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14 OctOber 2021 Inhalation sives may also play other roles in a formulation. For example, due to their viscosity-enhancing properties and thixotropic nature, they may act as suspending and stabilizing agents. Additionally, by increasing the droplet size of the spray, the increased formula- tion viscosity may play a part in controlling where, within the nasal cavity, spray droplets would be deposited and reduce the possibility of unintended lung delivery [23]. Cellulose and derivatives. Cellulose is a polysaccha- ride consisting of a linear chain of several hundred to more than 10,000 β(1→4) linked D-glucose units. Cellulose derivatives used as mucoadhesives include carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellu- lose (HPMC) [24]. CMC, specifically the sodium salt (NaCMC) is an extensively used mucoadhesive polymer. It is an anionic polymer that generates more hydrogen bonding than non-ionic polymers, thereby possessing better mucoadhesion. HPMC is used not only for mucoadhesion but also as a con- trolled release mechanism. It is a non-ionic polymer lacking a proton-donating carboxylic group, which causes lesser hydrogen bonding than CMC. HPMC exhibits thermal gelation, increasing the viscosity as the temperature is raised. HPC, like HPMC, is a non-ionic, water-soluble, cellulose ether with the thickening and stabilizing properties characteristic of other water-soluble cellulose polymers. While HPC and HPMC are insensitive to electrolytes, CMC is affected both by ionic strength and pH. Chitosan and derivatives. Chitosan is a cationic polysaccharide comprised of glucosamine and N-acetyl glucosamine copolymers linked by β(1→4) glycosidic bonds, and is obtained by the partial deacetylation of chitin [19]. Chitosan polymers vary in their degree of deacetylation, molecular weight (50 kDa to 2,000 kDa), and viscosity [25]. Chitosan has one primary amino and two free hydroxy groups for each C 6 building unit [26], giv- ing the capability of both hydrogen bonding and covalent bonding. e high charge density of the amino groups enables chitosan to chemically react with anionic systems, giving rise to a strong elec- trostatic interaction with the negatively charged mucosal glycoproteins. Microspheres can be pre- pared by reacting chitosan with controlled amounts of multivalent anions, resulting in intermolecular cross-linking. ese microspheres can provide con- trolled release of drugs, improve the bioavailability of degradable substances (such as proteins) and improve the uptake of hydrophilic substances across the epithelial layers. Unfortunately, the solubility and mucoadhesive nature of chitosan requires an acidic pH (pH < 6), which can limit its use, as many biologics are not stable at low pH. As a result, vari- ous chitosan derivatives have also been investigated. between the lipid composition of liposomes and cell membranes enables liposomes to be used as physio- logically acceptable drug delivery systems [17]. One example of a phospholipid is phosphatidylcholine, which is the major component of lecithin. Surfactants. Surfactants are compounds that are commonly used to lower the surface tension (or interfacial tension) between two liquids, for example, when formulating and stabilizing emulsions. ey are amphiphilic molecules, containing both hydro- philic and hydrophobic groups. Surfactants can be used as very effective permeation enhancers, increas- ing the fluidity of cell membrane lipids. However, epithelial toxicity, ciliostatic activity and nasal irrita- tion are some drawbacks [18]. Non-ionic surfactants are generally less irritating and better tolerated than anionic and cationic surfactants. Examples of non- ionic surfactants that have been used in intranasal drug delivery systems are Poloxamer 188, Polysor- bate 20 and Polysorbate 80. iomers. iomers enhance the permeabil- ity of drugs via the reversible opening of the tight junctions between epithelial cells. ey have the potential benefit of not being absorbed through the nasal mucosa, as can happen with lower molecular weight enhancers. (For more information on thio- mers, see the section on mucoadhesives.) Other delivery systems. In addition to penetra- tion enhancers, other delivery systems have been investigated to increase the efficiency of drug deliv- ery—including cell-penetrating peptides, enzyme inhibitors (to reduce drug inactivation by mucosal proteases and reductases), polymeric nanoparticle carriers, microemulsions and nanoemulsions. Mucoadhesives e nasal cavity is lined with a layer of mucus and hairs (cilia) that trap inhaled particles and patho- gens. e cilia are in a constant wavelike movement, sweeping the mucus and entrapped particles towards the pharynx for ingestion and clearance by the gastrointestinal tract [2, 5, 7]. is process of muco- ciliary clearance limits the residence time of particles within the nasal cavity to 15-20 minutes. Mucoad- hesives are used in liquid nasal spray formulations to increase the viscosity of the mucus. is, in turn, inhibits the effect of ciliary beating, impairing muco- ciliary clearance, and increasing the residence time of the drug on the nasal mucosa to allow more time for passive diffusion. Additionally, mucoadhesives can provide sustained drug release and reduce the degradation of vulnerable, small molecular weight and peptide-based drugs [19]. e inclusion of mucoadhesives can have the effect of increasing the viscosity of a formulation, leading to a narrower spray plume and larger spray droplets [20-22]. As with penetration enhancers, mucoadhe-