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Yongwei Gu,1– 3,* Qing Gu,4,* Qing Yang,1,2 Meng Yang,3 Shengzhang Wang,5 Jiyong Liu1– 3 1Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China; 4Department of Pharmacy, Jingan District Zhabei Central Hospital, Shanghai 200070, People’s Republic of China; 5Institute of Biomechanics, Department of Aeronautics and Astronautics, Fudan University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengzhang WangDepartment of Aeronautics and Astronautics, Institute of Biomechanics, Fudan University, Shanghai 200433, People’s Republic of ChinaTel/Fax +86-21-65647825Email szwang@fudan.edu.cnJiyong LiuDepartment of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of ChinaTel/Fax +86-21-64175590Email liujiyong@fudan.edu.cnBackground: 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 (Kp) 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 Kp 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 Kps 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 Kp of PAE in SC was 2.00× 10− 6 cm2/h. The Kp 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 |
