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 CaCl(2) or aqueous ZnSO(4) 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 4-6µm. Aqueous cross-linking led to a significant size increase (10-15µm), whereas ethanolic cross-linking did not. The substantial drug loss (∼50%) during aqueous CaCl(2) cross-linking could be avoided by using aqueous ZnSO(4) or ethanolic CaCl(2) solutions. Protein release from microparticles cross-linked with ethanolic CaCl(2) solutions was much faster than in the case of aqueous CaCl(2) 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.

Alginate-poloxamer microparticles for controlled drug delivery to mucosal tissue.

PURPOSE: The aim of this study was to prepare and characterize novel hydrogel-based delivery systems allowing for the controlled release of drugs to mucosal surfaces. METHODS: Terbutaline sulfate and bovine serum albumin (BSA)-loaded alginate-poloxamer microparticles were prepared by a w/o-emulsion- and external gelation method. The microparticles were characterized by optical and scanning electron microscopy, laser light diffraction, atomic absorption spectroscopy, energy-dispersive X-ray analysis, via complexation with 1,9-dimethyl methylene blue and using dialysis bags as well as modified Franz diffusion cells for in vitro drug-release measurements. RESULTS: Using heptane as organic phase, homogeneous and almost spherical microparticles were obtained with a high-loading efficiency (>90%). The resulting drug-release patterns could effectively be adjusted by varying the "alginate:poloxamer" blend ratio. In addition, the particle size, morphology, calcium and chloride content as well as alginate-release rates could be altered. Erosion was the predominant release mechanism for BSA. Special attention needs to be paid to the microparticle recovery procedure, which can significantly affect key properties such as the resulting drug-release patterns. CONCLUSIONS: The novel hydrogel-based microparticles offering mild conditions for incorporated drugs (e.g., proteins) provide an interesting potential as controlled delivery systems for mucosal surfaces.