Inhalation

catalent.com samuelsson (cont'd): significant risks 10,11 . Lastly, nasal sprays avoid the risks of needle stick and injection injuries, especially in situations where the patient lacks gross motor control (e.g., patient is having a seizure). Oral administration is often the preferred format for drug self-administration, but suffers from first pass metabolism, slow onset of action and many of the systemic side effects seen with IV. Higher doses are typically used to offset the impact of hepatic metabolism, which can lead to gastrointestinal discomfort or toxicity, and ultimately limit an oral drug's development path. While a portion of a nasal spray will also end up in the gastrointestinal tract, the concentration of a nasally delivered drug is typically orders of magnitude lower than that needed for comparable oral delivery, thus significantly mitigating the risks of side effects 12 . In general, intranasal delivery can overcome a number of challenges associated with oral and intravenous administration, especially for CNS conditions (see Table A). The potential for nose-to-brain delivery as a targeted route of drug delivery is great; however, there are a few challenges, such as a limited understanding of the nasal mucosa 13 , avoidance of immunogenicity through optimized formulation 13 , and patient-to-patient variability in nasal passage architecture or obstruction. While systemic and enteric side effects are generally lower with nasal sprays, patients can experience throat irritation, nasal discomfort and other side effects of the nose, throat or eyes 1 . Furthermore, the pathway may not work for all molecule types, and device manufacturers and formulators continue to look for ways to maximize residence time and absorption at olfactory receptors and the nasal mucosa, respectively, and minimize mucociliary clearance into the stomach. Beyond nose-to-brain, intranasal administration can also be used for systemic drug delivery. The nasal mucosa is well- vascularized and thinner than the intestinal mucosa, allowing for rapid drug absorption directly into the bloodstream, bypassing intestinal and hepatic metabolism. Similar to that seen with nose-to-brain, this route allows for rapid onset of action, non-invasive delivery and the potential for lower dose requirements relative to that needed for oral administration. However, compared to IV, higher doses are needed and one should be cognizant of potential accumulation in the brain via the parallel nose-to-brain path. intranasal oral intravenous speed (onset of action) ++ - ++ convenience ++ + - minimal side effects ++ - + patient comfort + ++ - avoidance of first-pass metabolism ++ - ++ self administration ++ ++ - dose accuracy ++ + ++ minimizes api needed ++ - ++ 5

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