基于多功能巯基化聚合物的口服黄连整体降糖给药系统的研究与评价

The subject is based on traditional theory of Chinese medicine. Rhizoma coptidis is used to clear away heat, eliminate dampness for raising the Yin of the loss. Combined with modern pharmacology and modern traditional Chinese medicine preparation, a microsphere drug delivery system for Rhizoma coptidis alkaloids were developed by two ways of Hypoglycemic role, which possess multifuctions, such as high drug loading, mucoadhesive property, pH-sensitive, control release and promoting drug absorption by transmembrane. The Rhizoma coptidis alkaloids microsphere can transport Efficiently, which have a triggered sustained release in the intestinal tract in physiological pH. Firstly, the thiolated polymer was preparated. And then microspheres were prepared. The drug could release through pH-sensitive material of Eudragit L100. The bioadhesion effect for local target was carry out by thiol covalent bond. Technologies such as SEM and DSC will be used to characterize microspheres and the mucoadhesive properties of microspheres are studied by fluorescence microscope, fluorospectro photometer and in vivo imaging system in terms of qualitative, quantitative and timing analysis, respectively. Absorption mechanism of drug promoted by carriers is explained. Rhizoma coptidis s loaded microspheres will be gived to diabetic rats induced to proving the validity of the formulation. In a word, this delivery system is a promising novel tool to lower blood sugar levels for Rhizoma coptidis in the intestinal tract. These correlational studies have not yet been reported.

本项目建立在中医药传统理论基础上，运用黄连清热燥湿，泻火解毒，清热以养耗损之阴，同时结合现代药理学和中药制剂学，以黄连生物碱降糖的两种作用途径为药理学基础，构建了一种集高效包载、高粘附力、pH敏感缓慢释放、局部靶向及促进药物吸收的多种功能黄连生物碱微球。将黄连生物碱设计在pH响应型微球载体中，药物在肠道靶点缓慢释放及高效转运。首先合成巯基化壳聚糖聚合物，然后构建巯基聚合物微球载体，利用尤特奇L100材料的pH 敏感性实现药物控制释放。利用巯基形成高效的生物粘附作用达到局部靶向。以SEM和DSC等技术对载体进行分析。以活体成像系统对载体的生物粘附性质进行定性、定量、定时全面考查。结合细胞模型研究载体促进药物吸收的机理，为巯基聚合物介导药物吸收提供实验基础和理论支持。应用糖尿病模型大鼠进行口服降糖实验，考查吸收和降糖效果。该体系为促进黄连生物碱药物口服降糖提供新的研究策，相关研究未见报道。

本项目建立在中医药传统理论基础上，运用黄连清热燥湿，泻火解毒，清热以养耗损之阴，同时结合现代药理学和现代中药制剂学，以黄连生物碱降糖的两种作用途径为药理学基础，构建了一种集高效包载、高粘膜粘附力、pH敏感缓慢释放局部靶向及促进药物吸收的多种功能黄连生物碱微球。首先合成巯基化壳聚糖聚合物，然后构建巯基聚合物微球载体，利用尤特奇 L100材料的 pH 敏感性实现药控制释放。利用巯基形成高效的生物粘附作用达到局部靶向。以 SEM、XRD、DSC等技术对载体和药物进行分析。结合细胞模型研究载体促进药物吸收的机理，应用糖尿病模型大鼠进行口服降糖实验，考查药物口服吸收和降糖效果。黄连提取最优的条件是：黄连饮片，加8倍量1.5%的硫酸溶液，煎煮3次，每次40 min。纯化最佳工艺为：黄连提取液用Ca(OH)2调节pH 5～6，滤液加HCl调节pH 1-2，加5%NaCl，冰箱冷藏静置过夜，沉淀物干燥。巯基化聚合物中含有自由巯基含量为288.3±24.7 μmol/g，二硫键测定结果显示为321.5±21.8 μmol/g. 与chitosan比较，Chitosan-GSH展示出了更强的生物黏附能力，延长了约53倍。最优处方制备过程为：将黄连生物碱提取物溶解在含有1%醋酸的chitosan-GSH溶液中（提取物与载体材料比例：1.72:10），加入0.3%（w/v）TPP溶液。在释放的前4 h大约有36%的药物从微球中释放出来。但是在4h以后，介质转变为pH6.8介质后，药物缓慢的释放出来。TCML-Alk 组五种生物碱的AUC0-∞分别为小檗碱：134.13±53.12 ng/mL*h、巴马汀：81.72±33.58 ng/mL*h、表小檗碱：17.73±7.68 ng/mL*h、黄连碱：76.70±11.98 ng/mL*h和药根碱：27.35±9.12 ng/mL*h。相比于，TCML-Alk组的AUC0-∞是API组1.85-4倍。药物吸收机制及细胞毒结果成功的在细胞水平证明了巯基化壳聚糖微球增加药物吸收是打开紧密连接增加生物碱的吸收，其安全性也从细胞水平证明了新合成的巯基化壳聚糖口服用药的安全性。再一次为将来黄连降糖新药研究奠定了重要的基础。该体系为促进黄连生物碱药物口服降糖提供新的研究策略。