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

具有生物降解特性的基于环状低聚糖的结肠特异性递送系统的设计和评价

• 批准号: 11672265
• 负责人: UEKAMA Kaneto
• 金额: $ 2.5万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672265/
• 关键词: Cyclodextrin; Colon specific delivery; Biodegradable drug carrier; Ester-type prodrug; Colonic microflora; Prednisolone; Inflammatory bowel disease rats; Alleviation of side effect; n-酪酸

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.

环糊精的生物可降解特性被发现是有用的，作为一个来源的位点特异性的药物输送到结肠和作为一个前体部分的糖皮质激素前体药物的建设与低副作用。泼尼松龙琥珀酸酯（Prednisolone succinate，PDD）是一种典型的糖皮质激素，通过酯键与CyD的仲羟基相连。酯结合物的水解是通过CyDs的C_2和C_3羟基之间以及PD的C_2和C_3羟基之间的酰基迁移进行<17><21>的，酯结合物在大鼠血液和肠匀浆中稳定，不含内容物，其水解速率与磷酸盐缓冲液中的水解速率基本相同。PDsuc/α-CyD酯偶联物经口和结肠内给药对炎症性肠病模型大鼠的抗炎作用与直接结肠内给药PD相当，但通过胸腺/体重比的变化监测PD的不良反应，PDsuc/α-CyD酯偶联物的给药可显着减轻PD的不良反应。这些数据表明，由于减轻了全身副作用，同时保持了治疗效果，PDE 2/α-CyD酯缀合物可用作结肠特异性递送的延迟释放型前药。因此，PDsuc（类固醇）/CyD酯缀合物作为新型IBD（炎症性肠道疾病）治疗前药可能特别有用。

项目成果

F.Hirayama and K.Uekama: "Cyclodextrin-based Controlled Drug Release System."Advanced Drug Delivery Reviews. 36. 125-141 (1999)

F.Hirayama 和 K.Uekama：“基于环糊精的控制药物释放系统”。高级药物输送评论。

H.Yano, F.Hirayama, H.Arima, K.Uekama: "Prednisolone-appended α-Cyclodextrin : Alleviation of Systemic Adverse Effect of Prednisolone after Intracolonic Administration in 2,4,6-Trinitrobenzene-sulfonic Acid-Induced Colitis Rats."J.Pharm.Sci.. 90(in press)

H.Yano、F.Hirayama、H.Arima、K.Uekama：“添加泼尼松龙的 α-环糊精：在 2,4,6-三硝基苯磺酸诱导的结肠炎大鼠结肠内给药后减轻泼尼松龙的全身不良反应。 “J.Pharm.Sci..90（印刷中）

H.Yano: "Preparation of Prednisolone-appended α-, β-, and γ-Cyclodextrins : Substitution at Secondary Hydroxyl Groups and In Vitro Hydrolysis Behavior."J.Pharm.Sci.. 90・4. 493-503 (2001)

H. Yano：“添加泼尼松龙的 α-、β- 和 γ-环糊精的制备：二级羟基的取代和体外水解行为”。 J.Pharm.Sci. 90・4 (2001)。

H.Yano: "Prednisolone-appended α-Cyclodextrin : Alleviation of Systemic Adverse Effect of Prednisolone after Intracolonic Administration in 2,4,6-Trintrobenzenesulfonic Acid-Induced Colitis Rats."J.Pharm.Sci.. 90(印刷中). (2001)

H. Yano：“添加泼尼松龙的 α-环糊精：在 2,4,6-三硝基苯磺酸诱导的结肠炎大鼠结肠内给药后减轻泼尼松龙的全身不良反应。J.Pharm.Sci.. 90（出版中）。” (2001)

F.Hirayama: "Release Characteristics of a Short-chain Fatty Acid, n-Butylic Acid, from Its β-Cyclodextrin Ester Conjugates in Rat Biological Media."J.Pharm.Sci.. 89・11. 1486-1495 (2000)

F. Hirayama：“在大鼠生物培养基中从 β-环糊精酯缀合物中释放短链脂肪酸、正丁酸的特性。J.Pharm.Sci. 89・1495 (2000)。”