Physical-chemical characterization of octreotide encapsulated in commercial glucose-star PLGA microspheres.

Sandostatin LAR is an injectable long-acting release (LAR) microsphere formulation for octreotide based on a biodegradeable glucose star copolymer of D,L-lactic and glycolic acids (PLGA-glu), which is primarily used for the treatment of patients with acromegaly. There currently is no generic Sandostatin LAR (SLAR) approved in the United States despite expiration of patent coverage. To understand better this important formulation, SLAR was assessed for its composition and physical-chemical properties. Octreotide release kinetics was monitored under physiological conditions over 56 days together with several bioerosion parameters (mass loss, water uptake, pH of release media, polymer molecular weight (Mw), and confocal microscopy after BODIPY uptake). A significant increase in amount of released peptide occurred after day 14. After one day of incubation in PBST octreotide was not extractable completely from SLAR during 2 h of extraction process, but complete extraction was accomplished after 24 h, which suggested strong and non-covalent PLGA-octreotide interactions occurred beginning in the initial release phase. Leuprolide is considered as a cationic peptide competitor for octreotide-PLGA interactions and its presence in the release medium resulted in more continuous octreotide release from SLAR, which was linearly correlated with the mass loss from the polymer (i.e., an indication of erosion-controlled release). These data strongly suggest that octreotide forms a salt with acid end groups of linear PLGA chains that are either present as impurities in, and/or produced by the degradation of, the PLGA-Glu. This salt is expected to catalyze octreotide acylation and extend peptide release beyond that is driven by erosion-control. The characterization studies of physicochemical properties of SLAR described here could be useful for development and regulatory evaluation of generic octreotide microspheres as well as new polymer formulations in which the polymer strongly interacts with encapsulated peptides.