α-萜品醇脂肪酸酯对格列美脲经皮促渗透作用考察及皮肤刺激性评价  

Penetration Enhancement and Skin Irritation of O-Acylterpineol Derivatives in Transdermal Delivery of Glimepiride

作　　者：李燕[1] 王春艳[1] 任博 赵利刚 王慧丽[1] Li Yan;Wang Chunyan;Ren Bo;Zhao Ligang;Wang Huili(Department of Pharmacy,Tangshan Maternal and Child HealthHospital,Hebei Tangshan 063000,China;School of Pharmacy,North China University of Science and Technology;Tangshan Key Laboratory of Novel Preparations and Drug Release Technology)

机构地区：[1]唐山市妇幼保健院药剂科,河北唐山063000 [2]华北理工大学药学院 [3]唐山市新型药物制剂与释药技术重点实验室

出　　处：《中国药师》2019年第6期997-1002,共6页China Pharmacist

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

摘　　要：目的:本文以α-萜品醇(TER)为先导化合物与直链脂肪酸通过酯化反应合成系列萜品醇酯[丁酸萜品醇酯(TERC4)、己酸萜品醇酯(TER-C6)、庚酸萜品醇酯(TER-C7)、癸酸萜品醇酯(TER-C10)、十二酸萜品醇酯(TER-C12)、十四酸萜品醇酯(TER-C14)、十八酸萜品醇酯(TER-C18)、油酸萜品醇酯(TER-dC18)],并考察α-萜品醇酯对格列美脲(GMPD)的促渗透活性及优选促透剂的皮肤刺激性。方法:采用水平扩散池以离体家兔皮肤为屏障进行体外透过试验,系统考察了α-萜品醇酯类衍生物及常用促透剂[L-薄荷醇(M)、月桂氮艹卓酮(azone)、N-甲基吡咯烷酮(NMP)]对GMPD的促渗活性并确定最优处方。采用家兔自身对照,单次/多次给药皮肤刺激性实验及组织学评价法考察TER及TER-C14对家兔皮肤的刺激性。结果:在肉豆蔻酸异丙酯(IPM)溶液中,所有促渗剂均有显著的促透作用(P<0.05);TER-C14、TER-dC18的促渗作用均显著高于TER(P<0.05);而制成压敏胶分散型(DIA)贴剂后,仅TER、TER-C6、TER-C14、TER-dC18及M均有显著促渗作用(P<0.05),当5%TER-C14与5%M联合应用时,GMPD的24 h累积透过量是空白组的3.95倍。皮肤刺激性实验及组织学评价结果均表明TER和TER-C14均无明显的刺激性。结论:α-萜品醇酯衍生物对GMPD有显著促透活性且皮肤刺激性低,可作为促透剂候选化合物进一步深入研究。Objective:To synthesize a series of terpene alcohol esters[2-(4-methylcyclohex-3-en-l-yl)propan-2-yl butanoate(TER-C4),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl hexanoate(TER-C6),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl heptanoate(TER-C7),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl decanoate(TER-C10),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl dodecanoate(T-C12),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl tetradecanoate(TER-C14),2-(4-methylcyclohex-3-en-l-yl)propan-2-yl stearate(TER-C18)and(E)-2-(4-methylcyclohex-3-en-l-yl)propan-2-yl octadec-9-enoate(TER-dC18)]by esterification of alpha-terpene alcohols(TER)with straight-chain fatty acids,and investigate the penetration enhancement of alpha-terpene alcohol esters on glimepiride(GMPD)and the skin irritation of the optimized penetration enhancers.Methods:The in vitro permeation studies of GMPD were conducted in side-by-side diffusion cells,the penetration effects of O-acylterpineol,l-menthol(M),azone and N-methylpyrrolidone(NMP)on the permeation behavior of GMPD were also investigated,and then the optimal formulation was determined.Histological experiments and skin irritation assays were also applied to study the irritation of TER and TER-C14 by the self-contrasted method in rabbits.Results:The results of penetration experiment showed that almost all the enhancers had enhancing effects on the penetration of GMPD in isopropyl myristate(IPM)solution(P<0.05),and TER-C14 and TER-dC18 showed obviously higher penetration enhancement than that of TER(P<0.05).While in the DIA patches,only TER,M,TER-C6 and TER-dC18 could promote the penetration of GMPD.The combinations of 5%TER-C14 and 5%M could provide the highest penetration amounts of GMPD(3.95-fold)when compared to the control group(P<0.05).The skin simulative experimental results showed that TER and TER-TET had no obvious skin irritation.Conclusion:O-Acylterpineol derivatives with low skin irritation have significant promoting effects on the penetration of GMPD,which indicates that O-acylterpineol needs to be further studi

关 键 词：萜品醇脂肪酸酯酯 格列美脲 经皮渗透 压敏胶分散型贴剂 皮肤刺激性 

分 类 号：R945[医药卫生—微生物与生化药学] R965.1[医药卫生—药剂学]