托氟啶固体脂质纳米粒的制备及其小鼠体内药动学

Preparation and pharmacokinetics in mice of N3-O-toluyl-flulorouracil solid lipid nanoparticles

目的制备托氟啶(TFu)固体脂质纳米粒(TFu-SLN),并对其进行理化性质评价和小鼠体内药动学研究。方法HPLC法测定体内外TFu的含量;用薄膜分散法制备TFu-SLN;透射电镜观察纳米粒形态;激光粒度分析仪测定其粒径、粒度分布和zeta电位;以TFu50%乙腈溶液为对照,采用动态膜透析法分别考察TFu-SLN在磷酸盐缓冲液(pH7.4)、人工胃液(pH1.2)、人工肠液(pH6.8)以及人工胃液2h后转入人工肠液中至48h的体外释药情况;以TFu水混悬液组为对照,考察小鼠口服TFu-SLN后药动学性质。结果所制备的TFu-SLN呈球形或类球形,平均粒径为(156.5±s0.5)nm,zeta电位为(-30±4)mV,平均包封率为(84±4)%,平均载药量为(2.1±0.9)%。体外释放结果表明将TFu制成固体脂质纳米粒可明显延缓药物释放的时间。小鼠口服TFu-SLN相对于口服TFu水混悬液的生物利用度为209%。结论薄膜分散法制备的TFu固体脂质纳米粒包封率较高,具有一定的缓释能力,生物利用度较高,对促进难溶性药物口服具有一定意义。

AIM To prepare N3-O-toluyl-flulorouracil （TFu） solid lipid nanoparticles （SLN）, evaluate the physicochemical properties and study the bioavailability in mice after oral administration. METHODS The content of TFu was determined by HPLC. TFu-SLN was prepared by the film-dispersion method, the morphology of nanoparticles was observed by transmission electron microscopy. The particle size, polydispersity, and zeta potential were measured by laser particle size analyzer. The released kinetics of TFu-SLN in vitro of different media, such as the phosphate buffer solution （PBS, pH 7.4）, artificial gastric juice （pH 1.2）, artificial intestinal juice （pH 6.8）, and artificial gastric juice （2 h） followed by artificial intestinal juice （2 - 48 h）, were studied by dynamic dialysis system using TFu solution （50% acetonitrile） as control. Taking the TFu aqueous suspension as control, the pharmacokinetic properties of TFu-SLN in mice after oral administration were studied. RESULTS The morphology of TFu-SLN was approximately spherical. The average particle size of TFu- SLN obtained was （156.5 ± s 0.5） nm. The zeta potential was （-30 ± 4） mY. Encapsulating efficiency was （84 ± 4） %. Drug loading was （2.1 ± 0.9）%. It was indicated that the TFu-SLN could efficiently improve the release behaviors of TFu from SLN in the four different media. It was found that the relative biological availability of TFu in SLN increased significantly to 209% comparing with that of the TFu aqueous suspension after oral administration in mice. CONCLUSION TFu-SLN prepared by the film-dispersion method has higher entrapment efficiency, enhanced sustained-release behavior and higher bioavailability than TFu aqueous suspension after oral administration in mice. It appears that SLN offer a promising delivery system to reach high oral bioavailability for poorly soluble drugs.