目的通过Beagle犬长期给药毒性试验及免疫原性试验,评价重组人胰岛素注射液(Insulin R)与原研药(Humulin R)的生物相似性。方法进行Beagle犬sc Insulin R 30 d停药14 d长期给药毒性试验,Insulin R剂量为0.5、1.0、1.5 IU/kg,Humulin R剂量为1.5 IU/kg,检测指标包括一般状况、进食量、体温、心电图、血液学、凝血、血清生化、电解质及尿液等,于给药期结束及停药期结束分两次剖杀动物,测定主要脏器的脏器系数并进行常规病理组织学检查;ELISA法检测Beagle犬血清的免疫原性。结果 Beagle犬重复sc Insulin R 30 d毒性试验中,中、高剂量组部分动物出现食欲降低、食量减少,高剂量1只雄性动物出现流涎、站立不稳、心率加速、抽搐等低血糖症状,中、高剂量组动物心率增加;原研药组与Insulin R高剂量组毒性反应相当;Beagle犬给予Insulin R 30 d未检测到抗药抗体。结论 Beagle犬sc Insulin R 30 d时的最大无毒反应剂量为0.5 IU/kg,相当于临床等效剂量的0.5倍,且未产生抗药抗体,与Humulin R具有较好的临床前生物相似性。 Objective To evaluate the biological similarity of Insulin R and Humulin R by long-term toxicity test and immunogenicity test in Beagle dogs. Methods Long-term toxicity test was performed on sc Insulin R 30 d in Beagle dogs for 14 days. The dosage of Insulin R was 0.5,1.0,1.5 IU / kg and the dosage of Humulin R was 1.5 IU / kg. The detection indexes included general condition, food intake, Body temperature, electrocardiogram, hematology, blood coagulation, serum biochemistry, electrolytes and urine. At the end of the administration period and the end of the withdrawal period, the animals were divided into two sections to determine the organ coefficients of major organs and routine histopathological examination The immunogenicity of Beagle dog’s serum was detected by ELISA. Results Beagle dogs repeated sc-Insulin R 30 d toxicity test. Some animals in medium and high dose groups showed decreased appetite and reduced appetite. Hypoglycemia symptoms such as salivation, standing instability, accelerated heart rate and convulsions were observed in a single male at a high dose , And the heart rate increased in the high-dose group. The toxicity of the high-dose Insulin R group was equal in the original drug-treated group and no detectable antibody was detected in the Insulin R 30-day Beagle dog. Conclusion The maximum non-toxic dose of sc Insulin R at 30 d was 0.5 IU / kg, which is equivalent to 0.5 times of the equivalent clinical dose, and did not produce any drug-resistant antibody. It had better preclinical bio-similarity with Humulin R .