Evaluation of the Stratum Corneum Retention Abilities of Monoterpenes and Sesquiterpenes: Strategy for the Discovery of Potent Penetration Enhancers.

Predicting skin penetration enhancers (PEs) from numerous terpenes is of interest for the development of the transdermal drug delivery system (TDDS) and remains a great challenge. In this study, the stratum corneum (SC) retention abilities of 3 sesquiterpenes and 3 monoterpenes from Alpiniae Officinarum Rhizoma were compared. The sesquiterpenes included caryophyllene oxide (CPO), δ-cadinene, and β-caryophyllene, while the monoterpenes contained 4-terpineol, β-pinene, and 1,8-cineole. Long-chain sesquiterpenes showed much higher SC-retention abilities than short-chain monoterpenes. The SC-retention abilities of terpenes were directly correlated with their disturbance effects on skin-barrier function (r = 0.9661, p < 0.01). Molecular dynamics (MD) simulation, molecular docking, and attenuated total reflection Fourier-transform infrared (ATR-FTIR) analysis revealed that sesquiterpenes more easily bound to SC components compared with monoterpenes. Consequently, steered molecular dynamics (SMD) simulations were performed using a novel model containing both a mixed ceramide (CER) lipid membrane and keratins. This model was used to predict the SC-retention ability of terpenes and their effects on skin-barrier disturbance. Based on these results, CPO and δ-cadinene were identified as potent PE candidates. The in vivo penetration-enhancement effects of the obtained sesquiterpenes through assessing skin permeation of FITC-Dextran-4000 (FD-4k) were comparable to azone whereas the toxicity of them was significantly lower than azone. In conclusion, we established a feasible approach to identify the potent PEs from numerous terpenes by evaluating the SC-retention ability using SMD simulation.