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

Abstract

The purpose of these studies was to enhance mucosal and systemic antibody production in response to increased local residence time of a whole inactivated influenza virus administered as a dry powder nasal vaccine formulation. Spray-freeze-drying (SFD) particles suitable for nasal delivery were characterized for physico-chemical properties and stability. Mucoadhesive compounds (MA) were characterized for their effects on nasal residence time of vaccine powders in rats compared with published in vitro data and elicited immune responses. SFD particles (D(50) = 26.9 microm) were spherical with a specific surface area of 1.25 m(2)/g. Thermal analysis indicated SFD powders were amorphous and demonstrated improved stability with respect to liquid formulations under various storage conditions. In vitro physico-chemical studies and in vivo scintigraphic imaging experiments indicated sodium alginate (SA) and carboxymethylcellulose-high molecular weight (CMC-HMW) powder formulations most significantly increased residence time in Brown Norway rats. Intramuscular delivery provided equivalent serum antibody titers to intranasal (IN) powder without MA, in the presence of CMC-HMW, SA, and hydroxypropyl methylcellulose (HPMC-HMW) after initial dosing and all formulations except IN powder with chitosan after boosting. IN liquid provided equivalent serum antibody titers to all IN powders after the initial vaccination and significantly greater serum antibody titers than IN powder with chitosan after boosting. Trends were consistent between residence time studies and immune response; however, no statistically significant differences between powder and liquid formulations were observed. It was concluded that enhanced serum and mucosal antibody responses were elicited by a dry powder nasal vaccine, specifically, administered in the presence of sodium alginate.

Physicochemical Characterization and Water Vapor Sorption of Organic Solution Advanced Spray-Dried Inhalable Trehalose Microparticles and Nanoparticles for Targeted Dry Powder Pulmonary Inhalation Delivery

“…There were three endothermic peaks observed for raw trehalose dihydrate which are characteristic for order-to-disorder thermotropic phase transitions. Similar DSC thermograms were obtained for single crystals of trehalose dihydrate (35) and for raw trehalose dihydrate powder (20). The two endothermic order-to-disorder peaks at ∼100°C and 140°C correspond to two dehydration processes due to the loss of unbound water at ∼100°C (i.e., vaporization of unbound water) and vaporization of the bound water molecules at 140°C which vaporize at a temperature significantly greater than 100°C due to thermodynamically favorable H-bonding of the water molecules within the trehalose dihydrate crystal lattice.…”

“…Carbohydrates (17,18) are commonly used as cryoprotectants and thermoprotectants. Trehalose can be successfully included in inhalation formulations that contain biotherapeutic drugs (biologics) (19), including aqueous solution spray-freeze-dried formulations to produce large trehalose particles for nasal vaccination delivery (20). It has many advantages over other sugars, such as less hygroscopicity, an absence of internal hydrogen bonds that allows more flexible formation of hydrogen bonds with drugs, low chemical reactivity, and high glass transition temperature (21).…”

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“…In dry powder formulations Preservatives are not needed, because they do not support microbial growth and are more stable than solution. For these reasons, the dried powder is the most commonly studied formulation for the nasal drug delivery, including small hydrophobic drugs, peptide drugs, and vaccine 78 prepared dry powder nasal influenza vaccine formulation by using sprayfreezedrying method; the results indicated that the powders were amorphous and more stable with respect to liquid formulations. In vivo experiments demonstrated that the powders significantly increased residence time in rats and elicit enhanced serum and mucosal antibody response.…”

Simplifying Influenza Vaccination During Pandemics: Sublingual Priming and Intramuscular Boosting of Immune Responses with Heterologous Whole Inactivated Influenza Vaccine

“…The instability of liquid influenza vaccine is an important problem in stockpiling of H5N1 vaccines (18). Influenza vaccines can be stabilized by incorporating them into a glassy matrix of a sugar, e.g., inulin, dextran, or trehalose, for example, by means of freeze-drying techniques (19)(20)(21)(22).…”