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With recent advances in devices and formulations, many more conditions are expected to be treatable with nasal delivery. Trans-nasal pulmonary administration remains in its infancy but is poised to grow as evidenced by its rapid adoption to routine use in many intensive care units worldwide. We believe the next decade should see significant advances in both. 12 June 2020 Inhalation Nasal and trans-nasal lung deposition of aerosols Ronan MacLoughlin, PhD, MBS a and James B. Fink, PhD, RTT b a Aerogen Limited b Aerogen Pharma Corporation Topical administration is primarily used to treat inflammation of the nasal mucosa during both acute and chronic pathologies such as rhinosinusitis and allergic rhinitis. It is also used in the treatment of nasal congestion and/or obstruction. 2-6 Topical administration is also used for immunization, by delivering vaccines to the mucosal surface. The majority of infectious diseases are mediated through the mucosal surfaces of the body. Many diseases, such as measles, pneumonia, meningitis and influenza are associated with the exposure of pathogenic microor- ganisms to the respiratory mucosal surfaces and are therefore considered logical candidates for targeted nasal vaccines. e advantage of intranasal vaccination includes the ability to elicit local and remote immune responses, increasing the strength of the response. Further, immunization strategies make use of rela- tively simple devices that allow for vaccination of large populations both non-invasively and quickly, e.g., the FluMist ® quadrivalent influenza vaccine (Seqirus, Summit, NY, US). Systemic access is also possible via the nose. Blood is supplied to the nasal vasculature and enables the basic functions of the nasal cavity such as heating and humid- ification, olfaction, mucociliary clearance and various immunological functions. e cavity itself has a rela- tively large surface area of approximately 155 cm 2 . Per- meation is dependent on the lipophilicity of the drug, and can occur either passively via the paracellular path- way or both passively and actively via the transcellular pathway. Several formulation strategies are employed to increase retention or permeability and are described in more detail below. Using the nasal route to deliver medications to the CNS and the brain has also been reported. e con- nection between the nasal cavity and the CNS through the olfactory region has been investigated extensively to establish its feasibility in acting as a direct drug transport route to the CNS and the brain. 7, 8 is drug transport route has garnered much interest as it may circumvent the blood-brain barrier, which is, in gen- eral, highly effective in preventing most drugs from entering the brain. Introduction Therapeutic delivery via the nasal route is a well- established means of both topical and systemic tar- geting, and facilitates an easy- to- access, non- invasive means of drug administration. Broadly, presentation of therapeutics at the nose allows for targeting of spe- cific areas within the respiratory tract; both the upper respiratory tract (via the nasal passages) and the lower respiratory tract (via trans-nasal delivery to the lungs). e requirements of both targets demand different approaches and delivery devices, but between them, allow for an exceptionally wide selection of topically and systemically targeted therapeutics to be adminis- tered, ranging from bronchodilators and vaccines to migraine and schizophrenia modulating formulations to small proteins such as insulin, and more. Here we discuss these two targeting modalities as well as barriers to efficient targeted delivery and our per- spectives on future prospects for nasal and trans-nasal targeted delivery. Nasal deposition e nasal anatomy, with its mucosal surface and dense vascularity, has been shown to facilitate topical depo- sition for both local action and rapid systemic absorp- tion. ere are several advantages associated with this delivery approach. It is a convenient and non-invasive method that also avoids losses of the active pharmaceu- tical ingredient (API) that typically occur at the liver, and absorption of the API and onset of drug activity are rapid. In addition, bioavailability for small molecules is reportedly high. Disadvantages include the poten- tial histological toxicity of absorption enhancers used in formulations, the nasal cavity represents a smaller absorptive surface area compared with the gastrointes- tinal tract and the potential for irreversible damage to the nasal mucosal cilia from repeated exposure to for- mulation excipients. 1 erapeutic targets e development of therapies for intranasal delivery focuses on three primary fields linked to pharmaceu- tical targeting: topical, systemic and central nervous system (CNS) action.

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