Mechanics-guided parametric modeling of intranasal spray devices and formulations for targeted drug delivery to the nasopharynx

TL;DR

Mechanics-guided parametric modeling addresses how intranasal spray device and formulation parameters influence targeted nasopharyngeal deposition. The authors combine CT-derived upper airway geometries with Large Eddy Simulation (LES) of inhaled flow and Lagrangian particle tracking to map deposition efficiency $\xi$ across particle size $d$, density $\rho$, and plume angle $\theta$, with experimental validation in a 3D-printed model. They identify optimal regions where $d \in [25,45]$ μm and $\theta \le 30^\circ$ yield substantial deposition (mean $\xi \approx 11.37\%$ in the optimal region), and show higher densities shift deposition toward anterior regions due to inertial impaction. This work provides a rational, CFD-informed design framework for enhancing intranasal drug delivery to infection-prone nasopharyngeal tissue, while noting limitations such as limited anatomies and monodisperse assumptions that warrant further study.

Abstract

Improving the efficacy of nasal sprays by enhancing targeted drug delivery to intra-airway tissue sites prone to infection onset is hypothesized to be achievable through an optimization of key device and formulation parameters, such as the sprayed droplet sizes, spray cone angle, and formulation density. This study focuses on the nasopharynx, a primary locus of early viral entry, as the optimal target for intranasal drug delivery. 3D anatomical upper airway geometries reconstructed from high-resolution computed tomography scans were used to numerically evaluate a cone injection approach, with inert particles mimicking the motion of sprayed droplets within an underlying inhaled airflow field. We have considered monodisperse sprayed particles sized between 10 to 50 microns, six densities ranging from 1.0 to 1.5 g/ml for the constituent formulation, and twelve plume angles spanning 1 to 70 degrees subtended by the spray jet at the nozzle position. Large Eddy Simulation-based modeling of the inhaled airflow physics within the anatomical domains was coupled with a Lagrangian particle-tracking framework to derive the drug deposition trend at the nasopharynx. The resulting globally averaged deposition contour map, obtained by interpolating the outcomes for the discrete test parameters, revealed that nasopharyngeal deposition peaked for droplet sizes 25 to 45 microns and plume angles equal to or less than 30 degrees. In addition, the formulation density of 1.0 g/ml yielded the highest mean deposition rate, over the tested range of sprayed particle sizes and plume angles. The findings were experimentally validated through representative physical spray tests conducted in a 3D-printed replica of one of the test geometries and collectively demonstrate that rational optimization of the intranasal spray design is attainable, with substantial enhancement of targeted drug delivery to the nasopharynx.

Figures (10)

• Figure 1: Envisioned 3D contour map: The vertical axis represents the deposition efficiency ($\xi$) and the two horizontal axes represent two controllable input delivery parameters (e.g., spray plume angle of the delivery device, particle sizes of drug solution, nozzle exit speed of the delivery device, viscosity of the solution, delivery axis orientation, drug solution density etc.). For this study, the two chosen input variable axes are particle size range ($d$; 10 -- 50 $\mu$m) and a range of plume angle of delivery device ($\theta$; 15° -- 70°), with 6 different drug solution densities (1.0 -- 1.5 g/ml). 24 different contour plots were generated for each test airway (number of airways is 4; 2 for each subject). Hence, the results comprise 24 generated plots (see Figs. \ref{['fig6']} and \ref{['fig7']}). By averaging the data across geometries and test formulation densities (see Fig. \ref{['fig8']} and specifically Fig. \ref{['fig9']}), this study identifies the equivalent of the red region (illustrated on the cartoon parametric map above) that captures the suitable conditions for maximal targeted deposition efficiency.
• Figure 2: Test upper airway geometries: Panels (a)-(c) respectively show the axial, sagittal, and coronal views of the computed tomography (CT)-based anatomical reconstruction of AG$_1$ (anatomical geometry 1). Similarly, panels (d)-(f) respectively show the axial, sagittal and coronal views of the CT-based reconstruction of AG$_2$ (anatomical geometry 2). The nasopharynx is colored blue in the visuals borojeni2017ijnmbe. The solid yellow arrows indicate the airflow inlet and outlet regions for the inhalation simulations, with their directions aligning with the direction of mean flux. $g$ implies the gravity direction in the simulations. Additionally, the visuals in (c) and (f) show the geometry-specific length scales. (a)-(c) have the same scale and (d)-(f) have the same scale.
• Figure 3: Schematic workflow: This computational study assesses the nasopharyngeal deposition rates ($\xi$) for discrete combinations of formulation densities ($\rho$), plume angles ($\theta$), and sprayed particle diameters ($d$). The deposition heatmaps (included in the results) give interpolated visuals from the discrete assessments. As per the schematics in Fig. \ref{['fig1']}, the input parameter $i$ and input parameter $j$ are $d$ and $\theta$ (in no specific order). We generate $\xi$ for a wide range of $d$ and $\theta$, for six specific $\rho$. Eventually, the 'globally averaged' $\xi$ is obtained, by averaging the nasopharyngeal deposition assessments for all $\rho$ and test geometries (with two layers of averaging, as illustrated above).
• Figure 4: Representative flow field and sprayed particle trajectories: (a) Sample airflow velocity streamlines within AG$_1$ mimicking 15 l/min inhalation. These representative streamlines initiate from 25 random points on each nostril (i.e., a total of 50 streamlines are shown above). (b) Sample spatial trajectories of intra-nasally sprayed particles, with $\rho =$ 1.0 g/ml, $\theta =$ 15°, and $d =$ 18 $\mu$m.
• Figure 5: Setup for experimental validation: Panel (a) shows the front view of the experimental setup, comprising the following numbered components: (1) a 2.5 CFM vacuum pump, (2) a 3D-printed nasal airway model, (3) a flow rate meter, (4) a pressure gauge, (5) a spray cone angle indicator, and (6) an air filter. Inset $a_i$ shows the side view of the setup. Panel (b) demonstrates the LuerVaxTM spray device (an Aptar Pharma product) used in the experiments. The spray plume angle is $\theta = 49\degree$. Panel (c) presents the 3D CAD visual of the nasal airway cast, with the nasopharyngeal region constructed as a removable plug system for ease of measuring the local deposits. See Fig. \ref{['fig2']}f, for the length scale of the life-size anatomical reconstruction. Panel (d) illustrates the procedure of the experimental spray trials, with the dotted red arrow representing the spray axis cutting through the nasopharynx. Panel (e) shows the removable nasopharyngeal plug. Panel (f) provides a representative image taken after one of the spray trials, while panel (g) shows the corresponding image-processed view of (f).