A systematic approach to determination of permeation enhancer action efficacy and sites: Molecular mechanism investigated by quantitative structure-activity relationship.,Journal of Controlled Release

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A systematic approach to determination of permeation enhancer action efficacy and sites: Molecular mechanism investigated by quantitative structure-activity relationship.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-03-10 , DOI: 10.1016/j.jconrel.2020.03.014
Degong Yang ₁ , Chao Liu ₁ , Peng Quan ₁ , Liang Fang ₁

Affiliation

The present study was to systematically evaluate the enhancement action efficacy and sites of chemical permeation enhancer (CPEs), which provided references for the reasonable application of CPEs and the formula optimization of transdermal patch. Enhancement action efficacy was characterized using an indicator of comprehensive enhancement effect (ERcom). In addition, enhancement action sites were evaluated using a novel enhancement action parameter (βR/P), which was derived from the release enhancement effect (ERrelease) and skin permeation enhancement effect (ERpermeation) using seven CPEs with different physicochemical properties. Then the molecular mechanism was revealed by quantitative structure-activity relationship. Hydrophilic CPEs obtained highest ERrelease indicated that its enhancement action site was polymer matrix according to βR/P value (>1), due to CPEs formed the strongest hydrogen bonds with polymer, thereby undermined drug-polymer interaction according to the results of FT-IR, MDSC and molecular docking. CPEs with high log P, molecular weight and polarizability showed highest ERpermeation, which indicated that its enhancement action site was skin according to its βR/P value <1, due to it interacted with skin lipid strongly and obtained the lowest diffusion rate in skin. Thus, it increased the disruption level of highly ordered arrangement of intercellular lipid bilayers, which was characterized by ATR-FTIR, Raman, confocal laser scanning microscopy and molecular dynamics simulation. In conclusion, physicochemical properties of CPEs determined its enhancement action efficacy and sites in transdermal drug delivery process, which permitted rational selection of CPEs and the development of safer and more efficacious transdermal patch.

中文翻译：

确定渗透促进剂作用功效和部位的系统方法：通过定量构效关系研究分子机制。

本研究旨在系统评价增强作用的功效和化学渗透促进剂（CPEs）的位点，为合理应用CPE和优化透皮贴剂的配方提供参考。使用综合增强效果指标（ERcom）来表征增强作用功效。此外，使用新的增强作用参数（βR/ P）对增强作用部位进行了评估，该参数来自使用具有不同理化性质的7种CPE的释放增强作用（ERrelease）和皮肤渗透增强作用（ERpermeation）。然后通过定量构效关系揭示了分子机理。亲水性CPE的ER释放最高，表明其增强作用部位是根据βR/ P值（> 1）的聚合物基质，因为CPE与聚合物形成最强的氢键，从而根据FT-IR结果破坏了药物-聚合物相互作用，MDSC和分子对接。log P，分子量和极化率高的CPE表现出最高的ER渗透率，这表明其增强作用部位是根据其βR/ P值<1的皮肤，因为它与皮肤脂质之间的相互作用很强，并且在皮肤中的扩散率最低。因此，它增加了细胞间脂质双层的高度有序排列的破坏水平，其特征在于ATR-FTIR，拉曼，共聚焦激光扫描显微镜和分子动力学模拟。结论，

更新日期：2020-03-10

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