超临界流体乳液萃取制备载药微胶囊关键技术

The aim of this research is to achieve good control over the structure of microcapsules and to meet medical standard through the combination of traditional Double Emulsification Solvent Evaporation (DESE) method and Supercritical Fluid Extraction technology. This research is comprised of three stages, i.e., drug-loaded microcapsules preparation based on double emulsion method, Supercritical Fluid Emulsion Extraction (SFEE) and the hydrodynamics involved in the supercritical fluid extraction process. The key issues in this research include the preparation of double emulsion, the control over the diffusion rate of solvent, the adjustment of supercritical fluid parameters, the characterization of the microstructures and the preparation of microparticles that exhibit good optical properties. The aim of this research project is to lay the groundwork for control and optimization of microcapsule structures by determining the coupling effect caused by physical parameters and operational parameters on the internal microstructure of the microcapsules; to assist the customized design of specific drugs by determining the relationship between drug loading rate/drug type and internal structures of the microcapsules. To develop a cutting-edge drug-loaded microencapsulation technology --- supercritical fluid extraction of double emulsion, and develop a new generation of drug loaded microcapsules whose comprehensive performances such as structural performance and bioactivity are improved; to delve the mechanism related to the supercritical fluid extraction of double emulsion process, to seek the apply-to-all laws that rule the drug-loaded microcapsule preparation process proposed in this research; to study the effects of different supercritical fluid parameters on the encapsulation proficiency and the performance of the microcapsules produced by Supercritical Fluid Extraction of Double Emulsion technology.

本项目将传统多重乳液溶剂蒸发(DESE)微粒制备技术与超临界流体技术相结合制备微胶囊，使微胶囊结构可控的同时，力求载药达到医药标准。研究内容分三阶段：DESE法制备微胶囊、超临界流体乳液萃取法(SFEE)制备载药微胶囊和超临界萃取装置流体动力学研究。关键点有多重乳状液的配制；溶剂扩散速率的控制；超临界流体参数的调节；微观结构表征；可视化示踪微粒的制备和选择。研究目标：确定DESE法制备微胶囊的物性参数和操作参数对微胶囊内部结构的耦合作用规律，实现微囊结构可控；确定载药种类和载药量与微胶囊结构间的关系，以期根据用药需求定向设计；结合超临界流体技术，形成一种新型制备载药微胶囊的先进工艺—超临界多重乳液萃取技术，发展一种结构和生化等综合性能优良的新一代载药微胶囊；对SFEE法制备载药微囊工艺和机理进行研究，得到该方法微胶囊制备的普适规律；研究SFEE法物性参数和操作条件对微胶囊性能的影响。

超临界乳液萃取法(SFEE)将超临界微粒制备技术与乳液法微粒制备技术相结合，是可应用于超细微粒制备的新型绿色技术。SFEE过程微粒直接在水体系中生成，且具有粒径分布均匀、球形度高、分散性好等优点。.对SFEE萃取过程中溶剂/CO2气液相平衡及混合密度进行分析研究，预测溶剂/CO2二元体系在水相中混合过程的相行为。借助带视窗的高压反应釜及PIV流场测试技术，对溶剂/scCO2在水体系中的混合相行为及溶剂/scCO2混合流动进行研究，明确了SFEE过程中溶剂与scCO2混合过程的传质路径：二者在水相中接触并在气液界面发生对流扩散，而不是单纯的水相中的分子扩散问题，为混合过程强化提供了新途径。.对SFEE法溶剂溶除过程中釜内流场及溶剂浓度分布情况进行分析研究。提出溶剂溶除过程是影响SFEE中溶剂去除效率的关键过程之一，采用SFEE分步萃取法，并通过引入曝气和强磁力搅拌加强溶剂/scCO2混合效果，使溶剂去除效率显著提高，溶剂残留量大幅降低。.采用SFEE法对O/W型乳液进行萃取结果表明：调节载药浓度和聚合物浓度分别是改变纳米混悬剂和复合混悬剂中微粒粒径的有效手段。对于复合微囊而言，表面活性剂浓度对包埋率的影响最为显著，但出于对乳液稳定性考虑，增大聚合物浓度是提高药物包埋率的最有效手段。.将SFEE法与多重乳状液技术结合，制备具有多重载药功能、内部具有闭孔结构的复合空心微囊。W/O/W型多重乳状液内外水相间存在化学势差和水传递现象，水在有机相中的溶解度c和扩散系数D是决定液膜透过性的关键因素。PCL/溶剂/CO2三元体系发生相分离可引起有机相液膜中聚合物贫相的产生导致微囊结构破坏。该工艺可实现微囊内部结构可控以及疏水性药物和亲水性药物的双重载药，为给药系统复合设计提供一种新途径。.采用SFEE技术，以O/W和W/O/W多重乳液作为处理对象，制备纳米药物混悬剂、药物/聚合物复合混悬剂和多重载药闭孔微囊结构，同时具备乳液法制备微粒分散性好和粒径、结构方便控制的特点，以及超临界流体微粒制备技术绿色环保、有机溶剂去除彻底的优势，为新型给药体系的设计和制备奠定研究基础。