【作者】 宿彦伟；

【导师】 沈慧凤；

【作者基本信息】 上海医药工业研究院 ， 药剂学， 2000， 硕士

【摘要】 本文以烟酸（nicotinic acid，niacin）为水溶性模型药物，研究了Carbopol在口服缓释制剂中的应用。先对Carbopol在不同介质中的膨胀性和粘性进行了基础研究，并与HPMC K4M作比较。系统考察了各种处方因素和溶出条件对释药速率的影响，探索了缓释片的释药机制；对比研究了在缓释制剂中应用Carbopol的三种制备工艺：包括粉末直接压片法、快速搅拌制粒法和Carbopol颗粒外加法，重点考察了Carbopol颗粒外加法工艺，在此基础上筛选了与国外制剂具有相似体外释放度的处方，考察了其稳定性。最后以进口制剂作对照，对自制烟酸缓释片进行了兔体内的生物利用度试验。 Carbopo1934P、974P与971P为三种可口服的药用高分子材料，在人工胃液和人工肠液中的膨胀度有明显差异，在不同介质中粘度测定结果表明：Carbopol受pH及离子强度的影响较大，而HPMC K4M相对较小。 在处方因素考察中发现Carbopol的型号、含量以及处方中所有的填充剂，均对主药的释药速率有影响，而Carbopol的粒度、压片压力对释放度影响不明显。在考察溶出方法和溶出介质时，发现使用蓝法或桨法体外释放度有明显的不同；溶出介质的pH及离子强度，对主药的释药速率影响较大。 对制备工艺的研究表明，Carbopol颗粒外加法与其它两种工艺比较，工艺简单，操作方便，缓释效果与粉末压片法接近，比快速搅拌制粒法好。抗湿性实验表明Carbopol颗粒外加法制备的片剂表面易吸潮，薄膜包衣后片剂硬度增大，但释药速率基本不变。 在处方筛选中发现，Carbopol与HPMC联用后缓释效果比单用明显增强，通过红外光谱可知两者在pH4.0-6.8的溶液中可能形成内在复合物；对筛选的处方进行加速稳定性实验，结果表明光照、高温、高湿均使释药速率有所减慢，外观及含量无明显变化：三个月加速实验表明，缓释片内在质量稳定。 采用离子对色谱法建立了血浆中烟酸的测定方法，用兔子进行了进口片与自制片的药代动力学研究。结果表明自制片与进口片的达峰时间和达峰浓度无显著性差异，其相对生物利用度为116.8％，两者生物等效。更多还原

【Abstract】 Nicotinic acid (niacin) was used as a water-soluble drug model to investigate the application of Carbopol on sustained release oral matrix tablets. Carbopol934P. 974P and 971 P are the oral pharmaceutical grades of Carbomer and currently being utilized as polymeric matrices for controlling drug release in pharmaceutical dosage forms. The swelling and adhesiveness of Carbopol in different mediums were investigated .The result indicated the swelling of Carbopol was significantly different in simulated gastric fluid(SGF) and simulated intestic fluid(SIF).The adhesiveness of Carbopol was strongly affected by pH and ionic strength compared with HPMCK4m. The influence of composition factors and dissolution conditions on in vitro dissolution behavior was evaluated. The result showed dissolution rate was affected by the content and type of Carbopol, filler, dissolution method, pH and ionic strength of dissolution medium, but the particle size of Carbopol and hardness of tablets had little influence. A novel wet granulation method- Carbopol extragranular addition was studied in details. It is a simple and manageable process compared with general wet granulation and has the advantage of avoiding agglomeration of Carbopol during granulation. The formulation of sustained release nicotinic acid tablet (SRNAT) using the combination of Carbopol974P and HPMCK4m was screened. It has similar in vitro dissolution characteristics to the imported tablet. Pharmacokinetic studies were carried out in six healthy rabbits after a single oral administration of the self-prepared and imported SRNAT in a randomized crossover way. The results demonstrated that the two preparations were bioequivalent.更多还原