口服胰岛素毫微球的体外释药及对糖尿病大鼠的降血糖作用

为研制一种生物利用度较高而降血作用时间短的口服INS制剂。制备了胰岛素聚氰基丙烯酸烷基酯毫微球(INS-NP)。其平均粒径为252.4nm,胰岛素的结合率为70.1%±2.3%。INS-NP的体外释药符合双指数函数式,酸性介质中释放更快。Wistar大鼠po不同剂量的INS-NP和胰岛素溶液(INS-SOL),结果显示10u·kg^-1和20u·kg^-1的INS-NP可显著降低血糖,但两个剂量间无显著性差异而INS SOL无降糖作用。用曲线上面积比较poINS-NP和scINS-SOL后的降糖作用,结果前者的相对生物利用度为7.58%。在血糖下降的时间范围内,体外释药的百分率与降糖速率间有一定相关性。

IN VITRO RELEASE KINETICS AND HYPOGLYCEMIC EFFECT ON DIABETIC RATS AFTER ORAL ADMINISTRATION OF INSULIN LOADED NANOPARTICLES

The insulin-loaded polyalkylcyanoacrylate nanoparticles (INS-NP) were made with Dextran 70 as the stabilizer. The mean diameter of INS-NP was 252.4 nm with a poly dispersity of 0.005. The associating ratio of insulin to the nanoparticles reached 70.1% +/- 2.3%, while the loading capacity was 0.14 u.mg-1. Studies on in vitro release kinetics showed that release profiles can be well modelled using a biexponential function. The burst effect was obvious, and a faster release was observed in acidic media. After various doses of INS-NP were intragastrically given to diabetic rats, significant decrease of glucose level was achieved in the 10 and 20 u.kg-1 groups, with no significant difference between these two doses. The relative bioavailability after p.o. administration of INS-NP 10 u.kg-1 over s.c. administration of insulin solution 1 u.kg-1 was 7.58% calculated by the area over the curve of glucose level (%) versus time profiles. The correlation was obvious between the % of insulin released at pH 7.0 and the % of glucose decreased within the first 7 hours. Hence, an oral insulin preparation with rather high bioavailability was provided in this study, and its shorter effective time will make it more convenient for the control of the glucose level in clinics.