發(fā)布時間：2018-01-15 21:40

  本文關(guān)鍵詞：富馬酸替諾福韋酯片劑的研究　出處：《河北醫(yī)科大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 富馬酸替諾福韋酯 處方 工藝 質(zhì)量研究 影響因素試驗

【摘要】：目的:富馬酸替諾福韋酯(Tenofovir Disoproxil Fumarate),C19H30N5O10P.C4H4O4,白色至類白色結(jié)晶性粉末,是一種新型核苷類逆轉(zhuǎn)錄酶抑制劑,用于治療成人人類免疫缺陷病毒感染和乙型肝炎病毒感染。本品為前藥,在體內(nèi)以替諾福韋起效;生物藥劑學(xué)分類:III類,高溶解低通透。2001年,由Gilead Sciences Inc.在美國上市,主要用于治療人類HIV感染,可與其他抗逆轉(zhuǎn)錄病毒藥物聯(lián)用,具有很好的抗HBV活性。歐盟和FDA在2008年4月和8月,又批準(zhǔn)富馬酸替諾福韋酯用于治療乙肝,是抗乙肝藥物最好的之一。本課題研究基于ICHQ8\9\10\11質(zhì)量風(fēng)險管理和質(zhì)量源于設(shè)計理念,旨在通過以原研產(chǎn)品為參比制劑,處方篩選過程中采用溶出一致性評價,同時嚴(yán)格用USP標(biāo)準(zhǔn)控制原料藥和制劑的質(zhì)量,保證體外溶出度和對照藥一致。以期達到原研制劑水平。依據(jù)FDA、ICH以及CFDA等指導(dǎo)原則進行處方、工藝、質(zhì)量和影響因素研究,確保本課題研究的產(chǎn)品質(zhì)量穩(wěn)定。方法:通過設(shè)計試驗對富馬酸替諾福韋酯片的輔料進行篩選,選定后確定輔料的具體比例,根據(jù)試驗結(jié)果確定片劑的處方。制備工藝研究的重點在于控制關(guān)鍵工藝步驟。通過設(shè)計試驗以及參考設(shè)備以往使用經(jīng)驗利用Mintab軟件最終確定了富馬酸替諾福韋酯片的制備工藝參數(shù)以及相應(yīng)的中控參數(shù)。富馬酸替諾福韋酯片質(zhì)量標(biāo)準(zhǔn)的建立過程中,性狀、溶出、有關(guān)物質(zhì)以及含量測定方法擬參考USP Pending Monograph Draft 1—For Public Comment Tenofovir Disoproxil Fumarate Tablets進行設(shè)定。按照《化學(xué)藥物穩(wěn)定性研究技術(shù)指導(dǎo)原則》進行影響因素試驗照質(zhì)量標(biāo)準(zhǔn)項下方法檢測其重點考察項目,以確定該處方的穩(wěn)定性。結(jié)果:最終確定的片劑處方:富馬酸替諾福韋酯為主藥,乳糖為填充劑,微晶纖維素為填充劑,預(yù)膠化淀粉加50%乙醇為粘合劑,交聯(lián)羧甲基纖維素納為崩解劑,硬脂酸鎂為潤滑劑,包衣粉用配制好的成品。通過對制劑的分析方法進行確認,最終確定了產(chǎn)品的質(zhì)量標(biāo)準(zhǔn),并采用擬定標(biāo)準(zhǔn)對小試樣品進行影響因素考察。影響因素試驗結(jié)果表明:富馬酸替諾福韋酯片對高溫、高濕、強光、酸堿環(huán)境都較為敏感。結(jié)論:通過對富馬酸替諾福韋酯片的處方篩選和生產(chǎn)工藝進行研究,最終確定了產(chǎn)品處方和工藝參數(shù)空間。在實驗室完成了一批小試樣品制備。結(jié)果表明,采用擬定的處方和工藝參數(shù)能夠生產(chǎn)出合格產(chǎn)品。通過對有關(guān)物質(zhì)檢查、溶出的方法學(xué)研究,最終確定了產(chǎn)品的質(zhì)量標(biāo)準(zhǔn),并對小試樣品進行了檢驗。結(jié)果表明,樣品質(zhì)量符合標(biāo)準(zhǔn)要求,檢驗方法準(zhǔn)確可靠。影響因素試驗表明富馬酸替諾福韋酯片對高溫、高濕、強光、酸堿環(huán)境都較為敏感。綜上所述,本制劑的處方設(shè)計合理,工藝路線可行,產(chǎn)品重現(xiàn)性好,所建立的分析方法可行,小試樣品驗合格、雜質(zhì)可控,可用于中試生產(chǎn)。
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R943

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本文編號：1430194