d-4-萜品醇丁酸酯的合成及其经皮促透活性评价  

Construction and Penetration Evaluation of d-4-methyl-1-(1-methylethyl)-3-cyclohexen-1-yl Butanoate as Novel Percutaneous Absorption Enhancer

作　　者：初天哲 王贺平 赵利刚 Chu Tianzhe;Wang Heping;Zhao Ligang(School of Pharmacy,North China University of Science and Technology,Tangshan,063210;Tangshan key laboratory of novel preparations and drug release technology,Tangshan,063210)

机构地区：[1]华北理工大学药学院,唐山063210 [2]唐山新型制剂与药物释放技术重点实验室,唐山063210

出　　处：《化学通报》2020年第10期929-934,共6页Chemistry

基　　金：国家自然科学基金项目(81603039);华北理工大学杰出青年基金项目(JQ201713)资助。

摘　　要：本文以d-4-萜品醇(d-4-TER)、丁酸为原料,采用酰氯酯化法合成标题化合物d-4-T-C4,并通过MS和1H NMR进行结构表征。通过体外渗透实验考察了d-4-T-C4对SR-FP的体外促透活性,并利用红外光谱法和分子对接技术研究其促透机制。加入d-4-T-C4时SR-FP的24h累计透过量(Q24h)为383.5±48.75μg·cm-2,分别为对照组和d-4-TER组的3.12、1.34倍,均有显著差异(P<0.05)。同时通过对药物进行手性拆分可以发现,d-4-T-C4对S-FP和R-FP的透过没有显著性差异(P>0.05)。促透机制为d-4-T-C4插入角质层脂质结构域,破坏药物与神经酰胺之间的氢键相互作用,增加脂质迁移率和药物的自由能,从而促进药物的渗透。d-4-T-C4对SR-FP具有显著的促透效果,有望作为新型促透剂在经皮给药系统中广泛应用。In this paper,d-4-terpineol(d-4-TER)and butyric acid were used as raw materials to synthesize d-4-methyl-1-(1-methylethyl)-3-cyclohexen-1-yl butanoate(d-4-T-C4)by esterification method,and the structure of the product was characterized by MS and 1H NMR.The penetration promoting activity of d-4-T-C4 on SR-FP was investigated,and its penetration mechanism was studied using infrared spectroscopy and molecular docking technology.When d-4-T-C4 was added,the accumulative 24 h premeation amount(Q24 h)of SR-FP was 383.5±48.75μg·cm-2,which was 3.12 and 1.34 times of the control group and d-4-TER group,respectively.However,the promoting ability of d-4-T-C4 on S-FP and R-FP were almost identical.Mechanism research showed that d-4-T-C4 insertes into the stratum corneum lipid domain,disrupting the hydrogen bonding interaction between the drug and ceramide,increasing lipid mobility and the free energy of the drug,thereby promoting drug penetration.d-4-T-C4 had a significant enhancing effect on the permeation of SR-FP through the skin and is expected to be widely used as a new type of penetration enhancer in transdermal drug delivery system.

关 键 词：d-4-萜品醇丁酸酯 酯化反应 促透剂 渗透机制 

分 类 号：TQ460.4[化学工程—制药化工]