Numerical and Machine Learning Analysis of the Parameters Affecting the Regionally Delivered Nasal Dose of Nano- and Micro-Sized Aerosolized Drugs

Abstract

The nasal epithelium is an important target for drug delivery to the nose and secondary organs such as the brain via the olfactory bulb. For both topical and brain delivery, the targeting of specific nasal regions such as the olfactory epithelium (brain) is essential, yet challenging. In this study, a numerical model was developed to predict the regional dose as mass per surface area (for an inhaled mass of 2.5 mg), which is the biologically most relevant dose metric for drug delivery in the respiratory system. The role of aerosol diameter (particle diameter: 1 nm to 30 µm) and inhalation flow rate (4, 15 and 30 L/min) in optimal drug delivery to the vestibule, nasal valve, olfactory and nasopharynx is assessed. To obtain the highest doses in the olfactory region, we suggest aerosols with a diameter of 20 µm and a medium inlet air flow rate of 15 L/min. High deposition on the olfactory epithelium was also observed for nanoparticles below 1 nm, as was high residence time (slow flow rate of 4 L/min), but the very low mass of 1 nm nanoparticles is prohibitive for most therapeutic applications. Moreover, high flow rates (30 L/min) and larger micro-aerosols lead to highest doses in the vestibule and nasal valve regions. On the other hand, the highest drug doses in the nasopharynx are observed for nano-aerosol (1 nm) and fine microparticles (1–20 µm) with a relatively weak dependence on flow rate. Furthermore, using the 45 different inhalation scenarios generated by numerical models, different machine learning models with five-fold cross-validation are trained to predict the delivered dose and avoid partial differential equation solvers for future predictions. Random forest and gradient boosting models resulted in R2 scores of 0.89 and 0.96, respectively. The aerosol diameter and region of interest are the most important features affecting delivered dose, with an approximate importance of 42% and 47%, respectively.

Influencing factors of particle deposition in the human nasal cavity

“…In addition, they found that the dominant effect on the deposition of nanoparticles is particle diffusion, the effect of flow rate on deposition is secondary, and the density‐induced changes are negligible, by comparing a large amount of data. Ali Farnoud et al evaluated the deposition characteristics of particles in the range of 1 nm–30 μm in various parts of the nasal cavity and found that, for nanoscale aerosols, the deposition dose increased with decreasing aerosol size, whereas for microaerosols, the deposition dose increased with increasing aerosol diameter, and furthermore, as the aerosol particle size increased, more aerosols tended to be deposited in the lower part of the nasal airways 27 (Figure 5 ). J. Dong et al studied nanoparticles in the range of 3–150 nm under low to moderate breathing conditions (4–20 L/min) and showed that for nanoparticles in this range, the total deposition efficiency was inversely proportional to the size of the particle diameter and the inhalation flow rate, that is., the larger the particles, the larger the inhalation flow rate and the lower the deposition efficiency 28 (Figure 6 ).…”

“… Comparison of the aerosol deposition efficiency (DE) inside the present nasal cavity and the other realistic nasal cavities reported in the literature scaled by Stokes number for unity density aerosol (d 2 Q). 27 …”