Formulation and characterization of exenatide-loaded PLGA microspheres prepared by coacervation

Bydureon^® is a once-weekly injection of poly(lactide-co-glycolide) (PLGA) microspheres containing exenatide acetate, a synthetic analog of the GLP-1 receptor agonist exendin-4. These microspheres are formulated by coacervation (i.e., phase separation), using a single-emulsion method. There remains a knowledge gap between how formulation variables affect product attributes and performance. We aimed to bridge this gap by evaluating the effect of formulation variables on encapsulating exenatide in PLGA microspheres at similar compositions to Bydureon^®. We first screened process variables without peptide to establish stability windows during coacervation, i.e., conditions that produced high yields of well-formed microspheres. We introduced exenatide during coacervation as a function of PLGA concentration, DCM (dichloromethane): water and DCM: Si oil (polydimethylsiloxane) volume ratios, hold time between Si oil addition and heptane bath immersion, and other manufacturing conditions. We evaluated the formulation yield, residual solvent content, encapsulation efficiency, and 24-h release. A PLGA concentration of 6% w/w was selected because of its wide range of stable formulations with varying DCM: Si oil phase volume ratios. The hold time between Si oil addition and heptane immersion was set at 1 min, although microspheres were stable between a range of 10 s to 2 min. The resultant formulations displayed elevated yields of > 50%, and a low in-vitro 24-h burst release of 2-6%. These formulations exhibited continuous release profiles of predominantly parent and glycolic acid acylated peptide for over 56 days in vitro, as expected by the commercial product. The framework of conditions and their effects on the formulations was established for loading exenatide in PLGA microspheres with desirable release characteristics. These results are useful for both microencapsulation of generic and new peptides in PLGA microspheres by coacervation.