基于包合/离子键双重作用强化苦参碱结肠靶向递药的研究

Matrine, isolated from Sophora alopecuroides of Ningxia, is widely used in the treatment of ulcerative colitis. However, matrine produces severe toxic effects of upper gastrointestinal tract, cannot reach an effective concentration in the colorectal area, and leads to low availability. Therefore, colon-specific delivery of matrine may reduce the systemic side effects and provide effective and safe therapy of ulcerative colitis that may reduce the dose and duration of therapy when compared with the conventional treatment. Film-coated pellets of matrine for colon drug delivery are difficult to be prepared through traditional pharmaceutical technologies, because the coating materials demand high quality, and the processes are complexly operated. The development of the supramolecular drug through inclusion complexation has opened up a new approach for designing novel drug delivery systems, which may have many advantages based on supramolecular assemblies, and have largely inspired interest. In this project, we will design and synthesize the supramolecular complexes of matrine for potential colon-specific drug delivery, using sulfoalkyl ether β-cyclodextrin as the host molecules and matrine as the guest molecule. The assembling behaviors of the supramolecular complexes of matrine are to be discussed by circular dichroism spectroscopy and NMR in solutions, and by X-ray diffractometer in solids. The in vitro release behaviors of the supramolecular complexes are to be investigated in enzymatic solutions and rat cecal contents, and the in vivo release behaviors after oral administration to rats are also readily to be examined. As an innovation of sulfoalkyl ether β-cyclodextrin in the pharmaceutical applications as host molecules, and a new formulation of matrine, the supramolecular complexes of matrine can work as an oral colon-specific drug delivery system.

苦参碱作为宁夏的优势天然产物原料药，对结肠炎具有良好的疗效。针对目前基于药剂学包衣技术制备苦参碱结肠定位微丸，对包衣材料要求高、包衣处方设计复杂、制备工艺繁琐、且质量控制难等问题，本项目从化学学科的角度，首先，以磺烷基醚β-环糊精为主体分子，通过电性吸引强化主客体的相互作用来制备苦参碱-磺烷基醚β-环糊精超分子复合物；其次，考察复合物在不同pH缓冲溶液中的稳定性，在大鼠体内外的释药性能，拟阐明主体分子带电侧链基长度、取代度与释药性能的关系；然后，用圆二色光谱法和核磁共振法研究主客体在液相中的键合行为，X-射线单晶衍射法研究复合物的固态空间结构，拟揭示主客体的分子组装行为，推测超分子复合物靶向递药的机理。采用超分子化学技术构建的磺烷基醚β-环糊精-苦参碱口服结肠靶向递药系统，与传统的药剂学技术相比，工艺过程简单，质量易于控制，将为苦参碱新剂型的研发提供新思路和理论基础。

天然药物苦参碱对溃疡性结肠炎具有良好的疗效，由于苦参碱体内消除半衰期较短（t1/2约为3.9 h），制成一般的口服制剂常需要每日口服3~4次，给药次数较为频繁，且对胃肠道刺激较大，常有头晕、恶心、呕吐、便秘等副作用。针对目前基于药剂学包衣技术制备苦参碱结肠定位微丸，对包衣材料要求高、包衣处方设计复杂、制备工艺繁琐、且质量控制难等问题，本项目从化学学科的角度，采用超分子化学技术，基于包合/离子键双重作用构建苦参碱-磺烷基醚β-环糊精超分子复合物。苦参碱-磺烷基醚β-环糊精超分子复合物在酸性条件下，苦参碱以质子化形式存在，带正电荷，可与带负电荷的磺烷基醚β-环糊精形成稳定的复合物，主客体分子间的电性吸引力可以强化超分子复合物的稳定性。苦参碱-磺烷基醚β-环糊精超分子复合物有一定的结肠靶向递药功能，提升苦参碱的生物利用度，其包合和离子键作用，对客体苦参碱的结肠递药有重要影响。苦参碱-磺烷基醚β-环糊精超分子复合物将苦参碱直接运至结肠组织，减少对非靶细胞和器官的损伤，以期为苦参碱新剂型的开发提供新思路。