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12 June 2024 Inhalation utility in a powder product [17]. Notable excipients for the purpose of nasal powder formulation are pro- vided in Table 1. Ingredients used as preservatives (benzalkonium chloride), for pH/buffering (sodium hydroxide, phosphate), and tonicity (sodium chlo- ride) are largely not useful for nasal powder formu- lation. However, those used as suspending agents (HPMC) and surfactants (polysorbates) do have utility. In addition to being a mucoadhesive agent, HPMC can be utilized to stabilize amorphous APIs, increasing solubility and, in turn, bioavailability. Sur- face active agents like polysorbates can be important tools to displace biologics/vaccines at the air-liquid interface during particle formation and drying [18]. Other ingredients have been thoroughly investi- gated to facilitate mucoadhesion, glass-forming sta- bilization and permeation enhancement. Chitosan, a biocompatible polysaccharide, is used in clinical investigations as both a nasal mucoadhesive and a permeability enhancer due to its capability to open tight junctions [19]. Utilization of chitosan during spray drying has been shown to increase feedstock viscosity (allowing for larger particles) and alter par- ticle morphology [20]. Sugars such as trehalose, dex- tran and mannitol are also of great utility due to their prolong the transit time toward the nasopharynx. However, their effect should be temporary so that healthy clearance functions in the nose can resume. Figure 1 presents an overview of the approach to powder delivery to the nasal passages. For small molecules, the manufacture of amorphous solid dispersions has been utilized extensively in oral drug delivery to enhance solubility and improve bio- availability of poorly water-soluble drugs [15]. e same approach can be utilized to create amorphous nasal powder to achieve rapid dissolution and absorp- tion, using well-established technologies (e.g., spray drying) and nasal excipients (e.g., HPMC) approved by the United States Food and Drug Administration (FDA) [16]. For more complex biopharmaceuticals and vaccines, the preservation of the structure, con- formation and encapsulation by a delivery vector is critical to consider and will be greatly affected by processing conditions, excipient selection and con- tainer closure. Excipient selection A limited number of excipients are utilized (approx- imately 60) in FDA-approved nasal products [14]. While the majority of these excipients are used in traditional liquid nasal products, some would have Table 1 Notable Excipients for Use in Dry Powder Nasal Products Excipient Function Reference In FDA-approved nasal products Hydroxypropyl methylcellulose (HPMC) Suspending agent, Mucoadhesion, Viscosity enhancer 14 Beta-cyclodextrin Bulking agent, Solubility, Absorption enhancer 33 Dodecylphosphocholine (DPC) Absorption enhancer 34 Carrageenan Mucoadhesion, Viscosity enhancer 14, 35 Commonly used in development Chitosan Mucoadhesion, Absorption enhancer, Adjuvant 36-38 Alginate Absorption enhancer 39-41 Mannitol Bulking agent 29, 42 Lactose Bulking agent 29, 42 Trehalose Bulking agent, Vitrifying agent 42, 43 Dextran Bulking agent, Vitrifying agent 44 Cyclodextrins Absorption enhancer 33 Hyaluronic acid Absorption enhancer 45 Polyvinylpyrrolidone (PVP) Mucoadhesion 46 Cellulose derivatives Mucoadhesion, Viscosity enhancer 29 Leucine Dispersion enhancer, Moisture protection 14