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

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