Preparation of prednisolone-appended alpha-, beta- and gamma-cyclodextrins: Substitution at secondary hydroxyl groups and in vitro hydrolysis behavior

The carboxyl group of prednisolone 21-hemisuccinate was conjugated to one o f the hydroxyl groups of alpha-, beta-, and gamma -cyclodextrins using a co upling agent, carbonyldiimidazole. The direct coupling produced prednisolon e-appended cyclodextrin conjugates in which the drug is selectively introdu ced at one of the secondary hydroxyl groups of cyclodextrins through an est er linkage. The aqueous solubility (> 50% w/v at 25 degreesC) of these conj ugates was much higher than those of prednisolone and its 21-hemisuccinate. Prednisolone was slowly released from the conjugate: the percents of predn isolone and its hemisuccinates released from the alpha-, beta-, and gamma - cyclodextrin conjugates were 49, 57, and 85%, respectively, for 24 h. The r elease pathway is proposed to be via two fast acyl migrations between the 2 - and 3-hydroxyl groups of cyclodextrins and between the 21- and 17-hydroxy l groups of prednisolone. The slow release of prednisolone from the ester c onjugates was in sharp contrast to the fast release of the prednisolone ami de conjugate reported previously. Because of relatively slow and/or site-sp ecific release properties, the present prednisolone-appended cyclodextrin c onjugates may be of value as an orally administered delayed-release and/or colon-specific prodrug. (C) 2001 Wiley-Liss, Inc. and the American Pharmace utical Association J Pharm Sci 90:493-503, 2001.