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  本文選題：法莫替丁　切入點：胃內(nèi)黏附微球　出處：《山東大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：法莫替丁(famotidine, Fam)為第3代H2受體拮抗劑,具有與H2受體結(jié)合選擇性強、作用強的特點。臨床上常用于治療消化性潰瘍,與同類藥物西咪替丁和雷尼替丁相比,其作用效果分別是20倍和7.5倍�，F(xiàn)已上市的劑型有片劑、口腔崩解片、口服混懸液、注射劑、散劑,以及與布洛芬的復(fù)方片劑。臨床應(yīng)用中存在的問題是,藥物在胃內(nèi)滯留時間短,胃壁細(xì)胞內(nèi)蓄積量低,半衰期短、血藥濃度波動大、藥物的療效不能充分發(fā)揮。由于法莫替丁是用于治療胃部疾病且在胃內(nèi)發(fā)揮療效的藥物,因此,臨床上迫切需要能使法莫替丁在胃內(nèi)滯留時間更長的制劑。本文使用胃黏附技術(shù)通過制備胃黏附微球,使藥物能在胃中維持較長的作用時間,具有較好的應(yīng)用前景。 本文的主要工作是：(1)對法莫替丁的主要理化性質(zhì)進行了測定,建立了胃黏附微球的質(zhì)量評價方法；(2)采用乳化-溶劑蒸發(fā)法制備了法莫替丁胃黏附微球；(3)對黏附微球的黏附性能進行了研究；(4)在家兔體內(nèi)進行了藥動學(xué)實驗,求得主要藥動學(xué)參數(shù),通過比較體外釋放度和體內(nèi)吸收的結(jié)果,對黏附微球的體內(nèi)外相關(guān)性進行了評價。 本文的主要研究方法是：(1)通過溶解度、油水分配系數(shù)的測定實驗對法莫替丁的理化性質(zhì)進行了探索；(2)通過建立線性關(guān)系、精密度試驗、穩(wěn)定性試驗、回收率實驗等,建立了含量測定和釋放度測定方法；(3)通過單因素考察和正交實驗設(shè)計實驗,對黏附微球的處方進行了篩選與優(yōu)化,并確立了最優(yōu)的工藝與處方。(4)通過對同一釋放曲線的不同數(shù)學(xué)模型(如零級、一級、Higuchi、Peppas)擬合,對微球的內(nèi)在釋放本質(zhì)進行了探討；(5)通過顯微鏡對微球表面形貌以及在介質(zhì)中的表面形態(tài)進行了觀察,還測定了粒度與粒度分布、圓整度、堆密度、休止角等理化指標(biāo),為微球的表觀特征進行了表征；(6)采用固相萃取技術(shù)和外標(biāo)法,通過高效液相色譜建立了藥物血藥濃度分析方法；采用兩制劑兩周期交叉實驗設(shè)計方案在家兔體內(nèi)進行了藥動學(xué)實驗,利用DAS2.0軟件求出了主要藥動學(xué)參數(shù)；利用藥動學(xué)公式以及方差分析評價了生物等效性、體內(nèi)外相關(guān)性,相對生物利用度等；(7)最后通過離體動物滯留實驗、剪切力測量實驗、分離力測量實驗和體內(nèi)滯留實驗,對胃黏附微球的黏附性能進行了評價。 本文的主要研究結(jié)果有：(1)法莫替丁隨pH增大其溶解度逐步減小,油水分配系數(shù)逐漸增大；(2)在約266nm處,法莫替丁有最大紫外吸收,以pH4.5磷酸鹽緩沖液作為介質(zhì),在2-20μg/ml范圍內(nèi),精密度、回收率、線性關(guān)系等良好,適宜法莫替丁的含量測定；以pH1.0鹽酸溶液作為介質(zhì),在4～～40μg/ml范圍內(nèi),精密度、回收率、線性關(guān)系等良好,適宜法莫替丁的釋放度測定；(3)以乙基纖維素為骨架材料,卡波姆934P為黏附材料,PEG6000為致孔劑、吐溫80為乳化劑、液狀石蠟為連續(xù)相,通過調(diào)節(jié)輔料適宜的比例,采用乳化-溶劑蒸發(fā)法,可制備出黏附性能較好的胃黏附微球；(4)胃黏附微球在pH1.0鹽酸溶液介質(zhì)中,其釋藥行為符合零級方程；(5)體內(nèi)外的滯留實驗表明,本制劑中卡波姆對黏附微球的黏附性能具有顯著性影響。(6)家兔體內(nèi)藥動學(xué)研究表明,自制的黏附微球具有緩釋、血藥濃度平緩的特征；藥物的體外釋放和體內(nèi)吸收存在相關(guān)性,可以用釋放度預(yù)測體內(nèi)的吸收過程；自制制劑的相對生物利用度約130%,與普通片相比,生物利用度具有顯著性差異,且在胃內(nèi)有較好的吸收。 本文的研究結(jié)論：自制的法莫替丁胃黏附微球體外釋放緩慢、可控,體內(nèi)吸收和血藥濃度平緩,生物利用度高,具有典型的胃內(nèi)黏附特征,達(dá)到了預(yù)期設(shè)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.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

【參考文獻】

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本文編號：1620160