A systematic approach to determination of permeation enhancer action efficacy and sites: Molecular mechanism investigated by quantitative structure−activity relationship

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.