Chiral 4-O-acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen
Chiral 4-O-acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen
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DOI：
10.1080/10717544.2020.1760403
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Zhao, Ligang
中科院分区：
文献类型：
--
作者：
Chu, Tianzhe;Wang, Chunyan;Zhao, Ligang
为了设计更有效的透皮吸收促进剂，以4-松油醇（4-TER）对映体和直链脂肪酸为原料，合成了4-O-酰基松油醇衍生物。它们对SR-氟比洛芬及其对映体的促进活性在全层兔皮肤上进行了测试，以及在体外和体内条件下的相关性。结果表明，d-4-O-酰基松油醇和l-4-O-酰基松油醇均具有显著的促渗作用，除d-4-甲基-1-（1-甲基乙基）-3-环己烯-1-基十八碳-9-烯酸酯（d-4-T-dC 18）外，d-4-O-酰基松油醇的促渗作用均高于l-4-O-酰基松油醇。通过衰减全反射-傅立叶变换红外光谱（ATR-FTIR）和分子模拟，证实了4-O-酰基松油醇促进药物透皮的机理。通过体外释药实验，探讨了促渗剂促进药物释放的机理。最后，通过体内组织学评价，研究了促进剂的相对安全性。结果表明，d-4-O-酰基松油醇和l-4-O-酰基松油醇能显著促进SR-氟比洛芬及其对映体的体外和体内透皮吸收，具有透皮吸收通量高、经皮毒性低的优点。
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.