**3. Results**

## **3.1. Numerical (ANSYS Fluent) assessment of olfactory delivery with nasal intubations**

**Figure 3a** shows the motion of 1 μm particles inside the nasal airway predicted using ANSYS Fluent. It is observed that particles that are released from the tip of the nostril move along the upper nasal cavity, while particles from the base of the nostril move along the nasal floor. At an inhalation rate of 20 L/min (normal breathing condition), it takes around 0.02–0.03 seconds for the particles to be delivered to the olfactory region after administration (**Figure 3a**). Faster movements of particles are noted in the middle passages and slow-moving aerosols are observed in the near-wall region. The numerical model in this study had been validated by comparing to *in vitro* deposition data measured in a comparable nasal replica. Good agreement was obtained between the numerically predicted and *in vitro* measurements in comparable nasal casts by Cheng et al. [46, 47] (**Figure 3b**). It is emphasized that the computational nasal airway model in this study and the *in vitro* nasal casts in Cheng et al. [46] were reconstructed from the same set of MRI images.

Numerical Simulation and Experimental Testing to Improve Olfactory Drug Delivery with Electric Field Guidance of... http://dx.doi.org/ 10.5772/65858 97

to the powder coating system integrated a charging reservoir (a 2-L bottle) to the nozzle of the charging gun (**Figure 2a**). An additional metal wire was added to extend the charging rod to the reservoir exit, with the wire's length being parallel with the direction of the flow of solid particles. A high voltage supply (Spectracoat coating system), which has an adjustable potential output of 0–100 kV, was connected to the rod. The solid particles were distributed out of a 4-mm-diameter nozzle and subsequently distributed into a multisectional nasal cast replica. Three copper-plated electrodes (A, B, C) were attached to the top of the nose replica, and one copper-plated electrode (D) was attached to the bottom of the replica. Charged dry powders were distributed from the powder coat gun for 20 seconds per trial. For the normal delivery, particles were administered into one nostril and exited through the nasopharynx (**Figure 2b**, upper panel). In contrast, for the bi-directional delivery, the bottom of the pharynx was blocked to simulate the uplifted soft palate, while particles were administered into one nostril and exited through the other (**Figure 2b**, lower panel). A vacuum pump (Robinair 3 CFM, Warren, MI) was connected to the exit of the nasal replica in each test case to simulate the respiration. An in-line flow meter (Omega, FL-510, Stamford, CT) was used to monitor the

The variable of interest in this study was the ratio of the olfactory dosage to the vestibuleturbinate dosage (i.e., olfactory-nasal dosage ratio). Results were represented as the main ± standard deviation (SD), with SD being calculated from five trials for each scenario. Statistical analysis software Minitab (State College, PA) was applied to analyze the deposition data. Tukey's method and analysis of variance (ANOVA) were implemented to assess the data variances. The difference was considered statistically significant if the *p*-value was <0.05.

**3.1. Numerical (ANSYS Fluent) assessment of olfactory delivery with nasal intubations**

**Figure 3a** shows the motion of 1 μm particles inside the nasal airway predicted using ANSYS Fluent. It is observed that particles that are released from the tip of the nostril move along the upper nasal cavity, while particles from the base of the nostril move along the nasal floor. At an inhalation rate of 20 L/min (normal breathing condition), it takes around 0.02–0.03 seconds for the particles to be delivered to the olfactory region after administration (**Figure 3a**). Faster movements of particles are noted in the middle passages and slow-moving aerosols are observed in the near-wall region. The numerical model in this study had been validated by comparing to *in vitro* deposition data measured in a comparable nasal replica. Good agreement was obtained between the numerically predicted and *in vitro* measurements in comparable nasal casts by Cheng et al. [46, 47] (**Figure 3b**). It is emphasized that the computational nasal airway model in this study and the *in vitro* nasal casts in Cheng et al. [46] were reconstructed

volumetric flow rate.

96 Advanced Technology for Delivering Therapeutics

*2.3.4. Statistical analysis*

**3. Results**

from the same set of MRI images.

**Figure 3.** Nasal particle motion and model validation. (a) Snapshots of particle motion at varying instants. (b) Good agreement in nasal deposition between the numerical predictions and experimental measurements of Cheng et al. [46, 47].

In this study, we first tested the feasibility of optimizing particle release positions (smart delivery concept) for intranasal olfactory drug delivery. Two protocols were tested, with the first termed as "vestibular intubation" where particles are released from a selective point in the vestibule (**Figure 4a**), while the second protocol being the "deep intubation" with the nebulizer nozzle inserted directly below the olfactory mucosa (**Figure 4a**). In principle, particles released into the upper vestibule moves along the upper nasal passage and therefore are more likely to deposit in the olfactory region. The computational simulations also confirm that it can deliver higher doses to the olfactory region for both particle sizes considered (150 nm and 1 μm). Furthermore, the deposition pattern appears to be focused close to the olfactory region. Considering the deep intubation protocol, the nozzle was inserted right below the olfactory mucosa so that filtration by the nasal valve and turbinate can be avoided. Therefore, elevated doses were predicted in the olfactory proximity with nonsignificant doses in the middle and inferior turbinate regions.

**Figure 4.** Two delivery protocols with selective particle releasing: vestibular intubation and deep intubation. (a) Streamlines and surface deposition. (b) Olfactory deposition rate with the vestibular and deep intubations in comparison to the conventional delivery method, which releases drugs to the entire nostril (control case).

The olfactory doses between the vestibular and deep intubation protocols, as well as the conventional delivery method, were compared on the basis of deposition fraction per area (%/cm2 ) (**Figure 4b**). The surface area of the olfactory mucosa in this study (**Figure 1c**) is 6.8 cm2 . Overall speaking, both intubation protocols significantly enhanced the olfactory targeting while the deep intubation outperformed the vestibular intubation. However, it is noted that even using the deep intubation method, very low fractions of administered dose (0.16%/cm2 or 1.09% in the olfactory region) were delivered to target, while nearly 99% was lost in other regions, causing tremendous waste and potentially significant unwanted side effects. Therefore, further efforts are needed to explore strategies that can precisely target drug particles to the olfactory region while minimizing drug loss to other tissues.

## **3.2. Sar‐Gel visualization of nasal deposition distributions**

Sar-Gel visualization of the local deposition inside the nasal replica is displayed in **Figure 5** for two common nasal spray products (Astelin and Nasonex). The angle of the spray plume was approximately 35o ± 0.8o for Astelin and 20o ± 0.5o for Nasonex. The majority of spray droplets were trapped by the narrow flow-limiting nasal valve. It is noted that the drug distribution is largely dictated by the physical properties of spray droplets. The high filtration by the slit-shaped nasal valve can be attributed to the high inertia of spray droplets that have large sizes (70–90 μm) and exit from the spray pumps with relatively high speeds. Dripping was absent in Astelin that had a wide spray plume angle, while dripping was observed in Nasonex that had a narrow plume and was prone to cause local droplet accumulation (**Figure 5a** vs. **5b**). Deposition of Astelin appeared to be more dispersed than Nasonex.

**Figure 5.** Deposition pattern in the nose with two nasal spray products: (a) Astelin and (b) Nasonex. The majority of spray droplets deposit in the nasal vestibule and valve region and cannot reach the olfactory region.

A commercially available jet nebulizer (Philips Respironics InnoSpire) was utilized to evaluate particle deposition in the nose. Nebulized aerosols were released into the nostril at an orientation 15o from the vertical direction. As shown in **Figure 6**, most administered droplets deposited in the anterior nose (vestibule and valve regions). Aerosol deposition in the middle and inferior turbinate was also observed, but at a lower level than the anterior nose. Almost no aerosol deposited in the superior meatus and olfactory region (dashed blue ellipse). The above deposition distribution is similar as that reported in Laube [48] who observed predominant doses in the anterior nose. Both **Figures 5** and **6** corroborate the observation that conventional nasal devices cannot deliver adequate doses to the olfactory mucosa, and thus advanced drug delivery systems are warranted in order to achieve clinical significant olfactory delivery.

**Figure 6.** Sar-Gel visualization of the nasal deposition pattern using a standard nebulizer. Even though some nebulized aerosols escape the nasal valve filtration, most of them deposit in the turbinate region and only a very small fraction reaches the olfactory region.
