基于增强增韧复合效应定向构建微针递药系统及其增效机制研究

Dissolving microneedles are designed to penetrate through the drug delivery barrier stratum corneum, which combining the efficient delivery of conventional injection with good patient compliance of transdermal drug delivery system. Therefore, dissolving microneedles can be used as versatile technique to enhance the transdermal delivery of various therapeutic agents in a manner of painless. Mechanical strength is the key to realize the successful penetration and creating micro-channels for drug diffusion. Since the composite materials is proposed to compensate the limitation of single material, microneedles with sufficient mechanical strength can be fabricated by using composite materials. However, majority of the literatures have been focused on the optimization of the microneedles for transdermal delivering various drugs, the studies were randomly conducted and the systemic theory on the relevant mechanism still remains unexplored. In our previous study, microneedles with sufficient mechanical strength were controllably developed based on synergistic reinforcement and toughening effect. Moreover, it was found that good correlation existed between the composite materials and mechanical strength. The purpose of this project is to systematically investigate the influencing of the material ratio on the mechanical strength, establish the relationship among the microscopic structure, mechanical parameters and mechanical strength, and clarify the mechanism of improved mechanical property, by extensively investigating the microscopic structures including molecular structure, interaction and condensed state, as well as the macroscopic property including modulus and toughness. Finally, various skins with different properties were used to extensively evaluate the interaction with microneedles.These studies will build a systemic theory based on composition material for microneedle preparation, which can provide a scientific guidance for the development of dissolving microneedle drug delivery systems.

可溶性微针结合了注射与经皮给药的双重优势，可突破角质层屏障对药物的阻滞效应，适用于多种药物的高效递送。可溶性微针的机械性能是确保其成功穿透皮肤形成递药微通道的关键。复合基质可弥补单一材料性能的局限，对可溶性微针的机械性能进行优化。目前大多研究集中于发掘微针在各类药物递释中的应用，相关研究的随机性较高，对复合体系提高机械性能的理论基础缺乏深入研究。申请人前期基于增强增韧复合效应定向构建了可溶性微针，且微针的机械性能与复合组分呈现良好的相关性。本课题拟在前期基础上，系统研究复合基质与微针机械性能的量效关系；通过剖析分子结构、相互作用及凝聚状态，结合材料的模量和韧性等力学参数，深入挖掘微观结构—力学参数—微针机械性能之间的关系，阐明增强增韧复合效应提高微针机械性能的机理；进一步探究皮肤的结构状态对微针刺入过程的影响。完善复合基质构建可溶性微针的基础理论体系，为该递药系统的研发提供科学依据。

可溶微针结合了传统注射与经皮给药的双重优势，可突破角质层屏障对药物的阻滞效应，适用于多种药物的高效递送。可溶性微针的机械性能是确保其成功穿透皮肤形成递药微通道的关键。但制备可溶微针的聚合物材料性能有限，难以同时满足强度和韧性的双重要求。复合基质可弥补单一材料性能的局限，对可溶性微针的机械性能进行优化。目前大多研究集中于发掘微针在各类药物递释中的应用，相关研究的随机性较高，对复合体系提高机械性能的理论基础缺乏深入研究。本项目基于增强增韧复合效应定向构建了可溶性微针，系统研究了复合基质与微针机械性能的量效关系，结果表明微针的机械性能与复合组分的类型、配比呈现良好的相关性。进一步通过剖析微观分子结构、相互作用及凝聚状态，结合材料的模量和韧性等力学参数，深入挖掘微观结构—力学参数—微针机械性能之间的关系，阐明了增强增韧复合效应综合调控微针机械性能的机理，为定向构建和优化可溶微针提供了保障；同时探究皮肤的结构状态对微针刺入过程的影响，以大分子多肽类药物和小分子化学药物为模型，构建了不同的可溶微针体系，并对体内外递药效率进行了系统研究。本项目完善了复合基质构建可溶微针的基础理论体系，为推进可溶微针的产业转化提供了重要的实验基础和科学依据。