α-萜品醇脂肪酸酯对美托洛尔的体内外经皮促透作用研究  

In vitro/in vivo Transdermal Absorption Enhancement ofα-O-Acylterpineol on Metoprolol

作　　者：李燕[1] 王春艳[1] 李云霞[1] 任博 赵琳琳 赵利刚 Li Yan;Wang Chunyan;Li Yunxia;Ren Bo;Zhao Linlin;Zhao Ligang(Department of Pharmacy,Tangshan Maternal and Child Health Hospital,Hebei Tangshan 063000,China;School of Pharmacy,North China University of Science and Technology;Tangshan Key Laboratory of Novel Preparations and Drug Release Techonlogy)

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》2020年第7期1335-1339,共5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);河北省“第三批青年拔尖人才”项目。

摘　　要：目的:本研究以α-萜品醇脂肪酸酯及N-甲基吡咯烷酮(NMP)、月桂氮艹卓酮(azone)、肉豆蔻酸异丙酯(IPM)、L-薄荷醇为促透剂制备美托洛尔压敏胶分散型贴剂,并考察优选α-萜品醇脂肪酸酯的刺激性及体内外促透活性。方法:体外渗透试验以兔皮为透过屏障,通过皮肤刺激性试验和体外细胞毒性试验评价优选促透剂的安全性,采用大耳兔在体研究含不同促透剂贴剂的体内药动学。结果:十四酸α-萜品醇酯(TER-C14)对美托洛尔促透效果最佳且在试验剂量下未引起大耳兔皮肤红斑,水肿等炎症反应,对人体皮肤细胞无明显毒性。大耳兔药动学研究结果表明空白组、萜品醇(TER)组及TER-C14组贴剂的稳态血药浓度(Css)测定值分别为156.6,223.6和311.9 ng·ml^-1,计算得到的对应的0~24 h的稳态血药浓度预测值(CssP)分别为237.7 ng·ml^-1、321.9 ng·ml^-1和418.8 ng·ml^-1。结论:TER-C14对美托洛尔贴剂体内外均有显著促透活性且皮肤刺激性低,有必要进一步研究拓宽其应用范围。Objective:To evaluate the percutaneous absorption of metoprolol(MET)respectively usingα-O-acylterpineol,Azone,NMP,menthol and isopropyl myristate as the enhancer,as well as to evaluate their irritation and enhancing activity in vitro and in vivo.Methods:The in vitro permeation studies of MET were conducted on the patches by using side-by-side diffusion cells.The irritation of enhancers was evaluated by skin irritation test and in vitro cytotoxicity experiment.MET pharmacokinetic parameters were determined after topical application of patches without enhancer or withα-terpineol(TER)and 2-(4-methylcyclohex-3-en-l-yl)propan-2-yl tetradecanoate(TER-C14)as the enhancers in rabbits in order to provide a steady-state plasma concentration(Css)as well to predict the steady-state plasma concentrations(CssP)from the in vitro permeability data.Results:The in vitro permeation studies indicated that TER-C14 was the optimal enhancer for the transdermal delivery of MET.Additionally,TER-C14 had no obvious toxicity both on rabbits and human skin cells.The Cssvalue after applying the patches without any enhancer or with TER and TER-C14 as the enhancers was 156.6 ng·ml^-1,223.6 ng·ml^-1 and 311.9 ng·ml^-1,and the CssPvalue calculated by in vitro data was 237.7 ng·ml^-1,321.9 ng·ml^-1 and 418.8 ng·ml^-1,respectively.Conclusion:TER-C14 with low skin irritation shows significantly transdermal promoting effect on MET both in vitro and in vivo,and it is necessary to further extend its application.

关 键 词：美托洛尔 α-萜品醇酯衍生物 压敏胶分散型贴剂 刺激性评价 体内研究 

分 类 号：R944.9[医药卫生—药剂学] R945[医药卫生—药学]