【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(duì)手性促透劑對(duì)映體l-薄荷醇(l-M)和d-薄荷醇(dM)進(jìn)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(duì)模型藥物進(jìn)行促透效果評(píng)價(jià),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(duì)照法進(jìn)行單次皮膚刺激和多次皮膚刺激,對(duì)其進(jìn)行皮膚刺激性評(píng)價(jià)。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(duì)薄荷醇酯進(jìn)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(guò)量與對(duì)照組相比顯著性增加。壓敏膠(DIA)貼劑中:對(duì)于META,l-M-DEC最顯著,累積透過(guò)量的促透比值(ER)為1.83;對(duì)于FP,d-M-TET最顯著,累積透過(guò)量的促透比值(ER)為2.33。3皮膚刺激性實(shí)驗(yàn)中,l-M-DEC、d-M-TET作為促透劑未出現(xiàn)紅斑、水腫等過(guò)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(jìn)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(zhǎng)度和最佳促透濃度,對(duì)于META,5%(w)的l-M-DEC促透效果最佳,而對(duì)于FP,3%(w)的d-M-TET促透效果最佳。并對(duì)兩種促透劑進(jìn)行皮膚刺激性試驗(yàn),證明其作為促透劑對(duì)皮膚無(wú)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(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943

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本文編號(hào)：2441232