Comparative Studies of the Enhancing Effects of Cyclodextrins on the Solubility and Oral Bioavailability of Tacrolimus in Rats

Abstract

The enhancing effects of cyclodextrins (CyDs) on the solubility, the dissolution rate, and the bioavailability of tacrolimus after oral administration to rats were examined and compared with those after administration of a PROGRAF® capsule containing the solid dispersion formulation of tacrolimus. Here we used natural CyDs and the hydrophilic β‐CyD derivatives; that is, 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 solubility of tacrolimus increased in the addition of β‐CyD, indicating that the cavity of β‐CyD comfortably fits the drug. Of the β‐CyD derivatives, DM‐β‐CyD had the greatest solubilizing activity and gave the Ap type phase solubility 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 dissolution 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 preparations of tacrolimus with an enhanced bioavailability and a reduced variability in absorption. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:690–701, 2001