手性薄荷醇酯衍生物对美托洛尔经皮促渗透作用的考察Effect of chiral isopropyl O-acylmenthol derivatives on in vitro permeation of metoprolol
王天涯,王春艳,李杨,赵利刚,韩刚
WANG Tianya,WANG Chunyan,LI Yang,ZHAO Ligang,HAN Gang
摘要(Abstract)：
目的考察在肉豆蔻酸异丙酯(isopropyl myristate,IPM)系统和压敏胶型贴剂系统中,合成得到的手性薄荷醇酯衍生物对美托洛尔(metoprolol,META)渗透行为的影响。方法采用卧式双室扩散池,进行离体兔皮的体外经皮渗透试验。结果分别以薄荷醇手性对映体(d-薄荷醇、l-薄荷醇)为先导化合物合成其脂肪酸酯衍生物:薄荷醇庚酸酯(l-M-HEP,d-M-HEP)、薄荷醇癸酸酯(l-M-DEC,d-M-DEC)、薄荷醇月桂酸酯(l-M-DOD,d-M-DOD)、薄荷醇十四酸酯(l-M-TET,d-MTET)、薄荷醇油酸酯(l-M-OA,d-M-OA)及薄荷醇硬脂酸酯(l-M-STE,d-M-STE)。在肉豆蔻酸异丙酯(IPM)系统中,只有癸酸薄荷醇酯(l-M-DEC,d-M-DEC)和月桂酸薄荷醇酯(l-M-DOD、d-M-DOD)对META有显著的促透作用(P<0.05);而制成压敏胶型贴剂后,手性薄荷醇酯衍生物对META促透作用排序:l-M-DEC>d-M-DOD≈l-M-DOD>d-M-DOD。结论手性薄荷醇酯衍生物作为促透剂(penetration enhancers,PE)在不同系统对META的促透能力不同。
Objective To investigate the penetration effects of chiral O-acylmenthol ester derivatives,on permeation behavior of metoprolol(META) in the isopropyl myristate(IPM) system and the dug in adhesive(DIA) patches. Methods The in vitro percutaneous permeability test was carried out with two-chamber cells and excised rabbit skin. Results To develop more effective compounds as penetration enhancers,chiral O-acylmenthol ester derivatives including 2-isopropyl-5-methylcyclohexyl heptanoate(l-M-HEP,d-M-HEP), 2-isopropyl-5-methylcyclohexyl decanoic(l-M-DEC, d-M-DEC), 2-isopropyl-5-methylcyclohexyl lauricate(l-M-DOD,d-M-DOD),2-isopropyl-5-methylcyclohexyl myristic(l-M-TET,d-M-TET),2-isopropyl-5-methylcyclohexyl oleic(l-M-OA,d-M-OA) and 2-isopropyl-5-methylcyclohexyl stearic(l-M-STE,d-M-STE) were synthesized from menthol(l-menthol,d-menthol) and fatty acid. The results of in vitro permeation experiment showed that penetration enhancers including l-M-DEC,d-M-DEC and l-M-DOD,d-M-DOD had significant enhancing effects on the penetration of META compared with control check(P < 0. 05). In the DIA patches only l-M-DEC and d-M-DEC could promote the penetration activity compared with control check(P < 0. 05) and the promoting effects are ordered as l-M-DEC > d-M-DOD ≈l-M-DOD > d-M-DOD. Conclusions The effects of different chiral O-acylmenthols ester derivatives as penetration enhancers on the percutaneous permeability of META in the various systems are different.
关键词(KeyWords)：
手性薄荷醇酯衍生物;美托洛尔碱;经皮渗透;促透剂
chiral O-acylmenthol ester derivatives;metoprolol;percutaneous permeability;penetration enhance
基金项目(Foundation): 国家自然科学基金资助项目(81603039);; 河北省自然科学基金石药联合基金资助项目(H2013209098);; 华北理工大学国家基金培育项目(GP201519)
作者(Author):
王天涯,王春艳,李杨,赵利刚,韩刚
WANG Tianya,WANG Chunyan,LI Yang,ZHAO Ligang,HAN Gang
DOI: 10.14066/j.cnki.cn21-1349/r.2018.03.001
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