Enhancement of Solubility, Dissolution Rate, and Oral Bioavailability of Rs-82856 by Complex Formation with Cyclodextrins

Abstract

RS-82856 is a new inotropic agent for treatment of congestive heart failure. Oral bioavailability was found to be very poor likely due to insufficient aqueous solubility (∼ 4.4 mcg/ml) and slow dissolution rate. Inclusion complexes with cyclodextrins were shown to enhance the solubility, dissolution rate and thereby oral bioavailability of the drug. Maximum solubilities of the drug complexes with alpha-, beta-, and gamma-cyclodextrin were 14, 30 and 55 times, respectively, more soluble than the uncomplexed drug. Phase solubility studies revealed a 1:l complexation constant of 136.5, 370.4, and 64.7 for alpha -, beta - and gamma-cyclodextrin complexes, respectively. The complexation between beta-cyclodextrin and the drug is apparently the strongest among the three cyclodextrins. Dissolution profiles of the beta-cyclodextrin complex indicated a dramatic increase in dissolution rate compared to that of the drug. However,a physical mixture of the beta-cyclodextrin and the drug gave an identical dissolution profile to that of the drug.The beta-cyclodextrin complex of the drug dissolves 90% with in 20 minutes while the free based is solves 25% with in the same time interval in water. In an acidic medium (ph 1.5) the beta-cyclodextrin complex and the free based is solve 90% and 30% respectively within 10 minutes.In asingle dose cross-over study in three dogs,the bioavailability of the beta-cyclodextrin complex was found to improve greatly over that of the drug. An increased C_max (2.5 times),and an increased AUC (2.5 times) were observed with the beta-cyclodextrin complex compared to the drug.