Hydrolysis behavior of prednisolone 21-hemisuccinate/beta-cyclodextrin amide conjugate: Involvement of intramolecular catalysis of amide group in drug release

Prednisolone 21-hemisuccinate/beta-cyclodextrin (beta-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the ami no group of mono(6-deoxy-6-amino)-beta-CyD through amide linkage. Prednisol one 21-hemisuccinate was intramolecularly transformed to prednisolone 17-he misuccinate, and the parent drug, prednisolone, was slowly released from th e 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37 degrees C; the drug release at 25 degrees C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/beta-CyD amide conjugate w as significantly faster (half life of 6.50 min at 25 degrees C) and gave pr ednisolone and mono(6-deoxy-6-succimino)-beta-CyD as products. The hydrolys is of the beta-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascri bed to the involvement of an intramolecular nucleophilic catalysis of the a mide group in the reaction. The succinic acid, bound to a drug through este r linkage at one carboxylic group and bound to a pro-moiety through amide l inkage at another carboxylic group, may be useful as a spacer for construct ion of the immediate release type prodrugs of CyDs.