Importance of the test medium for the release kinetics of a somatostatin analogue from poly( d,l-lactide- co-glycolide) microspheres

Abstract

The determination of in vitro release kinetics of peptides from poly( d,l-lactide- co-glycolide) (PLGA) microspheres generally requires optimization of the test conditions for a given formulation. This is particularly important when in vitro/in vivo correlation should be determined. Here, the somatostatin analogue vapreotide pamoate, an octapeptide, was microencapsulated into PLGA 50:50 by spray-drying. The solubility of this peptide and its in vitro release kinetics from the microspheres were studied in various test media. The solubility of vapreotide pamoate was approximately 20–40 μg/ml in 67 mM phosphate buffer saline (PBS) at pH 7.4, but increased to approximately 500–1000 μg/ml at a pH of 3.5. At low pH, the solubility increased with the buffer concentration (1–66 mM). Very importantly, proteins (aqueous bovine serum albumin (BSA) solution or human serum) appeared to solubilize the peptide pamoate, resulting in solubilities ranging from 900 to 6100 μg/ml. The release rate was also greatly affected by the medium composition. Typically, in PBS of pH 7.4, only 33±1% of the peptide were released within 4 days, whereas 53±2 and 61±0.9% were released in 1% BSA solution and serum, respectively. The type of medium was found critical for the estimation of the in vivo release. The in vivo release kinetics of vapreotide pamoate from PLGA microspheres following administration to rats were qualitatively in good agreement with those obtained in vitro using serum as release medium. Finally, sterilization by γ-irradiation had only a minor effect on the in vivo pharmacokinetics.