Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
J Control Release. 2020 Jun 10;322:1-12. doi: 10.1016/j.jconrel.2020.03.014. Epub 2020 Mar 10.
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 (ER). In addition, enhancement action sites were evaluated using a novel enhancement action parameter (β), which was derived from the release enhancement effect (ER) and skin permeation enhancement effect (ER) using seven CPEs with different physicochemical properties. Then the molecular mechanism was revealed by quantitative structure-activity relationship. Hydrophilic CPEs obtained highest ER indicated that its enhancement action site was polymer matrix according to β 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 ER, which indicated that its enhancement action site was skin according to its β 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.
本研究旨在系统评价化学渗透增强剂（CPEs）的增强作用效果和作用部位，为 CPEs 的合理应用和透皮贴剂的配方优化提供参考。采用综合增强效果指标（ER）来表征增强作用效果。此外，还采用一种新的增强作用参数（β）来评价增强作用部位，该参数是通过七种具有不同物理化学性质的 CPE 对释放增强效果（ER）和皮肤渗透增强效果（ER）的影响来推导出来的。然后通过定量构效关系揭示其分子机制。亲水性 CPEs 获得了最高的 ER，表明其作用部位是聚合物基质，根据 β 值（>1），因为 CPEs 与聚合物形成了最强的氢键，从而破坏了药物-聚合物相互作用，这与 FT-IR、MDSC 和分子对接的结果一致。具有高 log P、分子量和极化率的 CPEs 显示出最高的 ER，表明其作用部位是皮肤，根据其 β 值<1，因为它与皮肤脂质强烈相互作用，在皮肤中的扩散速率最低。因此，它增加了细胞间脂质双层高度有序排列的破坏程度，这一特征可以通过 ATR-FTIR、拉曼、共聚焦激光扫描显微镜和分子动力学模拟来表征。总之，CPEs 的物理化学性质决定了其在透皮给药过程中的增强作用效果和作用部位，这允许合理选择 CPEs，并开发更安全、更有效的透皮贴剂。
