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 of the hydroxyl groups of alpha-, beta-, and gamma-cyclodextrins using a coupling agent, carbonyldiimidazole. The direct coupling produced prednisolone-appended cyclodextrin conjugates in which the drug is selectively introduced at one of the secondary hydroxyl groups of cyclodextrins through an ester linkage. The aqueous solubility (> 50% w/v at 25 degrees C) of these conjugates was much higher than those of prednisolone and its 21-hemisuccinate. Prednisolone was slowly released from the conjugate: the percents of prednisolone and its hemisuccinates released from the alpha-, beta-, and gamma-cyclodextrin conjugates were 49, 57, and 85%, respectively, for 24-h. The release 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-hydroxyl groups of prednisolone. The slow release of prednisolone from the ester conjugates was in sharp contrast to the fast release of the prednisolone amide conjugate reported previously. Because of relatively slow and/or site-specific release properties, the present prednisolone-appended cyclodextrin conjugates may be of value as an orally administered delayed-release and/or colon-specific prodrug.
Yano
H
H
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Hirayama
F
F
Arima
H
H
Uekama
K
K
D003505:Cyclodextrins / Q000737:chemistry*; D006868:Hydrolysis; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D011239:Prednisolone / Q000737:chemistry*; D012995:Solubility
D003505:Cyclodextrins; D011239:Prednisolone