基于脑中风发病特点的银杏双组分口服二元时律释药系统的构建

Currently, the research and development of targeted or controlled release traditional Chinese medicine or other innovative medicine, is research single ingredient as the study object, ignoring the efficacy of Chinese medicine overall multi-component synergy. This project takes a holistic view of Chinese medicine as a guide to the structure of the components of traditional Chinese medicine ginkgo group was divided into twin study, based on a two-component ginkgo biopharmaceutical properties, when combined with the characteristics of the target disease, stroke onset law( often occurs at midnight), ginkgo build two component oral drug delivery system binary law. That is, in a two-component structure Ginkgetin lactone basic research background material: ①comprehensive study Ginkgetin lactone component biopharmaceutical properties, with particular attention solubility components, the permeability. ②Combined incidence of stroke characteristics, designed after taking the easy onset of the "constant speed release" after the first two-component ginkgo "quick release" system when the law is administered. ③Initial construction of the evaluation system for the drug delivery system, including the release behavior evaluation, and general evaluation of the efficacy of ginkgo contrast pharmaceutics, pharmacokinetics in vivo kinetics of the Beagle. In this study, structural components of traditional Chinese medicine to design their role model.

目前中药靶向、缓控释等创新中药的研发，多数以单一成分为研究对象，忽视了中药药效根本在于多成分整体协同作用。本课题组基于中医药整体观，以中药物质基础的组分结构理论为指导，结合靶病脑中风发病时律特点(多发突发于午夜至凌晨)，根据银杏黄酮与内酯组分的性质和作用特点，构建银杏双组分口服二元时律释药系统，研究重点在于：①全面考察银杏黄酮与内酯组分生物药剂学性质，尤其关注组分的溶解性、渗透性、油水分配系数等方面，②结合脑中风发病特点，设计由“速效初释部分”和“脉冲时控部分”两者组装而成的银杏双组分时律给药系统，其在服药后，前者先“快速释药”，后者在易发病期“恒速释药”达到全程起效目的。③针对该释药系统初步构建评价体系，包括释药行为评价、与普通银杏制剂药效学对比评价、比格犬体内药代动力学研究。本研究为其他中药多组分释药系统提供参考依据，对制备符合现代临床需求应用的中药多组分制剂起示范作用。

脑中风具有明显的午夜至清晨多发病的规律特征，银杏黄酮和银杏内酯对脑中风具有很好的疗效，但是由于银杏黄酮渗透性较差，银杏内酯水溶性较差，限制了其口服吸收，多方面原因导致当前银杏制剂口服生物利用度低，在一定程度上限制了其临床应用。针对银杏黄酮渗透性较差，银杏内酯水溶性较差，并考虑脑中风午夜至清晨多发病的特征，采用双组分多元释药模式，制备银杏黄酮-内酯组分多元控释释药系统。以提高银杏黄酮组分溶出度、内酯组分的渗透性，控制药物的释放速度，从而最大程度对抗脑中风时辰发病。本项目制备了银杏内酯黄酮组分自微乳-微丸缓控释多元释药系统，根据溶解度，筛选出合适的油相、表面活性剂和助表面活性剂；采用水滴定法绘制伪三元相图筛选出合适的Km值（表面活性剂与助表面活性剂的质量比）；在选定的Km值下进行进一步的处方研究；采用高效液相色谱法测出自微乳中银杏黄酮的含量；根据筛选出的制剂处方制成自微乳，再加入适当的辅料，自微乳可充当自粘合剂制成微丸；进行微丸的制剂评价。药动学实验发现，其在30min左右速释微丸达到最大血药浓度，控释微丸在口服给药后10小时达到最大血药浓度，药动学特点基本满足脑中风午夜至清晨发病时给药间隔。HE染色考察给药后心肌组织的病理状态，考察了对bcl-2，caspase-3，bax，NF-kBp65，MMP-9 和MMP-2的影响。此外制备了银杏内酯固体分散体释药系统，考察了对MDA，GSH，SOD，CAT，LDH，GPx等影响。对其药动学、药效学进行评估，发现自微乳-微丸给药系统和固体分散体给药系统都能提高银杏黄酮组分和银杏内酯组分生物利用度，银杏黄酮-内酯组分多元控释释药系统能满足脑中风发病时律特点释药。