含促渗剂低共熔物的纳米载体用于改善难溶性药物经皮渗透的性能与机制研究

How to promote drug (especially insoluble drug)penetration across the skin remains as a primary and difficult pointduring the development of transdermal drug delivery systems for Chinese medicine. Since the eutectic systems can be formed between some commonly-used natural enhancers (menthol, borneolet al) and/or some insoluble drugs, it will be a promising approach touse the eutectic mixtures containing these penetration enhancers as nano-carriers tosynchronously solubilizethese drugs and improve their skin penetration properties. In our present project, Glycyrrhizic flavonoids and paeonolare applied as the models, and the phase behavior of the eutectic mixtures and their potential interactions with drugs are analyzed. The nanoemulsions or nanosuspensions based these eutectic mixtures are prepared and characterized, and the liquid-solid transformation conditions between droplets and crystals and the phase behavior difference are tested before and after loaded with drugs. The obtained nano-preparations are investigated on their skin permeability and pharmacokineticparameters via different methods of both in vitro and in vivoapproach.The skin penetration depth and effect on skin structure of thenano-preparationsare also studied and compared. The penetration enhancement property and mechanism of eutectic systems with natural enhancers and their nano-carriers can be elucidated by comprehensively of all results. This study will lay foundations for innovative research and expanding application of traditional penetration enhancers from Chinese Materia Medica, and also provide an active exploration for development of novel pharmaceutical technologies with Chinese medicinal characteristics.

如何提高药物、尤其是难溶性药物的经皮吸收是中药透皮制剂研究的重点和难点。基于常用天然小分子促渗剂（薄荷脑、冰片等）之间及其与某些药物之间能形成低共熔物、可显著增加溶解度并改善透皮性能的特点，本项目提出“以含促渗剂的低共熔物制成的纳米载体用于同步增溶和促渗难溶性药物”的研究思路。分别以甘草黄酮和丹皮酚作为模型，考察促渗剂低共熔体系的相行为特征及其与药物的相互作用；将低共熔体系分别制成纳米乳或纳米结晶，表征所得纳米制剂的一般特性，分析“乳滴-结晶”的液固转化条件及载药前后的相行为差异；多种体内外方法测定所得载药纳米制剂的皮肤渗透参数及药物动力学特征，观测不同制剂的渗透深度及对皮肤的影响，比较其经皮吸收途径；综合分析上述结果，阐明促渗剂低共熔体系及其纳米载体的促渗机制和特点，为传统促渗剂的创新研究及拓展应用奠定基础，也是对中药特色制剂技术研究思路和方法的积极探索。

如何提高难溶性药物的经皮吸收是中药透皮制剂研究的热点和难点之一。传统中药外用制剂常添加薄荷脑、樟脑等作为促渗剂，现代研究则多利用纳米乳、纳米结晶等技术。如何将中药特点与现代技术有机结合值得思考和深入研究。.本项目经系统研究发现（1）天然小分子促渗剂（如薄荷脑与冰片、樟脑）或与难溶性药物（如薄荷脑-丹皮酚）之间能在一定范围内形成低共熔物，其相互作用以氢键为主。（2）所得低共熔物能显著改善难溶性模型药物的溶解度，其中甘草次酸在低共熔液中溶解度均比水中提高了10万倍以上，而光甘草定在低共熔物中的溶解度均显著优于其在肉豆蔻酸异丙酯、甘油等纳米乳常用油相和助表面活性剂中的溶解度。（3）低共熔物可作为油相进一步制成纳米乳及其凝胶剂，并用于载药和递药；甘草次酸、光甘草定溶于薄荷脑-樟脑低共熔物制得的纳米乳在载药量、粒径均匀度、放置稳定性等方面均优于IPM；薄荷脑-丹皮酚低共熔物（4:6，w/w）制得的纳米乳稳定性优于其它比例，且在一定环境条件下能转化为纳米混悬液。（4）含药低共熔物制成的纳米乳及微乳凝胶均表现良好的体外和在体皮肤渗透性和皮肤滞留性，优于药物的饱和溶液、同浓度混悬液或物理共混物。.综上，天然小分子促渗剂及其与难溶性药物之间形成的低共熔物能够同时发挥促渗、增溶、纳米载体的多重功能，是一种富有中药特色、简便高效的透皮促渗策略，对新型中药透皮制剂研发具有重要科学价值并潜在广泛应用前景。