【摘要】 目的筛选抗癫痫药物苯妥英钠(Phenytoin,PHT)的纳米药物载体构建工艺,并比较纳米粒与P糖蛋白拮抗剂(P-glycoprotein,Pgp)维拉帕米(Verapamil,VPM)对PHT的脑靶向分布作用。方法分别应用乳化聚合法和界面聚合法构建PHT聚氰基丙烯酸正丁酯纳米粒,添加1%的普郎尼克P85进行修饰,并进行体外特征鉴定;20只雌性SD大鼠,随机分为PHT组、PHT+VPM组(添加维拉帕米)、Emulsion Nano组(纳米粒由乳化聚合法合成)和Interfacial Nano组(纳米粒由界面聚合法合成)。4组给予PHT后分别在不同时间点取大脑微透析液和血液,最后处死大鼠分离肝脏和肾脏组织。高效液相色谱法检测各样本中苯妥英钠的浓度,苯妥英钠透过血脑屏障的转运率用脑组织间液时间药物浓度曲线的曲线下面积与血浆时间药物浓度曲线的曲线下面积的比值进行评估;苯妥英钠在外周组织的累积分布情况用给药300 min的肝脏/肾脏苯妥英钠药物浓度与血浆药物浓度的比值进行评估。结果界面聚合法合成的纳米粒较乳化聚合法具有较高的载药量和包埋率,而平均粒径和Zeta电位相近;Interfacial Nano组、Emulsion Nano组、PHT+VPM组与PHT组比较,脑组织间液和血浆苯妥英钠的曲线下面积比值分别提高了60.70%(P<0.01)、27.44%(P<0.05)和26.91%(P<0.05);Interfacial Nano组苯妥英钠药物浓度肝血比和肾血比明显下降,PHT+VPM组肝血比和肾血比明显升高,与PHT组比较差异均有统计学意义(P<0.05)。Emulsion Nano组与PHT组相近,差异无统计学意义。结论界面聚合法纳米粒制备工艺相对优于乳化聚合法。相对于VPM,添加1%的普郎尼克P85修饰的界面聚合法制备的纳米粒可明显提高PHT在脑组织中的分布,具有脑靶向输送作用。更多还原

【Abstract】 Objective Screening manufacture process of nano drug carrier of traditional antiepileptic drugs phenytoin,and attempt to explore the effect of nanoparticles on brain-targeted distribution of phenytoin compared with one of antagonists of P-glycoprotein verapamil.Methods Constructing phenytoin polybutylcyanoacrylate nanoparticles respectively by emulsion and interfacial polymerization method modified with 1% Pluronic P85,and identification the characterization in vitro;SD rats were randomly divided into PHT group,PHT+VPM group,Emulsion nano group and Interfacial nano group.Several dialysate and blood samples of different times were collected after PHT administration.liver and kidney were removed for tissues distribution study.Concentrations of PHT of different samples were detected by high performance liquid chromatography(HPLC).Ratio of area under curve(AUC)of time drug concentration curve of brain extracellular fluid and plasma of phenytoin was used to evaluate the brain distribution of phenytoin.Ratio of concentration of phenytoin of liver / kidney and plasma at 300 min time-point was used to evaluate accumulation and distribution of phenytoin in peripheral tissues.Results Interfacial polymerization method had higher load quantity and package embedding rate,and similar average particle size and zeta potential,relative to emulsion polymerization method;Compared with the PHT group,the PHT AUC ratios between brain extracellular fluid and plasma in Interfacial nano group,Emulsion nano group and PHT+VPM group,were significantly increased by 60.70%(P < 0.01),27.44%(P < 0.05)and 26.91%(P < 0.05),respectively;The hepatic blood ratio and renal blood ratio of Interfacial nano group decreased significantly(P < 0.05),while those of PHT+VPM group increased significantly(P <0.05),compared with PHT group.The differences of Emulsion nano group and PHT group were not statistically significant.ConclusionManufacture process of interfacial polymerization method for nano drug carrier is relatively better than the emulsion polymerization method.The nanoparticles constructed by interfacial polymerization method could significantly improve the distribution of PHT in brain tissue,modified by 1% Pluronic P85,relatively to the Pgp antagonist of VPM,with brain targeting delivery ability.更多还原