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Inhalation June 2020 13 connections between the nose and the brain are the olfactory bulb and the peripheral circulation. Figure 1 illustrates the nasal anatomy. Formulations Solutions and suspensions, the most common liquid formulations, are delivered as drops, sprays (pump- or propellant-driven) or aerosols (nebulizers). Powder formulations are also available and are administered by devices capable of aerosolizing powders. 10 Factors influencing therapeutic absorption in the nose are varied and widely considered to be a function of the combination of device and formulation. 11 Primary factors include drug concentration wherein absorp- tion follows first-order kinetics and wherein rates will depend on the initial concentration and the pH at the site of absorption. Nasal absorption is pH-dependent, and the local pH may be quite variable. Nasal pH ranges from 5.5 to 6.5 in adults and between 5.0 and 6.7 in infants and children. Complicating the matter further, pH varies with disease state and may become alkaline, for example, in acute cases of rhinitis and sinusitis. Additionally, mucociliary clearance has an effect. Mate- rials deposited in the nasal passages are generally cleared in less than 15 minutes but may take more than 30 min- utes if the mucociliary function is impaired. 12 In an effort to develop optimal formulation strate- gies for nasal targets, a variety of excipient classes are typically used in nasal formulations. 13, 14 Examples are shown in Table 1. Droplet/Particle size considerations The ideal droplet or particle size distribution for a nasal spray is considered to be one wherein the vast majority of droplets or particles are larger than 10 microns. 15, 16 e intent of this seemingly large size is to promote inertial impaction within the nasal passages Anatomy e complex internal nasal geometries, including the narrow anterior valve, poses a significant challenge to effective nasal targeted drug delivery. As compre- hensively described by Le Guellac, et al, 9 successful therapy requires delivery of a therapeutic to a specific anatomical site (local, systemic, CNS/brain) and the intended therapeutic action and consequent suc- cess depends on delivering sufficient drug to those sites. For example, the middle meatus, the maxillary sinuses and the ethmoid regions have been identified as important drug delivery sites for local treatment of inflammation and infection in rhinological pathol- ogies. Systemic delivery is enhanced by delivering drug to the middle and inferior turbinates, the septum and nasal floor around the turbinates. e anatomic Excipient class Rationale for use Examples Solubilizers Increase the concentration of drug in the liquid Glycol, alcohol Surfactants Modify nasal mucosa permeability for altered absorption profile Sodium laurylsulfate (SLS), Polyacrylic acid Bioadhesive polymers Increase residence time on the surface Methylcellulose, Carboxymethylcellulose Viscosity-modulating agents Increase the viscosity of the solution in order to prolong retention time and the therapeutic activity Hydroxypropyl cellulose Preservatives Prevent growth of microorganisms Parabens, ethylenediamine tetra- acetic acid (EDTA), benzalkonium chloride, phenyl ethyl alcohol Antioxidants Prevent drug degradation by oxidation Sodium meta bisulphite, sodium bisulfite, tocopherol Table 1 Formulation strategies for nasal preparations Figure 1 A diagram of the nasal anatomy Frontal sinus Olfactory bulb Cribriform plate of ethmoid bone Olfactory tract Septal olfactory nerves Nasal passages Vestibule Trachea

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