【作者】 李慧芳；

【导师】 张淑秋；

【作者基本信息】 山西医科大学 ， 药剂学， 2011， 硕士

【摘要】 胃漂浮片是根据流体动力学平衡原理（hydrodynamically balanced system，HBS）制成的一种特殊缓释剂型，这种缓释制剂比其他缓释制剂的优势在于该剂型可以长时间漂浮在胃液上不受胃排空的影响，在胃中滞留时间长。马来酸曲美布汀（trimebutine maleate，TMB）是一种直接作用于胃肠道平滑肌的胃功能调节剂，但是半衰期仅有2.7 h，给药间隔短，血药浓度波动较大，易发生毒副作用。本实验在实验室原有的工作基础上，根据马来酸曲美布汀酸性下具有良好溶解性能的特点，制备了马来酸曲美布汀胃漂浮片并且进行了制剂的药物动力学研究，评价了体外指标与体内药物动力学之间的特征。一、胃漂浮片漂浮性能的研究本实验以羟丙基甲基纤维素（HPMC）的K4M、K15M、K20M三种型号作为漂浮片的凝胶骨架材料，以乳糖、淀粉、十六醇、碳酸氢钠为添加剂，采用粉末直接压片，从吸水动力学、膨胀动力学、溶蚀动力学三个方面对片剂的漂浮性和完整性进行了考察。HPMCK20M直接压制的片剂快速崩解，不具备漂浮缓释的特征，HPMC K4M和HPMC K15M直接压制的片剂可持续漂浮，添加剂乳糖、淀粉、十六醇对片剂的影响相当，加入碳酸氢钠片剂的崩解加快。通过Higuchi动力学方程的拟合，阐明不同辅料对漂浮的影响，考察了片剂的漂浮机理。二、马来酸曲美布汀胃漂浮片的制备在实验室原有工作的基础上，以体外漂浮情况和释放度作为筛选指标，对处方和工艺进行了处方单因素考察。使用4因素（HPMC K15M、十六醇、碳酸氢钠、硬脂酸镁）3水平的正交设计来进行辅料性能的考察，并且选出最优处方。结果表明，碳酸氢钠对片剂的影响最大，其次是凝胶骨架材料（HPMC K15m），第三个是硬脂酸镁，第四是助漂剂（十六醇）。据中国药典（2005版）标准，对马来酸曲美布汀胃漂浮片的初步稳定性进行了研究，包括影响因素试验、加速实验，以外观、含量、释放度为重点检查项目，考察高温、高湿、光照对马来酸曲美布汀胃漂浮片性质的影响。稳定性的考察中表明，该制剂对湿度比较敏感，因此应保存在干燥的环境中。三、马来酸曲美布汀胃漂浮片犬体内药物动力学研究建立了反相-高效液相色谱法（RP-HPLC）测定全血浆中马来酸曲美布汀浓度的分析方法，通过对分析方法的确证，结果符合《中国药典（2005版）》的要求。选用健康家犬，以双周期交叉对照试验方法，单剂量（300 mg/只）分别给予马来酸曲美布汀胃漂浮片（受试制剂）和普通片剂（参比制剂）用WinNonlin软件求算药动学参数，并对实验数据进行统计分析。采用非隔室模型，受试制剂的C_max(ng·mL^-1)、T_max（h）、t_1/2（h）、k_a(h^-1)、AUC_0-t(ng·h·mL^-1)、AUC_0-∞(ng·h·mL^-1)分别为167.85±57.82、3.67±0.58、2.57±0.41、0.27±0.08、468.23±154.6、545.69±178.35；参比制剂的C_max(ng·mL^-1)、T_max（h）、t_1/2（h）、k_a(h^-1)、AUC_0-t(ng·h·mL^-1)、AUC_0-∞(ng·h·mL^-1)分别为475.41±186.80、0.75±0.25、2.43±0.18、0.29±0.03、650.64±173.2、740.48±185.62；相对生物利用度为90.05±26.99 %。结果表明其体内吸收过程胃漂浮制剂具有明显的缓释特征，体外释放百分数和体内吸收百分数之间相关性良好（r=0.951）。更多还原

【Abstract】 Floating tablets are desighed according to the principle of hydrodynamically balancedSystem. Unlike the conventional sustained release dosage forms, this kind of special sustainedrelease dosage’s advantages are that the tablets will float on the surface of gastric content whentaken orally and its gastric retention is rarely influenced. The tablets have along residence time inthe stomach. Trimebutine maleate has been used as a spasmolytic drug for gastrointestinalmuscle. Its biological half-life is about 2.7 hours, therefore it is normally administed in shorterintervals, and that may result in bigger fluctuation in plasma concentration and bigger sideeffects. The purpose of this research is to prepare trimebutine maleate floating tablet on the basisof orginal works in laboratory. The pharmacokinetics of the tablets was investigated, and thecorrelation between in vivo and in vitro and in vitro of the tablet was evaluated.1. studies on floating tablet’s floating characteristicsHPMC in K4M、K15M、K20M three models were prepared by using gel matrix materials,lactose、starch、cetyl alcohol and sodium bicarbonate as additives. The floatage and integritywere evaluated in four aspects, including water uptake kineties, swelling kineties and erodingkineties. The tablets directly pressed with HPMC K20M disintegrated rapidly and did not havethe characteristics of sustained-release. Tablets directly pressed with HPMC K4M and K15M cancontinuous floating. Lactose、starch and cetyl alcohol had similar impacts on the tablets. Sodiumbicarbonate can accelerate the disintegration, and help drug release. Based on the Higuchiequation, the influence of different excipients on floating and properties was assessed.2. Preparation of trimebutine maleate floating tabletOn basis of pre-experiments, a four-factor（HPMC K15M, NaHCO3, magnesium stearate andcetyl alcohol） at three-level orthogonal design was employed for formulation development andoptimization, and the floating capability and release of the drug were used as the evaluationindex. The result showed that in the influences of these materials, NaHCO₃ has biggest influenceon floating and release, and then HPMC K15m, magnesium stearate, cetyl alcohol.Followed Chinese Pharmacopoeia, the stability of the preparation were investigated, whichincluded influence factors and acceleration test. Under the strong light, high temperature, highhumidity condition, appearance of tablets, release and content determination were detected forthe stability studies. The results showed that the tablet was sensitive to moisture and should bekept in dry environment.3. Studies on trimebutine maleate floating tablet’s pharmacokinetics in dogs A RP-HPLC method was developed to determine the trimebutine maleate content in dogplasma, respectively. The linearity, specificity, and recovery of this method met with the ChineseParmacopoeia （2005 edition）. This method was used to study the pharmacokinetics oftrimebutine maleate in dogs. Test formulation and reference formulation were given orally todogs, and the experimental data of drugs was analyzed by WinNonlin and non-compartmentmodel theory. The C_max(ng·mL^-1)、T_max（h）、t_1/2（h）、k_a(h^-1)、AUC_0-t(ng·h·mL^-1)、AUC_0-∞(ng·h·mL^-1)of test preparations of trimebutine maleate were 167.85±57.82、3.67±0.58、2.57±0.41、0.27±0.08、468.23±154.6、545.69±178.35. The C_max(ng·mL^-1)、T_max（h）、t_1/2（h）、k_a(h^-1)、AUC_0-t(ng·h·mL^-1)、AUC_0-∞(ng·h·mL^-1)of reference preparationsof trimebutine maleate were 475.41±186.80、0.75±0.25、2.43±0.18、0.29±0.03、650.64±173.2、740.48±185.62, respectively. The relative bioavailability of trimebutine maleate floatingtablet was 90.05±26.99 %, compared with trimebutine maleate tablet. Trimebutine maleatefloating tablets were characterized with sustained-releasing. The oral absorption of trimebutinemaleate floating tablet was good correlated with the release rate in vitro（r=0.951）.更多还原