【作者】 崔颖；

【导师】 张韻慧；

【作者基本信息】 天津大学 ， 应用化学， 2008， 博士

【摘要】 经皮给药系统具有能够回避肝脏首过效应,药物释放平稳,给药方便的特点,目前不断有成熟产品上市。但是具有适宜的油水分配系数和较低的给药剂量药物通过经皮给药途径才能够达到体内有效药物浓度。盐酸普萘洛尔由于具有高度水溶性和较高的治疗剂量被选定为模型药物。萜类是目前公认的安全有效促渗剂,尤其是对于水溶性化合物。本文首先考察了不同结构(醚类、单环单萜、双环单萜和倍半萜)代表萜类促渗剂对盐酸普萘洛尔透皮性质的影响。实验选用的萜均能显著增加药物透皮速率、减少迟滞时间。进一步研究表明,上述萜能够不同程度增加药物角质层分配系数、改善角质层脂质流动性,对于脂质含量却没有影响。活化能实验结果表明,桉树脑和薄荷醇显著减小模型药物透皮活化能,薄荷醇与对照组比较没有显著差异,冰片、樟脑和红没药醇存在下,药物的透皮活化能显著增加。通过混合油相法确定了两个系统盐酸普萘洛尔微乳制剂的组成成分,并分别对两个系统进行相图绘制。根据相图特点,分别对两个系统采用单纯形网格法和单因素轮换法进行优化。优化结果:系统1为水19%,苯甲醇40%,吐温20 28%,丙二醇12%,系统2为水12.64%,油酸55.28%,吐温80 15.79%,乙醇15.79%。两系统均有良好的稳定性。由于系统2优化微乳具有更高的透皮速率(41.01μg/cm2h),因此对其进行离子对、角质层含水量、萜类促渗剂和增稠剂因素对透皮性质考察。离子对中,对硝基苯甲酸对优化微乳增渗作用显著。通过适量添加胆固醇不仅改变角质层含水量,增加优化微乳的透皮速率,同时使药物透皮吸收更加平稳。5%薄荷醇对微乳透皮速率影响大于离子对等因素。在使用薄荷醇基础上,增稠剂中aerosil200能够在不改变微乳结构情况下增加该制剂的黏度,结合体外实验确定用于体内实验微乳处方为油酸50.28%,吐温80 15.79%,乙醇15.79%,水12.64%,薄荷醇5.00%,在此基础上按重量添加aerosil200 5%。体内实验表明,微乳组较片剂组T1/2(Ke),Tpeak和MRT均显著提高,Cmax显著降低。这说明微乳组药物释放平稳,维持药效时间长,血药浓度波动小。本论文通过制备盐酸普萘洛尔的透皮微乳,解决了该药作为心血管药物在临床使用时存在的问题,提高了其在治疗过程中的安全性、有效性及患者的顺应性。更多还原

【Abstract】 Transdermal drug delivery system has characters as avoiding hepatic first pass effect, stability of drug release, convenience of drug administration, and mature products of this administration route were commercially available. But the drug having both appropriate oil/water partition coefficient and low daily dosage, can reach effective drug concentration in vivo through transdermal administration, for the reason of skin barrier.Hydrochloride propranolol was selected as the model drug for its water soluble character and high daily dosage. Terpenes were accepted commonly as safe and efficient transdermal enhancer, especially for that being hydrophilic. We studied effect of terpene enhancer with different structure on transdermal permeation profile of model drug. The results showed that all terpene selected enhanced transdermal permeation flux and decreased the lag time of hydrochloride propranolol. And further mechanism research showed that the terpenes increased SC partition coefficient of this drug, elevated fluidization of SC lipids, had no effect on lipids amount in SC. The results of activity energy calculation were abserved as that, compared with that of the control, cineol and menthanol decreased activity energy of model drug permeation, menthone didn’t change it, while bornel, camphor and bisaborlol increased activity energy.Two systems of microemulsion components were selected according to the results of solubility research of model drug in oil phase mixture, and the pseudo ternary phase diagram of them were draw. With characters of phase diagram, simplex lattice method and single factor alternative method were used to optimize formulation of microemulsion respectively. The results of optimization were like these showed as below. The optimized formulation of system1 was composed as that, water19%, benzoyl40%, tween20 28%, propranl glycol12%. The optimized formulation of system 2 was composed as that, water12.64%,oleic acid 55.28%,tween80 10.79%,ethanol10.79%. The optimized formula of both two system showed good stability. With the permeation flux into consideration, the optimized formula of system 2 were selected for further investigation, which were effect of ion pair, water content in SC, terpene concentration, rheology controller. Being the ion pair, o-nitro benzoic acid improved drug permeation flux significantly. The appropriate amount addition of cholesterol, which change water content in SC, increased not only permeation flux, but also the stability of drug release. And the extend of drug permeation enhancement by 5% menthanol was more significant than that by ion pair, water content in SC. aerosil200 increased the viscosity of optimized formula without change its microemulsion character. And the formula for in vivo investigation was designed as, oil acid 50.28%, tween 80 15.79%, ehtanol 15.79%, water12.64%,menthanol 5.00%,in which aerosil200 was added at 5% of components above(w/w).The results of research in vivo was showed that, compared with the tablet group, the T1/2(Ke),Tpeak and MRT were elevated significantly, and the Cmax was decreased in microemulsion group. The results illuminated that microemulsion prepared released drug stably, enlarged drug effect time and decreased fluctuant of blood-drug concentration.In this paper, we prepared transdermal microemulsion of hydrochloride propranolol, which is used as cardiovascular drug with some promble in clinical application. And the new route of administration improved safety, efficiency of the drug and compliance of patient更多还原