富马酸替诺福韦酯片剂的研究

发布时间：2018-01-15 21:40

本文关键词：富马酸替诺福韦酯片剂的研究　出处：《河北医科大学》2015年硕士论文　论文类型：学位论文

【摘要】：目的:富马酸替诺福韦酯(Tenofovir Disoproxil Fumarate),C19H30N5O10P.C4H4O4,白色至类白色结晶性粉末,是一种新型核苷类逆转录酶抑制剂,用于治疗成人人类免疫缺陷病毒感染和乙型肝炎病毒感染。本品为前药,在体内以替诺福韦起效;生物药剂学分类:III类,高溶解低通透。2001年,由Gilead Sciences Inc.在美国上市,主要用于治疗人类HIV感染,可与其他抗逆转录病毒药物联用,具有很好的抗HBV活性。欧盟和FDA在2008年4月和8月,又批准富马酸替诺福韦酯用于治疗乙肝,是抗乙肝药物最好的之一。本课题研究基于ICHQ8\9\10\11质量风险管理和质量源于设计理念,旨在通过以原研产品为参比制剂,处方筛选过程中采用溶出一致性评价,同时严格用USP标准控制原料药和制剂的质量,保证体外溶出度和对照药一致。以期达到原研制剂水平。依据FDA、ICH以及CFDA等指导原则进行处方、工艺、质量和影响因素研究,确保本课题研究的产品质量稳定。方法:通过设计试验对富马酸替诺福韦酯片的辅料进行筛选,选定后确定辅料的具体比例,根据试验结果确定片剂的处方。制备工艺研究的重点在于控制关键工艺步骤。通过设计试验以及参考设备以往使用经验利用Mintab软件最终确定了富马酸替诺福韦酯片的制备工艺参数以及相应的中控参数。富马酸替诺福韦酯片质量标准的建立过程中,性状、溶出、有关物质以及含量测定方法拟参考USP Pending Monograph Draft 1—For Public Comment Tenofovir Disoproxil Fumarate Tablets进行设定。按照《化学药物稳定性研究技术指导原则》进行影响因素试验照质量标准项下方法检测其重点考察项目,以确定该处方的稳定性。结果:最终确定的片剂处方:富马酸替诺福韦酯为主药,乳糖为填充剂,微晶纤维素为填充剂,预胶化淀粉加50%乙醇为粘合剂,交联羧甲基纤维素纳为崩解剂,硬脂酸镁为润滑剂,包衣粉用配制好的成品。通过对制剂的分析方法进行确认,最终确定了产品的质量标准,并采用拟定标准对小试样品进行影响因素考察。影响因素试验结果表明:富马酸替诺福韦酯片对高温、高湿、强光、酸碱环境都较为敏感。结论:通过对富马酸替诺福韦酯片的处方筛选和生产工艺进行研究,最终确定了产品处方和工艺参数空间。在实验室完成了一批小试样品制备。结果表明,采用拟定的处方和工艺参数能够生产出合格产品。通过对有关物质检查、溶出的方法学研究,最终确定了产品的质量标准,并对小试样品进行了检验。结果表明,样品质量符合标准要求,检验方法准确可靠。影响因素试验表明富马酸替诺福韦酯片对高温、高湿、强光、酸碱环境都较为敏感。综上所述,本制剂的处方设计合理,工艺路线可行,产品重现性好,所建立的分析方法可行,小试样品验合格、杂质可控,可用于中试生产。
[Abstract]:Objective: tenofovir Disoproxil Fumarate C19H30N5O10P.C4H4O4 was used. White to white crystalline powder is a novel nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection and hepatitis B virus infection in adults. Tenofovir is effective in vivo; Biopharmaceutical class: III, highly soluble and low permeable. In 2001, launched in the United States by Gilead Sciences Inc., used primarily for the treatment of human HIV infections. It can be used in conjunction with other antiretrovirals and has good antiviral activity. In April 2008 and August, the European Union and FDA also approved tenofovir fumarate for the treatment of hepatitis B. This research is based on ICHQ8\ 9\ 10\ 11 quality risk management and quality derived from the design concept, through the original product as a reference preparation. In the process of prescription screening, the consistency of dissolution was evaluated, and the quality of raw material and preparation was strictly controlled by USP standard, so as to ensure the dissolution rate in vitro was the same as that of control drug, in order to reach the level of original preparation, according to FDA. ICH, CFDA and other guiding principles were used to study the prescription, process, quality and influencing factors. Methods: the excipients of tenofovir fumarate tablets were screened by design test and the specific proportion of excipients was determined. According to the experimental results, the formulation of tablets is determined. The research of preparation process is focused on controlling the key technological steps. Fumaric acid is determined through design test and reference equipment experience in the past using Mintab software. Technical parameters of preparation of tenofovir ester tablets and corresponding central control parameters. Establishment of quality standard for tenofovir Fumarate tablets. Character, dissolution. Reference to USP Pending Monograph Draft 1-for Public Comment. Tenofovir Disoproxil Fumarate. According to the Technical guidelines for the study of Chemical Drug Stability, Tablets was used to test the key items under the quality standard of influencing factors test. Results: the final formulation: tenofovir fumarate as the main drug lactose as filler microcrystalline cellulose as filler pre-gelatinized starch and 50% ethanol as binder. Crosslinked carboxymethyl cellulose as disintegration agent, magnesium stearate as lubricant, coated powder prepared finished product. Through the analysis of the preparation method confirmed, the final quality standard of the product was determined. The experimental results showed that tenofovir fumarate tablets were sensitive to high temperature, high humidity and strong light. Conclusion: the formulation of tenofovir fumarate tablets and the production process were studied. Finally, the product prescription and process parameter space were determined. A batch of small scale samples were prepared in the laboratory. The results showed that the qualified product could be produced by using the formulated prescription and process parameters. The quality standard of the product was finally determined and the sample was tested. The results showed that the quality of the sample met the requirements of the standard. The test results showed that tenofovir fumarate tablets were sensitive to high temperature, high humidity, strong light and acid-base environment. In conclusion, the formulation of this preparation was reasonable and the technological route was feasible. The product has good reproducibility, the analytical method is feasible, the small scale sample is qualified, the impurity is controllable, and can be used in pilot-scale production.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R943

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