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This is the first publication on a complete validated bioanalytical method for estimation of olmesartan (OLM) and hydrochlorothiazide (HCTZ) in human K3 EDTA plasma that chromatographically resolves its olmesartan glucuronide. An API 4000 mass spectrometer was employed in this method where olmesartan d4 (OLMD4) and hydrochlorothiazide −13C, d2 (HCTZD2) served as the internal standard. Sample was prepared by solid phase extraction (SPE) technique using a polymer based, MCX cartridges and chromatographic resolution achieved on Synergi MAX RP-18A, (4.6 × 150 mm, 4 μm) column using a mobile phase of 0.2% formic acid solution/acetonitrile (30:70, v/v). Negative mass transitions (m/z) of OLM, HCTZ, OLMD4, and HCTZD2 were detected in multiple reactions monitoring (MRM) mode at 445.5 → 149.3, 296.0 → 269.0, 449.2 → 149.3, and 299.1→270.0, respectively. The linearity was checked over a concentration range of 4.051-2500.912 ng/mL for OLM and 0.506-304.109 ng/mL for HCTZ. Intra- and inter-run precision of OLM and HCTZ assay at four concentration levels were below 3.7% and 4.3%, and accuracy was within ±4.4% and 3.0%, respectively. Mean recoveries for OLM, HCTZ, and internal standards OLMD4 and HCTZD2 were 75.68, 77.60%, and 80.2, 89.1%, respectively. This method has been successfully applied to pharmacokinetic biostudy. [ABSTRACT FROM AUTHOR]

Orlistat is a non-systemic treatment for obesity. The drug inhibits lipase in the gastrointestinal track mainly in the lumen of the stomach and small intestine by binding reversibly with the active site of gastric and pancreatic lipases, preventing the absorption of ∼30-35% of dietary fat. The undigested triglycerides are not absorbed, resulting in a caloric deficit and positive effect in weight control. The objective of this study was to assess the bioequivalence of orlistat administered as a generic and reference capsule formulations using a pharmacodynamic end-point. A total of 60 healthy volunteers followed a 5-day run-in diet period to be accustomed to a low fat diet; subjects were then randomized to receive under fed conditions oral doses of orlistat (60 mg) 3-times daily for 10 days as the generic (Ranbaxy Laboratories) or reference (Alli™, GlaxoSmithKline) capsule formulations. Subjects followed a standardized diet (2500 kcal/day, ∼30% as fat) for the entire study. Feces were collected over the last 2 days of the run-in period (baseline) and over the last 5 days of the two treatment periods. The amount of fat in meals and feces were assayed using the validated FTIR method with a limit of detection of 1.00 g%, respectively. Fecal fat excretion over 24 h (FFE24SS, calculated as the amount of fat excreted in feces adjusted by the amount of fat ingested) was used as a pharmacodynamic end-point to assess the bioequivalence between the two orlistat formulations. An analyses of variance (ANOVA) was performed on the log-transformed FFE24SS parameter to establish bioequivalence of the generic product with respect to the innovator formulation. Mean FFE24SS values at baseline and after repeated oral administrations of the generic and innovator formulations of orlistat were 0.88%, 40.55% and 40.54%, respectively. The ratio of least-squares means (LSM) of FFE24SS of the generic to the innovator formulation was 101.90%, with 90% confidence intervals of 97.94-106.01%. Orlistat was well tolerated by subjects in both periods of study and no serious adverse events were observed during the study. In conclusion, mean FFE24SS values were used as pharmacodynamic end-points to assess bioequivalence between two formulations of orlistat. Results from this study suggest that the test formulation of Orlistat capsule is bioequivalent to the reference marketed Alli™ when administered to healthy volunteers as a multiple dose under fed conditions. [ABSTRACT FROM AUTHOR]

The objective of this cross-over bioavailability study on clarithromycin was to compare the bioavailability under fasting and five different diets, in 18 healthy adult male human volunteers using validated LC-MS/MS method. A single dose of clarithromycin 500 mg extended release tablet was administered at six occasions: after overnight fasting, after two vegetarian diets (high fat and low fat), two non-vegetarian diets (high fat and low fat), and low fat vegetarian rice. Serial blood samples were collected up to 36 h after dose. A statistically significant food effect was observed for all diets when compared to fasting treatment. [ABSTRACT FROM AUTHOR]

The objective of the work was to develop, optimize, and evaluate a self-microemulsifying drug delivery system of the poorly water-soluble drug, carvedilol. Solubility of carvedilol was determined in various vehicles. Ternary and pseudo-ternary phase diagrams were constructed to indentify the efficient self-emulsification region using oils, surfactants, and co-surfactants in aqueous environment. Optimized formulations were assessed for drug content, spectroscopic clarity, emulsification time, contact angle, zeta potential, particle size, and dissolution studies. Zeta potential was measured in the absence and presence of oleylamine, a positive charge inducer. On the basis of similarity and dissimilarity of particle size distribution, formulations were characterized using PCA and AHCA, a multivariate statistical analysis. Decrease in t50% and increase in DE attributed to small globule size and eventually higher surface area. The relevance of differences in t50% and DE was evaluated statistically by two-way ANOVA. DRIFTS, DSC, and X-RD studies indicated no incompatibility between drug, oil, and surfactants. The results of this study indicate that the SMEDD formulations of carvedilol owing to nanosize have the potential to enhance its absorption, without interaction or incompatibility between the ingredients. [ABSTRACT FROM AUTHOR]

The present study was aimed to develop Eudragit-based matrix system for transdermal delivery of methotrexate, an immunosuppressant drug for rheumatoid arthritis. Drug release followed zero order rather than first order or Higuchi type release kinetics. FT-IR, DSC and X-RD studies indicated no interaction between drug and polymer. The in-vitro dissolution rate constant, dissolution half life, and pharmacokinetic parameters (Cmax, tmax, AUC(s), t1/2, Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between test products but not within test products. Statistically, a good correlation was found between percent of drug absorbed from patches versus Cmax, and AUC(s). Percent of drug dissolved at a given time versus serum drug concentration was correlated statistically. The results of this study indicate that the polymeric matrix films of methotrexate hold potential for transdermal. [ABSTRACT FROM AUTHOR]

The objective of this crossover bioavailability study on amoxicillin was to compare the bioavailability under fasting and five different diets, in twelve healthy adult male human volunteers. A single dose of amoxicillin 500 mg capsule was administered at six occasions: after overnight fasting, after two vegetarian diets (high-fat and low-fat), two non-vegetarian diets (high-fat and low-fat) and milk. Serial blood samples were collected up to 8 h after dose. Plasma concentrations were determined using a validated LC-MS/MS method. Tmax increased and AUC and Cmax values decreased in the presence of food. The non-vegetarian diets affected the rate of absorption of amoxicillin more than the vegetarian diets. [ABSTRACT FROM AUTHOR]

A matrix dispersion type transdermal delivery system of tramadol was designed and developed using different concentrations and polymeric grades of Hydroxypropyl Methylcellulose (HPMC K4M, K15M & K100M). Formulations were selected on the basis of their drug release content and release pattern. Films were evaluated for their physicochemical characteristics, followed by in vitro and in vivo evaluation. The possible drug-polymer interaction was studied by FTIR, DSC and X-RD studies. These were evaluated for in vitro dissolution characteristic using Cygnus' sandwich patch holder. The drug release followed Higuchi kinetics (r = 0.979-998; P < 0.001). In vivo evaluation was carried out on healthy rabbits of either sex, following balanced incomplete block design. The in vitro dissolution rate constant, dissolution half life and pharmacokinetic parameters generated from plasma (tmax, Cmax, AUC(s), t1/2, Kel, and MRT) were evaluated statistically by two-way ANOVA. Statistically a good correlation was found between percent of drug absorbed from patches versus AUCs. Percent of drug dissolved at a given time versus plasma drug concentration correlated statistically. The results of this study indicate that the polymeric matrix type transdermal films of tramadol hold potential for transdermal delivery on the basis of their in vitro and pharmacokinetic results. [ABSTRACT FROM AUTHOR]