【作者】 刘秀洁；

【导师】 崔景斌；

【作者基本信息】 华东理工大学 ， 制药工程与技术， 2012， 硕士

【摘要】 双氯芬酸钠(DCS)是世界上使用最广泛的非甾体抗炎药之一。但其半衰期短,且存在明显的胃肠刺激、造成胃肠紊乱及溃疡等问题。为更好的发挥其药效,减少不良反应,延长作用时间,实验将DCS制成一种交联型巴布剂。本研究建立了DCS溶液的紫外分光光度测定法,该法准确可靠,操作方便快捷。考察不同介质中DCS的溶解度,并测定其油水分配系数,为实验设计和分析提供理论依据。通过对处方基质的筛选,最终选择部分中和的聚丙烯酸钠NP700为巴布剂基质骨架材料,卡波姆980和羧甲基纤维素钠(CMC-Na)为增粘剂,甘羟铝为交联剂,高岭土为填充剂,甘油为保湿剂,EDTA为交联调节剂,PEG400为消泡剂。通过单因素考察及正交试验法,以初粘力、持粘力和感官评价作为综合指标,优化巴布剂处方。采用Franz扩散池和离体小鼠皮肤,以促渗倍数和时滞为考察指标,研究DCS体外透皮扩散动力学行为。实验考察基质pH值以及几种促渗剂对DCS巴布剂体外透皮行为的影响。结果表明,DCS在pH6.5较pH5.5透皮速率低；与空白对照组相比,吐温80无明显促渗效果,氮酮促渗效果较小且时滞长,油酸、薄荷醇与冰片在浓度分别为3%、3%和1%促渗效果显著。经二元联合促渗研究,选择3%薄荷醇和1%冰片作为DCS的促渗剂。自制DCS巴布剂质量评价表明,巴布剂膏体外观、赋形性、含膏量、初粘力、皮肤追随性和膜残留量均符合要求,三个月的加速试验表明巴布剂性质稳定。体外释放研究表明DCS呈Higuchi模型释放,体外透皮速率为110.55μg·cm-2·h-1,12h累积透过率为38.86%。自制DCS巴布剂家兔体内药动学研究表明,DCS透皮效果好,生物利用度高,相对生物利用度为150.30%,且与体外透皮效果相关性良好。更多还原

【Abstract】 Diclofenac sodium, a kind of widely used nonsteroidal antiinflammatory drugs, has a lot of problems, such as having a short biologic half-life, stimulating gastrointestinal tract, causing gastrointestinal disorder, and gastric ulcer. In order to bring its effect into full play, reduce adverse effects, prolong its effect time, the study developed a kind of cross-linking cataplasm of DCS.Firstly, a method for analyzing DCS content with UV spectrophotometry was proposed. This method was accurate, reliable and easy to operate. Some physic-chemical properties of DCS were determined, such as the solubility in different mediums, oil-water partition coefficient. This research provided theory basis for the design and analysis during this study.With selection of each element, choosing sodium polyacrylate NP700 as framework material of cataplasm, Carbopol 980 and CMC-Na as tackifiers, dihydroxyaluminium aminoacetate as cross-linking agent, kaolin as filler, glycerol as humectant, EDTA as cross-linking regulator, PEG400 as defoaming agent. The single factor test and orthogonal test were used to design formulations with tacking strength, holding strength and sensory evaluation as comprehensive indicators.An improved Franz diffusion cell and excised mouse skin were applied, preliminarily studying percutaneous absorption of DCS with different pH and penetration enhancers in vitro with the enhancing rate and lag time as the indicators. The result showed that percutaneous rate of DCS at pH 6.5 was lower than pH 5.5. Compared with the blank group, tween 80 had no significant permeation effect on DCS; azone had a slight effect with longer lag time; oleic acid, menthol and borneol had significant effect on DCS with the content of 3%,3% and 1%, respectively. The result of joint effect of two kinds of penetration enhancers showed that 3% menthol and 1% borneol had the most significant effect.The result of quality evaluation showed that DCS cataplasm developed met the requirements in appearance, formability, ointment content, tacking strength, adhesion, residue and stability with accelerated test for three months. The drug release characteristic of DCS in vitro coincided with the Higuchi model; the percutaneous rate was 110.55μg·cm-2·h-1, and accumulated transmission rate was up to 38.86% for 12h. The research of pharmacokinetics of DCS cataplasm in rabbits showed that the relative bioavailability was 150.30%. And the transmission of DCS in vitro was well correlative with the absorption fraction in vivo.更多还原