FACTORS INFLUENCING THE RELEASE OF PEPTIDES AND PROTEINS FROM BIODEGRADABLE PARENTERAL DEPOT SYSTEMS

Design factors affecting release of octreotide and bovine serum albumin from microspheres and disk-shaped implants were studied. The polymers used were biodegradable branched poly (DL-lactide-co-glycolide-D-glucose) and linear poly (DL-lactide-co-glycolide). Octreotide, Sandostatin(R), is an octapeptide analogue of somatostatin. Bovine serum albumin served as a model compound. Microspheres were produced by a modified triple-emulsion technique, implants by compression moulding. In vivo studies in rats and rabbits revealed a continuous release of octreotide from microspheres over 1-2 months. This resulted in a corresponding decrease of pituitary volume in animals with estradiol induced pituitary hyperplasia. In vitro release studies demonstrated an increased release of peptide and protein with increasing loading levels and contrary to expectation with increasing polymer molecular weights. Composition and ionic strength of the in vitro release medium affected the release behaviour. The fractional release of octreotide from microspheres decreased with increasing ionic strength of the medium. Water uptake and pore formation of implants started as early as day one of exposure to phosphate buffer and increased slowly until approximately day 15, when fragmentation and erosion of the polymer were noticeable. Polymer molecular weights decreased within the same period of time at a constant rate. It was concluded from a mechanistical point of view, that pore-diffusion and bioerosion play an important role on the release of peptides and proteins, but are insufficient to describe the sequelae of events when these systems are exposed to an aqueous environment both in vivo and in vitro. Osmotic effects, swelling of the devices and ionic interactions e.g. such between polymer terminal carboxylic acid groups and basic polypeptides have to be taken into account to explain the release properties of these delivery systems.