托氟啶脂质体的研究

Studies on N_3-O-toluyl-Flulorouracil(TFu)Liposomes

目的研究托氟啶脂质体的制备方法并考察其在小鼠体内的生物利用度。方法采用薄膜分散-乳匀法制备托氟啶脂质体,用均匀设计法优化托氟啶脂质体的处方和制备工艺;考察脂质体形态、粒径、粒径分布、Zeta电位、包封率、稳定性及体外释药等特性,对脂质体进行质量评价。将托氟啶脂质体分别进行小鼠灌胃和静脉注射给药,眼底静脉丛取血,HPLC测定血药浓度,用DAS(1.0)软件计算药动学参数。结果所制得的脂质体形态圆整,大小均匀;平均粒径400 nm,多分散性指数0.448,Zeta电位-6.4 mV,平均包封率86.9%;脂质体的体外释药符合双相动力学数学模型。小鼠口服脂质体相对于口服托氟啶(TFu)混悬液的生物利用度为199%,小鼠静脉注射脂质体相对于注射TFu溶液的生物利用度为115%。结论采用薄膜分散-乳匀法制备TFu脂质体,工艺简单,包封率较高,且稳定性良好;托氟啶脂质体经小鼠口服给药提高了药物的生物利用度,注射脂质体与注射TFu乙醇-水溶液生物等效。

OBJECTIVE To prepare N3-O-toluyl-Flulorouracil （TFu）]iposomes, evaluate the physicochemic propen, study the pharmacokinetic ctlaracteristies and bioavailability in mice after oral or intravenous administration. METHODS TFu liposomes were prepared by the film dispersion-homogenization techniques. On the base of the single factor investigation, preparation conditions of TFu liposomes were optimized by the uniform design. The morphology of the liposomes was detected by transmission electron microscope. The Zeta potentials and the polydispersity were evaluated by laser scatter analysis. The entrapment efficiencies were determined by protamine aggregation method and the release characteristics in vitro were investigated. The venous blood was collected from the postorbital venous plexuses of mice after a single oral or intravenous administration of TFu liposomes. The plasma concentrations of TFu were measured using ftPI,C method,and pharmacokinetic parameters were calculated by DAS（1.0） program. RESULTS The liposomes were spherical vesicles with uniform sizes. The mean diameter of TFu liposomes was 400 nm, the polydispersity index was 0. 448, the Zeta potential was -6.4 mV, and the mean entrapment efficiency of TFu liposomes was 86. 96%. The release behavior of TFu from lipnsomes in vitro was fitted to the Bioexponential model. The pharmacokinetic study showed the relative bioavailability of TFu liposomes were 199% arid 115% after oral and intravenous administrated in mice, respectively. CONCLUSION TFu liposomes have a higher entrapment efficieney and better stability using the film dispersion-homogenization technique. The pharmacokinetic studies in mice indicated that TFu liposomes have higher bioavailability than the reference preparations after oral administration in mice. TFu liposomes are bloequivalent after i.v. administration in mice comparing with the reference preparations.