Hydrolysis Behavior of Prednisolone 21-Hemisuccinate/β-Cyclodextrin Amide Conjugate : Involvement of Intramolecular Catalysis of Amide Group in Drug Release

Abstract

Prednisolone 21-hemisuccinate/β-cyclodextrin (β-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the amino group of mono(6-deoxy-6-amino)-β-CyD through amide linkage. Prednisolone 21-hemisuccinate was intramolecularly transformed to prednisolone 17-hemisuccinate, and the parent drug, prednisolone, was slowly released from the 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37°C; the drug release at 25°C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/β-CyD amide conjugate was significantly faster (half life of 6.50 min at 25°C) and gave prednisolone and mono(6-deoxy-6-succimino)-β-CyD as products. The hydrolysis of the β-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascribed to the involvement of an intramolecular nucleophilic catalysis of the amide group in the reaction. The succinic acid, bound to a drug through ester linkage at one carboxylic group and bound to a pro-moiety through amide linkage at another carboxylic group, may be useful as a spacer for construction of the immediate release type prodrugs of CyDs.