紫杉醇纳米混悬剂的制备及其在动物体内药动学与组织分布研究

Preparation of Paclitaxel Nanosuspension and Study of Its Pharmacokinetic and Biodistrabution Behavior in Rats

目的制备紫杉醇纳米混悬剂,并考察其在大鼠体内的药动学及小鼠体内的组织分布特征。方法采用重结晶结合高压均质法制备紫杉醇纳米混悬剂,以纳米粒粒径和Zeta电位为指标,考察紫杉醇纳米混悬剂的影响因素,对制得的纳米混悬剂进行表征。采用高效液相色谱法测定大鼠血浆及小鼠组织中的紫杉醇浓度。结果紫杉醇纳米混悬剂粒径为214.4 nm,PI值为0.09,平均Zeta电位为-22.7 mV,体系稳定。紫杉醇纳米混悬剂和紫杉醇注射液在大鼠体内的消除半衰期分别为5.65和3.77 h;AUC分别为5.20和20.34μg.h.mL-1;MRT分别为3.20和2.75 h;CL分别为2.05和0.56 L.kg-1.h-1。与紫杉醇注射液相比,紫杉醇纳米混悬剂在小鼠肝、脾、脑组织中的药物含量显著增加。结论紫杉醇纳米混悬剂的处方简单,制备工艺稳定,且具有良好的肝、脾靶向性,对减轻药物不良反应,降低心、肾毒副作用具有一定的意义。

OBJECTIVE To prepare paclitaxel nanosuspensions,and to study the pharmacokinetics of paclitaxel nanosuspensions in rats and tissue distribution in mice.METHODS Taking the size of nanoparticals and Zeta electric potential as index,studied the influential factors of the preparation of paclitaxel nanosuspension by high pressure homogenization combinded with recrystallization.After intravenous administration of paclitaxel injection and paclitaxel nanosuspensions to rats,paclitaxel concentrations in plasma and tissue samples were collected at preplanned time intervals and determined by HPLC.RESULTS The diameter of paclitaxel nanoparticle was 214.4 nm,the polydispersity was 0.09.Zeta electric potential was-22.7 mV.The nanosuspension system was stable.In plasma,half-lifes（t1/2） of paclitaxel nanosuspensions and paclitaxel injection were calculated to be 5.65 and 3.77 h,respectively.AUCs were estimated to be 5.20 and 20.34 μg·h·mL-1,respectively.MRTs were 3.20 and 2.75 h,and CL were 2.05 and 0.56 L·kg-1·h-1,respectively.The study of biodistrabution in mice showed that nanosuspensions significantly increasing paclitaxel concentration in the organ like liver and spleen compared with paclitaxel injection.CONCLUSION The preparation of paclitaxel nanosuspension was practicable.The results of biodistrabution indicated that paclitaxel nanosuspension may increase paclitaxel concentration in the targeted site and decrease the side effects in heart and kidney.