In vitro performance of composition-equivalent PLGA microspheres encapsulating exenatide acetate by solvent evaporation

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.