Effects of nasal drug delivery device and its orientation on sprayed particle deposition in a realistic human nasal cavity
Introduction
The nasal route for therapeutic agent delivery is an attractive proposition due to the possibility of obtaining a systemic and local response, especially when rapid absorption and effect are desired [33], [5]. Nasal sprays are seen as a more efficient way compared with injection or pills to transport drugs with potential use in bypassing the blood-brain barrier [2]. Due to the filtration effect of anterior nostril, majority of sprayed droplets deposits in the anterior nasal cavity [1], [14], [21], [31]. A number of nasal spray studies have reported the low targeted area deposition rate using conventional nasal spray devices. For example, the deposition fraction in the olfactory region only accounts 0.5% of the total delivered therapeutic agents when the particle size is in submicron range [28], [34], and this value even becomes negligible for inertial particles [29]. Therefore, comprehensive understanding of nasal spray characteristics and its interaction with the human nasal cavity play essential roles in the design of nasal spray devices and their performance assessment when need.
The nasal cavity is a convoluted anatomy with its primary function to humidify and filter foreign aerosols from the inhaled air before it reaches the lungs (Fig. 1). The main nasal passage may serve as an efficient absorption surface for topically applied therapeutic agents due to the rich vascularization and large surface area proportion [5]. In particular, the olfactory region located at the uppermost of the nasal cavity is the only site in human body where the central nervous system (CNS) is in direct contact with the environment. Intranasally administered drugs once deposited in the olfactory region can migrate across the olfactory mucosa and reach the CNS within minutes, resulting in quick therapeutic onset [10]. However, the nasal anatomy exhibits narrow passageways highlighted by the anterior nasal valve, which limits the transport of sprayed droplets during intranasal spray. This triangular valve-like region has the smallest cross-sectional area located approximately 2–3 cm posterior from the nostril inlet [4] and acts as a flow limiting region [5] before expanding into the main nasal passage. Large aerosols that are unable to navigate through this narrow section can be captured easily. Therefore, the nasal valve presents a major obstacle for effective drug delivery into the main nasal passage where rapid absorption across the mucosa into the blood stream can occur.
Various nasal spray studies adopting human nasal cavity have found the main influences on spray particle deposition involve the nasal cavity geometry and spray parameters (such as droplet size, injected velocity) controlled by the design of nasal spray devices. The aqueous spray pump is the dominant delivery device in the nasal drug delivery market [22] which relies on an actuation force to atomize the drug formulation as it is discharged from the device. The underlying objective of the device is to deliver sufficient drug formulation to the target site.
Cheng et al. [3] evaluated four nasal spray pumps and found that spray plume angle and droplet size distribution were important factors in deposition. Foo et al. [7] found that insertion angle and plume angle are critical factors in determining deposition efficiency and this was confirmed by a number of computational simulations [15], [21], [8], [9]. Kundoor and Dalby [23] evaluated the effect of formulation and administration related variables and found that the deposition area decreased with increasing viscosity but this was mediated by an increase in droplet size and a narrowing of the spray plume. Frank et al. [8], [9] investigated effects of the deviated nasal septum on the distribution of spray particles and demonstrated that septal deviation significantly diminished drug delivery on the obstructed side. Our previous study numerically demonstrated the most important parameter was the particle's Stokes number which affects all other parameters on the deposition efficiency [15].
Based on these studies if a spray device can produce a combination of desirable spray characteristics (e.g. spray plume, viscosity, insertion angle, droplet size distribution) then more efficient drug delivery systems can be produced. Despite numbers of relevant studies have been conducted, majority of them were based on experimental measurements or numerical simulation exclusively, and the airflow obstruction effect due to the insertion of nasal spray devices into vestibule region was rarely considered. Although our latest study [14] numerically modelled this airway blockage at one of the nostrils during nasal spray administration, the nasal spray device was over simplified, and its insertion direction and depth was not well aligned with the nasal vestibule.
In the present study, a more realistic nasal spray administration assessment through a combined experimental and numerical approach was presented. Firstly, the initial particle conditions such as spray plume angle, break up length, particle velocity were acquired from Particle Droplet Image Analyser (PDIA). Then, numerical simulations considered the insertion of nasal spray bottle nozzle and human facial effects were conducted. To optimize the drug delivery performance, a spray nozzle orientation adjustment plane was proposed for spray nozzle˗nasal valve alignment.
Section snippets
Experimental apparatus
The experimental setup for this study is shown in Fig. 2. The main components used in the present study were similar with our previous studies [14], [16], which mainly includes the automated actuation system and the visualization system. In our previous studies, the pneumatic actuator was driven by constant pressure through pressure regulator to achieve a relatively steady spray plume, while this driven force failed to represent the human actuation behaviour. In the present study, a
Spray plume outline detection
The spray plume outline was detected by Sobel method, which was developed by Sobel [30]. It is a derivative based edge detection algorithm which is able to calculate the boundary of the spray cone by implements convolution with Sobel kernels. The subject edge was determined by determining the greatest gradient of change of the intensity of pixels. It gives the direction of the change of colour and the change rate in that direction. The Sobel method was applied through MATLAB coding on captured
Discussion and conclusions
This study provides a systematically nasal spray performance evaluation on the basis of high speed imaging for spray outline analysis, medical imaging (CT scan in this study) and CFD simulation. Influence factors such as breathing condition, spray direction (spray nozzle ˗ nasal valve alignment), and medication droplets size were considered.
Despite the nasal sprays provide non-invasive quick therapeutic onset and have been widely applied for the treatment of cold and allergy, poorly designed
Acknowledgements and disclosures
This work was supported by the Australian Research Council (Project ID: DP160101953), and the authors report no conflicts of interest in this work.
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