Minimizing the initial burst of octreotide acetate from glucose star PLGA microspheres prepared by the solvent evaporation method

Sandostatin long-acting release (SLAR) depot for 1-month controlled release of octreotide is a somatostatin analogue product that has been used extensively in the pharmacological treatment of acromegaly. The complexities in the SLAR coacervation manufacturing processes and the use of a unique glucose-star poly(lactic-co-glycolic acid) (PLGA-glu) may have contributed to the lack of US FDA-approved generic products referencing SLAR in the USA. To address this challenge, we encapsulated octreotide acetate by the commonly used solvent evaporation method in microspheres of a similar composition to SLAR, including the use of a comparable PLGA-glu. Based on our previous study that identified key formulation variables to prepare octreotide acetate/PLGA-glu microspheres, including lowering initial peptide pH and introducing an annealing step post loading, here we added NaCl to the external water phase to further improve the formulation. The resulting microspheres exhibited highly similar release and stability performance in vitro to SLAR, including an exceptionally low initial burst. The very low initial burst was also confirmed by pharmacokinetics in rats. Full erosion behavior analysis (polymer MW, water uptake and mass loss) revealed a slightly faster degradation of SLAR than the solvent evaporation formulations. Analysis of kinetics of dry Tg of the formulations reflected (a) the elevated residual solvent in SLAR and was not duplicated in the solvent evaporation formulations, and (b) the slightly higher Tg of peptide loaded formulations relative to than blank microspheres, consistent with the interaction of the acetate salt of octreotide with linear PLGA chains in the PLGA-glu. These data indicate that it is possible to prepare peptide loaded microspheres by the solvent evaporation method with extraordinarily similar performance to microspheres, such as those in SLAR, that are prepared by the low-burst release coacervation method.