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12 OctOber 2021 Inhalation pensions, such as Polysorbate 20 and 80, may also serve as penetration enhancers. Alkylsaccharides. Alkylsaccharides consist of an aliphatic hydrocarbon chain coupled to a sugar moi- ety. It has been reported that the alkyl maltosides, including dodecyl maltoside (DDM), enhance transmucosal delivery through both the transcellular and paracellular pathways—temporarily loosening the tight junctions between epithelial cells, as well as increasing the permeability of cell membranes, allowing drug to pass through. For DDM, bioavail- ability enhancement has been demonstrated from intranasal application of molecules (small molecules, therapeutic proteins, peptides and non-peptide macromolecules) of different molecular weights up to 30 kDa [9]. Bile salts and derivatives. Cholates (e.g., sodium glycocholate, sodium taurocholate) are bile salts that are synthesized from the lipid, cholesterol. Choles- terol is an essential structural component of animal cell membranes, modulating membrane fluidity and functioning in intracellular transport. Due to their structural similarity to cholesterol, it has been postulated that bile salts and their derivatives may cause fluidization of the nasal epithelial cell mem- branes, thereby increasing transcellular transport [7]. It has been reported that these materials have been shown to effectively promote nasal insulin and peptide drug absorption. Cyclodextrins. Cyclodextrins are cyclic oligosac- charides produced by the enzymatic degradation of starch. Typical cyclodextrins contain 6 to 8 α-D-glucopyranoside units connected by α(1→4) linkages in a ring, creating a cone shape. ere are three native cyclodextrins: α-cyclodextrin (a six sugar-ring molecule), β-cyclodextrin (a seven sugar- ring molecule), and γ-cyclodextrin (an eight sugar-ring molecule) enclosing a cavity of about 6, 8 and 10 Å, respectively [10, 11]. ese molecules have a hydrophilic outer surface and a relatively hydrophobic inner cavity that allows entrapment of a wide range of drug molecules, including proteins and peptides. ese inclusion complexes are formed by weak non-ionic interactions (e.g., van der Waals forces), hydrophobic bonding and hydrogen bond- ing between the cyclodextrin cavity and the drug molecule [12, 13]. Cyclodextrins can increase drug solubility at the absorption site and act as perme- ation enhancers by carrying the drug from the bulk solution to the lipophilic surface of biologi- cal membranes, where the drug molecules partition into the lipophilic membrane. Cyclodextrin/chi- tosan nanoparticles have been used to combine the solubilizing properties of anionic cyclodextrins and the mucoadhesive properties of cationic chitosan to prolong the residence time on, and the permeation through, the mucosal membrane [10]. the nasal cavity caused by mucociliary clearance (typically 15-20 minutes) necessitates formulation approaches to increase the contact time of the drug at the site of absorption, and the permeability of the mucosal membrane. One formulation approach that is becoming more widely investigated involves the use of penetration enhancers and/or mucoadhesives. e year 2020 saw rapid expansion in interest in the use of liquid nasal sprays for the prophylactic treatment of respiratory diseases, fueled by the phar- maceutical industry's response to the COVID-19 pandemic [3]. ese formulations are intended to be retained and act locally within the nasal cavity, the site of first infection. As such, it is important that the residence time of the drug within the nasal cavity is maximized—not to increase time for absorption, but to increase opportunity for the drug to interact with the virus within the nose and prevent it enter- ing deeper into the respiratory system. e use of mucoadhesives in these types of liquid nasal spray formulations may help achieve this objective. It is important to note that demonstrating the absence of undesirable biological effects is a major barrier to the introduction of new excipients intended to enhance absorption in the nose. For example, some penetration enhancers have been reported to be irritating to the nasal mucosa as well as having a detrimental effect on ciliary activity, thus impacting the integrity of the nasal defense mechanisms. Measuring the ciliary beat frequency of nasal epithelial tissue has been suggested as a tool in the search for safe nasal absorption enhancers [4]. Although mucoadhesives are not normally as irritat- ing to the nasal mucosa as penetration enhancers, they act by increasing the viscosity of the mucus. is, in turn inhibits the effect of ciliary beating, impairing mucociliary clearance [5]. e Inactive Ingredient Database [6] provides information on excipients used in FDA-approved drug products and can be used as a starting point when consider- ing formulation additives. Penetration enhancers ere are two primary mechanisms for absorption through the nasal mucosa—paracellular transport and transcellular transport [7]. Paracellular trans- port involves the transient opening of the tight junctions between adjacent cells to enable diffu- sion through the intercellular space. Transcellular transport involves the disruption of the integrity of the cell membrane lipid bilayer and increased membrane fluidity, thereby reversibly enabling the permeation of drugs. is can result in the opening of the aqueous pores due to calcium ion chelation and/or increase the intracellular delivery using functional moieties [8]. Some surfactants added to improve the physical stability of aqueous nasal sus-