口服型胰岛素微囊研制的初步报告

The primary report on mamufacturing the oral microcapsule containing insulin

目的 观察改变了材料分子量、微囊粒径后的聚丙交酯胰岛素微囊 (PL A- MCI)体外释药及大鼠口服后血糖的变化。方法 体外释药在磷酸盐缓冲液 (PBS)中进行 ,胰岛素测定用福林 -酚法。体内实验由糖尿病大鼠口服 PL A- MCI后每小时血糖测定反映 ,并与口服纯胰岛素的二组对照及同期饥饿对照组血糖进行比较。结果 PL A- MCI在 PBS中 3～ 7小时内释放了 5 1.0 %～ 73.4%的胰岛素 ,11小时后释放达稳态。口服 PL A- MCI后大鼠血糖下降达 80 .9± 10 .8%(n=10 ) ,显著高于口服等量纯胰岛素的正常大鼠 (31.0± 15 .1% ,n=6 )和糖尿病大鼠 (47.0± 2 7.9% ,n=5 )以及未服药同期饥饿对照糖尿病大鼠 (40 .0± 16 .7% ,n=7) (P均 <0 .0 0 1)。PL A- MCI与水预混 1小时后口服 ,体内降血糖峰时为 1～ 3小时 ,持续作用 10～ 12小时。PL A- MCI在 PBS液中温育 3周 ,电镜下仍见基本完整形态。结论 减少 PL A分子量 ,增加微球粒径加快了胰岛素从 PL A- MCI中的释放 ,提高了其口服后降血糖效应 ,并保持其缓慢降解特性 ,具有良好的安全性。

Objective In order to improve the blood glucose(BG) lowing effect of polylactide acid microcapsulated insulin (PLA MCI),we changed the molecular weight of PLA,diameter of microsphere and observed the release profile of this new PLA MCI in PBS buffer,as well as the changes of peripheral BG in diabetic rats after feeding.Methods Release profile in vitro was made in PBS buffer,the insulin was measured by follin phenol method.In vivo the BG lowing effect of PLA MCI was studied in 4 groups of rats.Group 1 was normal rats ( n =6), group 2 was diabetic rats ( n =5),all these rats in both groups were fed by 2.4mg of pure insulin.Group 3 was diabetic rats ( n =10) fed by PLA MCI contained 2.4 mg of insulin.Group 4 was starve DM rats control group without any oral drug ( n =7).In the rats of 4 groups BG were measured every hour until BG returned to control level.The BG changes were compared among 4 groups.Results In vitro during 3～7h about 51.0%～73.4% of insulin had been released from PLA MCI.In vivo the maximum BG decreases were 31.0±15.1% in group 1,47.0±27.9% in group 2,40.0±16.7% in group 4 and 80.9±10.8% in group 3 during 13 hours.The BG lowing effect of PLA MCI began at 30 minutes,the peak times were in 1 to 3 hours after ingestion,the effect persisted for 10～12 hours.Under the scanning electron microscope the PLA MCI showed a intact shape but with many small hole surface after incubation in PBS and 1% lipase for 3 weeks.Conclusion By decrease of the molecular weight of PLA,and thinning wall of microsphere as well as increase of the diameter of microsphere,the insulin release rate was increased from PLA MCI, which also improved BG lowing effect in vivo after ingestion.Since PLA MCI still kept its slow degradation after 3 weeks,it may be in a good safety after ingestion.