Olfactory Drug Delivery in Rodents: Deposition and Pharmacokinetics.

Olfactory drug delivery (ODD) is a route of administration that precisely targets the olfactory cleft, a region of the upper nasal cavity with privileged access to the brain. ODD offers better brain delivery compared to traditional intranasal (IN) delivery (e.g., nasal spray), which has imprecise, off-target drug deposition to the lower nasal cavities, with very little (if any) deposition at the olfactory region. ODD has immense potential for the noninvasive delivery of medication to the brain for the treatment of mental health and neurological disorders. Previously, we defined successful ODD as deposition of at least 50% of a dose to the olfactory cleft compared to the surrounding nasal cavities, assessed with a nasal endoscope. In this study, we investigate whether ODD is associated with increased brain uptake and compare the ODD, IN, and intravenous (IV) routes of administration across a range of compounds. First, using positron emission tomography (PET) imaging in rats, we demonstrate that ODD consistently targets the olfactory cleft, facilitating the brain uptake of fluorodeoxyglucose and fluorothymidine (FLT). These results successfully replicate previous work demonstrating direct nose-to-brain delivery of the poor blood-brain barrier penetrating molecule FLT. Additionally, we evaluated compounds that were selected for diversity of physiological properties and indications and demonstrated that for certain molecules, ODD offers superior brain delivery compared to IN and IV and demonstrates greater consistency than traditional IN administration. Remarkably, the volume of liquid required for ODD is approximately an order of magnitude smaller than that for the IN or IV methods, reducing variability in dosing, off-target deposition, and cost. These findings suggest that adopting the ODD method could enhance the accuracy, precision, and reproducibility of dosing across intranasal drug delivery applications. Importantly, ODD offers a consistent (less variable), accurate, and targeted method for improving the deliverability of medication to the brain.