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

• Published in: Drug delivery 2020-01, Vol.27 (1), p.723-735
• Main Authors: Chu, Tianzhe, Wang, Chunyan, Wang, Jing, Wang, Heping, Geng, Dandan, Wu, Chensi, Zhao, Linlin, Zhao, Ligang
• Format: Article
• Language: English
• Subjects: Adjuvants, Pharmaceutic - chemical synthesis; Adjuvants, Pharmaceutic - chemistry; Adjuvants, Pharmaceutic - pharmacology; Administration, Cutaneous; Animals; Chiral 4-O-acylterpineol derivatives; Drug delivery systems; Drug Delivery Systems - methods; Drug Liberation; Drugs; Fatty acids; Flurbiprofen - administration & dosage; Flurbiprofen - chemistry; Flurbiprofen - pharmacokinetics; Investigations; Male; Maternal & child health; penetration mechanism; Permeability; permeation enhancers; Pharmaceutical industry; Pharmacy; Rabbits; Skin - drug effects; Skin - metabolism; Skin Absorption - drug effects; Solubility; Stereoisomerism; the in vitro and in vivo correlation; transdermal drug delivery; Transdermal medication; Transdermal Patch
• ISSN: 1071-7544; 1521-0464
• DOI: 10.1080/10717544.2020.1760403

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.