Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats.

Arima, Hidetoshi; Yunomae, Kiyokazu; Miyake, Kouzou; Irie, Tetsumi; Hirayama, Fumitoshi; Uekama, Kaneto.

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. Journal of Pharmaceutical Sciences

Abstract

The enhancing effects of cyclodextrins (CyDs) on the soly., the dissoln. rate, and the bioavailability of tacrolimus after oral administration to rats were examd. and compared with those after administration of a PROGRAF capsule contg. the solid dispersion formulation of tacrolimus. Here we used natural CyDs and the hydrophilic β-CyD derivs.; i.e., randomly methylated-β-cyclodextrin (RM-β-CyD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD), and sulfobutyl ether β-cyclodextrins (SBE-β-CyDs). Of the natural CyDs, the soly. of tacrolimus increased in the addn. of β-CyD, indicating that the cavity of β-CyD comfortably fits the drug. Of the β-CyD derivs., DM-β-CyD had the greatest solubilizing activity and gave the Ap type phase soly. curve as defined by Higuchi and Connors, suggesting the formation of higher-order complexes. The result of van't Hoff plot suggests that the enthalpy is dominant for the complexation of tacrolimus with DM-β-CyD. The dissoln. rate of tacrolimus was markedly augmented by the complexation with DM-β-CyD, reflecting its solubilizing activity. An in vivo study revealed that DM-β-CyD increased the bioavailability of tacrolimus with low variability in the absorption after oral administration of the tacrolimus suspension to rats. The present results suggest that DM-β-CyD is particularly useful in designing oral prepns. of tacrolimus with an enhanced bioavailability and a reduced variability in absorption.