低分子肝素pH敏感混合聚合物纳米粒大鼠体内生物利用度研究

Bioavailability of low molecular weight heparin p H-sensitive polymeric nanoparticles in rats

目的建立生色底物法测定大鼠血浆中低分子肝素(LMWH)含量的方法,研究p H敏感巯基壳聚糖/O-羧甲基壳聚糖(TCS/O-CMC)混合聚合物纳米粒在SD大鼠体内的相对生物利用度。方法采用生色底物法以SD大鼠为研究对象,测定LMWH注射液、LMWH溶液、p H敏感TCS纳米粒和p H敏感TCS/O-CMC混合聚合物纳米粒单剂量给药后的血药浓度,并用Win Nonlin软件计算药动学参数和生物利用度。结果 LMWH溶液、p H敏感TCS纳米粒和p H敏感TCS/O-CMC混合聚合物纳米粒的药动学参数如下:Cmax分别为(0.103±0.025)、(0.425±0.046)和(0.522±0.042)U/ml。AUC0→∞分别为(0.5±0.3)、(4.7±1.0)和(8.0±2.0)U·ml-1·h。相对生物利用度分别为2.10%、20.70%和34.98%(P<0.05)。结论 p H敏感TCS/O-CMC混合聚合物纳米粒可显著提高LMWH的口服生物利用度。

Objective To establish a chromogenic substrate method for content determination of low molecular weight heparin（LMWH） in rat plasma, and to investigate the relative bioavailability of p H-sensitive thiolated chitosan/O-carboxymethyl chitosan（TCS/O-CMC） polymeric nanoparticles in SD rats. Methods The chromogenic substrate method was used and the SD rats were included as the subjects in the study. The plasma concentrations were deter-mined after the rats were given single dose of LMWH injection, LMWH solution, p H sensitive-TCS nanoparticles and p H-sensitive TCS/O-CMC polymeric nanoparticles. The pharmacokinetic parameters and bioavailability were calculat-ed by using Win Nonlin software. Results The pharmacokinetic parameters of LMWH solution, p H sensitive-TCS nanoparticles and p H-sensitive TCS/O-CMC polymeric nanoparticles were as follows： Cmax was（0.103 ±0.025）,（0.425±0.046） and（0.522±0.042）U/ml, respectively. AUC0→∞was（0.5±0.3）,（4.7±1.0） and（8.0±2.0）U·ml^-1·h, respectively. The relative bioavailability was 2.10%, 20.70% and 34.98%, respectively（P〈0.05）. Conclusion p H-sensitive TCS/O-CMC polymeric nanoparticles can significantly increase the oral bioavailability of LMWH.