Abstract：
The once-weekly Bydureon® (Bdn) PLGA microsphere formulation encapsulating the GLP-1 receptor agonist, exenatide acetate, is an important complex injectable product prepared by coacervation for the treatment of type 2 diabetic patients. Encapsulation by coacervation is useful to minimize an undesirable initial burst of exenatide, but it suffers from manufacturing difficulties such as process scale-up and batch-to-batch variations. Herein we prepared exenatide acetate-PLGA formulations of similar compositions using the desirable alternative double emulsion-solvent evaporation technique. After screening several process variables, we varied the PLGA concentration, the hardening temperature, and the collected particle size range, and determined the resulting drug and sucrose loading, initial burst release, in vitro retention kinetics, and peptide degradation profiles using Bdn as a positive control. All formulations exhibited a triphasic release profile with a burst, lag, and rapid release phase, although the burst release was greatly decreased to <5% for some. Marked differences were observed in the peptide degradation profiles, particularly the oxidized and acylated fractions, when the polymer concentration was varied. For one optimal formulation, the release and peptide degradation profiles were similar to Bdn microspheres, albeit with an induction time shift of one week, likely due to the slightly higher Mw of PLGA in Bdn. These results highlight the effects of key manufacturing variables on drug release and stability in composition-equivalent microspheres encapsulating exenatide acetate and indicate the potential of manufacturing the microsphere component of Bdn by solvent evaporation.
摘要：
每周一次的Bydureon®(Bdn)PLGA微球制剂封装GLP-1受体激动剂，醋酸艾塞那肽,是通过凝聚制备的用于治疗2型糖尿病患者的重要复杂可注射产品。凝聚封装可用于最大程度地减少艾塞那肽的不良初始爆发，但它遭受制造困难，如工艺放大和批次间的变化。在本文中,我们使用所需的替代双重乳液-溶剂蒸发技术制备了类似组成的醋酸艾塞那肽-PLGA制剂。在筛选了几个过程变量之后，我们改变了PLGA的浓度,硬化温度,和收集的粒径范围，并确定了所得的药物和蔗糖负载，初始爆发释放，体外保留动力学，和使用Bdn作为阳性对照的肽降解谱。所有制剂均表现出具有突释的三相释放曲线，滞后，和快速释放阶段，尽管一些人的爆发释放大大降低至<5%。在肽降解谱中观察到明显的差异，特别是氧化和酰化的馏分，当聚合物浓度变化时。对于一个最佳配方，释放和肽降解曲线与Bdn微球相似，尽管入职时间偏移一周，可能是由于Bdn中PLGA的Mw略高。这些结果突出了关键制造变量对包封乙酸艾塞那肽的组合物等效微球中的药物释放和稳定性的影响,并且表明通过溶剂蒸发制造Bdn的微球组分的潜力。
