of more than 90%, as indicated by its low threshold. Comparison of the contributions of the compounds to different environmental aspects indicated that typical pollutants varied based on specific evaluation targets and therefore should be comprehensively considered. This study provides important information and scientific methodology to elucidate the impacts of odourant compounds to the environment and odour pollution. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Fabrication of mesoporous silica shells on solid silica spheres using anionic surfactants and their potential application in controlling drug release.

    Science.gov (United States)

    El-Toni, Ahmed Mohamed; Khan, Aslam; Ibrahim, Mohamed Abbas; Al-Hoshan, Mansour; Labis, Joselito Puzon

    2012-11-06

    In this work, mesoporous shells were constructed on solid silica cores by employing anionic surfactante. A co-structure directing agent (CSDA) has assisted the electrostatic interaction between negatively charged silica particles and the negatively charged surfactant molecules. Synthetic parameters such as reaction time and temperature had a significant impact on the formation of mesoporous silica shelld and their textural properties such as surface area and pore volume. Core-mesoporous shell silica spheres were characterized by small angle X-ray scattering, transmission electron microscopy, and N(2) adsorption–desorption analysis. The synthesized particles have a uniformly mesoporous shell of 34–65 nm and possess a surface area of ca. 7–324 m2/g, and pore volume of ca. 0.008–0.261 cc/g. The core-mesoporous shell silica spheres were loaded with ketoprofen drug molecules. The in vitro drug release study suggested that core-mesoporous shell silica spheres are a suitable nanocarrier for drug molecules offering the possibility of having control over their release rate.

  19. Pain management in peripheral arterial obstructive disease: oral slow-release oxycodone versus epidural l-bupivacaine.

    Science.gov (United States)

    Samolsky Dekel, B G; Melotti, R M; Gargiulo, M; Freyrie, A; Stella, A; Di Nino, G

    2010-06-01

    To compare the effectiveness of oral slow-release oxycodone (group OX, n=18) with that of epidural l-bupivacaine (group LRA, n=13) for the control of moderate/severe pain of advanced-stage peripheral arterial obstructive disease (PAOD) patients. Observational and retrospective analysis of advanced stage and hospitalised PAOD patients treated for pain management for at least 7 days prior to surgery or discharged from the hospital without surgery. The outcome measures were pain intensity using the visual analogue scale under static, (VASs) and dynamic (VASd) conditions; vital signs, treatment side effects and patient satisfaction. In both groups, pain control was satisfactory and VAS scores median were VASs<3 and VASd<4; under dynamic conditions, pain control was better in the LRA group (p<0.01). Against few and transient side effects, most patients (n=30) found both pain treatments good or excellent. Results should be confirmed by studies with larger samples. In the perioperative setting, the epidural infusion of local anaesthetics, such as l-bupivacaine, is an effective technique for pain control in PAOD patients; for patients with contraindication for this technique or for non-surgical or outpatients, slow-release oxycodone is suggested as a possible alternative for the control of severe pain in these patients. Copyright (c) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  20. Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications.

    Science.gov (United States)

    Rassu, G; Nieddu, M; Bosi, P; Trevisi, P; Colombo, M; Priori, D; Manconi, P; Giunchedi, P; Gavini, E; Boatto, G

    2014-10-15

    The aim of this study was to encapsulate, thymol, in natural polymers in order to obtain (i) taste masking effect and, then, enhancing its palatability and (ii) two formulations for systemic and local delivery of herbal drug as adjuvants or substitutes to current medications to prevent and treat several human and animal diseases. Microspheres based on methylcellulose or hydroxypropyl methylcellulose phthalate (HPMCP) were prepared by spray drying technique. Microparticles were in vitro characterized in terms of yield of production, drug content and encapsulation efficiency, particle size, morphology and drug release. Both formulations were in vivo orally administered and pharmacokinetic analysis was carried out. The polymers used affect the release and, then, the pharmacokinetic profile of thymol. Encapsulation into methylcellulose microspheres leads to short half/life but bioavailability remarkably increases compared to the free thymol. In contrast, enteric formulation based on HPMCP shows very limited systemic absorption. These formulations could be proposed as alternative or adjuvants for controlling pathogen infections in human or animal. In particular, methylcellulose microspheres can be used for thymol systemic administration at low doses and HPMCP particles for local treatment of intestinal infections. Copyright © 2014 Elsevier GmbH. All rights reserved.

  1. Radiation-induced defects, energy storage and release in nitrogen solids

    Science.gov (United States)

    Savchenko, E.; Khyzhniy, I.; Uyutnov, S.; Bludov, M.; Barabashov, A.; Gumenchuk, G.; Bondybey, V.

    2017-02-01

    New trends in the study of radiation effects in nitrogen solids with a focus on the defect-induced processes are presented. An electron beam of subthreshold energy was used to generate radiation defects via electronic subsystem. Experimental techniques developed enabled us to detect neutral and charged defects of both signs. Defect production and desorption were monitored using optical and current emission spectroscopy: cathodoluminescence CL, thermally stimulated luminescence TSL and exoelectron emission TSEE along with the detection of postdesorption. Our results show stabilization and accumulation of radiation defects - ionic centres of both signs (N4 +, N3 +, N3 -), trapped electrons and radicals (N, N3). The neutralization reactions: N4 ++e-→N4 *→N2 *(a‘1Σu -)+N2 *(a‘1Σu -) +ΔE 1 →N2 +N2 +2hν+ΔE 2 and N3 ++e-→N*(2D)+N2(1Σg +)+ΔE 3→N(4S)+N2(1Σg +)+h γ+ΔE 3 are shown to be the basis of defect production and anomalous low-temperature post-desorption ALTpD. The part played by pre-existing and radiation-induced defects in energy storage is discussed.

  2. A possible crystal defect mediated mechanism governing energy release in solid organic secondary explosives

    Science.gov (United States)

    Henson, Bryan; Smilowitz, Laura

    2013-03-01

    Work has been ongoing in our group for several years to produce a global chemistry model of thermal ignition for the solid organic secondary explosive octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) valid over the entire temperature range of energetic response from thermal ignition to detonation. We have made considerable progress recently, resulting in the first broadly accurate model of this type for HMX. We have also recently provided the first theory of the phenomenon of melt acceleration in the thermal decomposition which indicates a universal mechanism applicable to this entire class of materials. The success of these models derives from the kinetic rate equations used, which are based upon rates activated by energies of vaporization and sublimation. The equations can be reduced to dimensionless form, yielding melt accelerated rates of thermal decomposition, ignition and detonation which are functions of two rate constants, one proportional to the liquid activity and another that can be interpreted as the simultaneous occupation of two defect states of the crystal. In this reduced form, data from a number of secondary explosives may be superposed on common curves. In this talk we explore the possibility that the underlying mechanism responsible for this behavior is linked to the equilibrium population of a crystal defect described by a vacancy in contact with local disorder.

  3. Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats.

    Science.gov (United States)

    Barnard, L; Barnes Heller, H; Boothe, D M

    2018-01-01

    Repeated PO dosing of anti-epileptic drugs may contribute to poor compliance in treated cats. Intermediate-release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5-45 μg/mL). Approved extended-release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. In healthy cats, serum levetiracetam concentration will remain above 5 μg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. 7 healthy cats. Extended-release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. The median dosage of 86.2 mg/kg, (range, 80-94.3) achieved a mean maximum concentration (Cmax ) of 89.8 ± 25.8 μg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 μg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 μg/mL at 12 and 24 hours, respectively. The half-life was 4.1 ± 1.0 hours. The drug was well tolerated. A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 μg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  4. Investigation of protein distribution in solid lipid particles and its impact on protein release using coherent anti-Stokes Raman scattering microscopy

    DEFF Research Database (Denmark)

    Christophersen, Philip C.; Birch, Ditlev; Saarinen, Jukka

    2015-01-01

    -destructive method for elucidating the distribution of lysozyme in SLMs. The interpretation of protein distribution and release during lipolysis enabled elucidation of protein release mechanisms. In future, CARS microscopy analysis could facilitate development of a wide range of protein-lipid matrices with tailor-made......The aim of this study was to gain new insights into protein distribution in solid lipid microparticles (SLMs) and subsequent release mechanisms using a novel label-free chemical imaging method, coherent anti-Stokes Raman scattering (CARS) microscopy. Lysozyme-loaded SLMs were prepared using...... different lipids with lysozyme incorporated either as an aqueous solution or as a solid powder. Lysozyme distribution in SLMs was investigated using CARS microscopy with supportive structural analysis using electron microscopy. The release of lysozyme from SLMs was investigated in a medium simulating...

  5. Analysis of volatile compounds released during the grinding of roasted coffee beans using solid-phase microextraction.

    Science.gov (United States)

    Akiyama, Masayuki; Murakami, Kazuya; Ohtani, Noboru; Iwatsuki, Keiji; Sotoyama, Kazuyoshi; Wada, Akira; Tokuno, Katsuya; Iwabuchi, Hisakatsu; Tanaka, Kiyofumi

    2003-03-26

    A dynamic solid-phase microextraction (SPME) method to sample fresh headspace volatile compounds released during the grinding of roasted coffee beans was described and the analytical results using gas chromatography/mass spectrometry (GC/MS) and GC/olfactometry (GC/O) were compared to those of the conventional static SPME sampling methods using ground coffee. Volatile compounds released during the grinding of roasted coffee beans (150 g) were obtained by exposing the SPME fiber (poly(dimethylsiloxane)/divinylbenzene, PDMS/ DVB) for 8 min to nitrogen gas (600 mL/min) discharged from a glass vessel in which the electronic coffee grinder was enclosed. Identification and characterization of volatile compounds thus obtained were achieved by GC/MS and GC/O. Peak areas of 47 typical coffee volatile compounds, separated on total ion chromatogram (TIC), obtained by the dynamic SPME method, showed coefficients of variation less than 5% (n = 3) and the gas chromatographic profile of volatile compounds thus obtained was similar to that of the solvent extract of ground coffee, except for highly volatile compounds such as 4-hydroxy-2,5-dimethyl-3(2H)-furanone and 4-ethenyl-2-methoxyphenol. Also, SPME dilution analysis of volatile compounds released during the grinding of roasted coffee beans showed linear plots of peak area versus exposed fiber length (R (2) > 0.89). Compared with those of the headspace volatile compounds of ground coffee using GC/MS and GC/O, the volatile compounds generated during the grinding of roasted coffee beans were rich in nutty- and smoke-roast aromas.

  6. Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: in vitro and animal approaches.

    Science.gov (United States)

    Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio

    2016-01-01

    Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications.

  7. A comparative study between melt granulation/compression and hot melt extrusion/injection molding for the manufacturing of oral sustained release thermoplastic polyurethane matrices.

    Science.gov (United States)

    Verstraete, G; Mertens, P; Grymonpré, W; Van Bockstal, P J; De Beer, T; Boone, M N; Van Hoorebeke, L; Remon, J P; Vervaet, C

    2016-11-20

    During this project 3 techniques (twin screw melt granulation/compression (TSMG), hot melt extrusion (HME) and injection molding (IM)) were evaluated for the manufacturing of thermoplastic polyurethane (TPU)-based oral sustained release matrices, containing a high dose of the highly soluble metformin hydrochloride. Whereas formulations with a drug load between 0 and 70% (w/w) could be processed via HME/(IM), the drug content of granules prepared via melt granulation could only be varied between 85 and 90% (w/w) as these formulations contained the proper concentration of binder (i.e. TPU) to obtain a good size distribution of the granules. While release from HME matrices and IM tablets could be sustained over 24h, release from the TPU-based TSMG tablets was too fast (complete release within about 6h) linked to their higher drug load and porosity. By mixing hydrophilic and hydrophobic TPUs the in vitro release kinetics of both formulations could be adjusted: a higher content of hydrophobic TPU was correlated with a slower release rate. Although mini-matrices showed faster release kinetics than IM tablets, this observation was successfully countered by changing the hydrophobic/hydrophilic TPU ratio. In vivo experiments via oral administration to dogs confirmed the versatile potential of the TPU platform as intermediate-strong and low-intermediate sustained characteristics were obtained for the IM tablets and HME mini-matrices, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. From solid to liquid: Assessing the release of carbon from soil into solution in response to forest management

    Science.gov (United States)

    James, J. N.; Gross, C. D.; Butman, D. E.; Harrison, R. B.

    2016-12-01

    Dissolved organic matter (DOM) is a crucial conduit for internal cycling of carbon within soils as well as for the transfer of organic matter out of soil and into aquatic systems. Little is known about how the quantity, quality, lability and chemical characteristics of DOM changes in response to human management of forest soils. To examine the processes that release soil organic matter (SOM) into solution, we gathered samples from adjacent native and industrially managed Eucalyptus grandis plantation forests across Sao Paulo State, Brazil and from adjacent old-growth and Douglas-fir (Pseudotsuga menzisii) plantation forests in the coastal Pacific Northwest. Samples from each soil horizon were taken from soil profiles excavated to at least 1.5 m at each site. Water extractable organic matter (WEOM) was extracted twice from each sample using 0.5 M K2SO4 and Milli-Q water to quantify both dissolved and exchange phase organic matter. These extracts were measured for total organic carbon (TOC), 13C and 14C, and chemical characteristics were assessed by fluorescence spectroscopy (EEMs and SUVA254). At the same time, solid phase characteristics of the soil samples were quantified, including bulk density, pH, total carbon and nitrogen, microbial biomass, and 13C and 14C. Characterization of bulk SOM was undertaken by Fourier Transform Infrared Spectroscopy (FTIR) by subtracting mineral matrix spectra of each sample from the bulk spectra. Organic matter lability was assessed by incubations using difference in TOC for WEOM extracts and repeated measurement of CO2 efflux for bulk SOM. All together, these analyses permit a unique snapshot of the natural separation of organic matter from solid into liquid phase through the entire soil profile. Initial results reveal that small but measureable quantities of WEOM may be released from deep B and C horizons in soil, and that this material is labile to microbial decomposition. By identifying differences in SOM and DOM cycling due to

  9. An orally administered butyrate-releasing derivative reduces neutrophil recruitment and inflammation in dextran sulphate sodium-induced murine colitis.

    Science.gov (United States)

    Simeoli, Raffaele; Mattace Raso, Giuseppina; Pirozzi, Claudio; Lama, Adriano; Santoro, Anna; Russo, Roberto; Montero-Melendez, Trinidad; Berni Canani, Roberto; Calignano, Antonio; Perretti, Mauro; Meli, Rosaria

    2017-06-01

    Butyrate has shown benefits in inflammatory bowel diseases. However, it is not often administered orally because of its rancid smell and unpleasant taste. The efficacy of a more palatable butyrate-releasing derivative, N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), was evaluated in a mouse model of colitis induced by dextran sodium sulphate (DSS). Male 10 week-old BALB/c mice received DSS (2.5%) in drinking water (for 5 days) followed by DSS-free water for 7 days (DSS group). Oral FBA administration (42.5 mg·kg-1 ) was started 7 days before DSS as preventive (P-FBA), or 2 days after DSS as therapeutic (T-FBA); both treatments lasted 19 days. One DSS-untreated group received only tap water (CON). FBA treatments reduced colitis symptoms and colon damage. P-FBA and T-FBA significantly decreased polymorphonuclear cell infiltration score compared with the DSS group. FBA reversed the imbalance between pro- and anti-inflammatory cytokines (reducing inducible NOS protein expression, CCL2 and IL-6 transcripts in colon and increasing TGFβ and IL-10). Morever, P-FBA and T-FBA limited neutrophil recruitment (by expression and localization of the neutrophil granule protease Ly-6G), restored deficiency of the butyrate transporter and improved intestinal epithelial integrity, preventing tight-junction impairment (zonulin-1 and occludin). FBA, similar to its parental compound sodium butyrate, inhibited histone deacetylase-9 and restored H3 histone acetylation, exerting an anti-inflammatory effect through NF-κB inhibition and the up-regulation of PPARγ. FBA reduces inflammatory intestinal damage in mice indicating its potential as a postbiotic derivative without the problems associated with the oral administration of sodium butyrate. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British

  10. Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in vivo study.

    Science.gov (United States)

    Sakurai, Atsushi; Sakai, Toshiro; Sako, Kazuhiro; Maitani, Yoshie

    2012-01-01

    The purpose of this study was establishing a solid dispersion formulation containing a low glass transition temperature (T(g)) and poorly water-soluble drug. Drug/polymer blends with differing physicochemical stabilities and oral absorption were prepared from copolyvidone (PVP-VA), polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) by a hot melt extrusion. HPMC drastically increased the drug oral absorption property, while PVP-VA or PVP stabilized solid dispersions during storage by increasing the T(g) in proportion to polymer concentration. Experimental T(g) values corresponded closely with theoretical T(g) values; indeed, the T(g) values of solid dispersion with HPMC did not increase significantly compared to the T(g) value for the drug alone. A solid dispersion formulation incorporating two different polymers-HPMC and either PVP-VA or PVP-maintained increased T(g), physicochemical stability, solubility, and bioavailability of the solid dispresions owing to each polymer. These findings suggested that both oral absorption and physicochemical stability of low-T(g) drug will be improved using less amount of solid dispersion of combined two polymers than polymer alone.

  11. The tropical white rot fungus, Lentinus squarrosulus Mont.: lignocellulolytic enzymes activities and sugar release from cornstalks under solid state fermentation.

    Science.gov (United States)

    Isikhuemhen, Omoanghe S; Mikiashvili, Nona A; Adenipekun, Clementina O; Ohimain, Elijah I; Shahbazi, Ghasem

    2012-05-01

    Lentinus squarrosulus Mont., a high temperature tolerant white rot fungus that is found across sub-Saharan Africa and many parts of Asia, is attracting attention due to its rapid mycelia growth and potential for use in food and biodegradation. A solid state fermentation (SSF) experiment with L. squarrosulus (strain MBFBL 201) on cornstalks was conducted. The study evaluated lignocellulolytic enzymes activity, loss of organic matter (LOM), exopolysaccharide content, and the release of water soluble sugars from degraded substrate. The results showed that L. squarrosulus was able to degrade cornstalks significantly, with 58.8% LOM after 30 days of SSF. Maximum lignocellulolytic enzyme activities were obtained on day 6 of cultivation: laccase = 154.5 U/L, MnP = 13 U/L, peroxidase = 27.4 U/L, CMCase = 6.0 U/mL and xylanase = 14.5 U/mL. L. squarrosulus is a good producer of exopolysaccharides (3.0-5.13 mg/mL). Glucose and galactose were the most abundant sugars detected in the substrate during SSF, while fructose, xylose and trehalose, although detected on day zero of the experiment, were absent in treated substrates. The preference for hemicellulose over cellulose, combined with the high temperature tolerance and the very fast growth rate characteristics of L. squarrosulus could make it an ideal candidate for application in industrial pretreatment and biodelignification of lignocellulosic biomass.

  12. Effects of food on pharmacokinetics of immediate release oral formulations of aspirin, dipyrone, paracetamol and NSAIDs – a systematic review

    Science.gov (United States)

    Moore, Robert Andrew; Derry, Sheena; Wiffen, Philip J; Straube, Sebastian

    2015-01-01

    Aims It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states. Methods A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (tmax), and its extent (Cmax) was conducted. Delayed-release formulations were not included. Results Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting tmax was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed tmax was 1.30 to 2.80 times longer than fasted tmax. Cmax was typically reduced, with greater reduction seen with more rapid absorption (fed Cmax only 44–85% of the fasted Cmax for aspirin, diclofenac, ibuprofen and paracetamol). Conclusion There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public. PMID:25784216

  13. Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations.

    Science.gov (United States)

    Sferrazza, Gianluca; Siviero, Paolo D; Nicotera, Giuseppe; Turella, Paola; Serafino, Annalucia; Blandizzi, Corrado; Pierimarchi, Pasquale

    2017-09-01

    Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.

  14. Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake.

    Science.gov (United States)

    Luo, Yangchao; Teng, Zi; Li, Ying; Wang, Qin

    2015-05-20

    The poor stability of solid lipid nanoparticles (SLN) under acidic condition resulted in large aggregation in gastric environment, limiting their application as oral delivery systems. In this study, a series of SLN was prepared to investigate the effects of surfactant/cosurfactant and chitosan coating on their physicochemical properties as well as cellular uptake. SLN was prepared from Compritol 888 ATO using a low-energy method combining the solvent-diffusion and hot homogenization technique. Poloxamer 188 and polyethylene glycol (PEG) were effective emulsifiers to produce SLN with better physicochemical properties than SLN control. Chitosan-coated SLN exhibited the best stability under acidic condition by forming a thick layer around the lipid core, as clearly observed by transmission electron microscope. The intermolecular interactions in different formulations were monitored by Fourier transform infrared spectroscopy. Chitosan coating also significantly improved the mucoadhesive property of SLN as determined by Quartz Crystal Microbalance. In vitro drug delivery assays, cytotoxicity, and cellular uptake of SLN were studied by incorporating coumarin 6 as a fluorescence probe. Overall, chitosan-coated SLN was superior to other formulations and held promising features for its application as a potential oral drug delivery system for hydrophobic drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Freeze dried solid dispersion of exemestane: A way to negate an aqueous solubility and oral bioavailability problems.

    Science.gov (United States)

    Kaur, Shamandeep; Jena, Sunil K; Samal, Sanjaya K; Saini, Vaishali; Sangamwar, Abhay T

    2017-09-30

    This study was envisaged to demonstrate the potential of exemestane loaded phospholipid/sodium deoxycholate solid dispersions (EXE-PL/SDC-SDs) on the solubility and oral bioavailability of EXE. Initial studies were performed to screen the best suitable phospholipid among lysophosphatidylcholine, Phospholipon® P80H and Lipoid® E80S for solid dispersion preparation. Further studies were carried out to optimize the molar concentration of phospholipid and sodium deoxycholate (SDC) for EXE-PL/SDC-SDs preparation. Optimized EXE-PL/SDC-SDs was prepared using Lipoid® E80S and SDC in 1:4M concentration, respectively and lyophilized using 10% w/w 2-hydroxypropyl-β-cyclodextrin (2-HPCD). The physical state of EXE in lyophilized formulation was confirmed by DSC and PXRD. Lyophilized formulation exhibits a significant increase in solubility and dissolution rate as compared to free drug EXE. Apparent permeability study was performed on Caco-2 cell line for 2h. The lyophilized EXE-PL/SDC-SDs exhibits 4.6-fold increase in absorptive transport as compared to EXE. Pharmacokinetic study in fasted female Sprague-Dawley rats revealed a 2.3-fold increase in AUC 0-72h . Thus, the results suggest that PL/SDC-SDs is a promising carrier for EXE delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery. Effect of drug loading on release kinetics.

    Science.gov (United States)

    Huang, Jingjun; Wigent, Rodney J; Bentzley, Catherine M; Schwartz, Joseph B

    2006-08-17

    In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.

  17. Pharmacokinetics of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Stark, Jeffrey G; Engelking, Dorothy; McMahen, Russ; Sikes, Carolyn

    2017-04-01

    A novel formulation for treating attention-deficit/hyperactivity disorder (ADHD) has recently been developed-amphetamine extended-release orally disintegrating tablets (AMP XR-ODTs). In this study, we assessed the rate of absorption and exposure of AMP XR-ODT under fasted conditions in children with ADHD. Children (6-12 years) with ADHD were enrolled in a single-dose, open-label, single-period pharmacokinetic (PK) study. Patients were stratified by age (6-7, 8-9, and 10-12 year olds) and were dosed with 18.8-mg AMP XR-ODT under fasted conditions. Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from time zero-infinity (AUCinf), weight-normalized clearance (CL/F), and weight-normalized volume of distribution (Vz/F) were assessed. The geometric mean and 95% confidence intervals (CIs) were calculated for weight-normalized CL/F and Vz/F in each age group to determine if the 95% CIs were within the target range of 60%-140%. A total of 28 children completed the study. The 95% CIs for the geometric mean CL/F/kg and Vz/F/kg for both d- and l-amphetamine fell within the target range of 60%-140% for each age group, thus meeting the primary end point. Four participants experienced treatment-related adverse events, including vomiting (n = 3), abdominal pain (n = 2), dry mouth (n = 1), and insomnia (n = 1). AMP XR-ODT, a novel formulation that does not require swallowing an intact tablet or capsule, was well tolerated and demonstrated a PK profile consistent with once-daily dosing in children with ADHD.

  18. A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats.

    Science.gov (United States)

    Boyd, Ben J; Khoo, Shui-Mei; Whittaker, Darryl V; Davey, Greg; Porter, Christopher J H

    2007-08-01

    Liquid crystalline phases that are stable in excess water, formed using lipids such as glyceryl monooleate (GMO) and oleyl glycerate (OG), are known to provide a sustained release matrix for poorly water soluble drugs in vitro, yet there has been no report of the use of these materials to impart oral sustained release behaviour in vivo. In the first part of this study, in vitro lipolysis experiments were used to compare the digestibility of GMO with a second structurally related lipid, oleyl glycerate, which was found to be less susceptible to hydrolysis by pancreatic lipase than GMO. Subsequent oral bioavailability studies were conducted in rats, in which a model poorly water soluble drug, cinnarizine (CIN), was administered orally as an aqueous suspension, or as a solution in GMO or OG. In the first bioavailability study, plasma samples were taken over a 30 h period and CIN concentrations determined by HPLC. Plasma CIN concentrations after administration in the GMO formulation were only sustained for a few hours after administration while for the OG formulation, the plasma concentration of cinnarizine was at its highest level 30 h after dosing, and appeared to be increasing. A second study in which CIN was again administered in OG, and plasma samples taken for 120 h, revealed a Tmax for CIN in rats of 36 h and a relative oral bioavailability of 344% when compared to the GMO formulation (117%) and the aqueous suspension formulation (assigned a nominal bioavailability of 100%). The results indicate that lipids that form liquid crystalline structures in excess water, may have application as an oral sustained release delivery system, providing they are not digested rapidly on administration.

  19. Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water-soluble drugs II. In-vivo evaluation.

    Science.gov (United States)

    Nguyen, Tri-Hung; Hanley, Tracey; Porter, Christopher J H; Larson, Ian; Boyd, Ben J

    2010-07-01

    Lipid-based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic-phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained-release drug-delivery systems for poorly water-soluble drugs. In this study the potential of PHY and GMO to serve as sustained-release lipid vehicles for a model poorly-water-soluble drug, cinnarizine, was assessed and compared to that of an aqueous suspension formulation. Small-angle X-ray scattering was used to confirm the nanostructure of the liquid-crystalline matrix in the presence of the selected model drug, cinnarizine. Oral bioavailability studies were conducted in rats, and disposition of lipid and drug in segments of the gastrointestinal tract was determined over time. Differences in the digestibility and stability of formulations under digestion conditions were investigated using an in-vitro lipolysis model. The oral bioavailability of cinnarizine using the PHY formulation was 41%, compared to 19% for the GMO formulation and 6% for an aqueous suspension. The PHY formulation provided a T(max) for cinnarizine of 33 h, with absorption apparent up to 55 h after administration. In contrast, the T(max) for the GMO formulation was only 5 h. The PHY formulation was retained in the stomach for extended periods of time, with 56% of lipid remaining in the stomach after 24 h, in contrast to less than 1% of the GMO formulation after 8 h, suggesting that gastric retention was a key aspect of the prolonged period of absorption, which correlated with the formulations' relative susceptibility to in-vitro lipolysis and degradation. PHY provides a dramatic sustained-release effect for cinnarizine on oral administration, which is linked to gastric retention of the formulation and its ability to resist digestive processing. Poorly digested liquid crystal lipid formulations therefore offer a novel class of sustained-release

  20. Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder ?

    OpenAIRE

    Mizuno, Kei; Yoneda, Tetsuya; Komi, Masanori; Hirai, Toshinori; Watanabe, Yasuyoshi; Tomoda, Akemi

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) stud...

  1. An evaluation of the adhesion of solid oral dosage form coatings to the oesophagus.

    Science.gov (United States)

    Smart, John D; Dunkley, Sian; Tsibouklis, John; Young, Simon

    2015-12-30

    There is a requirement for the development of oral dosage forms that are adhesive and allow extended oesophageal residence time for localised therapies, or are non-adhesive for ease of swallowing. This study provides an initial assessment of the in vitro oesophageal retention characteristics of several widely utilised pharmaceutical coating materials. To this end, a previously described apparatus has been used to measure the force required to pull a coated disc-shaped model tablet across a section of excised oesophageal tissue. Of the materials tested, the well-studied mucoadhesive polymer sodium alginate was found to be associated with significant oesophageal adhesion properties that was capable of 'self-repairing'. Hydroxypropylmethylcellulose exhibited less pronounced bioadhesive behaviour and blending this with plasticiser or with low molecular weight polymers and surfactants did not significantly affect this. Low molecular weight water soluble polymers, were found to behave similarly to the uncoated glass control disc. Polysorbates exhibited bioadhesion behaviour that was majorly influenced by the nature of the surfactant. The insoluble polymer ethylcellulose, and the relatively lipophilic surfactant sorbitan monooleate were seen to move more readily than the uncoated disc, suggesting that these may have a role as 'easy-to-swallow' coatings. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Fate of orally administered {sup 15}N-labeled polyamines in rats bearing solid tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Masaki; Samejima, Keijiro; Goda, Hitomi; Niitsu, Masaru [Josai Univ., Sakado, Saitama (Japan). Faculty of Pharmaceutical Sciences; Xu Yongji [Qingdao Univ. of Science and Technology (China). Inst. of Chemical and Molecular Technology; Takahashi, Masakazu [Sasaki Inst., Tokyo (Japan); Hashimoto, Yoshiyuki [Kyoritsu Coll. of Pharmacy, Tokyo (Japan)

    2003-03-01

    We studied absorption, distribution, metabolism, and excretion of polyamines (putrescine, spermidine, and spermine) in the gastrointestinal tract using {sup 15}N-labeled polyamines as tracers and ionspray ionization mass spectrometry (IS-MS). The relatively simple protocol using rats bearing solid tumors provided useful information. Three {sup 15}N-labeled polyamines that were simultaneously administered were absorbed equally from gastrointestinal tract, and distributed within tissues at various concentrations. The uptake of {sup 15}N-spermidine seemed preferential to that of {sup 15}N-spermine since the concentrations of {sup 15}N-spermidine in the liver and tumors were higher, whereas those of {sup 15}N-spermine were higher in the kidney, probably due to the excretion of excess extracellular spermine. Most of the absorbed {sup 15}N-putrescine seemed to be lost, suggesting blood and tissue diamine oxidase degradation. Concentrations of {sup 15}N-spermidine and {sup 15}N-spermine in the tumor were low. We also describe the findings from two rats that were administered with {sup 15}N-spermine. The tissue concentrations of {sup 15}N-spermine were unusually high, and significant levels of {sup 15}N-spermidine were derived from {sup 15}N-spermine in these animals. (author)

  3. Inhibitory effect of orally-administered sulfated polysaccharide ascophyllan isolated from ascophyllum nodosum on the growth of sarcoma-180 solid tumor in mice.

    Science.gov (United States)

    Jiang, Zedong; Abu, Ryogo; Isaka, Shogo; Nakazono, Satoru; Ueno, Mikinori; Okimura, Takasi; Yamaguchi, Kenichi; Oda, Tatsuya

    2014-04-01

    We evaluated the antitumor activity of crude extract and ascophyllan prepared from Ascophyllum nodosum in sarcoma-180 solid tumor-bearing mice with continuous intraperitoneal (i.p.) administration at a dose of 50 mg/kg body weight/day or oral administration at a dose of 500 mg/kg body weight/day. Ascophyllan and crude extract administered via the oral route showed greater antitumor effects than via i.p. route, and the tumor sizes in mice treated with ascopyllan and crude extract were reduced by a mean of 68.7±6.8% and 42.4±24.8% by the oral route, and 41.4±16.1% and 13.6±20.6% by i.p. route compared to control mice. Splenic natural killer cell activity in the mice treated with ascophyllan and crude extract by i.p. route was significantly enhanced, while only a slight increase of this activity was observed in orally-treated mice. Furthermore, increase in spleen weight of tumor-bearing mice was slightly suppressed by oral administration of ascophyllan, whereas i.p. administration resulted in further enlargement. Analysis of serum cytokines revealed that oral treatment with ascophyllan resulted in significant increase of tumor necrosis factor-α and interleukin-12 levels. Since ascophyllan showed no direct cytotoxic effect on sarcoma-180 cells, orally-administered ascophyllan is suggested to exhibit its antitumor activity through the activation of the host immune system.

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

    Science.gov (United States)

    Wang, Zhouhua; Chen, Bao; Quan, Guilan; Li, Feng; Wu, Qiaoli; Dian, Linghui; Dong, Yixuan; Li, Ge; Wu, Chuanbin

    2012-01-01

    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. 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 release commercial carbamazepine tablets. 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.

  5. Effect of pore size of three-dimensionally ordered macroporous chitosan-silica matrix on solubility, drug release, and oral bioavailability of loaded-nimodipine.

    Science.gov (United States)

    Gao, Yikun; Xie, Yuling; Sun, Hongrui; Zhao, Qinfu; Zheng, Xin; Wang, Siling; Jiang, Tongying

    2016-01-01

    To explore the effect of the pore size of three-dimensionally ordered macroporous chitosan-silica (3D-CS) matrix on the solubility, drug release, and oral bioavailability of the loaded drug. 3D-CS matrices with pore sizes of 180 nm, 470 nm, and 930 nm were prepared. Nimodipine (NMDP) was used as the drug model. The morphology, specific surface area, and chitosan mass ratio of the 3D-CS matrices were characterized before the effect of the pore size on drug crystallinity, solubility, release, and in vivo pharmacokinetics were investigated. With the pore size of 3D-CS matrix decreasing, the drug crystallinity decreased and the aqueous solubility increased. The drug release was synthetically controlled by the pore size and chitosan content of 3D-CS matrix in a pH 6.8 medium, while in a pH 1.2 medium the erosion of the 3D-CS matrix played an important role in the decreased drug release rate. The area under the curve of the drug-loaded 3D-CS matrices with pore sizes of 930 nm, 470 nm, and 180 nm was 7.46-fold, 5.85-fold, and 3.75-fold larger than that of raw NMDP respectively. Our findings suggest that the oral bioavailability decreased with a decrease in the pore size of the matrix.

  6. Estimation by a 24-hour study of the daily dose of intra-oral mercury vapor inhaled after release from dental amalgam

    Energy Technology Data Exchange (ETDEWEB)

    Berglund, A. (Univ. of Umea (Sweden))

    1990-10-01

    The difficulties associated with estimations of daily doses of inhaled mercury vapor released from dental amalgam are considerable. Existing data are often unreliable, especially if they are based on a single or a small series of samples of intra-oral concentrations of mercury vapor before, during, and after chewing stimulation. In the present paper, the aim was to obtain a more representative estimation of the daily dose of mercury vapor inhaled from amalgam fillings by measurement of amounts of mercury vapor released in the oral cavity during 24 h, under conditions that were as normal as possible. A series of measurements was carried out on each of 15 subjects, with at least nine occlusal surfaces restored with dental amalgam, and on five subjects without any amalgam restorations. The subjects had to follow a standardized schedule for 24 h, whereby they ate, drank, and brushed their teeth at pre-determined time periods. The amount of mercury vapor released per time unit was measured at intervals of 30-45 min by means of a measuring system based on atomic absorption spectrophotometry. None of the subjects was professionally exposed to mercury, and all of their amalgam fillings were more than one year old. Study casts were made for each subject, and the area of the amalgam surfaces was measured. Samples of urine and saliva were analyzed so that values for the mercury concentrations and the rate of release of mercury into saliva could be obtained. The average frequency of fish meals per month was noted.

  7. Predicted radionuclide release from reactor-related unenclosed solid objects dumped in the Sea of Japan and the Pacific Ocean, east coast of Kamchatka

    Energy Technology Data Exchange (ETDEWEB)

    Mount, M.E. [Lawrence Livermore National Lab., CA (United States); Lynn, N.M.; Warden, J.M. [Royal Naval Coll., Greenwich (United Kingdom)

    1996-06-01

    Between 1978 and 1991 reactor-related solid radioactive waste was dumped by the former Soviet Union as unenclosed objects in the Pacific Ocean, east coast of Kamchatka, and the Sea of Japan. This paper presented estimates for the current (1994) inventory of activation and corrosion products contained in the reactor-related unenclosed solid objects. In addition, simple models derived for prediction of radionuclide release from marine reactors dumped in the Kara Sea are applied to certain of the dumped objects to provide estimates of radionuclide release to the Pacific Ocean, east coast of Kamchatka, and Sea of Japan environments. For the Pacific Ocean, east coast of Kamchatka, total release rates start below 0.01 GBq yr{sup -1} and over 1,000 years, fall to 100 Bq yr{sup -1}. In the Sea of Japan, the total release rate starts just above 1 GBq yr{sup - 1}, dropping off to a level less than 0.1 GBq yr{sup -1}, extending past the year 4,000.

  8. Controlling Heat Release from a Close-Packed Bisazobenzene-Reduced-Graphene-Oxide Assembly Film for High-Energy Solid-State Photothermal Fuels.

    Science.gov (United States)

    Zhao, Xiaoze; Feng, Yiyu; Qin, Chengqun; Yang, Weixiang; Si, Qianyu; Feng, Wei

    2017-04-10

    A closed-cycle system for light-harvesting, storage, and heat release is important for utilizing and managing renewable energy. However, combining a high-energy, stable photochromic material with a controllable trigger for solid-state heat release remains a great challenge for developing photothermal fuels (PTFs). This paper presents a uniform PTF film fabricated by the assembly of close-packed bisazobenzene (bisAzo) grafted onto reduced graphene oxide (rGO). The assembled rGO-bisAzo template exhibited a high energy density of 131 Wh kg-1 and a long half-life of 37 days owing to inter- or intramolecular H-bonding and steric hindrance. The rGO-bisAzo PTF film released and accumulated heat to realize a maximum temperature difference (DT) of 15 °C and a DT of over 10 °C for 30 min when the temperature difference of the environment was greater than100 °C. Controlling heat release in the solid-state assembly paves the way to develop highly efficient and high-energy PTFs for a multitude of applications. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. THE PROCESS OF MASS TRANSFER ON THE SOLID-LIQUID BOUNDARY LAYER DURING THE RELEASE OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE FROM TABLETS IN A PADDLE APPARATUS.

    Science.gov (United States)

    Kasperek, Regina; Zimmer, Lukasz; Poleszak, Ewa

    2016-01-01

    The release study of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) from two formulations of the tablets in the paddle apparatus using different rotation speeds to characterize the process of mass transfer on the solid-liquid boundary layer was carried out. The dissolution process of active substances was described by values of mass transfer coefficients, the diffusion boundary layer thickness and dimensionless numbers (Sh and Re). The values of calculated parameters showed that the release of DIC and PAP from tablets comprising potato starch proceeded faster than from tablets containing HPMC and microcrystalline cellulose. They were obtained by direct dependencies between Sh and Re in the range from 75 rpm to 125 rpm for both substances from all tablets. The description of the dissolution process with the dimensionless numbers make it possible to plan the drug with the required release profile under given in vitro conditions.

  10. ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.

    Science.gov (United States)

    Bagai, Rakesh; Fan, Weiwen; Ma, Patrick C

    2010-06-01

    ARQ-197 is an oral, selective c-Met inhibitor under development by ArQule Inc, in partnership with Daiichi Sankyo Co Ltd and Asian licensee Kyowa Hakko Kirin Co Ltd, for the potential treatment of solid tumors, including NSCLC, hepatocellular carcinoma and pancreatic cancer, as well as microphthalmia transcription factor-driven tumors. c-Met, a key cell surface receptor tyrosine kinase involved in diverse regulatory functions, is often aberrantly activated in human cancers. While the precise mechanism of action of ARQ-197 remains undefined, data from preclinical studies have demonstrated that ARQ-197 inhibits c-Met activation in numerous human tumor cell lines and specifically targets c-Met in various cancer types; uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner. Phase I/II clinical trials demonstrated promise in terms of both tolerability and tumor response. Intriguingly, dose-limiting adverse effects were hematological in nature. Combinational trials are also ongoing to take advantage of the signaling crosstalk between c-Met and other oncogenic signaling systems. Prioritization of the clinical development of c-Met inhibitors, such as ARQ-197, among different tumor disease types is a key challenge at present; an improved understanding of the prediction of molecular determinants in tumors with respect to c-Met kinase as the driver oncogenic receptor, and of the prediction of tumor response, is still urgently needed.

  11. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.

    Science.gov (United States)

    Papadopoulos, K P; El-Rayes, B F; Tolcher, A W; Patnaik, A; Rasco, D W; Harvey, R D; LoRusso, P M; Sachdev, J C; Abbadessa, G; Savage, R E; Hall, T; Schwartz, B; Wang, Y; Kazakin, J; Shaib, W L

    2017-10-03

    ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-valueARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.British Journal of Cancer advance online publication, 3 October 2017; doi:10.1038/bjc.2017.330 www.bjcancer.com.

  12. A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors.

    Science.gov (United States)

    Hong, David S; Rosen, Peter; Lockhart, A Craig; Fu, Siqing; Janku, Filip; Kurzrock, Razelle; Khan, Rabia; Amore, Benny; Caudillo, Isaac; Deng, Hongjie; Hwang, Yuying C; Loberg, Robert; Ngarmchamnanrith, Gataree; Beaupre, Darrin M; Lee, Peter

    2015-07-30

    This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors. Three to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208. Fifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed. In this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.

  13. Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms.

    Science.gov (United States)

    Korasa, Klemen; Vrečer, Franc

    2018-01-01

    Over the last two decades, regulatory agencies have demanded better understanding of pharmaceutical products and processes by implementing new technological approaches, such as process analytical technology (PAT). Process analysers present a key PAT tool, which enables effective process monitoring, and thus improved process control of medicinal product manufacturing. Process analysers applicable in pharmaceutical coating unit operations are comprehensibly described in the present article. The review is focused on monitoring of solid oral dosage forms during film coating in two most commonly used coating systems, i.e. pan and fluid bed coaters. Brief theoretical background and critical overview of process analysers used for real-time or near real-time (in-, on-, at- line) monitoring of critical quality attributes of film coated dosage forms are presented. Besides well recognized spectroscopic methods (NIR and Raman spectroscopy), other techniques, which have made a significant breakthrough in recent years, are discussed (terahertz pulsed imaging (TPI), chord length distribution (CLD) analysis, and image analysis). Last part of the review is dedicated to novel techniques with high potential to become valuable PAT tools in the future (optical coherence tomography (OCT), acoustic emission (AE), microwave resonance (MR), and laser induced breakdown spectroscopy (LIBS)). Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Population Pharmacokinetics of Ganciclovir after Intravenous Ganciclovir and Oral Valganciclovir Administration in Solid Organ Transplant Patients Infected with Cytomegalovirus▿

    Science.gov (United States)

    Caldés, A.; Colom, H.; Armendariz, Y.; Garrido, M. J.; Troconiz, I. F.; Gil-Vernet, S.; Lloberas, N.; Pou, L.; Peraire, C.; Grinyó, J. M.

    2009-01-01

    A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CLCR) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49·(CLCR/57) liter/h (57 was the mean population value of CLCR); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h−1; bioavailability was 0.825; and lag time was 0.382 h. The CLCR was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure. PMID:19738014

  15. In vivo Biocompatibility, Biodistribution and Therapeutic Efficiency of Titania Coated Upconversion Nanoparticles for Photodynamic Therapy of Solid Oral Cancers.

    Science.gov (United States)

    Lucky, Sasidharan Swarnalatha; Idris, Niagara Muhammad; Huang, Kai; Kim, Jaejung; Li, Zhengquan; Thong, Patricia Soo Ping; Xu, Rong; Soo, Khee Chee; Zhang, Yong

    2016-01-01

    Despite the advantages of using photodynamic therapy (PDT) for the treatment of head and neck tumors, it can only be used to treat early stage flat lesions due to the limited tissue penetration ability of the visible light. Here, we developed near-infrared (NIR) excitable upconversion nanoparticle (UCN) based PDT agent that can specifically target epithelial growth factor receptor (EGFR) overexpressing oral cancer cells, in a bid to widen the application of PDT against thick and solid advanced or recurrent head and neck cancers. In vivo studies using the synthesized anti-EGFR-PEG-TiO2-UCNs following systemic administration displayed no major sub-acute or long term toxic effects in terms of blood biochemical, hematological or histopathological changes at a concentration of 50 mg/kg. NIR-PDT even in the presence of a 10 mm tissue phantom placed over the xenograft tumor, showed significant delay in tumor growth and improved survival rate compared to conventional chlorin-e6 (Ce6) PDT using 665 nm red light. Our work, one of the longest study till date in terms of safety (120 d), PDT efficacy (35 d) and survival (60 d), demonstrates the usefulness of UCN based PDT technology for targeted treatment of thick and bulky head and neck tumors.

  16. 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

  17. Alginate Microencapsulation for Oral Immunisation of Finfish: Release Characteristics, Ex Vivo Intestinal Uptake and In Vivo Administration in Atlantic Salmon, Salmo salar L.

    Science.gov (United States)

    Ghosh, Bikramjit; Nowak, Barbara F; Bridle, Andrew R

    2015-12-01

    This study examined the feasibility of alginate microcapsules manufactured using a low-impact technology and reagents to protect orally delivered immunogens for use as immunoprophylactics for fish. Physical characteristics and protein release kinetics of the microcapsules were examined at different pH and temperature levels using a microencapsulated model protein, bovine serum albumin (BSA). Impact of the microencapsulation process on contents was determined by analysing change in bioactivity of microencapsulated lysozyme. Feasibility of the method for oral immunoprophylaxis of finfish was assessed using FITC-labelled microcapsules. These were applied to distal intestinal explants of Atlantic salmon (Salmo salar) to investigate uptake ex vivo. Systemic distribution of microcapsules was investigated by oral administration of FITC-labelled microcapsules to Atlantic salmon fry by incorporating into feed. The microcapsules produced were structurally robust and retained surface integrity, with a modal size distribution of 250-750 nm and a tendency to aggregate. Entrapment efficiency of microencapsulation was 51.2 % for BSA and 43.2 % in the case of lysozyme. Microcapsules demonstrated controlled release of protein, which increased with increasing pH or temperature, and the process had no significant negative effect on bioactivity of lysozyme. Uptake of fluorescent-labelled microcapsules was clearly demonstrated by intestinal explants over a 24-h period. Evidence of microcapsules was found in the intestine, spleen, kidney and liver of fry following oral administration. Amenability of the microcapsules to intestinal uptake and distribution reinforced the strong potential for use of this microencapsulation method in oral immunoprophylaxis of finfish using sensitive immunogenic substances.

  18. Development of solid SEDDS, VII: Effect of pore size of silica on drug release from adsorbed self-emulsifying lipid-based formulations.

    Science.gov (United States)

    Gumaste, Suhas G; Serajuddin, Abu T M

    2017-12-15

    Lipid-based self-emulsifying drug delivery systems (SEDDS) are usually liquids, and they can be converted into solid dosage forms by adsorbing onto silicates. However, most commercially available silicates are mesoporous with small pore sizes of 1 to 50nm that lead to incomplete emulsification of SEDDS inside the pores and thus incomplete drug release. The objective of this study was to investigate the impact of silica pore size on the extent of drug release from SEDDS solidified by adsorbing onto macroporous silicas with different pore sizes. Silicas with average pore sizes of approx. 150nm, 500nm and 5μm were synthesized using the colloidal crystal templating method. A model poorly water-soluble drug, probucol, was dissolved in liquid SEDDS containing different lipid to surfactant ratios, and the formulations were then adsorbed onto equal weights of silicas (1:1 w/w ratio). Drug release from freshly prepared formulations and after storing at 40°C/60% RH for up to 6months was studied using a modified USP type 2 method with mini paddles and 50mL of 0.01M HCl (pH~2) at 37°C. Drug release was also studied similarly from silicas that were precoated with PVP K-30 at 5, 10, 20 and 30% w/w levels before adsorption of SEDDS. Freshly prepared formulations containing relatively higher lipid:surfactant ratio of 7:3% w/w exhibited 17, 40 and 60% drug release from uncoated (neat) silicas with pore sizes of 150nm, 500nm and 5μm, respectively, while the more hydrophilic formulations containing 3:7 w/w lipid:surfactant ratio had, respectively, 50, 65 and 85% drug release. No decrease in drug release was observed when the formulations were exposed to 40°C/60% RH for up to 6months. When the silicas were precoated with 20% PVP, the drug release was almost complete (>80%), which remained unchanged even after 6months of storage irrespective of the composition of adsorbed liquid SEDDS. Both pore size and composition of SEDDS had major impacts on drug release from silicas

  19. An in vitro evaluation of fenugreek mucilage as a potential excipient for oral controlled-release matrix tablet.

    Science.gov (United States)

    Nokhodchi, Ali; Nazemiyeh, Hossein; Khodaparast, Afagh; Sorkh-Shahan, Tarifeh; Valizadeh, Hadi; Ford, J L

    2008-03-01

    A polysaccharide mucilage derived from the seeds of fenugreek, Trigonella foenum-graceum L (family Fabaceae) was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel hypomellose K4M was used as a standard controlled release polymer for comparison purposes. In this study the effect of lactose on the release behaviour of propranolol hydrochloride from matrices formulated to contain the fenugreek mucilage also was investigated. An increase in concentration of the mucilage in matrices resulted in a reduction in the release rate of propranolol hydrochloride comparable to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug:mucilage ratio. However, the mechanism of release from matrices containing drug:mucilage ratios of 1:1, 1:1.25, 1:1.5, and 1:2 remained the same. The kinetics of release, utilising the release exponent n, showed that the values of n were between 0.46-0.57 indicating that the release from fenugreek mucilage matrices was predominantly by diffusion. The presence of lactose in matrices containing mucilage increased the release rate of propranolol hydrochloride. This is due to a reduction in tortuoisity and increased pore size of channels caused by lactose through which propranolol diffuses and therefore diffusion of water into the tablet is facilitated.

  20. Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties.

    Science.gov (United States)

    Gudin, Jeff; Levy-Cooperman, Naama; Kopecky, Ernest A; Fleming, Alison B

    2015-11-01

    Oxycodone DETERx® is an extended-release (ER), microsphere-in-capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx® capsules compared with intact and crushed reformulated OxyContin® tablets and crushed immediate-release oxycodone tablets (IR oxycodone). This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx® (intact or crushed), OxyContin® (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations. Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx® resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx® was bioequivalent to intact Oxycodone DETERx® and exhibited a numerically lower Cmax . Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin® were significantly higher compared with intact OxyContin® and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin® was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin®. These data demonstrate that when crushed and taken orally, Oxycodone DETERx® maintains its EXTENDED-release profile, while crushed OxyContin® shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx® may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing. Wiley Periodicals, Inc.

  1. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials.

    Science.gov (United States)

    Abu Hashim, Hatem; Ghayaty, Essam; El Rakhawy, Mohamed

    2015-10-01

    We sought to evaluate the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH). Searches were conducted on PubMed, SCOPUS, and CENTRAL databases to August 2014, and reference lists of relevant articles were screened. The search was limited to articles conducted on human beings and females. The PRISMA Statement was followed. Seven randomized controlled trials (n = 766 women) were included. Main outcome measures were the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment; rate of irregular vaginal bleeding; and the hysterectomy rate per woman randomized. The Cochrane Collaboration risk of bias tool was used for quality assessment. Metaanalysis was performed with fixed effects model. LNG-IUS achieved a highly significant therapeutic response rate compared with oral progestins after 3 months of treatment (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.39-3.82; P = .001, 5 trials, I(2) = 0%, n = 376), after 6 months of treatment (OR, 3.16; 95% CI, 1.84-5.45; P therapeutic response following LNG-IUS compared with oral progestins for non-atypical simple as well as complex EH (OR, 2.51; 95% CI, 1.14-5.53; P = .02, 6 trials, I(2) = 0%, n = 290; and OR, 3.31; 95% CI, 1.62-6.74; P = .001, 4 trials, I(2) = 0%, n = 216, respectively). Compared with oral progestins, LNG-IUS achieved significantly fewer hysterectomies (OR, 0.26; 95% CI, 0.15-0.45; P therapeutic effect rates and lower hysterectomy rates than oral progestins and should be offered as an alternative to oral progestins in these cases. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

    Directory of Open Access Journals (Sweden)

    Johan Holmkvist

    Full Text Available BACKGROUND: Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1 have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897 on estimates of glucose stimulated insulin release. METHODOLOGY/PRINCIPAL FINDINGS: Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC 277+/-160 vs. (AC 280+/-164 vs. (AA 299+/-200 pmol/l, p = 0.008 after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007, incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02 among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228. CONCLUSION: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

  3. Anaerobic stabilization of waste activated sludge at different temperatures and solid retention times: Evaluation by sludge reduction, soluble chemical oxygen demand release and dehydration capability.

    Science.gov (United States)

    Li, Xiyao; Peng, Yongzhen; He, Yuelan; Wang, Shuying; Guo, Siyu; Li, Lukai

    2017-03-01

    Anaerobic treatment is the most widely used method of waste activated sludge (WAS) stabilization. Using a semi-continuous stirring tank with condensed WAS, we investigated effects of decreasing the solid retention time (SRT) from 32days to 6.4days on sludge reduction, soluble chemical oxygen demand (SCOD) release and dehydration capability, along with anaerobic digestion operated at medium temperature (MT-AD) or anaerobic digestion operated at room temperature (RT-AD). Results showed that effects of temperature on SCOD release were greater at SRT of 32d and 6.4d. When SRT was less than 8d, total solids (TS), volatile solids (VS) and capillary suction time (CST) did not change significantly. CST was lowest at SRT of 10.7days, indicating best condition for sludge dehydration. Principal component analysis (PCA) showed that the most optimum SRT was higher than 10.7d both in MT-AD or RT-AD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. [Development of a simple oral short test with the TSH releasing hormone (TRH) and its use in thyroid diagnosis].

    Science.gov (United States)

    Staub, J J; Girard, J; Gemsenjäger, E

    1976-12-11

    A simple test with 40 mg of oral TRH after overnight fasting was developed and can be characterized as follows: This short oral TRH test has been found to be a most valuable thyroid function test for detection of hyper- and hypothyroidism. It is as reliable as the intravenous TRH test. Oral TRH produces much stronger and more prolonged TSH stimulation similar to that of a depot preparation. Therefore, the incidence of euthyroid controls with absent or subnormal TSH response to TRH is definitely lower than after intravenous TRH. In patients with low TSH response after i.v. TRH the oral TRH test is of particular diagnostic value in distinguishing euthyroid function from TSH suppression or pituitary failure. 40 mg or oral TRH produces reliable stimulation of T3 in most euthyroid subjects. In patients with hyper- and hypothyroidism no increase of T3 is obserable. Oral TRH allows simultaneous assessment of pituitary TSH and thyroid reserve in a single test. The practical advantages (side effects in only 2% [for i.v. TRH 60%], only 1 or 2 blood samples, fewer sampling errors and no i.v. injection) outweigh the disadvantages (longer duration of the test, dependence on food intake and gastrointestinal absorption).

  5. Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system.

    Science.gov (United States)

    Haseeb, Muhammad Tahir; Hussain, Muhammad Ajaz; Bashir, Sajid; Ashraf, Muhammad Umer; Ahmad, Naveed

    2017-03-01

    Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach. Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material. Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM. LSH tablets exhibited dynamic swelling-deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion. These finding indicates that LSH holds potential to be developed as sustained release material for tablet.

  6. Carbon and nitrogen substrates consumption, ammonia release and proton transfer in relation with growth of Geotrichum candidum and Penicillium camemberti on a solid medium.

    Science.gov (United States)

    Aldarf, Mazen; Amrane, Abdeltif; Prigent, Yves

    2002-05-09

    It is difficult to determine fungal biomass growing on a solid medium directly. Therefore, indirect ways of measuring this growth have to be used instead. For this purpose, the kinetics of growth, of substrate consumption and of release of metabolites must be correlated. This has been carried out for Geotrichum candidum and Penicillium camemberti growing on a gelified lactic acid+peptone medium. Peptone was shown to be preferred by G. candidum as a carbon and energy source, in contrast to the behaviour observed for P. camemberti. At the end of growth, G. candidum released about three times more ammonia than P. camemberti. In both cases, the total number of protons consumed during growth was close to the sum of the number of moles of metabolized lactic acid and formed ammonia. During the main part of growth, constant biomass on substrate yields (peptone, lactic acid) was observed for both microorganisms. Therefore, in pure solid cultures, the biomass concentration of both species could be deduced either from DeltapH or from the reduction of substrates. From the above, an estimate of G. candidum biomass in mixed culture could be derived from the determination of ammonia release.

  7. Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method

    DEFF Research Database (Denmark)

    Cui, Fude; Yang, Mingshi; Jiang, Yanyan

    2003-01-01

    that the particle size of microspheres was determined mainly by the agitation speed. The dissolution rate of nitrendipine from microspheres was enhanced significantly with increasing the amount of dispersing agents, and sustained by adding retarding agents. The release rate of microspheres could be controlled...... as amorphous state. The release profiles and content of the microspheres stored at a temperature of 40 degrees C and a relative humidity of 75% were unchanged during 3 months of accelerating condition of storage. And the relative bioavailability of the sustained-release microspheres compared with the Baypress...

  8. The Type 2 Diabetes Associated Minor Allele of rs2237895 KCNQ1 Associates with Reduced Insulin Release Following an Oral Glucose Load

    DEFF Research Database (Denmark)

    Brunak, Søren; Holmkvist, J; Banasik, K

    2009-01-01

    Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895...... for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228. CONCLUSION: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk...

  9. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

    Directory of Open Access Journals (Sweden)

    Franke RM

    2015-08-01

    Full Text Available Ryan M Franke, Terri Morton, Krishna Devarakonda Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA Abstract: This analysis evaluated the single-dose population pharmacokinetics (PK of biphasic immediate-release (IR/extended-release (ER oxycodone (OC/acetaminophen (APAP 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18–55 years old participants (three trials and nondependent recreational users of prescription opioids (one trial with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet, 15/650 mg (two tablets, or 30/1,300 mg (four tablets under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F and volume of distribution (V/F of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant. Keywords: acetaminophen, acute pain, biphasic, extended release, fixed

  10. Interaction between paliperidone extended release and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative, in a schizophrenic patient.

    Science.gov (United States)

    Yasui-Furukori, Norio; Hashimoto, Kojiro; Kubo, Kazutoshi; Tomita, Tetsu

    2013-01-01

    Until now there has been no information available on drug interaction between paliperidone and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative. The patient in the case presented here was a 39-year-old man with a 15-year history of schizophrenia. The patient's usual treatment of 2 mg/day of risperidone was changed to 3 mg/day of paliperidone extended release. He experienced worsening psychotic symptoms after switching from risperidone to paliperidone while he was also receiving TS-1. Retrospective analyses showed plasma concentration of paliperidone was consistently lower during the treatment with TS-1 than without TS-1. This case suggests there is drug interaction between paliperidone extended-release tablets and TS-1.

  11. Investigation on Secondary Structure Perturbations of Proteins Embedded in Solid Lipid Matrices as a Novel Indicator of their Biological Activity upon In Vitro Release

    DEFF Research Database (Denmark)

    Zeeshan, Farrukh; Tabbassum, Misbah; Jorgensen, Lene

    2018-01-01

    Protein biologics are prone to conformational changes during formulation development. Limited methods are available for conformational analysis of proteins in solid state and in the presences of formulation excipients. The aim of this study was to investigate the secondary structures of proteins...... encased in solid lipid matrices as a novel indicator of their stability upon in vitro release. Model proteins namely catalase and lysozyme were incorporated into lipid namely Precirol® AT05 (glycerol palmitostearate, melting point 58°C) at 30% w/w loading using melting and mixing and wet granulation...... methods. Attenuated total reflectance (ATR-FTIR) spectroscopy, size-exclusion chromatography (SEC) and biological activity analyses were performed. The information about secondary structure was acquired using second derivative analysis of amide-I band (1600-1700 cm(-1)). ATR analysis demonstrated...

  12. Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form.

    Science.gov (United States)

    Pattani, Aditya; McKay, Paul F; Curran, Rhonda M; McCaffrey, Joanne; Gupta, Prem N; Lowry, Deborah; Kett, Vicky L; Shattock, Robin J; McCarthy, Helen O; Malcolm, R Karl

    2012-04-05

    A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Spray coating of microcontainers with eudragit using ferromagnetic shadow masks for controlled oral release of poorly water soluble drugs

    DEFF Research Database (Denmark)

    Nielsen, Line Hagner; Keller, Stephan Sylvest; Boisen, Anja

    2013-01-01

    of controlling the drug release of poorly soluble drugs from the microcontainers. METHODS: Cylindrical microcontainers (inner diameter of 240 μm) were fabricated in SU-8, using photolithography on silicon substrate. The microcontainers were filled with either cinnarizine (weak base) or amorphous furosemide salt...... clamping to the substrate and therefore precise deposition of the polymer on the microcontainers to form a lid. The release of cinnarizine and amorphous furosemide salt from the coated microcontainers was performed in fasted biorelevant gastric (pH 1.6) and intestinal media (pH 6.5), respectively. RESULTS....... It was possible to control the drug release of cinnarizine by using Eudragit L-100 in the gastric medium and also possible to control the release of amorphous furosemide salt by the Eudragit E-100 coating in the intestinal medium. CONCLUSIONS: The ferromagnetic shadow masks made it possible to deposit a lid...

  14. Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release: A technical note

    OpenAIRE

    Chowdary, K. P. R.; Rao, Y. Srinivasa

    2003-01-01

    Thus, large spherical microcapsules with a coat consisting of alginate and a mucoadhesive polymer (sodium CMC, methylcellulose, Carbopol, or HPMC) could be prepared by an orifice-ionic gelation process. The microcapsules exhibited good mucoadhesive properties in an in vitro test. Glipizide release from these mucoadhesive microcapsules was slow and extended over longer periods of time and depended on composition of the coat. Drug release was diffusion controlled and followed zero-order kinetic...

  15. Novel inorganic solid controlled-release inhibitor for Q235-b anticorrosion treatment in 1 M HCl

    Science.gov (United States)

    Cui, Jun; Shi, Ruirui; Pei, Yuansheng

    2017-09-01

    Borate was regarded as an interesting material for a broad range of applications. Here, we had prepared a novel borate-based controlled-release inhibitor to improve the anticorrosion performance of Q235-b in 1 M HCl. The effective components released by the inhibitor were boron and sodium, and its anticorrosion performance was investigated by various electrochemical methods The potentiodynamic polarization curve results indicated that the borate-based inhibitor showed a clear anodic-type inhibitor characteristic, and a great improvement of the resistance was obtained from the electrochemical impedance spectroscopy, resulting from the formation of a passive film with Fesbnd Osbnd B structure on the Q235-b surface. The formation process followed the Langmuir isotherm well, and the passive film showed a self-healing capability, which confirmed by the electrochemical noise. Further, the anticorrosion capability of the inhibitor gradually increased with the increasing release time. After 21 days of release, the boron concentration reached 125 mg L-1, the anticorrosion efficiency was over 97%, and a smooth surface was observed on the Q235-b surface from electron microscopy. According to these results, we believed that the borate-based controlled-release inhibitor displayed a satisfactory capability to suppress corrosion on the Q235-b surface in 1 M HCl. The present work provided a novel concept for the development of corrosion inhibitor.

  16. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    Science.gov (United States)

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

  17. Pilot Inter-Laboratory Studies for Evaluating Weathering-Induced Release of Carbon Nanotubes from Solid Matrices

    Science.gov (United States)

    Nanomaterials are increasingly being used in polymer composites to enhance the properties of these materials. Here we present results of a pilot inter-laboratory study to simulate the effects of weathering on the potential release of multiwalled carbon nanotubes (MWCNT) from thei...

  18. Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a β-lactamase to prevent intravenous antibiotic-associated dysbiosis of the colon.

    Science.gov (United States)

    Bristol, Andrew; Hubert, Steven; Hofmann, Felix; Baer, Hans

    2017-12-20

    SYN-004 (ribaxamase) delayed release drug product is a multi-particulate, hard capsule for oral delivery of a recombinant β-lactamase enzyme designed to degrade β-lactam antibiotics administered intravenously, and thus prevent colon dysbiosis. Here we describe the development of the SYN-004 enteric coated pellet formulation, which has been tested in multiple clinical trials. Since the SYN-004 drug substance is a buffered liquid, several binder excipients in different ratios were tested to facilitate binding of SYN-004 to sugar spheres. The binding systems were evaluated by droplet pre-evaluation and film casting tests. The most promising formulations were produced in small scale fluidized bed application runs and analyzed by dissolution tests and complementary analytical assays. Hydroxypropyl cellulose was selected as the preferred SYN-004 binding excipient. The formulation included a second, outer coat containing the enteric EUDRAGIT® L 30 D-55 polymer-based formulation to achieve gastric protection, and rapid SYN-004 release in the intestinal tract, when the pH rises above 5.5. Additional formulation improvements resulted in an increase in the SYN-004 load compared to a predecessor oral enzyme formulation (Ipsat P1A). Thus, a novel formulation and process for an orally administered enzyme was developed and used to manufacture drug product for clinical trials. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Fabrication of Mesoporous Silica Shells on Solid Silica Spheres Using Anionic Surfactants and Their Potential Application in Controlling Drug Release

    OpenAIRE

    El-Toni, Ahmed; Khan, Aslam; Ibrahim, Mohamed; Al-Hoshan, Mansour; Labis, Joselito

    2012-01-01

    In this work, mesoporous shells were constructed on solid silica cores by employing anionic surfactante. A co-structure directing agent (CSDA) has assisted the electrostatic interaction between negatively charged silica particles and the negatively charged surfactant molecules. Synthetic parameters such as reaction time and temperature had a significant impact on the formation of mesoporous silica shelld and their textural properties such as surface area and pore volume. Core-mesoporous shell...

  20. Eudragit E PO as a complementary material for designing oral drug delivery systems with controlled release properties: comparative evaluation of new interpolyelectrolyte complexes with countercharged eudragit L100 copolymers.

    Science.gov (United States)

    Moustafine, R I; Bukhovets, A V; Sitenkov, A Y; Kemenova, V A; Rombaut, P; Van den Mooter, G

    2013-07-01

    The design of new interpolyelectrolyte complexes (IPEC) between countercharged polymers (Eudragit EPO (EPO) and Eudragit L100 (L100)) was investigated. The formation and chemical composition of three new IPECs between EPO and L100 was established by elemental analysis. The structure and solid state properties of the synthesized IPEC were investigated using Fourier transform infrared (FTIR) spectroscopy and modulated temperatre differential scanning calorimetry (MTDSC). The binding ratio of a unit molecule of EPO with L100 was found to range between 1:0.98 (Z = 1.02) and 1:0.50 (Z = 2.00) while increasing the pH from 6.0 to 7.0. As a result of electrostatic interaction between the copolymer chains, the glass transition temperature of the IPEC increased significantly. Considerable pH-sensitive swelling in acidic and neutral media was observed for different type of IPECs. Through evaluation of diffusion-transportation properties of the IPECs, basic mechanisms controlling the delivery of chemically different drugs (diclofenac sodium and theophylline) were obtained. The results of swelling and release of the model drugs from the polycomplex matrices confirm that they have potential to be used in oral controlled drug delivery.

  1. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.

    Science.gov (United States)

    McKenna, Jeffrey M; Halley, Frank; Souness, John E; McLay, Iain M; Pickett, Stephen D; Collis, Alan J; Page, Kenneth; Ahmed, Imtiaz

    2002-05-23

    Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathology in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial organic synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compounds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purification of the final compounds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a number of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biological investigation.

  2. Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone.

    Science.gov (United States)

    Chamsai, Benchawan; Limmatvapirat, Sontaya; Sungthongjeen, Srisagul; Sriamornsak, Pornsak

    2017-12-01

    Low bioavailability of oral manidipine (MDP) is due to its low water solubility. The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone. In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated. The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo. The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.

  3. Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro-in silico approach.

    Science.gov (United States)

    Cvijić, Sandra; Aleksić, Ivana; Ibrić, Svetlana; Parojčić, Jelena

    2017-10-29

    Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro-in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro-in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.

  4. The release of trapped gases from amorphous solid water films. I. "Top-down" crystallization-induced crack propagation probed using the molecular volcano.

    Science.gov (United States)

    May, R Alan; Smith, R Scott; Kay, Bruce D

    2013-03-14

    In this (Paper I) and the companion paper (Paper II; R. May, R. Smith, and B. Kay, J. Chem. Phys. 138, 104502 (2013)), we investigate the mechanisms for the release of trapped gases from underneath amorphous solid water (ASW) films. In prior work, we reported the episodic release of trapped gases in concert with the crystallization of ASW, a phenomenon that we termed the "molecular volcano." The observed abrupt desorption is due to the formation of cracks that span the film to form a connected pathway for release. In this paper, we utilize the "molecular volcano" desorption peak to characterize the formation of crystallization-induced cracks. We find that the crack length distribution is independent of the trapped gas (Ar, Kr, Xe, CH4, N2, O2, or CO). Selective placement of the inert gas layer is used to show that cracks form near the top of the film and propagate downward into the film. Isothermal experiments reveal that, after some induction time, cracks propagate linearly in time with an Arrhenius dependent velocity corresponding to an activation energy of 54 kJ∕mol. This value is consistent with the crystallization growth rates reported by others and establishes a direct connection between crystallization growth rate and the crack propagation rate. A two-step model in which nucleation and crystallization occurs in an induction zone near the top of the film followed by the propagation of a crystallization∕crack front into the film is in good agreement with the temperature programmed desorption results.

  5. Solid-phase microextraction of volatile organic compounds released from leaves and flowers of Artemisia fragrans, followed by GC and GC/MS analysis.

    Science.gov (United States)

    Movafeghi, A; Djozan, Dj; Torbati, S

    2010-08-01

    The chemical composition of the volatile organic compounds (VOCs) released from the leaves and flowers of Artemisia fragrans Willd. (Asteraceae) was investigated using headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography (GC) and/or GS/mass spectrometry (GC/MS). The efficiency and reliability of different fibres such as modified pencil lead and commercial polyacrylate (PA) as well as polydimethylsiloxane (PDMS) were evaluated, and pencil lead was selected to be the most suitable fibre for the extraction and sampling of the compounds. The extraction and chromatographic conditions were also optimised. Under the optimal conditions, a range of VOCs released from the leaves and flowers of A. fragrans were identified and compared. Accordingly, some bioactive components such as camphor, 1,8-cineole, alpha-terpinolene, gamma-terpinene and carvacrol were the main compounds in the VOCs released from either flowers or leaves. However, the nature and level of the volatiles in studied parts of the plant were notably varied.

  6. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors

    Science.gov (United States)

    Deutsch, Eric; Moyal, Elizabeth Cohen-Jonathan; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2017-01-01

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions. PMID:28915584

  7. Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

    Science.gov (United States)

    Zhang, Xiaoyu; Li, Qi; Ye, Mingzhu; Zhao, Zhinan; Sun, Jiayi; Yang, Xinggang; Pan, Weisan

    2018-02-01

    The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

  8. WARP3D-Release 10.8: Dynamic Nonlinear Analysis of Solids using a Preconditioned Conjugate Gradient Software Architecture

    Science.gov (United States)

    Koppenhoefer, Kyle C.; Gullerud, Arne S.; Ruggieri, Claudio; Dodds, Robert H., Jr.; Healy, Brian E.

    1998-01-01

    This report describes theoretical background material and commands necessary to use the WARP3D finite element code. WARP3D is under continuing development as a research code for the solution of very large-scale, 3-D solid models subjected to static and dynamic loads. Specific features in the code oriented toward the investigation of ductile fracture in metals include a robust finite strain formulation, a general J-integral computation facility (with inertia, face loading), an element extinction facility to model crack growth, nonlinear material models including viscoplastic effects, and the Gurson-Tver-gaard dilatant plasticity model for void growth. The nonlinear, dynamic equilibrium equations are solved using an incremental-iterative, implicit formulation with full Newton iterations to eliminate residual nodal forces. The history integration of the nonlinear equations of motion is accomplished with Newmarks Beta method. A central feature of WARP3D involves the use of a linear-preconditioned conjugate gradient (LPCG) solver implemented in an element-by-element format to replace a conventional direct linear equation solver. This software architecture dramatically reduces both the memory requirements and CPU time for very large, nonlinear solid models since formation of the assembled (dynamic) stiffness matrix is avoided. Analyses thus exhibit the numerical stability for large time (load) steps provided by the implicit formulation coupled with the low memory requirements characteristic of an explicit code. In addition to the much lower memory requirements of the LPCG solver, the CPU time required for solution of the linear equations during each Newton iteration is generally one-half or less of the CPU time required for a traditional direct solver. All other computational aspects of the code (element stiffnesses, element strains, stress updating, element internal forces) are implemented in the element-by- element, blocked architecture. This greatly improves

  9. Gold nanoflowers with mesoporous silica as "nanocarriers" for drug release and photothermal therapy in the treatment of oral cancer using near-infrared (NIR) laser light

    Science.gov (United States)

    Song, Wenzhi; Gong, Junxia; Wang, Yuqian; Zhang, Yan; Zhang, Hongmei; Zhang, Weihang; Zhang, Hu; Liu, Xin; Zhang, Tianfu; Yin, Wanzhong; Yang, Wensheng

    2016-04-01

    In this experiment, we successfully developed nanocarriers in the form of gold nanoflowers coated with two layers of silica for the purposes of drug loading and NIR (near-infrared) photothermal therapy for the treatment of oral cancer. The gold nanoflowers converted NIR laser energy into heat energy. The cores were coated with a thin silica layer (AuNFs@SiO2) to protect the gold nanoflowers from intraparticle ripening. The second layer was mesoporous silica (AuNFs@SiO2@mSiO2), which acted as a nanocarrier for anticancer drug (DOX) loads. The mean effective diameter of the nanoparticles was approximately 150-200 nm, whereas the peak absorption of the AuNFs was 684 nm. After the AuNFs were encapsulated by the silica shells, the plasmonic absorption peak of AuNFs@SiO2 and AuNFs@SiO2@mSiO2 exhibited a red shift to 718 nm. When exposed to an 808 nm NIR laser, these crystals showed an obvious photothermal conversion in the NIR region and a highly efficient release of DOX. Biocompatibility was assessed in vitro using Cell Counting Kit-8 assays, and the results showed that the nanocarriers induced no obvious cytotoxicity. This nanomaterial could be considered a new type of material that shows promising potential for photothermal-chemotherapy against malignant tumours, including those of oral cancers.

  10. Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

    Science.gov (United States)

    Zhu, Bing; Nestorov, Ivan; Zhao, Guolin; Meka, Venkata; Leahy, Mark; Kam, Jeanelle; Sheikh, Sarah I

    2017-11-01

    Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 μg, ethinyl estradiol 35 μg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification. © 2017, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

  11. Evaluation of Potential Drug–Drug Interaction Between Delayed‐Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women

    Science.gov (United States)

    Nestorov, Ivan; Zhao, Guolin; Meka, Venkata; Leahy, Mark; Kam, Jeanelle; Sheikh, Sarah I.

    2017-01-01

    Abstract Delayed‐release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti‐inflammatory and neuroprotective properties. This 2‐period crossover study was conducted to evaluate the potential for drug–drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 μg, ethinyl estradiol 35 μg). Forty‐six healthy women were enrolled; 32 completed the study. After the lead‐in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration–time curve over the dosing interval and peak plasma concentration contained within the 0.8–1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol–based OCs may be used with DMF without dose modification. PMID:28783872

  12. Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple

    DEFF Research Database (Denmark)

    Osterballe, M; Scheller, R; Stahl Skov, P

    2003-01-01

    BACKGROUND: The aim of the study was to examine the diagnostic value of skin prick test (SPT), scratch-chamber test (SCT), histamine release (HR) and specific immunoglobulin E (IgE) in birch-allergic patients with oral allergy syndrome to apple. METHODS: Ten birch-allergic patients with oral...... allergy syndrome to apple and 10 control subjects were included. All were tested with SPT, SCT, HR and specific IgE [CAP, Pharmacia, Sweden and Magic Lite (ML), ALK-ABELLO, Denmark]. RESULTS: The SPT with apple, acetone extract of apple (A72) and commercial apple extract showed sensitivities of 0.80, 0.......90 and 0.10, respectively. The SCT with the same extracts showed sensitivities of 0.30, 0.50 and 0.20, respectively. The sensitivity of specific IgE to apple were 0.90 (CAP) and 0.10 (ML). The sensitivity of the HR test was 90% (A72), and 25% using the commercial extract. CONCLUSION: The SPT and HR test...

  13. A Canadian, multicentre study comparing the efficacy of a levonorgestrel-releasing intrauterine system to an oral contraceptive in women with idiopathic menorrhagia.

    Science.gov (United States)

    Endrikat, Jan; Shapiro, Heather; Lukkari-Lax, Eeva; Kunz, Michael; Schmidt, Werner; Fortier, Michel

    2009-04-01

    To evaluate the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) compared with a combined oral contraceptive containing 1 mg norethindrone acetate and 20 mg ethinyl estradiol (OC1/20) in reducing menstrual blood loss (MBL) in women with idiopathic menorrhagia. A prospective, randomized, open-label study was conducted in nine centres in Canada. Healthy women over 30 years of age suffering from idiopathic menorrhagia were treated either with LNG-IUS (n = 20) or with OC1/20 (n = 19) over 12 months. The primary endpoint was the change in MBL from baseline to 12 months. Secondary endpoints included treatment success (defined as a MBL score menorrhagia severity score. In both treatment groups, MBL decreased significantly from baseline to 12 months (P menorrhagia severity score was consistently lower in the LNG-IUS group at all study time points and was significantly lower (P = 0.045) at six months. Both treatments were well tolerated. Both the LNG-IUS and the combined oral contraceptive effectively decreased menstrual blood loss in women with idiopathic menorrhagia. The overall clinical benefit was more pronounced with LNG-IUS than with OC1/20.

  14. Gold nanoflowers with mesoporous silica as “nanocarriers” for drug release and photothermal therapy in the treatment of oral cancer using near-infrared (NIR) laser light

    Energy Technology Data Exchange (ETDEWEB)

    Song, Wenzhi; Gong, Junxia [Jilin University, Department of Stomatology, China-Japan Union Hospital (China); Wang, Yuqian [Jilin University, China-Japan Union Hospital, Scientific Research Center (China); Zhang, Yan [Jilin University, Department of Stomatology, China-Japan Union Hospital (China); Zhang, Hongmei [Jilin University, China-Japan Union Hospital, Scientific Research Center (China); Zhang, Weihang; Zhang, Hu; Liu, Xin; Zhang, Tianfu [Jilin University, Department of Stomatology, China-Japan Union Hospital (China); Yin, Wanzhong, E-mail: yinwanzhong88@hotmail.com [First Clinical Hospital of Jilin University, Department of Otorhinolaryngology (China); Yang, Wensheng, E-mail: wsyang@mail.jlu.edu.cn [College of Chemistry, The Key Laboratory of Surface and Interface Chemistry of Jilin Province (China)

    2016-04-15

    In this experiment, we successfully developed nanocarriers in the form of gold nanoflowers coated with two layers of silica for the purposes of drug loading and NIR (near-infrared) photothermal therapy for the treatment of oral cancer. The gold nanoflowers converted NIR laser energy into heat energy. The cores were coated with a thin silica layer (AuNFs@SiO{sub 2}) to protect the gold nanoflowers from intraparticle ripening. The second layer was mesoporous silica (AuNFs@SiO{sub 2}@mSiO{sub 2}), which acted as a nanocarrier for anticancer drug (DOX) loads. The mean effective diameter of the nanoparticles was approximately 150–200 nm, whereas the peak absorption of the AuNFs was 684 nm. After the AuNFs were encapsulated by the silica shells, the plasmonic absorption peak of AuNFs@SiO{sub 2} and AuNFs@SiO{sub 2}@mSiO{sub 2} exhibited a red shift to 718 nm. When exposed to an 808 nm NIR laser, these crystals showed an obvious photothermal conversion in the NIR region and a highly efficient release of DOX. Biocompatibility was assessed in vitro using Cell Counting Kit-8 assays, and the results showed that the nanocarriers induced no obvious cytotoxicity. This nanomaterial could be considered a new type of material that shows promising potential for photothermal-chemotherapy against malignant tumours, including those of oral cancers.

  15. Differential pharmacokinetics of diclofenac potassium for oral solution vs immediate-release tablets from a randomized trial: effect of fed and fasting conditions.

    Science.gov (United States)

    Chen, Cuiping; Bujanover, Shay; Kareht, Stephanie; Rapoport, Alan M

    2015-02-01

    To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet. Diclofenac potassium for oral solution is the only nonsteroidal anti-inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food. This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a ≥7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and

  16. Investigation of the potential for mercury release from flue gas desulfurization solids applied as an agricultural amendment.

    Science.gov (United States)

    Briggs, Christian W; Fine, Rebekka; Markee, Melissa; Gustin, Mae Sexauer

    2014-01-01

    The potential for beneficial use of flue gas desulfurization-derived gypsum (FGDG), a coal combustion byproduct, as an agricultural soil amendment is currently being debated. This study investigated the hypothesis that Hg released to air from FGDG will be reduced when amended to planted and bare soils. The potential for enhanced methylmercury (MeHg) production and Hg uptake by plants in soils amended with FGDG was also investigated. Flue gas desulfurization-derived gypsum from three sources was homogenized into three soils at 4.5, 45, and 170 t ha and applied at 4.9 t ha as a thin layer to simulate tilled and no-till applications, respectively. Twenty-four-hour Hg flux was measured from unamended and FGDG-amended soils on a seasonal time step over 1 yr and after disturbing, watering, and planting. Methylmercury in soil, irrigation drainage, and total Hg in plant tissues were quantified. Results should be interpreted within the confines of the experimental setting and materials used for this study. Total Hg concentrations in soils, homogenized with FGDG, were below that considered representative of soil with background values (<100 ng g). Emissions from amended soils were higher initially relative to unamended soils but became similar over time. Significantly less Hg (2%) was lost to the air from FGDG-amended soils (90 g FGDG added for lowest application) than that released from the FGDG alone (30-70%) (50 g FGDG) over 1 yr. Total Hg and MeHg in irrigation drainage and total Hg concentrations measured in plants were similar for amended and unamended soils. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

  17. Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial

    Directory of Open Access Journals (Sweden)

    Isbel Nicole M

    2009-07-01

    Full Text Available Abstract Background The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin® ES administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA-treated peritoneal dialysis (PD patients than conventional oral iron supplementation (Ferrogradumet®. Methods Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp®, Amgen for ≥ 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control or HIP (1 tablet twice daily for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA. Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration, and occurrence of adverse events (especially gastrointestinal adverse events. Discussion This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. Trial Registration Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

  18. CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors

    Directory of Open Access Journals (Sweden)

    Markus Chmielewski

    2017-12-01

    Full Text Available Adoptive therapy with chimeric antigen receptor (CAR-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206− M1 macrophages and NKG2D+ NK cells increased in number, whereas Tregs, suppressive CD103+ DCs, and M2 macrophages decreased, suggesting that “iIL18 TRUCKs” can be used to sensitize large solid tumor lesions for successful immune destruction.

  19. A Single-Dose, Two-Way Crossover, Open-Label Bioequivalence Study of an Amphetamine Extended-Release Oral Suspension in Healthy Adults.

    Science.gov (United States)

    Sikes, Carolyn; Stark, Jeffrey G; McMahen, Russ; Engelking, Dorothy

    2017-11-01

    The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d- and l-amphetamine concentrations, and pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUCinf were calculated to determine bioequivalence. Safety was monitored throughout the study. The 90% confidence intervals (CIs) for the log-transformed Cmax, AUC0-5, AUC5-last, and AUCinf fell within the accepted 80% to 125% range for establishing bioequivalence for d- and l-amphetamine. The most common adverse events were nausea and decreased appetite. AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.

  20. Naturalistic exploration of the effect of osmotic release oral system-methylphenidate on remission rate and functional improvement in Taiwanese children with attention-deficit-hyperactivity disorder.

    Science.gov (United States)

    Tzang, Ruu-Fen; Wang, Ya-Ching; Yeh, Chin-Bin; Hsu, Cheng-Dien; Liang, Hsin-Yi; Yang, Pin-Chen; Liu, Hung-Jen; Huang, Yu-Shu; Cheng, Helen; Hsu, Ya-Chen; Liu, Shen-Ing; Pan, Chia-Ho; Huang, Ya-Fen; Huang, Chi-Fen; Wu, Yu-Yu; Huang, Yu-Hsin; Liu, Hui-Ching; Chang, Hsueh-Ling

    2012-02-01

    To determine the differences in the remission rate, recovery rate, functional improvement, and treatment adherence related to treatment with short-acting immediate-release methylphenidate (IR-MPH) and long-acting osmotic-release oral system-methylphenidate (OROS-MPH) in a naturalistic setting among Taiwanese children with attention-deficit-hyperactivity disorder (ADHD). A total of 757 children with ADHD, aged 6-18 years, was evaluated using the following in order determine functional improvement and treatment adherence: the Chinese version of the Swanson, Nolan, and Pelham, version IV scale (SNAP-IV-C), Clinical Global Impression-ADHD-Severity (CGI-S) to measure remission and recovery rates, the Chinese version of the Social Adjustment Inventory for Children and Adolescents (CSAICA), and caregiver's satisfaction rate, treatment adherence, and frequency of adverse effects. According to the SNAP-IV-C scores, the remission rate was 30.72%, and the recovery rate was 16.38%. Compared to short-acting IR-MPH, OROS-MPH was associated with greater functional improvement and treatment adherence among children with ADHD. OROS-MPH treatment at the adequate dosage can achieve higher remission and recovery rates, produce greater functional improvement, and result in better treatment adherence than IR-MPH treatment. © 2012 The Authors. Psychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology.

  1. Physical and Biological Release of Poly- and Perfluoroalkyl Substances (PFASs) from Municipal Solid Waste in Anaerobic Model Landfill Reactors.

    Science.gov (United States)

    Allred, B McKay; Lang, Johnsie R; Barlaz, Morton A; Field, Jennifer A

    2015-07-07

    A wide variety of consumer products that are treated with poly- and perfluoroalkyl substances (PFASs) and related formulations are disposed of in landfills. Landfill leachate has significant concentrations of PFASs and acts as secondary point sources to surface water. This study models how PFASs enter leachate using four laboratory-scale anaerobic bioreactors filled with municipal solid waste (MSW) and operated over 273 days. Duplicate reactors were monitored under live and abiotic conditions to evaluate influences attributable to biological activity. The biologically active reactors simulated the methanogenic conditions that develop in all landfills, producing ∼140 mL CH4/dry g refuse. The average total PFAS leaching measured in live reactors (16.7 nmol/kg dry refuse) was greater than the average for abiotic reactors (2.83 nmol/kg dry refuse), indicating biological processes were primarily responsible for leaching. The low-level leaching in the abiotic reactors was primarily due to PFCAs ≤C8 (2.48 nmol/kg dry refuse). Concentrations of known biodegradation intermediates, including methylperfluorobutane sulfonamide acetic acid and the n:2 and n:3 fluorotelomer carboxylates, increased steadily after the onset of methanogenesis, with the 5:3 fluorotelomer carboxylate becoming the single most concentrated PFAS observed in live reactors (9.53 nmol/kg dry refuse).

  2. Oral processing characteristics of solid meal components and relationship with foord composition, sensory attributes and expected satiation.

    NARCIS (Netherlands)

    Forde, R.M.; Kuijk, van N.; Thaler, T.; Graaf, de C.; Martin, N.A.

    2013-01-01

    Background: The modern food supply is often dominated by a large variety of energy dense, softly textured foods that can be eaten quickly. Previous studies suggest that particular oral processing characteristics such as large bite size and lack of chewing activity contribute to the low satiating

  3. Early pregnancy loss in women stimulated with gonadotropin-releasing hormone antagonist protocols according to oral contraceptive pill pretreatment.

    Science.gov (United States)

    Bellver, José; Albert, Carmen; Labarta, Elena; Pellicer, Antonio

    2007-05-01

    To evaluate and compare the risk of early pregnancy loss in patients stimulated with GnRH antagonist protocols according to oral contraceptive pill (OCP) pretreatment. Retrospective case-control study. Instituto Valenciano de Infertilidad. University of Valencia. Spain. One thousand five hundred thirty-nine patients, aged <36, stimulated with GnRH antagonists for IVF between January 1, 2000 and November 1, 2005. Reproductive outcome was compared based on the application (or not) of OCP pretreatment: 944 women were included in the OCP group and 595 in the non-OCP group. The Student's t test was used for statistics. Pregnancy, biochemical pregnancy, ectopic pregnancy, early clinical pregnancy loss, early pregnancy loss, and ongoing pregnancy rates. No significant differences were observed in any of the outcome parameters. Early pregnancy loss rates were similar: 23% in the OCP pretreatment group versus 19.2% in the non-OCP pretreatment group. However, longer periods of ovarian stimulation and higher doses of gonadotropins needed to be employed in the OCP group. There is not sufficient evidence to confirm OCP pretreatment as a risk factor for miscarriage in patients stimulated with GnRH antagonist protocols.

  4. In vitro dissolution profile study of mucolytic drug ambroxol hydrochloride from solid oral dosage form by UHPLC-MS/MS

    OpenAIRE

    Vujović Maja M.; Jokanović Milan; Nikolić Goran M.

    2017-01-01

    In this paper a simplified dissolution test was performed for the release of ambroxol from tablets according to the European Pharmacopoeia. In vitro, three different dissolution media; 0.1 M HCl pH 1.2, acetate buffer (ABS) pH 4.5 and phosphate buffer (PBS) pH 6.8 were used for the simulation of the gastrointestinal conditions at temperature of 37.0±0.5°C. The drug release was evaluated by a new ultra - high performance liquid chromatography (UHPLC) - tande...

  5. From solid to liquid: assessing the release of organic matter into soil solution in response to land-use conversion in Brazilian Oxisols

    Science.gov (United States)

    James, Jason; Gross, Cole; Dwivedi, Pranjal; Bernardi, Rodolpho; Guerrini, Irae; Harrison, Rob; Butman, David

    2017-04-01

    horizons may be less likely to be intercepted, and thus preferentially leached to groundwater. Native Cerrado forests had substantially more roots compared to Eucalyptus, and also released substantially larger quantities of DOM from their O horizons. Processes operating at the interface between solid and liquid, terrestrial and aquatic are a key unknown in the global carbon cycle. This research permits a unique snapshot into the relationship between DOM and SOM and the response of these pools to land-use change in Brazil.

  6. Simultaneous Screening and Quantification of 29 Drugs of Abuse in Oral Fluid by Solid-Phase Extraction and Ultraperformance LC-MS/MS

    DEFF Research Database (Denmark)

    Linnet, Kristian; Badawi, Nora; Simonsen, Kirsten W.

    2009-01-01

    Background: The European DRUID (Driving under the Influence of Drugs, Alcohol And Medicines) project calls for analysis of oral fluid (OF) samples, collected randomly and anonymously at the roadside from drivers in Denmark throughout 2008–2009. To analyze these samples we developed an ultra...... performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for detection of 29 drugs and illicit compounds in OF. The drugs detected were opioids, amphetamines, cocaine, benzodiazepines, and {Delta}-9-tetrahydrocannabinol. Method: Solid-phase extraction was performed with a Gilson ASPEC XL......4 system equipped with Bond Elut Certify sample cartridges. OF samples (200 mg) diluted with 5 mL of ammonium acetate/methanol (vol/vol 90:10) buffer were applied to the columns and eluted with 3 mL of acetonitrile with aqueous ammonium hydroxide. Target drugs were quantified by use of a Waters...

  7. Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain.

    Science.gov (United States)

    Imanaka, Keiichiro; Tominaga, Yushin; Etropolski, Mila; van Hove, Ilse; Ohsaka, Masaki; Wanibe, Mikio; Hirose, Keiichiro; Matsumura, Taka

    2013-10-01

    This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25-200 mg bid) or oral oxycodone HCl CR (5-40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: NCT01165281. This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was -0.06 (95% confidence interval [CI], -0.506 to 0.383). The upper limit of the 95% CI was tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). Tapentadol ER (25-200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5-40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR.

  8. Effect of filtration on morphine and particle content of injections prepared from slow-release oral morphine tablets

    Directory of Open Access Journals (Sweden)

    Brandon Susan

    2009-12-01

    Full Text Available Abstract Background Injections of mixtures prepared from crushed tablets contain insoluble particles which can cause embolisms and other complications. Although many particles can be removed by filtration, many injecting drug users do not filter due to availability, cost or performance of filters, and also due to concerns that some of the dose will be lost. Methods Injection solutions were prepared from slow-release morphine tablets (MS Contin® replicating methods used by injecting drug users. Contaminating particles were counted by microscopy and morphine content analysed by liquid chromatography before and after filtration. Results Unfiltered tablet extracts contained tens of millions of particles with a range in sizes from 400 μm. Cigarette filters removed most of the larger particles (> 50 μm but the smaller particles remained. Commercial syringe filters (0.45 and 0.22 μm produced a dramatic reduction in particles but tended to block unless used after a cigarette filter. Morphine was retained by all filters but could be recovered by following the filtration with one or two 1 ml washes. The combined use of a cigarette filter then 0.22 μm filter, with rinses, enabled recovery of 90% of the extracted morphine in a solution which was essentially free of tablet-derived particles. Conclusions Apart from overdose and addiction itself, the harmful consequences of injecting morphine tablets come from the insoluble particles from the tablets and microbial contamination. These harmful components can be substantially reduced by passing the injection through a sterilizing (0.22 μm filter. To prevent the filter from blocking, a preliminary coarse filter (such as a cigarette filter should be used first. The filters retain some of the dose, but this can be recovered by following filtration with one or two rinses with 1 ml water. Although filtration can reduce the non-pharmacological harmful consequences of injecting tablets, this remains an unsafe

  9. A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014.

    Science.gov (United States)

    Messersmith, Wells A; Shapiro, Geoffrey I; Cleary, James M; Jimeno, Antonio; Dasari, Arvind; Huang, Bo; Shaik, M Naveed; Cesari, Rossano; Zheng, Xianxian; Reynolds, Jennifer M; English, Patricia A; McLachlan, Karen R; Kern, Kenneth A; LoRusso, Patricia M

    2015-01-01

    To estimate the maximum tolerated dose (MTD) for continuous oral administration of the γ-secretase inhibitor PF-03084014, determine the recommended phase II dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. This open-label, phase I study consisted of a dose-finding portion based on a 3+3 design, followed by an expansion cohort. PF-03084014 was administered orally, twice daily (BID) for 21 continuous days. Tested doses ranged from 20 to 330 mg BID. In the expansion cohort, patients were to receive the estimated MTD or a lower dose of PF-03084014. A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related adverse events were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response, and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent downmodulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation. ©2014 American Association for Cancer Research.

  10. Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms.

    Science.gov (United States)

    Katz, P O; Koch, F K; Ballard, E D; Bagin, R G; Gautille, T C; Checani, G C; Hogan, D L; Pratha, V S V

    2007-01-15

    Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner. To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH. Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons). Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.

  11. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.

    Science.gov (United States)

    Sandborn, William J; Regula, Jaroslaw; Feagan, Brian G; Belousova, Elena; Jojic, Njegica; Lukas, Milan; Yacyshyn, Bruce; Krzeski, Piotr; Yeh, Chyon-Hwa; Messer, Christi A; Hanauer, Stephen B

    2009-12-01

    It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

  12. Remission in children and adolescents diagnosed with attention-deficit/hyperactivity disorder via an effective and tolerable titration scheme for osmotic release oral system methylphenidate.

    Science.gov (United States)

    Chou, Wen-Jiun; Chen, Shin-Jaw; Chen, Ying-Sheue; Liang, Hsin-Yi; Lin, Chih-Chien; Tang, Ching-Shu; Huang, Yu-Shu; Yeh, Chin-Bin; Chou, Miao-Chun; Lin, Dai-Yueh; Hou, Po-Hsun; Wu, Yu-Yu; Liu, Hung-Jen; Huang, Ya-Fen; Hwang, Kai-Ling; Chan, Chin-Hong; Pan, Chia-Ho; Chang, Hsueh-Ling; Huang, Chi-Fen; Hsu, Ju-Wei

    2012-06-01

    The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks. We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV [SNAP-IV]), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed. Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score ADHD, and an appropriate dosage of medication according to the patient's weight. The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme.

  13. Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial.

    Science.gov (United States)

    Åsberg, Anders; Humar, Atul; Rollag, Halvor; Jardine, Alan G; Kumar, Deepali; Aukrust, Pål; Ueland, Thor; Bignamini, Angelo A; Hartmann, Anders

    2016-05-01

    The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  14. Oral Delivery of Bovine Lactoferrin Using Pectin- and Chitosan-Modified Liposomes and Solid Lipid Particles: Improvement of Stability of Lactoferrin.

    Science.gov (United States)

    Yao, Xudong; Bunt, Craig; Cornish, Jillian; Quek, Siew-Young; Wen, Jingyuan

    2015-10-01

    A critical problem associated with delivery of bovine lactoferrin (bLf) by the oral route is low bioavailability, which is derived from the enzymatic degradation in the gastrointestinal tract and poor permeation across the intestinal epitheliums. Particulate carrier systems have been identified to protect bLf against proteolysis via encapsulation. This study aimed to evaluate the physico-chemical stability of bLf-loaded liposomes and solid lipid particles (SLPs) modified by pectin and chitosan when exposed to various stress conditions. Transmission electron microscopy results showed liposomes and SLPs had a classic shell-core structure with polymer layers surrounded on surface, but the structure appeared to be partially broken after digestion in simulated intestinal fluid (SIF). Although HPLC and sodium dodecyl sulphate-polyacrylamide gel electrophoresis methods qualitatively and quantitatively described either liposomes or SLPs could retain intact bLf against proteolysis in SIF to some extent, all liposome formulations showed rapid rate of lipolysis mediated by pancreatic enzymes. On the other hand, all SLP formulations showed higher heat resistance and greater electrolyte tolerance compared to liposome formulations. After 180 days storage time, liposome-loaded bLf was completely degraded, whereas almost 30% of intact bLf still remained in SLP formulations. Overall, SLPs are considered as primary choice for oral bLf delivery. © 2015 John Wiley & Sons A/S.

  15. In vitro dissolution profile study of mucolytic drug ambroxol hydrochloride from solid oral dosage form by UHPLC-MS/MS

    Directory of Open Access Journals (Sweden)

    Vujović Maja M.

    2017-01-01

    Full Text Available In this paper a simplified dissolution test was performed for the release of ambroxol from tablets according to the European Pharmacopoeia. In vitro, three different dissolution media; 0.1 M HCl pH 1.2, acetate buffer (ABS pH 4.5 and phosphate buffer (PBS pH 6.8 were used for the simulation of the gastrointestinal conditions at temperature of 37.0±0.5°C. The drug release was evaluated by a new ultra - high performance liquid chromatography (UHPLC - tandem mass spectrometry (MS/MS method. The method was validated to meet requirements as per ICH guidelines which include linearity, specificity, precision, accuracy and robustness. The corresponding dissolution profiles showed more than 80% drug release within 30 minutes without significant differences. Further, the developed and validated UHPLC-MS/MS method could find a useful application in the process of production, quality control and bioavailability/bioequivalence studies of new pharmaceutical formulations of drugs in order to achieve a safe therapeutic efficacy. [Projekat Ministarstva nauke Republike Srbije, br. 175045

  16. Effect of osmotic-release oral system methylphenidate on learning skills in adolescents with attention-deficit/hyperactivity disorder: an open-label study.

    Science.gov (United States)

    Na, Kyoung-Sae; Lee, Soyoung Irene; Hong, Sungdo David; Kim, Ji-Hoon; Shim, Se-Hoon; Choi, Jeewook; Yang, Jaewon; Lee, Moon-Soo; Joung, Yoo-Sook; Kim, Eui-Jung; Park, Joon-Ho

    2013-07-01

    We evaluated the effect of osmotic-release oral system (OROS) methylphenidate on learning skills in adolescents with attention-deficit/hyperactivity disorder (ADHD). In an open-label study, 121 adolescents with ADHD were administered flexible doses of OROS methylphenidate for 12 weeks. The efficacy of methylphenidate on ADHD symptoms was evaluated by ADHD Rating Scale (ARS) and Clinical Global Impression Scale (CGI). Learning Skills Test (LST) was used to measure the learning skills of the participants at the baseline and the endpoint. Continuous performance test, visuospatial and verbal working memory, verbal fluency, and inhibition were evaluated before and after the 12 weeks of treatment. The mean total and subscores of LST were significantly increased after the 12-week treatment with OROS methylphenidate. Executive functions were also improved during the trial, with the exception of inhibition measured by the Stroop Test. To the best of our knowledge, this is the first study to examine the influence of OROS methylphenidate on learning skill. As a result, OROS methylphenidate was effective in enhancing learning skills in adolescents with ADHD.

  17. Delayed-release oral suspension of omeprazole for the treatment of erosive esophagitis and gastroesophageal reflux disease in pediatric patients: a review

    Directory of Open Access Journals (Sweden)

    Alice Monzani

    2010-03-01

    Full Text Available Alice Monzani, Giuseppina Oderda1Department of Pediatrics, Università del Piemonte Orientale, Novara, ItalyAbstract: Omeprazole is a proton-pump inhibitor indicated for gastroesophageal reflux disease and erosive esophagitis treatment in children. The aim of this review was to evaluate the efficacy of delayed-release oral suspension of omeprazole in childhood esophagitis, in terms of symptom relief, reduction in reflux index and/or intragastric acidity, and endoscopic and/or histological healing. We systematically searched PubMed, Cochrane and EMBASE (1990 to 2009 and identified 59 potentially relevant articles, but only 12 articles were suitable to be included in our analysis. All the studies evaluated symptom relief and reported a median relief rate of 80.4% (range 35%–100%. Five studies reported a significant reduction of the esophageal reflux index within normal limits (<7% in all children, and 4 studies a significant reduction of intra-gastric acidity. The endoscopic healing rate, reported by 9 studies, was 84% after 8-week treatment and 95% after 12-week treatment, the latter being significantly higher than the histological healing rate (49%. In conclusion, omeprazole given at a dose ranging from 0.3 to 3.5 mg/kg once daily (median 1 mg/kg once daily for at least 12 weeks is highly effective in childhood esophagitis.Keywords: proton pump inhibitors, children, ranitidine, H2-blockers

  18. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia.

    Science.gov (United States)

    Sayed, Gamal H; Zakherah, Mahmoud S; El-Nashar, Sherif A; Shaaban, Mamdouh M

    2011-02-01

    To compare the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) with that of a low-dose combined oral contraceptive (COC) in reducing fibroid-related menorrhagia. In this single-center, open, randomized clinical trial, 58 women with menorrhagia who desired contraception were randomized to receive a LNG-IUS or COC. The outcomes included treatment failure, defined as the need for another treatment; menstrual blood loss (MBL) by the alkaline hematin method and a pictorial assessment chart (PBAC); hemoglobin levels; and "lost days." Treatment failed in 6 women (23.1%) in the LNG-IUS group and 11 (37.9%) in the COC group, for a hazard ratio of 0.46 (95% CI, 0.17-1.17, P=0.101). Using the alkaline hematin test, the reduction of MBL was significantly greater in the LNG-IUS group (90.9% ± 12.8% vs 13.4% ± 11.1%; Pmenorrhagia. Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  19. Sensitive, automatic method for the determination of diazepam and its five metabolites in human oral fluid by online solid-phase extraction and liquid chromatography with tandem mass spectrometry

    DEFF Research Database (Denmark)

    Jiang, Fengli; Rao, Yulan; Wang, Rong

    2016-01-01

    A novel and simple online solid-phase extraction liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of diazepam and its five metabolites including nordazepam, oxazepam, temazepam, oxazepam glucuronide, and temazepam glucuronide...... consuming a single oral dose of 10 mg diazepam were analyzed to demonstrate the applicability of this method....

  20. Reduction of relative centrifugal forces increases growth factor release within solid platelet-rich-fibrin (PRF)-based matrices: a proof of concept of LSCC (low speed centrifugation concept).

    Science.gov (United States)

    El Bagdadi, K; Kubesch, A; Yu, X; Al-Maawi, S; Orlowska, A; Dias, A; Booms, P; Dohle, E; Sader, R; Kirkpatrick, C J; Choukroun, J; Ghanaati, S

    2017-03-21

    Purpose The present study evaluated the platelet distribution pattern and growth factor release (VEGF, TGF-β1 and EGF) within three PRF (platelet-rich-fibrin) matrices (PRF, A-PRF and A-PRF+) that were prepared using different relative centrifugation forces (RCF) and centrifugation times. Materials and methods immunohistochemistry was conducted to assess the platelet distribution pattern within three PRF matrices. The growth factor release was measured over 10 days using ELISA. Results The VEGF protein content showed the highest release on day 7; A-PRF+ showed a significantly higher rate than A-PRF and PRF. The accumulated release on day 10 was significantly higher in A-PRF+ compared with A-PRF and PRF. TGF-β1 release in A-PRF and A-PRF+ showed significantly higher values on days 7 and 10 compared with PRF. EGF release revealed a maximum at 24 h in all groups. Toward the end of the study, A-PRF+ demonstrated significantly higher EGF release than PRF. The accumulated growth factor releases of TGF-β1 and EGF on day 10 were significantly higher in A-PRF+ and A-PRF than in PRF. Moreover, platelets were located homogenously throughout the matrix in the A-PRF and A-PRF+ groups, whereas platelets in PRF were primarily observed within the lower portion. ​Discussion the present results show an increase growthfactor release by decreased RCF. However, further studies must be conducted to examine the extent to which enhancing the amount and the rate of released growth factors influence wound healing and biomaterial-based tissue regeneration. ​Conclusion These outcomes accentuate the fact that with a reduction of RCF according to the previously LSCC (described low speed centrifugation concept), growth factor release can be increased in leukocytes and platelets within the solid PRF matrices.

  1. 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

  2. Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function.

    Directory of Open Access Journals (Sweden)

    Silke A Herzberg-Schäfer

    Full Text Available BACKGROUND: To date, fasting state- and different oral glucose tolerance test (OGTT-derived measures are used to estimate insulin release with reasonable effort in large human cohorts required, e.g., for genetic studies. Here, we evaluated twelve common (or recently introduced fasting state-/OGTT-derived indices for their suitability to detect genetically determined β-cell dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1364 White European individuals at increased risk for type 2 diabetes was characterized by OGTT with glucose, insulin, and C-peptide measurements and genotyped for single nucleotide polymorphisms (SNPs known to affect glucose- and incretin-stimulated insulin secretion. One fasting state- and eleven OGTT-derived indices were calculated and statistically evaluated. After adjustment for confounding variables, all tested SNPs were significantly associated with at least two insulin secretion measures (p≤0.05. The indices were ranked according to their associations' statistical power, and the ranks an index obtained for its associations with all the tested SNPs (or a subset were summed up resulting in a final ranking. This approach revealed area under the curve (AUC(Insulin(0-30/AUC(Glucose(0-30 as the best-ranked index to detect SNP-dependent differences in insulin release. Moreover, AUC(Insulin(0-30/AUC(Glucose(0-30, corrected insulin response (CIR, AUC(C-Peptide(0-30/AUC(Glucose(0-30, AUC(C-Peptide(0-120/AUC(Glucose(0-120, two different formulas for the incremental insulin response from 0-30 min, i.e., the insulinogenic indices (IGI(2 and IGI(1, and insulin 30 min were significantly higher-ranked than homeostasis model assessment of β-cell function (HOMA-B; p<0.05. AUC(C-Peptide(0-120/AUC(Glucose(0-120 was best-ranked for the detection of SNPs involved in incretin-stimulated insulin secretion. In all analyses, HOMA-β displayed the highest rank sums and, thus, scored last. CONCLUSIONS/SIGNIFICANCE: With AUC(Insulin(0

  3. 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 (r2 > 0

  4. Municipal solid waste compost as a novel sorbent for antimony(V): adsorption and release trials at acidic pH.

    Science.gov (United States)

    Diquattro, Stefania; Garau, Giovanni; Lauro, Gian Paolo; Silvetti, Margherita; Deiana, Salvatore; Castaldi, Paola

    2017-12-08

    The ability of two municipal solid waste composts (MSW-Cs) to sorb antimony(V) in acidic conditions (pH 4.5) was investigated. Sorption isotherms and kinetics showed that both MSW-Cs could sorb antimony(V), even if in different amounts (~ 0.18 and 0.24 mmol g-1 of Sb(V) by MSW-C1 and MSW-C2, respectively). These differences were ascribed to the chemical composition of composts, as well as to the total acidity of their humic substances. The Sb(V) sorption by both MSW-Cs followed a pseudo-second-order kinetic model, while the sorption isotherms data fitted the Freundlich model better than the Langmuir one. The humic acids extracted from composts contributed to 4.26 and 8.24% of Sb(V) sorption by MSW-C1 and MSW-C2 respectively. SEM-EDX spectra of the MSW-C+Sb(V) systems showed a certain association of Ca(II) with Sb(V), while sequential extraction procedures indicated that more than 80% of the Sb(V) sorbed was strongly retained by MSW-Cs. On the other hand, treatment with oxalic acid at pH 4.5 favored the release of more than 98 and 65% of the Sb(V) sorbed by MSW-C1 and MSW-C2 respectively, supporting a possible role of calcium in Sb(V) retention. The results from this study suggest that MSW-Cs could be used as amendments for the in-situ immobilization of Sb(V) in acidic-polluted soils.

  5. Rapid onset of treatment effects on psychosis, depression, and mania in patients with acute exacerbation of schizoaffective disorder following treatment with oral extended-release paliperidone.

    Science.gov (United States)

    Fu, Dong-Jing; Turkoz, Ibrahim; Bossie, Cynthia A; Patel, Hiren; Alphs, Larry

    2016-03-15

    Patients with schizoaffective disorder (SCA) experience complicated interplays of psychotic, depressive, and manic symptoms. Paliperidone extended-release (pali ER) tablets have been shown to be efficacious in these patients, but treatment response has not been studied relative to the onset of effects for these symptom domains. In a pooled analysis of data from two 6-week, randomized, placebo-controlled studies, the onset of treatment effects with oral pali ER was evaluated by symptom domain (psychosis, depression, mania) in patients with an acute SCA exacerbation. Subjects were categorized as having prominent psychotic (Positive and Negative Syndrome Scale score >70), depressive (Hamilton Rating Scale for Depression-21 score ≥16), or manic (Young Mania Rating Scale score ≥16) symptoms at baseline. Of the 614 patients in these analyses, 597 (97.2%), 411 (66.9%), and 488 (79.5%) had prominent psychotic, depressive, and manic symptoms at baseline, respectively. Pali ER treatment was associated with rapid and significant improvement of all three symptom domains versus placebo within 1 week of initiation, regardless of whether treatment was given as monotherapy or in combination with mood stabilizers and/or antidepressants. Adverse events were similar to those reported in the original published studies. This post hoc analysis of two phase 3 trials requires confirmation in prospective studies. This pooled analysis suggests that treatment with pali ER is associated with rapid control of psychotic, depressive, and manic symptoms in patients with SCA. Its findings support the benefit of pali ER as a primary treatment for the management of SCA. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder☆

    Science.gov (United States)

    Mizuno, Kei; Yoneda, Tetsuya; Komi, Masanori; Hirai, Toshinori; Watanabe, Yasuyoshi; Tomoda, Akemi

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD. PMID:24179790

  7. Comparison of the efficacy and adverse effects of sustained-release buprenorphine hydrochloride following subcutaneous administration and buprenorphine hydrochloride following oral transmucosal administration in cats undergoing ovariohysterectomy.

    Science.gov (United States)

    Catbagan, Davina L; Quimby, Jessica M; Mama, Khursheed R; Rychel, Jessica K; Mich, Patrice M

    2011-04-01

    To compare the efficacy and adverse effects of sustained-release (SR) buprenorphine following SC administration and buprenorphine following oral transmucosal (OTM) administration in cats undergoing ovariohysterectomy. Animals-21 young healthy female cats. As part of anesthetic premedication (0 hours), 10 cats received buprenorphine (0.02 mg/kg) via OTM administration with additional doses at 12, 24, 36, 48, and 60 hours and 11 cats received an equivalent total dose as a single SC injection of SR buprenorphine (0.12 mg/kg). The SR product contained buprenorphine hydrochloride in a proprietary SR matrix. All other anesthetic drugs and a single postoperative dose of meloxicam were administered similarly to all cats. Behavioral and physiologic variables were recorded, and signs of pain were assessed by use of 2 pain assessment scales and von Frey filament testing in each cat prior to premedication administration (baseline), during recovery from anesthesia (RFA), and at 12, 24, 36, 48, 60, and 72 hours. Heart rate increased and temperature (determined via microchip transponder thermometry) decreased from baseline values during RFA in both groups. Compared with baseline values, pain scores were increased during RFA and at the 12- and 24-hour time points in both groups; von Frey scores were higher during RFA. Behavioral and physiologic variables did not differ significantly between groups at any time point. In cats undergoing ovariohysterectomy, SC administration of a preoperative dose of SR buprenorphine appeared to have comparable efficacy and adverse effect profile as that of twice-daily OTM administration of buprenorphine before and after surgery.

  8. Efficacy of osmotic-release oral system (OROS) methylphenidate for mothers with attention-deficit/hyperactivity disorder (ADHD): preliminary report of effects on ADHD symptoms and parenting.

    Science.gov (United States)

    Chronis-Tuscano, Andrea; Seymour, Karen E; Stein, Mark A; Jones, Heather A; Jiles, Cynthia D; Rooney, Mary E; Conlon, Charles J; Efron, Lisa A; Wagner, Stephanie A; Pian, Jessica; Robb, Adelaide S

    2008-12-01

    A preliminary study to examine the efficacy of osmotic-release oral system (OROS) methylphenidate for attention-deficit/hyperactivity disorder (ADHD) symptoms and parenting behaviors in mothers with ADHD who had children with ADHD. Participants included 23 mother-child dyads in which both were diagnosed with DSM-IV ADHD. Mothers underwent a 5-week, double-blind titration (placebo, 36 mg/day, 54 mg/day, 72 mg/day, 90 mg/day) to an optimal dose of OROS methylphenidate, followed by random assignment to 2 weeks of placebo or their maximally effective dose. Primary outcome measures included maternal ADHD symptoms (Conners' Adult ADHD Rating Scale) and parenting (Alabama Parenting Questionnaire). Secondary outcomes included side effects ratings. Data were collected from December 2004 until August 2006. During Phase 1, mothers reported significant decreases in inattention (p effects on inattention (d = 0.46) and hyperactivity/impulsivity (d = 0.38) were found for those randomly assigned to medication versus placebo. In addition, medium to large medication effects were found on maternal involvement (d = 0.52), poor monitoring/supervision (d = 0.70), and inconsistent discipline (d = 0.71), with small effects on corporal punishment (d = 0.42). During both phases, few adverse effects were noted. OROS methylphenidate was well tolerated and was associated with significant improvement in maternal ADHD symptoms and parenting. Variable effects on parenting suggest that behavioral interventions may be necessary to address impairments in parenting among adults with ADHD. clinicaltrials.gov Identifier: NCT00318981. Copyright 2008 Physicians Postgraduate Press, Inc.

  9. Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Mizuno, Kei; Yoneda, Tetsuya; Komi, Masanori; Hirai, Toshinori; Watanabe, Yasuyoshi; Tomoda, Akemi

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.

  10. Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

    Science.gov (United States)

    Dubbelman, Anne-Charlotte; Upthagrove, Alana; Beijnen, Jos H; Marchetti, Serena; Tan, Eugene; Krone, Kimberly; Anand, Suraj; Schellens, Jan H M

    2012-11-01

    This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors. Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ≤10 days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400 mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2. The majority of radioactivity was recovered in feces (mean 61 %; range 52-69 %), as compared with urine (mean 16 %; range 13-21 %). Only 6-19 % of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue. Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.

  11. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.

    Science.gov (United States)

    Jones, Robin L; Kim, Edward S; Nava-Parada, Pilar; Alam, Salma; Johnson, Faye M; Stephens, Andrew W; Simantov, Ronit; Poondru, Srinivasu; Gedrich, Rich; Lippman, Scott M; Kaye, Stan B; Carden, Craig P

    2015-02-15

    We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study. Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. ©2014 American Association for Cancer Research.

  12. Novel insights into excipient effects on the biopharmaceutics of APIs from different BCS classes: Lactose in solid oral dosage forms.

    Science.gov (United States)

    Kubbinga, Marlies; Moghani, Laura; Langguth, Peter

    2014-09-30

    Excipients encompass a wide range of properties that are of importance for the resulting drug product. Regulatory guidelines on biowaivers for immediate release formulations require an in depth understanding of the biopharmaceutic effects of excipients in order to establish bioequivalence between two different products carrying the same API based on dissolution tests alone. This paper describes a new approach in evaluating biopharmaceutic excipient effects. Actually used quantities of a model excipient, lactose, formulated in combination with APIs from different BCS classes were evaluated. The results suggest that companies use different (relative) amounts depending on the characteristics of the API. The probability of bioinequivalence due to a difference in lactose content between test and reference products was classified as low for BCS class I APIs and medium for BCS class II and III APIs, whereas a high probability was assigned to the combination of lactose and BCS class IV APIs. If repeated for other excipients, this retrospective, top-down approach may lead to a new database and more widespread applications of the biowaiver approach. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial.

    Science.gov (United States)

    Hanauer, S B; Sandborn, W J; Dallaire, C; Archambault, A; Yacyshyn, B; Yeh, C; Smith-Hall, N

    2007-12-01

    Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.

  14. Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared with 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial

    Science.gov (United States)

    Hanauer, Stephen B; Sandborn, William J; Dallaire, Christian; Archambault, André; Yacyshyn, Bruce; Yeh, Chyon; Smith-Hall, Nancy

    2007-01-01

    BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day. PMID:18080055

  15. Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs.

    Science.gov (United States)

    Hammami, Muhammad M; De Padua, Sophia J S; Hussein, Rajaa; Al Gaai, Eman; Khodr, Nesrine A; Al-Swayeh, Reem; Alvi, Syed N; Binhashim, Nada

    2017-12-08

    The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale. We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%-125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined. Mean (SD) age and body-mass-index of 700 healthy volunteers (28-80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic

  16. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial.

    Science.gov (United States)

    Hanauer, Stephen B; Sandborn, William J; Kornbluth, Asher; Katz, Seymour; Safdi, Michael; Woogen, Scott; Regalli, Gino; Yeh, Chyon; Smith-Hall, Nancy; Ajayi, Funmilay

    2005-11-01

    Preliminary data have shown that delayed release oral mesalamine (Asacol) dosed at 4.8 g/day provided additional efficacy benefit compared to 1.6 g/day in patients with mildly to moderately active ulcerative colitis. Additionally, Asacol dosed at 2.4 g/day has been proved to be more effective than 1.6 g/day. Whether 4.8 g/day of mesalamine (dosed with an investigational 800 mg tablet) is more effective than Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients with moderately active ulcerative colitis is unknown. A randomized, double-blind, controlled trial (ASCEND II) was conducted to evaluate the efficacy of 4.8 g/day of mesalamine in adults with active ulcerative colitis. Three hundred eighty-six patients with mild to moderate ulcerative colitis were randomized for treatment with mesalamine 2.4 g/day (400 mg tablet) or 4.8 g/day (800 mg tablet) for 6 wk. The primary efficacy population was 268 patients with moderately active ulcerative colitis treated with 2.4 g/day (n = 139) or 4.8 g/day (n = 129). The primary endpoint was the proportion of patients in each treatment group that achieved overall improvement ("treatment success," defined as either complete remission or a clinical response to therapy) from baseline at week 6. Seventy-two percent of patients receiving 4.8 g/day of mesalamine for moderate ulcerative colitis (89/124 patients) achieved treatment success at week 6, compared with 59% of those who received 2.4 g/day (77/130 patients) (p= 0.036). Both regimens were well tolerated. Adverse events and clinically significant changes in laboratory results were similar in both treatment groups. Patients with moderately active ulcerative colitis treated with 4.8 g/day of mesalamine (800 mg tablet) are significantly more likely to achieve overall improvement at 6 wk compared to patients treated with 2.4 g/day.

  17. Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors.

    Science.gov (United States)

    Siu, Lillian L; Pili, Roberto; Duran, Ignacio; Messersmith, Wells A; Chen, Eric X; Sullivan, Rana; MacLean, Martha; King, Serina; Brown, Shirley; Reid, Gregory K; Li, Zuomei; Kalita, Ann M; Laille, Eric J; Besterman, Jeffrey M; Martell, Robert E; Carducci, Michael A

    2008-04-20

    MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies. A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs. Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103. At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.

  18. First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

    Science.gov (United States)

    Brunetto, André T; Ang, Joo Ern; Lal, Rohit; Olmos, David; Molife, L Rhoda; Kristeleit, Rebecca; Parker, Ann; Casamayor, Isabel; Olaleye, Muyibat; Mais, Anna; Hauns, Bernhard; Strobel, Vera; Hentsch, Bernd; de Bono, Johann S

    2013-10-01

    This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.

  19. An innovative solid oral nutritional supplement to fight weight loss and anorexia: open, randomised controlled trial of efficacy in institutionalised, malnourished older adults.

    Science.gov (United States)

    Pouyssegur, Valerie; Brocker, Patrice; Schneider, Stéphane M; Philip, Jean Luc; Barat, Philippe; Reichert, Ewa; Breugnon, Frederic; Brunet, Didier; Civalleri, Bruno; Solere, Jean Paul; Bensussan, Line; Lupi-Pegurier, Laurence

    2015-03-01

    To evaluate the impact of a solid nutritional supplement on the weight gain of institutionalised older adults>70 years with protein-energy malnutrition. The innovation of these high-protein and high-energy cookies was the texture adapted to edentulous patients (Protibis®, Solidages, France). An open, multicentre, randomised controlled trial. Seven nursing homes. One hundred and seventy-five malnourished older adults, aged 86±8 years. All participants received the standard institutional diet. In addition, Intervention group participants received eight cookies daily (11.5 g protein; 244 kcal) for 6 weeks (w0-w6). Five visits (w-4, w0, w6, w10 and w18). Percentage of weight gain from w0 to w6 (body mass in kg). Appetite, rated using a numerical scale (0: no appetite to 10: extremely good appetite); current episodes of pressure ulcers and diarrhea. Average weight increased in Intervention group (n=88) compared with Control group (n=87) without cookies supplementation (+1.6 versus -0.7%, P=0.038). Weight gain persisted 1 month (+3.0 versus -0.2%, P=0.025) and 3 months after the end of cookies consumption (+3.9 versus -0.9%, P=0.003), with diarrhea reduction (P=0.027). There was a synergistic effect with liquid/creamy dietary supplements. Subgroup analysis confirmed the positive impact of cookies supplementation alone on weight increase (P=0.024), appetite increase (P=0.009) and pressure ulcers reduction (P=0.031). The trial suggested that, to fight against anorexia, the stimulation of touch (finger food; chewing, even on edentulous gums) and hearing (intra-oral sounds) could be valuable alternatives to sight, smell and taste alterations. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Analysis of HHV-6 mutations in solid organ transplant recipients at the onset of cytomegalovirus disease and following treatment with intravenous ganciclovir or oral valganciclovir.

    Science.gov (United States)

    Bounaadja, Lotfi; Piret, Jocelyne; Goyette, Nathalie; Boivin, Guy

    2013-09-01

    Human herpesvirus 6 (HHV-6) and human cytomegalovirus (HCMV) are major opportunistic pathogens in solid organ transplant (SOT) recipients. The use of antivirals for the treatment of HCMV disease can result in the development of drug resistance mutations in HCMV and also potentially in HHV-6. The emergence of HHV-6 drug resistance mutations was evaluated in SOT recipients at the onset of HCMV disease and following treatment with ganciclovir (GCV) or valganciclovir (VGCV). Detection of HHV-6 was performed by real-time PCR from whole blood samples serially obtained from SOT recipients treated for HCMV disease with an induction dose of intravenous GCV or oral VGCV for 21 days followed by VGCV maintenance for 28 days in both arms. Baseline and last positive HHV-6 samples were tested for mutations in the genes encoding the protein kinase (U69) and the DNA polymerase (U38). The rate of HHV-6 viraemia among SOT patients with HCMV disease at baseline was 3.2% (5/155). All isolates belonged to the HHV-6B species. Mutations L213I and Y479H were detected at baseline and at later times in the U69 kinase. Mutation L213I was previously reported as polymorphism whereas the role of mutation Y479H in drug resistance is unknown. Mutations D854E and E855Q found in the DNA polymerase were known as natural variants. The incidence of HHV-6 viraemia in SOT recipients with established HCMV disease before initiation of antiviral therapy was low. Treatment with GCV or VGCV did not induce the emergence of HHV-6 drug resistance mutations. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. 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

    Objective: Reliadol® (Nycomed Denmark A/S) is a new modified-release morphine formulation undergoing clinical evaluation. It consists of a mixture of rapid- and modified-release microencapsulated granules of morphine. The study aims were to investigate the single-dose pharmacokinetics of morphine...... adverse events were nausea and headache. Conclusions: Reliadol® is likely to be suitable for once-daily administration in patients with chronic pain because of its unique plasma concentration versus time profile resulting from the mixture of rapid- and modified-release morphine pellets....

  2. Identifying a compound modifying a cellular response, comprises attaching cells having a reporter system onto solid supports, releasing a library member, screening and identifying target cells

    DEFF Research Database (Denmark)

    2011-01-01

    The present invention relates to methods for identifying compounds capable of modulating a cellular response. The methods involve attaching living cells to solid supports comprising a library of test compounds. Test compounds modulating a cellular response, for example via a cell surface molecule...... may be identified by selecting solid supports comprising cells, wherein the cellular response of interest has been modulated. The cellular response may for example be changes in signal transduction pathways modulated by a cell surface molecule....

  3. Sensitive, automatic method for the determination of diazepam and its five metabolites in human oral fluid by online solid-phase extraction and liquid chromatography with tandem mass spectrometry.

    Science.gov (United States)

    Jiang, Fengli; Rao, Yulan; Wang, Rong; Johansen, Sys Stybe; Ni, Chunfang; Liang, Chen; Zheng, Shuiqing; Ye, Haiying; Zhang, Yurong

    2016-05-01

    A novel and simple online solid-phase extraction liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of diazepam and its five metabolites including nordazepam, oxazepam, temazepam, oxazepam glucuronide, and temazepam glucuronide in human oral fluid. Human oral fluid was obtained using the Salivette(®) collection device, and 100 μL of oral fluid samples were loaded onto HySphere Resin GP cartridge for extraction. Analytes were separated on a Waters Xterra C18 column and quantified by liquid chromatography with tandem mass spectrometry using the multiple reaction monitoring mode. The whole procedure was automatic, and the total run time was 21 min. The limit of detection was in the range of 0.05-0.1 ng/mL for all analytes. The linearity ranged from 0.25 to 250 ng/mL for oxazepam, and 0.1 to 100 ng/mL for the other five analytes. Intraday and interday precision for all analytes was 0.6-12.8 and 1.0-9.2%, respectively. Accuracy ranged from 95.6 to 114.7%. Method recoveries were in the range of 65.1-80.8%. This method was fully automated, simple, and sensitive. Authentic oral fluid samples collected from two volunteers after consuming a single oral dose of 10 mg diazepam were analyzed to demonstrate the applicability of this method. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Mechanical properties and drug release of venlafaxine HCl solid mini matrices prepared by hot-melt extrusion and hot or ambient compression.

    Science.gov (United States)

    Avgerinos, Theodoros; Kantiranis, Nikolaos; Panagopoulou, Athanasia; Malamataris, Stavros; Kachrimanis, Kyriakos; Nikolakakis, Ioannis

    2017-10-26

    Objective/significance: To elucidate the role of plasticizers in different mini matrices and correlate mechanical properties with drug release. Cylindrical pellets were prepared by hot-melt extrusion (HME) and mini tablets by hot (HC) and ambient compression (AC). Venlafaxine HCl was the model drug, Eudragit(®) RSPO the matrix former and citric acid or Lutrol(®) F127 the plasticizers. The matrices were characterized for morphology, crystallinity, and mechanical properties. The influence of plasticizer's type and content on the extrusion pressure (Pe) during HME and ejection during tableting was examined and the mechanical properties were correlated with drug release parameters. Resistance to extrusion and tablet ejection force were reduced by Lutrol(®) F127 which also produced softer and weaker pellets with faster release, but harder and stronger HC tablets with slower release. HME pellets showed greater tensile strength (T) and 100 times slower release than tablets. Pe correlated with T and resistance to deformation of the corresponding pellets (r(2) = 0.963 and 0.945). For both HME and HC matrices the decrease of drug release with T followed a single straight line (r(2) = 0.990) and for HME the diffusion coefficient (De) and retreat rate constant (kb) decreased linearly with T (r(2) = 0.934 and 0.972). Lutrol(®) F127 and citric acid are efficient plasticizers and Lutrol(®) F127 is a thermal binder/lubricant in HC compression. The different bonding mechanisms of the matrices were reflected in the mechanical strength and drug release. Relationships established between T and drug release parameters for HME and HC matrices may be useful during formulation work.

  5. Sucrose esters with various hydrophilic-lipophilic properties: novel controlled release agents for oral drug delivery matrix tablets prepared by direct compaction.

    Science.gov (United States)

    Chansanroj, K; Betz, G

    2010-08-01

    Sucrose esters (SE) are esters of sucrose and fatty acids with various hydrophilic-lipophilic properties which have attracted interest from being used in pharmaceutical applications. This study aimed to gain insight into the use of SE as controlled release agents for direct compacted matrix tablets. The study focused on the effect of hydrophilic-lipophilic properties on tableting properties and drug release. Sucrose stearate with hydrophilic-lipophilic balance (HLB) values ranging from 0 to 16 was systematically tested. Tablet formulations contained SE, metoprolol tartrate as a highly soluble model drug and dibasic calcium phosphate dihydrate as a tablet formulation filler in the ratio 1:1:2. The compaction behaviour of matrix tablets was compared with the compacts of individual starting materials as reference. SE incorporation improved the plasticity, compressibility and lubricating property of powder mixtures. The hydrophilic-lipophilic properties of SE affected tableting properties, drug release rate and release mechanism. Increasing hydrophilicity corresponding to the increased monoesters in SE composition increased the relative porosity, elastic recovery and tensile strength of the tablets due to the increased hydrogen bonding between the monoesters. This also facilitated the swelling behaviour of SE, which sustained the drug release rate. A sustained release effect prevailed in tablets containing SE with HLB values of 3-16. The ability to improve the tableting properties as well as sustain the drug release rate of the highly soluble model drug via gelation of SE highlights SE as promising controlled release regulators for direct compacted matrix tablets comprising drugs with various solubilities according to the Biopharmaceutics Classification System. Copyright 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  6. A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors.

    Science.gov (United States)

    Pant, S; Saleh, M; Bendell, J; Infante, J R; Jones, S; Kurkjian, C D; Moore, K M; Kazakin, J; Abbadessa, G; Wang, Y; Chen, Y; Schwartz, B; Camacho, L H

    2014-07-01

    Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination. Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration). Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine. The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. NCT00874042. © The Author 2014. Published by Oxford University Press

  7. Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies

    NARCIS (Netherlands)

    Deenen, Maarten J.; Klümpen, Heinz-Josef; Richel, Dick J.; Sparidans, Rolf W.; Weterman, Mariette J.; Beijnen, Jos H.; Schellens, Jan H. M.; Wilmink, Johanna W.

    2012-01-01

    Background Everolimus is an oral mTOR-inhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients

  8. The Birth Weight Lowering C-Allele of rs900400 Near LEKR1 and CCNL1 Associates with Elevated Insulin Release following an Oral Glucose Challenge

    DEFF Research Database (Denmark)

    Andersson, Ehm A; Harder, Marie N; Pilgaard, Kasper

    2011-01-01

    participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA...... study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample. Methods For 4,744 of 6,784 Inter99...... of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals....

  9. Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate

    OpenAIRE

    Douglas Rossi Jesus; Lorena Neris Barbosa; Thiago Bruno Lima Prando; Leonardo Franco Martins; Francielli Gasparotto; Karla Moraes Rocha Guedes; Douglas Cardoso Dragunski; Emerson Luiz Botelho Lourenço; Paulo Roberto Dalsenter; Arquimedes Gasparotto Junior

    2015-01-01

    The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameter...

  10. Oral Herpes

    Science.gov (United States)

    ... Dry Mouth Burning Mouth Tooth Decay See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities ... care. NIDCR > Image Gallery > Oral Health > Oral Herpes Oral Herpes Main Content Title: Oral Herpes Description: Herpes ( ...

  11. Oral Warts

    Science.gov (United States)

    ... Dry Mouth Burning Mouth Tooth Decay See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities ... care. NIDCR > Image Gallery > Oral Health > Oral Warts Oral Warts Main Content Title: Oral Warts Description: Warts ...

  12. Abuse-deterrent features of an extended-release morphine drug product developed using a novel injection-molding technology for oral drug delivery.

    Science.gov (United States)

    Skak, Nikolaj; Elhauge, Torben; Dayno, Jeffrey M; Lindhardt, Karsten

    A novel technology platform (Guardian™ Technology, Egalet Corporation, Wayne, PA) was used to manufacture morphine abuse-deterrent (AD), extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO® ER [morphine sulfate] ER tablets; Egalet Corporation), a recently approved morphine product with AD labeling. The aim of this article is to highlight how the features of Guardian™ Technology are linked to the ER profile and AD characteristics of morphine-ADER-IMT. The ER profile of morphine-ADER-IMT is attributed to the precise release of morphine from the polymer matrix. The approved dosage strengths of morphine-ADER-IMT are bioequivalent to corresponding dosage strengths of morphine ER (MS Contin®; Purdue Pharma LP, Stamford, CT). Morphine-ADER-IMT was very resistant to physical manipulations intended to reduce particle size, with injection molding differentiate morphine-ADER-IMT from other approved AD opioids that deter abuse using physical and chemical barriers. The high degree of flexibility of the Guardian™ Technology enables the development of products that can be tailored to almost any desired release profile; as such, it is a technology platform that may be useful for the development of a wide range of pharmaceutical products.

  13. Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach.

    Science.gov (United States)

    Otsuka, Keiichi; Wagner, Christian; Selen, Arzu; Dressman, Jennifer

    2015-05-01

    To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model. Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro-in-silico-in-vivo approach could be a useful tool for facilitating formulation development of drug products. © 2015 Royal Pharmaceutical Society.

  14. Understanding the performance of melt-extruded poly(ethylene oxide)-bicalutamide solid dispersions: characterisation of microstructural properties using thermal, spectroscopic and drug release methods.

    Science.gov (United States)

    Abu-Diak, Osama A; Jones, David S; Andrews, Gavin P

    2012-01-01

    In this article, we have prepared hot-melt-extruded solid dispersions of bicalutamide (BL) using poly(ethylene oxide) (PEO) as a matrix platform. Prior to preparation, miscibility of PEO and BL was assessed using differential scanning calorimetry (DSC). The onset of BL melting was significantly depressed in the presence of PEO, and using Flory-Huggins (FH) theory, we identified a negative value of -3.4, confirming miscibility. Additionally, using FH lattice theory, we estimated the Gibbs free energy of mixing which was shown to be negative, passing through a minimum at a polymer fraction of 0.55. Using these data, solid dispersions at drug-to-polymer ratios of 1:10, 2:10 and 3:10 were prepared via hot-melt extrusion. Using a combination of DSC, powder X-ray diffractometry and scanning electron microscopy, amorphous dispersions of BL were confirmed at the lower two drug loadings. At the 3:10 BL to PEO ratio, crystalline BL was detected. The percent crystallinity of PEO was reduced by approximately 10% in all formulations following extrusion. The increased amorphous content within PEO following extrusion accommodated amorphous BL at drug to polymer loadings up to 2:10; however, the increased amorphous domains with PEO following extrusion were not sufficient to fully accommodate BL at drug-to-polymer ratios of 3:10. Copyright © 2011 Wiley-Liss, Inc.

  15. Controlled-release nanoencapsulating microcapsules to combat inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Baek JS

    2017-06-01

    Full Text Available Jong-Suep Baek,1 Eng Wan Yeo,1 Yin Hao Lee,2 Nguan Soon Tan,2 Say Chye Joachim Loo1,3 1School of Materials Science and Engineering, Nanyang Technological University, Singapore; 2School of Biological Sciences, Nanyang Technological University, Singapore; 3Singapore Centre on Environmental Life Sciences Engineering (SCELSE, Nanyang Technological University, Singapore Abstract: The World Health Organization (WHO has reported that globally 235 million people suffer from chronic and other inflammatory diseases. The short half-lives of nonsteroidal anti-inflammatory drugs (NSAIDs and their notoriety in causing gastrointestinal discomforts, warrants these drugs to be released in a controlled and sustained manner. Although polymeric particles have been widely used for drug delivery, there are few reports that showcase their ability in encapsulating and sustaining the release of NSAIDs. In this paper, polymeric nanoencapsulating microcapsules loaded with NSAIDs were fabricated using solid/water/oil/water emulsion solvent evaporation method. Two NSAIDs, ibuprofen and naproxen, were first pre-loaded into nanoparticles and then encapsulated into a larger hollow microcapsule that contained the third NSAID, celecoxib. A high encapsulation efficiency (% of these NSAIDs was achieved and a sustained release (up to 30 days of these drugs in phosphate-buffered saline was observed. Then, a gastrointestinal drug – cimetidine (CIM – was co-loaded with the NSAIDs. This floating delivery system exhibited excellent buoyancy (~88% up to 24 h in simulated gastric fluid. It also allowed a sequential release of the drugs, whereby an immediate release of CIM followed by NSAIDs was observed. Drug release of the NSAIDs observed Fickian diffusion mechanism, whereas CIM observed non-Fickian diffusion. Therefore, this delivery system is a promising platform to control the delivery of NSAIDs to combat inflammatory diseases, thereby protecting against possible gastrointestinal

  16. A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors.

    Science.gov (United States)

    Heath, Elisabeth I; Bible, Keith; Martell, Robert E; Adelman, Daniel C; Lorusso, Patricia M

    2008-02-01

    SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean Cmax and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 microg/ml and 0.103 to 0.553 microg h/ml, respectively. The CL and Vss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032

  17. Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis.

    Science.gov (United States)

    Sandborn, William J; Korzenik, Joshua; Lashner, Bret; Leighton, Jonathan A; Mahadevan, Uma; Marion, James F; Safdi, Michael; Sninsky, Charles A; Patel, Raman M; Friedenberg, Keith A; Dunnmon, Preston; Ramsey, David; Kane, Sunanda

    2010-04-01

    The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis (UC) began with sulfasalazine and was driven by sulfapyridine toxicity. This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently. This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets) compared with twice-daily dosing for maintaining remission in UC patients. A multicenter, randomized, investigator-blinded, 12-month, active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6-2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission. The primary end point was maintenance of clinical remission at month 6. A total of 1023 patients were randomized and dosed. The primary objective of noninferiority was met. At month 6, 90.5% of patients receiving once-daily dosing had maintained clinical remission, compared with 91.8% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -2.3 to 4.9). At month 12, 85.4% of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -4.6 to 4.7). Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events. Once-daily dosing of delayed-release mesalamine at doses of 1.6-2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC. 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate.

    Science.gov (United States)

    Jesus, Douglas Rossi; Barbosa, Lorena Neris; Prando, Thiago Bruno Lima; Martins, Leonardo Franco; Gasparotto, Francielli; Guedes, Karla Moraes Rocha; Dragunski, Douglas Cardoso; Lourenço, Emerson Luiz Botelho; Dalsenter, Paulo Roberto; Gasparotto Junior, Arquimedes

    2015-01-01

    The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

  19. Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate

    Directory of Open Access Journals (Sweden)

    Douglas Rossi Jesus

    2015-01-01

    Full Text Available The large consumption of biodegradable films from cassava starch acetate (FCSA as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

  20. Acute load-dependent effects of oral whey protein on gastric emptying, gut hormone release, glycemia, appetite, and energy intake in healthy men.

    Science.gov (United States)

    Hutchison, Amy T; Piscitelli, Diana; Horowitz, Michael; Jones, Karen L; Clifton, Peter M; Standfield, Scott; Hausken, Trygve; Feinle-Bisset, Christine; Luscombe-Marsh, Natalie D

    2015-12-01

    In healthy individuals, intraduodenal whey protein load-dependently modulates gastrointestinal motor and hormonal functions and suppresses energy intake. The effect of oral whey, particularly the impact of load, has not been evaluated. The purpose of this study was to quantify gastric emptying of 30 and 70 g of oral whey protein loads and their relation to gastrointestinal hormone, glycemic, and appetitive responses. On 3 separate occasions in a randomized, double-blind order, 18 lean men [mean ± SEM age: 24.8 ± 1.4 y; body mass index (in kg/m(2)): 21.6 ± 0.5] received iso-osmolar, equally palatable drinks (∼450 mL) containing 30 g pure whey protein isolate (L), 70 g pure whey protein isolate (H), or saline (control). Gastric emptying (with the use of 3-dimensional ultrasound), plasma cholecystokinin, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, insulin, glucagon, total amino acids, and blood glucose were measured for 180 min after consumption of the drinks, and energy intake at a buffet-style lunch was quantified. Gastric emptying of the L and H drinks was comparable when expressed in kilocalories per minute (L: 2.6 ± 0.2 kcal/min; H: 2.9 ± 0.3 kcal/min) and related between individuals (r = 0.54, P drinks were comparable until ∼45-60 min after ingestion, after which time the responses became more differentiated. Blood glucose was modestly reduced after the H drink between t = 45 and 150 min when compared with the L drink (all P drinks compared with control (P protein is independent of load and determines the initial gastrointestinal hormone response. This study was registered at www.anzctr.org.au as 12611000706976. © 2015 American Society for Nutrition.

  1. Effect of low-level laser therapy on inflammatory mediator release during chemotherapy-induced oral mucositis: a randomized preliminary study.

    Science.gov (United States)

    Silva, Geisa Badauy Lauria; Sacono, Nancy Tomoko; Othon-Leite, Angélica Ferreira; Mendonça, Elismauro Francisco; Arantes, Adriano Moraes; Bariani, César; Duarte, Luciana Garcia Lobo; Abreu, Mauro Henrique Nogueira; Queiroz-Júnior, Celso Martins; Silva, Tarcília Aparecida; Batista, Aline Carvalho

    2015-01-01

    Patients undergoing hematopoietic stem cell transplantation (HSCT) are submitted to a conditioning regimen of high-dose chemotherapy, with or without radiation therapy, which usually results in oral ulcerations and mucosal barrier breakdown. Oral mucositis (OM) is a common and debilitating toxicity side effect of autologous and allogeneic HSCT. The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) on the severity of OM and inflammatory mediator (TNF-α, IL-6, IL-1β, IL-10, TGF-β, metalloproteinases, and growth factors) levels in saliva and blood of HSCT patients. Thirty patients were randomly assigned to two groups: control (n = 15) and laser (n = 15). LLLT was applied from the first day of the conditioning regimen until day 7 post-HSCT (D + 7). Saliva and blood were collected from patients on admission (AD), D-1, D + 3, D + 7, and on marrow engraftment day (ME). Clinical results showed less severe OM in the laser group (p levels in saliva on D + 7 (p = 0.04). Significant differences were also observed for IL-10 on D + 7 and on ME in blood plasma, when compared to the control group (p < 0.05). No significant differences were seen in saliva or blood for the other inflammatory mediators investigated. LLLT was clinically effective in reducing the severity of chemotherapy-induced OM in HSCT patients, and its mechanism of action does not seem to be completely linked to the modulation of pro- or anti-inflammatory cytokines, growth factors or matrix metalloproteinases.

  2. Design and in vitro and in vivo characterization of mucoadhesive matrix pellets of metformin hydrochloride for oral controlled release: a technical note.

    Science.gov (United States)

    Ige, Pradum Pundlikrao; Gattani, Surendra Ganeshlal

    2012-03-01

    The aim of the current work was to design and develop matrix pellets of hydroxy propyl methyl cellulose K200M and microcrystalline cellulose in an admixture for a mucoadhesive gastroretentive drug delivery system. Pellets containing metformin hydrochloride (500 mg) were prepared by the pelletization technique using an extruder-spheronizer. Pellets were characterized by differential scanning calorimetry (DSC), x-ray diffraction (XRD), scanning electron microscopy (SEM), circularity, roundness, percent drug content, percent production yield, in vitro swelling, ex vivo mucoadhesion, in vitro drug release and in vivo x-ray imaging studies. Optimized pellets were sufficiently porous spheroids, free flowing, had smooth surfaces, had yields up to 75.45 ± 0.52% and had drug content up to 96.45 ± 0.19%. The average particle size of formulations MF2 and MF6 were 1.13 ± 0.41 mm and 1.22 ± 0.18 mm, respectively. Formulation MF6 exhibited strong adhesion, about 94.67%, to goat mucosal tissue, and the desired in vitro swelling, with a sustained drug release profile for 12 h and with retention in the upper small intestine of rabbits for 10 h. We conclude that hydroxy propyl methyl cellulose K200M and microcrystalline cellulose at a 2.80:1.00 w/w ratio could be an effective carrier for multiple unit controlled delivery of metformin hydrochloride.

  3. A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol.

    Science.gov (United States)

    Kim, Kyeong Soo; Yang, Eun Su; Kim, Dong Shik; Kim, Dong Wuk; Yoo, Hye Hyun; Yong, Chul Soon; Youn, Yu Seok; Oh, Kyung Taek; Jee, Jun-Pil; Kim, Jong Oh; Jin, Sung Giu; Choi, Han Gon

    2017-11-01

    To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, C max , and T max values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

  4. Releasing metal catalysts via phase transition: (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 as a redox stable anode material for solid oxide fuel cells.

    Science.gov (United States)

    Xiao, Guoliang; Wang, Siwei; Lin, Ye; Zhang, Yanxiang; An, Ke; Chen, Fanglin

    2014-11-26

    Donor-doped perovskite-type SrTiO3 experiences stoichiometric changes at high temperatures in different Po2 involving the formation of Sr or Ti-rich impurities. NiO is incorporated into the stoichiometric strontium titanate, SrTi0.8Nb0.2O3-δ (STN), to form an A-site deficient perovskite material, (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 (Ni-STN), for balancing the phase transition. Metallic Ni nanoparticles can be released upon reduction instead of forming undesired secondary phases. This material design introduces a simple catalytic modification method with good compositional control of the ceramic backbones, by which transport property and durability of solid oxide fuel cell anodes are largely determined. Using Ni-STN as anodes for solid oxide fuel cells, enhanced catalytic activity and remarkable stability in redox cycling have been achieved. Electrolyte-supported cells with the cell configuration of Ni-STN-SDC anode, La0.8Sr0.2Ga0.87Mg0.13O3 (LSGM) electrolyte, and La0.6Sr0.4Co0.2Fe0.8O3 (LSCF) cathode produce peak power densities of 612, 794, and 922 mW cm(-2) at 800, 850, and 900 °C, respectively, using H2 as the fuel and air as the oxidant. Minor degradation in fuel cell performance resulted from redox cycling can be recovered upon operating the fuel cells in H2. Such property makes Ni-STN a promising regenerative anode candidate for solid oxide fuel cells.

  5. Does switching from oral extended-release methylphenidate to the methylphenidate transdermal system affect health-related quality-of-life and medication satisfaction for children with attention-deficit/hyperactivity disorder?

    Directory of Open Access Journals (Sweden)

    Landgraf Jeanne M

    2009-12-01

    Full Text Available Abstract Background To evaluate health-related quality of life (HRQL and medication satisfaction after switching from a stable dose of oral extended-release methylphenidate (ER-MPH to methylphenidate transdermal system (MTS via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD. Methods In a 4-week, multisite, open-label study, 171 children (164 in the intent-to-treat [ITT] population aged 6-12 years diagnosed with ADHD abruptly switched from a stable dose of oral ER-MPH to MTS nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. Subjects remained on the scheduled dose for the first week, after which the dose was then titrated to an optimal effect. The ADHD Impact Module-Children (AIM-C, a disease-specific validated HRQL survey instrument measuring child and family impact, was used to assess the impact of ADHD symptoms on the lives of children and their families at baseline and study endpoint. Satisfaction with MTS use was assessed via a Medication Satisfaction Survey (MSS at study endpoint. Both the AIM-C and MSS were completed by a caregiver (parent/legally authorized representative. Tolerability was monitored by spontaneous adverse event (AE reporting. Results AIM-C child and family HRQL mean scores were above the median possible score at baseline and were further improved at endpoint across all MTS doses. Similar improvements were noted for behavior, missed doses, worry, and economic impact AIM-C item scores. Overall, 93.8% of caregivers indicated a high level of satisfaction with their child's use of the study medication. The majority of treatment-emergent AEs (> 98% were mild to moderate in intensity, and the most commonly reported AEs included headache, decreased appetite, insomnia, and abdominal pain. Seven subjects discontinued the study due to intolerable AEs (n = 3 and application site reactions (n = 4. Conclusion This study demonstrates that MTS, when carefully

  6. β-Casein nanoparticle-based oral drug delivery system for potential treatment of gastric carcinoma: stability, target-activated release and cytotoxicity.

    Science.gov (United States)

    Shapira, Alina; Davidson, Irit; Avni, Noa; Assaraf, Yehuda G; Livney, Yoav D

    2012-02-01

    We studied a potential drug delivery system comprising the hydrophobic anticancer drug paclitaxel entrapped within β-casein (β-CN) nanoparticles and its cytotoxicity to human gastric carcinoma cells. Paclitaxel was entrapped by stirring its dimethyl sulfoxide (DMSO) solution into PBS containing β-CN. Cryo-TEM analysis revealed drug nanocrystals, the growth of which was blocked by β-CN. Entrapment efficiency was nearly 100%, and the nanovehicles formed were colloidally stable. Following encapsulation and simulated digestion with pepsin (2 hours at pH=2, 37 °C), paclitaxel retained its cytotoxic activity to human N-87 gastric cancer cells; the IC(50) value (32.5 ± 6.2 nM) was similar to that of non-encapsulated paclitaxel (25.4 ± 2.6 nM). Without prior simulated gastric digestion, β-CN-paclitaxel nanoparticles were non-cytotoxic, suggesting the lack of untoward toxicity to bucal and esophageal epithelia. We conclude that β-CN shows promise to be useful for target-activated oral delivery of hydrophobic chemotherapeutics in the treatment of gastric carcinoma, one of the leading causes of cancer mortality worldwide. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs II - The Digestion of Trilaurin Protects Desmopressin from Proteolytic Degradation

    DEFF Research Database (Denmark)

    Christophersen, Philip Carsten; Zhang, Long; Müllertz, Anette

    2014-01-01

    , which is the same rank order as the lipid degradation rate. A reverse rank order was found for the protection of desmopressin from enzymatic degradation due to spatial separation of desmopressin from the protease. TG12 accelerated the release of desmopressin from all lipid particles when added as either...

  8. Oral Biology, Oral Pathology, and Oral Treatments

    National Research Council Canada - National Science Library

    Nammour, Samir; Zeinoun, Toni; Yoshida, Kenji; Brugnera Junior, Aldo

    2016-01-01

    ..., and reproduction in any medium, provided the original work is properly cited. Oral biology, oral pathology, and oral treatments are interesting fields in dentistry. The rapid evolution of technologies ...

  9. The efficacy and safety of valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection in children after solid organ transplantation.

    Science.gov (United States)

    Lapidus-Krol, E; Shapiro, R; Amir, J; Davidovits, M; Steinberg, R; Mor, E; Avitzur, Y

    2010-09-01

    Routine prophylaxis for CMV with valganciclovir is common in adult recipients but data to support its use in children are scarce. The aim of this study was to compare the efficacy and safety of valganciclovir vs. ganciclovir in a pediatric cohort. We performed a retrospective analysis of 92 children after KTx and/or LTx. All children have received IV ganciclovir for two wk, and then oral ganciclovir (TID; n = 41) before 2004, or valganciclovir (OD; n = 51) thereafter. Treatment was given for three months in R+/D+ or R+/D- recipients and for six months in R-/D+. Patients were followed for one yr post transplant. Both groups were comparable in their demographic and transplant-related history. Symptomatic CMV infection/disease developed in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups, respectively (P-NS). Time-to-onset of CMV infection was comparable in both groups (P-NS); rates of acute allograft rejection were similar in both groups (3.9% vs. 9.8%). Risk factors for CMV infection included young age, serostatus of R-/D+, and allograft from cadaver donor. No significant side effects were noted in both groups. As in adults, valganciclovir appears to be as efficacious and safe as oral ganciclovir. Valganciclovir should be considered as a possible prophylactic treatment for CMV in pediatric recipients of KTx or LTx.

  10. Low-dose oral prolonged-release oxycodone/naloxone for chronic pain in elderly patients with cognitive impairment: an efficacy–tolerability pilot study

    Directory of Open Access Journals (Sweden)

    Petrò E

    2016-03-01

    Full Text Available Emiliano Petrò,1 Elena Ruffini,1 Melania Cappuccio,2 Valeria Guerini,2 Gloria Belotti,3 Sara Fascendini,4 Cristina Licini,4 Claudio Marcassa51Rehabiliation and Alzheimer Unit, San Pietro Polyclinic, Ponte San Pietro, 2Alzheimer Center, P. Gusmini Foundation, Vertova, 3Santa Maria Ausiliatrice Foundation, Bergamo, 4Alzheimer Center, Briolini Hospital FERB ONLUS, Gazzaniga, 5Cardiology, Maugeri Foundation IRCCS, Veruno, ItalyObjective: This pilot study evaluated the efficacy and safety of prolonged-release oxycodone/naloxone (OXN-PR in older subjects with chronic pain and mild-to-moderate cognitive impairment.Methods: This was a prospective, observational, open-label study of 45-day duration. Patients with moderate-to-severe chronic pain and naïve to strong opioids were recruited from nursing homes and Alzheimer’s disease centers. OXN-PR was initiated at low doses (5 mg od or bid and increased to a maximum of 20 mg bid. The primary efficacy endpoint was a pain intensity reduction of ≥30% from baseline (T0 to 15 days after OXN-PR initiation, as assessed by a numerical rating scale or the Pain Assessment in Advanced Dementia scale. Other assessments included the Barthel activities of daily living index, Neuropsychiatric Inventory, Bowel Function Index, and adverse events.Results: The analysis included 53 patients (mean age, 83.0 years; mean Mini-Mental State Examination score, 18.6 with severe pain (median Numerical Rating Scale/Pain Assessment in Advanced Dementia 6 and substantial impairment in daily functioning (mean Barthel index, 32.2. The primary endpoint was achieved by 92.4% of patients. OXN-PR significantly reduced mean pain intensity from baseline to study end (numerical rating scale, 6.6±1.0 vs 2.3±1.1, P<0.0001; Pain Assessment in Advanced Dementia, 6.9±1.6 vs 0.9±0.8, P<0.0001. Substantial improvements from T0 to T45 in daily functioning (mean Barthel index, 32.2±16.8 vs 53.7±23.9, P<0.0001 and neuropsychiatric symptoms

  11. 21 CFR 343.90 - Dissolution and drug release testing.

    Science.gov (United States)

    2010-04-01

    ... as contained in USP 23 at page 139. (g) Aspirin effervescent tablets for oral solution. Aspirin effervescent tablets for oral solution must meet the dissolution standard for aspirin effervescent tablets for... delayed-release tablets. Aspirin delayed-release capsules and aspirin delayed-release tablets must meet...

  12. [Clinical Value of "iEat®" in Terminal Cancer Patients Who Have Difficulty with Oral Intake of a Solid Diet].

    Science.gov (United States)

    Kawabata, Ryohei; Iseki, Chihiro; Kimura, Yutaka; Yoshikawa, Masato; Kameda, Chizu; Matsumura, Tae; Won, Masayo; Koga, Chikato; Murakami, Masahiro; Hirota, Masaki; Noura, Shingo; Ikenaga, Masakazu; Shimizu, Junzo; Hasegawa, Junichi

    2015-11-01

    The usefulness of "iEatR" was explored in a study of 13 terminal cancer patients who had difficulty ingesting a solid diet, but could ingest a liquid diet. The patients were given a questionnaire on the flavor, appearance, and ease of consumption after sampling 2 kinds of "iEatR". Patients wishing to continue consuming this diet were able to purchase "iEatR" at their own expense and were then surveyed regarding their ongoing consumption of "iEatR". The types of cancers were esophageal in 3 patients, gastric in 7, and pancreatic in 3. In the questionnaire, 10 of the 13 patients rated the flavor as good and 12 rated the appearance and ease of eating as good. Eleven of the 13 patients purchased "iEatR", and 61.5% of patients were still consuming "iEatR" at least 2 times per week 2 weeks after the sampling. No change in the Common Terminology Criteria for Adverse Events grade was seen in any of the patients."iEatR", which emphasizes appearance and taste, is associated with improved satisfaction in terminal cancer patients who have difficulty ingesting solids, suggesting it is useful as a diet for these patients.

  13. Mechanistic Studies of the N-formylation of Edivoxetine, a Secondary Amine-Containing Drug, in a Solid Oral Dosage Form.

    Science.gov (United States)

    Hoaglund Hyzer, Cherokee S; Williamson, Michele L; Jansen, Patrick J; Kopach, Michael E; Scherer, R Brian; Baertschi, Steven W

    2017-05-01

    Edivoxetine (LY2216684 HCl), although a chemically stable drug substance, has shown the tendency to degrade in the presence of carbohydrates that are commonly used tablet excipients, especially at high excipient:drug ratios. The major degradation product has been identified as N-formyl edivoxetine. Experimental evidence including solution and solid-state investigations, is consistent with the N-formylation degradation pathway resulting from a direct reaction of edivoxetine with (1) formic acid (generated from decomposition of microcrystalline cellulose or residual glucose) and (2) the reducing sugar ends (aldehydic carbons) of either residual glucose or the microcrystalline cellulose polymer. Results of labeling experiments indicate that the primary source of the formyl group is the C1 position from reducing sugars. Presence of water or moisture accelerates this degradation pathway. Investigations in solid and solution states support that the glucose Amadori Rearrangement Product does not appear to be a direct intermediate leading to N-formyl degradation of edivoxetine, and oxygen does not appear to play a significant role. Solution-phase studies, developed to rapidly assess propensity of amines toward Maillard reactivity and formylation, were extended to show comparative behavior with example systems. The cyclic amine systems, such as edivoxetine, showed the highest propensity toward these side reactions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. 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.

  15. Effects of hormone therapy on the endometrium in postmenopausal women: a one year randomized trial of low dose oral estradiol in association with a levonorgestrel-releasing intrauterine system or drospirenone

    Directory of Open Access Journals (Sweden)

    Luiza Schvartzman

    2013-09-01

    Full Text Available OBJECTIVES: to compare the endometrial effects and uterine bleeding patterns associated with treatment using (1 levonorgestrel-releasing intrauterine system (LNG-IUS and estradiol (1 mg/day, p.o. or (2 orally administered drospirenone (2 mg/day andestradiol (1 mg/day. METHODS: thirty-four patients (aged 52.53 ± 4.44 in the LNG-IUS group and 53.15 ± 4.018 in the DRSP group were randomized. The severity of menopausal symptoms was evaluated using the Kupperman index every three months. Transvaginal ultrasound, hysteroscopy and histological evaluation were repeated after 12 months. During this period, patients kept menstrual calendars. All categorical variables were described as percentages. Variables were tested for normal distribution and Student's t test was applied for independent samples and ANOVA forrepeated measures when appropriate. Data were considered to be significant when p<0.05. RESULTS: slight vaginal bleeding was reported in the first month of treatment by 53.3% of patients from the LNG-IUS/estradiol group compared with 7.7% of patients from the drospirenone/estradiol group. There were no differences in endometrial thickness between the two groups throughout the study period. End-of-study histological findings showed atrophic endometrium in 53.3% of patients in the LNG-IUS/estradiol group compared with 76.9% of patients in the drospirenone/estradiol group. CONCLUSIONS: our results suggest good endometrial protection with both HT regimens.

  16. Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention-Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission.

    Science.gov (United States)

    Goodman, David W; Starr, H Lynn; Ma, Yi-Wen; Rostain, Anthony L; Ascher, Steve; Armstrong, Robert B

    2017-01-01

    To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects (-17.1 [12.44] vs -11.7 [13.30]; P ADHD. OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. ClinicalTrials.gov identifier: NCT00937040.

  17. Drug transport mechanism of oral antidiabetic nanomedicines.

    Science.gov (United States)

    Gundogdu, Evren; Yurdasiper, Aysu

    2014-01-01

    Over the last few decades, extensive efforts have been made worldwide to develop nanomedicine delivery systems, especially via oral route for antidiabetic drugs. Absorption of insulin is hindered by epithelial cells of gastrointestinal tract, acidic gastric pH and digestive enzymes. Recent reports have identified and explained the beneficial role of several structural molecules like mucoadhesive polymers (polyacrylic acid, sodium alginate, chitosan) and other copolymers for the efficient transport and release of insulin to its receptors. Insulin nanomedicines based on alginate-dextran sulfate core with a chitosan-polyethylene glycol-albumin shell reduced glycaemia in a dose dependent manner. Orally available exendin-4 formulations exerted their effects in a time dependent manner. Insulin nanoparticles formed by using alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin showed a threefold increase of the hypoglycemic effect in comparison to free insulin in animal models. Solid lipid nanoparticles showed an enhancement of the bioavailability of repaglinide (RG) within optimized solid lipid nanoparticle formulations when compared with RG alone. Nanoparticles represent multiparticulate delivery systems designed to obtain prolonged or controlled drug delivery and to improve bioavailability as well as stability. Nanoparticles can also offer advantages like limiting fluctuations within therapeutic range, reducing side effects, protecting drugs from degradation, decreasing dosing frequency, and improving patient compliance and convenience.

  18. A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors.

    Science.gov (United States)

    Mita, M; Gordon, M; Rejeb, N; Gianella-Borradori, A; Jego, V; Mita, A; Sarantopoulos, J; Sankhala, K; Mendelson, D

    2014-09-01

    Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advanced or metastatic solid tumors. MSC1992371A was administered on days 1 and 8 (schedule 1) or on days 1, 2, and 3 (schedule 2) of a 21-day cycle. The study was expanded with a third schedule (study drug on days 1-3 and 8-10). Adverse events were monitored throughout the study. Antitumor efficacy, drug pharmacokinetics, and pharmacodynamics were evaluated. Ninety-two patients were enrolled. MSC1992371A was dosed over eight levels in schedules 1 and 2, and the MTD was determined as 74 mg/m(2) per cycle for both schedules and as 60 mg/m(2) in schedule 3, albeit only in three patients due to discontinuation of the study. Overall, the most common grade 3 or 4 treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anemia, and fatigue. The most frequent dose-limiting toxicity over all schedules was neutropenia. MSC1992371A plasma concentrations tended to increase with increasing dose levels. Although no complete or partial responses were seen, stable disease ≥3 months was observed in 11 patients. Analysis for markers of target modulation and pharmacodynamics effects was unsuccessful. MSC1992371A was generally well tolerated in patients, with mainly transient hematologic toxicities apparent at an MTD of 60-74 mg/m(2)/21-day cycle, independent of dosing frequency.

  19. First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.

    Science.gov (United States)

    Beatty, Gregory L; O'Dwyer, Peter J; Clark, Jason; Shi, Jack G; Bowman, Kevin J; Scherle, Peggy A; Newton, Robert C; Schaub, Richard; Maleski, Janet; Leopold, Lance; Gajewski, Thomas F

    2017-07-01

    Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1.Experimental Design: Fifty-two patients with advanced solid malignancies were treated with epacadostat [50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity.Results: One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients.Conclusions: Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing. Clin Cancer Res; 23(13); 3269-76. ©2017 AACR. ©2017 American Association for Cancer Research.

  20. A phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies.

    Science.gov (United States)

    Forouzesh, Bahram; Takimoto, Chris H; Goetz, Andrew; Diab, Sami; Hammond, Lisa A; Smetzer, Leslie; Schwartz, Garry; Gazak, Robert; Callaghan, John T; Von Hoff, Daniel D; Rowinsky, Eric K

    2003-11-15

    This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 weeks every 4-week schedule. The study also sought to determine the maximum tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m(2), which was equivalent to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m(2). Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m(2); and a modified continual reassessment model was used for dose assignment to determine the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m(2). The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m(2), which was determined to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clinically relevant levels of oxidized hemoglobin (methemoglobin) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with

  1. Oral Cancer

    Science.gov (United States)

    ... NIDCR Home Oral Health Diseases and Conditions Gum Disease TMJ Disorders Oral Cancer Dry Mouth Burning Mouth Tooth Decay See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities Diabetes Heart Disease HIV/ ...

  2. Oral Cancer

    Science.gov (United States)

    Oral cancer can form in any part of the mouth. Most oral cancers begin in the flat cells that cover the ... your mouth, tongue, and lips. Anyone can get oral cancer, but the risk is higher if you are ...

  3. Oral Health and Women

    Centers for Disease Control (CDC) Podcasts

    2009-05-12

    This women's health podcast focuses on the importance of maintaining good oral health during pregnancy.  Created: 5/12/2009 by Office of Women’s Health (OWH) and National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 5/12/2009.

  4. Development and Evaluation of Solid Lipid Nanoparticles of Raloxifene Hydrochloride for Enhanced Bioavailability

    Directory of Open Access Journals (Sweden)

    Anand Kumar Kushwaha

    2013-01-01

    Full Text Available Raloxifene hydrochloride (RL-HCL is an orally selective estrogen receptor modulator (SERM with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.

  5. Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability.

    Science.gov (United States)

    Kushwaha, Anand Kumar; Vuddanda, Parameswara Rao; Karunanidhi, Priyanka; Singh, Sanjay Kumar; Singh, Sanjay

    2013-01-01

    Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.

  6. Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.

    Science.gov (United States)

    Soria, Jean-Charles; Baselga, José; Hanna, Nasser; Laurie, Scott A; Bahleda, Rastislav; Felip, Enriqueta; Calvo, Emiliano; Armand, Jean-Pierre; Shepherd, Frances A; Harbison, Christopher T; Berman, David; Park, Jong-Soon; Zhang, Steven; Vakkalagadda, Blisse; Kurland, John F; Pathak, Ashutosh K; Herbst, Roy S

    2013-05-01

    BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408, a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Creelan BC

    2017-08-01

    Full Text Available Ben C Creelan,1 Dmitry I Gabrilovich,2 Jhanelle E Gray,1 Charles C Williams,1 Tawee Tanvetyanon,1 Eric B Haura,1 Jeffrey S Weber,3 Geoffrey T Gibney,4 Joseph Markowitz,5 Joel W Proksch,6 Scott A Reisman,6 Mark D McKee,7 Melanie P Chin,6 Colin J Meyer,6 Scott J Antonia11Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA; 2The Wistar Institute, Philadelphia, PA, USA; 3Laura and Isaac Perlmutter Cancer Center, New York, NY, USA; 4Department of Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 5Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA; 6Reata Pharmaceuticals, Inc., Irving, TX, USA; 7AbbVie, Inc., North Chicago, IL, USABackground: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729 with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity.Methods: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression.Results: Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action

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

    Science.gov (United States)

    Desai, Samixa; Poddar, Aditi; Sawant, Krutika

    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. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6–12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting

    Science.gov (United States)

    Childress, Ann C.; Kollins, Scott H.; Cutler, Andrew J.; Marraffino, Andrea; Sikes, Carolyn R.

    2017-01-01

    Abstract Objective: Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. Methods: Children aged 6–12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). Results: The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p classroom setting. Clinical Trial Registry: NCT01835548 (ClinicalTrials.gov). PMID:27183299

  10. Effect of methylphenidate on the quality of life in children with epilepsy and attention deficit hyperactivity disorder: and open-label study using an osmotic-controlled release oral delivery system.

    Science.gov (United States)

    Yoo, Hanik K; Park, Subin; Wang, Hee-Ryung; Lee, Joong Sun; Kim, Kunwoo; Paik, Kyoung-Won; Yum, Mi Sun; Ko, Tae-Sung

    2009-12-01

    This open study explored whether methylphenidate could be tolerated and effective in improving the quality of life (QOL) and attention deficit hyperactivity disorder (ADHD) symptoms of children with epilepsy and ADHD. Twenty-five subjects (aged 10.1 +/- 3.0 years) with ADHD and epilepsy were recruited at an outpatient clinic in Seoul, Korea. We used the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), ADHD rating scale (ARS) and clinical global impression (CGI) in this study. Osmotic-controlled release oral delivery system (OROS) methylphenidate, 1.0 +/- 0.4 mg/kg/day, was administered for 55.2 +/- 7.5 days. The QOL subscales including physical restriction (p = 0.005), self-esteem (p = 0.002), memory (p < 0.001), language (p = 0.005), other cognition (p < 0.001), social interaction (p = 0.002), behaviour (p < 0.001), general health (p = 0.002) and QOL (p < 0.001) were significantly increased and the ARS (p < 0.001) and CGI-Severity of illness scores (p < 0.001) were significantly reduced after medication. Although 60% of subjects had experienced adverse effects, most were tolerable and only two subjects withdrew from the study owing to unbearable adverse effects (anorexia and insomnia). Two subjects had seizure attacks during the study period without having to discontinue the trial drug. Despite limitations related to the small sample size and the open design of the present pilot study, our results suggest that OROS methylphenidate may be well tolerated and effective in reducing ADHD symptoms and improving QOL in this patient population.

  11. Delayed-Release Oral Mesalamine 4.8 g/day (800 mg tablets Compared with 2.4 g/day (400 mg tablets for the Treatment of Mildly to Moderately Active Ulcerative Colitis: The ASCEND I Trial

    Directory of Open Access Journals (Sweden)

    Stephen B Hanauer

    2007-01-01

    Full Text Available BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC, but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease.

  12. Stearic acid based, systematically designed oral lipid nanoparticles for enhanced brain delivery of dimethyl fumarate.

    Science.gov (United States)

    Kumar, Pramod; Sharma, Gajanand; Kumar, Rajendra; Malik, Ruchi; Singh, Bhupinder; Katare, Om Prakash; Raza, Kaisar

    2017-12-01

    Dimethyl fumarate is a frequent prescription for the management of numerous neurological disorders. Despite immense promises, DMF is associated with various problems such as multiple dosing (2-3 oral doses daily) and lower brain permeability. Our aim was to enhance the oral bioavailability and increase the brain concentrations of dimethyl fumarate. Solid lipid nanoparticles were systematically formulated by optimizing the composition based on the desired attributes viz. particle size, entrapment efficiency and amount of drug released in 6 h. Results & conclusion: The developed system offered nanometric particle size with entrapment efficiency > 90%. Enhanced Caco-2 cells cellular uptake by optimized solid lipid nanoparticless with superior pharmacokinetic and higher brain biodistribution were observed.

  13. Spray-dried curcumin nanoemulsion: A new road to improvement of oral bioavailability of curcumin.

    Science.gov (United States)

    Hu, Liandong; Hu, Qiaofeng; Yang, Chenchen

    2018-01-01

    In this study a new soluble solid curcumin nanoemulsion powder was prepared using spray-drying technology to improve the solubility and bioavailability of curcumin. The liquid nanoemulsion consisted of curcumin, Capryol 90, Transcutol P, and Cremophor RH40. The solid nanoemulsion was prepared by spray-drying the liquid nanoemulsion in laboratory spray dryer, using lactose as solid carrier. The in vitro release from powder formulation was 97.6% within 15 min while the release from the curcumin crystalline was about 10%. An oral pharmacokinetic study was conducted in rats and the relative bioavailability of spray-dried curcumin powder significantly increased compared with that of curcumin crystalline. The Cmax value of solid curcumin nanoemulsion powder was 5.5-fold greater than the value of the curcumin crystalline in aqueous suspension. The absorption mechanism of the spray-dried curcumin powders was discussed. The results indicate that spray-drying in combination with nanoemulsion was a powerful methodology for improving the dissolution rate and oral bioavailability of curcumin.

  14. Características da sucção nutritiva na liberação da via oral em recém-nascidos pré-termo de diferentes idades gestacionais Characteristics of nutritive sucking in the release for oral feeding in preterm newborns of different gestational ages

    Directory of Open Access Journals (Sweden)

    Raquel Coube de Carvalho Yamamoto

    2009-01-01

    Full Text Available OBJETIVO: Analisar as características da sucção nutritiva na liberação da via oral em recém-nascidos pré-termo (RNPT de diferentes idades gestacionais. MÉTODOS: A amostra constou de 32 RNPT, avaliados no momento da liberação para alimentação por via oral, dividida em dois grupos: Grupo 1 (G1 com idade gestacional inferior a 34 semanas; e Grupo 2 (G2 com idade gestacional igual ou superior a 34 semanas. O desempenho da sucção nutritiva foi avaliado observando-se presença ou ausência de blocos de sucção, número e tempo das sucções nos três primeiros blocos apresentados, e presença ou ausência de coordenação entre sucção/deglutição/respiração (S/D/R. Nenhum RNPT recebeu estimulação fonoaudiológica prévia. RESULTADOS: O G2 apresentou, na maioria dos RNPT, presença de coordenação entre S/D/R, além de melhor desempenho em relação ao número e ao tempo de sucção nos blocos de sucção quando comparado ao G1. Na correlação do número versus tempo de sucção por bloco, o G1 apresentou resultados aproximados aos do G2. Considerando-se a classificação quanto ao desenvolvimento intra-útero adequado para a idade gestacional, os RNPT do G1 apresentaram desempenho semelhante aos do G2, no primeiro e segundo blocos, observando-se queda, no G1, apenas no terceiro bloco. CONCLUSÃO: O melhor desempenho no padrão de sucção nutritiva foi apresentado pelo G2, sugerindo que a idade gestacional corrigida dos RNPT interfere diretamente nos resultados obtidos na avaliação da sucção nutritiva. Assim sendo, esta também é uma variável a ser considerada para liberação da alimentação por via oral.PURPOSE: To analyze the characteristics of nutritive sucking in preterm infants of different gestational ages after the medical prescription for oral feeding. METHODS: The sample comprised 32 preterm infants who were evaluated at the time they were released for oral feeding. The subjects were divided into two groups

  15. 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.

  16. Oral myiasis

    Directory of Open Access Journals (Sweden)

    Thalaimalai Saravanan

    2015-01-01

    Full Text Available Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy.

  17. [Oral ulcers].

    Science.gov (United States)

    Bascones-Martínez, Antonio; Figuero-Ruiz, Elena; Esparza-Gómez, Germán Carlos

    2005-10-29

    Ulcers commonly occur in the oral cavity, their main symptom being pain. There are different ways to classify oral ulcers. The most widely accepted form divides them into acute ulcers--sudden onset and short lasting--and chronic ulcers--insidious onset and long lasting. Commonest acute oral ulcers include traumatic ulcer, recurrent aphthous stomatitis, viral and bacterial infections and necrotizing sialometaplasia. On the other hand, oral lichen planus, oral cancer, benign mucous membrane pemphigoid, pemphigus and drug-induced ulcers belong to the group of chronic oral ulcers. It is very important to make a proper differential diagnosis in order to establish the appropriate treatment for each pathology.

  18. A comparison between the administration of oral prolonged-release oxycodone-naloxone and transdermal fentanyl in patients with moderate-to-severe cancer pain: a propensity score analysis

    Directory of Open Access Journals (Sweden)

    Roberto A

    2017-09-01

    Full Text Available A Roberto,1 MT Greco,2 L Legramandi,3 F Galli,3 M Galli,4 O Corli1 1Pain and Palliative Care Research Unit, Oncology Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, 2Department of Clinical Sciences and Community, University of Milan, Milan, Italy, 3Methodology for Clinical Research Laboratory, Oncology Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, 4Scientific Medical Communication srl, Novara, Italy Background: Opioids are the most important pharmacological treatment for moderate-to-severe cancer pain, but side effects limit their use. Transdermal fentanyl (TDF and oral prolonged-release oxycodone-naloxone (OXN-PR are effective in controlling chronic pain, with less constipation compared to other opioids. However, TDF and OXN-PR have never been directly compared.Patients and methods: Cancer patients with moderate-to-severe chronic pain were consecutively enrolled in two prospective 28-day trials, received either TDF or OXN-PR, and were assessed at baseline and after 7, 14, 21, and 28 days. The primary endpoint was 28-day analgesic response rate (average pain intensity decrease ≥30% from baseline. Other outcome measures included opioid daily dose changes over time; need for adjuvant analgesics; number of switches; premature discontinuation; presence and severity of constipation; and other adverse drug reactions. To compare the efficacy and the safety of TDF and OXN-PR, we used the propensity score analysis to adjust for heterogeneity between the two patient groups.Results: Three hundred ten out of 336 patients originally treated (119 TDF and 191 OXN-PR were included in the comparative analysis. The amount of responders was comparable after TDF (75.3% and OXN-PR administration (82.9%, not significant [NS]. The final opioid daily dose expressed as morphine equivalent was 113.6 mg for TDF and 44.5 mg for OXN-PR (p<0.0001. A daily opioid dose escalation >5% was less common after

  19. First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Tianhong Li

    2016-03-01

    Full Text Available Abstract Background ASP3026 is a second-generation anaplastic lymphoma kinase (ALK inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Methods Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25–800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD, the recommended phase II dose (RP2D, and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. Results The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration–time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38 %, fatigue (35 %, and vomiting (35 %. Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma, eight patients achieved partial response (overall response rate 50 %; 95 % confidence interval 25–75 % and seven patients (44 % achieved stable disease. Conclusions ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. Trial registration ClinTrials.gov: NCT01284192

  20. Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems.

    Science.gov (United States)

    Thenmozhi, Kathavarayan; Yoo, Young Je

    2017-09-01

    Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability. Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison. The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated. The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2 h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine. Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.

  1. Renin release

    DEFF Research Database (Denmark)

    Schweda, Frank; Friis, Ulla; Wagner, Charlotte

    2007-01-01

    The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located...

  2. Release of the Prays oleae pheromone as a consequence of supramolecular structure: study of the β-cyclodextrin-(Z)-tetradec-7-en-1-al complex by X-ray crystallography and NMR spectroscopy in the solid state and in solution

    National Research Council Canada - National Science Library

    Yannakopoulou, Konstantina; Ripmeester, John A; Mavridis, Irene M

    2002-01-01

    ...)-tetradec-7-en-1-al (sex pheromone of the olive pest Prays oleae) from the solid complex was investigated, in an effort to correlate the supramolecular structure with the macroscopic property of spontaneous liberation of the pheromone...

  3. A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic-release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents.

    Science.gov (United States)

    Soutullo, César; Banaschewski, Tobias; Lecendreux, Michel; Johnson, Mats; Zuddas, Alessandro; Anderson, Colleen; Civil, Richard; Higgins, Nicholas; Bloomfield, Ralph; Squires, Liza A; Coghill, David R

    2013-09-01

    There are limited head-to-head data comparing the efficacy of long-acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents. This was a post hoc analysis of a randomized, double-blind, parallel-group, dose-optimized, placebo-controlled, phase III study. The phase III study was carried out in 48 centres across ten European countries. The phase III study enrolled children and adolescents (aged 6-17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher. Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks. In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30% reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41

  4. Rotary Release Mechanism With Fusible Link

    Science.gov (United States)

    Sevilla, Donald R.; Blomquist, Richard S.

    1996-01-01

    Rotary release mechanism includes fusible rotary link made of alloy that melts at relatively low temperature of 60 degrees C. When solid, link couples driving shaft to driven shaft. When necessary, link melted to temporarily decouple two shafts. Upon cooling below melting temperature link hardens, so it once again couples two shafts. Release mechanism extremely compact alternative to pyrotechnic release device. Basic concept applied to such other mechanisms as pin pullers, pin pushers, electrical-disconnection mechanisms, and clutches.

  5. Delayed-Release Oral Mesalamine 4.8 g/day (800 mg tablets) Compared with 2.4 g/day (400 mg tablets) for the Treatment of Mildly to Moderately Active Ulcerative Colitis: The ASCEND I Trial

    OpenAIRE

    Hanauer, Stephen B.; Sandborn, William J.; Christian Dallaire; André Archambault; Bruce Yacyshyn; Chyon Yeh; Nancy Smith-Hall

    2007-01-01

    BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease.PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I...

  6. In vitro biorelevant models for evaluating modified release mesalamine products to forecast the effect of formulation and meal intake on drug release.

    Science.gov (United States)

    Andreas, Cord J; Chen, Ying-Chen; Markopoulos, Constantinos; Reppas, Christos; Dressman, Jennifer

    2015-11-01

    Postprandial administration of solid oral dosage forms greatly changes the dissolution environment compared to fasted state administration. The aims of this study were to investigate and forecast the effect of co-administration of a meal on drug release for delayed and/or extended release mesalamine formulations as well as design of in vitro tests to distinguish among formulations in a biorelevant way. Five different mesalamine formulations (Asacol® 400 mg, Mezavant® 1200 mg, Pentasa® 500 mg and Salofalk® in the 250 mg and 500 mg strengths) were investigated with biorelevant dissolution methods using the USP apparatus III and USP apparatus IV (open loop mode) under both fasted and fed state conditions, as well as with the dissolution methods described in pharmacopeia for delayed and extended release mesalamine products. Using the biorelevant experimental conditions proposed in this study, changes in release in the proximal gut due to meal intake are forecast to be minimal for Asacol®, Mezavant®, Pentasa® and Salofalk® 500 mg, while for Salofalk® 250 mg release was predicted to occur much earlier under fed state conditions. The USP apparatus III generally tended to result in faster dissolution rates and forecast more pronounced food effects for Salofalk® 250 mg than the USP apparatus IV. The biorelevant dissolution gradients were also able to reflect the in vivo behavior of the formulations. In vitro biorelevant models can be useful in the comparison of the release behavior from different delayed and extended release mesalamine formulations as well as forecasting effects of concomitant meal intake on drug release. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Calculation of the inventory and near-field release rates of radioactivity from neutron-activated metal parts discharged from the high flux isotope reactor and emplaced in solid waste storage area 6 at Oak Ridge National Laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Kelmers, A.D.; Hightower, J.R.

    1987-05-01

    Emplacement of contaminated reactor components involves disposal in lined and unlined auger holes in soil above the water table. The radionuclide inventory of disposed components was calculated. Information on the composition and weight of the components, as well as reasonable assumptions for the neutron flux fueling use, the time of neutron exposure, and radioactive decay after discharge, were employed in the inventory calculation. Near-field release rates of /sup 152/Eu, /sup 154/Eu, and /sup 155/Eu from control plates and cylinders were calculated for 50 years after emplacement. Release rates of the europium isotopes were uncertain. Two release-rate-limiting models were considered and a range of reasonable values were assumed for the time-to-failure of the auger-hole linear and aluminum cladding and europium solubility in SWSA-6 groundwater. The bounding europium radionuclide near-field release rates peaked at about 1.3 Ci/year total for /sup 152,154,155/Eu in 1987 for the lower bound, and at about 420 Ci/year in 1992 for the upper bound. The near-field release rates of /sup 55/Fe, /sup 59/Ni, /sup 60/Co, and /sup 63/Ni from stainless steel and cobalt alloy components, as well as of /sup 10/Be, /sup 41/Ca, and /sup 55/Fe from beryllium reflectors, were calculated for the next 100 years, assuming bulk waste corrosion was the release-rate-limiting step. Under the most conservative assumptions for the reflectors, the current (1986) total radionuclide release rate was calculated to be about 1.2 x 10/sup -4/ Ci/year, decreasing by 1992 to a steady release of about 1.5 x 10/sup -5/ Ci/year due primarily to /sup 41/Ca. 50 refs., 13 figs., 8 tabs.

  8. Oral Cancer Exam

    Medline Plus

    Full Text Available ... for providing oral care. NIDCR > OralHealth > Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens during an oral cancer examination. Quick and painless, the exam can detect ...

  9. Development, validation and transfer of a near infrared method to determine in-line the end point of a fluidised drying process for commercial production batches of an approved oral solid dose pharmaceutical product.

    Science.gov (United States)

    Peinado, Antonio; Hammond, Jonathan; Scott, Andrew

    2011-01-05

    Pharmaceutical companies are progressively adopting and introducing the principles of Quality by Design with the main purpose of assurance and built-in quality throughout the whole manufacturing process. Within this framework, a Partial Least Square (PLS) model, based on Near Infrared (NIR) spectra and humidity determinations, was built in order to determine in-line the drying end point of a fluidized bed process. The in-process method was successfully validated following the principles described within The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH Q2 (r1) - Validation of Analytical Procedures: Text and Methodology. However, in some aspects, the cited guidelines were not appropriate to in-process methods developed and validated exclusively with in-line samples and implemented in dynamic systems, such as drying processes. In this work, a customized interpretation of guidelines has been adopted which provided the framework of evidence to support a validated application. The application has been submitted to the United States Food and Drug Administration (FDA) and The European Medicines Agency (EMA) during applications for grant of licences. Representatives from these Regulatory Authorities have specifically reviewed this novel application during on-site inspections, and have subsequently approved both the product and this application. Currently, the NIR method is implemented as a primary in-line method to control the drying end point in real-time (to below a control limit of not greater than 1.2% w/w) for commercial production batches of an approved, solid, oral-dose medicine. The implementation of this in-process method allows real-time control with benefits including a reduction in operation time and labour; sample handling and waste generation; and a reduced risk to product quality in further unit operations due to improved consistency of intermediate output at this stage. To date

  10. Solid Matter

    CERN Document Server

    Angelo, Joseph A

    2011-01-01

    Supported by a generous quantity of full-color illustrations and interesting sidebars, Solid Matter introduces the basic characteristics and properties of solid matter. It briefly describes the cosmic connection of the elements, leading readers through several key events in human pre-history that resulted in more advanced uses of matter in the solid state. Chapters include:. -Solid Matter: An Initial Perspective. -Physical Behavior of Matter. -The Gravity of Matter. -Fundamentals of Materials Science. -Rocks and Minerals. -Metals. -Building Materials. -Carbon Earth's Most Versatile Element. -S

  11. Oral medicine

    African Journals Online (AJOL)

    Correspondence to: P Botha (p.mbotha@mweb. co.za). Clinical setting. The causes of oral signs and symptoms could include medicine side-effects, trauma, autoimmune disease, nutritional deficiency, fungal infection (Fig. 1), premalignant disease (Fig. 2), oral carcinoma (Fig. 3), or sequelae of cancer treatment. What is.

  12. Oral disease in relation to future risk of dementia and cognitive decline: prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial

    NARCIS (Netherlands)

    Batty, G.D.; Li, Q.; Huxley, R.; Zoungas, S.; Taylor, B.A.; Neal, B.; Galan, B.E. de; Woodward, M.; Harrap, S.B.; Colagiuri, S.; Patel, A.; Chalmers, J.

    2013-01-01

    OBJECTIVE: Examine the association of oral disease with future dementia/cognitive decline in a cohort of people with type 2 diabetes. METHODS: A total of 11,140 men and women aged 55-88 years at study induction with type 2 diabetes participated in a baseline medical examination when they reported

  13. Oral disease and subsequent cardiovascular disease in people with type 2 diabetes: a prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.

    NARCIS (Netherlands)

    Li, Q.; Chalmers, J.; Czernichow, S.; Neal, B.; Taylor, B.A.; Zoungas, S.; Poulter, N.; Woodward, M.; Patel, A.; Galan, B.E. de; Batty, G.D.

    2010-01-01

    AIMS/HYPOTHESIS: While there are plausible biological mechanisms linking oral health with cardiovascular disease (CVD) and mortality rates, no study, to our knowledge, has examined this association in a representative population of people with type 2 diabetes. METHODS: We used the Action in Diabetes

  14. A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads

    DEFF Research Database (Denmark)

    Rose, C S; Grarup, N; Krarup, N T

    2009-01-01

    An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic...

  15. Oral Health and Older Adults

    Centers for Disease Control (CDC) Podcasts

    2008-10-27

    This podcast discusses the importance of older adults maintaing good oral health habits. It is primarily targeted to public health and aging services professionals.  Created: 10/27/2008 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 10/27/2008.

  16. A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine.

    Science.gov (United States)

    Mahmah, Osama; Tabbakh, Rami; Kelly, Adrian; Paradkar, Anant

    2014-02-01

    To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40°C/75% RH) over 8 weeks. Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations. © 2013 Royal Pharmaceutical Society.

  17. Mini-tablets: a contemporary system for oral drug delivery in targeted patient groups.

    Science.gov (United States)

    Aleksovski, Aleksandar; Dreu, Rok; Gašperlin, Mirjana; Planinšek, Odon

    2015-01-01

    Mini-tablets represent a new trend in solid dosage form design, with the main goal of overcoming some therapeutic obstacles such as impaired swallowing and polypharmacy therapy, and also offering some therapeutic benefits such as dose flexibility and combined release patterns. Mini-tablets are a promising patient-friendly drug delivery system. Mini-tablets are tablets with a diameter ≤ 3 mm produced on conventional tablet presses equipped with multiple tooling. Mini-tablet production is similar to the production of standard tablets but requires excellent powder flow due to the small dies, exact control of process parameters and special caution during tablet press assembly in order to avoid tool damage. Mini-tablets (coated or uncoated and single- or multiple-unit systems) are mainly developed as patient-friendly systems for pediatric and geriatric patients and also for personalized medicine because they offer improved swallowing and flexible dosing, combining various release kinetics, doses and active compounds in only one system. Mini-tablets may also be successfully used as multiple-unit modified release systems (extended release, delayed-colon release, pulsatile and bi-modal release and gastroretentive systems) providing improved drug bioavailability compared with single-unit systems. Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing and a combination of different release patterns and/or different active compounds (decreasing dosing frequency and/or polypharmacy therapy problems). In terms of complete expression of the benefits of mini-tablets over other oral dosage forms on the market, further investigation in formulation possibilities and development of suitable dosing devices is of essential importance.

  18. Oral Hygiene

    DEFF Research Database (Denmark)

    Sørensen, Marie Toftdahl; Villadsen, Dorte Buxbom

    The aim of the study was to explore how adults with schizo- phrenia describe their lived experiences with oral hygiene. 23 adults with schizophrenia were interviewed within a period of four months in late 2015. Transcriptions of the interviews were analysed using the Reflective Lifeworld Research...... phenomenological approach of Dahlberg, Dahlberg, and Nyström. The essence of the phenomenon, oral hygiene, is described as a challenge: a mixture of ability and assigning priority; a challenge in which significant others, for better or worse, play an important role. We recommend a systematic cooperation between...... health care professionals and adults with schizophrenia in order to improve oral health, well-being and recovery....

  19. Oral leukoplakia

    DEFF Research Database (Denmark)

    Holmstrup, Palle; Dabelsteen, Erik

    2016-01-01

    The idea of identifying oral lesions with a precancerous nature, i.e. in the sense of pertaining to a pathologic process with an increased risk for future malignant development, of course is to prevent frank malignancy to occur in the affected area. The most common oral lesion with a precancerous...... nature is oral leukoplakia, and for decades it has been discussed how to treat these lesions. Various treatment modalities, such as systemic therapies and surgical removal, have been suggested. The systemic therapies tested so far include retinoids, extracts of green tea, inhibitors of cyclooxygenase-2...

  20. 28 CFR 80.9 - No oral opinion.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false No oral opinion. 80.9 Section 80.9 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) FOREIGN CORRUPT PRACTICES ACT OPINION PROCEDURE § 80.9 No oral opinion. No oral clearance, release or other statement purporting to limit the...

  1. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults.

    Science.gov (United States)

    Winslow, David H; Bowden, Charles H; DiDonato, Karen P; McCullough, Pamela A

    2012-11-01

    To evaluate safety and efficacy of phentermine 15 mg plus extended-release topiramate 92 mg for treatment of moderate to severe obstructive sleep apnea (OSA) in obese adults. This phase 2, randomized, double-blind, placebo-controlled study included 2-week screening and 28-week treatment periods. Overnight polysomnography was performed at baseline, Week 8, and Week 28. Single-center study conducted from August 2008 to September 2009. Forty-five subjects with moderate to severe OSA not receiving positive airway pressure (PAP) treatment with body mass index of 30-40 kg/m(2). Subjects were randomized to receive placebo (n = 23) or phentermine 15 mg plus extended-release topiramate 92 mg (n = 22). Both groups received lifestyle-modification counseling. Primary endpoint, change in apnea-hypopnea index (AHI), significantly favored phentermine 15 mg plus extended-release topiramate 92 mg (-31.5 events/h, 95% CI: -40.0, -22.9) over placebo (-16.6 events/h, 95% CI: -25.0, -8.2) at Week 28 (P =0.0084). At Week 28, there was a 10.2% (95% CI: -12.7, -7.6; 10.8 kg, 95% CI: -13.5, -8.0) mean decrease in weight in the phentermine 15 mg plus extended-release topiramate 92 mg group compared with 4.3% (95% CI: -6.6, -2.0; 4.7 kg, 95% CI: -7.2, -2.2) in the placebo group (P = 0.0006) and a positive, significant (P = 0.0003) correlation between percent change in weight and change in AHI. Significant improvements in overnight oxygen saturation and reduction in blood pressure compared with placebo were observed. Phentermine 15 mg plus extended-release topiramate 92 mg was well tolerated with low adverse event rates. Phentermine 15 mg plus extended-release topiramate 92 mg induced significant weight reductions and concomitant improvements in OSA and related symptoms vs placebo. This suggests weight loss mediated by phentermine 15 mg plus extended-release topiramate 92 mg may be useful in treatment of moderate to severe OSA in obese subjects unable or unwilling to comply with PAP treatment.

  2. Oral cancer

    Science.gov (United States)

    Complications of oral cancer may include: Complications of radiation therapy, including dry mouth and difficulty swallowing Disfigurement of the face, head, and neck after surgery Other spread ( metastasis ) of the cancer

  3. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Dry Mouth Burning Mouth Tooth Decay See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities ... OralHealth > Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens ...

  4. Oral Cancer Exam

    Science.gov (United States)

    ... Dry Mouth Burning Mouth Tooth Decay See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities ... OralHealth > Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens ...

  5. Oral Thrush (For Parents)

    Science.gov (United States)

    ... Giving Teens a Voice in Health Care Decisions Oral Thrush KidsHealth > For Parents > Oral Thrush Print A ... A en español Muguet (candidiasis oral) What Is Oral Thrush? Oral thrush is a very common yeast ...

  6. Disparities in Oral Health

    Science.gov (United States)

    ... 2020: Oral Health Objectives Site Map Disparities in Oral Health Recommend on Facebook Tweet Share Compartir Oral health ... to get and keep dental insurance. Disparities in Oral Health Some of the oral health disparities that exist ...

  7. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens during an oral cancer examination. Quick and painless, the exam can detect oral cancer early—when it can ...

  8. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Dental Research See All Continuing Education Practical Oral Care for People With Developmental Disabilities – This booklet presents ... developmental disabilities and offers strategies for providing oral care. NIDCR > OralHealth > Topics > Oral Cancer > Oral Cancer Exam ...

  9. Solid Rocket Testing at AFRL (Briefing Charts)

    Science.gov (United States)

    2016-10-21

    19b. TELEPHONE NUMBER (Include area code) 10/21/2016 Briefing Charts 01 October 2016 - 31 October 2016 Solid Rocket Testing at AFRL Robert Antypas Air...Unclassified SAR 18 R. Antypas N/A Solid Rocket Testing at AFRL 21 Oct 2016 Robert Antypas AFRL/RQRO -Distribution A: Approved for Public Release...Distribution Unlimited. PA#16492 2 Agenda • Solid Rocket Motors • History of Sea Level Testing • Small Component Testing • Full-scale Testing • Altitude

  10. Diclofenac transdermal patch versus the sustained release tablet: A ...

    African Journals Online (AJOL)

    Conclusion: Transdermal films of diclofenac, formulated with permeation enhancers, may have greater therapeutic advantages over conventional oral tablets in terms of prolonged release and improvement of patient compliance in rheumatoid arthritis. Keywords: Analgesic activity, Diclofenac, Permeation enhancer, ...

  11. Characterization, in Vivo and in Vitro Evaluation of Solid Dispersion of Curcumin Containing d-α-Tocopheryl Polyethylene Glycol 1000 Succinate and Mannitol.

    Science.gov (United States)

    Song, Im-Sook; Cha, Jin-Sun; Choi, Min-Koo

    2016-10-17

    The aim of this study was to prepare a solid dispersion formulation of curcumin to enhance its solubility, dissolution rate, and oral bioavailability. The formulation was prepared with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mannitol using solvent evaporation and freeze-drying methods, which yielded a solid dispersion composed of curcumin, TPGS, and mannitol at a ratio of 1:10:15 (w/w/w). The solubility and dissolution rate of the curcumin solid dispersion markedly improved compared with those of curcumin powder and a physical mixture of curcumin, TPGS, and mannitol. About 90% of the curcumin was released from the solid dispersion formulation within 10 min. After administering the formulation orally to rats, higher plasma concentrations of curcumin were observed, with increases in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 86- and 65-fold, respectively, compared with those of curcumin powder. The solid dispersion formulation effectively increased intestinal permeability and inhibited P-gp function. These effects increased the anti-proliferative effect of curcumin in MDA-MB-231 breast cancer cells. Moreover, 2 h incubation with curcumin powder, solid dispersion formulation, and its physical mixture resulted in differential cytotoxic effect of paclitaxel in P-gp overexpressed LLC-PK1-P-gp and MDA-MB-231 cells through the inhibition of P-gp-mediated paclitaxel efflux. In conclusion, compared with curcumin, a solid dispersion formulation of curcumin with TPGS and mannitol could be a promising option for enhancing the oral bioavailability and efficacy of curcumin through increased solubility, dissolution rate, cell permeability, and P-gp modulation.

  12. VB12-coated Gel-Core-SLN containing insulin: Another way to improve oral absorption.

    Science.gov (United States)

    He, Haibing; Wang, Puxiu; Cai, Cuifang; Yang, Rui; Tang, Xing

    2015-09-30

    To improve the oral absorption of insulin, a novel carrier of Vitamin B12 (VB12) gel core solid lipid nanopaticles (Gel-Core-SLN, GCSLN) was designed with a gel core, lipid matrix and VB12-coated surface. VB12-stearate was synthesized and characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Sol-gel conversion following ultrasonic heating and double emulsion technology were combined to implant the insulin-containing gel into solid lipid nanoparticles (SLN). The influence of the mode of administration, food, the amount of VB12-stearate and the particle size on the oral absorption of insulin incorporated in the VB12-GCSLN was investigated. The determined partition coefficient (LogP) of VB12-stearate in a dichloromethane (DCM)-water system was 3.4. This new structure of VB12-GCSLN had higher insulin encapsulation efficiency (EE) of 55.9%, a lower burst release of less than 10% in the first 2h. In vivo studies demonstrated that stronger absorption of insulin with a relative pharmacological availability (PA) of 9.31% compared with the normal insulin-loaded SLN and GCSLN and fairly stable blood glucose levels up to 12h were maintained without any sharp fluctuations. This study suggests that VB12-GCSLN containing insulin appears to be a promising nano carrier for oral delivery of biomacromolecules with relatively high pharmacological availability. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Solid electrolytes

    Science.gov (United States)

    Abraham, Kuzhikalail M.; Alamgir, Mohamed

    1993-06-15

    This invention pertains to Li ion (Li.sup.+) conductive solid polymer electrolytes composed of solvates of Li salts immobilized (encapsulated) in a solid organic polymer matrix. In particular, this invention relates to solid polymer electrolytes derived by immobilizing complexes (solvates) formed between a Li salt such as LiAsF.sub.6, LiCF.sub.3 SO.sub.3 or LiClO.sub.4 and a mixture of aprotic organic solvents having high dielectric constants such as ethylene carbonate (EC) (dielectric constant=89.6) and propylene carbonate (PC) (dielectric constant=64.4) in a polymer matrix such as polyacrylonitrile, poly(tetraethylene glycol diacrylate), or poly(vinyl pyrrolidinone).

  14. Study of reaction and heat release from solid combustion in strong magnetic field; Kyojiba wo riyoshita hikinshitsu kotai nensho shori no hanno to netsu no seigy ni kansuru kiso kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Ito, K.; Fujita, O.; Iiya, M.; Kudo, K. [Hokkaido University, Sapporo (Japan)

    1997-02-01

    To establish the inhomogeneous solid combustion control technology, effects of the strong magnetic field on the solid combustion were examined. When applying the sufficiently strong magnetic field, it is possible to control the air flow in combustion field by utilizing the force applying to constituent oxygen with large susceptibility. Based on this possibility, combustion experiments of expanded polystyrene plates were conducted between the magnetic poles of electro-magnet having the maximum flux density of 1 T and the maximum magnetic field gradient of 0.5 T/cm. To observe the effects of magnetic field without the effects of natural convection, combustion experiments of acrylic sheets were conducted between the magnetic poles of electro-magnet having the maximum flux density of 0.6 T and the magnetic field gradient of about 0.1 T/cm under the microgravity conditions between 10{sup -4} and 10{sup -5}g using a microgravity test facility. Consequently, prospective combustion results could be obtained, in which the force of flame received from the magnetic field is almost equivalent to the buoyancy of flame. It was demonstrated that combustion can be controlled by the magnetic field. 1 ref., 3 figs., 1 tab.

  15. Oral drug therapy in elderly with dysphagia: between a rock and a hard place!

    Directory of Open Access Journals (Sweden)

    Logrippo S

    2017-01-01

    Full Text Available Serena Logrippo,1,2 Giovanna Ricci,3 Matteo Sestili,4 Marco Cespi,2 Letizia Ferrara,4 Giovanni F Palmieri,2 Roberta Ganzetti,4 Giulia Bonacucina,2 Paolo Blasi2 1School of Advanced Studies, 2School of Pharmacy, 3School of Law, University of Camerino, Camerino, 4Italian National Research Centers on Ageing (INRCA, Ancona, Italy Abstract: Demographic indicators forecast that by 2050, the elderly will account for about one-third of the global population. Geriatric patients require a large number of medicines, and in most cases, these products are administered as solid oral solid dosage forms, as they are by far the most common formulations on the market. However, this population tends to suffer difficulties with swallowing. Caregivers in hospital geriatric units routinely compound in solid oral dosage forms for dysphagic patients by crushing the tablets or opening the capsules to facilitate administration. The manipulation of a tablet or a capsule, if not clearly indicated in the product labeling, is an off-label use of the medicine, and must be supported by documented scientific evidence and requires the patient’s informed consent. Compounding of marketed products has been recognized as being responsible for an increased number of adverse events and medical errors. Since extemporaneous compounding is the rule and not the exception in geriatrics departments, the seriousness and scope of issues caused by this daily practice are probably underestimated. In this article, the potential problems associated with the manipulation of authorized solid oral dosage forms are discussed. Keywords: geriatric medicine, dysphagia, compounding, modified-release formulations, gastrointestinal tract toxicity

  16. DETERMINATION OF METAL IONS RELEASED BY STAINLESS ...

    African Journals Online (AJOL)

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    their tendency to undergo electrochemical corrosion while in contact with physiological fluids. The electrochemical reaction resulting to the release of metal ions is coupled with a corresponding reduction reaction of constituents in the aqueous environment to maintain charge neutrality [3]. The oral cavity is warm and damp, ...

  17. A modified commercial gas chromatograph for the continuous monitoring of the thermal degradation of sunflower oil and off-line solid phase extraction gas-chromatography-mass spectrometry characterization of released volatiles.

    Science.gov (United States)

    Ontañon, I; Sanz, J; Escudero, A; de Marcos, S; Ferreira, V; Galbán, J

    2015-04-03

    A homemade flow cell attached to a commercial Gas Chromatograph equipped with a Flame Ionization Detector (FID) has been designed for the continuous monitoring of volatile compounds released during heating edible oils. Analytical parameters such as mass of sample, temperature and flow rates have been optimized and the obtained results have been compared with the corresponding thermographs from standard TG systems. Results show that under optimum conditions, the profiles of volatiles released upon heating are comparable to the profiles of TG curves, suggesting that the FID based system could be an alternative to TGA. Additionally, volatiles have been retained in a Lichrolut EN(®) resin, eluted and analyzed by Gas Chromatography-Mass Spectrometry. In this case, forty five compounds have been identified (acids, alcohols, alkanes, aldehydes, ketones and furans) and compared with the FID signals, working both in air or nitrogen atmosphere. It has been concluded that the oxidative thermal degradation is prevented in the presence of a nitrogen atmosphere. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. 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.

  19. Oral myiasis

    Directory of Open Access Journals (Sweden)

    Treville Pereira

    2010-01-01

    Full Text Available Myiasis is a relatively rare condition arising from the invasion of body tissues or cavities of living animals or humans by maggots or larvae of certain species of flies. It is an uncommon clinical condition, being more frequent in underdeveloped countries and hot climate regions, and is associated with poor hygiene, suppurative oral lesions; alcoholism and senility. Its diagnosis is made basically by the presence of larvae. The present article reports a case of oral myiasis involving 20 larvae in a patient with neurological deficiency.

  20. Randomised clinical trial: delayed-release oral mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing--ASCEND I and II combined analysis.

    Science.gov (United States)

    Lichtenstein, G R; Ramsey, D; Rubin, D T

    2011-03-01

    Recent studies have focused on the importance of mucosal healing in ulcerative colitis (UC). However, it was still unclear whether higher doses of delayed-release mesalazine (mesalamine) could provide additional benefit. To examine how two doses of delayed-release mesalazine (4.8 g/day and 2.4 g/day) from ASCEND I and II compare in their relative ability to heal colonic mucosa over time. Primary data from two prospective 6-week, double-blind, randomised studies in patients with mildly to moderately active UC were pooled and analysed retrospectively. The mucosal healing analysis focuses on moderately active UC patients (n=391), comprising a majority of patients (84%). Additional analyses examined the relationship between mucosal healing and dose, clinical response to therapy and patient quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ). At week 3, mucosal healing (endoscopy subscore of 0 or 1) was achieved in 65% of moderately active UC patients on 4.8 g/day and 58% of patients on 2.4 g/day (P=0.219). At week 6, this increased to 80% for 4.8 g/day and 68% for 2.4 g/day (P=0.012). Healing rates with the higher dose were also greater across all extents of disease and in patients with prior steroid use. At 6 weeks, clinical response to therapy and mucosal healing were found to be well correlated (kappa=0.694). Likewise, the change in IBDQ at week 6 showed a significant relationship with mucosal healing (Pdelayed-release mesalazine at 4.8 g/day vs. 2.4 g/day. © 2011 Blackwell Publishing Ltd.

  1. Oral leukoplakia

    DEFF Research Database (Denmark)

    Kjærgaard Larsen, Marie; Sorensen, J. A.; Godballe, C.

    2016-01-01

    BACKGROUND AND AIM: Oral leukoplakia (OL) is a common premalignant lesion. The possible benefits of specific interventions in preventing a malignant transformation of OL are not well understood. This review assesses different invasive treatment techniques for OL and evaluate the optimal treatment...

  2. 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

  3. Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

    Science.gov (United States)

    Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y

    2011-01-01

    Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product. PMID:22238508

  4. Oral care.

    Science.gov (United States)

    Hitz Lindenmüller, Irène; Lambrecht, J Thomas

    2011-01-01

    Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing/recovering from chemo-/radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases. The use of a toothbrush is the most important measure for oral hygiene. Toothbrushes with soft bristles operated carefully by hand or via an electric device help to remove plaque and to avoid mucosal trauma. A handlebar with a grip cover can be helpful for manually disabled patients or for those with reduced motor skills. In case of oral hygiene at the bedside or of patients during/after chemo-/radiotherapy a gauze pad can be helpful for gently cleaning the teeth, gums and tongue. The use of fluoride toothpaste is imperative for the daily oral hygiene. Detergents such as sodium lauryl sulphate improve the cleaning action but may also dehydrate and irritate the mucous membrane. The use of products containing detergents and flavouring agents (peppermint, menthol, cinnamon) should therefore be avoided by bedridden patients or those with dry mouth and sensitive mucosa. Aids for suitable interdental cleaning, such as dental floss, interdental brushes or dental sticks, are often complicated to operate. Their correct use should be instructed by healthcare professionals. To support dental care, additional fluoridation with a fluoride gel or rinse can be useful. Products further containing antiseptics such as chlorhexidine or triclosan reduce the quantity of bacteria in the mouth. For patients undergoing or having undergone radio-/chemotherapy, a mouthwash that concomitantly moisturizes the oral mucosa is advisable. Copyright © 2011 S. Karger AG, Basel.

  5. Silica-based systems for oral delivery of drugs, macromolecules and cells.

    Science.gov (United States)

    Diab, Roudayna; Canilho, Nadia; Pavel, Ileana A; Haffner, Fernanda B; Girardon, Maxime; Pasc, Andreea

    2017-11-01

    According to the US Food and Drug Administration and the European Food Safety Authority, amorphous forms of silica and silicates are generally recognized to be safe as oral delivery ingredients in amounts up to 1500mg per day. Silica is used in the formulation of solid dosage forms, e.g. tablets, as glidant or lubricant. The synthesis of silica-based materials depends on the payload nature, drug, macromolecule or cell, and on the target release (active or passive). In the literature, most of the examples deal with the encapsulation of drugs in mesoporous silica nanoparticles. Still to date limited reports concerning the delivery of encapsulated macromolecules and cells have been reported in the field of oral delivery, despite the multiple promising examples demonstrating the compatibility of the sol-gel route with biological entities, likewise the interest of silica as an oral carrier. Silica diatoms appear as an elegant, cost-effective and promising alternative to synthetic sol-gel-based materials. This review reports the latest advances silica-based systems and discusses the potential benefits and drawbacks of using silica for oral delivery of drugs, macromolecules or cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. EVALUATION OF CHEMICAL RELEASES AND WORKER EXPOSURES FROM FILTER PRESS OPERATIONS

    Science.gov (United States)

    The exposures (inhalation and dermal) and releases (air, water, solids, and process streams) associated with the filtration of industrial wastewater sludge from an electronics manufacturing plant were characterized. Chemical releases and worker exposures for a target chemical (t...

  7. News/Press Releases

    Data.gov (United States)

    Office of Personnel Management — A press release, news release, media release, press statement is written communication directed at members of the news media for the purpose of announcing programs...

  8. Oral Health and Aging

    Science.gov (United States)

    ... please turn JavaScript on. Feature: Oral Health and Aging Oral Health and Aging Past Issues / Summer 2016 Table of Contents Jerrold ... they may need. Read More "Oral Health and Aging" Articles Oral Health and Aging / 4 Myths About ...

  9. Oral Cancer Facts

    Science.gov (United States)

    ... Events Get involved Dental Research Resources Contact Sitemap Oral Cancer Facts Home » Oral Cancer Facts Oral Cancer Facts ... needed on the Check Your Mouth website. How oral cancer develops We know that all cancers (neoplastic transformations) ...

  10. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens during an oral cancer examination. Quick and painless, the exam can detect ...

  11. A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.

    Science.gov (United States)

    Barmat, Larry I; Chantilis, Samuel J; Hurst, Bradley S; Dickey, Richard P

    2005-02-01

    To compare the effects of oral contraceptive (OC) pill pretreatment in recombinant FSH/GnRH-antagonist versus recombinant FSH/GnRH-agonist stimulation in in vitro fertilization (IVF) patients, and to evaluate optimization of retrieval day. Prospective, randomized, multicenter study. Private practice and university centers. Eighty patients undergoing IVF who met the appropriate inclusion criteria. Four study centers recruited 80 patients. The OC regimen began on cycle days 2 to 4 and was discontinued on a Sunday after 14 to 28 days. The recombinant FSH regimen was begun on the following Friday. The GnRH-agonist group was treated with a long protocol; the GnRH-antagonist was initiated when the lead follicle reached 12 to 14 mm. When two follicles had reached 16 to 18 mm, hCG was administered. The primary outcome measures were the number of cumulus-oocyte complexes, day of the week for oocyte retrieval, and total dose and days of stimulation of recombinant FSH. Secondary efficacy variables included pregnancy and implantation rate; serum E(2) levels on stimulation day 1; serum E(2), P, and LH levels on the day of hCG administration; follicle size on day 6 and day of hCG administration; the total days of GnRH-analogue treatment; total days on OC; total days from end of OC to oocyte retrieval; and the cycle cancellation rate. Patient outcomes were similar for the days of stimulation, total dose of gonadotropin used, two-pronuclei embryos, pregnancy (44.4% GnRH-antagonist vs. 45.0% GnRH-agonist, P=.86) and implantation rates (22.2% GnRH-antagonist vs. 26.4% GnRH-agonist, P=.71). Oral contraceptive cycle scheduling resulted in 78% and 90% of retrievals performed Monday through Friday for GnRH-antagonist and GnRH-agonist. A one day delay in OC discontinuation and recombinant FSH start would result in over 90% of oocyte retrievals occurring Monday through Friday in both groups. The OC pretreatment in recombinant FSH/GnRH-antagonist protocols provides a patient

  12. Preparation and Evaluation of Sustained Release Matrix Tablets of ...

    African Journals Online (AJOL)

    Erah

    Purpose: To prepare oral sustained release matrix tablets of a highly water soluble drug, tramadol hydrochloride, and to evaluate the effect of .... (IRAffinity-1, Shimadzu). Their spectra were obtained over the wave number range of ... square root kinetic model describes a time- dependent release process. The value of n.

  13. Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release.

    Science.gov (United States)

    Dolinina, Ekaterina S; Parfenyuk, Elena V

    2017-01-01

    Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer-Peppas model and Hixson-Crowell model. The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Oral strip technology: overview and future potential.

    Science.gov (United States)

    Dixit, R P; Puthli, S P

    2009-10-15

    Over the recent past, many of the research groups are focusing their research on this technology. Amongst the plethora of avenues explored for rapid drug releasing products, Oral Strip Technology (OST) is gaining much attention. The advantages of OST are the administration to pediatric and geriatric patient population where the difficulty of swallowing larger oral dosage forms is eliminated. This technology has been used for local action, rapid release products and for buccoadhesive systems that are retained for longer period in the oral cavity to release drug in controlled fashion. OST offers an alternate platform for molecules that undergo first pass metabolism and for delivery of peptides. The review article is an overview of OST encompassing materials used in OST, critical manufacturing aspects, applications, commercial technologies and future business prospects of this technology.

  15. Release of copper from embedded solid copper bullets into muscle and fat tissues of fallow deer (Dama dama), roe deer (Capreolus capreolus), and wild boar (Sus scrofa) and effect of copper content on oxidative stability of heat-processed meat.

    Science.gov (United States)

    Schuhmann-Irschik, I; Sager, M; Paulsen, P; Tichy, A; Bauer, F

    2015-10-01

    When venison with embedded copper bullets was subjected to different culinary processing procedures, the amount of copper released from the embedded bullet was affected more by the retention period of the bullet in the meat during cool storage, than by the different heating protocols. The presence of copper fragments had no significant effect on levels of thiobarbituric acid reactive substances (TBARS). Conversely, TBARS in lean meat (fallow deer, wild boar, roe deer) were significantly affected by culinary treatment (higher TBARS in boiled and boiled-stored meat than in meat barbecued or boiled in brine). In pork-beef patties doped with up to 28mg/kg Cu, TBARS increased after dry-heating and subsequently storing the meat patties. The amount of copper doping had no effect on TBARS for 0 and 7days of storage, but a significant effect at day 14 (fat oxidation retarded at higher Cu doses). Evidence is presented that wild boar meat may be more sensitive to fat oxidation than pork-beef. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Toward a detailed characterization of oil adsorbates as "solid liquids".

    Science.gov (United States)

    Kutza, Claudia; Metz, Hendrik; Kutza, Johannes; Syrowatka, Frank; Mäder, Karsten

    2013-05-01

    Solid lipid formulation systems are used to overcome oral bioavailability problems of poorly water-soluble drugs. One promising process is the conversion of a liquid lipid system in a free flowing powder by use of adsorbing excipients. The aim of this study was the detailed characterization of solid-liquid interactions in oil adsorbed to Fujicalin and Neusilin which were manufactured by means of dual asymmetric centrifugation or conventional mortar/pestle blending. The adsorption strength of the excipients was investigated by Benchtop-NMR and ESR spectroscopy revealing the highest adsorption power for the Neusilin products. The adsorbate production methods as well as the storage of the excipients impact their adsorption properties. Environmental scanning electron microscopy (ESEM) and confocal laser scanning microscopy (CLSM) show that dual asymmetric centrifugation leads to a smoothing of the particle surface, whereas the mortar/pestle blending results in an uneven surface and particle destruction. The oil distribution at the particles is inhomogeneous for both production methods. The micropolarity of the adsorbed oil was investigated by ESR spectroscopy and multispectral fluorescence imaging. The adsorbing process on Neusilin leads to an increased micropolarity of the oil component. The release of the oil component in aqueous media could be verified by Benchtop-NMR and multispectral fluorescence imaging. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. FORMULATION AND EVALUATION OF PRAVASTATIN SODIUM IMMEDIATE RELEASE TABLETS

    OpenAIRE

    Devanand Pinate; Ravikumar; Mahesh Kumar S; Senthil A; Raut Rahul; Narayanaswamy V B

    2012-01-01

    The aim of present investigation is to develop immediate release formulation of Pravastatin sodium for oral drug delivery by using suitable concentration of superdisintegrants. Croscarmellose sodium (AC-DI-SOL), povidone, MCC, Magnesium oxide, magnesium stearate were used to formulate the Immediate release tablet. Croscarmellose sodium was used as superdisintegrant and povidone was used as a binder to control the release of drug. Optimization of superdisintegrant concentration that can contro...

  18. Controlled Dissolution of Griseofulvin Solid Dispersions from Electrosprayed Enteric Polymer Micromatrix Particles: Physicochemical Characterization and in Vitro Evaluation.

    Science.gov (United States)

    Roine, Jorma; Kaasalainen, Martti; Peurla, Markus; Correia, Alexandra; Araújo, Francisca; Santos, Hélder A; Murtomaa, Matti; Salonen, Jarno

    2015-07-06

    The oral bioavailability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bioavailability can be improved by enhancing the physicochemical properties of the drug (e.g., dissolution rate, permeation across the gastrointestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseofulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micromatrix particles, which were produced by electrospraying. Similar micromatrix particles were also produced with griseofulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micromatrices. The in vitro drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micromatrix particles, were investigated. The micromatrix particles were found to be gastro-resistant, while at pH 6.8 the griseofulvin was released very rapidly in a fast-dissolving form. Compared to free griseofulvin, the permeability of encapsulated griseofulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micromatrix particles. The griseofulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bioavailability of poorly water-soluble or otherwise problematic drugs.

  19. [Oral complications of chemotherapy of malignant neoplasms].

    Science.gov (United States)

    Obralić, N; Tahmiscija, H; Kobaslija, S; Beslija, S

    1999-01-01

    Function and integrity disorders of the oral cavity fall into the most frequent complication of the chemotherapy of leucemias, malignant lymphomas and solid tumors. Complications associated with cancer chemotherapy can be direct ones, resulting from the toxic action of antineoplastic agents on the proliferative lining of the mouth, or indirect, as a result of myelosuppression and immunosuppression. The most frequent oral complications associated with cancer chemotherapy are mucositis, infection and bleeding. The principles of prevention and management of oral complications during cancer chemotherapy are considered in this paper.

  20. Orlistat accelerates gastric emptying and attenuates GIP release in healthy subjects

    DEFF Research Database (Denmark)

    Enç, Feruze Yilmaz; Ones, Tunç; Akin, H Levent

    2008-01-01

    Orlistat, an inhibitor of digestive lipases, is widely used for the treatment of obesity. Previous reports on the effect of orally ingested orlistat together with a meal on gastric emptying and secretion of gut peptides that modulate postprandial responses are controversial. We investigated......, implying that inhibition of fat absorption modifies determinants of gastric emptying of a meal. Orlistat administered similar to its use in obesity treatment accelerates gastric emptying of a solid mixed meal with a moderate energy load and profoundly attenuates release of GIP without appreciably altering...... plasma responses of CCK, GLP-1, and PP. Since GIP is being implemented in the development of obesity, its role in weight control attained by orlistat awaits further investigation....

  1. Premature: growth and its relation to oral skills.

    Science.gov (United States)

    Vargas, Camila Lehnhart; Berwig, Luana Cristina; Steidl, Eduardo Matias dos Santos; Prade, Leila Sauer; Bolzan, Geovana; Keske-Soares, Márcia; Weinmann, Angela Regina Maciel

    2015-01-01

    To evaluate the influence of oral motor skills of premature infants on their oral feeding performance and growth, during neonatal hospitalization. Fifty-one newborns hospitalized in the neonatal intensive care unit of a hospital in Southern Brazil, between July 2012 and March 2013, were evaluated. The evaluation of oral feeding skills, according to Lau and Smith, was applied after prescription for starting oral feeding. The oral feeding performance was analyzed using the following variables: days taken to start independent oral feeding and hospital discharge. Growth was measured by weight, length, and head circumference, using the curves of Fenton, at birth, first and independent oral feeding, and hospital discharge. At birth, 71% preterm infants were proper for gestational age, most of them were males (53%), with average of 33.6 (±1.5) weeks of gestational age. The gestational age in the assessment did not influence the oral feeding performance of the premature infant and did not differ between levels. Time of transition from tube feeding to oral feeding and hospital stay was shorter when the oral skills were higher. At birth, there was a tendency of low weight and low oral feeding performance. Level IV premature infants in the release of oral feeding presented higher weights. The level of oral skills of the premature infant interfered positively on time of feeding transition from tube to independent oral feeding and hospital stay. Growth, represented by weight gain, was not affected by the level of oral skill.

  2. The Effect of Seasons Temperature and Nitrogen Release on Cow ...

    African Journals Online (AJOL)

    BSN

    maximum weekly rates of nitrogen release after digestion were 2.62 % for cow dung and 3.06% for pig dung. .... volatile solids remain in an anaerobic digester is an important factor in the digestion process. The solids retention time. (SRT) represents the average time ..... Energy Research Centre, University of Nigeria.

  3. [Sustained-release Opioids: Morphine, Oxycodone and Tapentadol].

    Science.gov (United States)

    Takahashi, Yoshika; Iseki, Masako

    2015-11-01

    Opioid analgesics are widely used for managing moderate to severe pain. In cancer pain management sustained-release opioids are used for continuous pain as well as immediate-release opioids for breakthrough pain. Sustained-release drugs have the advantage of stabilizing the blood concentration, although it takes some time to exert their effects. In Japan, the currently available oral sustained-release opioids include six types of sustained-release morphine (three are once-a-day formulations, while the rest are twice-a-day), one type of oxycodone and tapentadol. In this article, we will discuss the pharmacokinetic properties of MS Contin, Morphes, Kadian, P guard and Pacif as sustained-release morphine, Oxycontin as sustained-release oxycodone and Tapenta as sustained-release tapentadol.

  4. Compounding of slow-release niacinamide capsules: feasibility and characterization.

    Science.gov (United States)

    Radojkovic, Branko; Milić, Jela; Calija, Bojan

    2012-01-01

    The purpose of this study was to assess the feasibility of extemporaneous compounding of slow-release oral dosage form of niacinamide and to evaluate its release kinetics. The model formulation (preparation) was developed in the form of powder-filled hard gelatin capsules. Two slow-release preparations with different ratios of hypromellose have been prepared and evaluated in comparison with an immediate-release preparation. The dissolution tests were performed as per United States Pharmacopoeia requirements: Type I Apparatus, over 7 hours. Both slow-release preparations, containing 40% and 60% v/v hypromellose, respectively, have showed slow release kinetics. The dissolution profiles were significantly different, with similarity factor f2niacinamide capsules can be successfully compounded using hypromellose as a sole release rate modifier, and that the release mechanism is comparable to hydrophilic polymer matrix-based systems.

  5. Controlled release of vitamin B2 using mesoporous materials functionalized with amine-bearing gate-like scaffoldings.

    Science.gov (United States)

    Bernardos, Andrea; Aznar, Elena; Coll, Carmen; Martínez-Mañez, Ramón; Barat, Jose Manuel; Marcos, Ma Dolores; Sancenón, Félix; Benito, Angel; Soto, Juan

    2008-11-12

    A study on the controlled release of vitamin B(2) in pure water from mesoporous silica-based materials containing a pH- and anion-controlled nano-supramolecular gate-like ensembles built up by anchoring suitable polyamines on the external surface is reported (solid S1). This solid contains the vitamin (the delivered molecule) onto the pores, whereas the amine-based gate-like ensemble is anchored on the pore outlets. To obtain solid S1 the mesoporous MCM-41 support was first synthesized using tetraethyl orthosilicate (TEOS) as hydrolytic inorganic precursor and the surfactant hexadecyltrimethylammonium bromide (CTAB) as porogen species. Calcination of the mesostructured phase resulted in the starting solid. Then, first the vitamin and the latter an excess of 3-[2-(2-aminoethylamino)ethylamino]propyl-trimethoxysilane were added to the suspension containing the MCM-41 scaffolding and stirred. Solid S1 was characterized using standard solid state procedures. It was found that the functionalization process and the inclusion of the vitamin on the pores do not modify the mesoporous structure of the starting material. Delivery studies in water were carried out at pH 2 and 7. At pH 2 all the anions studied (sulfate, phosphate, GMP and ATP) strongly hinder vitamin release (C(anion)=1 x 10(-2) mol dm(-3)), whereas at pH 7 the delivery was observed for sulfate and GMP whereas the gate remained closed in the presence of ATP and phosphate. Selective delivery at neutral pH and no-liberation in acidic conditions can also be controlled with ATP and GMP using a suitable concentration of anion. The remarkable anion-controllable response of the gate-like ensembl