**1. Introduction**

Drug delivery for treating neurological disorders such as brain tumors is often forestalled by the blood-brain-barrier (BBB), a network of endothelial cells with tight junctions in the brain's capillaries. The BBB, which can effectively protect the central nervous system (CNS) from pathogens, also prevents therapeutically agents from the diseased tissues in the CNS [1]. For years, the BBB has thwarted the utilizations of many new neurological medications for the treatment of CNS diseases such as brain tumors, depression, and Alzheimer's disease [2, 3].

Intranasal drug delivery to the olfactory epithelium is a noninvasive technique in which medications can bypass the BBB and enter the brain, eliciting a quick uptake and action onset of the therapeutic agents [3, 4]. However, there are many challenges that preclude effective drug delivery to the olfactory region. Very low doses can be delivered to the olfactory region (<1%) via the nasal route using standard nasal devices such as nasal pumps and sprays [5, 6]. It is primarily due to the complicated structure of the human nose, which is composed of convoluted, narrow, and passages. The olfactory mucosa is located at the uppermost part of the nose and is poorly ventilated due to its secluded location [7, 8]. As a result, standard nasal devices have limited success in olfactory drug delivery in that they rely on aerodynamic forces or particle inertia to drive medications to the target area [9]. After administration, particles travel passively with the nasal airflow. Thus, the behavior and fate of these aerosols are primarily dependent on their release positions and initial speeds. Due to the complex nasal structure, most of the medications will be trapped by the nasal valve and turbinate, with very few left that can make their final journey to the olfactory mucosa [10].

Nasal deposition of inhaled aerosols in humans has been extensively investigated both experimentally and numerically. Despite the high variability among subjects, these studies have persistently demonstrated that intranasal drug delivery can be influenced by multiple factors, including patient breathing, nasal devices, administration technique, and drug formulation. Furthermore, local or cellular-level deposition has been shown to be a more appropriate parameter than the total deposition in predicting adverse health effects or therapeutic outcomes. However, reports of local doses are still rare in comparison with extensive reports of total deposition fractions in the literature.

New techniques have been under active investigation to improve the olfactory delivery efficiency. Wang et al. [11] proposed to insert a catheter into the nose and administer drugs beneath the olfactory region. However, due to its invasive nature, this method has the risk to damage the wall tissues when guiding the catheter to the olfactory proximity, and patient compliance is expected to be low. Gizurarson [12] tested a nozzle with a narrow spray angle in hope that aerosols can penetrate into the posterior nose and the olfactory mucosa. A high pressure was necessary for this technique to overcome the nasal resistance so that particles can penetrate into the superior meatus. Hoekman and Ho [13] proposed to use a swirling flow in additional to the narrow spray plume so that particles can penetrate deeper into the upper posterior nose. Persistent higher doses in the olfactory region with swirling flows were measured in rats relative to nonswirling flows. However, extrapolating rat data to humans is

difficult because of large interspecies discrepancies [14]. For instance, the olfactory region of a Sprague-Dawley rat covers 45% of the nasal surface, while only 5.2% of the human nasal surface is lined by the olfactory epitheliums in humans [15]. Realizing that a particle released into the nostril at a different location will follow a specific path, Si et al. [6] release drug particles from a selected site in the nostril (termed as point release). Improved dosage in the olfactory region was demonstrated using the point releasing than the traditional whole nostril releasing; however, the improvements are limited and still fall short of the doses to be clinically significant. Considering all the techniques aforementioned, it is noticed that once the particles are released into the nose the particle motions are dictated solely by the aerodynamic force. Due to the complex structure of the nasal structure, most particles will deposit in the nasal valve and turbinate region and only a low percentage of particles penetrate into the olfactory region.

**1. Introduction**

90 Advanced Technology for Delivering Therapeutics

[2, 3].

Drug delivery for treating neurological disorders such as brain tumors is often forestalled by the blood-brain-barrier (BBB), a network of endothelial cells with tight junctions in the brain's capillaries. The BBB, which can effectively protect the central nervous system (CNS) from pathogens, also prevents therapeutically agents from the diseased tissues in the CNS [1]. For years, the BBB has thwarted the utilizations of many new neurological medications for the treatment of CNS diseases such as brain tumors, depression, and Alzheimer's disease

Intranasal drug delivery to the olfactory epithelium is a noninvasive technique in which medications can bypass the BBB and enter the brain, eliciting a quick uptake and action onset of the therapeutic agents [3, 4]. However, there are many challenges that preclude effective drug delivery to the olfactory region. Very low doses can be delivered to the olfactory region (<1%) via the nasal route using standard nasal devices such as nasal pumps and sprays [5, 6]. It is primarily due to the complicated structure of the human nose, which is composed of convoluted, narrow, and passages. The olfactory mucosa is located at the uppermost part of the nose and is poorly ventilated due to its secluded location [7, 8]. As a result, standard nasal devices have limited success in olfactory drug delivery in that they rely on aerodynamic forces or particle inertia to drive medications to the target area [9]. After administration, particles travel passively with the nasal airflow. Thus, the behavior and fate of these aerosols are primarily dependent on their release positions and initial speeds. Due to the complex nasal structure, most of the medications will be trapped by the nasal valve and turbinate, with very

Nasal deposition of inhaled aerosols in humans has been extensively investigated both experimentally and numerically. Despite the high variability among subjects, these studies have persistently demonstrated that intranasal drug delivery can be influenced by multiple factors, including patient breathing, nasal devices, administration technique, and drug formulation. Furthermore, local or cellular-level deposition has been shown to be a more appropriate parameter than the total deposition in predicting adverse health effects or therapeutic outcomes. However, reports of local doses are still rare in comparison with

New techniques have been under active investigation to improve the olfactory delivery efficiency. Wang et al. [11] proposed to insert a catheter into the nose and administer drugs beneath the olfactory region. However, due to its invasive nature, this method has the risk to damage the wall tissues when guiding the catheter to the olfactory proximity, and patient compliance is expected to be low. Gizurarson [12] tested a nozzle with a narrow spray angle in hope that aerosols can penetrate into the posterior nose and the olfactory mucosa. A high pressure was necessary for this technique to overcome the nasal resistance so that particles can penetrate into the superior meatus. Hoekman and Ho [13] proposed to use a swirling flow in additional to the narrow spray plume so that particles can penetrate deeper into the upper posterior nose. Persistent higher doses in the olfactory region with swirling flows were measured in rats relative to nonswirling flows. However, extrapolating rat data to humans is

few left that can make their final journey to the olfactory mucosa [10].

extensive reports of total deposition fractions in the literature.

Previous studies have suggested that charged particles under an appropriate electric field can improve nasal and pulmonary drug deliveries [16–18]. Improved dosing of charged particles has been demonstrated in the respiratory tract of both humans and animals [19–29]. Noticing that low olfactory deposition mainly result from the lack of control over particle dynamics in the nose, Xi et al. [25] numerically investigated the transport and deposition of charged particles under different electric strengths and showed that significantly enhanced olfactory dosage is practical by optimizing the electric field strength and particle releasing locations. Similarly, enhanced olfactory dosing can also be attained by using magnetic control of ferromagnetic particles. Preliminary computational simulations predicted a 45.0% deposition fraction for ferromagnetic particles, and the optimal particle diameter is around 15 μm [25].

One issue of intranasal drug delivery of nebulized droplets or small particles is the unwanted dosages into the lungs. One strategy to address this issue is the bi-directional delivery method, which administers medications into one nostril when the patient blows into the apparatus [30]. This method takes advantage of the nature that the soft palate lifts up during exhalation through the mouth, which closes the oropharynx and separates the nasal cavity from the rest of the respiratory tract. As a result, particle penetration into the lungs can be avoided. Moreover, the particles enter one nostril and exit from the other, which allows an increased time for drug deposition. This method did show an increase in medications depositing in the nasal cavity but failed to provide a practical way of dispensing an appreciable amount of medications to the olfactory region [31, 32]. It is hypothesized that by combining the electric guidance of charged particles with the bi-directional strategy, the olfactory dosage can be further enhanced.

The objective of this chapter is to improve the targeted delivery of neurological medications to the olfactory region using both computational modeling and *in vitro* experiments in an image-based nasal airway model. Different strategies were explored to control the intranasal particle motions in order to maximize the dose to the olfactory region and minimize the drug losses in other regions. These strategies include point release, vestibular intubation, deep intubation, and electric guidance of charged particles. Effect of breathing conditions, such as normal inhalation and bi-directional breathing, was also considered.
