Transdermal Drug Delivery of Flavonoid Compounds and Nanoparticles: Uptake, Interaction, Mechanism, and QSAR Studies

Licorice is considered one of the most essential herbs. When combined with other medications, it can mitigate the toxicity of certain herbs and enhance the efficacy of others to some extent. The primary components of licorice are flavonoid compounds. However, as a transdermal preparation, the mechanism of drug delivery for licorice remains only partially understood. In this study, molecular dynamics simulations were employed to investigate the uptake process of 20 different flavonoids by the stratum corneum. We analyzed the proportion of time that flavonoid molecules spent in the stratum corneum (SC). Six flavonoid molecules that remained within the bilayer for an extended period─Licochalcone A, Licochalcone D, Liquiritin, Xambioona, Licorice glycoside C1, and Licorice glycoside B─were selected for further investigation. The results indicated that flavonoid molecules are continuously interacting with the SC surface and are ultimately absorbed by the SC bilayer through various mechanisms. Umbrella sampling simulations revealed that glycyrrhiza flavonoid drugs must overcome a significant free energy barrier to enter the SC and reach the center of the SC bilayer. The energy barriers, listed in descending order, are as follows: Licochalcone A > Licorice glycoside B > Licochalcone D > Licorice glycoside C1 > Liquiritin > Xambioona. We constructed nanoemulsion particles with lecithin, ceramide, and cholesterol as the shell, using Licorice glycoside C1 as the core. When these nanoemulsion particles are absorbed by the SC, the shell modifies the structure of the SC. Finally, we established a quantitative structure-activity relationship (QSAR) model of ΔG to predict the difficulty of the membrane permeation process for flavonoids. These studies contribute to a deeper understanding of the transdermal drug delivery mechanisms of flavonoids.