两种晶型尼莫地平片剂在恒河猴体内药代动力学研究

发布时间：2018-11-05 18:24

【摘要】：尼莫地平(nimodipine)是选择性作用于脑血管平滑肌的钙拮抗剂,存在着多晶型现象。本文用粉末X射线衍射表征了两种片剂晶型,通过体外溶出实验比较了两种片剂的溶出度,利用LC-MS建立恒河猴血浆中尼莫地平测定方法,并研究了尼莫地平两种晶型原料药制成的片剂在恒河猴体内的药代动力学特性。结果显示,两种片剂晶型上存在差异,参比片剂比晶型片剂溶出度高1.3%,恒河猴口服两种晶型片剂各2.5 mg·kg~(-1)后,晶型片剂血药峰浓度相比参比片剂高了37.3%,曲线下面积增加29.8%,拟合计算后的最大血药浓度(C_(max))分别为(381.4±327.3)和(178.0±214.8)μg·L~(-1)。药时曲线下面积(AUC_(0-t))分别为(853.1±500.7)和(646.5±430.3)μg·L~(-1)·h。这提示不同晶型尼莫地平片在恒河猴体内血药浓度变化有一定差异,控制尼莫地平晶型对于保证药物的临床治疗效果具有重要意义,也说明了仿制药一致性评价工作开展的必要性与迫切性。
[Abstract]:Nimodipine (nimodipine) is a calcium antagonist that selectively acts on cerebral vascular smooth muscle. The crystal forms of two tablets were characterized by powder X-ray diffraction. The dissolution of the two tablets was compared by dissolution experiments in vitro. A method for the determination of nimodipine in rhesus monkey plasma was established by LC-MS. The pharmacokinetics of nimodipine tablets in rhesus monkey was studied. The results showed that there were differences in crystal form between the two tablets. The dissolution rate of reference tablets was 1.3% higher than that of crystal type tablets. After oral administration of two kinds of crystalline tablets in rhesus monkey, the dissolution rate was 2.5 mg kg~ (-1). The peak concentration of crystal tablets was 37.3% higher than that of reference tablets, and the area under the curve increased by 29.8%. The maximum plasma concentration (C _ (max) was (381.4 卤327.3) 渭 g / L ~ (-1) and (178.0 卤214.8) 渭 g / L ~ (-1), respectively. The area under the drug time curve (AUC_ (0-t) was (853.1 卤500.7) 渭 g / L ~ (-1) h and (646.5 卤430.3) 渭 g / L ~ (-1) h, respectively. The results suggest that there are some differences in the plasma concentration of nimodipine tablets in rhesus monkeys, and the control of nimodipine crystal type is of great significance to ensure the clinical therapeutic effect of the drug. It also shows the necessity and urgency of the evaluation of generic drug consistency.
【作者单位】：中国医学科学院北京协和医学院药物研究所药物筛选研究中心药物靶点研究和新药筛选北京市重点实验室;中国医学科学院北京协和医学院药物研究所药物晶型研究中心晶型药物研究北京市重点实验室;
【基金】：国家重点研发计划专项(2016YFC1000900) 国家自然科学青年基金资助项目(81603100) 抗毒药物与毒理学国家重点实验室开放课题(TMC201510) 中国医学科学院医学与健康科技创新工程(2016-I2M-3-007)
【分类号】：R965

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