Enhancement of Solubility and Bioavailability of Candesartan Cilexetil using Natural P-Glycoprotein Inhibitors

Na Zulal,Pk Lakshmi

doi:10.4314/tjpr.v14i1.4

Abstract

Purpose: To enhance the otherwise poor solubility and bioavailability of candesartan cilexetil (CDS).Methods: This study involved enhancing drug solubility by various solid dispersion (SD) methods. The drug: carrier ratio was as follows: for urea (1:2, 1:4 and 1:6; for polyethylene glycol 6000 (PEG, 1:2 and 1:4, 1:8); and mannitol (1:2, 1:4 and 1:6. Piperin and quercetin (natural P-glycoprotein inhibitors) were used as bioavailability enhancers. Bioavailability stdies were carried out in a rat model with the SDs formulated in a suspension form and administered by the oral route.Results: All the carriers enhanced drug dissolution in water 2 to 4-fold depending on drug/carrier ratio. Release kinetics from solid dispersions made with mannitol showed zero order drug release. Urea and PEG 6000-based solid dispersions showed 1st order drug release kinetics. FTIR studies confirmed transformation to an amorphous form of CDS in mannitol solid dispersion; this was buttressed by release kinetic studies. Bioavailability of the drug in the animals was enhanced by 27 and 68 % when quercetine and piperine, respectively, were incorporated.Conclusion: Formation of solid dispersion enhances the solubility and bioavailability of CDS when natural P-glycoprotein inhibitors such as piperin and quercetin are incorporated as enhancers.Keywords: Solid dispersion, Candesartan, Cilexetil, Bioavailability, P- Glycoprotein, Piperin, Quercetin

Highlights

Candesartan cilexetil (CDS), which is an angiotensin II receptor antagonist, is a prodrug that releases candesartan during absorption
CDS was approved by the US Food and Drug Administration (FDA) in 1998 and patented under the name of ‘Tab Atacand’ [1]
It has the highest affinity for AT1 receptor, where it suppresses the maximal response to angiotensin compared to any other angiotensin II receptor antagonist [2]

Summary

Introduction

Candesartan cilexetil (CDS), which is an angiotensin II receptor antagonist, is a prodrug that releases candesartan during absorption. CDS was approved by the US Food and Drug Administration (FDA) in 1998 and patented under the name of ‘Tab Atacand’ [1]. It has the highest affinity for AT1 receptor, where it suppresses the maximal response to angiotensin compared to any other angiotensin II receptor antagonist [2]. CDS undergoes passive absorption, and Pglycoprotein efflux transportation decreases its bioavailability. This has been shown in a study on the transport characteristics [4], intestinal absorptive characteristics and efflux mechanisms (P-gp transportation) in human intestinal Caco-2 cell line. CDS is sensitive to pH, light and pressure which cause hydrolysis, disesterification [7] and crystalline changes [8]

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Results

Conclusion