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

Abstract

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)-3cyclohexen-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.

The enhancing effect and promoting mechanisms of the stereoisomeric monoterpene alcohol esters as enhancers for drugs with different physicochemical properties

“…4 . The consequents of the IVIVC showed that the in vitro permeation test could be used to forecast the in vivo performance of patches (R 2 >0.8783) [24] .

Fig.

…”

Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers

“…848 The effects of linalool on the enantioselective skin permeation of naproxen has been also explored, 849 as well as the enhancement mechanisms of transdermal enantioselective delivery of flurbiprofen by chiral 4-O-acylterpineol. 850 Very recently, studies focused on the enantioselective permeability of chiral lipid bilayers have been reported. 851 Henriques, Craik, and co-workers showed that the chiral environment of lipid bilayers can modulate the function of membrane-active peptides contrary the view that peptide− lipid interactions are achiral.…”

“…l -Menthol has higher permeation-enhancing effects on ( S )-metoprolol than on ( R )- and rac -metoprolol . The effects of linalool on the enantioselective skin permeation of naproxen has been also explored, as well as the enhancement mechanisms of transdermal enantioselective delivery of flurbiprofen by chiral 4-O-acylterpineol . Very recently, studies focused on the enantioselective permeability of chiral lipid bilayers have been reported .…”

Chiral Supramolecular Hydrogel Enhanced Transdermal Delivery of Sodium Aescinate to Modulate M1 Macrophage Polarization Against Lymphedema

“…This is particularly important for regulating drug penetration by interacting with and modifying the conformation of intercellular proteins. [ 51 , 52 ] So far, many studies have explored the differences in the transdermal penetration of drug enantiomers; however, to date, little attention has been paid to the stereoselectivity effects of chiral supramolecular hydrogels in transdermal delivery and their mechanism of drug penetration. Based on this, it is necessary to study the differences and mechanisms of chiral supramolecular hydrogels in promoting drug penetration in order to better enhance drug transdermal delivery.…”