Improvement of Dissolution and Bioavailability of Nitrendipine by Inclusion in Hydroxypropyl-β-cyclodextrin

Abstract

A significant increase in solubility and dissolution rate of nitrendipine, a slightly soluble calcium channel blocker, was achieved by inclusion complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complex was prepared by solvent evaporation method and characterized by phase solubility method, x-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. The solubility of nitrendipine increased linearly as a function of HP-β-CD concentration, resulting in AL-type phase solubility diagram which revealed a formation of inclusion complex in a molar ratio of 1:1, with the apparent association constant of 108.3 M−1. The in vitro dissolution rate of nitrendipine in pH 7.4 phosphate buffer was in the order of inclusion complex, physical mixture, and nitrendipine powder. These three different forms of nitrendipine were administered orally to rats with a dose of 10 mg/kg equivalent to nitrendipine. The AUC of inclusion complex was significantly larger than that of nitrendipine powder. Tmax of inclusion complex was significantly shorter and Cmax was significantly higher than those of nitrendipine powder. Cmax of physical mixture was higher than that of nitrendipine powder. Tmax of physical mixture, however, remained the same. The results indicated that the bioavailability of nitrendipine could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.