中药复方缓释制剂均衡释药机制的研究

Balanced release of complex composition is the basic condition and rule in using slow-release preparation of Traditional Chinese Medicine compound according with the theoretical direction of Chinese medicine, which is also the basic difference between slow-release preparation of Traditional Chinese Medicine and that of pharmaceutical chemicals.How slow-release preparation of Traditional Chinese Medicine compound do the release mechanism corresponding to the balanced release? We propose the project according to the early work which has solved the key technique of balanced release of complex composition in slow-release preparation of Traditional Chinese Medicine compound,and combine with results of domestic and foreign study on release mechanism. We choose the complex presccriptionof Herbal Ephedrae and Herbal Datuta ("Chuan Ping") as representative materia to prepare model preparation with equipments and improved accessories of traditonal Chinese drugs pharmaceutics.By the chemical and quantitative metry combined with physical methods of Microscope, Texture analyzer, NIR microscopy imaging analyzer, Underwater camera, and Laser particle size analyzer, and by analyzing the banlance release of index composition, changes of preparation morphosis, and comparing delivery degree between the balanced and non balanced release preparation in vitro with monitoring the shedding particles from preparation. The physical changes during releasing and dynamic changes when particles shedding can explain the correlations between erosion - diffusion and balanced release, and can clear how do the complex composition balanced release. We try to find the mathematical model on drug balanced release fitting self characteristic balanced release of slow-release preparation of Traditional Chinese Medicine compound and lay a good foundation for the performulation of slow-release preparation of Traditional Chinese Medicine compound and modified slow-release accessories of Traditional Chinese Medicine, and technical industrialization

复杂成分均衡释放是中药复方缓释制剂符合中医理论指导用药最基本的条件和原则，也是中药与化学药缓控释制剂根本不同点。符合均衡释放的中药复方缓释制剂释药机制如何？在前期已解决中药缓释制剂均衡释药关键技术问题的基础上，综合国内外释药机制研究成果，设计本项目：以麻黄、洋金花组方（喘平）为代表方，以改良传统中药制剂辅料和技术制备喘平模型制剂，以化学量化法，结合体式显微镜、质构仪、近红外显微成像、水下摄像和激光粒度仪等物理方法，从指标成分均衡释放、制剂形态结构变化和制剂脱落颗粒动态监测等分析，比较均衡释放与非均衡释放缓释制剂体外释放度和释药过程中制剂物理变化、脱落颗粒动态变化，阐述溶蚀-扩散过程中制剂表面颗粒脱落（溶散）与均衡释药的关系和复杂成分如何实现均衡释放，尝试建立适合中药缓释制剂自身特色的均衡释药数学模型，为中药缓释制剂处方设计和改良的传统中药缓释辅料、技术产业化提供依据。

本项目以改良辅料Ⅰ及改良辅料Ⅱ为缓释材料，喘平方（麻黄、洋金花等）为模型药物，制备出满足复杂成分均衡释放缓释的中药复方缓释制剂。通过研究体外释放度、制剂物理变化、释药动态变化、脱落颗粒等相关内容，发现：① 缓释效果优良、体外药物释放符合Ritger-peppas模型，即药物扩散和骨架溶蚀共同作用。② 缓释制剂遇水膨胀后呈现3个区域：溶蚀前沿、扩散前沿和溶胀前沿。当凝胶强度大时，药物的体外释放以药物扩散为主，而凝胶强度基本维持在一定水平时，药物的体外释放由药物扩散与骨架溶蚀共同控制。③ 缓释制剂在体外药物释放过程中，遇到溶出介质时首先会在外表面形成一层凝胶，但同时伴有少量脱落颗粒的出现，随着时间的增加，溶出介质中慢慢地会有更多脱落颗粒出现，提示缓释片可能存在着新的释药模式：溶蚀-溶散-扩散机制。④ 采用基于剥鳞法则建立了各指标成分新的药物释放数学模型：A 麻黄碱Mt/M∞=(12.784t+56.263)Meq-0.2406、B 伪麻黄碱Mt/M∞=(12.686t+56.695)Meq-0.2484 C东莨菪碱Mt/M∞=(13.217t+52.058)Meq-0.2419，同时推测出伴有脱落颗粒的亲水溶胀型骨架药物的二元释药系统新模型。