Background: Skin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (K p) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin.
Methods: A multilayer geometry skin model was established and the K p of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug K ps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment.
Results: Coarse-grained modeling of molecular dynamic simulation was successfully established and the K p of PAE in SC was 2.00× 10^{− 6} cm²/h. The K p of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58× 10^{− 5} cm²/h and 3.20× 10^{− 5} cm²/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment.
Discussion: This study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.
Keywords: nano transdermal drug delivery system, skin pharmacokinetics, finite element analysis, multilayer geometry model, diffusion coefficient, paeonol nanoemulsion