Hideki Yano, Fumitoshi Hirayama, Hidetoshi Arima, Kaneto Uekama *

Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan

Abstract

The titled compound is a cyclodextrin derivative in which prednisolone 21-succinate (PDsuc) is covalently bound to one of the secondary hydroxyl groups of α-cyclodextrin (α-CyD) via an ester linkage. In this study, the PDsuc-appended α-CyD ester conjugate (PDsuc/α-CyD conjugate) was intracolonically administered to rats with 2,4,6-trinitrobenzensulfonic acid-induced colitis, and its antiinflammatory and systemic adverse effects were compared with those of prednisolone (PD) alone and the PD/2-hydroxypropyl-β-CyD complex (PD/HP-β-CyD complex), which is a noncovalent inclusion complex. Colonic damage score, ratio of distal colon wet weight to body weight, and myeloperoxidase activity were evaluated as measures of the therapeutic effect of PD, whereas the ratio of thymus wet weight to body weight was evaluated as a measure of the side effect of PD. The local　antiinflammatory activity increased in the order of PD alone PDsuc/α-CyD conjugate < PD/HP-β-CyD complex. As to systemic adverse effect, the PD/HP-β-CyD complex and PD alone caused thymolysis at doses of 5-10 mg/kg. In contrast, the PDsuc/α-CyD conjugate showed no clear systemic adverse effect at the same doses. The low adverse effect of the conjugate may be ascribed to the slow release of PD in the colon, which keeps the local concentration in the colon at a low but constant level. The results suggest that the PDsuc/α-CyD conjugate can alleviate the systemic adverse effect of PD while maintaining the therapeutic activity of PD. This kind of knowledge will be useful in the rational design of steroid prodrugs for the colon-specific drug delivery system. 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2103-2112, 2001