The implications of lipids mobility, drug-enhancers (surfactants)-skin interaction and TRPV1 on licorice flavonoids permeability

Abstract

Abstract Licorice flavonoids (LFs) attained a considerable interest in cosmetic and skin ailments treatments, however, their lipophilic nature restricts their application. In this paper, we systematically investigated the enhancement efficacy and mechanisms of different penetration enhancers (surfactants) on ten LFs compounds. Herein, the aim was to unveil how seven different enhancers modified the stratum corneum (SC) surface and influence the drug-enhancers-skin interaction, and to relate these effects to permeation enhancing effects of ten LFs compounds in the liquids. The enhancing efficacy was evaluated by ERpermeation, ERretention and ERcom, which was conducted on the porcine skin. It was summarized that heat capsaicin (CaP) and lipophilic Plurol® Oleique CC 497 (POCC) caused the most significance of SC lipids fluidity, SC water loss and surface structures alterations, thereby resulting in a higher permeation enhancing effects than other surfactants. Moreover, CaP could completely occupied drug-skin interaction sites, while POCC only occupied most drug-skin interactions. The enhancing efficacy of both POCC and capsaicin was dependent on the log P values of LFs. For impervious LFs with low drug solubility, enhancing their drug solubility helped them permeate into the SC interface. For high-permeation LFs, their permeation was hardly enhanced or inhibited ascribed to the strong drug-enhancer-skin strength in the SC. More importantly, drug-surfactant-skin energy possessed a good negative correlation with the LFs permeation amount for most LFs molecules. Additionally, transient receptor potential vanilloid 1 (TRPV1) rather than transient receptor potential melastatin 8 (TRPM8) mediated LFs permeation enhancement by capsaicin. The study provided novel insights for drug permeation enhancement from the viewpoint of molecular pharmaceutics, as well as the scientific utilization of LFs compounds and surfactants in topical or transdermal formulations.