Novel preparation techniques for alginate–poloxamer microparticles controlling protein release on mucosal surfaces

The objective of this study was to develop novel preparation techniques for protein-loaded, controlled release alginate–poloxamer microparticles with a size range suitable for pulmonary administration. Bovine serum albumin (BSA)-loaded microparticles were prepared by spray-drying aqueous polymer-drug solutions, followed by cross-linking the particles in aqueous or ethanolic CaCl2 or aqueous ZnSO4 solutions. The microparticles were characterized with respect to their morphology (optical and scanning electron microscopy), particle size (laser light diffraction), calcium content (atom absorption spectroscopy), alginate content (complexation with 1,9-dimethyl methylene blue) and in vitro drug release (modified Franz diffusion cell). The spray-dried microparticles were spherical in shape with a size range of 4–6 μm. Aqueous cross-linking led to a significant size increase (10–15 μm), whereas ethanolic cross-linking did not. The substantial drug loss (∼50%) during aqueous CaCl2 cross-linking could be avoided by using aqueous ZnSO4 or ethanolic CaCl2 solutions. Protein release from microparticles cross-linked with ethanolic CaCl2 solutions was much faster than in the case of aqueous CaCl2 solutions, probably due to the lower calcium content. The salt concentration and temperature of the cross-linking solutions also affected the composition of and drug release from the microparticles. Cross-linked alginate–poloxamer microparticles can be produced in a size range appropriate for deep lung delivery and with controlled protein release kinetics (time frame: hours to days) with these novel preparation techniques. The systems offer an interesting potential for the controlled mucosal delivery of protein drugs.