發(fā)布時間：2019-03-16 11:22

【摘要】：目的化學(xué)促透法是經(jīng)皮給藥系統(tǒng)應(yīng)用最廣泛、最有效的促透方法之一,但理想的促透劑少之又少。本研究對手性促透劑對映體l-薄荷醇(l-M)和d-薄荷醇(dM)進行結(jié)構(gòu)改造,旨在尋找出較改造前更高效、安全及不易揮發(fā)的手性促透劑。方法以l-M和d-M與不同脂肪酸合成手性薄荷醇酯類衍生物,用1H-NMR和MS確定其結(jié)構(gòu)。以美托洛爾(META)、氟比洛芬(FP)兩種藥物為模型藥物,手性薄荷醇酯類衍生物為促透劑,分別在肉豆蔻酸異丙酯(IPM)系統(tǒng)及壓敏膠分散型(DIA)貼劑中對模型藥物進行促透效果評價,篩選出具有顯著促透效果的促透劑。采用家兔同體左右側(cè)自身對照法進行單次皮膚刺激和多次皮膚刺激,對其進行皮膚刺激性評價。結(jié)果1以l-M和d-M及不同的脂肪酸為原料,合成了12種薄荷醇酯類衍生物: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對薄荷醇酯進行結(jié)構(gòu)確證。2部分薄荷醇酯類衍生物在肉豆蔻酸異丙酯(IPM)系統(tǒng)和壓敏膠(DIA)貼劑中使META及FP的累積透過量與對照組相比顯著性增加。壓敏膠(DIA)貼劑中:對于META,l-M-DEC最顯著,累積透過量的促透比值(ER)為1.83;對于FP,d-M-TET最顯著,累積透過量的促透比值(ER)為2.33。3皮膚刺激性實驗中,l-M-DEC、d-M-TET作為促透劑未出現(xiàn)紅斑、水腫等過敏反應(yīng)。結(jié)論手性薄荷醇酯類衍生物作為一類新型促透劑,在IPM系統(tǒng)及壓敏膠貼劑中可促進模型藥物META及FP的透皮吸收。手性薄荷醇酯作為促透劑存在最優(yōu)疏水鏈長度和最佳促透濃度,對于META,5%(w)的l-M-DEC促透效果最佳,而對于FP,3%(w)的d-M-TET促透效果最佳。并對兩種促透劑進行皮膚刺激性試驗,證明其作為促透劑對皮膚無刺激性。
[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.
【學(xué)位授予單位】：華北理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943

【參考文獻】

相關(guān)期刊論文 前10條

1 俞文英;榮毅;郭霞;葉金翠;;萜烯類手性促進劑對氟比洛芬經(jīng)皮滲透對映體選擇性的影響[J];中國醫(yī)院藥學(xué)雜志;2015年06期

2 趙利剛;李燕;呂立勛;趙琳琳;;鹽酸司來吉蘭壓敏膠分散型貼劑的制備及質(zhì)量評價[J];中國醫(yī)藥工業(yè)雜志;2014年05期

3 孟楠;;布洛芬微乳的制備及其透皮吸收探討[J];中國藥物經(jīng)濟學(xué);2014年03期

4 高媛媛;孔明;程曉杰;王志國;陳西廣;;載MD-CPT透明質(zhì)酸納米微乳經(jīng)皮給藥作用于瘢痕修復(fù)的研究[J];生物化學(xué)與生物物理進展;2014年02期

5 孔明;程曉杰;陳西廣;;經(jīng)皮給藥中納米制劑與皮膚的質(zhì)構(gòu)效關(guān)系[J];生物化學(xué)與生物物理進展;2013年10期

6 王佳;戴鼎震;;薄荷醇對經(jīng)皮給藥后皮膚角質(zhì)層的結(jié)構(gòu)觀察[J];金陵科技學(xué)院學(xué)報;2013年03期

7 王佳;孫靜靜;陳俊紅;戴鼎震;;冰片和薄荷醇對伊維菌素體外透皮效果的研究[J];安徽農(nóng)業(yè)科學(xué);2013年27期

8 杜麗娜;金義光;;經(jīng)皮給藥系統(tǒng)研究進展[J];國際藥學(xué)研究雜志;2013年04期

9 趙利剛;李燕;方亮;呂立勛;趙琳琳;;托特羅定壓敏膠分散型貼劑在大鼠體外/內(nèi)的透過性評價[J];中國醫(yī)藥工業(yè)雜志;2013年06期

10 盛平;張瑞濤;王暉;黃釗;傅曉華;;地西泮在體鼻腔吸收動力學(xué)及薄荷醇對其吸收促進作用的研究[J];中國醫(yī)院用藥評價與分析;2013年05期

相關(guān)博士學(xué)位論文 前3條

1 陳陽;不飽和薄荷醇類似物脂肪酸酯類兩親性經(jīng)皮吸收促進劑促透活性研究[D];沈陽藥科大學(xué);2014年

2 王曼力;香芹醇酯類衍生物經(jīng)皮促透作用及其可逆性評價[D];沈陽藥科大學(xué);2013年

3 趙利剛;新型薄荷醇酯類衍生物經(jīng)皮促透作用評價及其促透機理的初步研究[D];沈陽藥科大學(xué);2009年

，

本文編號：2441232