α-萜品醇脂肪酸酯对美洛昔康经皮促渗透作用的考察

Effect of O-acylterpineol derivatives on transdermal delivery of meloxicam

目的:本研究以α-萜品醇为先导化合物与饱和直链脂肪酸合成系列萜品醇酯衍生物,包括:丁酸萜品醇酯(T-BUT)、己酸萜品醇酯(T-HEX)、庚酸萜品醇酯(T-HEP)、癸酸萜品醇酯(T-DEC)、月桂酸萜品醇酯(T-DOD)、肉豆蔻酸萜品醇酯(T-TET)、硬脂酸萜品醇酯(T-STE)、油酸萜品醇酯(T-OA),并考察α-萜品醇酯类衍生物对美洛昔康(MLXC)的促透活性。方法:采用双室扩散池以离体兔皮为屏障进行体外渗透实验,系统考察了合成萜品醇酯及常用促透剂[N-甲基吡咯烷酮(NMP)、月桂氮卓酮(azone)、薄荷醇(M)]在肉豆蔻酸异丙酯(IPM)系统和压敏胶型贴剂系统中对MLXC渗透行为的影响。结果:与不加促透剂(空白)相比,浓度为5%的α-萜品醇,T-BUT,T-HEX,T-HEP,M及NMP对MLXC均有显著的促透作用(P<0.05);与萜品醇相比,NMP和T-HEX的促渗作用均显著提高(P<0.05);而制成压敏胶分散型(DIA)贴剂后,仅α-萜品醇,T-HEX,M,NMP表现出促透作用(P<0.05),当5%NMP与5%T-HEX联用时,MLXC的8 h累积透过量是空白组的5.08倍。结论:合成的α-萜品醇脂肪酸酯对MLXC有显著促透作用,有望成为一种有应用价值的促透剂。

Objective： To develop O-acylterpineol derivative as transdermal penetration enhancers for meloxican（MLXC）,including 2-（4-methylcyclohex-3-en-l-yl） propan-2-yl butanoate（T-BUT）,2-（4-methylcyclohex-3-en-l-yl） propan-2-yl hexanoate（T-HEX）,2-（4-methylcyclohex-3-en-l-yl） propan-2-yl heptanoate（T-HEP）,2-（4-methylcyclohex-3-en-l-yl） propan-2-yl decanoate（T-DEC）,2-（4-methylcyclohex-3-en-l-yl） propan-2-yl dodecanoate（T-DOD）,2-（4-methylcyclohex-3-en-l-yl） propan-2-yl tetradecanoate（T-TET）,2-（4-methylcyclohex-3-en-l-yl）propan-2-yl stearate（T-STE） and（E）-2-（4-methylcyclohex-3-en-l-yl） propan-2-yl octadec-9-enoate（T-OA）.Methods： The compounds were synthesized by using α-terpineol and fatty acid. The in vitro permeation studies of MLXC were conducted in isopropyl myristate（IPM） solution or from patches in side-by-side diffusion cells,and the enhancing effects of O-acylterpineol,l-menthol,azone and N-methylpyrrolidone（NMP） on the permeation behavior of MLXC were also investigated. Results： The results of in vitro permeation experiment showed that the compounds including 5% terpineol,5% T-BUT,5% T-HEX,5% T-HEP,5% menthol and 5% NMP had significant enhancingeffects on the penetration of MLXC compared with the control（P 0. 05）,additionally,NMP and T-HEX had higher penetration activity than terpineol（P 0. 05）. While in the DIA patches only α-terpineol,menthol,T-HEX and NMP could promote the penetration of MLXC. The combination of 5% NMP and 5% T-HEX could provide the largest penetration amount of MLXC within 8 h（5. 08-fold） compared with the control group（P 0. 05）. Conclusion：O-acylterpineol derivatives have significant promoting effects on the penetration of MLXC,which indicates that O-acylterpineol might be a promising enhancer.