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

In order to devise more effective penetration enhancers, 4--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 -flurbiprofen and its enantiomers were tested across full-thickness rabbit skin, as well as to correlate under and conditions. The permeation studies indicated that both -4--acylterpineol and -4--acylterpineol had significant enhancing effects, interestingly, -4--aclyterpineol had higher enhancing effects than -4--aclyterpineol with the exception of -4-methyl-1-(1-methylethyl)-3-cyclohexen-1-yl octadec-9-enoate (-4-T-dC18). The mechanism of 4--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 release experiment. Finally, a relative safety skin irritation of enhancers was also investigated by histological evaluation. The present research suggested that -4--aclyterpineol and -4--aclyterpineol could significantly promote the penetration of -flurbiprofen and its enantiomers both and , with the superiorities of high flux and low dermal toxicity.