液相色谱串联质谱法分析血浆中美金刚浓度及其生物等效性研究

发布时间：2019-06-14 20:16

【摘要】：背景随着人口老龄化的日趋明显,中国将成为世界各国中阿尔茨海默病(Alzheimer disease, AD)患者人数及增长速度的首位,如何防治阿尔茨海默病将是一个严重的公共卫生问题。美金刚是目前世界上唯一一个批准用于治疗中度至重度AD患者的谷氨酸受体拮抗剂。由于国外专利到期,国内许多家企业都加快了盐酸美金刚仿制药的研发,按照CFDA相关法规必须进行生物等效性研究。美金刚的研发和生产国产化,将大大降低治疗费用的成本,为社会及患者带来实质性的利益。 目的建立液相色谱串联质谱法(LC-MS/MS, liquid chromatography-tandem mass spectrometry method)测定人血浆中美金刚的浓度的方法。考察盐酸美金刚受试制剂与参比制剂单次给药的相关药代动力学参数及相对生物利用度,评价两种制剂的生物等效性。 方法样品经醋酸乙酯：二氯甲烷萃取后,以甲醇：水=95：5(V:V,含0.005mol·L-1甲酸铵和0.1%甲酸)为流动相,以AgilentEclipse plus C18(4.6mm×150mm,3.5μm)柱进行分离；采用电喷雾电离源,正离子检测采用多反应监测(MRM)的方式进行,用于定量分析盐酸美金刚的离子对为180.0-163.0。 采用单中心、开放、随机分组,两组健康受试者分别服用受试制剂和参比制剂10mg,用LC-MS/MS法测定血浆中美金刚浓度,分析相关药代动力学参数包括平均药时曲线图、AUC、Cmax、Tmax等数据,进行生物等效性研究。 结果血浆中美金刚测定线性范围为0.2-30μg·L-1,最低定量下限为0.2μg·L-1,r均大于0.99。准确度及精密度良好,提取回收率大于70%,介质效应不影响药物的质量测定。盐酸美金刚片受试制剂AUC(0-t)的90%置信区间为参比制剂相应参数的98.6%-101.8%,受试制剂AUC(0-∞)的90%置信区间为参比制剂相应参数的98.6%-102.1%；受试制剂Cmax的90%置信区间为参比制剂相应参数的96.3%-103.9%；受试制剂Cmax的90%置信区间为参比制剂相应参数的96.3%-103.9%,在参比制剂的75.0%-133.0%范围。经非参数检验,受试制剂与参比制剂的Tmax差异无统计学意义(P0.05)。 结论液相色谱串联质谱法选择性强、灵敏度高、重现性好,能快速、准确测定人血浆中美金刚浓度。根据对40名健康受试者单次口服受试与参比两种制剂进行药代动力学参数的分析和比较,这两种制剂具有生物等效性。图5幅,表23个,参考文献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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