Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model

Abstract

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45-60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45-60°, a nozzle angle ranging 5-10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables.

Keywords: head position; intranasal drug delivery; liquid film translocation; nasal spray; nose-to-brain (N2B); soft-mist inhaler; vertex-to-floor.

Figure 1

Nasal model and delivery experimental setup: (a) diagram of the human nose and olfactory (OL) region with anatomical features preventing effective olfactory delivery viewed from lateral, front, and top directions; (b) transparent nasal cast with four sections (front nose, middle upper (UpM), middle lower (LowM), back nose) and the delineated olfactory (OL) region using two landmarks (solid green and blue arrows); and (c) delivery experimental setup with adjustable nozzle angle (left panel) and head orientation (right panel).

Figure 2

Measured viscosity of nasal spray solutions with varying methyl cellulose concentrations (% w/v).

Figure 3

High-speed images of the spray droplets from the soft mist inhaler during the first 300 ms after actuation in two stages: (a) spray discharge (0–30 ms) and (b) spray plume decay (30–300 ms).

Figure 4

Nozzle angle effects on the nasal spray dosimetry in a nasal cast with a vertex-to-floor head position: (a) fluorescent visualization of the spray distributions after one and two actuations using different nozzle angles (α: 0–15°); (b) quantification of total and regional deposition after two doses; and (c) deposition fractions (DF) in four nasal regions using different nozzle angles (α: 0–15°). UpM: middle upper; LowM: middle lower.

Figure 5

Nozzle angle effects on the nasal spray dosimetry in a nasal cast with a head position tilted backward 60° from the supine position (i.e., 60° BW tilt): (a) spray distribution after one and two actuations for nozzle angles α of 0–15°; (b) quantified depositions after applying two doses; and (c) deposition fractions (DF) in four nasal regions for nozzle angles α: 0–15°. UpM: middle upper; LowM: middle lower.

Figure 6

Snapshots of the dynamic liquid translocation in the nasal cast with a 60° BW tilt head position from supine and a nozzle angle of 10° from the nostril normal (a) after the first dose (0–4 s), and (b) after the second dose (0–60 s, or 4–64 s if counted from the first dose).

Figure 7

Effects of delivery variables (head orientation, dose number, and inhalation flow rate) on the regional spray dosimetry: (a) head orientation of 45° and 30° BW tilt from the supine position (no flow); (b) effect of 10 L/min inhalation flow rate and dose number; (c) spray dosimetry at 20 L/min. Here, 45_10_1: head orientation of 45°, inhalation rate of 10 L/min, and 1 dose; 45_10_2: head orientation of 45°, inhalation rate of 10 L/min, and 2 doses; similarly for 60_10_1 and 60_10_2.

Figure 8

Effects of solution viscosity on the regional spray dosimetry with varying methyl cellulose concentrations (% w/v): (a) spray deposition distributions; (b) regional dosimetry vs. viscosity.

Figure 9

Comparison of nasal spray deposition between the left and right nasal passages: (a) surface deposition at the nozzle angle of 10° with no flow; (b) surface deposition at the nozzle angle of 10° at an inhalation flow rate of 20 L/min; (c) quantified regional dosimetry in the left passage at 0 and 20 L/min with nozzle angles of 5° and 10°; (d) comparison of dosimetry between the left and right nasal passages at 0 L/min.

Figure 10

Image-based dosimetry: (a) estimation diagram and (b) olfactory deposition fraction.

Figure 11

Box plots: (a) middle-upper nose coverage variability (overall, vs. head orientation, and vs. nozzle degree), and (b) comparison of deposition variability among five regions.

Figure 12

Box plots of the regional deposition fractions from sixty test cases in response to varying delivery variables: (a) the number of applied doses, (b) inhalation flow rate, (c) head orientation, (d) nozzle angle, and (e) spray solution viscosity by varying methyl cellulose concentrations. Regions of interest: front nose, middle-upper nose, and olfactory region.