Efficacy and safety of permeation enhancers: A kinetic evaluation approach and molecular mechanism study in the skin.

This study sought to provide approach for evaluating and predicting the efficacy and safety of permeation enhancers on the basis of their kinetic distribution behavior in the skin dictated by physicochemical properties. Herein, the efficacy-safety regularity of eight permeation enhancers were studied with ex vivo skin permeation study, small-angle X-ray scattering, MTT assay, H&E staining, and in vivo skin erythema analysis, classifying into the following three categories: high enhancement-low irritation, medium enhancement-high irritation, and low enhancement-low irritation. These three modes were positively correlated with the distribution amount of permeation enhancers in the skin layers and verified by the in vitro tape-stripping study. The kinetic parameter, effective-safety index (IES), was proposed to describe the regularity of enhancement effect tendency and irritation risk, and the relationship between IES and physicochemical properties of permeation enhancers was analyzed with multiple regression analysis. According to the results of modulated temperature differential scanning calorimetry and dielectric spectrum, permeation enhancers with high lipophilicity and low polarity had IES > 1, suggesting high enhancement effect and low irritation due to their higher affinity with the stratum corneum (SC) than with epidermis (EP). Permeation enhancers with medium lipophilicity and medium polarity exhibited 0 < IES ≤ 1, showing medium enhancement effect and high irritation, as determined by their comparable affinity with the SC and epidermis (EP). However, permeation enhancers with low lipophilicity and high polarity had IES → 0, demonstrating low enhancement effect and irritation, as indicated by their poor affinity with the SC. In summary, different physicochemical properties of permeation enhancers influenced their affinities with skin layers, resulting in their different enhancement effect and irritation potential. This study will provide a theoretical basis and criteria for evaluating and predicting the safety and efficacy of permeation enhancers, which will enable a more rational selection of permeation enhancers in the optimization of transdermal patches.