经皮给药系统中脂肪酸类促透剂进出角质层的动态行为及其机制研究

In transdermal drug delivery system, the penetration enhancement of chemical enhancers was a dynamic behavior, which involved three processes including passing in, acting on and passing out of stratum corneum. However, the majority of domestic and foreign researchers only conducted static researches focusing on the process of acting on stratum corneum. These researchers neglected that the dynamic behavior of chemical enhancers passing in and out of stratum corneum also influenced the full play of enhancing effect. The severe lack of dynamic behavior research became the important bottleneck that restrained chemical enhancers to give full play of their enhancing potential. This project focused on the dynamic behavior of fatty acids possessing alkyl chain of various length or different esterification extent. Based on laser confocal Raman spectroscopy and drug skin permeation experiments, this project aimed to explore the dynamic behavior rules of these chemical enhancers passing in and out of stratum corneum as well as the influence of dynamic behavior on penetration enhancing effect. Moreover, the mechanisms of dynamic behavior were further elucidated at molecular level from multiple aspects including the intermolecular interaction, free volume of polymers, structural morphology of stratum corneum lipid, which may provide new idea for promoting the full play of enhancing potential of penetration enhancers. In summary, this project broke through the limitation that only static research of chemical enhancer was focused on. From a novel research view, this project made our understanding of penetration enhancement of chemical enhancers more comprehensive and was a brand new attempt in the research area of chemical enhancer.

在经皮给药系统中，化学促透剂发挥促透作用是一个“动态”的行为，包括进角质层、作用于角质层、出角质层三个过程。然而，目前国内外研究者却只是针对“作用于角质层”过程进行静态行为研究，忽略了进出角质层的过程同样可能影响化学促透剂促透作用的发挥。化学促透剂动态行为研究的严重匮乏，将成为限制其促透潜能充分发挥的重要瓶颈。本项目以脂肪酸类促透剂为研究对象，基于激光共聚焦拉曼光谱法和药物经皮透过等实验，将探索不同烃基链长度或不同酯化程度的脂肪酸进出角质层的动态行为规律以及动态行为对其促透效果的影响。同时，将从分子间相互作用、聚合物自由体积、角质层脂质的结构形态等方面，深入阐述脂肪酸类促透剂进出角质层的动态行为机制，为此类促透剂促透潜能的充分发挥提供新思路。本项目将打破现有研究只关注化学促透剂静态行为的局限性，将从全新的研究视角深化人们对化学促透剂促透作用的认识，是化学促透剂研究领域的一次全新尝试。

在经皮给药系统中，化学促透剂发挥促透作用是一个“动态”的行为，包括进角质层、作用于角质层、出角质层三个过程。然而，目前国内外研究者却只是针对“作用于角质层”过程进行静态行为研究，忽略了进出角质层的过程同样可能影响化学促透剂促透作用的发挥。化学促透剂动态行为研究的严重匮乏，将成为限制其促透潜能充分发挥的重要瓶颈。本实验采用体外透皮实验、体内药动学、TEWL的方法评价化学促透剂的促透潜能。采用定量检测和共聚焦拉曼光谱观测化学促透剂在皮肤和贴剂中的分布。从分子层面研究化学促透剂进角质层的作用机制，包括FT-IR实验、分子对接、分子动态模拟、流变学实验。另外，合成降解型促透剂亮氨酸月桂醇酯、丝氨酸月桂醇酯，对其进出角质层速率及有效性和安全性进行考察。研究结果表明，化学促透剂本身的释放行为明显限制了其促透潜能。体内外的数据结果显示，通过借助PEG400改善油酸的释放，油酸的促透效果明显增加，促渗比从2.69增至4.10，AUClast 从 1574 ± 87 增至 2664 ± 249 ng·h/mL。改善油酸释放行为的作用机制为减弱油酸与压敏胶之间的相互作用和影响压敏胶的刚性硬度。另一方面，将月桂醇用亮氨酸及丝氨酸进行酯化，对月桂醇进出角质层的行为具有调控作用。与月桂醇相比，经亮氨酸月桂醇酯与丝氨酸月桂醇酯处理过后的皮肤具有更高的药物经皮透过量。总的来说，本项目建立了化学促透剂在经皮给药系统中的动态行为追踪，为化学促透剂促透潜能的充分发挥提供新思路。将从全新的研究视角深化人们对化学促透剂促透作用的认识，是化学促透剂研究领域的一次全新尝试。