Exendin-4长效微球的制备及其对2型糖尿病大鼠的降糖作用研究  

In Vitro/in Vivo Evaluation of Microspheres Containing Exendin-4 for Treatment of Type 2 Diabetes Mellitus

作　　者：闫嘉茵[1] 艾国[2,3] 单成启[3] 程远国[3] 

机构地区：[1]郑州大学第一附属医院药学部,郑州450052 [2]空军航空医学研究所,北京100142 [3]军事医学科学院微生物流行病研究所,北京100071

出　　处：《中国药学杂志》2014年第11期925-930,共6页Chinese Pharmaceutical Journal

摘　　要：目的 制备Exendin-4长效微球注射剂,考察其理化性质并在2型糖尿病大鼠体内做药动学和药效学分析。方法 以乳酸-羟基乙酸共聚物[poly（lactide-co-glycolide）,PLGA]为包裹材料,分别采用复乳法（W/O/W）、固体/油/油法（S/O/O）和固体/油/水法（S/O/W）制备了Exendin-4微球。以微球形态、粒径及其分布、微球载药量以及包封率、体外释药曲线、药物稳定性等作为微球的质量评价指标,选择合适的制备方法 。培养2型糖尿病大鼠模型,考察微球的体内释放和降血糖效果。结果 W/O/W法制备出的Exendin-4微球流动性良好,形态圆整,粒径均匀（25-30μm）,Exendin-4的结构保持完好,微球的包封率高（82.2%）,突释低（15.2%）,28 d的累积释放量在90%以上。Exendin-4微球在体内的释放与体外相关性良好（r=0.962 3）,对2型糖尿病大鼠有持续的降血糖作用。结论 采用复乳法,可以制备含Exendin-4的PLGA微球用于糖尿病的治疗。OBJECTIVE To prepare poly（lactic-co-glycolic acid） （PLGA） microspheres of Exendin-4 and evaluate its characteristics. METHODS Exendin-4 microspheres were prepared by different preparation methods （W/O/W, S/O/O and S/O/W method） and characterized for encapsulation efficiency by high-performance liquid chromatography （HPLC）, particle size by laser particle size analyzer, surface morphology by scanning electron microscopy （SEM）, and Exendin-4 stability by circular dichroism （CD）. Release rate in vitro was determined, and the microspheres were administered subcutaneously to type 2 diabetic rats to determine its pharmacokinetics and pharmacodynamics. RESULTS Exendin-4 was successfully encapsulated into PLGA microspheres by W/O/W method. The average size was 25 -30 μm. Exendin-4 encapsulation efficiency was 82. 2%. CD confirmed that the structural integrity of the peptide was intact. The burst release in 24 h was 15.2% and the cumulated release in 28 d was up to 90% in vitro. Animal study demonstrated the drug release from microspheres in vivo and in vitro had a good correlation（ r = 0. 962 3 ） and the blood glucose level was controlled for 4 weeks by Exendin-4 microspheres. CONCLUSION The PLGA microspberes can be used for the controlled delivery of Exendin-4.

关 键 词：EXENDIN-4 乳酸-羟基乙酸共聚物 微球 2型糖尿病 

分 类 号：R944[医药卫生—药剂学]