立体异构单萜醇油酸酯的制备及促透活性评价

Syntheses and Enhancing Effect Evaluation of the Stereoisomeric Monoterpene Alcohol Oleates

本文以互为立体异构体的香叶醇(GER)、橙花醇(NER)为先导化合物,采用酰氯酯化法合成油酸香叶醇酯(GER-dC18)、油酸橙花醇酯(NER-dC18),并考察GER、NER、GER-dC18、NER-dC18作为促透剂对多奈哌齐(DNP)的促透活性差异。通过体外释放试验、红外光谱法和分子模拟技术初步探究其促透机制,结果发现,所选用促透剂不仅能够促进DNP从压敏胶中释放,而且能够作用于角质层脂质及角蛋白并促进水合作用来降低角质层的屏障功能,从而增加DNP的经皮透过。其中,(E)构型的GER-dC18对DNP具有最优的促透效果,有望为经皮制剂的开发提供关键的辅料。

In the present research,(E)-3,7-dimethyl-2,6-octadien-1-yl-octadec-9-enoate(GER-dC18) and(Z)-3,7-dimethyl-2,6-octadien-1-yl-octadec-9-enoate(NER-dC18) were synthesized by geraniol(GER)/nerol(NER) and oleic acid using acyl chloride esterification method. The percutaneous absorption of Donepezil(DNP) was evaluated using GER, NER, GER-dC18, NER-dC18 as the enhancer, respectively. In addition, the promoting mechanism was explored by in vitro release experiment, ATR-FTIR and molecular simulation technology. It was found that the selected penetration enhancers not only could promote the release of DNP from pressure-sensitive adhesive, but also could act on the lipid and keratin of the stratum corneum and promote hydration of skin to reduce the barrier function of stratum corneum, thus increasing the transdermal penetration of DNP. GER-dC18 had the optimal penetration promotion effect on DNP, which was expected to provide the important excipient for the development of transdermal drug delivery system.