title: Time dependence of the enhancement effect of chemical enhancers: Molecular mechanisms of enhancing kinetics.
abstract: Chemical enhancers are widely used for facilitating drug penetration in transdermal drug delivery system (TDDS). However, there is a lack of knowledge about how the enhancement effect changes over time. In this study, on the basis of kinetic parameters of enhancement effect, molecular details of the dynamic enhancement process was described and a new hypothesis of the recovery mechanism of the skin barrier function was proposed. Using pretreated skin and flurbiprofen patch, the effects of Azone (AZ) and menthyl decanoate (MT-10) were evaluated with in vitro permeation experiment and further confirmed by confocal laser scanning microscopy (CLSM) and TEWL. The results showed that the enhancement ratio (ER) increased firstly, then reached a plateau and finally decreased. The enhancement effect of MT-10 was slower (Tonset, MT-10>Tonset, AZ), weaker (ERmax, MT-10<ERmax, AZ) and shorter (Teff, MT-10<Teff, AZ) than that of AZ. According to the results of CLSM, ATR-FTIR and molecular dynamic simulation, the dynamic enhancement effect was caused by the variation of the diffusion coefficient of intercellular lipid in the stratum corneum (SC), which was dependent on the affinity between enhancers and lipid. Moreover, the skin barrier function recovered although a large amount of enhancers still existed in the SC. Additionally, according to the results of ATR-FTIR, molecular docking and skin retention study, the dynamic effect of AZ on the skin protein only induced skin irritation but showed no influence on drug penetration, so did the amount of the enhancer. In conclusion, dynamic enhancement effect was caused by the dynamic effect of the enhancer on the SC intercellular lipid, and the skin barrier function recovered by accepting the enhancer as a new component of the lipid bilayer.
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Quan
authors.affiliation: School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China. Electronic address: zhao09081@163.com.
authors.forename: Yongshan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China. Electronic address: fangliang2003@yahoo.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001381:Azepines / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005480:Flurbiprofen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D014677:Pharmaceutical Vehicles / Q000378:metabolism*; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects; D057968:Transdermal Patch
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; D014677:Pharmaceutical Vehicles; C035229:laurocapram; D005480:Flurbiprofen
keywords: Chemical enhancer; Dynamic enhancement effect; Enhancing kinetics; Molecular dynamic modeling; Skin irritation; Transdermal drug delivery system