The development of biodegradable microspheres for sustained release of proteins using a stable polymer aqueous-aqueous emulsion technology

In spite of extensive research efforts since the mid-1970s, the development of dosage forms that can provide sustained release delivery of therapeutic proteins from polymer based dosage forms has been unsatisfactory. In this work, a novel approach has been taken to stabilize proteins in poly(lactic-co-glycolic acid) (PLGA) microspheres. This biodegradable microsphere protein drug delivery system was manufactured using a stable polymer aqueous emulsion technology that differs from conventional emulsions, such as oil-in-water or water-in-oil, in that both phases (dispersed and continuous) are aqueous. The emulsion system consisted of a protein, dextran and PEG (polyethylene glycol) mixture in water, with sodium alginate as the surface active agent. The mixture was homogenized, subsequently lyophilized, and then washed with an organic solvent to remove the PEG. The resultant glassy particles consisting of the structurally delicate proteins were protected by the dextran. These composite microspheres were approximately spherical and range in diameter from 2--5 mum when observed under microscope. The proteins load into the dextran because of preferential partitioning from the PEG while in solution. This process was done under conditions that are free of chemical or physical hazards, such as organic solvents, elevated temperature, high surface tension, high shear stress, and concentrated salts.; X-ray photoelectron spectroscopic (XPS) study confirmed the existence of a surface phase of the glassy particles rich in alginate. The surface alginate phase was not detected for the same system without protein loaded in the dispersed phase, suggesting that alginate was less interactive with proteins.; In a moisture-induced protein denaturation study, the protective effect of this system on proteins was examined by incubating beta-galactosidase at 37°C in a hydrated state. The protected proteins showed excellent resistance to denaturation compared to those incubated under identical conditions in the same medium.; For release kinetics of microencapsulated proteins, a comparative study was carried out between Bovine Serum Albumin (BSA) loaded in PLGA microspheres through the dextran glassy particles and those loaded in other conventional methods. (Abstract shortened by UMI.)...