手性薄荷醇酯的制备及其促透活性评价

发布时间：2019-03-16 11:22

【摘要】：目的化学促透法是经皮给药系统应用最广泛、最有效的促透方法之一,但理想的促透剂少之又少。本研究对手性促透剂对映体l-薄荷醇(l-M)和d-薄荷醇(dM)进行结构改造,旨在寻找出较改造前更高效、安全及不易挥发的手性促透剂。方法以l-M和d-M与不同脂肪酸合成手性薄荷醇酯类衍生物,用1H-NMR和MS确定其结构。以美托洛尔(META)、氟比洛芬(FP)两种药物为模型药物,手性薄荷醇酯类衍生物为促透剂,分别在肉豆蔻酸异丙酯(IPM)系统及压敏胶分散型(DIA)贴剂中对模型药物进行促透效果评价,筛选出具有显著促透效果的促透剂。采用家兔同体左右侧自身对照法进行单次皮肤刺激和多次皮肤刺激,对其进行皮肤刺激性评价。结果1以l-M和d-M及不同的脂肪酸为原料,合成了12种薄荷醇酯类衍生物:薄荷醇油酸酯(l-M-OA、d-M-OA)、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-MDOD)、薄荷醇十四酸酯(l-M-TET、d-M-TET)及薄荷醇硬脂酸酯(l-M-STE、d-M-STE)。利用1HNMR和MS对薄荷醇酯进行结构确证。2部分薄荷醇酯类衍生物在肉豆蔻酸异丙酯(IPM)系统和压敏胶(DIA)贴剂中使META及FP的累积透过量与对照组相比显著性增加。压敏胶(DIA)贴剂中:对于META,l-M-DEC最显著,累积透过量的促透比值(ER)为1.83;对于FP,d-M-TET最显著,累积透过量的促透比值(ER)为2.33。3皮肤刺激性实验中,l-M-DEC、d-M-TET作为促透剂未出现红斑、水肿等过敏反应。结论手性薄荷醇酯类衍生物作为一类新型促透剂,在IPM系统及压敏胶贴剂中可促进模型药物META及FP的透皮吸收。手性薄荷醇酯作为促透剂存在最优疏水链长度和最佳促透浓度,对于META,5%(w)的l-M-DEC促透效果最佳,而对于FP,3%(w)的d-M-TET促透效果最佳。并对两种促透剂进行皮肤刺激性试验,证明其作为促透剂对皮肤无刺激性。
[Abstract]:Aim Chemical penetration method is one of the most widely used and effective methods in percutaneous drug delivery system, but there are few ideal transdermal agents. In this study, the enantiomers of enantiomeric l-menthol and d-menthol (dM) were modified to find a more efficient, safe and non-volatile chiral enhancer than that of the pre-modified enantiomers, l-menthol (l-menthol) and d-menthol (d-menthol). Methods Chiral menthol ester derivatives were synthesized with different fatty acids, and the structures of chiral menthol esters were determined by 1H-NMR and MS. Using metoprolol (META), flurbiprofen (FP) as model drug and chiral menthol ester derivatives as transmissive agents, The model drugs were evaluated in isopropyl myristic (IPM) system and pressure sensitive adhesive dispersible (DIA) patch respectively, and the translucent promoters with remarkable penetration promoting effect were screened out. Single skin stimulation and multiple skin stimulation were performed in rabbits by the same-sided and left-right auto-control method, and the skin irritation was evaluated. Results 1Twelve menthol esters derivatives were synthesized from lm, dm, and different fatty acids: menthol oleate (1), menthol heptate (1), and their derivatives were menthol oleate (1), menthol heptate (1), and menthol heptate (1), which were synthesized from different fatty acids, and 12 kinds of menthol esters were synthesized. Menthol decanoate (dm DEC), menthol lauric acid ester (dMDOD), menthol tetra-ester (dm Tet) and menthol stearic acid ester (lm m stearate), and menthol stearic acid ester (MSTE) and menthol decanoate (dm DEC), menthol lauric acid ester (dMDOD), menthol tetraester (dm) and menthol stearate (LMSTE), D-M-STE) The structure of menthol ester was confirmed by 1HNMR and MS. The cumulative permeability of META and FP in isopropyl myristic (IPM) system and pressure sensitive adhesive (DIA) patch increased significantly compared with the control group. Pressure sensitive adhesive (DIA) patch: for META,l-M-DEC is the most significant, cumulative permeability ratio of (ER) is 1.83; For FP,d-M-TET, the ratio of cumulative permeability to permeability (ER) was 2.33.3 in the skin irritation test. As a transdermal enhancer, there were no allergic reactions such as erythema, edema and so on. Conclusion Chiral menthol ester derivatives, as a new type of transdermal enhancer, can promote the transdermal absorption of model drugs META and FP in IPM system and pressure sensitive adhesive. The chiral menthol ester has the best hydrophobic chain length and the best transmissibility concentration as a transmissive agent, which is the best for l-M-DEC of META,5% (w) and the best for d-M-TET of FP,3% (w). The skin irritation test of two kinds of transdermal enhancers proved that they were non-irritating to the skin as a transdermal enhancer.
【学位授予单位】：华北理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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