In situ gelling nasal inserts for influenza vaccine delivery.

Purpose: The objective of this study was to investigate the potential of rapidly gelling nasal inserts as vaccine delivery system.

Methods: Nasal inserts were prepared by freeze-drying hydrophilic polymer solutions containing influenza split vaccine. In vitro vaccine release from polymer solutions and inserts and the vaccine hemagglutination activity were determined. In vivo immunization studies in mice and rats were performed with nasal solutions and nasal inserts.

Results: The in vitro release of proteins (vaccine) from polymeric solutions and inserts was incomplete because of the high molecular weight of the proteins. The release rate was controlled by the polymer (Lutrol F68 > PVP 90 > HPMC K15M > Carbopol > chitosan > or = carrageenan = xanthan gum) because of differences in solution viscosity and possible polymer-protein interactions. Xanthan gum, a negatively charged polymer with intrinsic adjuvanticity, enhanced the serum IgG as well as the nasal IgA response in in vivo studies with nasal vaccine solutions. Poly-l-arginine and cationic lipid were the best performing adjuvants. Solutions containing vaccine with xanthan gum and cationic lipid were effectively stabilized with 0.4 M NaCl.

Discussion: The specific activity of the major vaccine protein, hemagglutinin, was not significantly affected by the addition of polymers and the freeze-drying process during insert preparation. The addition of cationic lipid as adjuvant decreased the hemagglutination activity, which strongly indicated inhibition of the protein binding site to erythrocytes. Inserts prepared from xanthan gum and cationic lipid stabilized with NaCl showed a reduced protein activity but were superior to the cationic lipid alone.

Conclusion: Rat immunization with solid nasal inserts based on xanthan gum containing the influenza vaccine, with or without an additional cationic lipid adjuvant, resulted in similar IgG levels as the pure nasal liquid vaccine formulation.