环糊精第一、二面羟基的选择性修饰及其结肠释药特性的研究

Cyclodextrins (CDs) are well-known cyclic oligosaccharides consisted of six to eight α-1,4-linked D-glucopyranose units, and have been widely used as an excipient in the pharmaceutical industry for improving some properties of drugs, such as solubility, stability, absorption and/or bioavailability, by forming the inclusion complexes. However, the inclusion equilibrium is disadvantageous when drug targeting is to be attempted, because the complex dissociates before it reaches the organs or tissues to which it is to be delivered. Now, CD’s conjugates, where CDs are modified with drug molecules, may work as a source of colon-targeted delivery of drugs. In our previous experiments, we found that the selective modifications of cyclodextrins with drug molecules can provide a versatile means for construction of not only colon targeted delivery systems, but also rate controlled release systems. In addition, it is important to note that the secondary conjugate released the drug more slowly than the primary one. In order to construct the rate controlled release systems of colon, we will design and synthesize the selective modifications of cyclodextrins with three kinds of drugs, such as acetic acid，n-butyric acid, ketoprofen, ibuprofen, 5-fluorouracil acetic acid, and metronidazole, where the drugs are covalently attached to cyclodextrins on the primary or secondary hydroxyl side. In order to reveal the mechanisms of the rate controlled release of drugs, the in vitro release behaviors of the conjugates are to be investigated in enzymatic solutions (α-amylase and carboxyl esterase), and the in vivo release behaviors after oral administration to rats are also readily to be examined. The conformations of the self inclusion complexes of the conjugates are to be discussed by circular dichroism spectroscopy, NMR, and X-ray diffractometer. As an innovation of cyclodextrins in the pharmaceutical applications based on the chemistry principles, the selective modifications of cyclodextrins with drug molecules will be a promisingly potential formulation in the colon-specific drug delivery.

药物分子改性的环糊精共轭物，能够实现药物的口服结肠靶向给药。本项目组前期工作中发现：药物分子选择性修饰改性的环糊精共轭物，不但可以起到结肠靶向给药的作用，而且环糊精第二面共轭物的缓释药性能优于其第一面共轭物，共轭物位置异构导致空间立体构象差异，进而产生空间位阻，是其缓释药物的可能机理。本研究拟在前期工作基础上，选择三种类型的药物分子（脂肪酸类、苯环类、杂环类）对环糊精进行选择性修饰改性，制备其环糊精第一、二面的共轭物，通过大鼠体内外的释药性能评价，建立共轭物位置异构与释药特性的关系；然后，采用圆二色、核磁共振和单晶衍射等技术，研究共轭物分子的空间构象及其自包结组装行为，从分子构象、空间位阻角度探讨共轭物位置异构体缓释药物的可能机理。环糊精包合物是目前环糊精的主要应用形式，从化学学科的角度，药物分子对环糊精进行选择性修饰改性，实现其结肠靶向给药且缓释，将为环糊精应用新方式的开发提供新思路。

在化学制药工业中，环糊精的传统应用方式是：与药物形成包合物，用于改善药物的溶解度、稳定性、生物利用度等。然而，环糊精包合物，是分子间的非共价结合，易受体内物质如类脂、胆固醇的影响，在胃肠中不稳定，达不到理想的口服结肠靶向给药效果。药物分子修饰改性的环糊精共轭物，用于构建口服结肠靶向给药系统，可以有效地避免这个问题。本项目选用结肠疾病类药物和非甾体抗炎药为模型药物，按结构类型分为三类：①短链脂肪酸类化合物，如乙酸、正丁酸；②苯环类化合物，如酮洛芬、布洛芬；③杂环类化合物，如5-氟尿嘧啶、甲硝唑。较为系统地研究药物对β-环糊精的选择性修饰，制备其环糊精第一、二面的共轭物，通过大鼠体内外的释药性能评价，建立共轭物位置异构与释药特性的关系。实验表明，环糊精共轭物位置异构与结肠释药特性之间存在关联，药物连接在环糊精第二面羟基上时，药物的缓释性能优于药物连接在环糊精的第一面羟基上。本项目实施的意义在于：“老材料新用途”，从化学学科的角度，药物分子对β-环糊精第一、二面羟基进行选择性修饰改性，实现其结肠靶向给药且缓释，为环糊精应用新方式的开发提供新思路、积累理论基础。另外，课题组较为系统的研究了对甲苯磺酸对环糊精的选择性修饰，探索出a、β、r-环糊精的选择性修饰方法，为中间体对甲苯磺酰-环糊精共轭物的制备提供合成方法。