【作者】 李昕皓；

【导师】 周长征；

【作者基本信息】 山东中医药大学 ， 药剂学， 2017， 硕士

【摘要】 富马酸替诺福韦二吡呋酯是由吉利德科学公司研发的核苷酸逆转录酶抑制剂,2001年首次在美国上市,临床主要用于治疗人类免疫缺陷病毒(HIV)感染,并可与其他抗逆转录病毒药物联用。2002年2月首次获欧盟许可本品与其他抗逆转录病毒药物联合用于经早期病毒学治疗失败的HIV-1感染者。2003年5月Gilead Sciences公司宣布,欧洲药品委员会已批准在15个欧盟成员国扩大替诺福韦酯的适应症,用于未曾接受抗逆转录病毒药物治疗的H IV感染者。2008年,获准在中国上市。至今,已有包括中国在内的100多个国家批准其用于与其他抗病毒药物合用治疗HIV,是多个治疗指南推荐使用的一线抗HIV药物。本研究在参照原研的基础上,对富马酸替诺福韦二吡呋酯的处方和制备工艺进行研究,同时,进行质量研究和稳定性考察,确定了合理的处方和可行的制备工艺,实现本品的产业化生产。研究内容包括:(1)富马酸替诺福韦二吡呋酯片的处方研究以含量、有关物质和溶出曲线为主要考察指标,先进性工艺筛选实验,在确定工艺为湿法制粒压片工艺后,又对填充剂、崩解剂、粘合剂、润滑剂等辅料的种类和用量进行筛选,并通过小试验证和中试放大研究,确定富马酸替诺福韦二吡呋酯片的处方组成。(2)富马酸替诺福韦二吡呋酯片的工艺参数研究采用常规湿法制粒压片的方法制备富马酸替诺福韦二吡呋酯片,以中间品的流动性、成形性和片剂的外观性状、崩解时限和溶出曲线为评价指标,重点研究原料药粒度及片剂硬度对制剂的影响。经三批小试和三批中试放大实验,确定富马酸替诺福韦二吡呋酯片的制备工艺。(3)富马酸替诺福韦二吡呋酯片的质量研究建立了以高效液相法检测富马酸替诺福韦二吡呋酯片含量和有关物质及溶出度的方法,并进行了相应的方法学研究,结果表明方法专属性好,灵敏、准确、可控。(4)富马酸替诺福韦二吡呋酯片的稳定性研究用确定的处方工艺制备样品,样品放置高温、高湿和光照下考察影响因素,并进行了加速和长期稳定性考察,实验结果表明,本品的外观性状、含量、有关物质、溶出度等指标在实验过程中未有明显变化,证明本研究产品稳定性良好。本研究结果表明富马酸替诺福韦二吡呋酯片处方设计合理,制备工艺可行,产品稳定性好,与原研产品质量一致,完全可替代原研产品,为富马酸替诺福韦二吡呋酯片工业化生产提供了坚实的理论和实验依据。更多还原

【Abstract】 Dinofloxacin fumarate is a nucleotide reverse transcriptase inhibitor developed by Gilles Scientific,which was first introduced in the United States in 2001 and is clinically used to treat human immunodeficiency virus(HIV)infections and Can be combined with other antiretroviral drugs.February 2002 for the first time by the European Union license This product and other antiretroviral drugs used in the early virological treatment failed HIV-1 infection.In May 2003,Gilead Sciences announced that the European Medicines Committee had approved the expansion of tenofovir dipivoxil in 15 EU member states for H IV infection who had not received antiretroviral therapy.In 2008,was approved to be listed in China.So far,more than 100 countries,including China,have approved their use in combination with other antiviral drugs to treat HIV,which is recommended for use in multiple treatment guidelines.In this study,the prescription and preparation process of tenofovir dipivoxil fumarate were studied on the basis of the original research.At the same time,the quality research and stability study were carried out to determine the reasonable prescription and feasible preparation process,To achieve the industrialization of the product production.The research includes:(1)The formulation of tenofovir dipivoxil fumarate tabletsBased on the content,related substances and dissolution curves as the main indicators,advanced technology screening experiments,in determining the process for the wet granulation tabletting process,but also on the filler,disintegrating agent,adhesives,lubricants and other auxiliary materials And the dosage was used to determine the formulation of tenofovir dipivoxil fumarate tablets by small test and pilot study.(2)Study on the Processing Parameters of Tenofovir Dipyridine Fumarate TabletsThe results showed that the tenofovir dipivoxil fumarate tablets were prepared by conventional wet granulation granules.The flowability,formability and appearance of the tablets,the time of disintegration and the dissolution curve were used as the evaluation indexes.The effects of particle size and tablet hardness on the preparation were studied.The preparation process of tenofovir dipivoxil fumarate tablets was determined by three batches of small test and three batches of pilot experiment.(3)quality of tenofovir dipivoxil fumarate tabletsThe method of detecting the content and related substances and the dissolution of tenofovir dipivoxil fumarate in high performance liquid phase method was established,and the corresponding methodological study was carried out.The results showed that the method was specific,sensitive and accurate,Controllable.(4)The stability of tenofovir dipivoxil fumarate tabletsThe samples were prepared by the established prescription process.The samples were exposed to high temperature,high humidity and light.The results showed that the appearance,content,related substances,dissolution and other indexes of the product were accelerated and long-term stability.There was no obvious change in the course of the experiment,which proved that the product was stable.The results show that the formulation of tenofovir dipivoxil fumarate tablets is reasonable,the preparation process is feasible,the product stability is good,consistent with the quality of the original research products,completely replace the original research products,The industrial production of povidone tablets provides a solid theoretical and experimental basis.更多还原