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.

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

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

Directory of Open Access Journals (Sweden)

J Gordon Millichap

2005-07-01

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

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

Science.gov (United States)

Bjarnadottir, G D; Johannsson, M; Magnusson, A; Rafnar, B O; Sigurdsson, E; Steingrimsson, S; Asgrimsson, V; Snorradottir, I; Bragadottir, H; Haraldsson, H M

2017-09-01

Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (pusers and non-users. To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

3D extrusion printing of high drug loading immediate release paracetamol tablets.

Science.gov (United States)

Khaled, Shaban A; Alexander, Morgan R; Wildman, Ricky D; Wallace, Martin J; Sharpe, Sonja; Yoo, Jae; Roberts, Clive J

2018-03-01

The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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

African Journals Online (AJOL)

matrix tablets and to systematically optimize its drug release using varying levels of xanthan gum and hydroxypropyl ... stomach and improve oral bioavailability of drugs that have ... which can affect its sustained release formulation. [19].

Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects.

Science.gov (United States)

Darwish, Mona; Bond, Mary; Tracewell, William; Robertson, Philmore; Yang, Ronghua

2015-01-01

A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included

Aminoclay–lipid hybrid composite as a novel drug carrier of fenofibrate for the enhancement of drug release and oral absorption

Directory of Open Access Journals (Sweden)

Yang L

2016-03-01

Full Text Available Liang Yang, Yating Shao, Hyo-Kyung Han BK Plus Project Team, College of Pharmacy, Dongguk University, Goyang, South Korea Abstract: This study aimed to prepare the aminoclay–lipid hybrid composite to enhance the drug release and improve the oral bioavailability of poorly water-soluble fenofibrate. Antisolvent precipitation coupled with an immediate freeze-drying method was adopted to incorporate fenofibrate into aminoclay–lipid hybrid composite (ALC. The optimal composition of the ALC formulation was determined as the ratios of aminoclay to krill oil of 3:1 (w/w, krill oil to fenofibrate of 2:1 (w/w, and antisolvent to solvent of 6:4 (v/v. The morphological characteristics of ALC formulation were determined using scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction, which indicated microcrystalline state of fenofibrate in ALC formulation. The ALC formulation achieved almost complete dissolution within 30 minutes, whereas the untreated powder and physical mixture exhibited less than 15% drug release. Furthermore, ALC formulation effectively increased the peak plasma concentration (Cmax and area under the curve (AUC of fenofibric acid (an active metabolite in rats by approximately 13- and seven-fold, respectively. Furthermore, ALC formulation exhibited much lower moisture sorption behavior than the lyophilized formulation using sucrose as a cryoprotectant. Taken together, the present findings suggest that ALC formulation is promising for improving the oral absorption of poorly soluble fenofibrate. Keywords: aminoclay, omega-3 phospholipids, fenofibrate, drug release, oral absorption 

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.

Interchangeability and comparative effectiveness between generic and brand montelukast immediate release tablets after a single oral administration in healthy volunteers.

Science.gov (United States)

Zaid, Abdel Naser; Mousa, Ayman; Ghazal, Nadia; Bustami, Rana

2015-01-01

Montelukast is a leukotriene receptor antagonist. The release of leukotrienes causes narrowing and constricting in the respiratory airways. Blocking the action of these leukotrienes, montelukast can be used for the prophylaxis and treatment of chronic asthma. The aim of this study was to evaluate the interchangeability and comparative effectiveness between a generic and a brand montelukast 10 mg immediate release tablets (Broncast(®) and Singulair(®), respectively) after a single oral dose among Arab Mediterranean volunteers. An open-label, randomized two-period crossover bioequivalence design was conducted in 31 healthy male volunteers with a 1 week washout between each study period and under fasting conditions. The plasma drug concentration was assessed by using a previously validated LC MS/MS method. The ratio between the generic and brand of geometric least squares means was reported for both generic and brand products. Moreover, an in vitro dissolution study was conducted on generic and brand tablets using three different pH media, and similarity and non-similarity factors (f2 and f1) were calculated. The used bioanalytical method was found to be linear within the range 6.098-365.855 ng/mL. The correlation coefficient was close to 0.999 during the course of the study validation. Statistical comparison of the main pharmacokinetic parameters showed the inexistence of any significant difference between generic and the brand. The point estimates (ratios of geometric means) were 111.939, 111.711, and 112.169 % for AUC0-24, AUC0-∞, and Cmax, respectively. The 90 % confidence intervals (CIs) were within the pre-defined limits of 80.00-125.00 % as specified by the FDA and EMA for bioequivalence studies. F2 and f1 were higher than 50 and lower than 15, respectively in all selected pH media. Broncast(®) immediate release film coated tablets (10 mg/tablet) are bioequivalent to Singulair(®) immediate release film coated tablets (10 mg/tablet), with a

In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation

DEFF Research Database (Denmark)

Franek, F; Jarlfors, A; Larsen, F.

2015-01-01

Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step...... not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability....... for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq®, an extended release formulation...

Analgesic Efficacy of a New Immediate-Release/Extended-Release Formulation of Ibuprofen: Results From Single- and Multiple-Dose Postsurgical Dental Pain Studies.

Science.gov (United States)

Christensen, Steven; Paluch, Ed; Jayawardena, Shyamalie; Daniels, Stephen; Meeves, Suzanne

2017-05-01

Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P ibuprofen IR/ER, respectively (P ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses. © 2016, The American College of Clinical Pharmacology.

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

Science.gov (United States)

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

2013-02-01

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

Development and validation of an in vitro–in vivo correlation (IVIVC model for propranolol hydrochloride extended-release matrix formulations

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Chinhwa Cheng

2014-06-01

Full Text Available The objective of this study was to develop an in vitro–in vivo correlation (IVIVC model for hydrophilic matrix extended-release (ER propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid.

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

DEFF Research Database (Denmark)

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

1999-01-01

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

Pharmacokinetic comparison of sustained- and immediate-release oral formulations of cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period, crossover, single-dose, food-effect, and multiple-dose study.

Science.gov (United States)

Lee, Donghwan; Lim, Lay Ahyoung; Jang, Seong Bok; Lee, Yoon Jung; Chung, Jae Yong; Choi, Jong Rak; Kim, Kiyoon; Park, Jin Woo; Yoon, Hosang; Lee, Jaeyong; Park, Min Soo; Park, Kyungsoo

2011-12-01

A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower C(max) and a similar AUC to the immediate-release (IR) formulation. The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for C(max) and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased C(max) and AUC significantly (P food and 23 with a high

Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: a single and multiple-dose, randomized, open-label, parallel study in healthy male subjects.

Science.gov (United States)

Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan

2012-12-01

The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.

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

Directory of Open Access Journals (Sweden)

Xiaoxia Yang

Full Text Available 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.

Quality evaluation of extemporaneous delayed-release liquid formulations of lansoprazole.

Science.gov (United States)

Melkoumov, Alexandre; Soukrati, Amina; Elkin, Igor; Forest, Jean-Marc; Hildgen, Patrice; Leclair, Grégoire

2011-11-01

The quality attributes of extemporaneous delayed-release liquid formulations of lansoprazole for oral administration were evaluated. A novel liquid formulation (3 mg/mL) of Prevacid FasTab in an Ora-Blend vehicle was prepared and compared with the Prevacid FasTab 30 mg and Prevacid-sodium bicarbonate 1 M formulation (3 mg/mL). The latter formulation was combined with hydrochloric acid 0.1 N, and the remaining lansoprazole content was assayed by high-performance liquid chromatography (HPLC). A batch of delayed-release liquid formulation was prepared to evaluate content uniformity. For content assay, three samples were prepared for each evaluated condition and each sample was analyzed in triplicate by HPLC. The lansoprazole in the sodium bicarbonate formulation was extensively degraded by quantities of hydrochloric acid 0.1 N in excess of 100 mL. Storage time and temperature had a significant effect on lansoprazole stability in the Ora-Blend formulation. The drug remained stable for seven days when the formulation was stored at 4.5-5.5 °C, but storage at 21-22 °C or the reduction of pH with citric acid accelerated lansoprazole degradation. The amount of lansoprazole released from the Ora-Blend formulation during the buffer stage of the dissolution test decreased with increases in formulation storage time, in formulation storage temperature, and in the amount of lansoprazole released and degraded during the acid stage of the test. An extemporaneous formulation consisting of lansoprazole microgranules in Ora-Blend maintained acceptable quality attributes when stored for three days at 4.5-5.5 °C.

Formulation and evaluation of orally disintegrating clopidogrel tablets

Directory of Open Access Journals (Sweden)

Gamal Mohamed Mahrous

Full Text Available ABSTRACT Recent advances in drug delivery systems have aimed to achieve better patient compliance. One of these advances is the formulation of orally disintegrating tablets (ODTs that dissolve instantaneously, releasing drugs within a few seconds without the need of water. The main objective of this paper was to prepare and develop ODTs of clopidogrel. The ODTs were prepared by direct compression. The effect of three superdisintegrants, namely crospovidone, croscarmellose sodium, and sodium starch glycolate, using three different disintegration times on the dissolution rate was investigated. The prepared tablets were evaluated for hardness, friability, disintegration time and in vitro drug release. Furthermore, the interaction of clopidogrel with the formulation excipients was studied using differential scanning calorimetry (DSC. DSC studies revealed that there were no interactions between the drug and the excipients used. All tablets had hardness values in the range 4.0-5.2 kp and friability lower than 1%. The weight and drug content uniformity of all formulations was within official limits according to BP. In vitro drug release studies of the ODTs showed that more than 90% of the drug was released within ten minutes. A palatability test in human volunteers showed acceptable taste and mouth feel. Thus, the obtained results conclusively demonstrated successful rapid disintegration of the formulated tablets and acceptable palatability.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

Science.gov (United States)

Hiremath, Praveen S; Saha, Ranendra N

2008-10-01

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

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

Science.gov (United States)

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

2014-02-01

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

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

Science.gov (United States)

Hiremath, Praveen S; Saha, Ranendra N

2008-01-01

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

Oral controlled release drug delivery system and Characterization of oral tablets; A review

Directory of Open Access Journals (Sweden)

Muhammad Zaman

2016-01-01

Full Text Available Oral route of drug administration is considered as the safest and easiest route of drug administration. Control release drug delivery system is the emerging trend in the pharmaceuticals and the oral route is most suitable for such kind of drug delivery system. Oral route is more convenient for It all age group including both pediatric and geriatrics. There are various systems which are adopted to deliver drug in a controlled manner to different target sites through oral route. It includes diffusion controlled drug delivery systems; dissolution controlled drug delivery systems, osmotically controlled drug delivery systems, ion-exchange controlled drug delivery systems, hydrodynamically balanced systems, multi-Particulate drug delivery systems and microencapsulated drug delivery system. The systems are formulated using different natural, semi-synthetic and synthetic polymers. The purpose of the review is to provide information about the orally controlled drug delivery system, polymers which are used to formulate these systems and characterizations of one of the most convenient dosage form which is the tablets. 

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

OpenAIRE

Yoon, Seonghae; Lee, Howard; Kim, Tae-Eun; Lee, SeungHwan; Chee, Dong-Hyun; Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin

2014-01-01

Seonghae Yoon,1,* Howard Lee,2,* Tae-Eun Kim,1 SeungHwan Lee,1 Dong-Hyun Chee,3 Joo-Youn Cho,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, 3AbbVie Ltd., Seoul, Republic of Korea *These authors contributed equally to this work Background: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER...

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

International Nuclear Information System (INIS)

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. - 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.

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.

Correlation of dissolution and disintegration results for an immediate-release tablet.

Science.gov (United States)

Nickerson, Beverly; Kong, Angela; Gerst, Paul; Kao, Shangming

2018-02-20

The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets.

Science.gov (United States)

Karkossa, Frank; Klein, Sandra

2017-10-01

The objective of this test series was to elucidate the importance of selecting the right media composition for a biopredictive in-vitro dissolution screening of enteric-coated dosage forms. Drug release from immediate-release (IR) and enteric-coated (EC) aspirin formulations was assessed in phosphate-based and bicarbonate-based media with different pH, electrolyte composition and ionic strength. Drug release from aspirin IR tablets was unaffected by media composition. In contrast, drug release from EC aspirin formulations was affected by buffer species and ionic strength. In all media, drug release increased with increasing ionic strength, but in bicarbonate-based buffers was delayed when compared with that in phosphate-based buffers. Interestingly, the cation species in the dissolution medium had also a clear impact on drug release. Drug release profiles obtained in Blank CarbSIF, a new medium simulating pH and average ionic composition of small intestinal fluid, were different from those obtained in all other buffer compositions studied. Results from this study in which the impact of various media parameters on drug release of EC aspirin formulations was systematically screened clearly show that when developing predictive dissolution tests, it is important to simulate the ionic composition of intraluminal fluids as closely as possible. © 2017 Royal Pharmaceutical Society.

Design and evaluation of nicorandil extended-release tablet

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Ju-Young Kim

2015-04-01

Full Text Available The aim of this study was to design and evaluate extended-release formulations of a model drug, nicorandil, in order to achieve the desired steady-state plasma concentration of drug in vivo. Simulation was employed to estimate optimum dissolution and absorption rate of nicorandil. The dissolution test was employed using pH 1.2, 4.0, 6.8 buffer solution, or water, to measure the in vitro release behaviors of nicorandil formulations. A single dose (15 mg of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. The in vitro/in vivo relationship of the extended-release formulation was confirmed using in vitro dissolution profiles and plasma concentrations of drug in beagle dogs. Nicorandil was released completely within 30 min from the immediate-release tablets and released for 24 h from the extended-release tablets. The nicorandil plasma concentration could be modified by adjusting the drug release rate from the extended-release formulation. The release rate of nicorandil was the rate-limiting step in the overall absorption of drug from the extended-release formulations. These results highlight the potential of a nicorandil extended-release formulation in the treatment of angina pectoris.

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

Science.gov (United States)

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

2011-01-01

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

Formulation of cefuroxime axetil oral suspension and investigation of its pharmaceutical properties

Directory of Open Access Journals (Sweden)

Hadi Valizadeh

2011-12-01

Full Text Available Purpose: Cefuroxime is the second generation cephalosporin, which its intravenous and oral dosage forms are available. Oral route is the selective method for administration of most of the drugs. The aim of this study was formulating ‘for oral’ cefuroxime axetil suspensions. Methods: Minitab (ver.15 was used to design the formulations containing 125 mg of cefuroxime in 5 ml vehicle.After selecting the acceptable preparations, physical stability tests and other tests such as dissolution rate, pH, zeta potential and viscosity measurement of formulations were performed. Results: From all 33 formulations, only 9 were selected to further investigation. Considering no sedimentation, the sedimentation volume was determined to be 1. The degrees of flocculation were also equal to 1. All selected formulations released the drug between 81-100% in 30 minutes which was acceptable according to the USP32 criteria. The results of assay test also proved that all formulations contain the drug in acceptable range (91-106%. The viscosity curves showed that the systems were pseudo plastic and thixotrop. Conclusion: Designed cefuroxime axetil formulations had good qualities and could be added as a new product to Iran drug marketing.

Disintegration of Highly Soluble Immediate Release Tablets: A Surrogate for Dissolution

OpenAIRE

Gupta, Abhay; Hunt, Robert L.; Shah, Rakhi B.; Sayeed, Vilayat A.; Khan, Mansoor A.

2009-01-01

The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegrat...

Controlled-release tablet formulation of isoniazid.

Science.gov (United States)

Jain, N K; Kulkarni, K; Talwar, N

1992-04-01

Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.

Formulation and Pharmacokinetic Evaluation of Controlled-Release ...

African Journals Online (AJOL)

A coating layer was then applied with a mixture of HPMC, ethylcellulose, shellac, and HPMC phthalate. The effect of several formulation variables on in vitro drug release was studied; furthermore, the drug release kinetics of the optimized formulation was evaluated. The in vivo pharmacokinetics of the optimized formulation ...

Oral sustained release tablets of zidovudine using binary blends of natural and synthetic polymers.

Science.gov (United States)

Emeje, Martins; Olaleye, Olajide; Isimi, Christiana; Fortunak, Joseph; Byrn, Stephen; Kunle, Olobayo; Ofoefule, Sabinus

2010-01-01

Oral sustained release matrix tablets of zidovudine (ZDV) were prepared using different types, proportions and blends of carbopol 71G (C71) and a plant gum obtained from Abelmoschus esculentus (AEG). The effect of various formulation factors like polymer proportion, polymer type and pH of the dissolution medium on the in vitro release of the drug was studied, using the half change technique, in 900 ml of dissolution medium, at 100 rpm. Release kinetics were analyzed using Zero-order, Higuchi's square-root and Ritger-Peppas' empirical equations. In vitro release performance as revealed by the time taken for 70% of the drug to be released (t70%), showed that the release rate decreased with increase in polymer proportion. Matrix tablets containing 10 and 20% AEG were found to exhibit immediate-release characteristics. Matrix tablets containing 30% AEG showed t70% value of 204 min and extended the release up to 5 h, while matrix tablets containing 30% carbopol showed t70% value of 234 min and extended the release up to 6 h. Three blends of AEG and C71 at the ratio of 1:2, 2:1 and 1:3 showed t70% values of 132, 312 and 102 min respectively and extended the release up to 8 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed Fickian and anomalous release. Drug release from matrix tablets of zidovudine containing blends of AEG and C71 demonstrates the advantage of blending a natural and synthetic polymer over single polymer use.

Risk based In Vitro Performance Assessment of Extended Release Abuse Deterrent Formulations

Science.gov (United States)

Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Calderon, Silvia N.; Khan, Mansoor A.

2016-01-01

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. PMID:26784976

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.

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

Science.gov (United States)

Sonvico, Fabio; Conti, Chiara; Colombo, Gaia; Buttini, Francesca; Colombo, Paolo; Bettini, Ruggero; Barchielli, Marco; Leoni, Barbara; Loprete, Luca; Rossi, Alessandra

2017-09-28

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Formulation and Pharmacokinetic Evaluation of Controlled-Release ...

African Journals Online (AJOL)

The effect of several formulation variables on in ... The in vivo pharmacokinetics of the optimized formulation was compared ... Results: The core tablets exhibited extended release consisting of drug release from the embedded ... important factor in medical treatment with respect ... The solvents for high-performance liquid.

TURVA-2012: Formulation of radionuclide release scenarios

International Nuclear Information System (INIS)

Marcos, Nuria; Hjerpe, Thomas; Snellman, Margit; Ikonen, Ari; Smith, Paul

2014-01-01

TURVA-2012 is Posiva's safety case in support of the Preliminary Safety Analysis Report (PSAR) and application for a construction licence for a repository for disposal of spent nuclear fuel at the Olkiluoto site in south-western Finland. This paper gives a summary of the scenarios and the methodology followed in formulating them as described in TURVA-2012: Formulation of Radionuclide Release Scenarios (Posiva, 2013). The scenarios are further analysed in TURVA-2012: Assessment of Radionuclide Release Scenarios for the Repository System and TURVA-2012: Biosphere Assessment (Posiva, 2012a, 2012b). The formulation of scenarios takes into account the safety functions of the main barriers of the repository system and the uncertainties in the features, events, and processes (FEP) that may affect the entire disposal system (i.e. repository system plus the surface environment) from the emplacement of the first canister until the far future. In the report TURVA-2012: Performance Assessment (2012d), the performance of the engineered and natural barriers has been assessed against the loads expected during the evolution of the repository system and the site. Uncertainties have been identified and these are taken into account in the formulation of radionuclide release scenarios. The uncertainties in the FEP and evolution of the surface environment are taken into account in formulating the surface environment scenarios used ultimately in estimating radiation exposure. Formulating radionuclide release scenarios for the repository system links the reports Performance Assessment and Assessment of Radionuclide Release Scenarios for the Repository System. The formulation of radionuclide release scenarios for the surface environment brings together biosphere description and the surface environment FEP and is the link to the assessment of the surface environment scenarios summarised in TURVA-2012: Biosphere Assessment. (authors)

Formulation strategy towards minimizing viscosity mediated negative food effect on disintegration and dissolution of immediate release tablets.

Science.gov (United States)

Zaheer, Kamran; Langguth, Peter

2018-03-01

Food induced viscosity can delay disintegration and subsequent release of API from solid dosage form which may lead to severe reduction in the bioavailability of BCS type III compounds. Formulations of such tablets need to be optimized in view of this postprandial viscosity factor. In this study, three super disintegrants, croscarmellose sodium (CCS), cross-linked polyvinylpolypyrrolidone (CPD), and sodium starch glycolate (SSG) were assessed for their efficiency under simulated fed state. Tablets containing these disintegrants were compressed at 10 and 30 KN, while taking lactose as a soluble filler. In addition to other compendial tests, disintegration force of these formulations was measured by texture analysis. Comparison of parameters derived from force - time curves revealed a direct relation of maximum disintegration force (F max ) and disintegration force development rate (DFDR) with compressional force in fasted state, whereas an inverse relationship of F max and DFDR with compressional force was observed in fed state. The gelling tendency of disintegrants influenced the rate of release of API in simulated fed and fasted states when compressional force was changed. These observations recommend the evaluation of formulations in simulated fed state, in the development stage, with an objective of minimizing the negative impact of food induced viscosity on disintegration. Use of disintegrants that act without gelling or can counteract the effect of gelling is recommended for tablet formulations with reduced disintegration time (DT) and mean dissolution time (MDT) in fed state, respectively.

Terbinafine: novel formulations that potentiate antifungal activities.

Science.gov (United States)

Ma, Y; Chen, X; Guan, S

2015-03-01

Terbinafine, an orally and topically active antifungal agent, has been available for the treatment of dermatophytic infections and onychomycosis for more than a decade. In addition, oral administration has been shown to be associated with drug-drug interactions, hepatotoxicity, low concentration at the infected sites, gastrointestinal and systemic side effects and other adverse effects. Since topical drug delivery can provide higher patient compliance, allow immediate access to the infected site and reduce unwanted systemic drug exposure, an improved topical drug delivery approach with high permeability, sustained release and prolonged retainment could overcome the limitations and side effects caused by oral administration. Conventional topical formulations cannot keep the drug in the targeted sites for a long duration of time and hence a novel drug delivery that can avoid the side effects while still providing sustained efficacy in treatment should be developed. This brief review of novel formulations based on polymers and nanostructure carriers provides insight into the efficacy and topical delivery of terbinafine. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Design of amphotericin B oral formulation for antifungal therapy.

Science.gov (United States)

Liu, Min; Chen, Meiwan; Yang, Zhiwen

2017-11-01

Amphotericin B (AmB) remains the "gold standard" for systemic antifungal therapy, even though new drugs are emerging as the attractive antifungal agents. Since AmB has negligible oral absorption as a consequence of its unfavorable physicochemical characterizations, its use is restricted to parenteral administration which is accompanied by severe side effects. As greater understanding of the gastrointestinal tract has developed, the advanced drug delivery systems are emerging with the potential to overcome the barriers of AmB oral delivery. Much research has demonstrated that oral AmB formulations such as lipid formulations may have beneficial therapeutic efficacy with reduced adverse effects and suitable for clinical application. Here we reviewed the different formulation strategies to enhance oral drug efficacy, and discussed the current trends and future perspectives for AmB oral administration in the treatment of antifungal infections.

Critical appraisal of extended-release hydrocodone for chronic pain: patient considerations

Directory of Open Access Journals (Sweden)

Gould HJ III

2015-10-01

Full Text Available Harry J Gould III,1,3–7 Dennis Paul1–8 1Department of Neurology, 2Department of Pharmacology and Experimental Therapeutics, 3Department of Internal Medicine, Section of Physical Medicine and Rehabilitation, 4Department of Anesthesiology, 5Neuroscience Center of Excellence, 6Center of Excellence for Oral and Craniofacial Biology, 7Pain Mastery Center of Louisiana, 8Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA Abstract: Opioid analgesics are currently the most effective pharmacologic option for the management of both acute and chronic forms of moderate-to-severe pain. Although the “as-needed” use of immediate-release formulations is considered optimum for treating acute, painful episodes of limited duration, the scheduled dosing of extended-release formulations with immediate-release supplementation for breakthrough pain is regarded to be most effective for managing chronic conditions requiring around-the-clock treatment. The recent introduction of extended-release formulations of the opioid analgesic hydrocodone potentially broadened the possibility of providing pain relief for individuals for whom current formulations are either ineffective or not tolerated. However, reaction to the approval of the new formulations has fueled controversy over the general safety and need for opioid medications, in light of their potential for misuse, abuse, diversion, and addiction. Here, we discuss how the approval of extended-release formulations of hydrocodone and the emotionally charged controversy over their release may affect physician prescribing and the care available to patients in need of chronic opioid therapy for the management of pain. Keywords: opioid analgesics, patient risks, patient benefits, misuse, addiction

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

Science.gov (United States)

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

2013-01-01

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

On the exfoliating polymeric cellular dosage forms for immediate drug release.

Science.gov (United States)

Blaesi, Aron H; Saka, Nannaji

2016-06-01

The most prevalent pharmaceutical dosage forms at present-the oral immediate-release tablets and capsules-are granular solids. Though effective in releasing drug rapidly, development and manufacture of such dosage forms are fraught with difficulties inherent to particulate processing. Predictable dosage form manufacture could be achieved by liquid-based processing, but cast solid dosage forms are not suitable for immediate drug release due to their resistance to fluid percolation. To overcome this limitation, we have recently introduced cellular dosage forms that can be readily prepared from polymeric melts. It has been shown that open-cell structures comprising polyethylene glycol 8000 (PEG 8k) excipient and a drug exfoliate upon immersion in a dissolution medium. The drug is then released rapidly due to the large specific surface area of the exfoliations. In this work, we vary the molecular weight of the PEG excipient and investigate its effect on the drug release kinetics of structures with predominantly open-cell topology. We demonstrate that the exfoliation rate decreases substantially if the excipient molecular weight is increased from 12 to 100kg/mol, which causes the drug dissolution time to increase by more than a factor of ten. A model is then developed to elucidate the exfoliation behavior of cellular structures. Diverse transport processes are considered: percolation due to capillarity, diffusion of dissolution medium through the cell walls, and viscous flow of the saturated excipient. It is found that the lower exfoliation rate and the longer dissolution time of the dosage forms with higher excipient molecular weight are primarily due to the greater viscosity of the cell walls after fluid penetration. Copyright © 2016 Elsevier B.V. All rights reserved.

Extended‐Release Once‐Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate‐Release Tofacitinib and Impact of Food

Science.gov (United States)

Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C.

2016-01-01

Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. PMID:26970526

Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers.

Science.gov (United States)

Dadey, Eric

Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-∞, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80%-125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.

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.

Controlled release of diuron from an alginate-bentonite formulation: water release kinetics and soil mobility study.

Science.gov (United States)

Fernández-Pérez, M; Villafranca-Sánchez, M; González-Pradas, E; Flores-Céspedes, F

1999-02-01

The herbicide diuron was incorporated in alginate-based granules to obtain controlled release (CR) properties. The standard formulation (alginate-herbicide-water) was modified by the addition of different sorbents. The effect on diuron release rate caused by incorporation of natural and acid-treated bentonites in alginate formulation was studied by immersion of the granules in water under static conditions. The release of diuron was diffusion-controlled. The time taken for 50% release of active ingredient to be released into water, T(50), was calculated for the comparison of formulations. The addition of bentonite to the alginate-based formulation produced the higher T(50) values, indicating slower release of the diuron. The mobility of technical and formulated diuron was compared by using soil columns. The use of alginate-based CR formulations containing bentonite produced a less vertical distribution of the active ingredient as compared to the technical product and commercial formulation. Sorption capacities of the various soil constituents for diuron were also determined using batch experiments.

Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design.

Science.gov (United States)

Tak, Jin Wook; Gupta, Biki; Thapa, Raj Kumar; Woo, Kyu Bong; Kim, Sung Yub; Go, Toe Gyeong; Choi, Yongjoo; Choi, Ju Yeon; Jeong, Jee-Heon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2017-05-01

The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1 ), ratio of HPMC to drug in the SR layer (X 2 ), and ratio of Eudragit RL PO to drug in the SR layer (X 3 ). The dependent variables assessed were % drug released in distilled water at 30 min (Y 1 ), % drug released in pH 1.2 at 2 h (Y 2 ), and % drug released in pH 6.8 at 12 h (Y 3 ). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.

[Formulation optimization of panax notoginsenoside orally fast disintegration tablets].

Science.gov (United States)

Wang, Zhi; Wei, Li; Chen, Ting

2008-07-01

To optimize the formulation of panax notoginsenoside orally fast disintegrating tablets. Mannitol, microcrystalline cellulose (PH 102) and lactose 80 were used as diluent. A polynomial regression algorithm was used to evaluate the relationship between the controlling factor, compacting pressure and diluent ratio, and disintegration time, tensile strength of tablets. Optimum formulation and process parameters could be determined by contrast the contour plot of tensile strength to that of disintegration time. The disintegration time and tensile strength of panax notoginsenoside oral disintegrating tablets were good, and the taste was satisfactory. Panax notoginsenoside oral disintegrating tablets achieve the goal of design and this method can be fairly used in formulation screening.

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

Science.gov (United States)

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

2015-07-01

A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

Continuous-release formulation for environmental doses to moving receptors

International Nuclear Information System (INIS)

Piepho, M.G.

1981-01-01

Atmospheric dispersion models frequently assume a puff release or several puff releases, each of which are described separately. A dispersion model should better describe a continuous release as more puffs are assumed, but the computational cost and bookkeeping difficulty increases with additional puffs. A new formulism is derived in this work which replaces the puff approximation. With the new continuous release formulation, radioactive dose calculations to moving receptors are more accurately calculated without any great additional computation. There are several advantages of a continuous release formulation. With this formulation, a dose rate to a moving receptor is calculated as a function of time. The dose-rate will increase (decrease) as the bulk of the release gets closer (farther) to (from) the receptor which is at position x(t), y(t). The receptor may follow any x, y trajectory as a function of time, and the dose rate will be calculated along the path

Formulation and Evaluation of New Glimepiride Sublingual Tablets

Directory of Open Access Journals (Sweden)

Wafa Al-Madhagi

2017-01-01

Full Text Available Oral mucosal delivery of drugs promotes rapid absorption and high bioavailability, with a subsequent immediate onset of pharmacological effect. However, many oral mucosal deliveries are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. The aim of this research was to introduce a new glimepiride formula for sublingual administration and rapid drug absorption that can be used in an emergency. The new sublingual formulation was prepared after five trials to prepare the suitable formulation. Two accepted formulations of the new sublingual product were prepared, but one of them with disintegration time of 1.45 min and searching for preferred formulation, the binder, is changed with Flulac and starch slurry to prepare formula with disintegration time of 21 seconds that supports the aim of research to be used in an emergency. The five formulations were done, after adjusting to the binder as Flulac and aerosil with disintegration time of 21 seconds and accepted hardness as well as the weight variation. The assay of a new product (subglimepiride is 103% which is a promising result, confirming that the formula succeeded. The new product (subglimepiride is accepted in most quality control tests and it is ready for marketing.

Disintegration of highly soluble immediate release tablets: a surrogate for dissolution.

Science.gov (United States)

Gupta, Abhay; Hunt, Robert L; Shah, Rakhi B; Sayeed, Vilayat A; Khan, Mansoor A

2009-01-01

The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria.

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.

Formulation and evaluation of a bilayer tablet comprising of diclofenac potassium as orodispersible layer and diclofenac sodium as sustained release core

OpenAIRE

Abbas, Jabbar; Bashir, Sajid; Samie, Muhammad; Laghari, Sadaf

2017-01-01

Diclofenac a phenylacetic acid derivative has long been used as an anti-inflammatory and analgesic drug to treat certain conditions however its sustained release formulation with immediate release loading dose is desirable. The rationale of the current work was to develop and evaluate bilayer tablets with diclofenac potassium as orodispersible layer and diclofenac sodium as sustained release core. The diclofenac sodium core was prepared by wet granulation method while the...

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

Directory of Open Access Journals (Sweden)

Jurjen van der Schans

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

Formulation and Characterization of Sustained Release Floating ...

African Journals Online (AJOL)

Purpose: To formulate sustained release gastroretentive microballoons of metformin hydrochloride with the objective of improving its bioavailability. Methods: Microballoons of metformin hydrochloride were formulated by solvent evaporation and diffusion method using varying mixtures of hydroxypropyl methylcellulose ...

Formulation of Sustained-Release Diltiazem Matrix Tablets Using ...

African Journals Online (AJOL)

Erah

surface, their drug release behavior appears simple, but ... matrix material for the formulation of ..... formulation F5 (,) and reference formulations. ( , □). 0. 50. 100. 150. 200. 250. 300. 0. 3. 6 .... Coviello T, Matricardi P, Marianecci C, Alhaique F.

Development of a new esomeprazole delayed release gastro-resistant pellet formulation with improved storage stability.

Science.gov (United States)

Barmpalexis, Panagiotis; Grypioti, Agni

2018-06-01

This study describes the development of a new esomeprazole (ESO) delayed release gastro-resistant formulation with improved storage stability. A three-step (drug-, sub(seal)- and enteric-) coating process was employed with the aid of a fluid bed coater. Several formulation factors (namely, size and quantity of starting non-pareil sugar spheres, binder quantity during drug-layering, sub(seal)-coating polymer type, and quantity and enteric coating quantity) were evaluated and the whole process was modeled with the aid of feed-forward back-propagation artificial neural networks (ANNs). Results showed that the selection of small-sized starting spheres (45/60 mesh size) leads to pellet agglomeration, while as sub(seal)-coating weight gain increases a reduction in ESO dissolution rate is observed. The enteric-coating applied (Eudragit L30D-55) showed good gastro-resistant performance in both 0.1 N HCl and pH 4.5 media, while immediate release profiles with more than 85% of ESO being released in less than 30 min were obtained. The effect of cellulose-based sub(seal)-coating polymers, (namely, hydroxypropyl cellulose and hydroxypropylmethyl cellulose) on formulation's storage stability at 40 ± 2 °C/75 ± 5%RH indicated that only hydroxypropylmethyl cellulose was able to stabilize ESO delayed-release formulations in terms of assay, dissolution, impurities, and gastro-resistance performance. Finally, scanning electron microscopy (SEM) analysis revealed smooth and homogeneous external surface/coating layers in all three levels (drug-, sub(seal)-, and enteric- coating), while x-ray diffraction showed no polymorphic transformations.

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

Science.gov (United States)

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

2012-08-01

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

Formulation and evaluation of controlled-release of telmisartan microspheres: In vitro/in vivo study

Directory of Open Access Journals (Sweden)

Praveen Kumar Gaur

2014-12-01

Full Text Available The aim of this work was to design a controlled-release drug-delivery system for the angiotensin-II receptor antagonist drug telmisartan. Telmisartan was encapsulated with different EUDRAGIT polymers by an emulsion solvent evaporation technique and the physicochemical properties of the formulations were characterized. Using a solvent evaporation method, white spherical microspheres with particle sizes of 629.9–792.1 μm were produced. The in vitro drug release was studied in three different pH media (pH 1.2 for 2 hours, pH 6.8 for 4 hours, and pH 7.4 for 18 hours. The formulations were then evaluated for their pharmacokinetic parameters. The entrapment efficiency of these microspheres was between 58.6% and 90.56%. The obtained microspheres showed good flow properties, which were evaluated in terms of angle of repose (15.29–26.32, bulk and tapped densities (0.37–0.53 and 0.43–0.64, respectively, Carr indices and Hausner ratio (12.94–19.14% and 1.14–1.23, respectively. No drug release was observed in the simulated gastric medium up to 2 hours; however, a change in pH from 1.2 to 6.8 increased the drug release. At pH 7.4, formulations with EUDRAGIT RS 100 showed a steady drug release. The microsphere formulation TMRS-3 (i.e., microspheres containing 2-mg telmisartan gave the highest Cmax value (6.8641 μg/mL at 6 hours, which was three times higher than Cmax for telmisartan oral suspension (TOS. Correspondingly, the area under the curve for TMRS-3 was 8.5 times higher than TOS. Particle size and drug release depended on the nature and content of polymer used. The drug release mechanism of the TMRS-3 formulation can be explained using the Higuchi model. The controlled release of drug from TMRS-3 also provides for higher plasma drug content and improved bioavailability.

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

In vitro Evaluation of Nateglinide-Loaded Microspheres Formulated ...

African Journals Online (AJOL)

Keywords: Nateglinide, Microspheres, Micromeritics, Drug release, Ionic ... Oral drug delivery systems (DDS) are commonly divided into immediate release and modified release systems. ..... Albumin Microspheres for Potential Intramuscular.

Clinical studies with oral lipid based formulations of poorly soluble compounds

DEFF Research Database (Denmark)

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

2007-01-01

. Several drug products intended for oral administration have been marketed utilizing lipid and surfactant based formulations. Sandimmune((R)) and Sandimmune Neoral((R)) (cyclosporin A, Novartis), Norvir((R)) (ritonavir), and Fortovase((R)) (saquinavir) have been formulated in self-emulsifying drug delivery...... systems (SEDDS). This review summarizes published pharmacokinetic studies of orally administered lipid based formulations of poorly aqueous soluble drugs in human subjects. Special attention has been paid to the physicochemical characteristics of the formulations, when available and the impact...

Model‐Informed Development and Registration of a Once‐Daily Regimen of Extended‐Release Tofacitinib

Science.gov (United States)

Lamba, M; Hutmacher, MM; Furst, DE; Dikranian, A; Dowty, ME; Conrado, D; Stock, T; Nduaka, C; Cook, J

2017-01-01

Extended‐release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model‐informed, exposure–response (E‐R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E‐R analyses were conducted using validated clinical endpoints from phase II dose–response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration. PMID:27859030

Drug delivery systems with modified release for systemic and biophase bioavailability.

Science.gov (United States)

Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Formulation of Extended-Release Metformin Hydrochloride Matrix ...

African Journals Online (AJOL)

Methods: Various metformin hydrochloride formulations containing a hydrophobic carrier (stearic acid) and a hydrophilic polymer (polyethylene oxide) were prepared using a 32 factorial design. ... The release data were subjected to various release kinetic models and also compared with those of a commercial brand.

Cetirizine release from cyclodextrin formulated compressed chewing gum

DEFF Research Database (Denmark)

Stojanov, Mladen; Larsen, Kim Lambertsen

2012-01-01

release patterns, but with variations in the total amount released. Chewing gum formulated with cetirizine alone, demonstrated a release of 75% after 8 min of chewing. The presence of CDs resulted in increased cetirizine release. The analysis of variance (ANOVA) demonstrated that parameters with the most...... the statistical analysis (ANOVA) demonstrated significance in the release (P

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

Science.gov (United States)

Helmy, Sally A; El-Bedaiwy, Heba M

2014-11-01

Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated. © 2014, The American College of Clinical Pharmacology.

Impairment of the in vitro Release of Carbamazepine from Tablets

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Alija Uzunović

2010-08-01

Full Text Available Carbamazepine belongs to the class II biopharmaceutical classification system (BCS which is characterized by a high per-oral dose, a low aqueous solubility and a high membrane permeability. The bioavailability of such a drug is limited by the dissolution rate. The present study deals with the formulations of immediate release tablets of poorly soluble carbamazepine. As model tablets for this investigation, two formulations (named “A” and “B” formulations of carbamazepine tablets labeled to contain 200 mg were evaluated. The aim of this study was to establish possible differences in dissolution profile of these two formulations purchased from the local market.The increased crystallinity together with enlarged particle size, enhanced aggregation and decreased wettability of the drug, resulted in insufficient dissolution rate for formulation “B’.’ From the dissolution point of view, this formulation was inferior to the formulation “A, due to the solubilization effect.

Preparation and characterization of Slow Release Formulations of ...

African Journals Online (AJOL)

alginate beads and characterize the resulting slow release formulations (SRFs) using scanning electron microscopy (SEM), and Fourier Transform infrared spectroscopy (FTIR). Two sets of formulations were made by extrusion into 0.25 M calcium ...

Immediate Oral Rehabilitation of Atrophic Mandible

OpenAIRE

Batista Mendes GC; Padovan LEM; da Silva WS; Ribeiro-Junior PD

2016-01-01

The oral rehabilitation using osseointegrated implants in atrophic mandibles (AM) with severe bone resorption remains a surgical and prosthetic challenge, due to the risk of mandible fracture during implant surgery or under functional loading, paresthesia and pain. A patient with severe atrophic mandible was treated using a 2.0 locking system reconstruction plate combined with dental implants, in immediate loading system. Surgery was performed through intraoral approach and preserving mental ...

Controlled Release Formulation of Indomethacin Prepared With Bee ...

African Journals Online (AJOL)

Erah

2010-12-27

Dec 27, 2010 ... Results: The results show that, although the release rate of formulations F1 - F7 did not show any ... Keywords: Propolis (bee glue), Indomethacin, Controlled release, Zero order kinetics, Waxy materials ... focus of interest.

Intermediate release formulations of diclofenac potassium tablets for IVIVC.

Science.gov (United States)

Ali, Huma; Shoaib, Muhammad Harris; Zafar, Farya; Bushra, Rabia; Yasmin, Riffat; Siddiqui, Shehla; Alam, Zafar M

2016-07-01

In recent days response surface methodology (RSM) has widely been applied for development and optimization of cost effective formulations with required quality. Study comprised of three steps including micromeritic comparison of different powder blends of placebo and diclofenac potassium (DP), formulation designing with CCRD (Design Expert, version 7.0.0), and stability testing of selected formulations by using R Gui. Ten formulations (F11-F20) were developed using microcrystalline cellulose (Avicel PH-102) (X1) (13-72%), methocel K15M (X2) (6.59-23.4%) and magnesium stearate (X3) (1.32-4.68%), while responses were % friability and % drug release. Blending rate constant was determined at 3, 6, 9 and 12 minutes. The results of physicochemical parameters were found within acceptable limits. After in vitro testing at pH 1.2, pH 4.5 and pH 6.8, mechanism of drug release, kinetic analysis and statistical evaluation were carried out by model - independent, model-dependent and one-way ANOVA methods. Most formulations followed zero order kinetics at higher pH. Fickian release (0.326 ≤ n ≤0.449) was observed with β greater than 0.5 and less than 1. ANOVA indicated no significant variation within and between formulations as p-values were found to be > 0.05.

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

Science.gov (United States)

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

2015-10-01

Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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

2017-11-01

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

Bioavailability of immediate and controlled release formulations of lithium carbonate Biodisponibilidade de formulações de liberação imediata e controlada de carbonato de lítio

Directory of Open Access Journals (Sweden)

Luciana Vismari

2002-06-01

Full Text Available INTRODUCTION/OBJECTIVES: Controlled-release lithium formulations were developed to minimize elevated blood peaks, related to side-effects and intoxications. However, there is little information about the bioavailability of the only controlled-release lithium formulation available in Brazil. The objective of this study was to compare the bioavailability of controlled-release and immediate-release lithium formulations, after single and multiple doses. METHODS: Twelve healthy volunteers received 900 mg of immediate-release or controlled-release lithium carbonate in single or multiple doses during 9 days. After single dose administration, the following parameters were analyzed for each formulation: maximum lithium concentration (Cmax; time to reach Cmax (t max; area under the curve of serum concentration versus time (AUC0-12 and AUC0-¥ and the elimination half-life (t1/2 elim.. After multiple doses, Cmax; t max; AUC0-12; mean (Cmean and minimum drug concentration (Cmin and degree of fluctuation (DF were analyzed. A 90% confidence interval (90%CI for the ratio between the AUCs for each formulation was constructed. RESULTS/DISCUSSION: Following single dose, the two formulations were bioequivalent; however, they were not after multiple doses. This fact could be a consequence of methodological limitations of lithium level's measurements since, following single dose, these levels could not be detected at time periods 24 and 48h in many volunteers, compromising the calculation of t1/2 elim ,and consequently of the AUC0-¥ and the 90%CI to the ratio of these areas. Therefore, the bioequivalence found after single dose may be an unreliable result.INTRODUÇÃO/OBJETIVO: Formulações de liberação controlada de lítio foram produzidas para minimizar picos sangüíneos elevados relacionados a efeitos colaterais e intoxicações. No entanto, o único produto com liberação controlada de lítio disponível no Brasil possui poucas informações a respeito de

Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl.

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El Nabarawi, Mohamed A; Teaima, Mahmoud H; Abd El-Monem, Rehab A; El Nabarawy, Nagla A; Gaber, Dalia A

2017-01-01

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin ® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the C max of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The t max was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action.

Thiolation of arabinoxylan and its application in the fabrication of controlled release mucoadhesive oral films.

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Hanif, Muhammad; Zaman, Muhammad

2017-03-20

Mucoadhesion is an important property that helps oral drug delivery system to remain attached with buccal mucosa and hence to improve the delivery of the drug. The current study was designed to achieve the thiol modification of Arabinoxylan (ARX) and to develop a mucoadhesive oral film for the improved delivery of tizanidine hydrochloride (TZN HCl). Synthesis of thiolated arabinoxylan (TARX) was accomplished by esterification of ARX with thioglycolic acid (TGA). TARX was further used for the development of mucoadhesive oral films which were prepared by using a solvent casting technique. Formulation of the films was designed and optimized by using central composite design (CCRD), selecting TARX (X 1 ) and glycerol (X 2 ) as variables. Prepared film formulations were evaluated for mechanical strength, ex-vivo mucoadhesion, in-vitro drug release, ex-vivo drug permeation, surface morphology and drug contents. Thiolation of ARX was confirmed by fourier transform infra-red spectroscopy (FTIR) as a peak related to thiol group appeared at 2516 cm -1 . The claim of successful thiolation of ARX was strengthened by the presence of 2809.003 ± 1.03 μmoles of thiol contents per gram of the polymer, which was determined by Ellman's reagent method. From the results, it was observed that the films were of satisfactory mechanical strength and mucoadhesiveness with folding endurance greater than 300 and mucoadhesive strength 11.53 ± 0.17 N, respectively. Reasonable drug retention was observed during in-vitro dissolution (85.03% cumulative drug release) and ex-vivo permeation (78.90% cumulative amount of permeated drug) studies conducted for 8 h. Effects of varying concentrations of both polymer and plasticizer on prepared mucoadhesive oral films were evaluated by ANOVA and it was observed that glycerol can enhanced the dissolution as well as permeation of the drug while TARX has opposite impact on these parameters. In nutshell, TARX in combination with glycerolwas found

Oral piercings: immediate and late complications.

Science.gov (United States)

Vieira, Elma P; Ribeiro, Andre Luis Ribeiro; Pinheiro, João de Jesus V; Alves, Sérgio de M

2011-12-01

Oral piercings have a long history as part of religious, cultural, or sexual symbolism in many traditional tribes; currently, these ornaments have wide acceptance among young people. Several oral and systemic complications may be associated with this practice; however, limited data related to these complications can be obtained in the literature. This study includes 42 cases of oral piercings in 39 young adults, who were using or had used oral piercings, and the complications associated with their use. Immediate complications occurred in 29 cases, including excessive bleeding (69%) and pain (52.3%) as the most representative. Two cases of syncope were found. Late complications related to the piercing insertion site were observed in 97.6% of cases, with pain and swelling being present in 92.9% and 61.9% of cases, respectively. Dental pain and lacerations on the tongue represented the most prevalent complications associated with the surrounding tissues, accounting for 33.3% and 31% of cases. The use of oral piercings is related to a series of mainly local complications, and individuals who decide to use piercings should be aware of such complications. Individuals wishing to get a part of their body pierced should do so with qualified professionals and should regularly visit the dentist so that a regular control is achieved, thus ensuring the early detection of the adverse effects associated with this practice. Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Formulation and Optimization of Oral Mucoadhesive Patches of Myrtus Communis by Box Behnken Design.

Science.gov (United States)

Hashemi, Mahbubeh; Ramezani, Vahid; Seyedabadi, Mohammad; Ranjbar, Ali Mohamad; Jafari, Hossein; Honarvar, Mina; Fanaei, Hamed

2017-09-01

Purpose: Recurrent aphthous stomatitis (RAS) is the most common painful ulcerative disease of oral mucosa happening in ~20% of people. Aimed to develop Myrtus communis L. (Myrtle) containing oral patches, we applied box-behnken design to evaluate the effect of polymers such as Polyvinyl pyrrolidone (PVP), Gelatin, Methylcellulose (MC) and Pectin. Methods: The patches properties such as tensile strength, folding endurance, swelling index, thickness, mucoadhesive strength and the pattern of myrtle release were evaluated as dependent variables. Then, the model was adjusted according to the best fitted equation with box behnken design. Results: The results indicated that preparation of myrtle patch with hydrophilic polymers showed the disintegration time up to 24h and more. Using of polyvinyl pyrrolidone as a water soluble polymer and a pore-former polymer led to faster release of soluble materials from the patch to 29 (min -1 ). Also it decreases swelling index by increasing the patch disintegration. Gelatin and Pectin, with rigid matrix and water interaction properties, decreased the swelling ratio. Pectin increased the tensile strength, but gelatin produced an opposite effect. Thinner Myrtle patch (about 28µm) was obtained by formulation of methyl cellulose with equal ratio with polyvinyl pyrrolidone or gelatin. Conclusion: Altogether, the analysis showed that the optimal formulation was achieved with of 35.04 mg of Gelatin, 7.22 mg of Pectin, 7.20 mg of polyvinyl pyrrolidone, 50.52 mg of methyl cellulose and 20 mg of Myrtle extract.

Formulation of Sustained-Release Diltiazem Matrix Tablets Using ...

African Journals Online (AJOL)

Formulation of Sustained-Release Diltiazem Matrix Tablets Using Hydrophilic Gum Blends. A Moin, H.G Shivakumar. Abstract. Purpose: To develop sustained release matrix tablets of diltiazem hydrochloride (DTZ) using karaya gum (K) alone or in combination with locust bean gum (LB) and hydroxypropyl methylcellulose ...

Budget impact of switching from an immediate-release to a prolonged-release formulation of tacrolimus in renal transplant recipients in the UK based on differences in adherence

Directory of Open Access Journals (Sweden)

Muduma G

2014-03-01

Full Text Available Gorden Muduma,1 Isaac Odeyemi,1 Jayne Smith-Palmer,2 Richard F Pollock21Astellas Pharma Europe, Chertsey, UK; 2Ossian Health Economics and Communications, Basel, SwitzerlandBackground and aims: Advagraf is a once-daily prolonged-release formulation of tacrolimus with proven noninferiority to Prograf, a twice-daily immediate-release formulation of tacrolimus, in biopsy-proven acute rejection, graft survival and patient survival in renal transplant recipients. Advagraf is associated with improved adherence compared with Prograf, which may ultimately improve long-term outcomes. The present study assessed the budget impact of switching patients from Prograf to Advagraf in the UK.Materials and methods: A budget-impact model was constructed based on published data on acute rejection, graft failure, and mortality in the UK setting. Patients were assumed to convert from Prograf to Advagraf on a 1:1 milligram:milligram basis. In a study comparing the adherence rates between once-daily versus twice-daily formulations of tacrolimus, the proportion of patients taking the prescribed number of daily doses was 88.2% in Advagraf patients and 78.8% in Prograf patients. The model applied a relative risk of graft failure of 3.47 to nonadherent patients based on data from a 2004 meta-analysis (based on graft-failure rates of 1.3%–40.0% in adherent patients, compared with 6.1%–100% in nonadherent patients. Cost data were taken from the March 2013 British National Formulary and 2012–2013 National Health Service tariff information. The analysis was performed over a 5-year time horizon and future costs were not discounted, in line with International Society for Pharmacoeconomics and Outcomes Research guidelines.Results: Over a 5-year time horizon, the mean cost per patient (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection was £29,328 (standard deviation [SD] £2,844 for Advagraf

Controlled release of isoproturon, imidacloprid, and cyromazine from alginate-bentonite-activated carbon formulations.

Science.gov (United States)

Garrido-Herrera, F J; Gonzalez-Pradas, E; Fernandez-Pérez, M

2006-12-27

Different alginate-based systems of isoproturon, imidacloprid, and cyromazine have been investigated in order to obtain controlled release (CR) properties. The basic formulation [sodium alginate (1.50%), pesticide (0.30%), and water] was modified using different amounts of bentonite and activated carbon. The higher values of encapsulation efficiency corresponded to those formulations prepared with higher percentages of activated carbon, showing higher encapsulation efficiency values for isoproturon and imidacloprid than for cyromazine, which has a higher water solubility. The kinetic experiments of imidacloprid/isoproturon release in water have shown us that the release rate is higher in imidacloprid systems than in those prepared with isoproturon. Moreover, it can be deduced that the use of bentonite and/or activated carbon sorbents reduces the release rate of the isoproturon and imidacloprid in comparison with the technical product and with alginate formulation without modifying agents. The highest decrease in release rate corresponds to the formulations prepared with the highest percentage of activated carbon. The water uptake, permeability, and time taken for 50% of the active ingredient to be released into water, T50, were calculated to compare the formulations. On the basis of a parameter of an empirical equation used to fit the pesticide release data, the release of isoproturon and imidacloprid from the various formulations into water is controlled by a diffusion mechanism. The sorption capacity of the sorbents and the permeability of the formulations were the most important factors modulating pesticide release. Finally, a linear correlation of the T50 values and the content of activated carbon in formulations were obtained.

Formulation and characterization of modified release tablets containing isoniazid using swellable polymers.

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Akhtar, M F; Rabbani, M; Sharif, A; Akhtar, B; Saleem, A; Murtaza, G

2011-01-01

The aim of this work was to develop swellable modified release (MR) isoniazid tablets using different combinations of polyvinyl acetate (PVAc) and sodium-carboxymethylcellulose (Na-CMC). Granules were prepared by moist granulation technique and then compressed into tablets. In vitro release studies for 12 hr were carried out in dissolution media of varying pH i.e. pH 1.2, 4.5, 7.0 and 7.5. Tablets of all formulations were found to be of good physical quality with respect to appearance (width and thickness), content uniformity, hardness, weight variation and friability. In vitro release data showed that increasing total polymer content resulted in more retarding effect. Formulation with 35% polymer content exhibited zero order release profile and it released 35% of the drug in first hr, later on, controlled drug release was observed upto the 12(th) hour. Formulations with PVAc to Na-CMC ratio 20:80 exhibited zero order release pattern at levels of studied concentrations, which suggested that this combination can be used to formulate zero order release tablets of water soluble drugs like isoniazid. Korsmeyer-Peppas modeling of drug release showed that non-Fickian transport is the primary mechanism of isoniazid release from PVAc and Na-CMC based tablets. The value of mean dissolution time decreased with the increase in the release rate of drug clearly showing the retarding behavior of the swellable polymers. The application of a mixture of PVAc to Na-CMC in a specific ratio may be feasible to formulate zero order release tablets of water soluble drugs like isoniazid.

Pramipexole Extended Release: A Novel Treatment Option in Parkinson's Disease

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Wolfram Eisenreich

2010-01-01

Full Text Available Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole.

Formulation and Characterization of Acetaminophen Nanoparticles in Orally Disintegrating Films

Science.gov (United States)

AI-Nemrawi, Nusaiba K.

The purpose of this study is to prepare acetaminophen loaded nanoparticles to be cast directly, while still in the emulsion form, into Orally Disintegrating Films (ODF). By casting the nanoparticles in the films, we expected to keep the particles in a stable form where the nanoparticles would be away from each other to prevent their aggregation. Once the films are applied on the buccal mucosa, they are supposed to dissolve within seconds, releasing the nanoparticles. Then the nanoparticles could be directly absorbed through the mucosa to the blood stream and deliver acetaminophen there. The oral cavity mucosa is one of the most attractive sites for systemic drug delivery due to its high permeability and blood supply. Furthermore, it is robust and shows short recovery times after stress or damage, and the drug bypasses first pass effect and avoids presystemic elimination in the GI tract. Nanoencapsulation increases drug efficacy, specificity, tolerability and therapeutic index. These Nanocapsules have several advantages in the protection of premature degradation and interaction with the biological environment, enhancement of absorption into a selected tissue, bioavailability, retention time and improvement of intracellular penetration. The most important characteristics of nanoparticles are their size, encapsulation efficiency (EE), zeta potential (surface charge), and the drug release profiles. Unfortunately, nanoparticles tend to precipitate or aggregate into larger particles within a short time after preparation or during storage. Some solutions for this problem were mentioned in literature including lyophilization and spray drying. These methods are usually expensive and give partial solutions that might have secondary problems; such as low re-dispersion efficacy of the lyophilized NPs. Furthermore, most of the formulations of NPs are invasive or topical. Few formulas are available to be given orally. Fast disintegrating films (ODFs) are rapidly gaining interest

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

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Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration

Thermostability of the coating, antigen and immunostimulator in an adjuvanted oral capsule vaccine formulation.

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Longet, Stephanie; Aversa, Vincenzo; O'Donnell, Daire; Tobias, Joshua; Rosa, Monica; Holmgren, Jan; Coulter, Ivan S; Lavelle, Ed C

2017-12-20

Oral vaccines present an attractive alternative to injectable vaccines for enteric diseases due to ease of delivery and the induction of intestinal immunity at the site of infection. However, susceptibility to gastrointestinal proteolysis, limited transepithelial uptake and a lack of clinically acceptable adjuvants present significant challenges. A further challenge to mass vaccination in developing countries is the very expensive requirement to maintain the cold chain. We recently described the effectiveness of a Single Multiple Pill ® (SmPill ® ) adjuvanted capsule approach to enhance the effectiveness of a candidate enterotoxigenic Escherichia coli (ETEC) oral vaccine. Here it was demonstrated that this delivery system maintains the antigenicity of ETEC colonisation factor antigen I (CFA/I) and the immunostimulatory activity of the orally active α-Galactosylceramide (α-GalCer) adjuvant after storage of SmPill ® minispheres under room temperature and extreme storage conditions for several months. In addition, the internal structure of the cores of SmPill ® minispheres and antigen release features at intestinal pH were found to be preserved under all these conditions. However, changes in the surface morphology of SmPill ® minispheres leading to the antigen release at gastric pH were observed after a few weeks of storage under extreme conditions. Those modifications were prevented by the introduction of an Opadry ® White film coating layer between the core of SmPill ® minispheres and the enteric coating. Under these conditions, protection against antigen release at gastric pH was maintained even under high temperature and humidity conditions. These results support the potential of the SmPill ® minisphere approach to maintain the stability of an adjuvanted whole cell killed oral vaccine formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulation, preparation, and evaluation of novel orally disintegrating tablets containing taste-masked naproxen sodium granules and naratriptan hydrochloride.

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Stange, Ulrike; Führling, Christian; Gieseler, Henning

2014-04-01

The purpose of this study was to develop and manufacture novel freeze-dried orally disintegrating tablets (ODTs) for migraine therapy containing taste-masked naproxen sodium and naratriptan hydrochloride. The formulation was optimized based on freeze-drying of sucrose solutions with different binders (hydroxyethylstarch, sodium alginate, methylcellulose, and gelatin) and varying amounts of Eudragit® E-coated naproxen sodium granules. Excellent product performance of the ODTs in terms of hardness and disintegration time (hydrochloride, and taste-masked naproxen sodium granules corresponding to 200 mg of naproxen were then added, and the final batches of ODTs for migraine therapy were produced. The ODTs were fully characterized, and subsequently stored for 1 month at room temperature and at 40°C. The amount of free naproxen sodium after freeze-drying and storage was below the threshold bitterness value, and the coating remained intact. Additionally, the particle size distribution of taste-masked granules was preserved, and more than 90 % naproxen sodium was released after 30 min. Naratriptan hydrochloride was dissolved immediately after disintegration, hence facilitating buccal absorption of the active pharmaceutical ingredient. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Cubic phase nanoparticles for sustained release of ibuprofen: formulation, characterization, and enhanced bioavailability study

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Dian, Linghui; Yang, Zhiwen; Li, Feng; Wang, Zhouhua; Pan, Xin; Peng, Xinsheng; Huang, Xintian; Guo, Zhefei; Quan, Guilan; Shi, Xuan; Chen, Bao; Li, Ge; Wu, Chuanbin

2013-01-01

In order to improve the oral bioavailability of ibuprofen, ibuprofen-loaded cubic nanoparticles were prepared as a delivery system for aqueous formulations. The cubic inner structure was verified by cryogenic transmission electron microscopy. With an encapsulation efficiency greater than 85%, the ibuprofen-loaded cubic nanoparticles had a narrow size distribution around a mean size of 238 nm. Differential scanning calorimetry and X-ray diffraction determined that ibuprofen was in an amorphous and molecular form within the lipid matrix. The in vitro release of ibuprofen from cubic nanoparticles was greater than 80% at 24 hours, showing sustained characteristics. The pharmacokinetic study in beagle dogs showed improved absorption of ibuprofen from cubic nanoparticles compared to that of pure ibuprofen, with evidence of a longer half-life and a relative oral bioavailability of 222% (P ibuprofen-loaded cubic nanoparticles provide a promising carrier candidate with an efficient drug delivery for therapeutic treatment. PMID:23468008

In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation.

Science.gov (United States)

Franek, F; Jarlfors, A; Larsen, F; Holm, P; Steffansen, B

2015-09-18

Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq(®), an extended release formulation (ERF). Semi-mechanistic models of desvenlafaxine were built (using SimCyp(®)) by combining in vitro data on dissolution and permeation (mechanistic part of model) with clinical data (obtained from literature) on distribution and clearance (non-mechanistic part of model). The model predictions of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus), respectively. Desvenlafaxine apparent permeability (Papp) at varying apical pH was investigated using the Caco-2 cell line and extrapolated to effective intestinal permeability (Peff) in human duodenum, jejunum, ileum and colon. Desvenlafaxine pKa-values and octanol-water partition coefficients (Do:w) were determined experimentally. Due to predicted rapid dissolution after IRF administration, desvenlafaxine was predicted to be available for permeation in the duodenum. Desvenlafaxine Do:w and Papp increased approximately 13-fold when increasing apical pH from 5.5 to 7.4. Desvenlafaxine Peff thus increased with pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low Peff in the upper small intestine, which "delays" the predicted

Clinical pharmacology of novel anticancer agents : Focus on oral formulations

NARCIS (Netherlands)

de Weger, V.A.

2017-01-01

The taxanes paclitaxel and docetaxel have a low oral bioavailability, as a result of poor water solubility and high first-pass effect. The water-solubility could be improved by the development of solid dispersion formulations for oral use. In this thesis it is shown that the combination of the solid

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

Science.gov (United States)

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

2009-12-01

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

Formulation and evaluation of taste mask pellets of granisetron hydrochloride as oro dispersible tablet

Directory of Open Access Journals (Sweden)

Nilesh Choudhary

2015-09-01

Full Text Available Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due to the highest compliance of the patients, especially the geriatrics and pediatrics. In addition, patients suffering from dysphagia, motion sickness, repeated emesis and mental disorders prefer these medications because they cannot swallow large quantity of water. Further, drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated in these dosage forms. However, the requirements of formulating these dosage forms with mechanical strength sufficient to withstand the rigors of handling and capable of disintegrating within a few seconds on contact with saliva are inextricable. The purpose of this research was to mask the bitter taste of granisetron hydrochloride. To mask the taste Kollicoat(r Smartseal 30D was used as coating polymer for pellet coating. The coated pellets of the drug was directly compressed with different superdisintegrant as AC-Di-Sol, Explotab and Kollidon CL in different concentration 5.0-7.5% w/w into an ODT. The prepared tablets were evaluated for hardness, friability, weight variation, wetting time, wet absorption ratio, in-vitro disintegration time and in vitro dissolution studies. Tablets exhibited quick disintegration characteristics with Kollidon CL in concentration 7.5% w/w i.e., within 20 seconds, which is characteristic of orally disintegrating dosage forms. More than 98% of drug was released from the formulations within 15 minutes. Formulations subjected to stability testing as per the ICH guidelines for 3 months, indicated stability with no change in taste, hardness, drug content, disintegration time and dissolution profiles. Thus, the results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated dosage forms in the oral cavity.

Soft, chewable gelatin-based pharmaceutical oral formulations: a technical approach.

Science.gov (United States)

Dille, Morten J; Hattrem, Magnus N; Draget, Kurt I

2018-06-01

Hard tablets and capsules for oral drug delivery cause problems for people experiencing dysphagia. This work describes the formulation and properties of a gelatin based, self-preserved, and soft chewable tablet as an alternative and novel drug delivery format. Gelatin (8.8-10% in 24.7-29% water) constituted the matrix of the soft, semi-solid tablets. Three different pharmaceuticals (Ibuprofen 10%, Acetaminophen 15%, and Meloxicam 1.5%) were tested in this formulation. Microbial stability was controlled by lowering the water activity with a mixture of sorbitol and xylitol (45.6-55%). Rheological properties were tested applying small strain oscillation measurements. Taste masking of ibuprofen soft-chew tablets was achieved by keeping the ibuprofen insoluble at pH 4.5 and keeping the processing temperature below the crystalline-to-amorphous transition temperature. Soft-chew formulations showed good stability for all three pharmaceuticals (up to 24 months), and the ibuprofen containing formulation exhibited comparable dissolution to a standard oral tablet as well as good microbial stability. The rheological properties of the ibuprofen/gelatin formulation had the fingerprint of a true gelatin gel, albeit higher moduli, and melting temperature. The results suggest that easy-to-swallow and well taste-masked soft chewable tablet formulations with extended shelf life are within reach for several active pharmaceutical ingredients (APIs).

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Science.gov (United States)

Tanzi, Maria G; Undre, Nasrullah; Keirns, James; Fitzsimmons, William E; Brown, Malcolm; First, M Roy

2016-08-01

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation.

Science.gov (United States)

Liu, Chen; Chang, Daoxiao; Zhang, Xinhui; Sui, Hong; Kong, Yindi; Zhu, Rongyue; Wang, Wenping

2017-11-01

Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64 ± 1.64 μm and drug content of 0.230 ± 0.003 mg/cm 2 and disintegrated rapidly in 29 ± 8 s. The nanocrystal-loaded films with reconstituted particle size of 377.9 nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3 h for oral solution formulation to less than 0.8 h for OFDF formulations, and C max increased from 150 ng/mL for solution to 350 ng/mL for conventional OFDF or 830 ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

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.

The Experiment of Carbofuran Controlled Release Formulation Insecticide Application on Rice Plants

International Nuclear Information System (INIS)

Sulistyati, M.; Ulfa TS; Sofnie M Ch; Kuswadi AN

2004-01-01

Field test of carbofuran insecticide (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate) controlled release formulation on rice plants of IR-64 variety was carried out in Pusakanegara, West Java. This insecticide formulation was made by using the mixture of activated charcoal, tapioca, kaolin, Na-alginate as a filler matrix. Insecticide formulation was applied one week after transplanting. The observations were conducted on the number of tillers, damage level caused by Orseolia oryzae (Wood/Mason), Chilo suppressalis (Walker), and Cnaphalocrosis medinalis (Guen) on new young plants. The observation were carried out on three weeks after application of carbofuran insecticide formulation then every two weeks until harvest. The number of tillers were occurred at the treatments of controlled release formulation of 20kg/ha, 30kg/ha, and 40kg/ha dose rate on the third weeks, it was showed significant difference compared with commercial carbofuran, and the following weeks were no significant difference between the treatments. The attack of Orseolia oryzae was occurred at the treatments of controlled release formulation with dose rate of 30 kg/ha and 40 kg/ha on the seventh weeks, ninth weeks, and eleventh weeks, those attacks were significantly difference found compared with commercial carbofuran. The attack of Chilo suppressalis was occurred at the treatments of controlled release formulation of 40kg/ha dose rate on the fifth weeks, it was showed significant difference which was compared to untreated carbofuran. The attack of Cnaphalocrosis medinalis was occurred on the ninth weeks, three dose rate of controlled released formulation were showed significant differences which compared with commercial carbofuran and were showed 50% less than commercial carbofuran, while the grains dry weight were no significant difference between the treatments. (author)

Magnetic Resonance Imaging to Visualize Disintegration of Oral Formulations.

Science.gov (United States)

Curley, Louise; Hinton, Jordan; Marjoribanks, Cameron; Mirjalili, Ali; Kennedy, Julia; Svirskis, Darren

2017-03-01

This article demonstrates that magnetic resonance imaging can visualize the disintegration of a variety of paracetamol containing oral formulations in an in vitro setting and in vivo in the human stomach. The different formulations had unique disintegration profiles which could be imaged both in vitro and in vivo. No special formulation approaches or other contrast agents were required. These data demonstrate the potential for further use of magnetic resonance imaging to investigate and understand the disintegration behavior of different formulation types in vivo, and could potentially be used as a teaching tool in pharmaceutical and medical curricula. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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

2011-01-01

Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH’s intrinsic characteristics. PMID:21720502

The role of citric acid in oral peptide and protein formulations

DEFF Research Database (Denmark)

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

2014-01-01

not occur significantly at the acidic pH values where it effectively inhibits proteolysis, which is its dominant action in oral peptide formulations. On account of insulin's low basal permeability, inclusion of alternative permeation enhancers is likely to be necessary to achieve sufficient oral...

Formulation of cefuroxime axetil oral suspension and investigation of its pharmaceutical properties

OpenAIRE

Valizadeh, Hadi; Farajnia, Aynoor; Zakeri-Milani, Parvin

2011-01-01

Purpose: Cefuroxime is the second generation cephalosporin, which its intravenous and oral dosage forms are available. Oral route is the selective method for administration of most of the drugs. The aim of this study was formulating ‘for oral’ cefuroxime axetil suspensions. Methods: Minitab (ver.15) was used to design the formulations containing 125 mg of cefuroxime in 5 ml vehicle. After selecting the acceptable preparations, physical stability tests and other tests such as dissolution rate,...

In-vitro release of diclofenac diethylammonium from lipid-based formulations.

Science.gov (United States)

Parsaee, Siamak; Sarbolouki, Mohammad N; Parnianpour, Mohamad

2002-07-08

This article presents the preparation and topical performance of some new lipid-based formulations of diclofenac, namely (a) a diclofenac aqueous gel containing mixed micelles (sodium cholate:egg lecithin molar ratio 0.55); (b) diclofenac lotion that contains soya lecithin, ethanol and buffer; and (c) diclofenac lipogel containing egg lecithin, isopropyl myristate, propylene glycol and ethanol. Gel formulations were prepared using Carbomer 934. Release of diclofenac from all formulations was monitored via dialysis through Spectra/por membrane into phosphate buffer (0.2 M pH=7.4) using a Franz cell. Drug release profile and diffusion coefficients were compared with brand formulation (Geigy's Vlotaren Emulgel). Statistical analysis of data show that the diffusion coefficient of the drug from these formulations rank according to the following order: Diclofenac lotion (D=5.308x10(-7) cm(2)/s) >lipogel (D=2.102 x 10(-7) cm(2)/s) >Voltaren Emulgel (1.518 x 10(-7) cm(2)/s) >aqueous gel mixed micelle (0.966 x 10(-7) cm(2)/s). These results show that diclofenac lotion and lipogel maybe more suitable formulations than the conventional topical dosage form.

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

Directory of Open Access Journals (Sweden)

Fúlvia D. Marques

2012-01-01

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

Design of a controlled release liquid formulation of lamotrigine

Directory of Open Access Journals (Sweden)

V Kumar

2011-05-01

Full Text Available "n  "n  Background and the purpose of the study: Lamotrigine is a broad spectrum anticonvulsant drug widely used as mono- or adjunct- therapy in adults and children. The aim of this study was to develop controlled release liquid formulation of lamotrigine to improve bioavailability and compliance of pediatric and geriatric epileptic patients. "n  Methods: Multiple (w/o/w emulsion was prepared using one step emulsification technique. It was evaluated for entrapment efficiency (EE, morphology, zeta potential (ZP, polydispersity index (PI, rheology, thermal property, in vitro drug release behavior and stability. In vivo studies in albino mice were carried out using maximal electroshock seizure (MES test and strychnine induced seizure (SIS pattern test and results were compared with marketed formulation. "n  Results: The EE of the formulations varied from 84.37% to 98.11%. The ZP and PI values of the prepared batches were in the range of +23.46 to +28.07 and 0.256 and 0.365, respectively. Microscopic observation clearly indicated the stability of the emulsions during the storage period. All batches exhibited controlled in vitro drug release up to 12 hrs. Batch C11 exhibited significantly longer duration of protection of seizure in mice against MES and exhibited comparable efficacy in SIS as compared to the marketed formulation. "n  Major Conclusion: Multiple emulsion of lamotrigine compared to the marketed tablet showed plasma drug concentration within therapeutic range for longer time and comparable efficacy.

Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses.

Science.gov (United States)

Linardi, Renata L; Stokes, Ashley M; Keowen, Michael L; Barker, Steven A; Hosgood, Giselle L; Short, Charles R

2012-02-01

To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. 6 healthy adult horses. Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute period after each administration of the drug to determine serum drug concentration by use of gas chromatography-mass spectrometry analysis and to estimate pharmacokinetic parameters by use of a noncompartmental model. Horses were monitored for adverse effects. In treated horses, serum methadone concentrations were equivalent to or higher than the effective concentration range reported for humans, without induction of adverse effects. Oral pharmacokinetics in horses included a short half-life (approx 1 hour), high total body clearance corrected for bioavailability (5 to 8 mL/min/kg), and small apparent volume of distribution corrected for bioavailability (0.6 to 0.9 L/kg). The bioavailability of methadone administered orally was approximately 3 times that associated with intragastric administration. Absorption of methadone in the small intestine in horses appeared to be limited owing to the low bioavailability after intragastric administration. Better understanding of drug disposition, including absorption, could lead to a more appropriate choice of administration route that would enhance analgesia and minimize adverse effects in horses.

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

Directory of Open Access Journals (Sweden)

Li FQ

2011-04-01

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

Impact of vibration and agitation speed on dissolution of USP prednisone tablets RS and various IR tablet formulations.

Science.gov (United States)

Seeger, Nicole; Lange, Sigrid; Klein, Sandra

2015-08-01

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1-4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.

Formulation and In vitro/In vivo Evaluation of Sustained Release ...

African Journals Online (AJOL)

HP

ISSN: 1596-5996 (print); 1596-9827 (electronic). © Pharmacotherapy ... (DHL). Methods: DHL tablets were prepared by direct compression and consisted of .... subjected to 3D response surface methodology to determine the .... Table 3: Release of diltiazem HCl from the test formulations as per factorial design. Formulation ...

Preparation and Characterization of Azadirachtin Alginate-Biosorbent Based Formulations: Water Release Kinetics and Photodegradation Study.

Science.gov (United States)

Flores-Céspedes, Francisco; Martínez-Domínguez, Gerardo P; Villafranca-Sánchez, Matilde; Fernández-Pérez, Manuel

2015-09-30

The botanical insecticide azadirachtin was incorporated in alginate-based granules to obtain controlled release formulations (CRFs). The basic formulation [sodium alginate (1.47%) - azadirachtin (0.28%) - water] was modified by the addition of biosorbents, obtaining homogeneous hybrid hydrogels with high azadirachtin entrapment efficiency. The effect on azadirachtin release rate caused by the incorporation of biosorbents such as lignin, humic acid, and olive pomace in alginate formulation was studied by immersion of the granules in water under static conditions. The addition of the biosorbents to the basic alginate formulation reduces the rate of release because the lignin-based formulation produces a slower release. Photodegradation experiments showed the potential of the prepared formulations in protecting azadirachtin against simulated sunlight, thus improving its stability. The results showed that formulation prepared with lignin provided extended protection. Therefore, this study provides a new procedure to encapsulate the botanical insecticide azadirachtin, improving its delivery and photostability.

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

Energy Technology Data Exchange (ETDEWEB)

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

2015-01-15

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

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

International Nuclear Information System (INIS)

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

2015-01-01

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

Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies.

Science.gov (United States)

Jenner, Peter; Könen-Bergmann, Michael; Schepers, Cornelia; Haertter, Sebastian

2009-11-01

Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Three Phase I studies were conducted, all in healthy adult men aged food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375-4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC(0-24h,ss) of 17.4 ng.h/mL (vs 16.0 ng.h/mL for the IR formulation), C(max,ss) of 0.967 ng/mL (vs 1.09 ng/mL), and C(min,ss) of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC(0-30h) and 4.87% for C(max), and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC(0-30h) (within the bioequivalence limits of 80%-125%) and 134.1 for C(max). At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear

Investigation of the effects of certain formulation factors on release ...

African Journals Online (AJOL)

Objective: To study the effects of three formulation variables (PVP, stearic acid and Avicel PH101) on disintegration time and release properties of paracetamol tablets using a 23 factorial experimental design. Methodology: Three formulation variables; Polyvinyl pyrrolidone (factor A), Stearic acid (factor B) and Avicel PH 101 ...

Controlled Release Formulations of Auxinic Herbicides

Science.gov (United States)

Kowalski, Witold J.; Siłowiecki, Andrzej.; Romanowska, Iwona; Glazek, Mariola; Bajor, Justyna; Cieciwa, Katarzyna; Rychter, Piotr

2013-04-01

Controlled release formulations are applied extensively for the release of active ingredients such as plant protection agents and fertilizers in response to growing concern for ecological problems associated with increased use of plant protection chemicals required for intensive agricultural practices [1]. We synthesized oligomeric mixtures of (R,S)-3-hydroxy butyric acid chemically bonded with 2,4-D, Dicamba and MCPA herbicides (HBA) respectively, and determined their molecular structure and molecular weight dispersion by the size exclusion chromatography, proton magnetic resonance spectrometry and electro-spray ionization mass spectrometry. Further we carried out bioassays of herbicidal effectiveness of the HBA herbicides vs. series of dicotyledonous weeds and crop injury tests [2, 3, 4]. Field bioassays were accomplished according to the EPPO standards [5]. Groups of representative weeds (the development stages in the BCCH scale: 10 - 30) were selected as targets. Statistical variabilities were assessed by the Fisher LSD test for plants treated with the studied herbicides in form of HBA oligomers, the reference herbicides in form of dimethyl ammonium salts (DMA), and untreated plants. No statistically significant differences in the crop injuries caused by the HBA vs. the DMA reference formulation were observed. The effectiveness of the HBA herbicides was lower through the initial period (ca. 2 weeks) relative to the DMA salts, but a significant increase in the effectiveness of the HBA systems followed during the remaining fraction of each assay. After 6 weeks all observed efficiencies approached 100%. The death of weeds treated with the HBA herbicides was delayed when compared with the DMA reference herbicides. The delayed uptake observed for the HBA oligomers relative to the DMA salts was due to controlled release phenomena. In case of the DMA salts the total amount of active ingredients was available at the target site. By contrast, the amount of an active

Formulation and in vitro evaluation of sustained release matrix tablets using cross-linked natural gum.

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Jamil, Qurratul Ain; Masood, Muhammad Irfan; Jamil, Muhammad Nauman; Masood, Imran; Iqbal, Shahid Muhammad

2017-03-01

Polysaccharide gums because of their biocompatibility, biodegradability and non-immunogenic properties are considered as the best choice for preparing sustained release tablets as compared to their synthetic counterpart. The cross linking of natural gums in matrix tablets increase the sustained release property of matrix tablets. Isoniazid is a first line therapy of tuberculosis, belongs to BCS I with half-life of 3-4 hours. These characteristics make isoniazid a good candidate for sustained release dosage form. Karaya gum crossed linked with trisodium tri metaphosphate was used as release rate retardant for preparing isoniazid cross-linked matrix tablet. Total 8 sustained release formulations were prepared. Both granules and tablets were evaluated under in vitro condition against different parameters. Dissolution studies were performed with all eight formulations for 12 hours using USP apparatus I. Four formulations designated as F1, F2, F3, F4 have drug and karaya gum while other four formulations F5, F6, F7, F8 have drug and crossed linked polymer in ratios of 1:1, 1:2, 1:3 and 1:4 respectively. Dissolution data was analyzed by using different kinetic models. Best fit model for most efficient formulation was zero order while release mechanism was super case I. Formulation 8 showed sufficiently slow release kinetics and about 83% of drug was released in 10 hours, indicating that cross-linked karaya gum proved efficient in preparing sustained release tablets.

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology.

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Tian, Zhiqiang; Yu, Qin; Xie, Yunchang; Li, Fengqian; Lu, Yi; Dong, Xiaochun; Zhao, Weili; Qi, Jianping; Wu, Wei

2016-08-01

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles. NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references. NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation. Controlled release of integral NLCs is achieved by the osmotic pump strategy.

Formulation, optimization and evaluation of levocetirizine dihyrochloride oral thin strip

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J Gunjan Patel

2012-01-01

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

Agricultural production - Phase 2. Indonesia. Controlled release pesticide formulations

International Nuclear Information System (INIS)

Vollner, L.

1992-01-01

At the request of the Government of Indonesia, an IAEA expert undertook a two weeks mission from 2 to 15 April 1991, and continued it from the 9 to 22 November 1991 at the Center for Application of Isotopes and Radiation (CAIR) of the National Atomic Energy Agency, BATAN in Jakarta. Expert discussed the project and carried out experiments together with the staff of the center, introducing shellac (description in part II) as a candidate for controlled release formulations. Formulations of carbofuran, butachlor, 2,4-D and diazinon were carried out, using sand and cocconut shells as carriers. Release rates of a.i. into water have been checked and further work has been discussed. Expert assessed further needs for supply of instruments, accessories and chemicals. (author)

Oral controlled release drug delivery system and Characterization of oral tablets; A review

OpenAIRE

Muhammad Zaman; Junaid Qureshi; Hira Ejaz; Rai Muhammad Sarfraz; Hafeez ullah Khan; Fazal Rehman Sajid; Muhammad Shafiq ur Rehman

2016-01-01

Oral route of drug administration is considered as the safest and easiest route of drug administration. Control release drug delivery system is the emerging trend in the pharmaceuticals and the oral route is most suitable for such kind of drug delivery system. Oral route is more convenient for It all age group including both pediatric and geriatrics. There are various systems which are adopted to deliver drug in a controlled manner to different target sites through oral route. It includes dif...

Formulation and optimization of a novel oral fast dissolving film containing drug nanoparticles by Box-Behnken design-response surface methodology.

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Shen, Chengying; Shen, Baode; Xu, He; Bai, Jinxia; Dai, Ling; Lv, Qingyuan; Han, Jin; Yuan, Hailong

2014-05-01

The purpose of this study was to design and optimize a novel drug nanoparticles-loaded oral fast dissolving film (NP-OFDF) using Box-Behnken design-response surface methodology. Drug nanosuspensions produced from high pressure homogenization were transformed into oral fast dissolving film containing drug nanoparticles by casting methods. Herpetrione (HPE), a novel and potent antiviral agent with poor water solubility that was extracted from Herpetospermum caudigerum, was studied as the model drug. The formulations of oral fast dissolving film containing HPE nanoparticles (HPE-NP-OFDF) were optimized by employing Box-Behnken design-response surface methodology and then systematically characterized. The optimized HPE-NP-OFDF was disintegrated in water within 20 s with reconstituted nanosuspensions particle size of 299.31 nm. Scanning electron microscopy (SEM) images showed that well-dispersed HPE nanoparticles with slight adhesion to each other were exposed on the surface of film or embedded in film. The X-ray diffractogram (XRD) analysis suggested that HPE in the HPE-NP-OFDF was in the amorphous state. In-vitro release study, approximate 77.23% of HPE was released from the HPE-NP-OFDF within 5 min, which was more than eight times compared with that of HPE raw materials (9.57%). The optimized HPE-NP-OFDF exhibits much faster drug release rates compared to HPE raw material, which indicated that this novel NP-OFDF may provide a potential opportunity for oral delivery of drugs with poor water solubility.

Factors influencing immediate post-release survival of spectacled eiders following surgical implantation of transmitters with percutaneous antennae

Science.gov (United States)

Sexson, Matthew G.; Mulcahy, Daniel M.; Spriggs, Maria; Myers, Gwen E.

2014-01-01

Surgically implanted transmitters are a common method for tracking animal movements. Immediately following surgical implantation, animals pass through a critical recovery phase when behaviors may deviate from normal and the likelihood of individual survival may be reduced. Therefore, data collected during this period may be censored to minimize bias introduced by surgery-related behaviors or mortality. However, immediate post-release mortalities negate a sampling effort and reduce the amount of data potentially collected after the censoring period. Wildlife biologists should employ methods to support an animal’s survival through this period, but factors contributing to immediate post-release survival have not been formally assessed. We evaluated factors that potentially influenced the immediate post-release survival of 56 spectacled eiders (Somateria fischeri) marked with coelomically implanted satellite transmitters with percutaneous antennae in northern Alaska in 2010 and 2011. We modeled survival through the first 14 days following release and assessed the relative importance and effect of 15 covariates hypothesized to influence survival during this immediate post-release period. Estimated daily survival rate increased over the duration of the immediate post-release period; the probability of mortality was greatest within the first 5 days following release. Our top-ranking model included the effect of 2 blood analytes, pH and hematocrit, measured prior to surgical implantation of a transmitter. We found a positive response to pH; eiders exhibiting acidemia (low pH) prior to surgery were less likely to survive the immediate post-release period. We found a curvilinear response to hematocrit; eiders exhibiting extremely low or high pre-surgery hematocrit were also less likely to survive the immediate post-release period. In the interest of maximizing the survival of marked birds following release, hematological data obtained prior to surgical implantation of

Formulation And Evaluation Of Bilayer Tablet for Bimodal Release of Venlafaxine Hydrochloride

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Munira eMomin

2015-07-01

Full Text Available The aim of the present research was to develop a bilayer tablet of venlafexine hydrochloride for bimodal drug release. In the present investigation authors have tried to explore Fenugreek Mucilage (FNM for bioadhesive sustained release layer. The attempt has been made to combine FNM with well studied bioahesive polymers like Hydroxy Propyl Methyl Cellulose, Carbopol and Xanthan Gum. The formulations were evaluated for swelling Index, ex-vivo bioadhesion, water uptake studies, in-vitro drug release and dissolution kinetics was studied. Substantial bioadhesion force (2.4±0.023 gms and tablet adhesion retention time (24±2 hrs was observed with FNM and HPMC combination at 80:20 ratio. The dissolution kinetics followed the Higuchi model (R2 =0.9913 via a non-Fickian diffusion controlled release mechanism after the initial burst. The 32 full factorial design was employed in the present study. The type of polymers used in combination with FNM (X1 and percent polymer replaced with FNM (X2 were taken as independent formulations variables. The selected responses, bioadhesion force (0.11-0.25±0.023gm, amount of drug released in 10 h, Y10 (78.20–95.78±1.24 % and bioadhesive strength, (19-24±2hrs presented good correlation with the selected independent variables. Statistical analysis (ANOVA of the optimized bilayer formulations showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05 in the amount of drug released after 1 hr till 12 h from optimized formulations was observed. The natural mucilage like FNM could be successfully incorporated into tablet with only 20% replacement with HPMC and it showed good bioadhesiveness and sustained drug release.

Controlled Release Formulation of Indomethacin Prepared With Bee ...

African Journals Online (AJOL)

Abstract. Purpose: To prepare and evaluate new sustained release formulations of indomethacin based on extracts of propolis (bee glue). Methods: Standardization of propolis (bee glue) extracts was performed by high performance liquid chromatography (HPLC) and determination of the values of fat and fixed oils. Several ...

Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations in Vitro and in Vivo.

Science.gov (United States)

Takeshita, Keizo; Okazaki, Shoko; Shinada, Kyosuke; Shibamoto, Yuma

2017-01-01

Although magnetic resonance imaging (MRI) has potential in assessments of formulations, few studies have been conducted because of the size and expense of the instrument. In the present study, the processes of in vitro and in vivo release in a gelatin capsule formulation model were visualized using a compact MRI system with 1.5 T permanent magnets, which is more convenient than the superconducting MRI systems typically used for clinical and experimental purposes. A Gd-chelate of diethylenetriamine-N,N,N',N″,N″-pentaacetic acid, a contrast agent that markedly enhances proton signals via close contact with water, was incorporated into capsule formulations as a marker compound. In vitro experiments could clearly demonstrate the preparation-dependent differences in the release/disintegration of the formulations. In some preparations, the penetration of water into the formulation and generation of bubbles in the capsule were also observed prior to the disintegration of the formulation. When capsule formulations were orally administered to rats, the release of the marker into the stomach and its transit to the duodenum were visualized. These results strongly indicate that the compact MRI system is a powerful tool for pharmaceutical studies.

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

Directory of Open Access Journals (Sweden)

Devarakonda K

2015-09-01

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

Sustained release biodegradable solid lipid microparticles: Formulation, evaluation and statistical optimization by response surface methodology.

Science.gov (United States)

Hanif, Muhammad; Khan, Hafeez Ullah; Afzal, Samina; Mahmood, Asif; Maheen, Safirah; Afzal, Khurram; Iqbal, Nabila; Andleeb, Mehwish; Abbas, Nazar

2017-12-20

For preparing nebivolol loaded solid lipid microparticles (SLMs) by the solvent evaporation microencapsulation process from carnauba wax and glyceryl monostearate, central composite design was used to study the impact of independent variables on yield (Y1), entrapment efficiency (Y2) and drug release (Y3). SLMs having a 10-40 μm size range, with good rheological behavior and spherical smooth surfaces, were produced. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry pointed to compatibility between formulation components and the zeta-potential study confirmed better stability due to the presence of negative charge (-20 to -40 mV). The obtained outcomes for Y1 (29-86 %), Y2 (45-83 %) and Y3 (49-86 %) were analyzed by polynomial equations and the suggested quadratic model were validated. Nebivolol release from SLMs at pH 1.2 and 6.8 was significantly (p 0.85 value (Korsmeyer- Peppas) suggested slow erosion along with diffusion. The optimized SLMs have the potential to improve nebivolol oral bioavailability.

Comparison between self-formulation and compounded-formulation dexamethasone mouth rinse for oral lichen planus: a pilot, randomized, cross-over trial.

Science.gov (United States)

Hambly, Jessica L; Haywood, Alison; Hattingh, Laetitia; Nair, Raj G

2017-08-01

There is a lack of appropriate, commercially-available topical corticosteroid formulations for use in oral lichen planus (OLP) and oral lichenoid reaction. Current therapy includes crushing a dexamethasone tablet and mixing it with water for use as a mouth rinse. This formulation is unpleasant esthetically and to use in the mouth, as it is a bitter and gritty suspension, resulting in poor compliance. Thus, the present study was designed to formulate and pilot an effective, esthetically-pleasing formulation. A single-blinded, cross-over trial was designed with two treatment arms. Patients were monitored for 7 weeks. Quantitative and qualitative data was assessed using VAS, numeric pain scales, the Treatment Satisfaction Questionnaire for Medication-9, and thematic analysis to determine primary patient-reported outcomes, including satisfaction, compliance, quality of life, and symptom relief. Nine patients completed the pilot trial. Data analysis revealed the new compounded formulation to be superior to existing therapy due to its convenience, positive contribution to compliance, patient-perceived faster onset of action, and improved symptom relief. Topical dexamethasone is useful in the treatment of OLP. When carefully formulated into a compounded mouth rinse, it improves patient outcomes. © 2016 John Wiley & Sons Australia, Ltd.

Development of controlled release formulations of azadirachtin-A employing poly(ethylene glycol) based amphiphilic copolymers.

Science.gov (United States)

Kumar, Jitendra; Shakil, Najam A; Singh, Manish K; Singh, Mukesh K; Pandey, Alka; Pandey, Ravi P

2010-05-01

Controlled release (CR) formulations of azadirachtin-A, a bioactive constituent derived from the seed of Azadirachta indica A. Juss (Meliaceae), have been prepared using commercially available polyvinyl chloride, polyethylene glycol (PEG) and laboratory synthesized poly ethylene glycol-based amphiphilic copolymers. Copolymers of polyethylene glycol and various dimethyl esters, which self assemble into nano micellar aggregates in aqueous media, have been synthesized. The kinetics of azadirachtin-A, release in water from the different formulations was studied. Release from the commercial polyethylene glycol (PEG) formulation was faster than the other CR formulations. The rate of release of encapsulated azadirachtin-A from nano micellar aggregates is reduced by increasing the molecular weight of PEG. The diffusion exponent (n value) of azadirachtin-A, in water ranged from 0.47 to 1.18 in the tested formulations. The release was diffusion controlled with a half release time (t(1/2)) of 3.05 to 42.80 days in water from different matrices. The results suggest that depending upon the polymer matrix used, the application rate of azadirachtin-A can be optimized to achieve insect control at the desired level and period.

Whole mouth antimicrobial effects after oral hygiene: comparison of three dentifrice formulations.

Science.gov (United States)

Fine, Daniel H; Sreenivasan, Prem K; McKiernan, Marie; Tischio-Bereski, Debra; Furgang, David

2012-11-01

This study compared the antimicrobial effects of three commercial dentifrice formulations: sodium fluoride/triclosan/copolymer (TCN/C), stannous fluoride/sodium hexametaphosphate/zinc lactate (SnF(2)/SHMP) and sodium fluoride (NaF). Thirty-five adults (15 men and 20 women; average age 33 years and pockets oral sites and six organisms evaluated in each site, the TCN/C demonstrated significant reductions (49-83%) as compared with the other treatments (p oral sites in comparison with the NaF, or the SnF(2)/SHMP dentifrice formulations as seen 12 h after brushing. © 2012 John Wiley & Sons A/S.

Preparation and characterization of solid oral dosage forms containing soy isoflavones

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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.

Floating tablets for controlled release of ofloxacin via compression coating of hydroxypropyl cellulose combined with effervescent agent.

Science.gov (United States)

Qi, Xiaole; Chen, Haiyan; Rui, Yao; Yang, Fengjiao; Ma, Ning; Wu, Zhenghong

2015-07-15

To prolong the residence time of dosage forms within gastrointestinal trace until all drug released at desired rate was one of the real challenges for oral controlled-release drug delivery system. Herein, we developed a fine floating tablet via compression coating of hydrophilic polymer (hydroxypropyl cellulose) combined with effervescent agent (sodium bicarbonate) to achieve simultaneous control of release rate and location of ofloxacin. Sodium alginate was also added in the coating layer to regulate the drug release rate. The effects of the weight ratio of drug and the viscosity of HPC on the release profile were investigated. The optimized formulations were found to immediately float within 30s and remain lastingly buoyant over a period of 12 h in simulated gastric fluid (SGF, pH 1.2) without pepsin, indicating a satisfactory floating and zero-order drug release profile. In addition, the oral bioavailability experiment in New Zealand rabbits showed that, the relative bioavailability of the ofloxacin after administrated of floating tablets was 172.19%, compared to marketed common release tablets TaiLiBiTuo(®). These results demonstrated that those controlled-released floating tables would be a promising gastro-retentive delivery system for drugs acting in stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

Formulation studies for mirtazapine orally disintegrating tablets.

Science.gov (United States)

Yıldız, Simay; Aytekin, Eren; Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Ünlü, Nurşen

2016-01-01

Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab). Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900 mL 0.1 N HCl medium, 900 mL pH 6.8 phosphate buffer or 900 mL pH 4.5 acetate buffer at 37 ± 0.2 °C as dissolution medium. Ratio of Eudragit® E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit® E-100) was found closer to the reference product than A2 (4% Eudragit® E-100) and A3 (8% Eudragit® E-100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media. Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles. Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation.

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

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Abolfazl Aslani

2016-09-01

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

Prolonged release matrix tablet of pyridostigmine bromide: formulation and optimization using statistical methods.

Science.gov (United States)

Bolourchian, Noushin; Rangchian, Maryam; Foroutan, Seyed Mohsen

2012-07-01

The aim of this study was to design and optimize a prolonged release matrix formulation of pyridostigmine bromide, an effective drug in myasthenia gravis and poisoning with nerve gas, using hydrophilic - hydrophobic polymers via D-optimal experimental design. HPMC and carnauba wax as retarding agents as well as tricalcium phosphate were used in matrix formulation and considered as independent variables. Tablets were prepared by wet granulation technique and the percentage of drug released at 1 (Y(1)), 4 (Y(2)) and 8 (Y(3)) hours were considered as dependent variables (responses) in this investigation. These experimental responses were best fitted for the cubic, cubic and linear models, respectively. The optimal formulation obtained in this study, consisted of 12.8 % HPMC, 24.4 % carnauba wax and 26.7 % tricalcium phosphate, had a suitable prolonged release behavior followed by Higuchi model in which observed and predicted values were very close. The study revealed that D-optimal design could facilitate the optimization of prolonged release matrix tablet containing pyridostigmine bromide. Accelerated stability studies confirmed that the optimized formulation remains unchanged after exposing in stability conditions for six months.

Release behavior of drugs from various natural gums and polymers.

Science.gov (United States)

Singh, Anupama; Sharma, Pramod Kumar; Malviya, Rishabha

2011-01-01

Polymers are the high molecular weight compounds of natural or synthetic origin, widely used in drug delivery of formulations. These polymers are further classified as hydrophilic or hydrophobic in nature. Depending upon this characteristic, polymers exhibit different release behavior in different media. This property plays an important role in the selection of polymers for controlled, sustained or immediate release formulations. The review highlights the literatures related to the research made on several polymers regarding the release kinetics which made them a novel approach for modifying the action of the particular formulation.

Predicting release and transport of pesticides from a granular formulation during unsaturated diffusion in porous media

DEFF Research Database (Denmark)

Paradelo Pérez, Marcos; Soto-Gómez, Diego; Pérez-Rodrígez, Paula

2014-01-01

The release and transport of active ingredients (AIs) from controlled-release formulations (CRFs) have potential to reduce groundwater pesticide pollution. These formulations have a major effect on the release rate and subsequent transport to groundwater. Therefore the influence of CRFs should be...

Dissolution Model Development: Formulation Effects and Filter Complications

DEFF Research Database (Denmark)

Berthelsen, Ragna; Holm, Rene; Jacobsen, Jette

2016-01-01

This study describes various complications related to sample preparation (filtration) during development of a dissolution method intended to discriminate among different fenofibrate immediate-release formulations. Several dissolution apparatus and sample preparation techniques were tested. The fl....... With the tested drug–formulation combination, the best in vivo–in vitro correlation was found after filtration of the dissolution samples through 0.45-μm hydrophobic PTFE membrane filters....

Formulation and pharmacokinetics of multi-layered matrix tablets: Biphasic delivery of diclofenac

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Ehab Mostafa Elzayat

2017-07-01

Full Text Available The rapid availability of the drug at the site of action followed by maintaining its effect for a long period of time is of great clinical importance. Thus, the purpose of the present study was to prepare and evaluate multi-layered matrix tablets of diclofenac using Eudragit RL/RS blend to achieve both immediate and sustained therapeutic effects. Diclofenac potassium (25 mg was incorporated in an outer immediate release layer to provide immediate pain relief whereas diclofenac sodium (75 mg was incorporated in the inner core to provide extended drug release. Wet granulation was employed to prepare the inner core of the tablets that were further layered with an immediate release drug layer in the perforated pan coater. The in-vitro and in-vivo performance of the developed formulation was compared with the marketed products Voltaren® SR 75 mg and Cataflam® 25 mg. The in-vitro drug release of the prepared formulation showed similarity (f2 = 66.19 to the marketed product. The pharmacokinetic study showed no significant difference (p > 0.05 in AUC0-24 and Cmax between the test and reference formulations. The AUC0-24 values were 105.36 ± 83.3 and 92.87 ± 55.53 μg h/ml whereas the Cmax values were 11.25 ± 6.87 and 12.97 ± 8.45 μg/ml, for the test and reference, respectively. The multi-layered tablets were proved to be bioequivalent with the commercially available tablets and were in agreement with the observed in-vitro drug release results. Stable physical characteristics and drug release profiles were observed in both long term and accelerated conditions stability studies.

Profile of extended-release oxycodone/acetaminophen for acute pain

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Bekhit MH

2015-10-01

Full Text Available Mary Hanna Bekhit1–51David Geffen School of Medicine, 2Ronald Reagan UCLA Medical Center, 3UCLA Ambulatory Surgery Center, 4UCLA Wasserman Eye Institute, 5UCLA Martin Luther King Community Hospital, University of California Los Angeles, Los Angeles, CA, USA Abstract: This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen, are available solely in immediate-release (IR formulations. Keywords: opioid, analgesic, xartemis, acute postsurgical pain, substance abuse, acetaminophen, extended release 

Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers.

Science.gov (United States)

Wadher, K J; Kakde, R B; Umekar, M J

2011-03-01

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

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

Science.gov (United States)

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

2014-10-01

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

Sustained release biodegradable solid lipid microparticles: Formulation, evaluation and statistical optimization by response surface methodology

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Hanif Muhammad

2017-12-01

Full Text Available For preparing nebivolol loaded solid lipid microparticles (SLMs by the solvent evaporation microencapsulation process from carnauba wax and glyceryl monostearate, central composite design was used to study the impact of independent variables on yield (Y1, entrapment efficiency (Y2 and drug release (Y3. SLMs having a 10-40 μm size range, with good rheological behavior and spherical smooth surfaces, were produced. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry pointed to compatibility between formulation components and the zeta-potential study confirmed better stability due to the presence of negative charge (-20 to -40 mV. The obtained outcomes for Y1 (29-86 %, Y2 (45-83 % and Y3 (49-86 % were analyzed by polynomial equations and the suggested quadratic model were validated. Nebivolol release from SLMs at pH 1.2 and 6.8 was significantly (p 0.85 value (Korsmeyer- Peppas suggested slow erosion along with diffusion. The optimized SLMs have the potential to improve nebivolol oral bioavailability.

Development of sustained and dual drug release co-extrusion formulations for individual dosing.

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Laukamp, Eva Julia; Vynckier, An-Katrien; Voorspoels, Jody; Thommes, Markus; Breitkreutz, Joerg

2015-01-01

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification. Copyright © 2015 Elsevier B.V. All rights reserved.

Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations

Science.gov (United States)

Kizilbash, Arshi; Ngô-Minh, Cường

2014-01-01

Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710

Formulation and evaluation of sustained release matrix tablet of rabeprazole using wet granulation technique

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Ruqaiyah Khan

2014-01-01

Full Text Available Introduction: Rabeprazole, a member of substituted benzimidazoles, inhibits the final step in gastric acid secretions. This drug claims to cause fastest acid separation (due to higher pKa, and more rapidly converts to the active species to aid gastric mucin synthesis. The most significant pharmacological action of Rabeprazole is dose dependent suppression of gastric acid secretion; without anticholinergic or H2-blocking action. It completely abolishes the hydrochloric acid secretion as it is powerful inhibitor of gastric acid. Rabeprazole is acid labile and hence commonly formulated as an enteric coated tablet. The absorption of rabeprazole occurs rapidly as soon as tablet leaves the stomach. Aim: In the present study an attempt was made to formulate and evaluate Rabeprazole sustained release matrix tablet using wet granulation technique incorporating various polymers like HPMC-E15, Carbopol934, and sodium carboxymethyl cellulose (CMC. Materials and Methods: The Formulated tablets were evaluated for different physicochemical properties like rheological properties, weight variation, thickness, hardness, % friability, in vitro release studies and drug content. Results: Studies revealed that all the physicochemical parameters comply with the official standards. The in vitro release studies exhibits the release up to 90%, over a prolonged period of time which confirms the extended release profile of formulation, having better bioavailability as well as decreased dosing frequency with reduced doses. Conclusion: The sustained release matrix tablets of rabiprazole shown better bioavailability, efficacy and potency, when compared with official standards.

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

Science.gov (United States)

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

Plasma methylphenidate concentrations in youths treated with high-dose osmotic release oral system formulation.

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Stevens, Jonathan R; George, Robert A; Fusillo, Steven; Stern, Theodore A; Wilens, Timothy E

2010-02-01

Children and adolescents are being treated increasingly for attention-deficit/hyperactivity disorder (ADHD) with a variety of stimulants in higher than Food and Drug Administration (FDA)-approved doses and in combination with other medications. We sought to determine methylphenidate (MPH) concentrations in children and adolescents treated with high-dose, extended-release osmotic release oral system (OROS) MPH plus concomitant medications, and to examine MPH concentrations with respect to the safety and tolerability of treatment. Plasma MPH concentrations were measured by liquid chromatography-mass spectrometry 4-5 hours after administration of medication in a sample of youths diagnosed with ADHD. These youths were treated naturalistically with higher than FDA-approved doses of OROS MPH in addition to their concomitant medications. Markers of safety and tolerability (e.g., measures of blood pressure and heart rate) were also examined. Among the 17 patients (with a mean age of 16.2 +/- 2 years and a mean number of concurrent medications of 2.23 +/- 0.94), the mean plasma MPH concentration was 28 +/- 9.1 ng/mL, despite a mean daily dose of OROS MPH of 169 +/- 5 mg (3.0 +/- 0.8 mg/kg per day). No patient had a plasma MPH level >or=50 ng/mL or clinical signs of stimulant toxicity. No correlation was found between plasma MPH concentrations and OROS MPH dose or changes in vital signs. High-dose OROS MPH, used in combination with other medications, was not associated with either unusually elevated plasma MPH concentrations or with clinically meaningful changes in vital signs. Study limitations include a single time-point sampling of MPH concentrations, a small sample size, and a lack of outcome measures to address treatment effectiveness.

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide.

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Graves, Richard A; Ledet, Grace A; Glotser, Elena Y; Mitchner, Demaurian M; Bostanian, Levon A; Mandal, Tarun K

2015-08-30

Fenretinide is an anticancer drug with low water solubility and poor bioavailability. The goal of this study was to develop biodegradable polymeric nanoparticles of fenretinide with the intent of increasing its apparent aqueous solubility and intestinal permeability. Three biodegradable polymers were investigated for this purpose: two different poly lactide-co-glycolide (PLGA) polymers, one acid terminated and one ester terminated, and one poly lactide-co-glycolide/polyethylene glycol (PLGA/PEG) diblock copolymer. Nanoparticles were obtained by using an emulsification solvent evaporation technique. The formulations were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size analysis. Dissolution studies and Caco-2 cell permeation studies were also carried out for all formulations. Ultra high performance liquid chromatography coupled with mass spectrometry (UPLC/MS) and ultraviolet detection was used for the quantitative determination of fenretinide. Drug loading and the type of polymer affected the nanoparticles' physical properties, drug release rate, and cell permeability. While the acid terminated PLGA nanoparticles performed the best in drug release, the ester terminated PLGA nanoparticles performed the best in the Caco-2 cell permeability assays. The PLGA/PEG copolymer nanoparticles performed better than the formulations with ester terminated PLGA in terms of drug release but had the poorest performance in terms of cell permeation. All three categories of formulations performed better than the drug alone in both drug release and cell permeation studies. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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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.

Aerosol-Assisted Fast Formulating Uniform Pharmaceutical Polymer Microparticles with Variable Properties toward pH-Sensitive Controlled Drug Release

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Hong Lei

2016-05-01

Full Text Available Microencapsulation is highly attractive for oral drug delivery. Microparticles are a common form of drug carrier for this purpose. There is still a high demand on efficient methods to fabricate microparticles with uniform sizes and well-controlled particle properties. In this paper, uniform hydroxypropyl methylcellulose phthalate (HPMCP-based pharmaceutical microparticles loaded with either hydrophobic or hydrophilic model drugs have been directly formulated by using a unique aerosol technique, i.e., the microfluidic spray drying technology. A series of microparticles of controllable particle sizes, shapes, and structures are fabricated by tuning the solvent composition and drying temperature. It is found that a more volatile solvent and a higher drying temperature can result in fast evaporation rates to form microparticles of larger lateral size, more irregular shape, and denser matrix. The nature of the model drugs also plays an important role in determining particle properties. The drug release behaviors of the pharmaceutical microparticles are dependent on their structural properties and the nature of a specific drug, as well as sensitive to the pH value of the release medium. Most importantly, drugs in the microparticles obtained by using a more volatile solvent or a higher drying temperature can be well protected from degradation in harsh simulated gastric fluids due to the dense structures of the microparticles, while they can be fast-released in simulated intestinal fluids through particle dissolution. These pharmaceutical microparticles are potentially useful for site-specific (enteric delivery of orally-administered drugs.

Phenazopyridine-phthalimide nano-cocrystal: Release rate and oral bioavailability enhancement.

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Huang, Yu; Li, Jin-Mei; Lai, Zhi-Hui; Wu, Jun; Lu, Tong-Bu; Chen, Jia-Mei

2017-11-15

Both cocrystal and nanocrystal technologies have been widely used in the pharmaceutical development for poorly soluble drugs. However, the synergistic effects due to the integration of these two technologies have not been well investigated. The aim of this study is to develop a nano-sized cocrystal of phenazopyridine (PAP) with phthalimide (PI) to enhance the release rate and oral bioavailability of PAP. A PAP-PI nano-cocrystal with particle diameter of 21.4±0.1nm was successfully prepared via a sonochemical approach and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic light scattering (DLS) analysis. An in vitro release study revealed a significant release rate enhancement for PAP-PI nano-cocrystal as compared to PAP-PI cocrystal and PAP hydrochloride salt. Further, a comparative oral bioavailability study in rats indicated significant improvement in C max and oral bioavailability (AUC 0-∞ ) by 1.39- and 2.44-fold, respectively. This study demonstrated that this novel nano-cocrystal technology can be a new promising option to improve release rate and absorption of poorly soluble compounds in the pharmaceutical industry. Copyright © 2017 Elsevier B.V. All rights reserved.

A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis.

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Armas, Danielle; Holt, Robert J; Confer, Nils F; Checani, Gregg C; Obaidi, Mohammad; Xie, Yuli; Brannagan, Meg

2018-02-01

Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC 0-t , AUC 0-∞ , and C max were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice

Formulation and In vitro/In vivo Evaluation of Sustained Release ...

African Journals Online (AJOL)

Conclusion: A fair correlation between in vitro dissolution and in vivo data was found. The results obtained indicate successful development of a sustained release formulation of diltiazem. Keywords: Diltiazem, Matrix tablet, Hydroxypropyl methylcellulose Eudragit, In vitro/in vivo correlation, Optimization ...

Linking dissolution to disintegration in immediate release tablets using image analysis and a population balance modelling approach.

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Wilson, David; Wren, Stephen; Reynolds, Gavin

2012-01-01

In order to achieve an improved understanding of disintegration and dissolution phenomena for an immediate release tablet formulation, a technique to monitor the number and size of particles entrained within the dissolution media was developed in combination with a population balancing model. Tablets were first characterized for crushing force, disintegration time and dissolution performance using standard USP methodologies. The performance of the tablets was then assessed using a new measurement system which links a "QicPic" particle imaging device to a USP dissolution vessel. This system enables us to measure the number and size of particles generated during tablet dissolution. The population balance mathematical model allowed a tablet erosion rate to be manipulated to fit the experimental data. Results showed that tablets with differing crushing forces showed different dissolution behaviors that could be explained by differing rates of particle release into the dissolution media. These behaviors were then successfully modeled to provide a description of the dissolution and disintegration behavior of the tablets in terms of a tablet erosion rate. A new approach was developed that allowed the description of the dissolution behaviors of the tablets in terms of the rate that they release particles into solution. This was then successfully modeled in terms of a tablet erosion rate.

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

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

2015-09-01

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

Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir.

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Janković, Jovana; Djekic, Ljiljana; Dobričić, Vladimir; Primorac, Marija

2016-01-30

The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol(®), polysorbate 20, or Kolliphor(®) RH40), cosurfactant (Plurol(®) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18-31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave≤100nm, PdI<0.250) upon spontaneous dispersion in 0.1M HCl and phosphate buffer pH 7.2. SMEDDSs with the highest aciclovir loading capacity (24.06 mg/ml and 21.12 mg/ml) provided the in vitro drug release rates of 0.325 mg cm(-2)min(-1) and 0.323 mg cm(-2)min(-1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent. Copyright © 2015 Elsevier B.V. All rights reserved.

Formulation and Evaluation of Extended- Release Tablet of Zolpidem Tartrate by Wet Granulation Technique

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Fatemeh Pourhashem

2016-06-01

Full Text Available The goal of this study was to design and evaluate extended - release system of the hypnotic agent, Zolpidem tartrate usefulness for the treatment of insomnia. The half-life of this drug is about 1.9 - 3 hours that indicating it a candidate for the extended release formulation. Our investigation relates to development of extended drug delivery system based on Hydroxy propyl methyl cellulose (HPMCK4M as release retardant, polyvinyl pyrrolidone (PVP k30 as binder and Magnesium Stearate using Factorial design. In vitro release study of matrix tablets was carried out in 0.01N HCl for 2 hours. All prepared matrix tablets were evaluated for physicochemical evaluation and drug content. The formulation that had release profile according to United State Pharmacopoeia selected for stability study according to ICH guidelines.

Multi-unit dosage formulations of theophylline for controlled release applications.

Science.gov (United States)

Uhumwangho, Michael U; Okor, Roland S

2007-01-01

The study was carried out to investigate the drug release profiles of multi-unit dosage formulations of theophylline consisting of both the fast and slow release components in a unit dose. The fast release component consisted of conventional granules of theophylline formed by mixing the drug powder with starch mucilage (20% w/v) while the slow release component consisted of wax granulations of theophylline formed by triturating the drug powder with a melted Carnauba wax (drug:wax ratio, 4:1). The granules were either filled into capsules or tabletted. In the study design, the drug release characteristics of the individual fast or slow release particles were first determined separately and then mixed in various proportions for the purpose of optimizing the drug release profiles. The evaluating parameters were the prompt release in the first 1 h (mp), the maximum release (m infinity) and the time to attain it (t infinity). Total drug content in each capsule or tablet was 300 mg and two of such were used in dissolution studies. The release kinetics and hence the release mechanism was confirmed by measuring the linear regression coefficient (R2 values) of the release data. The release kinetics was generally most consistent with the Higuchi square root of time relationship (R2 = 0.95). indicating a diffusion-controlled mechanism. The mp (mg) and t infinity (h) values for capsules and tablets of the conventional granules were (420 mg, 3 h) and (348 mg, 5 h), respectively, while for the capsules and tablets of the wax granulations mp and t infinity values were (228 mg, 9 h) and (156 mg, 12 h), respectively, indicating that a combination of wax granulation and tableting markedly retarded drug release. In the multi-unit dose formulations where the conventional and wax granulations were mixed in the ratios 2:1, 1:1 and 1:2 (conventional: matrix), the m infinity and t infinity values for the capsules were (378 mg, 6 h), (326 mg, 6 h) and (272 mg, 7 h), reSpectively. The

Newly developed controlled release subcutaneous formulation for tramadol hydrochloride

Directory of Open Access Journals (Sweden)

Mostafa Mabrouk

2018-05-01

Full Text Available This study presents a drug delivery system of poly (Ɛ-caprolactone (PCL ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with β-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2–4 nm. The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol. Keywords: Tramadol, Polycaprolcatone, Subcutaneous membrane, Ribbons, β-Cyclodextrin, Controlled release

Inventory of oral anticancer agents : Pharmaceutical formulation aspects with focus on the solid dispersion technique

NARCIS (Netherlands)

Sawicki, E.; Schellens, J. H M; Beijnen, J. H.; Nuijen, B.

2016-01-01

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and

Aroma release in the oral cavity after wine intake is influenced by wine matrix composition.

Science.gov (United States)

Esteban-Fernández, Adelaida; Muñoz-González, Carolina; Jiménez-Girón, Ana; Pérez-Jiménez, María; Pozo-Bayón, María Ángeles

2018-03-15

The aim of this study has been to investigate if wine matrix composition might influence the interaction between odorants and oral mucosa in the oral cavity during a "wine intake-like" situation. Aroma released after exposing the oral cavity of three individuals to different wines (n=12) previously spiked with six target aromas was followed by an -in vivo intra-oral SPME approach. Results showed a significant effect of wine matrix composition on the intra-oral aroma release of certain odorants. Among the wine matrix parameters, phenolic compounds showed the largest impact. This effect was dependent on their chemical structure. Some phenolic acids (e.g. hippuric, caffeic) were associated to an increase in the intra-oral release of certain odorants (e.g. linalool, β-ionone), while flavonoids showed the opposite effect, decreasing the intra-oral release of aliphatic esters (ethyl hexanoate). This work shows for the first time, the impact of wine composition on oral-mucosa interactions under physiological conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stability of regularly prescribed oral liquids formulated with SyrSpend® SF.

Science.gov (United States)

Uriel, M; Gómez-Rincón, C; Marro, D

2018-04-02

The purpose of this research was to evaluate the stability of 12 oral liquid formulations frequently compounded in hospital and community settings formulated in a specific vehicle: SyrSpend® SF. The stability of melatonin, glycopyrrolate, ciclosporin, chloral hydrate, flecainide acetate, tiagabine HCl, labetalol HCl, ciprofloxacin HCl, spironolactone/hydrochlorothiazide, hydrocortisone, itraconazole and celecoxib in SyrSpend SF PH4 (liquid) was investigated at 0, 30, 60 and 90 days and stored at both controlled room temperature and refrigerated. Itraconazole samples were also investigated at 15 and 45 days. No change in odor, color or appearance was observed in the formulations during the test period. Based on the results, a beyond-use date of 30 days can be assigned to tiagabine HCl 1.0 mg/ml in SyrSpend SF when stored at controlled room temperature, and 90 days under refrigeration, improving stability data previously published using other vehicles. A beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml. In this case, stability is not enhanced by refrigeration. With the rest of the formulations, less than 10% API loss occurred over 90 days at either controlled room temperature or under refrigeration. Including for example itraconazole 20.0 mg/ml, thus providing extended stability compared to simple syrup and other oral liquid vehicles. The findings of this study show that SyrSpend SF is an appropriate suspending vehicle to be used for personalized formulations of the APIs studied here.

Formulation and In Vitro, In Vivo Evaluation of Effervescent Floating Sustained-Release Imatinib Mesylate Tablet

Science.gov (United States)

Kadivar, Ali; Kamalidehghan, Behnam; Javar, Hamid Akbari; Davoudi, Ehsan Taghizadeh; Zaharuddin, Nurul Dhania; Sabeti, Bahareh; Chung, Lip Yong; Noordin, Mohamed Ibrahim

2015-01-01

Introduction Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. Methodology Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. Results and Discussion Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent

Formulation and in vitro, in vivo evaluation of effervescent floating sustained-release imatinib mesylate tablet.

Directory of Open Access Journals (Sweden)

Ali Kadivar

Full Text Available Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT. Conventional imatinib mesylate (Gleevec tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets.Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M, with Sodium alginate (SA and Carbomer 934P (CP as release-retarding polymers, sodium bicarbonate (NaHCO3 as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec in 0.1 N HCl (pH 1.2 at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted.Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec. Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid.

Science.gov (United States)

Jhawat, Vikas; Gupta, Sumeet; Saini, Vipin

2016-11-01

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

Science.gov (United States)

Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulation, Development and Evaluation of delayed release capsules of Duloxetine Hydrochloride made of different Enteric Polymers

OpenAIRE

Pallavi Yerramsetty; J. Vijaya Ratna; Venkata Ramana Reddy; Praveen Kumar

2012-01-01

Delayed release systems have acquired a centre stage in the arena of pharmaceutical research and development. The present study involves formulation and evaluation of Duloxetine Hydrochloride delayed release capsules. Duloxetine Hydrochloride is an acid labile drug. It degrades in the acidic environment of the stomach thus leading to therapeutic inefficacy. Therefore it is necessary to bypass the acidic pH of the stomach which can be achieved by formulating delayed release dosage form by usin...

Formulation and evaluation of sustained release matrix tablets of pioglitazone hydrochloride using processed Aloe vera mucilage as release modifier

Directory of Open Access Journals (Sweden)

Manoj Choudhary

2015-01-01

Full Text Available Background: Natural gums and mucilage which hydrates and swells on contact with aqueous media are used as additives in the formulation of hydrophilic drug delivery system. Aim: The purpose of this study was to develop a new monolithic matrix system for complete delivery of Pioglitazone hydrochloride (HCl, in a zero-order manner over an extended time period using processed Aloe vera gel mucilage (PAG as a release modifier. Materials and Methods: The matrices were prepared by dry blending of selected ratios of polymer and ingredients using direct compression technique. Physicochemical properties of dried powdered mucilage of A. vera were studied. Various formulations of pioglitazone HCl and A. vera mucilage were prepared using different drug: Polymer ratios viz., 1:1, 1:2, 1:3, 1:4, 1:5 for PAG by direct compression technique. Results: The formulated matrix tablets were found to have better uniformity of weight and drug content with low statistical deviation. The swelling behavior and in vitro release rate characteristics were also studied. Conclusion: The study proved that the dried A. vera mucilage can be used as a matrix forming material for controlled release of Pioglitazone HCl matrix tablets.

IRIS Assessment Plan for Uranium (Scoping and Problem Formulation Materials)

Science.gov (United States)

In January 2018, EPA released the IRIS Assessment Plan for Uranium (Oral Reference Dose) (Scoping and Problem Formulation Materials). An IRIS Assessment Plan (IAP) communicates to the public the plan for assessing each individual chemical and includes summary informatio...

Extended release formulations for local anaesthetic agents.

Science.gov (United States)

Weiniger, C F; Golovanevski, L; Domb, A J; Ickowicz, D

2012-08-01

Systemic toxicity through overdose of local anaesthetic agents is a real concern. By encapsulating local anaesthetics in biodegradable carriers to produce a system for prolonged release, their duration of action can be extended. This encapsulation should also improve the safety profile of the local anaesthetic as it is released at a slower rate. Work with naturally occurring local anaestheticss has also shown promise in the area of reducing systemic and neurotoxicity. Extended duration local anaesthetic formulations in current development or clinical use include liposomes, hydrophobic based polymer particles such as Poly(lactic-co-glycolic acid) microspheres, pasty injectable and solid polymers like Poly(sebacic-co-ricinoleic acid) P(SA:RA) and their combination with synthetic and natural local anaesthetic. Their duration of action, rationale and limitations are reviewed. Direct comparison of the different agents is limited by their chemical properties, the drug doses encapsulated and the details of in vivo models described. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

Science.gov (United States)

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

Science.gov (United States)

Okur, Neslihan Üstündağ; Özdemir, Derya İlem; Kahyaoğlu, Şennur Görgülü; Şenyiğit, Zeynep Ay; Aşıkoğlu, Makbule; Genç, Lütfi; Karasulu, H Yeşim

2015-01-01

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

In vitro models for the prediction of in vivo performance of oral dosage forms

DEFF Research Database (Denmark)

Kostewicz, Edmund S; Abrahamsson, Bertil; Brewster, Marcus

2014-01-01

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection...... of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro...

Optimization of primaquine diphosphate tablet formulation for controlled drug release using the mixture experimental design.

Science.gov (United States)

Duque, Marcelo Dutra; Kreidel, Rogério Nepomuceno; Taqueda, Maria Elena Santos; Baby, André Rolim; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Consiglieri, Vladi Olga

2013-01-01

A tablet formulation based on hydrophilic matrix with a controlled drug release was developed, and the effect of polymer concentrations on the release of primaquine diphosphate was evaluated. To achieve this purpose, a 20-run, four-factor with multiple constraints on the proportions of the components was employed to obtain tablet compositions. Drug release was determined by an in vitro dissolution study in phosphate buffer solution at pH 6.8. The polynomial fitted functions described the behavior of the mixture on simplex coordinate systems to study the effects of each factor (polymer) on tablet characteristics. Based on the response surface methodology, a tablet composition was optimized with the purpose of obtaining a primaquine diphosphate release closer to a zero order kinetic. This formulation released 85.22% of the drug for 8 h and its kinetic was studied regarding to Korsmeyer-Peppas model, (Adj-R(2) = 0.99295) which has confirmed that both diffusion and erosion were related to the mechanism of the drug release. The data from the optimized formulation were very close to the predictions from statistical analysis, demonstrating that mixture experimental design could be used to optimize primaquine diphosphate dissolution from hidroxypropylmethyl cellulose and polyethylene glycol matrix tablets.

Pharmacological and clinical aspects of immediate release fentanyl preparations: Criteria for selection

NARCIS (Netherlands)

D.A. van der Kuip (Deirdre); C.Th. Zandvliet; A.H.J. Mathijssen (Ron); C.C.D. van der Rijt (Carin)

2012-01-01

textabstractIn palliative care, pain management is often hampered by episodes of breakthrough pain, characterised by a rapid onset and, on average, duration less than 1 h. Until recently, only immediate release morphine and oxycodon preparations were available for the treatment of these episodes but

Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

Science.gov (United States)

Yue, Yong; Collaku, Agron; Liu, Dongzhou J

2018-01-01

Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single-dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (T C≥4μg/mL ). Key secondary outcomes were area under the plasma concentration-time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC 0-t ), AUC from 0 to infinity (AUC 0-inf ), and maximum plasma acetaminophen concentration (C max ). T C≥4μg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas T C≥4μg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC 0-12 , AUC 0-t , and AUC 0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen. © 2017, The American College of Clinical Pharmacology.

Polymer nanocomposite particles of S-nitrosoglutathione: A suitable formulation for protection and sustained oral delivery.

Science.gov (United States)

Wu, Wen; Gaucher, Caroline; Fries, Isabelle; Hu, Xian-Ming; Maincent, Philippe; Sapin-Minet, Anne

2015-11-10

S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor with therapeutic potential for cardiovascular disease treatment. Chronic oral treatment with GSNO is limited by high drug sensitivity to the environment and limited oral bioavailability, requiring the development of delivery systems able to sustain NO release. The present work describes new platforms based on polymer nanocomposite particles for the delivery of GSNO. Five types of optimized nanocomposite particles have been developed (three based on chitosan, two based on alginate sodium). Those nanocomposite particles encapsulate GSNO with high efficiency from 64% to 70% and an average size of 13 to 61 μm compatible with oral delivery. Sustained release of GSNO in vitro was achieved. Indeed, chitosan nanocomposites discharged their payload within 24h; whereas alginate nanocomposites released GSNO more slowly (10% of GSNO was still remaining in the dosage form after 24h). Their cytocompatibility toward intestinal Caco-2 cells (MTT assay) was acceptable (IC50: 6.07 ± 0.07-9.46 ± 0.08 mg/mL), demonstrating their suitability as oral delivery systems for GSNO. These delivery systems presented efficient GSNO loading and sustained release as well as cytocompatibility, showing their promise as a means of improving the oral bioavailability of GSNO and as a potential new treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Dissolution efficiency and bioequivalence study using urine data from healthy volunteers: a comparison between two tablet formulations of cephalexin

Directory of Open Access Journals (Sweden)

Cristina Helena dos Reis Serra

2015-06-01

Full Text Available The aim of the present study was to assess the bioequivalence of two cephalexin tablet formulations available in the Brazilian market (product A as reference formulation and product B as test formulation. Dissolution efficiency (DE% was calculated for both formulations to evaluate their in vitrobiopharmaceutical features. The oral bioequivalence study was performed in twenty-four healthy volunteers in a crossover design. Single oral dose (tablet containing 500 mg of cephalexin of each product was administered with two weeks of washout period. Urinary concentrations of cephalexin were measured by high-performance liquid chromatography (HPLC method and pharmacokinetics parameters were estimated by urinary excretion data. The bioequivalence was determined by the following parameters: the cumulative amount of cephalexin excreted in the urine, the total amount of cephalexin excreted in the urine and the maximum urinary excretion rate of cephalexin. DE values of immediate-release cephalexin tablets (500 mg were 68.69±4.18% for product A and 71.03±6.63% for product B. Regarding the dissolution test of the two brands (A and B analysed, both were in compliance with the official pharmacopeial specifications, since the dissolution of both formulations was superior to 80% of the amount declared in the label after 45 minutes of test (A=92.09%±1.84; B=92.84%±1.08. The results obtained indicated that the products A and B are pharmaceutical equivalents. Confidence intervals for the pharmacokinetic parameters were in compliance with the international standards, indicating that products A and B can be considered bioequivalents and, therefore, interchangeable.

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

Science.gov (United States)

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

2016-11-01

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

Safety case for the disposal of spent nuclear fuel at Olkiluoto. Formulation of radionuclide release scenarios 2012

International Nuclear Information System (INIS)

2013-04-01

TURVA-2012 is Posiva's safety case in support of the Preliminary Safety Analysis Report (PSAR) and application for a construction licence for a repository for disposal of spent nuclear fuel at the Olkiluoto site in south-western Finland. This report presents the radionuclide release scenarios and the methodology followed in formulating them. The formulation of scenarios takes into account the regulatory framework, the knowledge acquired in the present safety case as well as in previous safety assessments, the safety functions of the barriers of the repository system and the uncertainties in the features, events, and processes (FEPs) that may affect the entire disposal system (i.e. repository system plus the surface environment) from the emplacement of the first canister until the far future. In the report Performance Assessment, the performance of the engineered and natural barriers has been assessed against the loads expected during the evolution of the repository system and the site. Uncertainties have been identified and these are taken into account in the formulation of radionuclide release scenarios. The uncertainties in the FEPs affecting the characteristics and evolution of the surface environment are taken into account in formulating the surface environment scenarios used ultimately for assessing radiation exposure. Formulating radionuclide release scenarios for the repository system links the reports Performance Assessment and Assessment of Radionuclide Release Scenarios for the Repository System. The formulation of radionuclide release scenarios for the surface environment brings together Biosphere Description and the surface environment FEPs and is the link to the assessment of the surface environment scenarios analysed in Biosphere Assessment. (orig.)

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics.

Science.gov (United States)

Bose, Anirbandeep; Wong, Tin Wui; Singh, Navjot

2013-04-01

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.

Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

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Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

2016-05-01

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation and evaluation of a novel matrix-type orally disintegrating Ibuprofen tablet.

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Tayebi, Hoda; Mortazavi, Seyed Alireza

2011-01-01

Orally disintegrating tablets (ODTs) are capable of turning quickly into a liquid dosage form in contact with the saliva, thus possessing the advantages of both the solid dosage forms particularly stability and liquid dosage forms specially ease of swallowing and pre-gastric absorption of drug. The aim of this study was to prepare a novel matrix-type buccal fast disintegrating ibuprofen tablet formulation using special polymers, water soluble excipients, super-disintegrants and quickly soluble granules. For this purpose different tablet formulations of ibuprofen were prepared. The amount of ibuprofen in each formulation was 100 mg. Eight groups of formulation were prepared (A-H series), accounting for a total number of 45 formulations. Formulations prepared were examined in terms of different physicochemical tests including powder/granule flowability, appearance, thickness, uniformity of weight, hardness, friability and disintegration time. Results of formulation F22a (in series F), was found to be acceptable, making it the chosen formulation for further studies. Then, by adding various flavorants and sweeteners to this formulation, complementary series of formulations, named G and H, were prepared. Following the comparison of their taste with each other through asking 10 volunteers, the most suitable formulation regarding the taste, being formulation F22s, was chosen as the ultimate formulation. This formulation had PVP, ibuprofen and croscarmellose as the intra-granular components and xylitol and saccharin as the extra-granular ingredients. Formulation F22s was found to be acceptable in terms of physicochemical tests conducted, showing quick disintegration within the buccal cavity, appropriate hardness and rather low friability. Hence formulation F22s was selected as the final formulation.

Compressional, mechanical and release properties of a novel gum in paracetamol tablet formulations

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Adedokun Musiliu O.

2014-09-01

Full Text Available The binding properties of Eucalyptus gum obtained from the incised trunk of Eucalyptus tereticornis, were evaluated in paracetamol tablet formulations, in comparison with that of Gelatin B.P. In so doing, the compression properties were analyzed using density measurements and the compression equations of Heckel, Kawakita and Gurham. In our work, the mechanical properties of the tablets were assessed using the crushing strength and friability of the tablets, while the drug release properties of the tablets were assessed using disintegration and dissolution times. The results of the study reveal that tablet formulations incorporating Eucalyptus gum as binder, exhibited faster onset and higher amount of plastic deformation during compression than those containing gelatin. What is more, the Gurnham equation could be used as a substitute for the Kawakita equation in describing the compression properties of pharmaceutical tablets. Furthermore, the crushing strength, disintegration and dissolution times of the tablets increased with binder concentration, while friability values decreased. We noted that no significant differences in properties exist between formulations derived from the two binders (p > 0.05 exist. While tablets incorporating gelatin exhibited higher values for mechanical properties, Eucalyptus gum tablets had better balance between mechanical and release properties - as seen from the CSFR/Dt values. Tablets of good mechanical and release properties were prepared using Eucalyptus gum as a binder, and, therefore, it could serve as an alternative binder in producing tablets with good mechanical strength and fast drug release.

Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

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Sateesh Kumar Vemula

2013-01-01

Full Text Available The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4 showed almost complete drug release in the colon (99.86% within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period. The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The Cmax of colon targeted tablets was 11956.15 ng/mL at Tmax of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

PLGA biodegradable nanoparticles containing perphenazine or chlorpromazine hydrochloride: effect of formulation and release.

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Halayqa, Mohammed; Domańska, Urszula

2014-12-22

In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles.

PLGA Biodegradable Nanoparticles Containing Perphenazine or Chlorpromazine Hydrochloride: Effect of Formulation and Release

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Mohammed Halayqa

2014-12-01

Full Text Available In our study, poly(dl-lactide-co-glycolide (PLGA nanoparticles loaded with perphenazine (PPH and chlorpromazine hydrochloride (CPZ-HCl were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol (PVA concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4 by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles.

Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations.

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Parejiya, Punit B; Barot, Bhavesh S; Patel, Hetal K; Shelat, Pragna K; Shukla, Arunkumar

2013-11-01

The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 3² full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t(50%) = 5.92 h, t(75%) = 11.9 h, t(90%) = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.

Formulation of Dipyridamole Sustained Release Tablet Using Floating System

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Lenny Mauilida Valentina

2011-06-01

Full Text Available Dipyridamole is a drug for prevention of postoperative thromboembolic complication of heart valve replacement and long term therapy of angina pectoris will be well absorbed in stomach. To maintain therapeutic plasma concentration in long time and to increase bioavalaibility is needed a sustained release dosage form having the long residence time in the stomach. The objective of this research was to make floating sustained release tablet of dipyridamole conforming to the requirement that was set up by dipyridamol therapeutic concentration. Tablets were made by wet granulation method using aquadest as a liquid binder, HPMC K4M, Ac-di-sol, Avicel PH 102, talk, and Mg stearat. Dissolution assay was carried out using type 2 release tester at rotation speed of 50 rpm in medium 900 mL HCl 0.1 N at 37 ± 0.5 °C for 8 hours. The formulation containing of 50 mg dipirydamole, HPMC K4M (30%, Ac-di-sol (20%, Avicel PH 102 (37%, talk (2%, and Mg stearat (1% released 59.61 ± 6.73% and 89.34 ± 5.87% of dipyridamole respectively after 4 and 8 hours that conformed to the requirement.

Role of various natural, synthetic and semi-synthetic polymers on drug release kinetics of losartan potassium oral controlled release tablets.

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Jayasree, J; Sivaneswari, S; Hemalatha, G; Preethi, N; Mounika, B; Murthy, S Vasudeva

2014-10-01

The objective of the present work was to formulate and to characterize controlled release matrix tablets of losartan potassium in order to improve bioavailability and to minimize the frequency of administration and increase the patient compliance. Losartan potassium controlled release matrix tablets were prepared by direct compression technique by the use of different natural, synthetic and semisynthetic polymers such as gum copal, gum acacia, hydroxypropyl methyl cellulose K100 (HPMC K100), eudragit RL 100 and carboxy methyl ethyl cellulose (CMEC) individually and also in combination. Studies were carried out to study the influence of type of polymer on drug release rate. All the formulations were subjected to physiochemical characterization such as weight variation, hardness, thickness, friability, drug content, and swelling index. In vitro dissolution studies were carried out simulated gastric fluid (pH 1.2) for first 2 h and followed by simulated intestinal fluid (pH 6.8) up to 24 h, and obtained dissolution data were fitted to in vitro release kinetic equations in order to know the order of kinetics and mechanism of drug release. Results of physiochemical characterization of losartan potassium matrix tablets were within acceptable limits. Formulation containing HPMC K100 and CMEC achieved the desired drug release profile up to 24 h followed zero order kinetics, release pattern dominated by Korsmeyer - Peppas model and mechanism of drug release by nonfickian diffusion. The good correlation obtained from Hixson-Crowell model indicates that changes in surface area of the tablet also influences the drug release. Based on the results, losartan potassium controlled release matrix tablets prepared by employing HPMC K100 and CMEC can attain the desired drug release up to 24 h, which results in maintaining steady state concentration and improving bioavailability.

Formulation and evaluation of controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum

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Gurpreet Arora

2011-01-01

Full Text Available The aim of study was to prepare controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum as natural polymer. Tablets were formulated by direct compression technology employing the natural polymer in different concentrations (5, 10, 15 and 20% w/w. The prepared batches were evaluated for drug assay, diameter, thickness, hardness and tensile strength, swelling index, mucoadhesive strength (using texture analyzer and subjected to in vitro drug release studies. Real-time stability studies were also conducted on prepared batches. In vitro drug release data were fitted in various release kinetic models for studying the mechanism of drug release. Tensile strength was found to increase from 0.808 ± 0.098 to 1.527 ± 0.10 mN/cm 2 and mucoadhesive strength increased from 13.673 ± 1.542 to 40.378 ± 2.345 N, with an increase in the polymer concentration from 5 to 20% (A1 to A4. Swelling index was reported to increase with both increase in the concentration of gum and the time duration. The in vitro drug release decreased from 97.76 to 83.4% (A1 to A4 with the increase in polymer concentration. The drug release from the matrix tablets was found to follow zero-order and Higuchi models, indicating the matrix-forming potential of natural polymer. The value of n was found to be between 0.5221 and 0.8992, indicating the involvement of more than one drug release mechanism from the formulation and possibly the combination of both diffusion and erosion. These research findings clearly indicate the potential of S. plebeian gum to be used as binder, release retardant and mucoadhesive natural material in tablet formulations.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

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Santoveña, Ana; Suárez-González, Javier; Martín-Rodríguez, Cristina; Fariña, José B

2017-03-01

The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

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Childress, Ann; Newcorn, Jeffrey; Stark, Jeffrey G; McMahen, Russ; Tengler, Mark; Sikes, Carolyn

2016-08-01

To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with

Encapsulation of Liposomes within pH Responsive Microspheres for Oral Colonic Drug Delivery

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M. J. Barea

2012-01-01

Full Text Available A novel liposome-in-microsphere (LIM formulation has been created comprising drug-loaded liposomes within pH responsive Eudragit S100 microspheres. The liposomes contained the model drug 5-ASA and were coated with chitosan in order to protect them during encapsulation within the microspheres and to improve site-specific release characteristics. In vitro drug release studies showed that LIMs prevented drug release within simulated stomach and small intestine conditions with subsequent drug release occurring in large intestine conditions. The formulation therefore has potential for oral colonic drug delivery.

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

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Imai K

2013-06-01

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

Improved oral bioavailability for lutein by nanocrystal technology: formulation development, in vitro and in vivo evaluation.

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Chang, Daoxiao; Ma, Yanni; Cao, Guoyu; Wang, Jianhuan; Zhang, Xia; Feng, Jun; Wang, Wenping

2018-08-01

Lutein is a kind of natural carotenoids possessing many pharmacological effects. The application of lutein was limited mainly due to its low oral bioavailability caused by poor aqueous solubility. Nanocrystal formulation of lutein was developed to improve the oral bioavailability in this study. The nanosuspension was prepared by the anti-solvent precipitation-ultrasonication method and optimized by Box-Behnken design, followed by freeze-drying to obtain lutein nanocrystals. The nanocrystals were characterized on their physical properties, in vitro dissolution and in vivo absorption performance. Lutein nanocrystals showed as tiny spheres with an average particle size of 110.7 nm. The result of diffractograms indicated that the percent crystallinity of lutein was 89.4% in coarse powder and then declined in nanocrystal formulation. The saturated solubility of lutein in water increased from 7.3 μg/ml for coarse powder up to 215.7 μg/ml for lutein nanocrystals. The dissolution rate of lutein nanocrystals was significantly higher than that of coarse powder or the physical mixture. The C max and AUC 0-24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension, respectively. These results indicated that the nanocrystal formulation could significantly enhance the dissolution and absorption of lutein and might be a promising approach for improving its oral bioavailability.

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties.

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Huang, Yuh-Tyng; Tsai, Tong-Rong; Cheng, Chun-Jen; Cham, Thau-Ming; Lai, Tsun-Fwu; Chuo, Wen-Ho

2007-11-01

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2(3) full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T(max) was prolonged (from 0.65 +/- 0.082 hr to 4.83 +/- 1.60 hr) and AUC(0-t) (from 734.88 +/- 230.68 ng/ml.hr to 1153.34 +/- 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.

Enhanced Dissolution and Oral Bioavailability of Piroxicam Formulations: Modulating Effect of Phospholipids

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Muhammad D. Hussain

2010-10-01

Full Text Available Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug. On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG was ranked as the first potent dissolution rate enhancer for the model drug. Subsequently, the solid dispersions of varying piroxicam/DMPG ratios were prepared and further investigated. Within the concentration range studied (6.4-16.7 wt %, the dissolution rate of piroxicam from the solid dispersions appeared to increase as a function of the carrier weight fraction, whereas the cumulative drug concentration was not significantly affected by piroxicam/DMPG ratio, presumably due to a unique phase behavior of the aqueous dispersions of this carrier phospholipid. Solid state analysis of DMPG-based formulations reveled that they are two-component systems, with a less thermodynamically stable form of piroxicam (Form II being dispersed within the carrier. Finally, oral bioavailability of piroxicam from the DMPG-based formulations in rats was found to be superior to that of the control, as indicated by the bioavailability parameters, cmax and especially Tmax (53 µg/mL within 2 h vs. 39 µg/mL within 5.5 h, respectively. Hence, DMPG was regarded as the most promising carrier phospholipid for enhancing oral bioavailability of piroxicam and potentially other Class II drugs.

Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options.

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Aungst, Bruce J

2017-04-01

For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability. An initial assessment of absorption potential may be made computationally, and high throughput in vitro assays are typically performed to prioritize compounds for in vivo studies. The initial pharmacokinetic study is a critical decision point in compound evaluation, and the importance of the effect the dosing vehicle or formulation can have on oral bioavailability, especially for poorly water soluble compounds, is emphasized. Dosing vehicles and bioavailability-enabling formulations that can be used for discovery and preclinical studies are described. Optimizing oral bioavailability within a chemical series or for a lead compound requires identification of the barrier limiting bioavailability, and methods used for this purpose are outlined. Finally, a few key guidelines are offered for consideration when facing the challenges of optimizing oral bioavailability in drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Sustained-release progesterone vaginal suppositories 1--development of sustained-release granule--.

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Nakayama, Ayako; Sunada, Hisakazu; Okamoto, Hirokazu; Furuhashi, Kaoru; Ohno, Yukiko; Ito, Mikio

2009-02-01

Progesterone (P) is an important hormone for the establishment of pregnancy, and its administration is useful for luteal insufficiency. Considering the problems of commercially available oral and injection drugs, hospital-formulated vaginal suppositories are clinically used. However, since the half-life of P suppositories is short, it is difficult to maintain its constant blood concentration. To sustain drug efficacy and prevent side-effects, we are attempting to develop sustained-release suppositories by examining the degree of sustained-release of active ingredients. In this study, we examined the combinations of granulation methods and release systems for the preparation of sustained-release granules of P, and produced 13 types of sustained-release granules. We also examined the diameter, content, and dissolution of each type of granules, and confirmed that the sustained-release of all types of granules was satisfactory. Among the sustained-release granules, we selected granules with a content and a degree of sustained-release suitable for sustained-release suppositories.

A New Environmentally Safe Formulation and of Low Cost for Prolonged Release System of Atrazine and Diuron

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Gracy karla da Rocha Cortes

2017-07-01

Full Text Available Diuron and atrazine were incorporated in new formulations developed with the purpose to improve herbicides action through release systems, as well as to reduce the environmental toxicity. A low cost formulation (ALG/ESC was obtained by combining sodium alginate (ALG with fish scales of the Piau fish (ESC from the Leporinus elongatus species. From the crosslinking of ALG/ESC with CaCl2, the formulation ALG/ESC-CaCl2 was obtained. For ALG/ESC-CaCl2, the results are successful, showing a prolonged release of 3.5 and 4.5 days for atrazine and diuron, respectively. Based on parameters of an empirical equation used to fit the herbicide release data, it appears that the release systems of diuron and atrazine from ALG/ESC-CaCl2 are by diffusion processes due to anomalous transport, which did not follow Fick’s laws of diffusion. DOI: http://dx.doi.org/10.17807/orbital.v9i3.994

Ketoprofen-loaded Eudragit electrospun nanofibers for the treatment of oral mucositis

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Reda RI

2017-03-01

Full Text Available Rana Ihab Reda,1 Ming Ming Wen,2 Amal Hassan El-Kamel1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 2Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt Purpose: The purpose of this study was to formulate ketoprofen (KET-loaded Eudragit L and Eudragit S nanofibers (NFs by the electrospinning technique for buccal administration to treat oral mucositis as a safe alternative to orally administered KET, which causes gastrointestinal tract (GIT side effects. Materials and methods: NFs were prepared by electrospinning using Eudragit L and Eudragit S. Several variables were evaluated to optimize NF formulation, such as polymer types and concentrations, applied voltage, flow rate and drug concentrations. Differential scanning calorimetry (DSC, Fourier transform infrared spectroscopy (FTIR and scanning electron microscopy (SEM and analyses of drug contents, hydration capacity, surface pH, drug release and ex vivo permeation were performed to evaluate the NFs. The selected formulation (F1 was evaluated in vivo on induced oral mucositis in rabbits. Results: SEM revealed that 20% polymer formed smooth and bead-free NFs. DSC results confirmed the amorphous nature of KET in the NFs. FTIR confirmed hydrogen bond formation between the drug and polymer, which stabilized the NFs. Both formulations (F1 and F2 had an acceptable surface pH. The drug loading was >90%. The amount of KET released from NF formulations was statistically significantly higher (P≤0.001 than that released from the corresponding solvent-casted films. The complete release of KET from F1 occurred within 2 hours. Ex vivo permeation study revealed that only a small fraction of drug permeated from F1, which was a better candidate than F2 for local buccal delivery. In vivo evaluation of F1 on oral mucositis induced in rabbits demonstrated that F1 reduced the clinical severity of mucositis in

Light-triggerable formulations for the intracellular controlled release of biomolecules.

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Lino, Miguel M; Ferreira, Lino

2018-05-01

New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations. Copyright © 2018 Elsevier Ltd. All rights reserved.

A review on oral liquid as an emerging technology in controlled drug delivery system.

Science.gov (United States)

Torne, Sangmesh Raosaheb; Sheela, Angappan; Sarada, N C

2017-12-03

The oral liquid drug delivery system (OLDDS) remains as the primary choice of dosage form, though challenging, for the pharmaceutical scientists. In the last two decades, Oral Liquid Controlled Release (OLCR) formulation has gained a lot of attention because of its advantages over the conventional dosage forms. The world of nanotechnology has paved multiple ways to administer the drug through oral cavity in liquid dosage form with an additional advantage of control over the release. In the current study, the various approaches towards the same have been discussed comprehensively to understand the different mechanisms of OLCR. This review also emphasizes on the existing techniques and the developments that have been made to improve on its efficacy including various formulation related factors. It also provides valuable insights into the role of polymers in the development of OLCR formulation that can be used in the management of Gastroesophageal reflux disease (GERD). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment.

Science.gov (United States)

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2017-10-28

Nanoparticles have demonstrated significant advancements in potential oral delivery of insulin. In this publication, we review the current status of polymeric, inorganic and solid-lipid nanoparticles designed for oral administration of insulin. Firstly, the structure and physiological function of insulin are examined. Then, the efficiency and shortcomings of insulin nanoparticle are discussed. These include the susceptibility to digestive enzyme degradation, instability in the acidic pH environment, poor mucus diffusion and inadequate permeation through the gastrointestinal epithelium. In order to optimise the nanocarriers, the following considerations, including polymer nature, surface charge, size, polydispersity index and morphology of nanoparticles, have to be taken into account. Some novel designs such as chitosan-based glucose-responsive nanoparticles, layer by layer technique-based nanoparticles and zwitterion nanoparticles are being adopted to overcome the physiological challenges. The review ends with some future directions and challenges to be addressed for the success of oral delivery of insulin-loaded nanoparticle formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Phototoxicity free quantum dot-based niosome formulation for controlled drug release and its monitoring

Science.gov (United States)

Kumar, Sunil; Kang, T. W.; Bala, Suman; Kamboj, Sunil; Jeon, H. C.

2018-04-01

A novel niosomes-based system composed of Hypromellose (HPMC) functionalized fluorescent, biocompatible ZnS:Mn quantum dots (QDs), and anti-HIV drug Tenofovir disoproxil fumarate (TDF) was designed. An appropriate ratio of surfactant Sorbitan Monostearate (SPAN-60) and cholesterol was used to obtain an optimal entrapment efficiency. Initially, after observing the successful interaction of HPMC with SPAN-60, the noisome formulation including (QDs + drug) and HPMC-coated QDs was synthesized by a wet chemical route and characterized by X-ray diffraction (XRD), Transmission electron microscope (TEM) and Selected Electron Diffraction (SAED). Secondly, (QDs + drug) loaded niosome formulations were studied by varying the ratio of SPAN-60 and cholesterol. Multiple studies were done to characterize the shape, size, viscosity, colloidal stability, and entrapment efficiency of (QDs + drug) loaded niosomes. Lastly, pH-dependent (QDs + drug) release profiles were studied by a spectroscopic technique considering the pH of the human gastrointestinal region to obtain the formulation stability of (QDs + drug) release from the niosome vesicles. These studies also include pH-dependent photo-stability measurements based on laser-induced multiphoton excitation technique in the Infrared region. The multiphoton time-resolved studies were completed to avoid the UV induced phototoxicity in the drug delivery modules. Current studies on the formulation of niosomes-based (QDs + drug) system laid a foundation to make a complete phototoxicity free system for tracking controlled drug release and its imaging.

Preparation and Evaluation of Novel In Situ Gels Containing Acyclovir for the Treatment of Oral Herpes Simplex Virus Infections

Directory of Open Access Journals (Sweden)

Binu Chaudhary

2014-01-01

Full Text Available The objective of this work was to develop an oral mucosal drug delivery system to facilitate the local and systemic delivery of acyclovir for the treatment of oral herpes infection caused by the herpes simplex virus (HSV. An in situ gelling system was used to increase the residence time and thus the bioavailability of acyclovir in oral mucosa. Temperature and pH trigged in situ gel formulations were prepared by cold method using polymers like poloxamer 407, carbopol 934, and HPMC. Glycerin and a mixture of tween 80 and ethanol (1 : 2 ratio were used as the drug dissolving solvent. The pH of carbopol containing formulation was adjusted to pH 5.8 while the pH of poloxamer solution was adjusted to pH 7. These formulations were evaluated for sol-gel transition temperature, gelling capacity, pH, viscosity, spreadability, gel strength, drug content, ex-vitro permeation, and mucoadhesion. The gelation temperatures of all the formulations were within the range of 28–38°C. All the formulations exhibited fairly uniform drug content (98.15–99.75%. Drug release study of all the formulations showed sustained release properties. The release of drug through these in situ gel formulations followed the Higuchi model and Korsmeyer peppas model mechanism.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

Science.gov (United States)

Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

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Bontha, Vijaya Kumar

2013-01-01

The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C max of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen. PMID:24260738

Formulation and Evaluation of Extended- Release Tablet of Zolpidem Tartrate by Wet Granulation Technique

OpenAIRE

Fatemeh Pourhashem; Mohammad Reza Avadi

2016-01-01

The goal of this study was to design and evaluate extended - release system of the hypnotic agent, Zolpidem tartrate usefulness for the treatment of insomnia. The half-life of this drug is about 1.9 - 3 hours that indicating it a candidate for the extended release formulation. Our investigation relates to development of extended drug delivery system based on Hydroxy propyl methyl cellulose (HPMCK4M) as release retardant, polyvinyl pyrrolidone (PVP k30) as binder and Magnesium S...

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

Science.gov (United States)

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

2007-01-01

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

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets.

Science.gov (United States)

Liu, Mengqi; Zhang, Shiming; Cui, Shuxia; Chen, Fen; Jia, Lianqun; Wang, Shu; Gai, Xiumei; Li, Pingfei; Yang, Feifei; Pan, Weisan; Yang, Xinggang

2017-11-01

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design.

Science.gov (United States)

Morovati, Amirhosein; Ghaffari, Alireza; Erfani Jabarian, Lale; Mehramizi, Ali

2017-01-01

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex ® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release "%" in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X 1 : Cetyl alcohol, X 2 : Starch 1500 ® , X 3 : HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X 1 : 37.10, X 2 : 2, X 3 : 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500 ® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too.

Preparation, characterization and ex vivo evaluation of an orally disintegrating film formulation containing pyrazinamide

CSIR Research Space (South Africa)

Adeleke, Oluwatoyin A

2015-10-01

Full Text Available Vivo Evaluation of an Orally Disintegrating Film Formulation Containing Pyrazinamide O. A. Adeleke 1, P-C. Tsai 2, B. B. Michniak-Kohn 2 1 Council for Scientific and Industrial Research, 2 Rutgers - The State University of New Jersey Purpose...

Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz.

Science.gov (United States)

Avachat, Amelia M; Parpani, Shreekrishna S

2015-02-01

Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 μg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 ± 0.21 nm and entrapment efficiency 91.40 ± 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium

Improved oral bioavailability of valsartan using proliposomes: design, characterization and in vivo pharmacokinetics.

Science.gov (United States)

Nekkanti, Vijaykumar; Venkatesan, Natarajan; Wang, Zhijun; Betageri, Guru V

2015-01-01

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6 ± 2.9% with a vesicle size of 364.1 ± 14.9 nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12 h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.

The cost-effectiveness of solifenacin vs fesoterodine, oxybutynin immediate-release, propiverine, tolterodine extended-release and tolterodine immediate-release in the treatment of patients with overactive bladder in the UK National Health Service.

Science.gov (United States)

Cardozo, Linda; Thorpe, Andrew; Warner, Juliet; Sidhu, Manpreet

2010-08-01

To assess the cost-effectiveness of solifenacin vs other antimuscarinic strategies commonly used in UK clinical practice, based on the results of a recent published review. Overactive bladder (OAB) syndrome is characterized by symptoms of urgency, frequency, incontinence and nocturia. Pharmacological treatment comprises oral antimuscarinic agents, which are divided into older-generation treatments, including oxybutynin, and new-generation treatments, comprising solifenacin, tolterodine, darifenacin and fesoterodine. The latter have reduced central nervous system penetration and have better selectivity for the M3 subclass of acetylcholine receptors, resulting in improved tolerability. A recent systematic review and meta-analysis of the efficacy and safety of antimuscarinics provided an opportunity for an economic evaluation of these agents using a rigorous assessment of efficacy. A cost-utility analysis was undertaken using a 1-year decision-tree model. Treatment success was defined separately for urgency, frequency and incontinence, with efficacy data taken from the recent review. Treatment persistence rates were taken from the Information Management System database. Utility values for the calculation of quality-adjusted life-years (QALYs) were taken from published sources. The analysis included costs directly associated with treatment for OAB, i.e. antimuscarinic therapy, consultations with general practitioners, and outpatient contacts. Resource use was based on expert opinion. Costs were reported at 2007/2008 prices. Extensive deterministic and probabilistic analyses were conducted to test the robustness of the base-case results. Solifenacin was associated with the highest QALY gains (per 1000 patients) for all three outcomes of interest, i.e. urgency (712.3), frequency (723.1) and incontinence (695.0). Solifenacin was dominant relative to fesoterodine, tolterodine extended-release (ER) and tolterodine immediate-release (IR), and cost-effective relative to

Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis.

Science.gov (United States)

Rençber, Seda; Karavana, Sinem Yaprak; Yılmaz, Fethiye Ferda; Eraç, Bayri; Nenni, Merve; Özbal, Seda; Pekçetin, Çetin; Gurer-Orhan, Hande; Hoşgör-Limoncu, Mine; Güneri, Pelin; Ertan, Gökhan

2016-01-01

This study aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing fluconazole for the local treatment of oral candidiasis. The suitability of the prepared formulations was assessed by means of particle size (PS), polydispersity index, and zeta potential measurements, morphology analysis, mucoadhesion studies, drug entrapment efficiency (EE), in vitro drug release, and stability studies. Based on the optimum NP formulation, ex vivo drug diffusion and in vitro cytotoxicity studies were performed. Besides, evaluation of the antifungal effect of the optimum formulation was evaluated using agar diffusion method, fungicidal activity-related in vitro release study, and time-dependent fungicidal activity. The effect of the optimum NP formulation on the healing of oral candidiasis was investigated in an animal model, which was employed for the first time in this study. The zeta potential, mucoadhesion, and in vitro drug release studies of various NP formulations revealed that chitosan-coated NP formulation containing EUDRAGIT(®) RS 2.5% had superior properties than other formulations. Concerning the stability study of the selected formulation, the formulation was found to be stable for 6 months. During the ex vivo drug diffusion study, no drug was found in receptor phase, and this is an indication of local effect. The in vitro antifungal activity studies showed the in vitro efficacy of the NP against Candida albicans for an extended period. Also, the formulation had no cytotoxic effect at the tested concentration. For the in vivo experiments, infected rabbits were successfully treated with local administration of the optimum NP formulation once a day. This study has shown that the mucoadhesive NP formulation containing fluconazole is a promising candidate with once-a-day application for the local treatment of oral candidiasis.

Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections

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Wiederhold NP

2015-12-01

Full Text Available Nathan P Wiederhold Departments of Pathology and Medicine/Infectious Diseases, University of Texas Health Science Center at San Antonio, South Texas Reference Laboratories, San Antonio, TX, USA Abstract: Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data

Formulation and in vitro evaluation of mucoadhesive controlled release matrix tablets of flurbiprofen using response surface methodology

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Ikrima Khalid

2014-09-01

Full Text Available The objective of the current study was to formulate mucoadhesive controlled release matrix tablets of flurbiprofen and to optimize its drug release profile and bioadhesion using response surface methodology. Tablets were prepared via a direct compression technique and evaluated for in vitro dissolution parameters and bioadhesive strength. A central composite design for two factors at five levels each was employed for the study. Carbopol 934 and sodium carboxymethylcellulose were taken as independent variables. Fourier transform infrared (FTIR spectroscopy studies were performed to observe the stability of the drug during direct compression and to check for a drug-polymer interaction. Various kinetic models were applied to evaluate drug release from the polymers. Contour and response surface plots were also drawn to portray the relationship between the independent and response variables. Mucoadhesive tablets of flurbiprofen exhibited non-Fickian drug release kinetics extending towards zero-order, with some formulations (F3, F8, and F9 reaching super case II transport, as the value of the release rate exponent (n varied between 0.584 and 1.104. Polynomial mathematical models, generated for various response variables, were found to be statistically significant (P<0.05. The study also helped to find the drug's optimum formulation with excellent bioadhesive strength. Suitable combinations of two polymers provided adequate release profile, while carbopol 934 produced more bioadhesion.

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

Science.gov (United States)

Sahu, Bhanu P.; Das, Malay K.

2014-04-01

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

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.

The impact of manufacturing variables on in vitro release of clobetasol 17-propionate from pilot scale cream formulations.

Science.gov (United States)

Fauzee, Ayeshah Fateemah Beebee; Khamanga, Sandile Maswazi; Walker, Roderick Bryan

2014-12-01

The purpose of the study was to evaluate the effect of different homogenization speeds and times, anchor speeds and cooling times on the viscosity and cumulative % clobetasol 17-propionate released per unit area at 72 h from pilot scale cream formulations. A 2(4) full factorial central composite design for four independent variables were investigated. Thirty pilot scale batches of cream formulations were manufactured using a Wintech® cream/ointment plant. The viscosity and in vitro release of CP were monitored and compared to an innovator product that is commercially available on the South African market, namely, Dermovate® cream. Contour and three-dimensional response surface plots were produced and the viscosity and cumulative % CP released per unit area at 72 h were found to be primarily dependent on the homogenization and anchor speeds. An increase in the homogenization and anchor speeds appeared to exhibit a synergistic effect on the resultant viscosity of the cream whereas an antagonistic effect was observed for the in vitro release of CP from the experimental cream formulations. The in vitro release profiles were best fitted to a Higuchi model and diffusion proved to be the dominant mechanism of drug release that was confirmed by use of the Korsmeyer-Peppas model. The research was further validated and confirmed by the high prognostic ability of response surface methodology (RSM) with a resultant mean percentage error of (±SD) 0.17 ± 0.093 suggesting that RSM may be an efficient tool for the development and optimization of topical formulations.

In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs

DEFF Research Database (Denmark)

Borkar, Nrupa Nitin; Holm, René; Yang, Mingshi

2016-01-01

.05) than after DLA-w/o administration, indicating that triglycerides and surfactants improved the oral absorption of DLA. Similarly, Cmax and AUC after dosing apomorphine-o/w were significantly higher (p≤0.05) than that of aqueous suspension. This suggested that lipids and lipolysis products possibly aided......In the present study, the differences in oral absorption of apomorphine and its diester prodrugs and the effect of lipid-based formulations on the absorption of apomorphine or its prodrugs were investigated. Apomorphine, dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA) were orally...

Evaluation of synthetic zeolites as oral delivery vehicle for anti-inflammatory drugs

Directory of Open Access Journals (Sweden)

Elham Khodaverdi

2014-05-01

Full Text Available Objective(s: In this research, zeolite X and zeolite Y were used as vehicle to prepare intestine targeted oral delivery systems of indomethacin and ibuprofen. Materials and Methods: A soaking procedure was implemented to encapsulate indomethacin or ibuprofen within synthetic zeolites. Gravimetric methods and IR spectra of prepared formulations were used to assess drug loading efficiencies into zeolite structures. Scanning Electron Microscopy (SEM was also utilized to determine morphologies changes in synthetic zeolites after drug loading. At the next stage, dissolution studies were used to predict the in vivo performance of prepared formulations at HCl 0.1 N and PBS pH 6.5 as simulated gastric fluid (SGF and simulated intestine fluid (SIF, respectively. Results: Drug loadings of prepared formulations was determined between 24-26 % w/w. Dissolution tests at SGF were shown that zeolites could retain acidic model drugs in their porous structures and can be able to limit their release into the stomach. On the other hand, all prepared formulations completely released model drugs during 3 hr in simulated intestine fluid. Conclusion: Obtained results indicated zeolites could potentially be able to release indomethacin and ibuprofen in a sustained and controlled manner and reduced adverse effects commonly accompanying oral administrations of NSAIDs.

Formulation and characterisation of self-microemulsifying drug delivery systems based on biocompatible nonionic surfactants

Directory of Open Access Journals (Sweden)

Đekić Ljiljana M.

2014-01-01

Full Text Available Development of self-dispersing drug delivery systems (SMEDDS is a modern strategy for oral delivery improvement of poorly soluble drugs. Self-microemulsifying drug delivery systems (SMEDDS are isotropic mixtures of oils and hydrophilic surfactants, which form oil-in-water (o/w microemulsions by dilution in aqueous media (e.g., gastrointestinal fluids. Formulation of SMEDDS carriers requires consideration of a large number of formulation parameters and their influences on process of self-microemulsifying and releasing of drug. The aim of this work was formulation and characterisation of SMEDDS for oral administration of ibuprofen. In the experimental work, two series of potential SMEDDS were prepared (M1-M10, using surfactant (Labrasol®, Gattefosse, cosurfactant (PEG-40 hydrogenated castor (Cremophor® RH40, and oil (medium chain triglycerides (Crodamol® GTCC and olive oil (Cropur® Olive, at surfactant-to-cosurfactant mass ratios (Km 9:1, 7:3, 5:5, 3:7, and 1:9, and 10 % or 20 % of the oil phase. Ibuprofen was dissolved in formulations in concentration of 10 %. Characterisation of the investigated formulations included evaluation of physical stability, self-microemulsification ability in 0,1M HCl (pH 1.2 and phosphate buffer pH 7.2 (USP and in vitro drug release. Formation of o/w microemulsions with the average droplet size (Z-ave up to 100 nm, was observed in dispersions of formulations prepared with 10% w/w of medium chain triglycerides, within the entire investigated range of the Km values (M1-M5. These formulations were selected as SMEDDS. Results of characterisation pointed out the importance of the type and concentration of the oil as well as the Km value for the self-microemulsying ability as well as drug release kinetics from the investigated SMEDDS. Ibuprofen relase was in accordance with the request of USP 30-NF 25 (at least 80 %, after 60 min from the formulations M1 (Km 9:1 and M5 (Km 1:9. Furthermore, ibuprofen release was

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

Directory of Open Access Journals (Sweden)

Alberto Bernareggi

2013-12-01

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

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

NARCIS (Netherlands)

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

2015-01-01

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

A novel pH-responsive interpolyelectrolyte hydrogel complex for the oral delivery of levodopa. Part II: characterization and formulation of an IPEC-based tablet matrix.

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Ngwuluka, Ndidi C; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Khan, Riaz A; Pillay, Viness

2015-03-01

This study was undertaken in order to apply a synthesized interpolyelectrolyte complex (IPEC) of polymethacrylate and carboxymethylcellulose as a controlled release oral tablet matrix for the delivery of the model neuroactive drug levodopa. The IPEC (synthesized in Part I of this work) was characterized by techniques such as Fourier Transform Infra-Red (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), Advanced DSC (ADSC), and Scanning Electron Microscopy (SEM). The tablet matrices were formulated and characterized for their drug delivery properties and in vitro drug release. FTIR confirmed the interaction between the two polymers. The IPEC composite generated tablet matrices with a hardness ranging from 19.152-27.590 N/mm and a matrix resilience ranging between 42 and 46%. An IPEC of polymethacrylate and carboxymethylcellulose was indeed an improvement on the inherent properties of the native polymers providing a biomaterial with the ability to release poorly soluble drugs such as levodopa at a constant rate over a prolonged period of time. © 2014 Wiley Periodicals, Inc.

Formulation and evaluation of bilayer tablets of metoclopramide hydrochloride and diclofenac sodium.

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Gattani, Surendra G; Khabiya, Sohan S; Amrutkar, Jitendra R; Kushare, Sachin S

2012-01-01

The main objective of the present research work was to develop a bilayer tablet of metoclopramide hydrochloride (MTH) and diclofenac sodium (DS) in separate layers to avoid incompatibility and thus to maximize the efficacy of both drugs in combination for the effective treatment of migraine headaches. MTH and DS were formulated as immediate and sustained release layers respectively. In vitro dissolution kinetic studies of an optimized (D10) batch of DS in both sustained release layer and bilayer tablet forms show good linearity of regression coefficient 0.9773 (first order equation). The results reveal that an optimized immediate release layer (M5) of MTH and a sustained release layer (D10) of DS might be suitable for the treatment of migraine by sequential release of the two drugs in a bilayer tablet. Migraine is a type of recurring headache of moderate to severe intensity associated with gastrointestinal, neurological, and autonomic symptoms. In migraine, a combination of pretreatment with antiemetics is required for symptomatic treatment, when nausea and vomiting are severe. In our present research, we have selected the metoclopramide hydrochloride (MTH) active ingredient for study because it has an antiemetic effect and is a prokinetic agent. MTH is more effective to counteract gastric stasis associated with migraine, and it enhances the rate of absorption of non-steroidal anti-inflammatory drugs (NSAIDs). In the present investigation we combine MTH and a second active ingredient, diclofenac sodium, as a formulated bilayer tablet to prevent degradation of MTH.

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

NARCIS (Netherlands)

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

2017-01-01

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

Preparation and pharmaceutical evaluation of glibenclamide slow release mucoadhesive buccal film

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Bahri-Najafi, R.; Tavakoli, N.; Senemar, M.; Peikanpour, M.

2014-01-01

Buccal mucoadhesive systems among novel drug delivery systems have attracted great attention in recent years due to their ability to adhere and remain on the oral mucosa and to release their drug content gradually. Buccal mucoadhesive films can improve the drug therapeutic effect by enhancement of drug absorption through oral mucosa increasing the drug bioavailability via reducing the hepatic first pass effect. The aim of the current study was to formulate the drug as buccal bioadhesive film, which releases the drug at sufficient concentration with a sustain manner reducing the frequency of the dosage form administration. One of the advantagees of this formulation is better patient compliances due to the ease of administration with no water to swallow the product. The mucoadhesive films of glibenclamide were prepared using hydroxypropyl methylcellulose (HPMC) K4M, K15M and Eudragit RL100 polymers and propylene glycol as plasticizer and co-solvent. Films were prepared using solvent casting method, and were evaluated with regard to drug content, thickness, weight variations, swelling index, tensile strength, ex vivo adhesion force and percentage of in vitro drug release. Films with high concentrations of HPMC K4M and K15M did not have favorable appearance and uniformity. The formulations prepared from Eudragit were transparent, uniform, flexible, and without bubble. The highest and the lowest percentages of swelling were observed for the films containing HPMC K15M and Eudragit RL100, respectively. Films made of HPMC K15M had adhesion force higher than those containing Eudragit RL100. Formulations with Eudragit RL100 showed the highest mean dissolution time (MDT). Drug release kinetics of all formulations followed Higuchi's model and the mechanism of diffusion was considered non-Fickian type. It was concluded that formulations containing Eudragit RL100 were more favorable than others with regard to uniformity, flexibility, rate and percentage of drug release. PMID

Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets.

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Desai, Divyakant; Wong, Benjamin; Huang, Yande; Tang, Dan; Hemenway, Jeffrey; Paruchuri, Srinivasa; Guo, Hang; Hsieh, Daniel; Timmins, Peter

2015-01-01

To investigate the influence of the pH of the dissolution medium on immediate release 850 mg metformin hydrochloride tablets. A traditional wet granulation method was used to manufacture metformin hydrochloride tablets with or without a disintegrant. Tablet dissolution was conducted using the USP apparatus I at 100 rpm. In spite of its pH-independent high solubility, metformin hydrochloride tablets dissolved significantly slower in 0.1 N HCl (pH 1.2) and 50 mM pH 4.5 acetate buffer compared with 50 mM pH 6.8 phosphate buffer, the dissolution medium in the USP. Metformin hydrochloride API compressed into a round 1200 mg disk showed a similar trend. When basket rotation speed was increased from 100 to 250 rpm, the dissolution of metformin hydrochloride tablets was similar in all three media. Incorporation of 2% w/w crospovidone in the tablet formulation improved the dissolution although the pH-dependent trend was still evident, but incorporation of 2% w/w croscarmellose sodium resulted in rapid pH-independent tablet dissolution. In absence of a disintegrant in the tablet formulation, the dissolution was governed by the erosion-diffusion process. Even for a highly soluble drug, a super-disintegrant was needed in the formulation to overcome the diffusion layer limitation and change the dissolution mechanism from erosion-diffusion to disintegration.

Platelet lysate mucohadesive formulation to treat oral mucositis in graft versus host disease patients: a new therapeutic approach.

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Del Fante, Claudia; Perotti, Cesare; Bonferoni, Maria Cristina; Rossi, Silvia; Sandri, Giuseppina; Ferrari, Franca; Scudeller, Luigia; Caramella, Carla Marcella

2011-09-01

Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2-8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.

Changes in general and oral health-related quality of life in immediate or conventionally loaded dental implants: a nonrandomized clinical trial.

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Dolz, Javier; Silvestre, Francisco J; Montero, Javier

2014-01-01

To evaluate changes in the general and oral health-related quality of life (using the European Quality of Life indicator and the Oral Health Impact Profile-49 [OHIP-49], respectively) of patients treated with conventionally or immediately loaded implants. This clinical trial consisted of a clinical oral examination and a questionnaire-based interview carried out before and after both surgery and definitive prosthetic rehabilitation in a consecutive sample of patients requiring dental implants. According to the clinical diagnosis and patient preference, patients were assigned to the immediate loading group (IL group; n = 29) or the conventional loading group (CL group; n = 75). The change summary scores and effect sizes were calculated in the intermediate stage and at the final follow-up, taking baseline scores as reference. The oral health-related quality of life and oral satisfaction after implant therapy were significantly better than at baseline, with an even greater benefit when the implants were loaded immediately than when prosthetic rehabilitation was delayed. However, there were no significant differences in between-group comparisons in the ratings of general health status. The effect size for the OHIP-49 exceeded the threshold value of 0.8 for the domains functional limitation, pain/discomfort, and psychological discomfort in both groups and also for physical disability and psychological disability in the IL group. A gradual improvement in oral well-being scores, but not in those of general well-being, were observed for both groups from the intermediate stage to the final evaluation. This benefit was markedly greater for the IL group.

Formulation and Characterization of Oral Mucoadhesive Chlorhexidine Tablets Using Cordia myxa Mucilage.

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Moghimipour, Eskandar; Aghel, Nasrin; Adelpour, Akram

2012-01-01

The dilution and rapid elimination of topically applied drugs due to the flushing action of saliva is a major difficulty in the effort to eradicate infections of oral cavity. Utilization a proper delivery system for incorporation of drugs has a major impact on drug delivery and such a system should be formulated for prolonged drug retention in oral cavity. The aim of the present study was the use of mucilage of Cordia myxa as a mucoadhesive material in production of chlorhexidine buccal tablets and its substitution for synthetic polymers such as HPMC. The influence of mucilage concentration on the physicochemical responses (hardness, friability, disintegration time, dissolution, swelling, and muco-adhesiveness strength) was studied and swelling of mucilage and HPMC were compared. The evaluated responses included pharmacopoeial characteristics of tablets, the force needed to separate tablets from mucosa, and the amount of water absorbed by tablets. In comparison to HPMC, the rise of mucilage concentration in the formulations increased disintegration time, drug dissolution rate, and reduced MDT. Also, compared to 30% HPMC, muco-adhesiveness strength of buccal tablets containing 20% mucilage was significantly higher. It can be concluded that the presence of Cordia myxa powdered mucilage may significantly affect the tablet characteristics, and increasing in muco-adhesiveness may be achieved by using 20% w/w mucilage.

Calcium alginate microspheres containing metformin hydrochloride niosomes and chitosomes aimed for oral therapy of type 2 diabetes mellitus.

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Maestrelli, Francesca; Mura, Paola; González-Rodríguez, María Luisa; Cózar-Bernal, María José; Rabasco, Antonio María; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla

2017-09-15

Metformin is an oral hypoglycemic agent used in the type 2 diabetes, whose poor bioavailability and short half-life make the development of effective extended-release formulations highly desirable. Different metformin-loaded chitosomal and niosomal formulations were developed and suitably characterized, but were unable to provide the desired sustained release. The entrapment of both kinds of colloidal dispersions in calcium alginate beads enabled to strongly reduce the amount of drug released at gastric level (from 18 up to a maximum of 30%), and to obtain a sustained release in simulated intestinal fluid, which was properly tuned by varying the percentage of calcium alginate in the beads. In vivo studies on rats revealed a significant improvement of metformin hypoglycemic effect when orally administered as chitosomal and even more as niosomal dispersion entrapped in alginate beads, not only with respect to the drug as such, but also to the alginate beads loaded with the plain drug. The more intense and sustained therapeutic effect with time provided by the drug-in niosomes-in alginate bead formulation could be very profitable for maintaining tight blood glucose levels over prolonged period of time after oral administration, allowing a reduction of its dose and related collateral effects, and improving patient compliance. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulation, characterization and pharmacokinetics of praziquantel-loaded hydrogenated castor oil solid lipid nanoparticles.

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Xie, Shuyu; Pan, Baoliang; Wang, Ming; Zhu, Luyan; Wang, Fenghua; Dong, Zhao; Wang, Xiaofang; Zhou, WenZhong

2010-07-01

The purpose of this study was to formulate praziquantel (PZQ)-loaded hydrogenated castor oil (HCO) solid lipid nanoparticles (SLN) to enhance the bioavailability and prolong the systemic circulation of the drug. PZQ was encapsulated into HCO nanoparticles by a hot homogenization and ultrasonication method. The physicochemical characteristics of SLN were investigated by optical microscope, scanning electron microscopy and photon correlation spectroscopy. Pharmacokinetics were studied after oral, subcutaneous and intramuscular administration in mice. The diameter, polydispersivity index, zeta potential, encapsulation efficiency and loading capacity of the nanoparticles were 344.0 +/- 15.1 nm, 0.31 +/- 0.08, -16.7 +/- 0.5 mV, 62.17 +/- 6.53% and 12.43 +/- 1.31%, respectively. In vitro release of PZQ-loaded HCO-SLN exhibited an initial burst release followed by a sustained release. SLN increased the bioavailability of PZQ by 14.9-, 16.1- and 2.6-fold, and extended the mean residence time of the drug from 7.6, 6.6 and 8.2 to 95.9, 151.6 and 48.2 h after oral, subcutaneous and intramuscular administration, respectively. The PZQ-loaded HCO-SLN could be a promising formulation to enhance the pharmacological activity of PZQ.

Provesicular granisetron hydrochloride buccal formulations: in vitro evaluation and preliminary investigation of in vivo performance.

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Ahmed, Sami; El-Setouhy, Doaa Ahmed; El-Latif Badawi, Alia Abd; El-Nabarawi, Mohamed Ahmed

2014-08-18

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first

Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

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Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

2015-06-01

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.

Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k: Formulation, optimization, in-vitro and in-vivo antidiabetic evaluation.

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Garg, Varun; Kaur, Puneet; Singh, Sachin Kumar; Kumar, Bimlesh; Bawa, Palak; Gulati, Monica; Yadav, Ankit Kumar

2017-11-15

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of polypeptide-k (PPK) is reported with the aim to achieve its oral delivery. Box-Behnken design (BBD) was adopted to develop and optimize the composition of SNEDDS. Oleoyl polyoxyl-6 glycerides (A), Tween 80 (B), and diethylene glycol monoethyl ether (C) were used as oil, surfactant and co-surfactant, respectively as independent variables. The effect of variation in their composition was observed on the mean droplet size (y1), polydispersity index (PDI) (y2), % drug loading (y3) and zeta potential (y4). As per the optimal design, seventeen SNEDDS prototypes were prepared. The optimized composition of SNEDDS formulation was 25% v/v Oleoyl polyoxyl-6 glycerides, 37% v/v Tween 80, 38% v/v diethylene glycol monoethyl ether, and 3% w/v PPK. The optimized formulation revealed values of y1, y2, y3, and y4 as 31.89nm, 0.16, 73.15%, and -15.65mV, respectively. Further the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, disintegration and dissolution properties. Both, liquid and solid-SNEDDS have shown release of >90% within 10min. The formulation was found stable with change in pH, dilution, temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline PPK was observed in amorphous state in solid SNEDDS when characterized through DSC and PXRD studies. The biochemical, hematological and histopathological results of streptozotocin induced diabetic rats shown promising antidiabetic potential of PPK loaded in SNEDDS at its both the doses (i.e. 400mg/kg and 800mg/kg) as compared to its naïve form at both the doses. The study revealed successful formulation of SNEDDS for oral delivery of PPK. Copyright © 2017 Elsevier B.V. All rights reserved.

Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin.

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Morçöl, T; Nagappan, P; Nerenbaum, L; Mitchell, A; Bell, S J D

2004-06-11

An oral delivery system for insulin was developed and functional activity was tested in a non-obese diabetic (NOD) mice model. Calcium phosphate particles containing insulin was synthesized in the presence of PEG-3350 and modified by aggregating the particles with caseins to obtain the calcium phosphate-PEG-insulin-casein (CAPIC) oral insulin delivery system. Single doses of CAPIC formulation were tested in NOD mice under fasting or fed conditions to evaluate the glycemic activity. The blood glucose levels were monitored every 1-2h for 12h following the treatments using an ACCU CHECK blood glucose monitoring system. Orally administered and subcutaneously injected free insulin solution served as controls in the study. Based on the results obtained we propose that: (1). the biological activity of insulin is preserved in CAPIC formulation; (2). insulin in CAPIC formulations, but not the free insulin, displays a prolonged hypoglycemic effect after oral administration to diabetic mice; (3). CAPIC formulation protects insulin from degradation while passing through the acidic environment of the GI track until it is released in the less acidic environment of the intestines where it can be absorbed in its biologically active form; (4). CAPIC formulation represents a new and unique oral delivery system for insulin and other macromolecules.

Methods and predictors of tampering with a tamper-resistant controlled-release oxycodone formulation.

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Peacock, Amy; Degenhardt, Louisa; Hordern, Antonia; Larance, Briony; Cama, Elena; White, Nancy; Kihas, Ivana; Bruno, Raimondo

2015-12-01

In April 2014, a tamper-resistant controlled-release oxycodone formulation was introduced into the Australian market. This study aimed to identify the level and methods of tampering with reformulated oxycodone, demographic and clinical characteristics of those who reported tampering with reformulated oxycodone, and perceived attractiveness of original and reformulated oxycodone for misuse (via tampering). A prospective cohort of 522 people who regularly tampered with pharmaceutical opioids and had tampered with the original oxycodone product in their lifetime completed two interviews before (January-March 2014: Wave 1) and after (May-August 2014: Wave 2) introduction of reformulated oxycodone. Four-fifths (81%) had tampered with the original oxycodone formulation in the month prior to Wave 1; use and attempted tampering with reformulated oxycodone amongst the sample was comparatively low at Wave 2 (29% and 19%, respectively). Reformulated oxycodone was primarily swallowed (15%), with low levels of recent successful injection (6%), chewing (2%), drinking/dissolving (1%), and smoking (word-of-mouth or the internet). Participants rated reformulated oxycodone as more difficult to prepare and inject and less pleasant to use compared to the original formulation. Current findings suggest that the introduction of the tamper-resistant product has been successful at reducing, although not necessarily eliminating, tampering with the controlled-release oxycodone formulation, with lower attractiveness for misuse. Appropriate, effective treatment options must be available with increasing availability of abuse-deterrent products, given the reduction of oxycodone tampering and use amongst a group with high rates of pharmaceutical opioid dependence. Copyright © 2015 Elsevier B.V. All rights reserved.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

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Lionberger, Robert A; Raw, Andre S; Kim, Stephanie H; Zhang, Xinyuan; Yu, Lawrence X

2012-04-01

FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

Relative bioavailability of single doses of prolonged-release tacrolimus administered as a suspension, orally or via a nasogastric tube, compared with intact capsules: a phase 1 study in healthy participants.

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Undre, Nasrullah; Dickinson, James

2017-04-04

Tacrolimus, an immunosuppressant widely used in solid organ transplantation, is available as a prolonged-release capsule for once-daily oral administration. In the immediate postsurgical period, if patients cannot take intact capsules orally, tacrolimus therapy is often initiated as a suspension of the capsule contents, delivered orally or via a nasogastric tube. This study evaluated the relative bioavailability of prolonged-release tacrolimus suspension versus intact capsules in healthy participants. A phase 1, open-label, single-dose, cross-over study. A single clinical research unit. In total, 20 male participants, 18-55 years old, entered and completed the study. All participants received nasogastric administration of tacrolimus 10 mg suspension in treatment period 1, with randomisation to oral administration of suspension or intact capsules in periods 2 and 3. Blood concentration-time profile over 144 hours was used to estimate pharmacokinetic parameters. Primary end point: relative bioavailability of prolonged-release intact capsule versus oral or nasogastric administration of prolonged-release tacrolimus suspension (area under the concentration-time curve (AUC) from time 0 to infinity post-tacrolimus dose (AUC 0-∞ ); AUC measured until the last quantifiable concentration (AUC 0-tz ); maximum observed concentration (C max ); time to C max (T max )). Tolerability was assessed throughout the study. Relative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC 0-tz and AUC 0-∞ of 1.05 (90% CI 0.96 to 1.14). Bioavailability was lower with suspension administered via a nasogastric tube versus intact capsules (17%; ratio 0.83; CI 0.76 to 0.92). C max was higher for oral and nasogastric suspension (30% and 28%, respectively), and median T max was shorter (difference 1.0 and 1.5 hours postdose, respectively) versus intact capsules (2.0 hours). Single 10�

The effect of additives on release and in vitro skin retention of flavonoids from emulsion and gel semisolid formulations.

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Dyja, R; Jankowski, A

2017-08-01

To assess the effect of two different additives (propylene glycol (PG) and polyethylene glycol 400 (PEG 400)) on release and in vitro skin retention of quercetin and chrysin from semisolid bases (amphiphilic creams and acidic carbomer gels). For obtaining semisolid formulations, flavonoids were pre-dissolved in the liquid (PG or PEG 400) or directly suspended in the semisolid base. Three chrysin formulations ('cream 0', 'PG-cream' and 'PEG 400-cream') and five quercetin formulations ('cream 0', 'PG cream', 'PEG 400 cream', 'gel 0' and 'PG gel') were prepared. The release studies were carried out in Franz diffusion cells by means of a cellulose membrane. The porcine ear skin was used in in vitro skin retention studies. The dissolution was a prerequisite to increase the release rates of tested flavonoids from obtained semisolid formulations. The cumulative amount of chrysin released after 6 h from 'PEG 400 cream' containing partly dissolved form of that flavonoid was higher than that from 'cream 0' or 'PG cream' containing its suspended form. The formulations containing quercetin dissolved in PG ('PG cream', 'PG gel') or PEG 400 ('PEG 400 cream') exhibited higher release rates of that flavonoid than corresponding semisolid suspensions ('cream 0' or 'gel 0'). The effects of both liquid additives (PG and PEG 400) on the cumulative amount of quercetin released after 6 h were comparable. However, there was no correlation between the release rate and the skin retention. The amounts of the flavonoids found in the skin were strongly affected by the type of the used solvent. While PG increased the skin retention of both flavonoids, PEG 400 had no effect on chrysin skin retention and delayed quercetin skin absorption. The proper choice of the solvent added to the semisolid base is crucial for enhanced skin delivery of the tested flavonoids. PG is more efficient absorption promoter than PEG 400 of both chrysin and quercetin. © 2017 Society of Cosmetic Scientists and the Soci

Tramadol extended-release in the management of chronic pain

Science.gov (United States)

McCarberg, Bill

2007-01-01

Chronic, noncancer pain such as that associated with osteoarthritis of the hip and knee is typically managed according to American College of Rheumatology guidelines. Patients unresponsive to first-line treatment with acetaminophen receive nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. However, many patients may have chronic pain that is refractory to these agents, or they may be at risk for the gastrointestinal, renal, and cardiovascular complications associated with their use. Tramadol, a mild opioid agonist and norepinephrine and serotonin reuptake inhibitor, is recommended by current guidelines for the treatment of moderate to moderately severe pain in patients who have not responded to previous oral therapy, or in patients who have contraindications to COX-2 inhibitors and nonselective NSAIDs. An extended-release (ER) formulation of tramadol was approved by the US Food and Drug Administration in September 2005. In contrast with immediate-release (IR) tramadol, this ER formulation allows once-daily dosing, providing around-the-clock analgesia. In clinical studies, tramadol ER has demonstrated a lower incidence of adverse events than that reported for IR tramadol. Unlike nonselective NSAIDs and COX-2 inhibitors, tramadol ER is not associated with gastrointestinal, renal, or cardiovascular complications. Although tramadol is an opioid agonist, significant abuse has not been demonstrated after long-term therapy. It is concluded that tramadol ER has an efficacy and safety profile that warrants its early use for the management of chronic pain, either alone or in conjunction with nonselective NSAIDs and COX-2 inhibitors. PMID:18488071

Novel technology to prepare oral formulations for preclinical safety studies.

Science.gov (United States)

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

Science.gov (United States)

Externbrink, Anna; Eggenreich, Karin; Eder, Simone; Mohr, Stefan; Nickisch, Klaus; Klein, Sandra

2017-01-01

Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release. Copyright © 2016 Elsevier B.V. All rights reserved.

A quality-by-design study for an immediate-release tablet platform: examining the relative impact of active pharmaceutical ingredient properties, processing methods, and excipient variability on drug product quality attributes.

Science.gov (United States)

Kushner, Joseph; Langdon, Beth A; Hicks, Ian; Song, Daniel; Li, Fasheng; Kathiria, Lalji; Kane, Anil; Ranade, Gautam; Agarwal, Kam

2014-02-01

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity 1 MPa, friability ≤ 0.2% weight loss, and disintegration time impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

NARCIS (Netherlands)

Buitelaar, J.K.; Ramos-Quiroga, J.A.; Casas, M.; Kooij, J.J.; Niemela, A.; Konofal, E.; Dejonckheere, J.; Challis, B.H.; Medori, R.

2009-01-01

The osmotic release oral system (OROS) methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety

Biodegradable microcontainers as an oral drug delivery system for poorly soluble drugs

DEFF Research Database (Denmark)

Nielsen, Line Hagner; Nagstrup, Johan; Keller, Stephan Sylvest

2013-01-01

PURPOSE: To fabricate microcontainers in biodegradable polylactic acid (PLLA) polymer films using hot embossing, and investigate the application of fabricated microcontainers as an oral drug delivery system for a poorly soluble drug. METHODS: For fabrication of the PLLA microcontainers, a film...... (produced by spray drying) using a simplified version of a screen printing technique. An enteric-resistant lid of Eudragit L-100 was subsequently spray coated onto the cavity of the microcontainers. Release of amorphous furosemide salt from the coated microcontainers was investigated using a μ-Diss profiler...... release from microcontainers in gastric medium, and facilitated an immediate release in the intestinal medium. The fabricated microcontainers therefore show considerable future potential as oral drug delivery systems....

[BIPADDLED SPLIT PECTORALIS MAJOR MYOCUTANEOUS FLAPS FOR IMMEDIATE RECONSTRUCTION OF ORAL MUCOSAL DEFECTS AND NECK DEFECTS AFTER RESECTION OF RECURRENT ORAL CANCER].

Science.gov (United States)

Chen, Jie; Jiang, Canhua; Li, Ning; Gao, Zhengyang; Chen, Lichun; Wu, Xiaoshan; Chen, Xinqun; Jian, Xinchun

2015-07-01

To investigate the feasibility of the bipaddled split pectoralis major myocutaneous flap for immediate reconstruction of oral mucosal defects and neck defects after resection of recurrent oral cancer. Six patients with oral mucosal defects combined with neck defects after recurrent oral cancer resection were treated with bipaddled split pectoralis major myocutaneous flap between September 2013 and September 2014. There were 5 males and 1 female with an average age of 54.7 years (range, 45-62 years), including 4 cases of recurrent tongue cancer, 1 case of recurrent mandibular gingival cancer, and 1 case of mouth floor carcinoma. All patients underwent local recurrence at 8 to 14 months after first operation, with no distant metastasis. The defects of the intraoral mucosa was 4.0 cm x 2.5 cm to 6.5 cm x 3.5 cm and the defect of the neck skin was 5.5 cm x 3.5 cm to 7.5 cm x 5.0 cm. The pectoralis major myocutaneous flaps (14.0 cm x 3.5 cm to 17.0 cm x 5.5 cm) were incised at the level of the 3rd to the 4th rib, and then split down along the muscle fiber till about 2 cm away from the thoracoacromial vessels, forming 2 independent skin paddles with 1-2 branch vessels to the pedicles of the distal ones. The distal skin paddles were used for oral reconstruction while the proximal paddles for repair of neck defects. The chest donor sites were sutured directly. Cervical haematoma and infection happened in 1 patient respectively after operation, and were cured after symptomatic treatment. All 6 split pectoralis major myocutaneous flaps with 12 skin paddles completely survived. All patients were followed up 6 to 18 months (mean, 11 months). One patient died of pulmonary metastasis at 8 months after operation and the other 5 survived without relapse or metastasis during follow-up. The intraoral paddles showed good shape with satisfactory speech function and swallowing recovery. The paddles also healed perfectly on the neck with flat outlooks, and all patients obtained full

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

Science.gov (United States)

Tsume, Yasuhiro; Amidon, Gordon L

2010-08-02

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

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

Science.gov (United States)

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Atorvastatin calcium loaded chitosan nanoparticles: in vitro evaluation and in vivo pharmacokinetic studies in rabbits

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Abdul Baquee Ahmed

2015-06-01

Full Text Available In this study, we prepared atorvastatin calcium (AVST loaded chitosan nanoparticles to improve the oral bioavailability of the drug. Nanoparticles were prepared by solvent evaporation technique and evaluated for its particle size, entrapment efficiency, zeta potential, in vitro release and surface morphology by scanning electron microscopy (SEM. In addition, the pharmacokinetics of AVST from the optimized formulation (FT5 was compared with marketed immediate release formulation (Atorva(r in rabbits. Particle size of prepared nanoparticles was ranged between 179.3 ± 7.12 to 256.8 ± 8.24 nm with a low polydispersity index (PI value. Zeta potential study showed that the particles are stable with positive values between 13.03 ± 0.32 to 46.90 ± 0.49 mV. FT-IR studies confirmed the absence of incompatibility of AVST with excipient used in the formulations. In vitro release study showed that the drug release was sustained for 48 h. Results of pharmacokinetics study showed significant changes in the pharmacokinetic parameter (2.2 fold increase in AUC of the optimized formulation as compared to marketed formulation (Atorva(r. Thus, the developed nanoparticles evidenced the improvement of oral bioavailability of AVST in rabbit model.

Immediate implant-supported oral rehabilitation using a photocurable plastic skull model and laser welding. A technical note on the screw-retained type: Part 1.

Science.gov (United States)

Tomotake, Yoritoki; Ishida, Osamu; Kanitani, Hideo; Ichikawa, Tetsuo

2002-01-01

This article describes a new procedure for immediate implant-supported oral rehabilitation using a photocurable resin skull model and a laser-welding apparatus. Preoperatively, the framework was fabricated on a photocurable resin skull model produced from a CT scan and individually designed guide template. The implants were immediately placed using the guide template; laser welding connected the components of framework. Despite the custom-made prosthesis, the total treatment from implant placement to superstructure placement can be completed within only 1 day. This procedure for immediate implant-supported oral rehabilitation using a photocurable resin skull model and a laser-welding apparatus may be useful for any implant system and patient.

Effect of sustained-release isosorbide dinitrate on post-prandial gastric emptying and gastroduodenal motility in healthy humans

DEFF Research Database (Denmark)

Madsen, Jan Lysgård; Rasmussen, S L; Linnet, J

2004-01-01

and gastroduodenal motility after a meal. Eleven healthy volunteers participated in a double-blind, placebo-controlled, cross-over study. Each subject ingested 40 mg isosorbide dinitrate orally as a sustained-release formulation or oral placebo, in random order. Gastric emptying and gastroduodenal motility were...... consecutive 15-min periods. A 40 mg single dose of sustained-released isosorbide dinitrate does not seem to alter gastric emptying or gastroduodenal motility after a meal.......Nitric oxide (NO) is an inhibitory neurotransmitter released by non-adrenergic and non-cholinergic neurons that innervate the smooth muscles of the gastrointestinal tract. We examined whether NO, derived from a sustained-release preparation of isosorbide dinitrate, influenced gastric emptying...

A nanostructured liquid crystalline formulation of 20(S)-protopanaxadiol with improved oral absorption.

Science.gov (United States)

Jin, Xin; Zhang, Zhen-Hai; Li, Song-Lin; Sun, E; Tan, Xiao-Bin; Song, Jie; Jia, Xiao-Bin

2013-01-01

As with many other anti-cancer agents, 20(S)-protopanaxadiol (PPD) has a low oral absorption. In this study, in order to improve the oral bioavailability of PPD, the cubic nanoparticles that it contains were used to enhance absorption. Therefore, the cubic nanoparticle loaded PPD were prepared through the fragmentation of the glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and were verified by transmission electron microscope, small angle X-ray scattering and differential scanning calorimetry. The in vitro release of 20(S)-protopanaxadiol from these nanoparticles was less than 5% at 12h. And then Caco-2 cell monolayer model was used to evaluate the absorption of PPD in vitro. Meanwhile the rat intestinal perfusion model and bioavailability were also estimated in vivo. The results showed that, in the Caco-2 cell model, the PPD-cubosome could increase the permeability values from the apical (AP) to the basolateral (BL) of PPD at 53%. The result showed that the four-site rat intestinal perfusion model was consistent with the Caco-2 cell model. And the result of a pharmacokinetic study in rats showed that the relative bioavailability of the PPD-cubosome (AUC(0-∞)) compared with the raw PPD (AUC(0-∞)) was 169%. All the results showed that the PPD-cubosome enhanced bioavailability was likely due to the increased absorption by the cubic nanoparticles rather than by the improved release. Hence, the cubic nanoparticles may be a promising oral carrier for the drugs that have a poor oral absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Dissolution of Intact, Divided and Crushed Circadin Tablets: Prolonged vs. Immediate Release of Melatonin

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Hui Ming Chua

2016-01-01

Full Text Available Circadin 2 mg prolonged-release tablet is the only licensed melatonin product available in the UK. Circadin is indicated for patients with primary insomnia aged 55 and over, but is more widely used “off-label” to treat sleep disorders especially in the paediatric population. Children and older people often have difficulty swallowing tablets and dividing the tablet is sometimes required to ease administration. The aim of this study was to measure the release profile of melatonin from Circadin tablets when divided or crushed, and compare this with release from intact tablets. Dissolution testing was also performed for unlicensed melatonin products for comparison. Dissolution tests were performed using the pharmacopoeial paddle apparatus, with melatonin release analyzed by high performance liquid chromatography. Melatonin content, hardness, friability, and disintegration of the products were also evaluated. The prolonged release of melatonin from Circadin tablets was unlike that of any other product tested. When divided into halves, Circadin preserved most of the prolonged-release characteristic (f2 = 58, whereas quarter-cut and crushed tablet had a more immediate melatonin release profile. Circadin is significantly less expensive and should be preferred to unlicensed medicines which are not pharmaceutically equivalent and offer less quality assurance.

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

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Zhu YB

2015-08-01

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

Mucoadhesive Hydrogel Films of Econazole Nitrate: Formulation and Optimization Using Factorial Design

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Balaram Gajra

2014-01-01

Full Text Available The mucoadhesive hydrogel film was prepared and optimized for the purpose of local drug delivery to oral cavity for the treatment of oral Candidiasis. The mucoadhesive hydrogel film was prepared with the poly(vinyl alcohol by freeze/thaw crosslinking technique. 32 full factorial design was employed to optimize the formulation. Number of freeze/thaw cycles (4, 6, and 8 cycles and the concentration of the poly(vinyl alcohol (10, 15, and 20% were used as the independent variables whereas time required for 50% drug release, cumulative percent of drug release at 8th hour, and “k” of zero order equation were used as the dependent variables. The films were evaluated for mucoadhesive strength, in vitro residence time, swelling study, in vitro drug release, and effectiveness against Candida albicans. The concentration of poly(vinyl alcohol and the number of freeze/thaw cycles both decrease the drug release rate. Mucoadhesive hydrogel film with 15% poly(vinyl alcohol and 7 freeze/thaw cycles was optimized. The optimized batch exhibited the sustained release of drug and the antifungal studies revealed that the drug released from the film could inhibit the growth of Candida albicans for 12 hours.

Comparison of New Formulation of Diclofenac Diethylamonium Emulgel with Standard Preparation

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SA Mostafavi

2006-07-01

Full Text Available Introduction & Objective: Oral route is a common route of administration for anti-inflammatory drugs including diclofenac. Due to some disadvantages of this route, the alternative routes of administrations are considered. The skin has been increasingly important in this regard, and many drugs have been formulated intradermal delivery systems. The purpose of this study was to prepare a topical diclofenac formulation emulgel with appropriate skin penetration and compare it with standard formulation. Materials & Methods: To prepare the formulation, we used the emulsion form. Several formulations containing different kinds and amounts of diclofenac salts, different emulsifying agents, and different HPMC concentrations were prepared. The skin penetration was evaluated by using Franz cell apparatus and the concentrations of diclofenac were determined in the receptor phase of Franz cell using spectrophotometer. The in vivo absorption of diclofenac was evaluated by determination of drug in urine. The concentration of drug was determined by HPLC. Results: In selected formulation, 85% of drug was released after 4 hours from formulation which was similar to drug released from standard formulation. The values of coefficient variation for HPLC method were utmost 15%. The range of variation in measurement was between 10 and 1000 ng/ml. Conclusion: The selected formulation had appropriate physicochemical properties. We were unable to measure drug concentrations in urine by the constructed HPLC, therefore it can be suggested that one should determine drug concentration in synovial fluid as the drug is concentrated in it.

Eco-friendly PEG-based controlled release nano-formulations of Mancozeb: Synthesis and bioefficacy evaluation against phytopathogenic fungi Alternaria solani and Sclerotium rolfsii.

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Majumder, Sujan; Shakil, Najam A; Kumar, Jitendra; Banerjee, Tirthankar; Sinha, Parimal; Singh, Braj B; Garg, Parul

2016-12-01

Controlled release (CR) nano-formulations of Mancozeb (manganese-zinc double salt of N,N-bisdithiocarbamic acid), a protective fungicide, have been prepared using laboratory-synthesized poly(ethylene glycols) (PEGs)-based functionalized amphiphilic copolymers without using any surfactants or external additives. The release kinetics of the developed Mancozeb CR formulations were studied and compared with that of commercially available 42% suspension concentrate and 75% wettable powder. Maximum amount of Mancozeb was released on 42nd day for PEG-600 and octyl chain, PEG-1000 and octyl chain, and PEG-600 and hexadecyl chain, on 35th day for PEG-1000 and hexadecyl chain, on 28th day for PEG-1500 and octyl chain, PEG-2000 and octyl chain, PEG-1500 and hexadecyl chain, and PEG-2000 and hexadecyl chain in comparison to both commercial formulations (15th day). The diffusion exponent (n value) of Mancozeb in water ranged from 0.42 to 0.62 in tested formulations. The half-release (t 1/2 ) values ranged from 17.35 to 35.14 days, and the period of optimum availability of Mancozeb ranged from 18.54 to 35.42 days. Further, the in vitro bioefficacy evaluation of developed formulations was done against plant pathogenic fungi Alternaria solani and Sclerotium rolfsii by poison food technique. Effective dose for 50% inhibition in mgL -1 (ED 50 ) values of developed formulations varied from 1.31 to 2.79 mg L -1 for A. solani, and 1.60 to 3.14 mg L -1 for S. rolfsii. The present methodology is simple, economical, and eco-friendly for the development of environment-friendly CR formulations of Mancozeb. These formulations can be used to optimize the release of Mancozeb to achieve disease control for the desired period depending upon the matrix of the polymer used. Importantly, the maximum amount of active ingredient remains available for a reasonable period after application. In addition, the developed CR formulations were found to be suitable for fungicidal applications, allowing

Effect of controlled release formulations of diuron and alachlor herbicides on the biochemical activity of agricultural soils.

Science.gov (United States)

Tejada, Manuel; Morillo, Esmeralda; Gómez, Isidoro; Madrid, Fernando; Undabeytia, Tomás

2017-01-15

The use of pesticides in agriculture is essential because it reduces the economic losses caused by pests, improving crop yields. In spite of the growing number of studies concerning the development and application of controlled release formulations (CRFs) of pesticides in agricultural soils, there are no studies about the effects of such formulations on the biochemical properties. In this paper the dissipation of diuron and alachlor in three agricultural soils for 127days, applied either as commercial or CRFs, was determined as well as their concomitant effects on soil biochemical properties. Dehydrogenase, urease, β-glucosidase and phosphatase activities were measured thought the experimental period. The application of alachlor as CRF increases its half-life time in soils, whereas no differences were noticed between diuron formulations due to its slower degradation, which takes longer than its release from the CRF. At the end of the incubation period, the enzymatic activities were the same after the use of diuron either as commercial or CRF, recovering the soil previous status. For alachlor formulations, no differences in enzymatic activities were again observed between both formulations, but their levels in soils were enhanced. Therefore, the use of these CRFs does not adversely affect the soil biochemical properties. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and Evaluation of Taste Masked Granular Formulation of Satranidazole by Melt Granulation Technique

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Harshal Ashok Pawar

2014-01-01

Full Text Available Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and in vitro release. The formulated granules were found to possess good flow property. FTIR studies confirmed that there was no interaction between drug and excipients. Scanning Electron Microscopy of drug and the optimized batch of granules was performed. The in vitro release of drug from granules was compared with marketed tablet formulation. The taste masked granules of optimized batch showed 87.65% release of drug in 1 hr which is comparable to that of marketed tablet formulation.

Pharmacokinetics of a Sustained-release Formulation of Meloxicam After Subcutaneous Administration to Hispaniolan Amazon Parrots (Amazona ventralis).

Science.gov (United States)

Guzman, David Sanchez-Migallon; Court, Michael H; Zhu, Zhaohui; Summa, Noémie; Paul-Murphy, Joanne R

2017-09-01

Meloxicam has been shown to have a safe and favorable pharmacodynamic profile with individual variability in Hispaniolan Amazon parrots (Amazona ventralis). In the current study, we determined the pharmacokinetics of a sustained-release formulation of meloxicam after subcutaneous administration to Hispaniolan Amazon parrots. Twelve healthy adult parrots, 6 males and 6 females, were used in the study. Blood samples were collected before (time 0) and at 0.5, 1, 2, 6, 12, 24, 48, 72, 96, and 120 hours after a single dose of the sustained-release meloxicam formulation (3 mg/kg SC). Plasma meloxicam concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. Plasma concentrations reached a mean C max of 23.4 μg/mL (range, 14.7-46.0 μg/mL) at 1.8 hours (range, 0.5-6 hours), with a terminal half-life of 7.4 hours (range, 1.4-40.9 hours). Individual variation was noticeable, such that some parrots (4 of 12 birds) had very low plasma meloxicam concentrations, similar to the high variability reported in a previous pharmacokinetic study of the standard meloxicam formulation in the same group of birds. Two birds developed small self-resolving scabs at the injection site. On the basis of these results, the sustained-release meloxicam formulation could be administered every 12 to 96 hours in Hispaniolan Amazon parrots to manage pain. Because of these highly variable results, the use of this formulation in this species cannot be recommended until further pharmacokinetic, safety, and pharmacogenomic evaluations are performed to establish accurate dosing recommendations and to understand the high pharmacokinetic variability.

Investigation of in situ gelling alginate formulations as a sustained release vehicle for co-precipitates of dextromethrophan and Eudragit S 100

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Maghraby Gamal Mohamed El

2014-03-01

Full Text Available Alginate vehicles are capable of forming a gel matrix in situ when they come into contact with gastric medium in the presence of calcium ions. However, the gel structure is pH dependent and can break after gastric emptying, leading to dose dumping. The aim of this work was to develop modified in situ gelling alginate formulations capable of sustaining dextromethorphan release throughout the gastrointestinal tract. Alginate solution (2 %, m/m was used as a vehicle for the tested formulations. Solid matrix of the drug and Eudragit S 100 was prepared by dissolving the drug and polymer in acetone. The organic solvent was then evaporated and the deposited solid matrix was micronized, sieved and dispersed in alginate solution to obtain candidate formulations. The release behavior of dextromethorphan was monitored and evaluated in a medium simulating the gastric and intestinal pH. Drug-polymer compatibility and possible solid-state interactions suggested physical interaction through hydrogen bonding between the drug and the polymer. A significant decrease in the rate and extent of dextromethorphan release was observed with increasing Eudragit S 100 concentration in the prepared particles. Most formulations showed sustained release profiles similar to that of a commercial sustained-release liquid based on ion exchange resin. The release pattern indicated strict control of drug release both under gastric and intestinal conditions, suggesting the potential advantage of using a solid dispersion of drug-Eudragit S 100 to overcome the problem of dose dumping after the rupture of the pH dependent alginate gels

Zein-alginate based oral drug delivery systems: Protection and release of therapeutic proteins.

Science.gov (United States)

Lee, Sungmun; Kim, Yeu-Chun; Park, Ji-Ho

2016-12-30

Reactive oxygen species (ROS) play an important role in the development of inflammatory bowel diseases. Superoxide dismutase (SOD) has a great therapeutic potential by scavenging superoxide that is one of ROS; however, in vivo application is limited especially when it is orally administered. SOD is easily degraded in vivo by the harsh conditions of gastrointestinal tract. Here, we design a zein-alginate based oral drug delivery system that protects SOD from the harsh conditions of gastrointestinal tract and releases it in the environment of the small intestine. SOD is encapsulated in zein-alginate nanoparticles (ZAN) via a phase separation method. We demonstrate that ZAN protect SOD from the harsh conditions of the stomach or small intestine condition. ZAN (200:40) at the weight ratio of 200mg zein to 40mg of alginate releases SOD in a pH dependent manner, and it releases 90.8±1.2% of encapsulated SOD at pH 7.4 in 2h, while only 11.4±0.4% of SOD was released at pH 1.3. The encapsulation efficiency of SOD in ZAN (200:40) was 62.1±2.0%. SOD in ZAN (200:40) reduced the intracellular ROS level and it saved 88.9±7.5% of Caco-2 cells from the toxic superoxide in 4 hours. Based on the results, zein-alginate based oral drug delivery systems will have numerous applications to drugs that are easily degradable in the harsh conditions of gastrointestinal tract. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization and in vitro release studies of oral microbeads containing thiolated pectin–doxorubicin conjugates for colorectal cancer treatment

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Kamonrak Cheewatanakornkool

2017-11-01

Full Text Available Novel oral microbeads were developed based on a biopolymer–drug conjugate of doxorubicin (DOX conjugated with thiolated pectin via reducible disulfide bonds. The microbeads were fabricated by ionotropic gelation with cations such as Al3+, Ca2+ and Zn2+. The results showed that using zinc acetate can produce the strongest microbeads with spherical shape. However, the microbeads prepared from thiolated pectin–DOX conjugate were very soft and irregular in shape. To produce more spherical microbeads with suitable strength, the native pectin was then added to the formulations. The particle size of the microbeads ranged from 0.87 to 1.14 mm. The morphology of the microbeads was characterized by optical and scanning electron microscopy. DOX was still in crystalline form when used in preparing the microbeads, as confirmed by powder X-ray diffractometry. Drug release profiles showed that the microbeads containing thiolated pectin–DOX conjugate exhibited reduction-responsive character; in reducing environments, the thiolated pectin–DOX conjugate could uncouple resulting from a cleavage of the disulfide linkers and consequently release the DOX. The best-fit release kinetics of the microbeads containing thiolated pectin–DOX conjugate, in the medium without reducing agent, fit the Korsmeyer–Peppas model while those in the medium with reducing agent fit a zero-order release model. These results suggested that the microbeads containing thiolated pectin–DOX conjugate may be a promising platform for cancer-targeted delivery of DOX, exploiting the reducing environment typically found in tumors.

Formulation and release of alaptide from cellulose-based hydrogels

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Zbyněk Sklenář

2012-01-01

Full Text Available The modern drug alaptide, synthetic dipeptide, shows regenerative effects and effects on the epitelisation process. A commercial product consisting of 1% alaptide hydrophilic cream is authorised for use in veterinary practice. This study focuses on the formulation of alaptide into semi-synthetic polymer-based hydrogels. The aim of the present study is to prepare hydrogels and to evaluate the liberation of alaptide from hydrogels. The hydrogels were prepared on the basis of three gel-producing substances: methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. To enhance the drug release from hydrogel humectants, glycerol, propylene glycol and ethanol in various concentrations were evaluated. The permeation of the alaptide from gels into the acceptor solution was evaluated with the use of the permeable membrane neprophane. The amount of drug released from prepared hydrogels was determined spectrophotometrically. Hydrogels with optimal alaptide liberation properties were subjected to the study of rheological properties in the next phase. The optimal composition of hydrogel as established in this study was 1% alaptide + 3% hydroxyethylcellulose with the addition of 10% glycerol as humectant. Due to the advantageous properties of hydrogels in wounds, alaptide could be incorporated into a hydrogel base for use in veterinary medicine.

Differential scanning calorimetry as a screening technique in compatibility studies of acyclovir extended release formulations

International Nuclear Information System (INIS)

Barboza, Fernanda M.; Vecchia, Debora D.; Tagliari, Monika P.; Ferreira, Andrea Granada; Silva, Marcos A.S.; Stulzer, Hellen K.

2009-01-01

Acyclovir (ACV) has been investigated during the past years, mainly due to its antiviral activity. Assessment of possible incompatibility between an active component and different excipients along with the evaluation of thermal stability are crucial parts of a normal study prior to the final formulation setting of a medicine. Thermal analysis studies were used as important and complementary tools during pre-formulation to determine the compatibility of drug excipients with the purpose of developing an acyclovir extended release formulation. Fourier transform infrared spectroscopy and X-ray powder diffraction analyses were also realized. The results showed that ACV only exhibited interaction which could influence the stability of the product in the binary mixtures of ACV/magnesium stearate. (author)

Slow release formulations of Bacillus thuringiensis israelensis (AM 65-52 and spinosyns: effectiveness against the West Nile vector Culex pipiens in Saudi Arabia

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Alaa Sulaiman Alsobhi

2016-07-01

Full Text Available Objective: To investigate the effectiveness of slow release formulations of Bacillus thuringiensis israelensis (AM 65-52 (B. thuringiensis israelensis and spinosyns against the West Nile vector Culex pipiens (Cx. pipiens in Saudi Arabia. Methods: We tested slow release insecticide formulations of Natular DT, Tap 60 and VectoBac granule against II instars of Cx. pipiens larvae in 50 L laboratory arenas. Results: Slow release formulations of B. thuringiensis israelensis and spinosyns gave continuous control against Cx. pipiens for several weeks. Natular DT was more effective over Tap 60 and VectoBac granule of about 1.3 and 5.8 times, respectively. Variations in the durations of effective control among the tested slow release formulations may reflect differences in their active ingredients and the mode of action. Conclusions: Our results highlighted the effectiveness of B. thuringiensis israelensis and spinosyns against an important West Nile vector, providing baseline data to develop ecofriendly mosquito control programs in Saudi Arabia.

Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies.

Science.gov (United States)

Markowitz, Michael; Fu, Dong-Jing; Levitan, Bennett; Gopal, Srihari; Turkoz, Ibrahim; Alphs, Larry

2013-07-11

Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available. This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity. Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p 70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar. This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

Characterization of new functionalized calcium carbonate-polycaprolactone composite material for application in geometry-constrained drug release formulation development.

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Wagner-Hattler, Leonie; Schoelkopf, Joachim; Huwyler, Jörg; Puchkov, Maxim

2017-10-01

A new mineral-polymer composite (FCC-PCL) performance was assessed to produce complex geometries to aid in development of controlled release tablet formulations. The mechanical characteristics of a developed material such as compactibility, compressibility and elastoplastic deformation were measured. The results and comparative analysis versus other common excipients suggest efficient formation of a complex, stable and impermeable geometries for constrained drug release modifications under compression. The performance of the proposed composite material has been tested by compacting it into a geometrically altered tablet (Tablet-In-Cup, TIC) and the drug release was compared to commercially available product. The TIC device exhibited a uniform surface, showed high physical stability, and showed absence of friability. FCC-PCL composite had good binding properties and good compactibility. It was possible to reveal an enhanced plasticity characteristic of a new material which was not present in the individual components. The presented FCC-PCL composite mixture has the potential to become a successful tool to formulate controlled-release dosage solid forms.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

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Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

2017-06-01

The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

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

Science.gov (United States)

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

2015-02-01

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

Soluplus®/TPGS-based solid dispersions prepared by hot-melt extrusion equipped with twin-screw systems for enhancing oral bioavailability of valsartan.

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Lee, Jae-Young; Kang, Wie-Soo; Piao, Jingpei; Yoon, In-Soo; Kim, Dae-Duk; Cho, Hyun-Jong

2015-01-01

Soluplus(®) (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)-based solid dispersion (SD) formulations were developed by hot-melt extrusion (HME) to improve oral bioavailability of valsartan (VST). HME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST. HME with a high shear rate produced by the twin-screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group. SP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs.

Immediate and long-term effects of polysaccharides-based formulations on human skin

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Flavio Bueno de Camargo Junior

2012-09-01

Full Text Available A new trend in cosmetic formulations is the use of biotechnological raw materials as the polysaccharides from Klebsiella pneumoniae, which are supposed to enhance cell renewal, improve skin hydration and micro-relief. Botanical extracts of Myrtus communis leaves contain different sugars, which may provide the same benefits. Thus, the objective of this study was to evaluate through objective and subjective analysis the immediate and long-term effects of cosmetic formulations containing polysaccharides biotechnologically-originated and / or the ones contained in Myrtus communis extracts. Three polysaccharide-based and placebo formulations were applied on the forearm skin of 40 volunteers. Skin hydration, transepidermal water loss (TEWL, viscoelasticity and skin micro-relief measurements were made before and 2 hours after a single application and after 15 and 30 day-periods of daily applications. Answers to a questionnaire about perceptions of formulation cosmetic features constituted the subjective analysis. All polysaccharide-based formulations enhanced skin hydration. Formulations with isolated or combined active substances improved skin barrier function as compared to placebo, in the short and long term studies. Formulations containing Myrtus communis extracts had the highest acceptance. Results suggest that daily use of formulations containing these substances is important for protection of the skin barrier function.Uma nova tendência em formulações cosméticas é a utilização de matérias-primas biotecnológicas como os polissacarídeos de Klebsiella pneumoniae, que pode aumentar a renovação celular e melhor a hidratação e micro-relevo da pele. Por outro lado, o extrato vegetal de Myrtus communis contém diferentes polissacarídeos, que também podem proporcionar benefícios à pele. Assim, o objetivo do estudo foi a avaliação dos efeitos imediatos e em longo prazo, de formulações cosméticas contendo polissacarídeos obtidos por

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

Science.gov (United States)

Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

2016-01-01

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

A Comparative Study of the Pharmacokinetics of Conventional and ...

African Journals Online (AJOL)

... a commercial brand of aceclofenac immediate release tablet (Zerodol® 100 mg). Methods: Each of two groups of twelve fasting volunteers received either the reference standard (Zerodol 100 mg tablets) or the test formulation (200 mg aceclofenac) orally once, using a cross-over design with a one week wash-out period.

Efficacy of ivermectin in injectable and oral paste formulations against eight-week-old Strongylus vulgaris larvae in ponies.

Science.gov (United States)

Klei, T R; Torbert, B J; Chapman, M R; Turk, M A

1984-01-01

A controlled test method was used to evaluate the efficacy of injectable micelle and oral paste formulations of ivermectin (22,23-dihydroavermectin B1) against 8-week-old Strongylus vulgaris larvae in experimentally infected pony foals. The dosage level of the drug in both formulations tested was 0.2 mg/kg. Ponies were euthanatized and necropsied 5 weeks after treatment. Based on the recovery of live vs dead S vulgaris from mesenteric arteries, both formulations were greater than 99% effective. Increased weight gains and marked reductions in the severity of arterial lesions were observed in treated ponies.

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

Science.gov (United States)

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

2017-12-01

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

Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

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Yuchen Wang

2017-02-01

Full Text Available Topiramate (TPM is effective for multiple seizure types and epilepsy syndromes in children and adults. Topiramate has adverse effects (including cognitive, depression, renal stones, but many of these are low incidence when started at a low dose and slowly titrated to 100 to 200 mg/day. Also, TPM has proven benefit for migraine, obesity, eating disorders, and alcohol use disorders, which can be comorbid in patients with epilepsy and may also be effective in subpopulations within specific psychiatric diagnoses. Recently approved extended-release formulations of TPM (Trokendi and Qudexy in the United States have reliable data supporting their safety and efficacy for patients with epilepsy. They have potential for more rapid titration within 1 month to 200 mg/day and have better patient retention than TPM immediate-release, but there are no robust double-blind randomized controlled trials comparing the different formulations. We expect the once per day extended-release formulations to improve medication adherence compared with the twice per day formulations. This has significant potential to improve outcomes in epilepsy and the other TPM-responsive disorders.

Residue and bio-efficacy evaluation of controlled release formulations of imidacloprid against pests in soybean (Glycine max).

Science.gov (United States)

Adak, Totan; Kumar, Jitendra; Dey, Debjani; Shakil, N A; Walia, S

2012-01-01

Controlled release (CR) formulations of imidacloprid (1-(6 chloro-3-pyridinyl methyl)-N- nitro imidazolidin-2- ylideneamine) were prepared using novel amphiphilic polymers synthesized from polyethylene glycol and aliphatic diacids employing encapsulation technique. The bioefficacy of the prepared CR formulations was evaluated against major pests of soybean, namely stem fly, Melanagromyza sojae Zehntmer and white fly, Bemisia tabaci Gennadius along with a commercial formulation at the experimental farm of Indian Agricultural Research Institute (IARI), New Delhi during kharif 2009 and 2010. Most of the CR formulations of imidacloprid gave significantly better control of the pests compare to its commercial formulations, however the CR formulations, Poly [poly (oxyethylene-1000)-oxy suberoyl] amphiphilic polymer based formulation performed better over others for controlling of both stem fly incidence and Yellow Mosaic Virus (YMV) infestation transmitted by white fly. Some of the developed CR formulations recorded higher yield over commercial formulation and control. Nodulation pattern of soybean was not affected due to treatment of CR and commercial formulations of imidacloprid. Also the residues of imidacloprid in seed and soil at harvest were not detectable for both CR and commercial formulations.

Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension.

Science.gov (United States)

Bravo González, Roberto Carlos; Huwyler, Jörg; Walter, Isabelle; Mountfield, Richard; Bittner, Beate

2002-10-01

Oral bioavailability of the highly lipophilic and poorly water-soluble immunosuppressive agent cyclosporin A (CyA) in two different formulations was investigated in male Wistar rats. An aqueous microsuspension and a self-dispersing formulation composed of the surface-active ingredients Solutol HS 15:Labrafil M2125CS:oleic acid=7:2:1 (v/v/v) were administered to the animals at a dose level of 20 mg/kg. In order to calculate the absolute oral bioavailability, CyA was additionally administered intravenously at 10 mg/kg as microsuspension. It was found that the oral bioavailability of CyA in the Solutol HS 15-based formulation was twofold higher as compared to the microsuspension (69.9+/-2.8 vs. 35.7+/-3.3%, P=0.001). By contrast, the time to reach maximum plasma concentration (t(max)) and the terminal half-life (t(1/2)) did not differ significantly with the different formulations (t(max): 7.0+/-1.0 vs. 6.3+/-1.7 h; t(1/2): 20.5+/-2.9 vs. 16.7+/-4.7 h). In vitro solubility experiments demonstrated a marked increase in the aqueous solubility of CyA in the presence of the self-dispersing formulation as compared to the micronized powder alone (solubility after 120 min at 37 degrees C: 136 vs. 23.2 microg/ml in human gastric juice; 133 vs. 10.8 microg/ml in simulated intestinal juice). Most likely, the enhanced systemic exposure of CyA in the self-dispersing formulation was caused by improved solubility of CyA in the gastrointestinal fluids in the presence of the surface-active ingredients. Additional factors that may have contributed to increased oral bioavailability are inhibition of metabolism and/or transport processes as well as permeability enhancement by the co-administered excipients.

Hydroxychloroquine niosomes: a new trend in topical management of oral lichen planus.

Science.gov (United States)

Bendas, Ehab R; Abdullah, Hamoud; El-Komy, Mohamed H M; Kassem, Mohamed A A

2013-12-31

The work aimed at studying a novel topical niosomal gel formulation of hydroxychloroquine for the management of oral lichen planus. Niosomes have been reported as conceivable vesicles to deliver drug molecules to the desired mucous membrane or skin layers. Hydroxychloroquine niosomes were designed using different methods of preparation. Tween 20 and cholesterol in molar ratio (1:0.5) were used. The prepared systems were characterized for entrapment efficiency, particle size and in vitro drug release. Different factors affecting the encapsulation of hydroxychloroquine in niosomes were studied vs. varying the type of surfactant, the cholesterol:surfactant molar ratio and the amount of the drug. The selected noisome formulation was dispersed in different gel formulations and evaluated according to the in vitro drug release and the physical stability. The results showed that the type of surfactant, cholesterol ratio and incorporated amount of drug altered the entrapment efficiency and the in vitro release of hydroxychloroquine from niosomes. The optimum formulation was prepared by reverse phase evaporation technique using Brij 98:cholesterol molar ratio (1:1.5) and containing 20mg of hydroxychloroquine and incorporated in 20% w/v Pluronic F-127 gel. A double-blind, controlled clinical study was performed using two groups of patients. Group A (n=11) who received hydroxychloroquine niosomal gel formulation, one application-a-day over 4 months showed 64.28% reduction in the size of lesions and the average score of pain was reduced from "4" to "1". Compared to placebo group B (n=5), who showed only 3.94% reduction in the lesion size and the average score of pain was remained "3". Our results suggest that these niosomal formulations could constitute a promising approach for the topical treatment of oral lichen planus in short time with less side effects and no recurrence after stopping the treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses.

Science.gov (United States)

Crosignani, N; Luna, S P; Dalla Costa, T; Pimenta, E L; Detoni, C B; Guterres, S S; Puoli Filho, J N; Pantoja, J C; Pigatto, M C

2017-08-01

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd ss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone. © 2017 John Wiley & Sons Ltd.

Absorption of controlled-release iron

International Nuclear Information System (INIS)

Cook, J.D.; Lipschitz, D.A.; Skikne, B.S.

1982-01-01

A multiple-dose double radioiron technic was used to compare absorption of iron administered as a controlled release (CR) capsule and as an elixir; both formulations contained 50 mg elemental iron as ferrous sulfate. When taken by normal subjects in the fasting state, mean absorption from the elixir and CR capsule averaged 4.92% and 4.38%, which gave a CR capsule:elixir ratio of 0.89. This difference was not significant, but when taken with meals that inhibit absorption of dietary iron by different degrees, absorption of the CR formulation was superior. CR capsule:elixir absorption ratios averaged 1.70 from a meal that is mildly inhibitory and 3.13 from a meal that causes more marked inhibition. It is concluded that CR iron formulations may offer a therapeutic advantage to patients who take oral iron with meals to avoid gastrointestinal side effects

Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration.

Science.gov (United States)

Sakloetsakun, Duangkamon; Dünnhaupt, Sarah; Barthelmes, Jan; Perera, Glen; Bernkop-Schnürch, Andreas

2013-10-01

The aim of the study is to develop a self-nanoemulsifying drug delivery system (SNEDDS) based on thiolated chitosan for oral insulin administration. The preparations were characterized by particle size, entrapment efficiency, stability and drug release. Serum insulin concentrations were determined after oral administration of all formulations. Insulin SNEDDS formulation was served as control. The optimized SNEDDS consists of 65% (w/w) miglyol 840, 25% (w/w) cremophor EL, 10% (w/w) co-solvents (a mixture of DMSO and glycerol). The formulations in the presence or absence of insulin (5mg/mL) were spherical with the size range between 80 and 160 nm. Entrapment efficiency of insulin increased significantly when the thiolated chitosan was employed (95.14±2.96%), in comparison to the insulin SNEDDS (80.38±1.22%). After 30 min, the in vitro release profile of insulin from the nanoemulsions was markedly increased compared to the control. In vivo results showed that insulin/thiolated chitosan SNEDDS displayed a significant increase in serum insulin (p-value=0.02) compared to oral insulin solution. A new strategy to combine SNEDDS and thiolated chitosan described in the study would therefore be a promising and innovative approach to improve oral bioavailability of insulin. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

The role of chitosan on oral delivery of peptide-loaded nanoparticle formulation.

Science.gov (United States)

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2017-12-01

Therapeutic peptides are conventionally administered via subcutaneous injection. Chitosan-based nanoparticles are gaining increased attention for their ability to serve as a carrier for oral delivery of peptides and vaccination. They offered superior biocompatibiltiy, controlled drug release profile and facilitated gastrointestinal (GI) absorption. The encapsulated peptides can withstand enzymatic degradation and various pH. Chitosan-based nanoparticles can also be modified by ligand conjugation to the surface of nanoparticle for transcellular absorption and specific-targeted delivery of macromolecules to the tissue of interest. Current research suggests that chitosan-based nanoparticles can deliver therapeutic peptide for the treatment of several medical conditions such as diabetes, bacterial infection and cancer. This review summarises the role of chitosan in oral nanoparticle delivery and identifies the clinical application of peptide-loaded chitosan-based nanoparticles.

Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet.

Science.gov (United States)

Cheng, Ching-Ling; Yu, Lawrence X; Lee, Hwei-Ling; Yang, Chyun-Yu; Lue, Chang-Sha; Chou, Chen-Hsi

2004-07-01

The biopharmaceutics classification system (BCS) allows biowaiver for rapid dissolving immediate-release (IR) products of Class I drugs (high solubility and high permeability). The possibility of extending biowaivers to Class III high solubility and low permeability drugs is currently under scrutiny. In vivo bioequivalence data of different formulations of Class III drugs would support such an extension. The objective of this work was to demonstrate the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride, that are rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of metformin was also explored. A randomized, open-label, two-period crossover study was conducted in 12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of metformin were followed for 24 h. No significant formulation effect was found for the bioequivalence metrics: areas under concentration-time curve (AUC0-t, AUC0-infinity) and maximal concentration (Cmax). The 90% confidence intervals for the ratio of means were found within the acceptance range of 80-125% for the log-transformed data. Based on these results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters of metformin in Chinese for both products were similar and were in good agreement with those reported for metformin IR tablets in other ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.

Effect of xanthan gum on the release of strawberry flavor in formulated soy beverage.

Science.gov (United States)

Xu, Jiao; He, Zhiyong; Zeng, Maomao; Li, Bingbing; Qin, Fang; Wang, Linxiang; Wu, Shengfang; Chen, Jie

2017-08-01

The effects of xanthan gum on the release of strawberry flavor compounds in formulated soy protein isolate (SPI) beverage were investigated by headspace gas chromatography (GC). Seven strawberry flavor compounds (limonene, ethyl hexanoate, (Z)-3-hexenyl acetate, ethyl 2-methylbutanoate, ethyl butanoate, (Z)-3-hexen-1-ol and diacetyl) could be detected by GC and hence analyzed the gas-matrix partition coefficients (K). The release of flavor compounds was restrained in SPI and/or xanthan gum solution. The retention of (Z)-3-hexen-1-ol, limonene and diacetyl significantly changed (pfuraneol) accelerated the release of ester compounds to some extent in different matrices. The above results demonstrated that presence of SPI and xanthan gum could bring about an imbalance in the strawberry flavor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Desktop 3D printing of controlled release pharmaceutical bilayer tablets.

Science.gov (United States)

Khaled, Shaban A; Burley, Jonathan C; Alexander, Morgan R; Roberts, Clive J

2014-01-30

Three dimensional (3D) printing was used as a novel medicine formulation technique for production of viable tablets capable of satisfying regulatory tests and matching the release of standard commercial tablets. Hydroxypropyl methylcellulose (HPMC 2208) (Methocel™ K100M Premium) and poly(acrylic acid) (PAA) (Carbopol(®) 974P NF) were used as a hydrophilic matrix for a sustained release (SR) layer. Hypromellose(®) (HPMC 2910) was used as a binder while microcrystalline cellulose (MCC) (Pharmacel(®) 102) and sodium starch glycolate (SSG) (Primojel(®)) were used as disintegrants for an immediate release (IR) layer. Commercial guaifenesin bi-layer tablets (GBT) were used as a model drug (Mucinex(®)) for this study. There was a favourable comparison of release of the active guaifenesin from the printed hydrophilic matrix compared with the commercially available GBT. The printed formulations were also evaluated for physical and mechanical properties such as weight variation, friability, hardness and thickness as a comparison to the commercial tablet and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). All formulations (standard tablets and 3D printed tablets) showed Korsmeyer-Peppas n values between 0.27 and 0.44 which indicates Fickian diffusion drug release through a hydrated HPMC gel layer. Copyright © 2013 Elsevier B.V. All rights reserved.

IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral (Scoping and Problem Formulation Materials)

Science.gov (United States)

In April 2018, EPA released the draft IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral. The IAP communicates to the public the plan for assessing each individual chemical and includes summary information on the IRIS Program’s scoping and initial proble...

IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral (Scoping and Problem Formulation Materials)

Science.gov (United States)

In April 2018, EPA released the draft IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral. An IRIS Assessment Plan (IAP) communicates to the public the plan for assessing each individual chemical and includes summary information on the IRIS Program’s sco...

Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability.

Science.gov (United States)

Allam, Ahmed N; Komeil, Ibrahim A; Fouda, Mohamed A; Abdallah, Ossama Y

2015-07-15

The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal(®) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal(®) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158±2.6 nm to 610±6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water-soluble molecules, such as CUR. Copyright © 2015 Elsevier B.V. All rights reserved.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

Science.gov (United States)

Bhaskar, Kesavan; Anbu, Jayaraman; Ravichandiran, Velayutham; Venkateswarlu, Vobalaboina; Rao, Yamsani Madhusudan

2009-01-01

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1) and NLC gel (B1) for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml). The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel PMID:19243632

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

Directory of Open Access Journals (Sweden)

Venkateswarlu Vobalaboina

2009-02-01

Full Text Available Abstract The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN and flurbiprofen nanostructured lipid carriers (FLUNLC by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1 and NLC gel (B1 for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml. The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel

Immediate versus delayed insertion of an etonogestrel releasing implant at medical abortion-a randomized controlled equivalence trial.

Science.gov (United States)

Hognert, Helena; Kopp Kallner, Helena; Cameron, Sharon; Nyrelli, Christina; Jawad, Izabella; Heller, Rebecca; Aronsson, Annette; Lindh, Ingela; Benson, Lina; Gemzell-Danielsson, Kristina

2016-11-01

Does a progestin releasing subdermal contraceptive implant affect the efficacy of medical abortion if inserted at the same visit as the progesterone receptor modulator, mifepristone, at medical abortion? A etonogestrel releasing subdermal implant inserted on the day of mifepristone did not impair the efficacy of the medical abortion compared with routine insertion at 2-4 weeks after the abortion. The etonogestrel releasing subdermal implant is one of the most effective long acting reversible contraceptive methods. The effect of timing of placement on the efficacy of mifepristone and impact on prevention of subsequent unintended pregnancy is not known. This multicentre, randomized controlled, equivalence trial with recruitment between 13 October 2013 and 17 October 2015 included a total of 551 women with pregnancies below 64 days gestation opting for the etonogestrel releasing subdermal implant as postabortion contraception. Women were randomized to either insertion at 1 hour after mifepristone intake (immediate) or at follow-up 2-4 weeks later (delayed insertion). An equivalence design was used due to advantages for women such as fewer visits to the clinic with immediate insertion. The primary outcome was the percentage of women with complete abortion not requiring surgical intervention within 1 month. Secondary outcomes included insertion rates, pregnancy and repeat abortion rates during 6 months follow-up. Analysis was per protocol and by intention to treat. Women aged 18 years and older who had requested medical termination of a pregnancy up to 63 days of gestation and opted for an etonogestrel releasing contraceptive implant were recruited in outpatient family planning clinics in six hospitals in Sweden and Scotland. Efficacy of medical abortion was 259/275 (94.2%) in the immediate insertion group and 239/249 (96%) in the routine insertion group with a risk difference of 1.8% (95% CI -0.4 to 4.1%), which was within the ±5% margin of equivalence. The insertion

Current Challenges and Future of Lipid nanoparticles formulations for topical drug application to oral mucosa, skin, and eye.

Science.gov (United States)

Guilherme, Viviane A; Ribeiro, Ligia N M; Tofoli, Giovana Radomille; Franz-Montan, Michelle; de Paula, Eneida; de Jesus, Marcelo Bispo

2017-11-21

Topical drug administration offers an attractive route with minimal invasiveness. It also avoids limitations of intravenous administration such as the first pass metabolism and presystemic elimination within the gastrointestinal tract. Furthermore, topical drug administration is safe, have few side effects, is easy to apply, and offers a fast onset of action. However, the development of effective topical formulations still represents a challenge for the desired effect to be reached, locally or systemically. Solid lipid nanoparticles and nanostructured lipid carriers are particular candidates to overcome the problem of topical drug administration. The nanometric particle size of lipid nanoparticles favors the physical adhesion to the skin or mucosal, what can also be attained with the formation of hybrid (nanoparticles/polymer) systems. In this review, we discuss the major challenges for lipid nanoparticles formulations for topical application to oral mucosa, skin, and eye, highlighting the strategies to improve the performance of lipid nanoparticles for topical applications. Next, we critically analyzed the in vitro and in vivo approaches used to evaluate lipid nanoparticles performance and toxicity. We addressed some major drawbacks related to lipid nanoparticle topical formulations and concluded the key points that have to be overcome to help them to reach the market in topical formulations to oral mucosa, skin and eye. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Oral Disintegration Tablets of Stavudine for HIV Management: A New Technological Approach.

Science.gov (United States)

Sankar, V; Ramakrishna, B; Devi, P Shalini; Karthik, S

2012-11-01

Stavudine oral disintegration tablets were formulated to minimize the bitter taste and to reduce the first-pass hepatic metabolism. The various precompression parameters like the angle of repose, bulk density, compressibility index and Hausner's ratio were determined for the powder blend. In this study, 14 formulations of stavudine oral disintegration tablet were prepared by direct compression method. The tablets were evaluated for weight variation, percentage friability, disintegration time, hardness, wetting time and water absorption ratio. The in vitro dissolution study results of the batch S1 (stavudine+crospovidone+sodium starch glycollate) are encouraging as highest dissolution rate (99.2% in 100 min) and lowest time of disintegration (56 s) was achieved. The in vivo drug release studies were carried out in rabbits and the relative bioavailability of formulation S1 was found to be 2.83 times greater than that of conventional tablets.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

Science.gov (United States)

Zhang, X; Duan, J; Kesisoglou, F; Novakovic, J; Amidon, G L; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

2017-08-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The Multimedia Environmental Pollutant Assessment System (MEPAS)reg-sign: Source-term release formulations

International Nuclear Information System (INIS)

Streile, G.P.; Shields, K.D.; Stroh, J.L.; Bagaasen, L.M.; Whelan, G.; McDonald, J.P.; Droppo, J.G.; Buck, J.W.

1996-11-01

This report is one of a series of reports that document the mathematical models in the Multimedia Environmental Pollutant Assessment System (MEPAS). Developed by Pacific Northwest National Laboratory for the US Department of Energy, MEPAS is an integrated impact assessment software implementation of physics-based fate and transport models in air, soil, and water media. Outputs are estimates of exposures and health risk assessments for radioactive and hazardous pollutants. Each of the MEPAS formulation documents covers a major MEPAS component such as source-term, atmospheric, vadose zone/groundwater, surface water, and health exposure/health impact assessment. Other MEPAS documentation reports cover the sensitivity/uncertainty formulations and the database parameter constituent property estimation methods. The pollutant source-term release component is documented in this report. MEPAS simulates the release of contaminants from a source, transport through the air, groundwater, surface water, or overland pathways, and transfer through food chains and exposure pathways to the exposed individual or population. For human health impacts, risks are computed for carcinogens and hazard quotients for noncarcinogens. MEPAS is implemented on a desktop computer with a user-friendly interface that allows the user to define the problem, input the required data, and execute the appropriate models for both deterministic and probabilistic analyses

Controlled release of 18-β-glycyrrhetic acid by nanodelivery systems increases cytotoxicity on oral carcinoma cell line

Science.gov (United States)

Cacciotti, Ilaria; Chronopoulou, Laura; Palocci, Cleofe; Amalfitano, Adriana; Cantiani, Monica; Cordaro, Massimo; Lajolo, Carlo; Callà, Cinzia; Boninsegna, Alma; Lucchetti, Donatella; Gallenzi, Patrizia; Sgambato, Alessandro; Nocca, Giuseppina; Arcovito, Alessandro

2018-07-01

The topical treatment for oral mucosal diseases is often based on products optimized for dermatologic applications; consequently, a lower therapeutic effect may be present. 18-β-glycyrrhetic acid (GA) is extracted from Glycirrhiza glabra. The first aim of this study was to test the cytotoxicity of GA on PE/CA-PJ15 cells. The second aim was to propose and test two different delivery systems, i.e. nanoparticles and fibers, to guarantee a controlled release of GA in vitro. We used chitosan and poly(lactic-co-glycolic) acid based nanoparticles and polylactic acid fibers. We tested both delivery systems in vitro on PE/CA-PJ15 cells and on normal human gingival fibroblasts (HGFs). The morphology of GA-loaded nanoparticles (GA-NPs) and fibers (GA-FBs) was investigated by electron microscopy and dynamic light scattering; GA release kinetics was studied spectrophotometrically. MTT test was used to assess GA cytotoxicity on both cancer and normal cells. Cells were exposed to different concentrations of GA (20–500 μmol l‑1) administered as free GA (GA-f), and to GA-NPs or GA-FBs. ROS production was evaluated using dichlorodihydrofluorescein as a fluorescent probe. Regarding the cytotoxic effect of GA on PE/CA-PJ15 cells, the lowest TC50 value was 200 μmol l‑1 when GA was added as GA-NPs. No cytotoxic effects were observed when GA was administered to HGFs. N-acetyl Cysteine reduced mortality induced by GA-f in PE/CA-PJ15 cells. The specific effect of GA on PE/CA-PJ15 cells is mainly due to the different sensitivity of cancer cells to ROS over-production; GA-NPs and GA-FBs formulations increase, in vitro, this toxic effect on oral cancer cells.

Role of Histamine Release Test for the Evaluation of Patients with Immediate Hypersensitivity Reactions to Clavulanic Acid

DEFF Research Database (Denmark)

Pineda, F.; Ariza, A.; Mayorga, C.

2015-01-01

Immediate hypersensitivity reactions to clavulanic acid (CLV) seem to be on the increase. Diagnosis is mainly based on skin testing and the drug provocation test (DPT), procedures that are not risk free. The aim of this study was to evaluate whether the histamine release test (HRT) could help eva...

Mesoporous silica formulation strategies for drug dissolution enhancement: a review.

Science.gov (United States)

McCarthy, Carol A; Ahern, Robert J; Dontireddy, Rakesh; Ryan, Katie B; Crean, Abina M

2016-01-01

Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture. This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered. Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.

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|info:eu-repo/dai/nl/071919570; Schellens, Jan H M|info:eu-repo/dai/nl/073926272; 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

Design, formulation and evaluation of Aloe vera chewing gum

Science.gov (United States)

Aslani, Abolfazl; Ghannadi, Alireza; Raddanipour, Razieh

2015-01-01

Background: Aloe vera has antioxidant, antiinflammatory, healing, antiseptic, anticancer and antidiabetic effects. The aim of the present study was to design and evaluate the formulation of Aloe vera chewing gum with an appropriate taste and quality with the indications for healing oral wounds, such as lichen planus, mouth sores caused by cancer chemotherapy and mouth abscesses as well as reducing mouth dryness caused by chemotherapy. Materials and Methods: In Aloe vera powder, the carbohydrate content was determined according to mannose and phenolic compounds in terms of gallic acid. Aloe vera powder, sugar, liquid glucose, glycerin, sweeteners and different flavors were added to the soft gum bases. In Aloe vera chewing gum formulation, 10% of dried Aloe vera extract entered the gum base. Then the chewing gum was cut into pieces of suitable sizes. Weight uniformity, content uniformity, the organoleptic properties evaluation, releasing the active ingredient in the phosphate buffer (pH, 6.8) and taste evaluation were examined by Latin square method. Results: One gram of Aloe vera powder contained 5.16 ± 0.25 mg/g of phenolic compounds and 104.63 ± 4.72 mg/g of carbohydrates. After making 16 Aloe vera chewing gum formulations, the F16 formulation was selected as the best formulation according to its physicochemical and organoleptic properties. In fact F16 formulation has suitable hardness, lack of adhesion to the tooth and appropriate size and taste; and after 30 min, it released more than 90% of its drug content. Conclusion: After assessments made, the F16 formulation with maltitol, aspartame and sugar sweeteners was selected as the best formulation. Among various flavors used, peppermint flavor which had the most acceptance between consumers was selected. PMID:26605214

Formulation and optimization of pH sensitive drug releasing O/W emulsions using Albizia lebbeck L. seed polysaccharide.

Science.gov (United States)

Varma, Chekuri Ashok Kumar; Jayaram Kumar, K

2018-04-30

Smart polymers, one of the class of polymers with extensive growth in the last few decades due to their wide applications in drug targeting and controlled delivery systems. With this in mind, the aim of the present study is to design and formulate smart releasing o/w emulsion by using Albizia lebbeck L. seed polysaccharide (ALPS). For this purpose, the physicochemical and drug release characteristics like emulsion capacity (EC), emulsion stability (ES), viscosity, microscopy, zeta potential, polydispersity index (PDI) and in-vitro drug release were performed. The EC and ES values were found to increase with an increased concentration of ALPS. The emulsion formulations were statistically designed by using 3 2 full factorial design. All the emulsions showed a shear-thinning behavior. The zeta potential and polydispersity index were found to be in the range of -35.83 mV to -19.00 mV and 0.232-1.000 respectively. Further, the percent cumulative drug release of the emulsions at 8 h was found to be in the range of 30.19-82.65%. The drug release profile exhibited zero order release kinetics. In conclusion, the ALPS can be used as a natural emulsifier and smart polymer for the preparation of pH sensitive emulsions in drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Development and Characterization of In Situ Oral Gel of Spiramycin

Directory of Open Access Journals (Sweden)

Avinash Sharma

2014-01-01

Full Text Available The present investigation deals with the optimization, formulation, and characterization of oral in situ gel of spiramycin. Sodium alginate and hydroxypropyl methylcellulose were used as cross-linking and viscosifying agents, respectively. Sodium bicarbonate was used as a floating agent. In preformulation studies, the melting point, pH, and partition coefficient were found to be 133°C, 9.5, and 0.193, respectively. The drug had retention time at around 2.65 minutes in high performance liquid chromatography (HPLC. During compatibility studies of drug with all polymers, we observed that there were no changes in the FTIR spectra of a mixture of drug and polymers. All the formulations showed good pourability. Floating time and total floating time were ~30 sec and >12 hours, respectively. During in vitro drug release studies, the drug was released from the formulation around 80–100% for 12–16 hrs. In TEM analysis, we found that the drug molecules were well entrapped in the polymer and the drug was released slowly for up to 12 hrs. In these studies, we found that the concentration of sodium alginate and HPMC had significant influence on floating lag time, gelling capacity, and cumulative percentage drug release. During antimicrobial studies, we found that the formulation containing spiramycin showed good zone of inhibition against different microbial strains (Staphylococcus aureus and Escherichia coli.

Formulation and Characterization of Aceclofenac -Aloe vera Transemulgel.

Science.gov (United States)

Raju, Y Prasanna; Haritha, K; Satyanarayana, Rao P; Vandana, K R; Bindu, D Thushara; Vinesha, V; Chowdary, V Harini

2015-01-01

The present research was aimed to formulate aceclofenac transemulgel using Aloe vera as gel base. The prepared formulations were subjected to physical characterization, in-vitro and in-vivo assessment. Aceclofenac, a hydrophobic potential non steroidal anti inflammatory drug, causes ulceration upon chronic oral administration, could be formulated into transemulgel to enhance therapeutic efficacy and to lower the unwanted side effects. The transemulgel was prepared from aqueous Aloe vera gel and aceclofenac emulsion. The prepared transemulgel was evaluated for its pH, viscosity, drug content, skin irritation, in-vitro diffusion and accelerated stability studies. The prepared aceclofenac-Aloe vera tranemulgel and commercial aceclofenac gel were subjected to pharmacodynamic studies in albino rats of Wistar strain employing carrageenan induced left hind paw edema method to assess the anti-inflammatory effect. The transemulgel showed a pH of 6.78 and viscosity of 18 cps. In-vitro diffusion data revealed better permeation characteristics. Topical application of formulation found no skin irritation. Stability study has proved the integrity of the formulation. The prepared aceclofenac Aloe vera transemulgel showed better in-vitro drug release when compared with the commercial aceclofenac gel formulation. Anti-inflammatory activity in treated rats showed the significant paw volume reduction at pAloe vera as gel base.

Nanoemulsion-based gel formulation of diclofenac diethylamine: design, optimization, rheological behavior and in vitro diffusion studies.

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Hamed, Rania; Basil, Marwa; AlBaraghthi, Tamadur; Sunoqrot, Suhair; Tarawneh, Ola

2016-12-01

Chronic oral administration of the non-steroidal anti-inflammatory drug, diclofenac diethylamine (DDEA), is often associated with gastrointestinal ulcers and bleeding. As an alternative to oral administration, a nanoemulsion-based gel (NE gel) formulation of DDEA was developed for topical administration. An optimized formulation for the o/w nanoemulsion of oil, surfactant and cosurfactant was selected based on nanoemulsion mean droplet size, clarity, stability, and flowability, and incorporated into the gelling agent Carbopol® 971P. Rheological studies of the DDEA NE gel were conducted and compared to those of conventional DDEA gel and emulgel. The three gels exhibited an elastic behavior, where G' dominated G″ at all frequencies, indicating the formation of strong gels. NE gel exhibited higher G' values than conventional gel and emulgel, which indicated the formation of a stronger gel network. Strat-M® membrane, a synthetic membrane with diffusion characteristics that are well correlated to human skin, was used for the in vitro diffusion studies. The release of DDEA from conventional gel, emulgel and NE gel showed a controlled release pattern over 12 h, which was consistent with the rheological properties of the gels. DDEA release kinetics from the three gels followed super case II transport as fitted by Korsmeyer-Peppas model.

Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan

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Jaydeep Patel

2011-01-01

Full Text Available Irbesartan (IRB is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg, Cremophor® EL (43.33%, Carbitol® (21.67% and Capryol® 90 (32%. SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB.

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

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

2014-06-05

Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poor water solubility and consequently by a low oral bioavailability. In this work, different nanocrystal orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution rate and saturation solubility. PRX nanocrystals were prepared by means of high pressure homogenization technique using poloxamer 188 as stabilizer. Three different ODTs were prepared with the same nanosuspension using different excipients in order to study their effect on the PRX dissolution properties. PRX nanocrystal size and zeta potential were determined by photon correlation spectroscopy. Additional characterization of PRX nanocrystal ODT was carried out by infrared spectroscopy, X-ray powder diffractometry, differential scanning calorimetry. Dissolution study was performed in distilled water (pH 5.5) and compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a PRX commercial ODT. All PRX nanocrystal ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystal ODT prepared using gelatin or croscarmellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and ODT prepared using xanthan gum. Overall results confirmed that improved PRX dissolution rate is due to the increased surface-to-volume ratio due to the nanosized drug particle but also revealed the important role of different excipients used. Copyright © 2014 Elsevier B.V. All rights reserved.

Formulation of enrofloxacin SLNs and its pharmacokinetics in emu ( Dromaius novaehollandiae) birds

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Senthil Kumar, P.; Arivuchelvan, A.; Jagadeeswaran, A.; Punniamurthy, N.; Selvaraj, P.; Richard Jagatheesan, P. N.; Mekala, P.

2015-08-01

The study was conducted to formulate the enrofloxacin solid lipid nanoparticles (SLNs) with sustained release profile and improved pharmacological activity and evaluate the pharmacokinetic behaviour of enrofloxacin SLNs after oral routes of administration in emus. The SLNs were prepared using tripalmitin as lipid carrier, Tween 80 and Span 80 as surfactants and polyvinyl alcohol (PVA) as a stabilizer by a hot homogenization coupled with ultrasonication method. The prepared enrofloxacin SLNs formulations were characterized for further investigation in emu birds. The pharmacokinetics of native enrofloxacin was studied after i.v. and oral bolus administration at 10 mg/kg in emu birds and compared with the disposition kinetics of enrofloxacin SLNs. Enrofloxacin and its metabolite ciprofloxacin in plasma were estimated using HPLC and the pharmacokinetic parameters were calculated by a non-compartmental analysis. The results demonstrated that the particle size, polydispersity index, zeta potential, encapsulation efficiency and loading capacity of the SLNs were 154.72 ± 6.11 nm, 0.42 ± 0.11, -28.83 ± 0.60 mV, 59.66 ± 3.22 and 6.13 ± 0.32 %, respectively. AFM and TEM images showed spherical to circular particles with well-defined periphery. In vitro drug release exhibited biphasic pattern with an initial burst release of 18 % within 2 h followed by sustained release over 96 h. Pharmacokinetic results showed that the t 1/2 β , AUC0-∞, V darea/ F, MRT and bioavailability were 3.107, 1.894, 1.594, 2.993 and 1.895 times enhanced ( p enrofloxacin administered orally. The ratio of AUC0- t cipro/AUC0- t enro after administration of native enrofloxacin and enrofloxacin SLNs was less than 10 %. The t 1/2 β and MRT of the metabolite were longer than those of the parent substance. The PK/PD results confirmed that the SLNs extended the enrofloxacin concentration upto 48 h against pathogens susceptible to 0.125 μg/mL in emus. The results indicated that SLNs might be a

Role of In Vitro Release Methods in Liposomal Formulation Development: Challenges and Regulatory Perspective.

Science.gov (United States)

Solomon, Deepak; Gupta, Nilesh; Mulla, Nihal S; Shukla, Snehal; Guerrero, Yadir A; Gupta, Vivek

2017-11-01

In the past few years, measurement of drug release from pharmaceutical dosage forms has been a focus of extensive research because the release profile obtained in vitro can give an indication of the drug's performance in vivo. Currently, there are no compendial in vitro release methods designed for liposomes owing to a range of experimental challenges, which has created a major hurdle for both development and regulatory acceptance of liposome-based drug products. In this paper, we review the current techniques that are most often used to assess in vitro drug release from liposomal products; these include the membrane diffusion techniques (dialysis, reverse dialysis, fractional dialysis, and microdialysis), the sample-and-separate approach, the in situ method, the continuous flow, and the modified United States Pharmacopeia methods (USP I and USP IV). We discuss the principles behind each of the methods and the criteria that assist in choosing the most appropriate method for studying drug release from a liposomal formulation. Also, we have included information concerning the current regulatory requirements for liposomal drug products in the United States and in Europe. In light of increasing costs of preclinical and clinical trials, applying a reliable in vitro release method could serve as a proxy to expensive in vivo bioavailability studies. Graphical Abstract Appropriate in-vitro drug release test from liposomal products is important to predict the in-vivo performance.

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

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

2015-01-01

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

Histamine release inhibitory activity of Piper nigrum leaf.

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Hirata, Noriko; Naruto, Shunsuke; Inaba, Kazunori; Itoh, Kimihisa; Tokunaga, Masashi; Iinuma, Munekazu; Matsuda, Hideaki

2008-10-01

Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.

A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

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Choi, Du Hyung; Lim, Jun Yeul; Shin, Sangmun; Choi, Won Jun; Jeong, Seong Hoon; Lee, Sangkil

2014-10-01

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Effects of Agar Gel Strength and Fat on Oral Breakdown, Volatile Release, and Sensory Perception Using in Vivo and in Vitro Systems.

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Frank, Damian; Eyres, Graham T; Piyasiri, Udayasika; Cochet-Broch, Maeva; Delahunty, Conor M; Lundin, Leif; Appelqvist, Ingrid M

2015-10-21

The density and composition of a food matrix affect the rates of oral breakdown and in-mouth flavor release as well as the overall sensory experience. Agar gels of increasing concentration (1.0, 1.7, 2.9, and 5% agarose) with and without added fat (0, 2, 5, and 10%) were spiked with seven aroma volatiles. Differences in oral processing and sensory perception were systematically measured by a trained panel using a discrete interval time intensity method. Volatile release was measured in vivo and in vitro by proton transfer reaction mass spectrometry. Greater oral processing was required as agar gel strength increased, and the intensity of flavor-related sensory attributes decreased. Volatile release was inversely related to gel strength, showing that physicochemical phenomena were the main mechanisms underlying the perceived sensory changes. Fat addition reduced the amount of oral processing and had differential effects on release, depending on the fat solubility or lipophilicity of the volatiles.

Potential application of surfactant systems in formulation of dosage forms with slightly soluble substances

Directory of Open Access Journals (Sweden)

Ibrić Svetlana R.

2012-01-01

Full Text Available In order to achieve fast release of ibuprofen, slightly soluble model substance (0.52104 mol/l, surfactant systems for oral use with different PEG-40 hydrogenated castor oil (C/diethylene glycol monoethyl ether (T ratios were investigated. Comparison between dissolution profiles for ibuprofen from formulated systems and from two commercial products, film tablets and soft capsules, is presented in this paper. Photon correlation spectroscopy has shown that after high dilution with water, surfactant systems were able to form micellar solutions. The size of micelles varies from 14.8 ± 0,075 nm to 16.2 ± 0,021 nm with increasing C/T ratio from 1:2 to 2:1. Although with increasing content of PEG-40 hydrogenated castor oil larger micelles have formed, lower values of polydispersity index indicated that more homogeneous distribution of micelles size was gained. Conductometric analysis has demonstrated that system composing of C/T ratio 2:1, has shown most pronounced interaction between droplets, which can be seen as high rise of electrical conductivity with increasing water content (% (wwater/wtotal in the sample. No significant difference in percolation threshold between formulations with different C/T ratios was observed. Different surfactant systems were adsorbed on magnesium aluminometasilicate, as adsorbent with high specific active surface (≈300 m2/g, in order to investigate potential influence of adsorbent on ibuprofen dissolution rate. Formulated systems, with or without adsorbent were filled in hard gelatin capsules. The dissolution profiles of ibuprofen from different formulations were obtained in 30 minutes by dissolution apparatus with rotating baskets and compared with dissolution profiles of ibuprofen from commercial products. For formulations without adsorbent faster release of ibuprofen in first minutes of dissolution test, showed formulations with C/T ratio 2:1 and 1:1. Magnesium aluminometasilicate, as adsorbent with high specific

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma

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Will OM

2016-10-01

Full Text Available Olga Maria Will,1,* Nicolai Purcz,2,* Athena Chalaris,3 Carola Heneweer,4,5 Susann Boretius,1 Larissa Purcz,2 Lila Nikkola,6 Nureddin Ashammakhi,6 Holger Kalthoff,7 Claus-Christian Glüer,1 Jörg Wiltfang,2 Yahya Açil,2 Sanjay Tiwari1 1Section Biomedical Imaging, Clinic for Radiology and Neuroradiology, MOIN CC, 2Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, 3Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 4Clinic for Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, 5Institute for Diagnostic and Interventional Radiology, University Hospital Cologne, Cologne, Germany; 6Department of Biomedical Engineering, Tampere University of Technology, Tampere, Finland; 7Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein, Kiel, Germany *These authors contributed equally to this work Abstract: Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(d,l-lactide-co-glycolide polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1 no treatment, 2 implanted scaffolds without diclofenac, 3 implanted scaffolds loaded with diclofenac, and 4 diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal

Physically Targeted Intravenous Polyurethane Nanoparticles for Controlled Release of Atorvastatin Calcium

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Eftekhari, Behnaz Sadat; Karkhaneh, Akbar; Alizadeh, Ali

2017-01-01

Background: Intravenous drug delivery is an advantageous choice for rapid administration, immediate drug effect, and avoidance of first-pass metabolism in oral drug delivery. In this study, the synthesis, formulation, and characterization of atorvastatin-loaded polyurethane (PU) nanoparticles were investigated for intravenous route of administration. Method: First, PU was synthesized and characterized. Second, nanoparticles were prepared in four different ratios of drug to polymer through two different techniques, including emulsion-diffusion and single-emulsion. Finally, particle size and polydispersity index, shape and surface morphology, drug entrapment efficiency (EE), drug loading, and in vitro release were evaluated by dynamics light scattering, scanning electron microscopy, and UV visible spectroscopy, respectively. Results: Within two methods, the prepared nanoparticles had a spherical shape and a smooth surface with a diversity of size ranged from 174.04 nm to 277.24 nm in emulsion-diffusion and from 306.5 nm to 393.12 in the single-emulsion method. The highest EE was 84.76%, for (1:4) sample in the emulsion-diffusion method. It has also been shown that in vitro release of nanoparticles, using the emulsion-diffusion method, was sustained up to eight days by two mechanisms: drug diffusion and polymer relaxation. Conclusion: PU nanoparticles, that were prepared by the emulsion-diffusion method, could be used as effective carriers for the controlled drug delivery of poorly water soluble drugs such as atorvastatin calcium. PMID:28532144

pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms.

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Liu, Lin; Yao, WenDong; Rao, YueFeng; Lu, XiaoYang; Gao, JianQing

2017-11-01

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

Natural gum as mucoadhesive controlled release carriers: evaluation of cefpodoxime proxetil by D-optimal design technique.

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Patil, Satish H; Talele, Gokul S

2014-03-01

The present study deals with the development of mucoadhesive controlled release tablets of Cefpodoxime Proxetil to increase the gastric residence time and thus prolong drug release, reduce dosing frequency and improve oral bioavailability. Tablets were prepared using sodium alginate and karaya gum, a natural polymer, with a synthetic polymer hydroxypropylmethylcellulose (K100LV) and Karaya gum with HPMC K100LV in various ratios to optimize the drug release profile using D-Optimal technique. Pre- and post-compression parameters of tablets prepared with various formulations (S1-S9, C1-C9) were evaluated. The FTIR and DSC studies revealed that no physiochemical interaction between excipients and drug. The formulation S7 showed prolonged drug release, and the mechanism of drug release from the optimized formulation was confirmed using the Korsmeyer-Peppas model to be non-Fickian release transport and n value was found 0.605 indicating both diffusion and erosion mechanism from these natural gums. The optimized formulation showed mucoadhesive strength >35 g. An in vivo study was performed on rabbits using an X-ray imaging technique. The radiological evidence suggests that the tablets adheres (more than 10 hours) to a rabbit's stomach. No significant changes were found in the physical appearance, drug content, mucoadhesive study and in vitro dissolution pattern after storage at 40 °C/75% relative humidity for 3 months.

A comparative histological study of alginate beads as a promising controlled release delivery for mefenamic acid.

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Sevgi, Ferhan; Kaynarsoy, Buket; Ozyazici, Mine; Pekcetin, Cetin; Ozyurt, Dogan

2008-01-01

The new mefenamic acid-alginate bead formulation prepared by ionotropic gelation method using 3 x 2(2) factorial design has shown adequate controlled release properties in vitro. In the present study, the irritation effects of mefenamic acid (MA), a prominent non-steroidal anti-inflammatory (NSAI) drug, were evaluated on rat gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. Wistar albino rats weighing 200 +/- 50 g were used during in vivo animal studies. In this work, biodegradable controlled release MA beads and free MA were evaluated according to the degree of gastric or duodenal damage following oral administration in rats. The gastric and duodenal mucosa was examined for any haemorrhagic changes. Formulation code A10 showing both Case II transport and zero order drug release and t(50) % value of 5.22 h was chosen for in vivo animal studies. For in vivo trials, free MA (100 mgkg(-1)), blank and MA (100 mgkg(-1)) loaded alginate beads (formulation code A10) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six rats orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of MA in alginate beads prevented the gastric lesions.

Synthesis and characterization of pH-sensitive drinkable nanoparticles for oral delivery of ibuprofen

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Agostini, Azzurra; Capasso Palmiero, Umberto; Barbieri, Sara D. A.; Lupi, Monica; Moscatelli, Davide

2018-06-01

Ibuprofen (IBU) is a widespread drug used to treat both acute and chronic disorders. It is generally taken orally but the free drug can induce the irritation of the gastric mucosa due to its acid nature. In literature, different approaches have been adopted to prevent the release in the stomach, such as physical entrapment with film-coated tablets and drug-conjugates. Nevertheless, these solutions have many disadvantages, including the fast release of the drug and the difficulty to swallow the tablet, especially for children who may vomit or refuse the tablet. For this reason, in this work, novel formulations are proposed that do not require the encapsulation of the drug into a solid form and, in turn, their assumption as a pill. IBU has been linked to different types of methacrylates via ester bond in order to produce pH-responsive macromolecular monomers. The novelty is related to the use of these drug-conjugates macromonomer for the production of nanoparticles (NPs) via emulsion polymerization (EP), using water as solvent. The final emulsion is able to load up to 30 mg ml‑1 of IBU, so less than 10 ml is required to be assumed to reach the minimum therapeutic dose of the drug (200 mg). Finally, the release of IBU from these novel drinkable formulations has been investigated in the gastric and intestinal simulated fluids to show the preferential release of IBU from the NPs in basic conditions. A comparison with an existing oral suspension has been performed to highlight the slower release in acid environment of these new formulations. Afterwards, the IBU loaded NPs were tested in vitro showing lower toxicity compared to the free drug.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics.

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Ahmed, Osama A A; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid-liquid phase separation method, according to the Box-Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Agricultural production - Phase 2. Indonesia. Controlled release pesticide formulations

International Nuclear Information System (INIS)

Vollner, L.

1991-01-01

At the request of the Government of Indonesia, an IAEA expert undertook a two weeks (of one month) mission from 2 to 15 April 1991 to the Center for Application of Isotopes and Radiation (CAIR) of BATAN in Jakarta. Expert held a seminar, discussed and carried out experiments on Controlled Release Formulations (CRF). Discussed further experiments, cleaned and reinstalled an ECD of the Shimadzu gas chromatograph and optimized the analytical conditions for chlorinated pesticides. He also developed a project for possible submission to the Government of Germany, to allow the staff of CAIR to undertake a more intensive research and to be able to set up training facilities in his research center in Munich/Germany. He furthermore assessed needs for supply of instruments, accessories and radiolabelled pesticides. An agreement for continuing the scientific and technical mission was obtained with the staff of CAIR, in connection with the DDT-RCM at the end of November 1991, provided approval by IAEA

Formulation of avanafil in a solid self-nanoemulsifying drug delivery system for enhanced oral delivery.

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Soliman, Kareem AbuBakr; Ibrahim, Howida Kamal; Ghorab, Mahmoud Mohammed

2016-10-10

Avanafil was incorporated into solid self-nanoemulsifying systems with the aim of improving its oral bioavailability. Labrafil, Labrafac, and Miglyol 812 N were investigated as oils, Tween 80 and Cremophor EL as surfactants, and Transcutol HP as a co-surfactant. Nine formulations produced clear solutions of 13.89-38.09nm globules after aqueous dilution. Adsorption of preconcentrate onto Aeroperl 300 Pharma at a 2:1 ratio had no effect on nanoemulsion particle size. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy indicated that avanafil was molecularly dispersed within the solid nanosystems. A formulation containing 10% Labrafil, 60% Tween 80, and 30% Transcutol HP had the highest drug loading (44.48mg/g) and an acceptable in vitro dissolution profile (96.42% within 30min). This formulation was chemically and physically stable for 6months under accelerated storage conditions and it produced a 3.2-fold increase in bioavailability in rabbits, as compared to conventional commercially available avanafil tablets (Spedra(®)). Copyright © 2016 Elsevier B.V. All rights reserved.

Atovaquone oral bioavailability enhancement using electrospraying technology.

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Darade, Aditya; Pathak, Sulabha; Sharma, Shobhona; Patravale, Vandana

2018-01-01

Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose and poor bioavailability are the main hurdles associated with atovaquone oral therapy. The present study reports development of atovaquone nanoparticles, using in house designed and fabricated electrospraying equipment, and the assessment of bioavailability and therapeutic efficacy of the nanoparticles after oral administration. Solid nanoparticles of atovaquone were successfully produced by electrospraying and were characterized for particle size and flow properties. Differential Scanning Calorimetry, X-ray Diffraction, Fourier Transform Infrared Spectroscopy studies were also carried out. Atovaquone nanoparticles along with proguanil hydrochloride and a suitable wetting agent were filled in size 2 hard gelatin capsules. The formulation was compared with Malarone® tablets (GSK) and Mepron® suspension (GSK) in terms of in vitro release profile and in vivo pharmacokinetic studies. It showed 2.9-fold and 1.8-fold improved bioavailability in rats compared to Malarone® tablets and Mepron® suspension respectively. Therapeutic efficacy of the formulation was determined using modified Peter's 4-day suppressive tests and clinical simulation studies using Plasmodium berghei ANKA infected Swiss mice and compared to Malarone®. The developed formulation showed a 128-fold dose reduction in the modified Peter's 4-day suppressive tests and 32-fold dose reduction in clinical simulation studies. Given that only one capsule a day of developed formulation is required to be administered orally compared to 4 Malarone® tablets once a day and that too at a significantly reduced dose, this nanoparticle formulation will definitely reduce the side-effects of the treatment and is also likely to increase patient compliance. Copyright © 2017. Published by Elsevier B.V.

Concanavalin A conjugated biodegradable nanoparticles for oral insulin delivery

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Hurkat, Pooja; Jain, Aviral; Jain, Ashish; Shilpi, Satish; Gulbake, Arvind; Jain, Sanjay K.

2012-11-01

Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modifying its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanoparticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.

Concanavalin A conjugated biodegradable nanoparticles for oral insulin delivery

Energy Technology Data Exchange (ETDEWEB)

Hurkat, Pooja; Jain, Aviral; Jain, Ashish; Shilpi, Satish; Gulbake, Arvind; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

2012-11-15

Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modifying its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanoparticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.

Application of freeze-drying technology in manufacturing orally disintegrating films.

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Liew, Kai Bin; Odeniyi, Michael Ayodele; Peh, Kok-Khiang

2016-01-01

Freeze drying technology has not been maximized and reported in manufacturing orally disintegrating films. The aim of this study was to explore the freeze drying technology in the formulation of sildenafil orally disintegrating films and compare the physical properties with heat-dried orally disintegrating film. Central composite design was used to investigate the effects of three factors, namely concentration of carbopol, wheat starch and polyethylene glycol 400 on the tensile strength and disintegration time of the film. Heat-dried films had higher tensile strength than films prepared using freeze-dried method. For folding endurance, freeze-dried films showed improved endurance than heat-dried films. Moreover, films prepared using freeze-dried methods were thicker and had faster disintegration time. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. Scanning electron microscopy showed that the freeze-dried films had more porous structure compared to the heat-dried film as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. The sildenafil film was palatable. The dissolution profiles of freeze-dried and heat-dried films were similar to Viagra® with f2 of 51.04 and 65.98, respectively.

Formulation and In Vitro Evaluation of Bilayer Tablets of Nebivolol Hydrochloride and Nateglinide for the Treatment of Diabetes and Hypertension

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Harika Ryakala

2015-01-01

Full Text Available Diabetes mellitus (DM and hypertension are two common diseases that often coexist. The most common cause of death in the diabetic patient is heart disease. In the present investigation we combine Nebivolol and Nateglinide for better patient compliance. IR layer was formulated using various superdisintegrants like Crospovidone, Croscarmellose sodium, and sodium starch glycolate and SR layer was formulated using polymers and gums like HPMC E15, ethyl cellulose, Gaur gum, and Xanthan gum. The disintegration and dissolution study of both layers showed that inclusion of surfactant (sodium lauryl sulphate to the tablet formulation (IR and dissolution medium (SR enhanced the release of drugs from both layers. Kinetic studies of optimized IR layer (NBL8 and SR layer (N9 showed good linearity with regression coefficient of 0.9714 (Higuchi model and 0.9931 (zero order kinetics, respectively. The above results reveal that the optimized IR layer of Nebivolol (NBL8 and SR layer of Nateglinide (N9 might be suitable for the treatment of diabetes and hypertension by sequential release of the two drugs in a bilayer tablet. IR-immediate release, SR-sustain release, NBL8-Nebivolol 8, N9-Nateglinide 9.

[Establishment of modern multi-component sustained-release preparations of oral traditional Chinese medicines].

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Xia, Hai-Jian; Zhang, Zhen-Hai; Liu, Dan; Yu, Dan-Hong; Jia, Xiao-Bin

2013-10-01

Traditional Chinese medicines have a long history, with a large quantity of efficient traditional Chinese medicines and prescriptions. However, the vast majority of pharmaceutical dose forms remain common preparations, with very few efficient, long-lasting and low-dose preparations. The sustain-release preparation allows sustained drug release in a longer period of time, maintains blood drug concentration, reduces the toxic effect and medication frequency, and improves medication compliance. Unlike monomer drugs, the material base of traditional Chinese medicine and compounds is multi-component, instead of single or several active monomers. Therefore, under the guidance of the Chinese medicine theories, modern multi-component sustained-release preparations were developed for oral traditional Chinese medicines, with the aim of finally improving the clinical efficacy of traditional Chinese medicines.

Formulation and Evaluation of a Sustained-Release Tablets of Metformin Hydrochloride Using Hydrophilic Synthetic and Hydrophobic Natural Polymers

OpenAIRE

Wadher, K. J.; Kakde, R. B.; Umekar, M. J.

2011-01-01

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study ...

Taste-masking assessment of orally disintegrating tablets and lyophilisates with cetirizine dihydrochloride microparticles

Directory of Open Access Journals (Sweden)

Aleksandra Amelian

2017-12-01

Full Text Available Orally disintegrating tablets and oral lyophilisates are novel attractive dosage forms that disintegrate or dissolve in the buccal cavity within seconds without necessity of drinking. The major limitation in designing of these dosage forms is unpleasant taste of the drug substance. Cetirizine dihydrochloride is a H1-antihistamine substance indicated for the treatment of allergy. It is characterized by extremely bitter taste, therefore in order to deliver cetirizine dihydrochloride using orodispersible formulations, effective taste-masking is required. The aim of this study was to investigate whether microparticles containing cetirizine dihydrochloride could be successfully used to formulate orally disintegrating tablets by direct compression method and oral lyophilisates by freeze-drying process. Taste masking of cetirizine dihydrochloride was achieved by the spray-drying technique using Eudragit® E PO as the drug agent carrier. Based on the preliminary studies, optimal compositions of microparticles, tablets and lyophilisates were chosen. Obtained dosage forms were characterized for drug content, disintegration time and mechanical properties. In order to determine whether the microparticles subjected to direct compression and freeze-drying process effectively mask the bitter taste of cetirizine dihydrochloride, the in vivo and in vitro evaluation was performed. The results showed that designed formulates with microparticles containing cetirizine dihydrochloride were characterized by appropriate mechanical properties, uniformity of weight and thickness, short disintegration time, and the uniform content of the drug substance. Taste-masking assessment performed by three independent methods (e-tongue evaluation, human test panel and the in vitro drug release revealed that microparticles with Eudragit® E PO are effective taste – masking carriers of cetirizine dihydrochloride and might be used to formulate orally disintegrating tablets and oral

Radiolabelling of potential colonic delivery systems by neutron activation. An evaluation based on physiochemical properties of excipients and formulations

International Nuclear Information System (INIS)

Ahrabi, Sayeh

1999-01-01

The effects of neutron irradiation on the physicochemical properties of some potential release-controlling excipients for oral delivery to colon (based on microbially degradable polysaccharide or a combination of pH- and time-dependent mechanisms) were initially investigated. The aim was to choose the most irradiation-resistant ones for the development of a colonic delivery system to be radiolabelled by the neutron activation procedure. However, no correlation between the extent of irradiation-induced changes of the release-controlling polymers and the in vitro properties of the final formulation was observed. Incorporation of samarium oxide (Sm 2 O 3 ) resulted in retardation of the drug release through the diffusion layer. The influence of neutron activation factors on the properties of some suppository combinations was also studied. The effect of the admixture of Sm 2 O 3 on the dissolution and disintegration of the suppositories was more profound than the effect of neutron irradiation. In hydrophilic suppositories, the effect of Sm 2 O 3 was dependent on the type, amount and the physicochemical characteristics of the incorporated drug. In lipophilic suppositories, the release-controlling effect of Sm 2 O 3 was hypothesised to be due to its insoluble micronised particles blocking the drug diffusion layer. The neutron activation procedure could be utilised for radiolabelling potential oral and rectal colonic drug delivery systems. However, to avoid alteration in the crucial in vitro characteristics of the formulations, the amount, the particle size and the aggregated particle characteristics of the lanthanide salt (e.g. Sm 2 O 3 or samarium stearate) together with the neutron irradiation dose should be controlled precisely for each dosage system. For the systems investigated in this work the release-controlling mechanism of the dosage form seems to be a key parameter to predict the extent of the influence of neutron activation factors on the in vitro properties

Controlled release systems containing solid dispersions: strategies and mechanisms.

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Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Park, Jun Bom; Lee, Beom-Jin

2011-10-01

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Advances in Nanotechnology for Efficacious and Stable Formulation Development

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Putcha, Lakshimi

2012-01-01

Current operational medical kits aboard the International Space Station (ISS) include an array of medications intended for the treatment of minor ambulatory care symptoms, first aid, and basic life support. All medications contained in the flight kits are commercially available off-the-shelf formulations used for treatment of illnesses on Earth. However, transport and stowage of supplies including medications for space missions are exposed to adverse environmental conditions and extended shelf-life demands. Proposed missions to Mars and near-Earth objects such as asteroid 1999 AO10 will present crew health risk that is different both quantitatively and qualitatively from those encountered on ISS missions. Few drug options are available at the present time for mitigation of crew health risk of planned space exploration missions. Alternatives to standard oral formulations that include sustained and targeted delivery technologies for preventive healthcare in space will be a welcome addition to the space formulary and may include controlled release topical, sub-cutaneous, intranasal and inhalation dosage forms. An example of such a technology development endeavor can be nanotechnology-based multi-stage drug cocktail and vaccine delivery systems. Nanostructures also have the ability to protect drugs encapsulated within them from physiologic degradation, target their delivery with sustained release and are suitable for per oral routes of administration. The use of nanostructures such as polymeric nanoparticles offers a non-invasive approach for penetrating the blood brain barrier. Finally, nanotechnology offers great potential for the development of safe and efficacious drug delivery systems for preventive health care in space and on Earth.

Formulation development and comparative in vitro study of metoprolol tartrate (IR) tablets.

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Husain, Tazeen; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Maboos, Madiha; Khan, Madeeha; Bashir, Lubna; Naz, Shazia

2016-05-01

The objective of the present work was to develop Immediate Release (IR) tablets of Metoprolol Tartrate (MT) and to compare trial formulations to a reference product. Six formulations (F1-F6) were designed using central composite method and compared to a reference brand (A). Two marketed products (brands B and C) were also evaluated. F1-F6 were prepared with Avicel PH101 (filler), Crospovidone (disintegrant) and Magnesium Stearate (lubricant) by direct compression. Pharmacopoeial and non-pharmacopoeial methods were used to assess their quality. Furthermore, drug profiles were characterized using model dependent and independent (f(2)) approaches. Brands B and C and F5 and F6 did not qualify the tests for content uniformity. Moreover, brand B did not meet weight variation criteria and brand C did not satisfy requirements for single point dissolution test. Of the trial formulations, F2 failed the test for uniformity in thickness while F4 did not disintegrate within time limit. Only F1 and F3 met all quality parameters and were subjected to accelerated stability testing without significant alterations in their physicochemical characteristics. Based on AIC and r(2)(adjusted) values obtained by applying various kinetic models, drug release was determined to most closely follow Hixson-Crowell cube root law. F1 was determined to be the optimized formulation.

Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate.

Science.gov (United States)

Biswas, Nikhil; Sahoo, Ranjan Kumar

2016-02-01

The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h. Copyright © 2015 Elsevier B.V. All rights reserved.

Implementation of Quality by Design for Formulation of Rebamipide Gastro-retentive Tablet.

Science.gov (United States)

Ha, Jung-Myung; Seo, Jeong-Woong; Kim, Su-Hyeon; Kim, Ju-Young; Park, Chun-Woong; Rhee, Yun-Seok; Park, Eun-Seok

2017-11-01

The purpose of the present study was to develop a rebamipide (RBM) gastro-retentive (GR) tablet by implementing quality by design (QbD). RBM GR tablets were prepared using a sublimation method. Quality target product profile (QTPP) and critical quality attributes (CQAs) of the RBM GR tablets were defined according to the preliminary studies. Factors affecting the CQAs were prioritized using failure mode and effects analysis (FMEA). Design space and optimum formulation were established through a mixture design. The validity of the design space was confirmed using runs within the area. The QTPP of the RBM GR tablets was the orally administered GR tablet containing 300 mg of RBM taken once daily. Based on the QTPP, dissolution rate, tablet friability, and floating property were chosen as CQAs. According to the risk assessment, the amount of sustained-release agent, sublimating material, and diluent showed high-risk priority number (RPN) values above 40. Based on the RPN, these factors were further investigated using mixture design methodology. Design space of formulations was depicted as an overlaid contour plot and the optimum formulation to satisfy the desired responses was obtained by determining the expected value of each response. The similarity factor (f2) of the release profile between predicted response and experimental response was 89.463, suggesting that two release profiles are similar. The validity of the design space was also confirmed. Consequently, we were able to develop the RBM GR tablets by implementing the QbD concept. These results provide useful information for development of tablet formulations using the QbD.

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

Science.gov (United States)

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

2012-12-01

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

Development and in vitro-in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin.

Science.gov (United States)

Xu, Man; Yu, Qing; Zhao, Qianru; Chen, Wei; Lin, Yuanjie; Jin, Yong

2016-01-01

The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability. The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7 mg/kg) in male Wistar rats. The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20 nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution. These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.

Application Test OF Carbofuran Insecticide Controlled Release Formulation On Rice Plants Of Cilosari Variety Have Been Carried Out

International Nuclear Information System (INIS)

Sulisyati, M.; Ulfa, T.S. et all

2000-01-01

this formulation was made by using a mixture of activated charcoal, tapioca, kaolin, Na-alginate as filter matrix and the second formulation using zeolite with couted shelak. The observation were done on the damage level caused by Orseo;ia oryzae (wood/mason), Chilo suppressalis (walker), and cnaphalocrosis medinalis (Guen) on new young plants. The observation were done every two weeks after transplanting until harvest. Both formulation have the same results showed that new young plants on the early stage growth showed no differences among the treatments, then becoming more different between controlled release formulation and commercial formulation or untreated plants. The attack of orseolia oryzae could be observed on every week of the observation but only on the fifth weeks were significant difference found. The attack of Chilo suppressalis on the seventh week showed significant difference, while the attack of cnaphalocrosis medinalis appeared on the seventh and ninth weeks showing no differences

[Abpm and duration of the antihypertensive effect: a study with a new formulation of sustained release losartan (CRONOS)].

Science.gov (United States)

Bendersky, Mario; Juncos, Luis; Waisman, Gabriel Dario; Piskorz, Daniel; Lopez-Santi, Ricardo; Montaña, Oscar; Caruso, Gustavo; Kotetzky, Martin; Penna, Maria; Gomez, Roberto

2012-01-01

Antihypertensive drugs action should last at least 24 h in order to enhance adherence, with positive impact on CV morbimortality. ABPM allow us to evaluate duration of action of drugs, against placebo, using Trough:Peak Ratio, antihypertensive effect in the last 4 h interdosis, and calculating the rate of BP morning surge. Losartán is an Antagonist At1 with good antihypertensive efficacy and renal, cardiac and cerebrovascular protection. Some studies shows less than 24 hs of action, that suggest twice a day dosing. The merge of a new formulation, Losartan Cronos, a bilayer tablet containing 50 mg of Losartan immediate release (IR) and 50 mg extended release (ER) would allow 24 h coverage, maintaining the previous advantages. To assess antihypertensive duration of action of Losartán Cronos in patients with essential hypertension throughout a 24-h dosing interval, using ABPM and response rates, AASI and Smoothness Index. 97 essential hypertensives, where included and received a single morning dose of Losartán Cronos (50 mg of regular release and 50 mg of controlled and retarded release) during 8 weeks. Performed valid ABPM post placebo and post active treatment. Results Mean age 58 (26-86), 60% women. 63% treatment naïve. The mean reduction in BP from baseline to week 8 (end of treatment) was statistically significant for all times analyzed (24 hours, daytime, night-time, and last 4 hours monitoring). There were no significant changes in 24h heart rate. BP morning surge (mmHg/hour) decreased from 4.53 to 3,68 (p=0.03).T:P Ratio was 0.91 for SBP and 1.14 for DBP. Smoothness Index: SBP 2.86 (95% CI 1.84-3.7) - DBP 3.17 (95% CI 2.03-3.9) 19 patients had adverse events, no-one cough, all mild, without discontinuations. Conclusion Losartán Cronos demonstrated efficacy and safety, decreases BP without significant effects in heart rate, it reduces the pulse pressure, and its effect lasts for 24 hs, assessed by T:P ratio, last 4 hours effects, decreasing morning surge

Qualitative analysis of controlled release ciprofloxacin/carbopol 934 mucoadhesive suspension

Directory of Open Access Journals (Sweden)

Subhashree Sahoo

2011-01-01

Full Text Available Mucoadhesive polymeric (carbopol 934 suspension of ciprofloxacin was prepared by ultrasonication and optimized with the aim of developing an oral controlled release gastro-retentive dosage form. The qualitative analysis of the formulation was performed by fourier transform infrared spectroscopy (FTIR, Raman spectroscopy, X-ray powder diffraction (XRD, and scanning electron microscopy (SEM analyses. FTIR (400 cm-1 to 4000 cm-1 region and Raman (140 to 2400 cm-1 region Spectroscopic studies were carried out and the spectra were used for interpretation. XRD data of pure drug, polymer and the formulation were obtained using a powder diffractometer scanned from a Bragg′s angle (2q of 10° to 70°. The dispersion of the particle was observed using SEM techniques. The particle size distribution and aspect ratio of particles in the polymeric suspension were obtained from SEM image analysis. The results from FTIR and Raman spectroscopic analyses suggested that, in formulation, the carboxylic groups of ciprofloxacin and hydroxyl groups of C934 undergo a chemical interaction leading to esterification and hydrogen bonding. The XRD data suggested that the retention of crystalline nature of ciprofloxacin in the formulation would lead to increase in stability and drug loading; decrease in solubility; and delay in release of the drug from polymeric suspension with better bioavailability and penetration capacity. The SEM image analysis indicated that, in the formulation maximum particles were having aspect ratio from 2 to 4 and standard deviation was very less which provided supporting evidences for homogeneous, uniformly dispersed, stable controlled release ciprofloxacin suspension which would be pharmaceutically acceptable.

Modulation of active pharmaceutical material release from a novel 'tablet in capsule system' containing an effervescent blend.

Science.gov (United States)

Gohel, Mukesh C; Sumitra G, Manhapra

2002-02-19

The objective of the present study was to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (HPMC or guar gum). The significance of factors such as type of plug (powder or tablet), plug thickness and the formulation of fill material on the release pattern of diltiazem HCl, a model drug, was investigated. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. A linear relationship was observed between weight of HPMC K15M and log % drug released at 4 h from the capsules containing the plug in powder form. In order to accelerate the drug release after a lag time of 4 h, addition of an effervescent blend, NaHCO(3) and citric acid, in the capsules was found to be essential. The plugs of HPMC in tablet form, with or without a water soluble adjuvant (NaCl or lactose) were used for obtaining immediate drug release after the lag time. Sodium chloride did not cause significant influence on drug release whereas lactose favourably affected the drug release. The capsules containing HPMC K15M tablet plug (200 mg) and 35 mg effervescent blend in body portion of the capsule met the selection criteria of less than 10% drug release in 4 h and immediate drug release thereafter. It is further shown that the drug release was also dependant on the type of swellable hydrophilic agent (HPMC or guar gum) and molecular weight of HPMC (K15M or 20 cPs). The results reveal that programmed drug delivery can be obtained from hard gelatin capsules by systemic formulation approach.

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

Science.gov (United States)

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

2015-11-06

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

In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability.

Science.gov (United States)

Zhu, Yuan; Zhang, Jiajia; Zheng, Qianfeng; Wang, Miaomiao; Deng, Wenwen; Li, Qiang; Firempong, Caleb Kesse; Wang, Shengli; Tong, Shanshan; Xu, Ximing; Yu, Jiangnan

2015-10-01

Capsaicin, as a food additive, has attracted worldwide concern owing to its pungency and multiple pharmacological effects. However, poor water solubility and low bioavailability have limited its application. This study aims to develop a capsaicin-loaded microemulsion to enhance the oral bioavailability of the anti-neuropathic-pain component, capsaicin, which is poorly water soluble. In this study, the microemulsion consisting of Cremophor EL, ethanol, medium-chain triglycerides (oil phase) and water (external phase) was prepared and characterized (particle size, morphology, stability and encapsulation efficiency). The gastric mucosa irritation test of formulated capsaicin was performed in rats to evaluate its oral feasibility, followed by the pharmacokinetic study in vivo. Under these conditions, the encapsulated capsaicin revealed a faster capsaicin release in vitro coupled with a greater absorption in vivo when compared to the free capsaicin. The oral bioavailability of the formulated capsaicin-loaded microemulsions was 2.64-fold faster than that of free capsaicin. No significant irritation was observed on the mucosa from the pathological section of capsaicin-loaded microemulsion treated stomach. These results indicate that the developed microemulsion represents a safe and orally effective carrier for poorly soluble substances. The formulation could be used for clinical trials and expand the application of capsaicin. © 2014 Society of Chemical Industry.

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.

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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.

Developing a new formulation of sodium phenylbutyrate.

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Guffon, Nathalie; Kibleur, Yves; Copalu, William; Tissen, C; Breitkreutz, Joerg

2012-12-01

Sodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control. A new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers. The in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (C(max)) or for area under the plasma concentration-time curve (AUC). CI for C(max) and AUC(0-inf) of NaPB were included in the bioequivalence range of 0.80-1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements. In vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

STUDIES ON NATURAL AND SYNTHETIC POLYMERS FOR CONTROLLED RELEASE MATRIX TABLET OF ACECLOFENAC

OpenAIRE

Abhishek S. Joshi *, Deepak A. Joshi , Avinash V. Dhobale , Sandhya S. Bundel , Vijay R. Chakote, Gunesh N. Dhembre

2018-01-01

The present study was aimed to design new oral controlled release matrix tablets of new NSAID Aceclofenac for once a day by using 10, 15, 20 and 25% of GG:HPMC and XG:HPMC mixture in the ratio 1:1 by wet granulation method. The prepared tablets subjected to in vitro drug release studies in pH 7.4 buffer solution. All the formulation meets the pre-compression and compression characteristics. All the tablets prepared with 10, 15, 20 and 25% of HPMC: XG mixture in the ratio 1:1 fails to meet the...

Design and characteristics of gellan gum beads for modified release of meloxicam.

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Osmałek, Tomasz; Milanowski, Bartłomiej; Froelich, Anna; Szybowicz, Mirosław; Białowąs, Wojciech; Kapela, Marcin; Gadziński, Piotr; Ancukiewicz, Katarzyna

2017-08-01

The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10 -2  M) was used as the cross-linking agent. Nine different polymer, drug and surfactant (Tween ® 80) mixtures were used for production of the beads. The quantitative compositions of the mixtures were generated with the application of the Design of Experiments (DoE) modulus from the STATISTICA Software. The prepared formulations revealed 7.2-27.0% of drug loading and 29.2-50.7% drug encapsulation efficiency. It turned out that 0.5% amount of gellan gum in the mixtures was not sufficient to obtain spherical beads. The morphology and surface of the dried beads were analyzed by SEM. Raman spectra confirmed that MLX did not undergo structural changes during production of the beads. The swelling behavior and degradation of the beads were evaluated in three simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8). The MLX in vitro release studies were conducted on USP apparatus IV, working in the open loop mode. The obtained results showed that MLX release from the dried beads was pH-dependent. The formulations obtained from mixtures containing 1.0 and 1.5% of gellan may be considered as oral dosage forms for MLX, intended to omit the stomach and release the drug in the distal parts of the gastrointestinal tract.

The Important Role of Carbohydrates in the Flavor, Function, and Formulation of Oral Nutritional Supplements

Directory of Open Access Journals (Sweden)

Smaro Kokkinidou

2018-06-01

Full Text Available Patients who are malnourished or at-risk for malnutrition often benefit from the consumption of oral nutritional supplements (ONS. ONS supply a range of micro- and macro-nutrients, and they can be used to supplement a diet or provide total nutrition. Since ONS are specially formulated products, all ONS ingredients—including carbohydrates—are added ingredients. This may seem to be at odds with the growing public health discourse on the need to reduce “added sugars” in the diet. However, carbohydrate is an essential nutrient for human health and is a critical ingredient in ONS. Helping to educate patients on the value of “added sugars” in ONS may be useful to improve compliance with nutritional recommendations when ONS are indicated. This perspective paper reviews the important roles of “added sugars” in ONS, in terms of flavor, function, and product formulation.

Ramizol® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation.

Science.gov (United States)

Wright, Leah; Rao, Shasha; Thomas, Nicky; Boulos, Ramiz A; Prestidge, Clive A

2018-04-11

Novel antibiotic Ramizol ® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. Ramizol ® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T max and T 1/2 when compared to the oral and IV routes. Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol ® . This formulation will allow further development of Ramizol ® for systemic infection eradication.

Sustained-release diclofenac potassium-loaded solid lipid microparticle based on solidified reverse micellar solution: in vitro and in vivo evaluation.

Science.gov (United States)

Chime, Salome Amarachi; Attama, Anthony Amaechi; Builders, Philip F; Onunkwo, Godswill C

2013-01-01

To formulate sustained-release diclofenac potassium-loaded solid lipid microparticles (SLMs) based on solidified reverse micellar solution (SRMS) and to evaluate the in vitro and in vivo properties. SRMS consisting of mixtures of Phospholipon® 90H and Softisan® 154 were used to formulate diclofenac potassium-loaded SLMs. Characterization based on the particle size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release was carried out in simulated intestinal fluid (pH 7.5). Anti-inflammatory and ulcerogenic properties were studied using rats. Maximum EE% of 95%, 94% and 93% were obtained for SLMs formulated with SRMS 1:1, 2:1 and 1:2, respectively. In vitro release showed about 85-90% drug release at 13 h. Diclofenac potassium-loaded SLMs showed good anti-inflammatory and gastro-protective properties. Diclofenac potassium-loaded SLMs based on SRMS could be used orally or parenterally under controlled conditions, for once daily administration.

Study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration.

Science.gov (United States)

Santoveña, A; Sánchez-Negrín, E; Charola, L; Llabrés, M; Fariña, J B

2014-12-30

This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses. Copyright © 2014 Elsevier B.V. All rights reserved.