依托泊苷静脉注射亚微乳的制备及其体内外评价  

Preparation and in vitro and in vivo evaluation of etoposide submicro-emulsion for intravenous injection

作　　者：田玲玲[1] 唐星[1] 何海冰[1] 王静[1] 

机构地区：[1]沈阳药科大学药学院,辽宁沈阳110016

出　　处：《药学学报》2007年第8期892-897,共6页Acta Pharmaceutica Sinica

摘　　要：本文旨在制备依托泊苷静脉注射亚微乳(ESE)并考察其体内外性质。采用高压均质法制备载药亚微乳,单因素试验考察处方工艺中影响制剂质量的因素,激光散射法和超滤离心法测定其粒径、zeta电位和包封率;长期留样观察其物理稳定性,恒温加速试验-威布尔分布拟合法考察其化学稳定性;以依托泊苷溶液为参比制剂,考察其在大鼠体内药代动力学行为。测得亚微乳平均粒径(189.9±54.6)nm,zeta电位-32.6 mV,包封率91.7%。4℃长期留样9个月物理稳定性无显著变化,加速试验预测4℃有效期(T0.9)约为665 d。亚微乳和溶液在大鼠体内药代动力学曲线均符合双隔室模型,药时曲线下面积(AUC0-t)分别为(18.30±8.74)和(19.32±6.45)μg.h.mL-1。结果表明ESE避免了有机增溶剂的使用,物理化学稳定性较溶液显著提高,且未改变体内药代动力学行为。The aim of this thesis is to prepare etoposide submicro-emulsion(ESE) for intravenous injection and investigate its characteristics in vitro and in vivo.High-pressure homogenization was used to prepare ESE,using 10%(w/w) soybean oil and 10%(w/w) medium-chain triglyceride as mixed oil phase,and 1.8%(w/w) fabaceous lecithin as emulsifier.The pH was adjusted to 5.5 with 0.1(mol·L^(-1)) NaOH to keep the most stability of ESE.The particle size distribution and zeta potential were measured using photon correlation spectroscopy.Ultrafiltration was used to estimate the relative percentages of etoposide in each phase.Long-term storage test and accelerated isothermal test-Weibull distribution method were used to estimate the physical and chemical stability of ESE.Plasma pharmacokinetics in rats was monitored by high performance liquid chromatography by comparison with etoposide nonaqueous solution at the same time.The mean particle size,zeta potential and entrapment efficiency of ESE were(189.9±54.6)nm,-32.6 mV and 91.7%,respectively.The emulsion was stable during 9 month storage at 4 ℃.The shelf life(T_(0.9)) of etoposide in lipid emulsion was estimated to be about 665 days at 4 ℃.The drug concentration-time curves of ESE and solution were similar and could be described by two compartment model.The area under the curve of concentration versus time from zero to the last time point and the mean residence time of ESE and solution were(18.30±8.74) and(19.32±6.45) μg·h·mL^(-1),and(1.46±0.32) and(1.71±0.52) h,respectively.Etoposide was incorporated in submicro-emulsion to improve its physical and chemical stability without addition of organic solvents with insignificant different characteristics in vivo when compared with solution.

关 键 词：依托泊苷 亚微乳 高压均质法 药代动力学 

分 类 号：R917.796[医药卫生—药物分析学]