盐酸地芬尼多渗透泵制剂的研究

发布时间：2018-01-18 10:22

本文关键词：盐酸地芬尼多渗透泵制剂的研究　出处：《南方医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：盐酸地芬尼多是目前治疗眩晕症常用的药物之一,具有减弱前庭刺激、抑制迷路功能、抑制恶心和呕吐在延髓化学感受性触发区及改善椎动脉血流量等药理特点,还有较弱抗胆碱作用。被广泛用于抗眩晕和止吐,临床主要用于运动病或中耳及内耳眩晕病所致眩晕。也适用于抗肿瘤药物、麻醉、射线照射等导致的恶心呕吐。目前,已有盐酸地芬尼多普通片剂上市,临床疗效确切。但由于其生物半衰期较短,约为3-4h,为维持药物治疗浓度,需日服3次,频繁的给药方式不仅造成患者的顺服性下降,而且导致血药浓度出现谷峰现象。本课题以盐酸地芬尼多为模型药物,分别制备了单层和双层渗透泵制剂,对二者的制剂处方、制备工艺和体外释放行为进行考察。并进行了盐酸地芬尼多双层渗透泵片的处方优化和制剂稳定性进行研究。本课题选取氯化钠和不同分子量的聚氧乙烯(PEO)用作片芯主辅料,聚乙二醇(PEG)和醋酸纤维素(CA)选作包衣材料,丙酮为有机包衣溶媒,制备盐酸地芬尼多双层渗透泵片。采用FDA推荐的f2相似因子法作为释放度评价指标,研究其片芯处方、包衣工艺、体外释放条件等对释药行为的影响。通过单因素考察,找出对12小时内体外累积释放度(Y1)和曲线拟合度(Y2)影响较为显著的因素:助推层PEO含量(A)、含药层氯化钠含量(B)及包衣增重(C)。将以上三个因素作为自变量,以12h累积释放度和释放曲线的拟合度为考察因变量,采用Box-Behnken设计-效应面法,进行三因素三水平的优化实验。得到优化处方,并按照最佳处方进行验证。试验结果显示,实际测得值与软件优化值基本一致,差异较小,优化处方制得的盐酸地芬尼多双层渗透泵片的体外释药曲线符合零级模型(r=0.9901),重现性好。本课题还对盐酸地芬尼多单层渗透泵片进行了初步单因素研究,对载药量、渗透压促进剂、包衣增重等影响释药行为的因素进行研究。最后,本文考察了自制盐酸地芬尼多双层渗透泵片的稳定性,影响因素实验表明:该制剂在置于60℃和4500Lx光照条件下10天后稳定,而在RH92.5%放置10天后,释药孔中有内容物流出,表明本制剂对湿度较敏感,因此应选择密封性能较好的包装材料。加速试验结果表明:在40℃、相对湿度75%的条件下,对模拟上市包装的三批样品进行加速试验,各项考察指标3个月内均在正常范围内,未见异常变化,后续试验正在进行中。长期试验结果表明:在25℃、相对湿度60%条件下,对模拟上市包装的三批样品进行长期试验,各项考察指标3个月内未见明显变化,后续试验正在进行中。
[Abstract]:Finney hydrochloride in the treatment of vertigo is one of the drugs commonly used at present, has weakened the vestibular stimulation, inhibition of the lost function, inhibition of nausea and vomiting in the medullary chemoreceptor trigger zone and improve the blood flow of vertebral artery and other pharmacological characteristics, and weaker anticholinergic effects. Widely used in anti vertigo and vomiting, clinical mainly for motion sickness or the middle ear and inner ear vertigo caused by vertigo. Also suitable for anticancer drugs, anesthesia, nausea and vomiting caused by irradiation. At present, the existing Finney hydrochloride ordinary tablets listed, clinical curative effect. But because of its biological half-life is short, about 3-4h, in order to maintain the concentration of drug therapy, need to take 3 days second, frequent administration not only cause compliance in patients with decreased, and cause the blood concentration of Gu Feng phenomenon. This subject to Finney hydrochloride as a model drug, were prepared by the single-layer and double-layer osmotic pump Preparation of the two formulation, preparation and in vitro release behavior were investigated. And the study optimized the prescription and preparation stability of multi bi layer osmotic pump tablets hydrochloride Finney. The study chooses sodium chloride and different molecular weight polyethylene (PEO) as core materials, polyethylene glycol (PEG) and cellulose acetate (CA) is selected as the coating materials and acetone as the organic solvent coating, preparation of Finney multi bi layer osmotic pump tablets. Recommended by FDA F2 similarity factor method as the evaluation index of the release, tablet formulation, coating process, effect of in vitro release conditions on drug release behavior. Through single factor within 12 hours of investigation, find out the in vitro cumulative release (Y1) and curve fitting (Y2) factors are significant: push layer PEO content (A), containing layer of sodium chloride content (B) and the coating weight (C). The above three factors as independent variable The amount, accumulative release rate and release curve fitting as the dependent variable in 12h, using Box-Behnken design and response surface method were optimized, three factors and three levels. The optimized formulation, and verified in accordance with the best prescription. The test results show that the actual measured values are basically the same, and software optimization difference optimized formulation of hydrochloric acid to Finney bi layer osmotic pump tablets in vitro release curve with zero order model (r=0.9901), with good reproducibility. This article also investigates the hydrochloride osmotic pump tablets Finney monolayer conducted a preliminary study of single factor, on drug loading, osmotic pressure accelerant, factors of coating weight etc. effect of drug release behavior. Finally, this paper examines the stability of self-made hydrochloride Finney bi layer osmotic pump tablets, showed that the experimental factors: the preparation in 60 C and 4500L light stable after 10 days under the conditions in the RH92.5% After 10 days, the drug release hole in content, indicating that the preparation is sensitive to humidity, so we should choose the good sealing performance of packaging materials. The results show that the acceleration test at 40 degrees C and 75% relative humidity conditions, the simulation of listed packaging in three batches of accelerated test, each index of 3 months were within the normal range, no abnormal changes, subsequent trials are underway. The long-term test results show that: in the 25 degrees, 60% relative humidity conditions, long-term simulation test on listed packaging three batch samples, significant changes in each index within 3 months no subsequent trials are ongoing.

【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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