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。
Nimodipine is a selective calcium channel antagonist of cerebral vessels smooth muscle and also has polymorphs. It hasn＇t been reported that different crystal forms influence the metabolism process in huge animals like rhesus monkeys in vivo. This article may provide reference in the control of the quality of nimodipine and quality consistency evaluation. The powder X-ray diffraction （PXRD） method was used to identify different crystal forms and the dissolution test in vitro was used to detect the dissolution. The LC-MS method of assay nimodipine in rhesus monkey plasm was established to determine pharmacokinetics characters of different tablets from different crystal forms in rhesus monkey in vivo. As a result, the tablets inherit difference crystal forms and the dissolution of reference tablets is 1.3% higher than crystal tablets. However, the maximal blood concentration （Cmax） of crystal tablet was 37.3% higher than reference tablet and AUC of crystal tablet was 29.8% higher than reference tablet. After administrated 2.5 mg·kg^-1 orally, calculated pharmacokinetics characters were observed as following： Cmax was 381.4±327.3 and 178.0±214.8μg.L^-1; AUC0-t was 853.1±500.7 and 646.5±430.3μg·L^-1.h respectively. The serum concentration result of differentnimodipine tablets in rhesus monkeys in vivo suggests that polymorphs has a significantly distinction, which points out that controlling the crystal forms of nimodipine is essential to ensure the therapeutic efficacy. It is essential to execute quality consistency evaluation.
出处
《药学学报》
CAS
CSCD
北大核心
2017年第12期1918-1923,共6页
Acta Pharmaceutica Sinica
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)
