【摘要】：背景隨著人口老齡化的日趨明顯,中國將成為世界各國中阿爾茨海默病(Alzheimer disease, AD)患者人數(shù)及增長速度的首位,如何防治阿爾茨海默病將是一個(gè)嚴(yán)重的公共衛(wèi)生問題。美金剛是目前世界上唯一一個(gè)批準(zhǔn)用于治療中度至重度AD患者的谷氨酸受體拮抗劑。由于國外專利到期,國內(nèi)許多家企業(yè)都加快了鹽酸美金剛仿制藥的研發(fā),按照CFDA相關(guān)法規(guī)必須進(jìn)行生物等效性研究。美金剛的研發(fā)和生產(chǎn)國產(chǎn)化,將大大降低治療費(fèi)用的成本,為社會(huì)及患者帶來實(shí)質(zhì)性的利益。 目的建立液相色譜串聯(lián)質(zhì)譜法(LC-MS/MS, liquid chromatography-tandem mass spectrometry method)測定人血漿中美金剛的濃度的方法�？疾禧}酸美金剛受試制劑與參比制劑單次給藥的相關(guān)藥代動(dòng)力學(xué)參數(shù)及相對(duì)生物利用度,評(píng)價(jià)兩種制劑的生物等效性。 方法樣品經(jīng)醋酸乙酯：二氯甲烷萃取后,以甲醇：水=95：5(V:V,含0.005mol·L-1甲酸銨和0.1%甲酸)為流動(dòng)相,以AgilentEclipse plus C18(4.6mm×150mm,3.5μm)柱進(jìn)行分離；采用電噴霧電離源,正離子檢測采用多反應(yīng)監(jiān)測(MRM)的方式進(jìn)行,用于定量分析鹽酸美金剛的離子對(duì)為180.0-163.0。 采用單中心、開放、隨機(jī)分組,兩組健康受試者分別服用受試制劑和參比制劑10mg,用LC-MS/MS法測定血漿中美金剛濃度,分析相關(guān)藥代動(dòng)力學(xué)參數(shù)包括平均藥時(shí)曲線圖、AUC、Cmax、Tmax等數(shù)據(jù),進(jìn)行生物等效性研究。 結(jié)果血漿中美金剛測定線性范圍為0.2-30μg·L-1,最低定量下限為0.2μg·L-1,r均大于0.99。準(zhǔn)確度及精密度良好,提取回收率大于70%,介質(zhì)效應(yīng)不影響藥物的質(zhì)量測定。鹽酸美金剛片受試制劑AUC(0-t)的90%置信區(qū)間為參比制劑相應(yīng)參數(shù)的98.6%-101.8%,受試制劑AUC(0-∞)的90%置信區(qū)間為參比制劑相應(yīng)參數(shù)的98.6%-102.1%；受試制劑Cmax的90%置信區(qū)間為參比制劑相應(yīng)參數(shù)的96.3%-103.9%；受試制劑Cmax的90%置信區(qū)間為參比制劑相應(yīng)參數(shù)的96.3%-103.9%,在參比制劑的75.0%-133.0%范圍。經(jīng)非參數(shù)檢驗(yàn),受試制劑與參比制劑的Tmax差異無統(tǒng)計(jì)學(xué)意義(P0.05)。 結(jié)論液相色譜串聯(lián)質(zhì)譜法選擇性強(qiáng)、靈敏度高、重現(xiàn)性好,能快速、準(zhǔn)確測定人血漿中美金剛濃度。根據(jù)對(duì)40名健康受試者單次口服受試與參比兩種制劑進(jìn)行藥代動(dòng)力學(xué)參數(shù)的分析和比較,這兩種制劑具有生物等效性。圖5幅,表23個(gè),參考文獻(xiàn)51篇。
[Abstract]:Background with the aging of the population, China will become the first number and growth rate of (Alzheimer disease, AD) patients in the world. How to prevent and cure Alzheimer's disease will be a serious public health problem. Mejingang is the only glutamate receptor antagonist approved in the world for the treatment of moderate to severe AD. Due to the expiration of foreign patents, many domestic enterprises have accelerated the research and development of metoclopharmaceuticals hydrochloric acid, according to the relevant CFDA laws and regulations must carry out bioequivalence research. The localization of R & D and production will greatly reduce the cost of treatment and bring substantial benefits to the society and patients. Objective to establish a method for the determination of Mejingang in human plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS, liquid chromatography-tandem mass spectrometry method). To investigate the pharmacokinetics parameters and relative bioavailability of single administration of metamphenicol hydrochloric acid and reference preparation, and to evaluate the bioequivalence of the two preparations. Methods the sample was extracted with ethyl acetate: dichloromethane, methanol: water = 95:5 (V 鈮，

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