Partitioning of dispersed nanoparticles in a realistic nasal passage for targeted drug delivery

Abstract

The complex nasal structure poses obstacles for efficient nasal drug administration beyond the nasal valve, especially when targeting the olfactory region. This study numerically detailed the naturally inhaled nanoparticle transport process from the initial releasing locations to the final deposited sites using a realistic human nasal passage. Dispersed nanoparticles at different coronal cross-sections were partitioned into multiple groups according to their final deposited locations. Results showed inhaled nanoparticles are more likely to move along the septum. Olfactory deposited particles entered the nose through the inner superior corner of the nostril; the middle meatus deposited particles entered the nose through the top third of the nostril; the inferior deposited particles entered via the bottom floor regions of the nostril. Therefore, targeted nasal inhalation therapies that intentionally release therapeutic particles from these recognized regions at the nostril plane can considerably improve the resultant topical disposition doses. However, it remains challenging to completely prevent undesired particle depositions as particles coming from the same location may produce multiple-sites depositions due to partition overlapping. Nevertheless, the fraction of undesired particle deposition is anticipated to be reduced at a great extent compared to unplanned releasing approaches.

Introduction

The nose has been recognized as a promising route for delivering drugs to treat nasal allergy, sinusitis, nasal congestion, and nasal infections. There are three distinct functional regions in the nose—the vestibule, respiratory and olfactory, and the desired therapeutic outcome for inhaled drugs relies on the effective deposition at targeted sites. The respiratory region (dominated by the inferior and middle meatus) is widely targeted as the main site for systemic entry of drugs for conventional delivery devices (Illum, 2000). Meanwhile, increasing evidences suggest nanoparticles depositing in the olfactory region can migrate to the brain via the olfactory bulb, bypassing the protection of the blood-brain-barrier (BBB). Therefore, the nose-to-brain route via the olfactory offers an attractive solution to directly deliver medications to the brain (Illum, 2004, Mistry et al., 2009), which can be used for the treatment of central nervous system (CNS) related disorders, such as epileptic conditions, psychosis, and neurodegenerative disease (D’Souza et al., 2005, Ugwoke et al., 2005, Hanson and Frey, 2008). Anatomically, the olfactory region is positioned on the top of the nasal cavity and accounts for around 10% of the total surface area (Schroeter et al., 2008, Dong et al., 2016). During inhalation, only a small fraction of inhaled air can reach the olfactory region (Xi and Longest, 2008), and the olfactory deposition efficiencies remain extremely low (less than 1%) (Dong et al., 2017b).

The use of the nasal cavity as a route for drug delivery has been an area of great interest to the pharmaceutical industry for few decades. Most drugs intended for local nasal action are delivered by spray pumps and pressurized metered-dose inhalers (pMDIs) (Harrison, 2000). Through direct delivery of therapeutic agents to the desired site of action, rapid onset of drug action, lower systemic exposure, and consequently, reduced side effects can be achieved (Zaki et al., 2006). However, as the primary function of the nasal cavity is to protect the delicate respiratory tracts from hazardous exposure, the anterior nasal valve greatly restricts the drug delivery efficiency and a large proportion of inhaled medication is wasted due to inertial impaction on the anterior vestibule (Shi et al., 2006, Xi et al., 2016, Inthavong et al., 2013). This triangular valve-like region has the smallest cross-sectional area located approximately 2–3 cm posterior from the nostril inlet (Cole, 2003) and acts as a flow limiting region before expanding into the main nasal passage. Most inertial particles generated by conventional devices are unable to navigate through this narrow section. Furthermore, most of the current drug delivery devices are solely rely on aerodynamic forces to transport therapeutic agents to the nasal mucosa, and once therapeutic particles are released, their movement is no longer controllable.

To investigate the particle dynamics following inhalation therapies and increase the deposition efficiencies at desired nasal regions, many intranasal drug delivery studies were performed. An early study of nasal spray drug delivery was performed by (Inthavong et al., 2006) and later improved on in (Fung et al., 2012, Inthavong et al., 2011, Inthavong et al., 2012) which showed that inertial impaction was the dominant deposition mechanism, and controlling spray parameters such as the atomized drug particle size, it’s swirl velocity, spray cone angle, and the insertion angle of the nasal spray device, all played a significant role. Si et al. (2013) numerically evaluated the effect of intubation depth on intranasal delivery performances. Their results revealed the front vestibular release gave high olfactory dosage than the posterior vestibular release, and deep intubations yielded better outcomes than vestibular intubations. However, due to the intricate and delicate nasal passages, the catheter cannot be intubated very close to the hidden olfactory mucosa without causing discomfort or tissue irritation. Xi et al. (2016) performed a magnetophoretic guided olfactory delivery study in a human nose, and a 1.5-fold increase in olfactory delivery efficiency was achieved relative to the baseline design. But this delivery approach requires the medication agents contain ferromagnetic materials, which may urge major modifications of drug formulas and largely restricts its application.

To avoid lung inhalation of delivered drug particles, Djupesland et al. (2004) proposed a novel delivery method termed as the breath-powered bidirectional delivery approach. This olfactory targeted approach takes advantage of the soft palate’s natural tendency to close the nasopharynx during exhalation through the month. In a follow-up work (Djupesland and Skretting, 2012) the deposition patterns produced by this new approach and traditional liquid spray pump approach were compared based on Gamma camera images. Results showed the bidirectional delivery approach produced significantly larger initial deposition in the upper and middle posterior regions, while the nasal spray approach achieved higher deposition in the lower anterior and posterior regions. In our latest study (Dong et al., 2017b), a numerical comparison between aerosol mask and breath-powered bidirectional approaches were performed. Our results revealed both diffusive 1 nm and inertial 10 µm particles can yield peak olfactory depositions, but the topical deposition efficiency is around 3%, which remains at an insufficient level.

Despite the particle transport and deposition characteristics in nasal cavities have been intensively studied, how to topically apply nasal drugs remains challenging. To avoid lung inhalation, many regulations require micron-sized particles to be used for nasal administration (FDA, 2013). However, the inherent limitations due to particles’ inertial effects largely restrict their bioavailability. For example, the deposition fraction in the olfactory region only accounts 0.5% of the total delivered therapeutics when the particle size is in submicron range (Xi and Longest, 2008), and this value even becomes negligible for inertial particles (Shi et al., 2007). In recent years, drug delivery by nanoparticles has shown the potential to enhance drug bioavailability and enable precision drug targeting (Si and Xi, 2016), and nose-to-brain drug delivery by nanoparticles has been applied in the treatment of neurological disorders (Ong et al., 2014, Phukan et al., 2016). But issues such as toxicity on the nasal mucosa, delivery only to specific targeted regions and variability in the adsorbed dose still yet to be addressed (Ong et al., 2014).

Studies in the literature have yet to investigate the relevance between particles’ upstream spatial distribution and their final deposited locations. Therefore, this study aims to establish the correlation between nanoparticle’s releasing positions and its deposition sites, which can facilitate the performance improvement of targeted nasal drug delivery from the inhalation exposure aspect. In this paper, the nanoparticle transport process was analysed in detail from the initial releasing locations to the final deposited sites using a realistic human nasal passage. Dispersed particles at different coronal cross-sections were partitioned into multiple groups according to their final deposition locations. The results allow pharmaceutical engineers to adjust the particle’s releasing position for different targeted regions, and the amount of undesired depositions at irrelevant regions in the respiratory tract can also be reduced. This study provides fundamental understandings for future conceptual and optimised designs towards smart nasal drug delivery devices.