Design and Evaluation of Cyclic-oligosaccharide-Based Colon Specific Delivery System Having Biodegradable Characteristics

环糊精(Cyds)具有生物可降解性，可作为结肠靶向给药的来源，也可作为构建低副作用糖皮质激素前药的亲和剂。强的松龙琥珀酸酯(PDSuc)是一种典型的糖皮质激素，通过酯键连接到环状化合物的一个次级羟基上。酯结合物的水解是通过环状结构中C_2和C_3羟基之间的酰基迁移以及PDC_&lt；17&gt；和C_&lt；21&gt；羟基之间的酰基迁移在分子内进行的。酯结合物在大鼠血液和肠匀浆中稳定，无含量，其水解率几乎与磷酸盐缓冲液中相同。PDSuc/α-Cyd酯结合物对炎症性肠病模型大鼠口服和结肠内给药的抗炎作用与直接给药后相当，但PDSuc/α-Cyd酯结合物可显著减轻PD的不良反应(胸腺/体重比的变化)。这些数据表明，PDSuc/α-Cyd酯结合物由于减轻了全身副作用，在保持治疗效果的同时，作为一种延迟释放类型的前药对结肠定位给药是有用的。因此，PDsuc(类固醇)/Cyd酯结合物作为新型IBD(炎症性肠病)治疗前药可能特别有用。

The biodegradable characteristics of cyclodextrins (CyDs) are found to be useful as a source of site-specific delivery of drugs to colon and as a pro-moiety for construction of glucocorticoid prodrug with low adverse effect. Prednisolone succinate (PDsuc), a typical glucocorticoid, was conjugated onto one of the secondary hydroxyl groups of CyDs through an ester bond. The hydrolysis of ester conjugates proceeded intramolecularly through both acyl migrations between the C_2 and C_3 hydroxyl groups of CyDs and between the C_<17> and C_<21> hydroxyl groups of PD.The ester conjugates were stable in rat blood and intestinal homogenates without contents, the hydrolysis rate being almost same as that in phosphate buffer. The anti-inflammatory effect after oral and intracolonic administrations of the PDsuc/α-CyD ester conjugate to inflammatory bowel disease model rats was comparable to those after a direct intracolonic administration of PD.However the adverse effect of PD monitored by change in thymus/body weight ratio, was significantly alleviated by the administrations of the PDsuc/α-CyD ester conjugate. These data indicated that the PDsuc/α-CyD ester conjugate is useful as a delayed release type prodrug for colon-specific delivery owing to alleviation of the systemic side effect, while maintaining the therapeutic effect. Therefore, the PDsuc (Steroid)/CyD ester conjugates may be particularly useful as novel IBD (Inflammatory Bowel Disease) therapeutic prodrugs.