Design of core-shell gel beads for time-programmed protein release.

Calcium alginate gel beads were coated with calcium poly(γ-glutamate) (Ca-γ-PGA) or its alkylate to modulate a release onset time of macromolecular drugs like proteins. Dextran release from coated alginate gel beads with γ-PGA increased the onset release time from 13 min for bare alginate beads to 49 min for γ-PGA-coated alginate gel beads with diameters of about 0.6 mm. The γ-PGA coating may act as a barrier to disintegration due to the swelling of alginate gels through ion exchange of Ca(2+) with Na(+) . As the osmotic pressure increases inside the γ-PGA capsule, the γ-PGA layer eventually delaminates to form flakes and enables drug release. To further increase the onset release time, we modified the carboxyl groups of γ-PGA with 1-bromobutane to increase the hydrophobicity of the coating layers. By incorporating 20 mol % butyl groups, the onset release time increased to 87 min. Even for proteins, the hydrophobic polymer coating of the gels was effective at increasing the lag time. Similar to the release of dextran, proteins, albumin (bovine serum albumin), immunoglobulin G, and fibrinogen showed an S-shaped release curve with onset release time, in which the onset release time depends on the molecular weight and their conformation. In conclusion, we successfully prepared modified alginate gel beads with injectable bead diameters and modulated the onset release time of macromolecular drugs.