【作者】 李璐；

【导师】 娄建石；

【作者基本信息】 天津医科大学 ， 药理学， 2011， 硕士

【摘要】 目的：筛选盐酸托莫西汀缓释片的处方,建立其血药浓度的测定方法,考察其药物代谢动力学特征。方法：本文以体外释放度为指标考察了HPMC的粘度、不同润湿剂、粘合剂以及压片压力对盐酸托莫西汀缓释片释放度的影响,确定了以HPMC为亲水凝胶缓释骨架材料、乙基纤维素和乳糖为稀释剂兼片剂释药速度调节剂、70%乙醇水溶液为润湿剂的缓释片处方。选用L9(34)正交设计表对盐酸托莫西汀缓释片的处方进行了优化筛选,选HPMC、乙基纤维素和乳糖为三个影响因素,HPMC取80mg、100mg和120mmg三个水平,乙基纤维素取10mg、20mmg和30mg三个水平,乳糖取40mg、50mmg和60mg三个水平,测定不同处方的体外释放度,选出最佳处方,对该制剂体外释药机理进行了探讨。采用高效液相色谱法进行大鼠体内血药浓度测定,考查该制剂在大鼠体内的药代动力学特征。结果：对缓释片的体外释药机理进行了初步研究。几种释药模型拟合结果表明,体外释放度曲线符合Weibull方程Lnln(1/(1-F))=1.0221nt-1.9942,r=0.9989。方程Ritger-Peppas拟合得释放参数n=0.6563,介于0.45-0.89之间,说明本缓释片的释放过程为扩散和溶蚀并存的现象,符合缓释片特性。建立了高效液相色谱法用于体外释放度的测定。盐酸托莫西汀在1μg.ml-1～20μg.ml-1浓度范围内药物浓度与峰面积线性关系良好,标准曲线A=520744C+132594(r=0.9999),低、中、高三种浓度的平均回收率为99.33%、99.37%、100.6%；日内精密度分别为1.3%、0.8%、0.7%；日间精密度分别为1.4%、1.1%、1.0%均小于2%。表明本方法准确、可靠、重现性好。建立了简便、准确、可靠的高效液相色谱法用于测定盐酸托莫西汀的血浆药物浓度。盐酸托莫西汀在20-800 ng·ml-1范围内呈现良好线性关系,标准曲线Y=0.0044X+0.0071 (r=0.9993)；最低检测限为20 ng·ml-1；低、中、高三种浓度的平均绝对回收率为83.46%、80.55%、77.59%；方法回收率分别为97.72%、96.78%、96.63%；日内精密度分别为3.1%、2.6%、3.4%；日间精密度分别为4.0%、3.0%、2.9%均小于5%该缓释片在大鼠体内符合一室模型规律,权重系数为1/C2,ke=0.0842h1,ka=0.1529 h-1,吸收tl/2a=4.54h,消除t1/2e=8.25h,tmax=8.69h, Cmax=464.59ng/ml, AUC=11484(ng/ml)·h。结论：该制剂处方合理,制备工艺可行,具备缓释制剂特征。含量测定方法灵敏度高、准确性好且简便易行。更多还原

【Abstract】 Objective:To screen the optimalizing prescription of sustained release tablet of atomoxetine hydrochloride, establish the assay method of the drug concentration in plasma and review the pharmacokinetic character.Methods:In this paper, the releasing degree in vitro was used as indicator to evaluate the effects of HPMC viscosity, moistening agent, adhesive and squash pressure on the sustained release tablet of atomoxetine hydrochloride. HPMC was selected as hydrophilic gel matrix, lactose and ethylcellulose (EC) as the diluents and the release regulator, and 70% alcohol as moistening agent. The prescription of sustained release tablet of atomoxetine hydrochloride was excellently screened with L9 (34) orthogonal design, and three influencing factors such as HPMC, EC and lactose were selected. The levels of HPMC were 80,100 and 120mg; the level of EC 10,20 and 30mg; the level of lactose 40,50 and 60mg, respectively. The releasing rate of each prescription in vitro was determined and analyzed so as to choose the best. By high performance liquid chromatography (HPLC) method, the atomoxetine hydrochloride plasma concentrations in rats were determined and the pharmacokinetic character was studied.Results:The releasing mechanism of sustained-release tablet was primarily studied. Several drug-releasing models were simulated and showed that the drug-releasing curve in vitro was consistent with Weibull equation Lnln(1/(1-F))=1.0221nt-1.9942, r=0.9989, The release parameter n obtained from Ritger-Peppas equation was 0.6563, between 0.45 and 0.89, indicating that the release mechanism was diffusion as well as matrix erosion, which accords with retard tablets.HPLC method was developed to determine the releasing degree in vitro. The concentration of atomoxetine hydrochloride and the peak areas were linear over the range of 1μg.ml-1～20μg.ml-1, A= 520744C+132594 (r=0.9999).The mean absolute recoveries of low, middle and high concentrations were 99.33%、99.37%、100.6%. The inter-day RSD were 1.3%,0.8%,and 0.7%; and the intra-day RSD were 1.4%, 1.1%, and 1.0%, The two kinds of RSD were both lower than 2% which showed this method was accurate, reliable and reproducible.HPLC method was established to determine the concentration of atomoxetine hydrochloride in plasma. The atomoxetine hydrochloride concentration had a good linear correlation in the range of 20-800ng-ml-1,Y=0.0044X+0.0071 (r=0.9993) The lowest detectable limit was 20ng·ml-1.The mean absolute recoveries of low, middle and high concentrations were 83.46%,80.55%,77.59%; The method recovery rates were 91.12%、96.1%、96.63%; The inter-day RSD were 3.1%、2.6%and 3.4%; and the intra-day RSD were 4.0%、3.0%and 2.9%, The two kinds of RSD were both lower than 5%.The pharmacokinetic parameters and character:one compartment model, Weight=1/C2, ke=0.0842h-1,ka=0.1529 h-1, t1/2a=4.54h, t1/2e=8.25h, Tmax=8.69h, Cmax=464.59ng/ml, AUC=11484(ng/ml).h.Conclusions:This preparation prescription is reasonable, and the preparation technology is feasible. This assay method is sensitive, accurate, simple and feasible.更多还原