Novel dry powder preparations of whole inactivated influenza virus for nasal vaccination Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Garmise, Robert Joseph
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Nasal dry powder vaccines may provide safe, effective, stable, and affordable alternatives to currently available influenza vaccines. It was proposed that maximal mucosal and systemic antibody production would be elicited by a whole inactivated influenza virus dry powder nasal vaccine formulation in response to increased local residence time. Full factorial designed experiments examining freezing rate, solute concentration, and annealing (freeze-drying) and solution feed rate, atomization airflow rate, and solute concentration (spray-freeze-drying (SFD)) were used to produce particles suitable for nasal delivery. Freeze-drying followed by milling and sieving produced heterogeneous-shaped particles below the targeted particle size, which weren't ideal for blending with mucoadhesive compounds (MA). Optimized SFD runs produced particles for human (D50=38.5[micrometer]) and rat (D50=26.9[micrometer]) delivery which were characterized for flow and thermal properties, surface area, true density, moisture content, and impact energy separation and demonstrated improved storage stability than liquid formulations. A modified cascade impactor was calibrated to characterize particles in the 10-20[micrometer] size range. Wettability, dissolution rate, and swelling indices were obtained as potential predictors of the effects MA may have on the residence time. Gamma scintigraphy allowed for visual imaging of nasal clearance, while residence time studies quantified mucociliary clearance rates. In vitro and in vivo experiments indicated that sodium alginate (SA) and carboxymethylcellulose (CMC-HMW) powder formulations had the greatest effect on increasing residence time in Brown Norway rats. A dose-response curve determined that a 2[microgram] dose was appropriate to quantify potential differences in antibody responses of formulations. IM delivery provided equivalent serum antibody titers to IN powder without MA, CMC-HMW, SA, and hydroxypropyl methylcellulose (HPMC-HMW) after initial dosing and IN liquid and IN powder without-MA, CMC-HMW, SA, and HPMC-HMW after boosting. IN liquid vaccine provided equivalent serum antibody titers to IN powder without-MA, CMC-HMW, SA, chitosan, and HPMC-HMW after the initial vaccination. IN liquid provided significantly greater serum antibody titers than IN powder with chitosan after boosting. While no significant differences between powder and liquid formulations were observed, trends are consistent with residence time studies with respect to eliciting an immune response. Maximal serum and mucosal antibodies were elicited following administration of IN powder with SA.
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  • In Copyright
Advisor
  • Hickey, Anthony J.
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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