法莫替丁胃内黏附微球的研究

发布时间：2018-03-16 13:39

本文选题：法莫替丁　切入点：胃内黏附微球　出处：《山东大学》2014年硕士论文　论文类型：学位论文

【摘要】：法莫替丁(famotidine, Fam)为第3代H2受体拮抗剂,具有与H2受体结合选择性强、作用强的特点。临床上常用于治疗消化性溃疡,与同类药物西咪替丁和雷尼替丁相比,其作用效果分别是20倍和7.5倍。现已上市的剂型有片剂、口腔崩解片、口服混悬液、注射剂、散剂,以及与布洛芬的复方片剂。临床应用中存在的问题是,药物在胃内滞留时间短,胃壁细胞内蓄积量低,半衰期短、血药浓度波动大、药物的疗效不能充分发挥。由于法莫替丁是用于治疗胃部疾病且在胃内发挥疗效的药物,因此,临床上迫切需要能使法莫替丁在胃内滞留时间更长的制剂。本文使用胃黏附技术通过制备胃黏附微球,使药物能在胃中维持较长的作用时间,具有较好的应用前景。本文的主要工作是：(1)对法莫替丁的主要理化性质进行了测定,建立了胃黏附微球的质量评价方法；(2)采用乳化-溶剂蒸发法制备了法莫替丁胃黏附微球；(3)对黏附微球的黏附性能进行了研究；(4)在家兔体内进行了药动学实验,求得主要药动学参数,通过比较体外释放度和体内吸收的结果,对黏附微球的体内外相关性进行了评价。本文的主要研究方法是：(1)通过溶解度、油水分配系数的测定实验对法莫替丁的理化性质进行了探索；(2)通过建立线性关系、精密度试验、稳定性试验、回收率实验等,建立了含量测定和释放度测定方法；(3)通过单因素考察和正交实验设计实验,对黏附微球的处方进行了筛选与优化,并确立了最优的工艺与处方。(4)通过对同一释放曲线的不同数学模型(如零级、一级、Higuchi、Peppas)拟合,对微球的内在释放本质进行了探讨；(5)通过显微镜对微球表面形貌以及在介质中的表面形态进行了观察,还测定了粒度与粒度分布、圆整度、堆密度、休止角等理化指标,为微球的表观特征进行了表征；(6)采用固相萃取技术和外标法,通过高效液相色谱建立了药物血药浓度分析方法；采用两制剂两周期交叉实验设计方案在家兔体内进行了药动学实验,利用DAS2.0软件求出了主要药动学参数；利用药动学公式以及方差分析评价了生物等效性、体内外相关性,相对生物利用度等；(7)最后通过离体动物滞留实验、剪切力测量实验、分离力测量实验和体内滞留实验,对胃黏附微球的黏附性能进行了评价。本文的主要研究结果有：(1)法莫替丁随pH增大其溶解度逐步减小,油水分配系数逐渐增大；(2)在约266nm处,法莫替丁有最大紫外吸收,以pH4.5磷酸盐缓冲液作为介质,在2-20μg/ml范围内,精密度、回收率、线性关系等良好,适宜法莫替丁的含量测定；以pH1.0盐酸溶液作为介质,在4～～40μg/ml范围内,精密度、回收率、线性关系等良好,适宜法莫替丁的释放度测定；(3)以乙基纤维素为骨架材料,卡波姆934P为黏附材料,PEG6000为致孔剂、吐温80为乳化剂、液状石蜡为连续相,通过调节辅料适宜的比例,采用乳化-溶剂蒸发法,可制备出黏附性能较好的胃黏附微球；(4)胃黏附微球在pH1.0盐酸溶液介质中,其释药行为符合零级方程；(5)体内外的滞留实验表明,本制剂中卡波姆对黏附微球的黏附性能具有显著性影响。(6)家兔体内药动学研究表明,自制的黏附微球具有缓释、血药浓度平缓的特征；药物的体外释放和体内吸收存在相关性,可以用释放度预测体内的吸收过程；自制制剂的相对生物利用度约130%,与普通片相比,生物利用度具有显著性差异,且在胃内有较好的吸收。本文的研究结论：自制的法莫替丁胃黏附微球体外释放缓慢、可控,体内吸收和血药浓度平缓,生物利用度高,具有典型的胃内黏附特征,达到了预期设想。
[Abstract]:Famotidine (famotidine, Fam) as the third generation of H2 receptor antagonist, H2 receptor binding and has strong selectivity, strong characteristics. Clinically used in the treatment of peptic ulcer, and compared to similar drug cimetidine and ranitidine, its effect is respectively 20 times and 7.5 times. Now listed has tablet. Oral disintegrating tablets, oral suspension, injection, powder, and Ibuprofen Tablets. The existed problems in the clinical application of drugs in the stomach, the short retention time of gastric parietal cell volume is low, short half-life, blood concentration fluctuation, drug efficacy can not fully play. Because of famotidine is used for the treatment of stomach diseases and therapeutic effect of drug in the stomach, therefore, an urgent clinical need to enable the preparation of famotidine stays longer Ding in the stomach. In this paper, through the preparation of gastric adhesion microspheres using gastric adhesion, the medicine can be in The longer function time of the stomach is maintained, and it has a good prospect of application.
The main work of this paper is: (1) the main physicochemical properties of famotidine Ding were determined, the establishment of the quality evaluation method of gastric mucoadhesive microspheres; (2) famotidine gastric mucoadhesive microspheres were prepared by emulsion solvent evaporation method; (3) adhesion on the adhesion of microspheres was studied; (4) in rabbits by pharmacokinetic experiment, obtained the main pharmacokinetic parameters by comparing the in vitro release and in vivo absorption results in vivo correlation of mucoadhesive microspheres were evaluated.
The main research methods of this paper are: (1) through the experimental determination of solubility, oil-water partition coefficient on the physicochemical properties of famotidine Ding was explored; (2) through the establishment of a linear relationship, the precision test, stability test, recovery test, established the determination and dissolution determination method; (3) through single factor and orthogonal design experiments on the adhesion of microspheres prescription were screened and optimized, and the optimal prescription and technology. (4) through different mathematical models on the same release curve (such as zero level, Higuchi, Peppas) fitting, internal release nature of the microspheres. The discussion; (5) through the microscope on the surface morphology of microspheres in the medium and surface morphology were observed, the size and the size distribution was determined, roundness, bulk density, angle of repose and other physical and chemical indicators, as the apparent characteristics of microspheres were characterized; (6) The solid phase extraction technology and external standard method was established for determination of blood concentration of drugs by high performance liquid chromatography; the two agent two period crossover experimental design was carried out in vivo pharmacokinetic experiments, the main pharmacokinetic parameters by using DAS2.0 software; the pharmacokinetic formula and variance analysis and evaluation bioequivalence, in vivo correlation, relative bioavailability; (7) the in vitro animal experimental retention shear force measurement experiment, separation, measurement and retention test, adhesion of gastric mucoadhesive microspheres were evaluated.
The main results of this study are: (1) famotidine with pH increasing its solubility decreased gradually, oil-water distribution coefficient increased; (2) at around 266nm, famotidine maximum UV absorption in phosphate buffer pH4.5 as the medium, in the 2-20 g/ml range, precision, recovery rate a good linear relationship, etc., suitable for the determination of famotidine; with pH1.0 hydrochloric acid solution as medium in 4 ~ 40 g/ml range, precision, recovery rate, linear relationship is good, suitable for famotidine release determination; (3) using ethyl cellulose as matrix material, Carbopol 934P as adhesive material, PEG6000 as porogen, Twain 80 as the emulsifying agent and liquid paraffin as the continuous phase, by adjusting the proportion of appropriate accessories, by emulsion solvent evaporation method, can be prepared by gastric mucoadhesive microspheres good adhesion properties; (4) gastric mucoadhesive microspheres in pH1.0 hydrochloric acid medium, the The drug release behavior with zero order equation; (5) showed that the retention experiments in vitro and in vivo, has significant effect on the adhesion of Bohm card adhesion microspheres in this preparation. (6) the pharmacokinetics in rabbits showed that self-made sustained-release mucoadhesive microspheres, characteristics of gentle blood concentration; in vitro drug release and the correlation between in vivo absorption, absorption process can be used to predict in vivo release; preparation of the relative bioavailability of about 130%, compared with the ordinary tablet, bioavailability has significant differences, and better absorption in the stomach.
The conclusion of this study is that the self-made famotidine gastric adhesive microspheres can release slowly and in vitro, and has a high bioavailability and a typical gastric adhesion characteristics, which achieves the expected idea.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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