Shravan Kumar Yamsani

Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: Formulation optimization, ex vivo and in vivo characterization

The purpose of the present study was to develop and optimize the microemulsion based transdermal therapeutic system for lacidipine (LCDP), a poorly water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of isopropyl myristate, Tween 80 and Labrasol. The microemulsion was optimized using a three-factor, three-level Box-Behnken design, the independent variables selected were isopropyl myristate, surfactant mixture (Tween 80 and Labrasol) and water; dependent variables (responses) were cumulative amount permeated across rat abdominal skin in 24h (Q(24); Y(1)), flux (Y(2)), and lag time (Y(3)). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equations were generated for responses Y(1), Y(2) and Y(3). The statistical validity of the polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with 10 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The gel of optimized formulation (ME-OPT) showed a flux of 43.7microgcm(-2)h(-1), which could meet the target flux (12.16microgcm(-2)h(-1)). The bioavailability studies in rabbits showed that about 3.5 times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of microemulsion gel compared to oral suspension. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. Microemulsion based transdermal therapeutic system of LCDP was developed and optimized using Box-Behnken statistical design and could provide an effective treatment in the management of hypertension.

Development of high performance liquid chromatography method for buspirone in rabbit serum: Application to pharmacokinetic study

A simple and sensitive high performance liquid chromatographic (HPLC) method for quantification of lacidipine (LCDP) in rabbit serum was developed and validated. LCDP and internal standard (IS), felodipine were extracted into n-hexane and dichloromethane (70:30) solvent system and separated using an isocratic mobile phase, on an Inertsil C18 column. The effluent was monitored by UV detector at 240 nm and at a flow rate of 1.0 mL min(-1). The linearity range of proposed method was 1-500 ng mL(-1). The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 15% and mean recovery was more than 94 and 95% for LCDP and IS, respectively and the method was found to be precise, accurate, and specific during the study. The method was successfully applied for pharmacokinetic study of lacidipine after application of LCDP microemulsion gel in rabbits.

Development of bioadhesive buccal tablets for felodipine and pioglitazone in combined dosage form: in vitro, ex vivo, and in vivo characterization.

The purpose of the present research was to develop bioadhesive buccal tablets for Felodipine (FDP) and Pioglitazone (PIO), low bioavailability drugs, in a combined dosage form for the management of diabetes and hypertension. Buccal tablets were prepared by direct compression method using bioadhesive polymers hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carbopol, alone or in combination of two polymers, and were evaluated for physicochemical properties, swelling index, in vitro bioadhesion, in vivo residence time, in vitro drug release, and ex vivo permeation through porcine buccal membrane. Formulation (PF6) showed peak detachment force (3.12 N), work of adhesion (0.72 mJ), swelling index (196%), erosion (10.8%), in vivo residence time of 280 min, in vitro drug release (99.65% and 98.96% in 6 h for FDP and PIO, respectively) with higuchi model release profile and permeated 66.1 and 64.6 % with a flux of 0.118 and 0.331 mg/h/cm2 of FDP and PIO through porcine buccal membrane. The bioavailability study for optimized formulation (PF6) in pigs showed 2.05- and 2.13-times statistically significant (p < 0.05) improvement in bioavailability for FDP and PIO, respectively, after administration of buccal tablets compared to oral suspension. The ex vivo–in vivo correlation was found to have a biphasic pattern and followed type A correlation. The stability of the PF6 was studied and no significant changes were detected in drug content and in vitro release and ex vivo permeation through porcine buccal membrane after 6 months.

Effect of Pomegranate Juice on Intestinal Transport and Pharmacokinetics of Nitrendipine in Rats

Pomegranate juice (PJ) is known to be a potent inhibitor of human cytochromes (CYP), particularly CYP2C9 and CYP3A4. The purpose of this study was to investigate the effect of oral PJ on the pharmacokinetics of nitrendipine (10 mg/kg) in rats. The effect of PJ was also investigated on the absorption kinetics of nitrendipine in rats using a single‐pass intestinal perfusion model. There was a significant increase in effective permeability, absorption rate constant and fraction of drug absorbed in the pretreated group when compared with the control group, probably due to inhibition of the P‐glycoprotein‐mediated efflux of the drug by PJ. In comparison with control, PJ treatment significantly increased the area under the concentration–time curve of oral nitrendipine. The peak plasma concentration of nitrendipine was also significantly increased by PJ. However, elimination half‐life of nitrendipine was not altered significantly in both PJ co‐administered and pretreated groups. These results suggest that PJ inhibits the intestinal metabolism of nitrendipine without inhibiting the hepatic metabolism in rats. Therefore, the concomitant use of PJ, as food supplement, and nitrendipine should be avoided, although further clinical studies need to be undertaken in order to confirm this finding. Copyright

SIMULTANEOUS DETERMINATION OF GLIMEPIRIDE AND ATORVASTATIN IN HUMAN SERUM BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY: APPLICATION TO PHARMACOKINETIC STUDY

A simple and sensitive high performance liquid chromatographic method for simultaneous quantification of glimepiride (GMP) and atorvastatin (ATN) in human serum was developed and validated. GMP, ATN, and internal standard (IS), pioglitazone (PG) were extracted into dichloromethane and methanol solvent system and separated using an isocratic mobile phase on an Inertsil C18 column. The eluent was monitored by UV detector at 230 nm. The linearity range of proposed method was 1–1600 ng mL−1 for each analyte. The retention times for GMP, ATN, and IS were found to be 9.8, 6.92, and 7.96 min, respectively. The intra-day and inter-day coefficient of variation and percentage error values of the assay method were less than 15% and mean recovery was more than 96, 93, and 95% for GMP, ATN, and IS, respectively, and the method was found to be precise, accurate, and specific. The method was successfully applied for pharmacokinetic study of GMP and ATN after oral administration to patients. The CMax, TMax, and AUC0–12 of GMP and ATN were found to be 355.3 ng mL−1, 3.1 hr, 2167.5 ng h mL−l and 12.6 ng mL−1, 2.6 hr, 80.8 ng h mL−l, respectively.

Effect of silymarin pretreatment on the bioavailability of domperidone in healthy human volunteers

Abstract Background: The aim of this study was to investigate the effect of silymarin pretreatment on domperidone oral bioavailability in humans. Methods: The rats were pretreated with silymarin for 7 days. The transport of domperidone across the rat intestine (duodenum, jejunum, ileum, and colon) was studied by using in vitro everted and non-everted sac methods. Samples were collected at preset time points and replaced with buffer. The drug content in the samples was estimated. The first part of the study included oral administration of 10 mg domperidone tablet alone, and blood was sampled from the antecubital vein. The second part of the study was conducted after a washout period of 2 weeks. Five hundred milligrams of silymarin was administered twice daily for 6 days. On day 7, one tablet each of 10 mg domperidone and 500 mg silymarin were administered concomitantly. Results: In the everted sac and non-everted sac study with silymarin pretreatment, domperidone transport increased from the duodenum, jejunum, ileum, and colon. The silymarin pretreatment increased the bioavailability of domperidone. There was a statistically significant difference in the pharmacokinetic parameters Cmax, T12

Evidence of stereoselective and segmental-dependant transport of chiral antidiabetic drug nateglinide along the rat small intestine: possible role of efflux transporters

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Development of a high-performance liquid chromatography method for simultaneous determination of pioglitazone and felodipine in pig serum: application to pharmacokinetic study

, AUC0–∞, and AUC0–24. Conclusions: The significant difference in absorption of domperidone on pretreatment with silymarin is due to the inhibition of P-glycoprotein and CYP3A. Silymarin, which inhibits CYP3A4, should be contraindicated for domperidone.

Iontophoretic delivery of lisinopril: Optimization of process variables by Box-Behnken statistical design

The purpose of the study was to investigate whether efflux and stereoselective mechanisms play any role in the transport of nateglinide (NA) enantiomers in rat. The transport of individual enantiomers and racemate was studied with and without the presence of an inhibitor for P-glycoprotein and MRP2, verapamil using duodenal, jejunal, and ileal intestinal sacs prepared from rat intestine. The intestinal samples were analyzed by a validated chiral HPLC method. Generally, higher concentrations of R-NA and its S-enantiomer were observed when the racemate was administered compared to administration of the individual enantiomers. Transport of NA enantiomers when co-incubated with verapamil was increased in the ileum by twofold to threefold with corresponding decreased secretion by almost threefold, while little change in the duodenum and jejunum. The transport of NA from everted sac segments (basal-to-apical side, secretion) was higher than the transport from the normal sac segments (apical-to-basal side, absorption) indicated an involvement of efflux-mediated transport. It has been found that the transport of NA is stereoselective and also regioselective, i.e., R-NA displayed higher efflux than S-NA and it was higher in ileum than the duodenum and jejunum. This study will really pave the way to understand how efflux transporters influence the absorption of chiral compounds when moving across the gastrointestinal tract.

Development of ultra fast liquid chromatographic method for simultaneous determination of nitrendipine and carvone in skin diffusate samples

A simple and sensitive high-performance liquid chromatographic method was developed and validated for simultaneous estimation of pioglitazone and felodipine in pig serum. The present method consists of protein precipitation, extraction of analytes from pig serum into dichloromethane and separation using reversed-phase C(18) column. Nitrendipine was used as an internal standard and the eluent was monitored by UV detector at 240 nm. The mobile phase used was acetonitrile and 50 mm ammonium acetate buffer at a flow rate of 1 mL/min. The retention times for pioglitazone, felodipine and nitrendipine were found to be 5.12, 10.53 and 7.14 min, respectively. The intraday and inter-day coefficient of variation and percent error values of assay method were less than 7% and mean recovery was more than 94% for each analyte, and the method was found to be precise, accurate and specific during study. The method was successfully applied for pharmacokinetic study of pioglitazone and felodipine from bioadhesive buccal tablet after buccal administration to pigs. The C(Max) , T(Max) , and AUC(0-24) of pioglitazone and felodipine from buccal tablet were found to be 394.6 ng/mL, 5.6 h, 2624.2 ng h/mL and 44.4 ng/mL, 5.5 h, 275.8 ng h/mL, respectively.