【作者】 王雪莹；

【导师】 阎雪莹；

【作者基本信息】 黑龙江中医药大学 ， 药剂学， 2008， 硕士

【摘要】 [目的]制备三氧化二砷骨髓靶向纳米粒,考察其粒径、包封率及形态;考察其体外释放行为;研究三氧化二砷纳米粒在大鼠体内的药动学情况,计算相关参数;考察三氧化二砷纳米粒在小鼠体内的分布情况,评价靶向性。[方法]采用复乳—溶剂挥发法制备PLGA载三氧化二砷纳米粒;运用透射电镜观察纳米粒形态,纳米粒度及Zeta电位分析仪测定纳米粒的粒径及分布;运用动态透析法分离未被包裹的三氧化二砷,氢化物发生—原子荧光法测定砷的含量,计算纳米粒的包封率;采用动态透析法测定三氧化二砷纳米粒的体外释放情况;采用电热板消解法处理给药后大鼠血液样品及小鼠脏器样品,氢化物发生—原子荧光法测定砷的含量;应用3P97药动学软件计算给药后大鼠体内药动学参数,以药物靶向指数和药物选择性指数评价给药后小鼠体内分布情况。[结果]复乳—溶剂挥发法制备PLGA载三氧化二砷纳米粒溶液透明,呈淡蓝色并带有乳光;透射电镜下观察纳米粒为类似球形但不规则,大小比较均匀,大多数集中在100nm左右;纳米粒度及Zeta电位分析仪测定结果显示,纳米粒的粒径分布均匀,平均粒径为80nm左右;原子荧光法测定游离三氧化二砷含量,计算包封率结果表明,三氧化二砷纳米粒的平均包封率可达80%以上;三氧化二砷纳米粒的体外释放曲线证明三氧化二砷的PLGA纳米粒释药缓慢,24h累积释放量接近40%,48h累积释放量仅达45%左右,无明显的突释现象;大鼠体内药动学参数显示,三氧化二砷生理盐水溶液与三氧化二砷PLGA纳米粒溶液的体内代谢存在较大差异,三氧化二砷PLGA纳米粒溶液体内代谢较慢;小鼠体内分布结果显示,三氧化二砷PLGA纳米粒可提高三氧化二砷的骨髓分布。[结论]应用复乳—溶剂挥发法成功的制备三氧化二砷PLGA纳米粒,方法简单可行;纳米粒粒径小而均匀,形态较好,包封率较高;三氧化二砷PLGA纳米粒释药缓慢,无突释效应;三氧化二砷PLGA纳米粒可明显增长大鼠的消除半衰期;三氧化二砷PLGA纳米粒可提高小鼠的骨髓分布,并减少肝脏的分布。更多还原

【Abstract】 [Object]As₂O₃ bone marrow targeted nanoparticles were prepared and the particle size, entrapment rate and morphology are determined.Also the in vitro release and the distribution were studied,to evaluate the efficacy of targeting.[Method]The W/O/W double emulsion-solvent evaporation method was employed to prepare As₂O₃-PLGA-NP,while the PLGA was selected as carrier material.The morphology of nanoparticle was screened by TEM.The particle size was measured by particle size and Zeta Potential Analyzer.Free As₂O₃ was separated from nanoparticle with dynamic dialysis and choose atomic fluorescence method to measure the drug content and in vitro release of As₂O₃.The plasma samples of rats and tissue samples of mice were dissociated by heating. The pharmacokinetic parameters were calculated by 3P97 computer program.And nanoparticle distribution in mice was evaluated by DTI and DSI.[Results]The nanoparticle solution looks like transparent and weak blue in color,with a little opalescence.TEM gave the morphology of nanoparticle is spherical and irregular in form. The mean diameter of nanoparticle is about 80 nm or so.The mean entrapment rate of As₂O₃-PLGA-NP came to more than 80%.In vitro release test illuminated the drug release of PLGA nanoparticle is slow.The cumulative percentage of drug is nearly to 40%after i.v. administration 24h and to 45%after 48h.The pharmacokinetic parameters and distribution results of As₂O₃-PLGA-NP suggested that the metabolism speed of As₂O₃-PLGA-NP is slower than As₂O₃ normal solution and As₂O₃-PLGA-NP can really promote the drug content in bone marrow.[Conclusion]W/O/W double emulsion evaporation is a simple and feasible method.The As₂O₃-PLGA-NP is in small and homogeneous size,good morphology and high entrapment rate.Drug released slowly and no burst release.As₂O₃-PLGA-NP could prolong the elimination half-life time in rats markedly,also it can increase the drug distribution in bone marrow of mice and reduce the drug distribution in liver.更多还原