乳液法制备载药微球过程中的溶剂效应与调控机制

The present project is the continuation and further study of NSFC 81360644. Drug-loaded microsphere has become a new hotspot of novel drug delivery system of Chinese medical preparations, yet it is badly lack of fundamental research. Solvent is necessary but invisible ingredient in microspheres, however the solvent effect becomes the key process factor which was neglected. In view of the direct influence of the solvents on formation of microspheres, it will be a more flexible and efficient approach to modulate the structure and properties of microspheres via the solvent effect. This project is aimed at the technical status and research requirements of drug-loaded microspheres by the emulsion method, and the active extracts of Chinese meteria medica with autofluorescence property were used as the model drugs. Firstly, the micro-droplet forming and confocal laser scanning techniques were combined to observe the formation of drops and real-time changing of particle shape and drug distribution, in order to analyze the dynamic effect of solvent evaporation. Secondly, the drug-loaded microspheres were fabricated under various conditions of solvents, and the obtained products were then tested on their morphology, construction, loading properties and release profiles to estimate the influence rules of solvents on microspheres. Lastly but not least, the data were transformed and analyzed to select the critical parameters and to construct the mathematic models. The quantitative relations of solvent and structure and properties of microspheres were described to elucidate the modulation mechanism of solvent effect. The project will provide important references for improving the research efficiency of microsphere preparations of Chinese Medicine, and also lay foundations for further study and better application of emulsion-related pharmaceutical techniques for microsphere fabrication.

本项目是国家自然科学基金项目的延续和深入。载药微球是中药新剂型研究的热点，但基础研究匮乏；溶剂是微球体系中 “必需而隐形的组份”，而溶剂效应则是被忽略的关键因素。基于溶剂对微球成型过程的直接影响，申请者提出“溶剂效应是调控微球构造和性能的更为灵活、有效的途径”的研究思路。本项目针对乳液法制备中药微球的研究需求，以自身具有荧光的中药有效部位为模型药物，联合微量乳滴成型及共聚焦扫描技术，观测乳滴形成、微球形态和药物分布的实时变化，考察溶剂移除的动态效应；在多种溶剂条件下制备载药微球，分析所得微球表面形态、内部结构及其载药、释药和溶蚀行为，推测溶剂效应对微球特征的影响规律；并通过对数据的挖掘和转换，进一步筛选关键参数、构建数学模型，表征溶剂与微球构造和性能之间的定量关系，阐明基于溶剂效应的调控机制。为提高中药微球制剂的研究效率提供重要参考，也为乳液法相关微球制剂技术的深入研究及推广应用奠定基础。

本项目选取乳液-溶剂挥发法制备载药微球过程中常用的溶剂体系，采用微量液滴成型及光学显微或激光共聚焦成像技术，观测乳滴形成、收缩和固化的系列过程，考察溶剂移除的动态效应；在不同溶剂体系条件下制备载药微球，表征所得微球的形态粒径、内部构造和载药释药行为；关联溶剂相关参数与微球性能参数，挖掘溶剂对载药微球构造和性能的影响规律，探索基于溶剂效应的预测和调控机制。.研究结果表明，乳滴形成初期溶剂挥发快、球体快速收缩，后期溶剂移除减慢、球体缓慢固化；纯溶剂液滴收缩较快，溶剂的收缩速率随着水溶性溶剂含量的增加而增加，以EA为主溶剂的液滴收缩速率高于以DCM为主溶剂的液滴收缩速率。溶剂不仅可以通过自身特性影响微球形成初期乳滴收缩过程和后期球体固化过程，同时还能通过与聚合物载体及药物的相互作用影响微球形成过程中的相分离过程，从而造成了成品微球在表面形态和内部构造方面的差异，极大地影响了载体和药物在微球内的分布及微球内药物的存在状态，并进一步决定了微球的载药和释药行为特征。微球形成过程中早期显著的相分离现象很有可能导致最终成品核壳结构的形成，进而提高载药量和包封率，达到降低突释、延长释药等多重目的。O/W法制备不同比例混合溶剂微球的粒径、E-E、突释、缓释均受溶剂效应的影响显著；等比例不同混合溶剂微球中以DCM为主溶剂制备载药微球时，溶剂仅对其突释及缓释性能具一定的影响；Et-Ac为主溶剂时主要溶剂特性参数均与所得微球的粒径、载药及释药性能显著相关；通过HSPiP软件计算和模拟所得的溶解球和汉森溶解度参数等方法有助于预判相分离的发生以及核壳结构的形成。.乳液法是目前制备载药微球的主要方法，阐明溶剂效应对所得微球结构性能的影响和调控机制具有重要意义，尤其有利于提高中药微球制剂的研究效率，并为中药微球制剂技术的深入研究及推广应用奠定基础。