Chiral 4-O-acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen

Drug Delivery

Chunyan Wang¹  Dandan Geng²  Linlin Zhao²  Ligang Zhao²  Heping Wang²  Jing Wang²  Chensi Wu²  Tianzhe Chu² 

[1] Department of Pharmacy, Tangshan Maternal and Child Health Hospital;School of Pharmacy, North China University of Science and Technology;

关键词: chiral 4-o-acylterpineol derivatives;    permeation enhancers;    transdermal drug delivery;    the in vitro and in vivo correlation;    penetration mechanism;   

DOI  :  10.1080/10717544.2020.1760403

来源: DOAJ

【 摘 要 】

In order to devise more effective penetration enhancers, 4-O-acylterpineol derivatives which were expected to be hydrolyzed into nontoxic metabolites by esterase in the living epidermis, were synthesized from 4-terpineol (4-TER) enantiomers and straight chain fatty acids. Their promoting activities on the SR-flurbiprofen and its enantiomers were tested across full-thickness rabbit skin, as well as to correlate under in vitro and in vivo conditions. The permeation studies indicated that both d-4-O-acylterpineol and l-4-O-acylterpineol had significant enhancing effects, interestingly, d-4-O-aclyterpineol had higher enhancing effects than l-4-O-aclyterpineol with the exception of d-4-methyl-1-(1-methylethyl)-3-cyclohexen-1-yl octadec-9-enoate (d-4-T-dC18). The mechanism of 4-O-acylterpineol facilitating the drug penetration across the skin was confirmed by Attenuated total reflection-Fourier transformed infrared spectroscopy (ATR-FTIR) and molecular simulation. The mechanism of penetration enhancers promoting drug release was explored by the in vitro release experiment. Finally, a relative safety skin irritation of enhancers was also investigated by in vivo histological evaluation. The present research suggested that d-4-O-aclyterpineol and l-4-O-aclyterpineol could significantly promote the penetration of SR-flurbiprofen and its enantiomers both in vitro and in vivo, with the superiorities of high flux and low dermal toxicity.

【 授权许可】

Unknown