尼莫地平脂肪乳注射液临床前药代动力学与安全性评价

发布时间：2018-07-13 15:50

【摘要】：尼莫地平(nimodipine)为二氢吡啶类钙拮抗剂，主要用于预防及治疗动脉瘤性蛛网膜下腔出血后脑血管痉挛所引发的缺血性神经损伤[1-2]。由于尼莫地平难溶于水，临床使用尼莫地平注射液时需加入23.7%的乙醇以增加药物的溶解度，并与生理盐水或葡萄糖等溶液进行混合滴注。由于溶剂极性和介电常数的变化易导致药物析出形成结晶，长期使用会产生较严重的刺激性并增加发生静脉炎症的风险[3]。脂肪乳剂是以脂肪酸甘油酯为分散相，以磷脂为乳化剂的水包油型亚微乳剂，具有提高难溶药物溶解度、减少静脉刺激性与延缓药物释放等作用[4-5]。为解决尼莫地平注射液临床使用时出现的问题，本课题组研制了尼莫地平脂肪乳注射液。本研究将对尼莫地平脂肪乳注射液的含量、体内药代动力学、组织分布及安全性进行评价。结果表明尼莫地平脂肪乳中尼莫地平的含量为0.873mg/ml，pH值为7.30，平均粒径为146.3nm，Zeta电位为-29.83mV。大鼠体内尼莫地平HPLC分析结果显示，高(5mg/kg)、中(2.5mg/kg)、低(1.25mg/kg)剂量的尼莫地平在大鼠体内均符合二室模型，消除半衰期(t1/2β)分别为30.06±5.88min、33.14±9.47min和16.18±2.39min，曲线下面积（AUCo-120）分别为32.35±4.71mg/L*min、67.13±17.87mg/L*min和141.55±33.50mg/L*min。结果提示尼莫地平脂肪乳注射液在大鼠体内基本符合线性药代动力学，并迅速代谢及消除。大鼠尾静脉给予中剂量尼莫地平脂肪乳注射液后，检测结果显示尼莫地平在大鼠体内组织分布均符合一室模型，脑、心、肝、脾、肺、肾的半衰期(t1/2)分别为11.77min、11.37min、26.26min、14.77min、12.06min和11.34min，曲线下面积（AUCo-120）分别为44.03mg/kg*min、60.39mg/kg*min、1.90mg/kg*min、36.94mg/kg*min、75.83mg/kg*min和103.43mg/kg*min；尼莫地平脂肪乳注射液与市售尼莫地平注射液生物等效性检测结果显示，平均相对生物利用度F为96.9±6.2%，受试制剂的AUCo-12和Cmax的90％可信限分别为80.8%~120.7%和92.5%~123.7%，受试制剂与参比制剂差异无统计学意义(P0.05)，证明两制剂生物等效。尼莫地平脂肪乳注射液的初步安全性评价项目包括大鼠舐足实验、溶血实验和耳缘血管刺激性实验。结果显示尼莫地平脂肪乳注射液对大鼠足趾部组织有一定刺激性，不宜用于皮下及肌肉注射；对红细胞无刺激性，不会引起溶血，可用于静脉注射；血管刺激性实验结果表明尼莫地平脂肪乳在两天内表现出一定的刺激性，两周后刺激反应消失，与市售注射液刺激性相当。研究结果提示尼莫地平脂肪乳在大鼠体内迅速代谢消除，，相关的药代动力学参数及安全评价性结果将为本制剂的研发和进一步优化提供基础。
[Abstract]:Nimodipine (nimodipine) is a dihydropyridine calcium antagonist, which is mainly used to prevent and treat ischemic nerve damage caused by cerebral vasospasm after aneurysm subarachnoid hemorrhage [1-2]. Because nimodipine is insoluble in water, it is necessary to add 23.7% ethanol in clinical use of nimodipine injection to increase the solubility of the drug and to mix it with saline or glucose solution. Due to the change of solvent polarity and dielectric constant, it is easy to precipitate and crystallize the drug. The long-term use will produce serious irritation and increase the risk of venous inflammation [3]. Fatty emulsion is an oil-in-water microemulsion with fatty acid glyceride as dispersion phase and phospholipid as emulsifier. It can improve the solubility of insoluble drugs, reduce intravenous irritation and delay drug release [4-5]. In order to solve the problems in clinical use of nimodipine injection, we developed nimodipine fat emulsion injection. In this study, the content, pharmacokinetics, tissue distribution and safety of nimodipine fat emulsion injection were evaluated. The results showed that the content of nimodipine in nimodipine fat emulsion was 0.873 mg / ml, pH was 7.30, and the average particle size was 146.3 nm 路ml ~ (-1) Zeta potential of -29.83 MV. The results of nimodipine analysis in rats showed that the high (5mg/kg), middle (2.5mg/kg) and low (1.25mg/kg) doses of nimodipine were in accordance with the two-compartment model in rats. The elimination half-life (t _ 1 / 2 尾) was 30.06 卤5.88 min ~ (33.14 卤9.47min) and 16.18 卤2.39 min, respectively. The area under the curve (AUCo-120) was 32.35 卤4.71 mg 路L ~ (-1) min ~ (-1) and 141.55 卤33.50 mg 路L ~ (-1) min 路min ~ (-1) respectively. The results suggest that nimodipine fat emulsion injection basically accords with the linear pharmacokinetics in vivo and is rapidly metabolized and eliminated. The results showed that the tissue distribution of nimodipine in rats was consistent with one compartment model, brain, heart, liver, spleen, lung, brain, heart, liver, spleen and lung. The half life of kidney (t 1 / 2) was 11.77 min / 11.37 min / 26.26 min / 14.77 min / 12.06 min and 11.34 min, respectively. The area under the curve (AUCo-120) was 44.03 mg / kg 路kg ~ (-1) 路min ~ (-1 / 2) of 60.39 mg 路kg ~ (-1) 路min ~ (-1) 路kg ~ (-1) 路min ~ (-1) of Nimodipine, 75.83 mg / kg 路kg ~ (-1) min and 103.43 mg / kg 路kg ~ (-1) min, respectively; the bioequivalence of nimodipine fat emulsion injection and Nimodipine injection was determined. The average relative bioavailability F was 96.9 卤6.2. The 90% confidence limits of AUCo-12 and Cmax of the tested preparations were 80.8% 120.7% and 92.5% 123.7%, respectively. There was no significant difference between the tested preparations and the reference preparations (P0.05), which proved that the two preparations were bioequivalent. The preliminary safety evaluation of nimodipine fat emulsion injection included lapping foot test, hemolysis test and auricular vascular irritation test. The results showed that Nimodipine fat emulsion injection was not suitable for subcutaneous and intramuscular injection of rat toe tissue, no irritation to erythrocytes, no hemolysis, and could be used for intravenous injection. The results of vascular irritation test showed that Nimodipine fat emulsion showed a certain irritation within two days, and the stimulation reaction disappeared after two weeks, which was similar to that of market injection. The results suggested that nimodipine fat emulsion could be metabolized rapidly in rats. The related pharmacokinetic parameters and safety evaluation results would provide a basis for the development and further optimization of Nimodipine fat emulsion.
【学位授予单位】：广东药学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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