目的 研究精蛋白重组人胰岛素注射液(预混50/50)与已上市的50/50混合重组人胰岛素注射液在Beagle犬体内的药动学和生物等效性。方法 采用单剂量试验制剂和参比制剂自身双交叉给药方案,12只健康Beagle犬分别皮下注射同剂量精蛋白重组人胰岛素注射液(预混50/50)和50/50混合重组人胰岛素注射液,给药后不同时间经静脉采集血浆标本,同时采用罗氏血糖仪同步测定动物血糖水平;放射免疫分析(RIA)法检测血药浓度;血药浓度数据用DAS 2.0药动学软件拟合计算参数,并进行生物等效性分析。结果 Beagle犬交叉sc 5 U/只试验制剂与参比制剂后,主要药动学参数分别为:平均t_1/2为(2.62±2.14)、(1.99±1.37)h;平均C_max为(108.30±26.90)、(104.60±18.45)μU/mL;平均t_max为(0.94±0.43)、(0.90±0.39)h;平均AUC_(0-t)为(362.3±73.6)、(351.7±53.9)μU/(mL·h)。血浆最低葡萄糖浓度(C_min)分别为(1.74±0.25)、(1.80±0.33)mmol/L,达到最低浓度所需时间(t_min)分别为(1.58±0.97)、(2.02±0.96) h。结论 精蛋白重组人胰岛素注射液(预混50/50)与50/50混合重组人胰岛素注射液在Beagle犬体内具有生物等效性。

Objective To investigate the pharmacokinetic and bioequivalence of Isophane Protamine Recombinant Human Insulin Injection (pre-mixed 50/50) and 50/50 Mixture Recombinant Human Insulin Injection after sc administration in Beagle dogs. Methods Twelve healthy Beagle dogs dogs were divided into two groups, and the dogs in two groups were separately singlely sc injected with Isophane Protamine Recombinant Human Insulin Injection (pre-mixed 50/50) and 50/50 Mixture Recombinant Human Insulin Injection in the same dose according to a randomized two-phase crossover. The plasma was sampled at different time points after sc administration, and the blood glucose levels were determined by Roche Glucose meter synchronously. The radioimmunoassay (RIA) method was used to determine the concentration of blood insulin at the different sample points. The pharmacokinetic parameters were calculated by DAS 2.0 Software. Results Beagle's dogs were treated with test preparation and reference preparation following single sc administration at the dose of 5 U/animal. The main pharmacokinetic parameters of test preparation and reference preparation were as following: The elimination half-life (t_1/2) was (2.62 ± 2.14) and (1.99 ± 1.37) h, the peak concentration (C_max) was (108.30 ± 26.90) and (104.60 ± 18.45) μU/mL, the peak time (t_max) was (0.94 ± 0.43) and (0.90 ± 0.39) h, and the area under the concentration-time curve (AUC_(0-t)) was (362.3 ± 73.6) and (351.7 ± 53.9) μU/(mL·h), respectively. What's more, the minimum blood glucose levels (C_min) of the tested and referenced samples were (1.74 ± 0.25) and (1.80 ± 0.33) mmol/L, respectively, and the t_min (time to reach minimum blood glucose level) was (1.58 ± 0.97) and (2.02 ± 0.96) h, respectively. Conclusion Isophane Protamine Recombinant Human Insulin Injection (pre-mixed 50/50) and 50/50 Mixture Recombinant Human Insulin Injection are bioequivalent in the therapy effect.

国家重大新药创制科技重大专项(2012ZX09304002)