微乳型丙泊酚纳米注射液的制备与评价

Preparation and evaluation of propofol injectable microemulsion

目的:制备微乳型丙泊酚纳米注射液,并对其进行体内外评价,为新型微乳型纳米注射液研究提供参考。方法:使用可注射用乳化剂和油制备丙泊酚纳米注射液,旋转黏度计测定其黏度,动态光散射法测定其粒径和Zeta电位,透射电镜测定其显微外观,透析法测定其游离药物浓度,并研究其体外溶血性和Beagle犬体内药动学性质。结果:黏度为1.5×10-3 Pa.s,粒径为(22.7±10.2)nm,Zeta电位为-5.82 mV;透射电镜照片显示微乳粒子外观近球状,游离药物浓度为(17.9±0.8)μg.mL-1(n=3),不引起溶血的发生;微乳与脂肪乳主要药动学参数t1/2α分别为(1.506±0.994)和(2.512±2.122)min,t1/2β分别为(42.221±43.878)和(49.095±42.521)min,V1分别为(1.947±1.17)和(3.546±3.836)L.kg-1,CL分别为(0.218±0.07)和(0.219±0.068)L.min-1.kg-1,AUC0～t分别为(17.916±6.772)和(16.968±5.395)mg.min.L-1,AUC0～∞分别为(20.488±7.729)和(19.750±5.504)mg.min.L-1,K10分别为(0.140±0.066)和(0.107±0.070)min-1,K12分别为(0.419±0.288)和(0.284±0.196)min-1,K21分别为(0.106±0.068)和(0.105±0.090)min-1。结论:丙泊酚纳米注射液粒径小于100 nm,游离药物浓度低,无溶血性,与脂肪乳体内药动学无显著差异,显示出良好的安全性。

Objective：Propofol injectable microemulsion was prepared and evaluated to provide some references for research and development of injectable microemulsion.Methods：Propofol injectable microemulsion was developed with injectable emulsifiers and oil.The viscosity,particle size,zeta potential and morphology were characterized,respectively,by rotation viscometer,dynamic light scattering and transmission electron microscope.The free propofol was determined by equilibrium dialysis method.The hemolytic activities and pharmacokinetic parameters in dogs were investigated.Results：The viscosity,particle size and the zeta potential were 1.5×10^-3Pa·s,（22.7±10.2）nm and-5.82mV,respectively;The transmission electron microscopic image showed a spherical shape.The concentration of free propofol in microemulsion was（17.9±0.8）μg·mL-1（n=3）.The microemusion did not cause hemolysis.The pharmacokinetic parameters of propofol injectable microemulsion and emulsion in dogs were as follows：t1/2α was（1.506±0.994） and（2.512±2.122）min,t1/2β was（42.221±43.878） and（49.095±42.521）min,V1 was（1.947±1.17） and（3.546±3.836）L·kg-1,CL was（0.218±0.07） and（0.219±0.068）L·min-1·kg-1,AUC0~t was（17.916±6.772） and（16.968±5.395）mg·min·L-1,AUC0~∞ was（20.488±7.729） and（19.750±5.504）mg·min·L-1,K10 was（0.140±0.066） and（0.107±0.070）min-1,K12 was（0.419±0.288） and（0.284±0.196）min-1,K21 was（0.106±0.068） and（0.105±0.090）min-1.Conclusion：Propofol injectable microemulsion shows a good safety with diameter less than 100nm,low free propofol and no hemolysis.No significant differences have been found among the main pharmacokinetic parameters in microemulsion and emulsion preparations.