洛索洛芬钠渗透泵型控释片的研究 硕士论文.doc
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1、 单位代码: 10369 学 号: 20070110 2010届硕士研究生学位论文洛索洛芬钠渗透泵型控释片的研究STUDY ON LOXOPROFEN SODIUM OSMOTIC PUMP CONTROLLED RELAESE TABLETS学科专业 药 剂 学 研究方向 药物新技术与新剂型 导 师 王 成 永 教 授 硕 士 生 杨 甜 2010年4月合肥目 录中文摘要 1英文摘要 3英文缩略词 5前言 6第一章 处方前研究及体外分析方法的建立1 仪器与试药 132 方法与结果 132.1 处方前研究 132.1.1 洛索洛芬钠的溶解度132.1.2 洛索洛芬钠在不同释放介质中的稳定性14
2、2.1.3 表观油水分配系数的测定142.2 含量测定方法的建立152.2.1 检测波长的确定152.2.2 色谱条件与系统适应性162.2.3 洛索洛芬钠对照品溶液的制备172.2.4 标准曲线的制备172.2.5 精密度试验182.2.6 稳定性试验192.2.7 重复性试验192.2.8 回收率试验202.2.9 洛索洛芬钠渗透泵片的含量测定202.3 释放度测定方法的建立212.3.1 检测波长的确定212.3.2 标准曲线的制备222.3.3 精密度试验222.3.4 释放介质中的稳定性232.3.5 回收率试验232.3.6 释放度测定方法243 讨论 244 小结 25第二章 洛
3、索洛芬钠渗透泵型控释片制备工艺的研究1 仪器与试药 262 方法与结果 262.1 洛索洛芬钠渗透泵型控释片的制备工艺及工艺流程图 262.1.1 制备工艺262.1.2 工艺流程图272.2 洛索洛芬钠渗透泵型控释片的单因素考察272.2.1 片芯处方的单因素考察272.2.2 包衣液处方的单因素考察322.2.3 体外释放条件对药物释放的影响362.3 正交试验优化处方382.4 处方的确定402.5 处方与工艺重复性考察412.6 释药曲线的拟合412.7 释药机理的初步研究423 讨论 424 小结 44第三章 洛索洛芬钠渗透泵型控释片的质量控制及稳定性研究1 仪器与试药 452 方法
4、与结果 452.1 外观性状452.2 释放度检查462.2.1 方法学考察462.2.2 释放曲线的绘制462.2.3 释放度限度的确定462.3 样品的含量测定及其限度462.4 有关物质分析方法的建立472.4.1 色谱条件472.4.2 最低检测限和定量限的确定472.4.3 降解产物对主药测定的影响472.4.4 洛索洛芬钠渗透泵型控释片有关物质检查482.5 洛索洛芬钠渗透泵型控释片初步稳定性研究482.5.1 考察项目与检测方法482.5.2 影响因素试验492.5.3 加速试验503 讨论 514 小结 52第四章 洛索洛芬钠渗透泵型控释片在大鼠体内初步药动学研究 1 仪器与试
5、药 532 方法与结果 532.1 受试制剂与参比制剂532.2 实验动物532.3 给药方案及血样采集532.4血浆样品的处理和测定542.5 体内分析方法的建立542.5.1 色谱条件542.5.2 方法的专属性542.5.3 标准曲线的制备552.5.4 精密度试验562.5.5 样品回收率试验562.5.6 血浆样品稳定性考察572.6 血药浓度测定结果582.7 相对生物利用度613 讨论 614 小结 62全篇小结 63参考文献 64综述 68个人简历 80致谢 81洛索洛芬钠渗透泵型控释片的研究中文摘要洛索洛芬钠(loxoprofen sodium)为苯丙酸类非甾体抗炎药,具有起
6、效迅速,抗炎强效且均衡,胃肠道刺激小的特点,临床上广泛用于治疗慢性风湿性关节炎、类风湿性关节炎、骨性关节炎、变形性关节炎、腰疼等。目前,洛索洛芬钠已上市的品种有普通片、分散片、口腔速崩片、颗粒剂、胶囊剂、贴剂。国内尚未见自主研制的缓控释制剂上市。将洛索洛芬钠制成渗透泵型控释片能够在一定时间范围内以恒定的释药速度释放出一定量的治疗药物,可以减少给药次数和保持平稳的血药浓度,为病人提供一种相比较而言较为安全、方便的服药方式。本文建立了紫外分光光度法用于渗透泵片释放度的测定,建立了高效液相色谱法用于渗透泵片含量测定和体内血药浓度的检测。以上分析方法准确可靠、方便快捷,满足分析要求。本文在充分考察药物
7、及各种辅料性质的基础上,以氯化钠、羟丙甲基纤维素K4M(HPMC K4M)、乳糖为片芯组成,以醋酸纤维素(CA)丙酮溶液、邻苯二甲酸二丁酯(DBP)和聚乙二醇400(PEG400)为包衣材料,制备了洛索洛芬钠渗透泵型控释片(loxoprofen sodium osmotic pump controlled release tablets)。从片芯处方、包衣液处方、体外释放条件等因素对洛索洛芬钠渗透泵型控释片的释药行为进行了单因素考察。在单因素考察及因素筛选的基础上,采用综合评分法,通过正交试验,优化处方。结果显示,优化的处方在12小时内呈零级释药特征,释药较完全,批间重现性良好。为控制渗透泵型
8、控释片的质量,根据洛索洛芬钠的理化性质和渗透型控释片的制剂特点,建立了本品的释放度、有关物质、含量的测定方法。结果显示方法准确、可行,能有效控制产品的质量,为制定该制剂的质量标准提供了一定的依据。参照药物稳定性试验指导原则的要求,以外观、释放度、含量、有关物质等项目作为考察指标,对洛索洛芬钠渗透泵型控释片进行影响因素试验(4500lx光照、60 高温及RH 92.5 %高湿)和加速试验。试验结果显示,各项考察指标在上述试验过程中均未发生明显变化,证明该制剂稳定性良好,本品的制备工艺研究和质量标准研究合理、方法可行。本文以市售普通片作为对照,对洛索洛芬钠渗透泵型控释片进行了药动学研究。利用高效液
9、相色谱法对体内血药浓度进行测定,两种制剂的峰浓度(Cmax)分别为8.37、23.45g/ml,达峰时间(Tpeak)分别为6.031、0.753h,药时曲线下面积(AUC)分别为62.197、54.936g/mlh,其相对生物利用度为113.22%。结果表明,自制渗透泵片具有出峰时间晚、峰值低、血药浓度平稳的特征。关键词:洛索洛芬钠;渗透泵型控释片;质量标准;药代动力学83洛索洛芬钠渗透泵型控释片的研究AbstractLoxoprofen sodium is a styrene-acrylic acid non-steroidal anti-inflammatory drugs with r
10、apid onset, potent anti-inflammatory and balanced, gentle stimulation of the gastrointestinal tract, which is widely used in clinical treatment of chronic rheumatismarthritis, rheumatoid arthritis, osteoarthritis, deformation arthritis, back pain and so on. Currently, loxoprofen sodium varieties hav
11、e been listed ordinary tablets, dispersible tablets, oral fast disintegrating tablets, granules, capsules, paste table.China has not yet independently developed controlled release formulations on the market.Made of the osmotic pump loxoprofen sodium controlled release tablet, it can release a consta
12、nt drug release rate of a certain amount of therapeutic drugs within a certain time, which can reduce injecting times and maintain a stable blood concentration,To provide a comparison of patients is more safe and convenient way of taking medicine.It was established by UV spectrophotometry for the os
13、motic pump tablets release test, high performance liquid chromatography (HPLC) for the determination of osmotic pump tablet and the blood concentration of the test.The above analysis method is accurate, convenient, meet the analysis requirements.On the basis of investigating the characters of loxopr
14、ofen sodium and various ingredients, useing sodium chloride, HPMC K4M, lactose-chip core, with cellulose acetate (CA) acetone, dibutyl phthalate(DBP) and polyethylene glycol 400(PEG400) for the coating material, prepared loxoprofen sodium osmotic pump controlled release tablets. For core with a slic
15、e prescription, clothing membrane prescription, in vitro release conditions as factors, loxoprofen sodium on osmotic pump tablets with drug release by the single factors studied. To single factor and factor-based screening, with integrated rate method, the orthogonal experimental design, optimizatio
16、n prescription.The results show that optimization of prescription drug release characteristics were zero-order in 12h, a more complete drug release, a good batch repeatability.According to the physico-chemical property of loxoprofen sodium and characteristic of osmotic pump tablets preparation, the
17、drug release rate, related substances and content, which were the quality controls of loxoprofen sodium osmotic pump tablets. The result showed that the method was accurate and feasible, which provide some reference for quality control of loxoprofen sodium osmotic pump tablets. Referencing guidance
18、principles of investigation on drug stability, the stability test of loxoprofen sodium osmotic pump tablets were carried(4500 lx strong-light test, 60 high-temperature test, RH92.5 % high-humidity test)by inspection of the character, drug release, related substance, content examination and so on. An
19、d then the acceleration test was carried on. The results indicated that loxoprofen sodium osmotic pump tablets were stable, nearly without any quality changes during the stability study. The preparation procedure and the quality control standard were reasonable and feasible.With the commercial loxop
20、rofen sodium tablets as the reference, the pharmacokinetics was studied by self-prepare loxoprofen sodium osmotic pump tablets. HPLC was employed to detect the loxoprofen sodium concentration in blood plasma. Two preparations of peak concentration (Cmax) were 8.37g/ml and 23.45g/ml, peak time (Tpeak
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