發(fā)布時間：2018-07-13 15:50

【摘要】：尼莫地平(nimodipine)為二氫吡啶類鈣拮抗劑，主要用于預防及治療動脈瘤性蛛網(wǎng)膜下腔出血后腦血管痙攣所引發(fā)的缺血性神經(jīng)損傷[1-2]。由于尼莫地平難溶于水，臨床使用尼莫地平注射液時需加入23.7%的乙醇以增加藥物的溶解度，并與生理鹽水或葡萄糖等溶液進行混合滴注。由于溶劑極性和介電常數(shù)的變化易導致藥物析出形成結晶，長期使用會產(chǎn)生較嚴重的刺激性并增加發(fā)生靜脈炎癥的風險[3]。 脂肪乳劑是以脂肪酸甘油酯為分散相，以磷脂為乳化劑的水包油型亞微乳劑，具有提高難溶藥物溶解度、減少靜脈刺激性與延緩藥物釋放等作用[4-5]。為解決尼莫地平注射液臨床使用時出現(xiàn)的問題，本課題組研制了尼莫地平脂肪乳注射液。本研究將對尼莫地平脂肪乳注射液的含量、體內(nèi)藥代動力學、組織分布及安全性進行評價。結果表明尼莫地平脂肪乳中尼莫地平的含量為0.873mg/ml，pH值為7.30，平均粒徑為146.3nm，Zeta電位為-29.83mV。 大鼠體內(nèi)尼莫地平HPLC分析結果顯示，高(5mg/kg)、中(2.5mg/kg)、低(1.25mg/kg)劑量的尼莫地平在大鼠體內(nèi)均符合二室模型，消除半衰期(t1/2β)分別為30.06±5.88min、33.14±9.47min和16.18±2.39min，曲線下面積（AUCo-120）分別為32.35±4.71mg/L*min、67.13±17.87mg/L*min和141.55±33.50mg/L*min。結果提示尼莫地平脂肪乳注射液在大鼠體內(nèi)基本符合線性藥代動力學，并迅速代謝及消除。大鼠尾靜脈給予中劑量尼莫地平脂肪乳注射液后，檢測結果顯示尼莫地平在大鼠體內(nèi)組織分布均符合一室模型，腦、心、肝、脾、肺、腎的半衰期(t1/2)分別為11.77min、11.37min、26.26min、14.77min、12.06min和11.34min，曲線下面積（AUCo-120）分別為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與市售尼莫地平注射液生物等效性檢測結果顯示，平均相對生物利用度F為96.9±6.2%，受試制劑的AUCo-12和Cmax的90％可信限分別為80.8%~120.7%和92.5%~123.7%，受試制劑與參比制劑差異無統(tǒng)計學意義(P0.05)，證明兩制劑生物等效。 尼莫地平脂肪乳注射液的初步安全性評價項目包括大鼠舐足實驗、溶血實驗和耳緣血管刺激性實驗。結果顯示尼莫地平脂肪乳注射液對大鼠足趾部組織有一定刺激性，不宜用于皮下及肌肉注射；對紅細胞無刺激性，不會引起溶血，可用于靜脈注射；血管刺激性實驗結果表明尼莫地平脂肪乳在兩天內(nèi)表現(xiàn)出一定的刺激性，兩周后刺激反應消失，與市售注射液刺激性相當。 研究結果提示尼莫地平脂肪乳在大鼠體內(nèi)迅速代謝消除，，相關的藥代動力學參數(shù)及安全評價性結果將為本制劑的研發(fā)和進一步優(yōu)化提供基礎。
[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 鹵5.88 min ~ (33.14 鹵9.47min) and 16.18 鹵2.39 min, respectively. The area under the curve (AUCo-120) was 32.35 鹵4.71 mg 路L ~ (-1) min ~ (-1) and 141.55 鹵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 鹵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.
【學位授予單位】：廣東藥學院
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R96

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