The Way to Spray: Modeling Nasal Spray Deposition

Intranasal drug delivery is an alternative method in addition to traditional oral and intravenous doses. Nasal drug delivery has proven to be a very effective technique for nicotine cessation (Hjalmarson et al., 1994), the influenza vaccine (Jackson et al. 1999), and drugs that need to be take continuously, such as insulin (Dondeti et al., 1995). Studies have found that for effective fast-acting body response, the drug needs to be deposited in the highly vascularized mucosal tissue lining the bony turbinates in the nasal cavity. Commercial nasal sprays are continuously optimizing parameters to develop the most effective deposition patterns. In this project, drug deposition is modeled using a simplified 2D depiction of the nasal passageway with uniformly-shaped, spherical spray particles. This problem is implemented in COMSOL by using 2D Navier Stokes fluid flow equations to model the airflow through the nose, and the Particle Tracing module to model the spray trajectory and deposition. The model output was validated by determining the percentages of particles in each region of the nasal passage - anterior, turbinate, posterior, and outlet - and comparing with published experimental data by Cheng et al (2001). A sensitivity analysis was done on the following parameters: particle density, particle size, nozzle spray angle, and nozzle penetration depth. It was found that this model was sensitive to only penetration depth. As penetration depth through the nostril increased, there was a decrease in the particle deposition in the anterior region of the nasal cavity and an increase in the percentage of particles that exited through the outlet. Deposition in the middle and posterior regions was not affected by variation in penetration depth. Our sensitivity analysis demonstrated that variations in spray angle, particle size, and density of the nasal spray fluid do not significantly affect deposition pattern. Therefore, when designing nasal sprays, as long as these parameters remain within the specified ranges, consistent deposition patterns will be achieved. This result also allows for further research on creating sprays that are more concentrated and have encapsulated drugs

Modelling the inhalation of drug particles in a human nasal cavity

A human nasal cavity was reconstructed from CT scans to make a Computational Fluid Dynamics (CFD) model. With this model, fluid flow and inhalation of aerosol analysis can be investigated. The surface of the interior nasal cavity is lined with highly vascularised mucosa which provides a means for direct drug delivery into the blood stream. Typical sprayed particles from a nasal spray device produce a particle size distribution with a mean diameter of 50μm, which leads to early deposition due to inertial impaction. In this study low-density drug particles and submicron particles (including nanoparticles) are used to evaluate their deposition patterns. It was found that the low-density particles lightens the particle inertial properties however the particle inertia is more sensitive to the particle size rather than the density. Moreover the deposition pattern for nano-particles is spread out through the airway. Thus an opportunity may exist to develop low-density and nanoparticles to improve the efficiency of drug delivery to target deposition on the highly vascularised mucosal walls. SciRes Copyright © 2010

A consensus research agenda for optimising nasal drug delivery

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors

Large-scale CFD and micro-particles simulations in a large human airways under sniff condition and drug delivery application

As we inhale, the air drawn through our nose undergoes successive accelerations and decelerations as it is turned, split, and recombined before splitting again at the end of the trachea as it enters the bronchi. Fully describing the dynamic behaviour of the airflow and how it transports inhaled particles poses a severe challenge to computational simulations. The dynamics of unsteady flow in the human large airways during a rapid and short inhalation (a so-called sniff) is a perfect example of perhaps the most complex and violent human inhalation inflow. Combining the flow solution with a Lagrangian computation reveals the effects of flow behaviour and airway geometry on the deposition of inhaled microparticles. Highly detailed large-scale computational fluid dynamics allow resolving all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code running on supercomputers can solve the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations, wall shear stresses, energy spectral and particle deposition on a rapid and short inhalation. Then in a second time, we will propose a drug delivery study of nasal sprayed particle from commercial product in a human nasal cavity under different inhalation conditions; sniffing, constant flow rate and breath-hold. Particles were introduced into the flow field with initial spray conditions, including spray cone angle, insertion angle, and initial velocity. Since nasal spray atomizer design determines the particle conditions, fifteen particle size distributions were used,each defined by a log-normal distribution with a different volume mean diameter. This thesis indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow and delivery of therapeutic aerosols, which could be applied to improve diagnosis and treatment.En una inhalación, el aire que atraviesa nuestra cavidad nasal es sometido a una serie de aceleraciones y deceleraciones al producirse un giros, bifurcaciones y recombinarse de nuevo antes de volver a dividirse de nuevo a la altura de la tráquea en la entrada a los bronquios principales. La descripción precisa y acurada del comportamiento dinámico de este fluido así como el transporte de partículas inhalada que entran con el mismo a través de una simulación computacional supone un gran desafío. La dinámica del fluido en las vías respiratorias durante una inhalación rápida y corta (también llamado sniff) es un ejemplo perfecto de lo que sería probablemente la inhalación en el ser humano más compleja y violenta. Combinando la solución del fluido con un modelo lagrangiano revela el comportamiento del flujo y el effecto de la geometría de las vías respiratorias sobre la deposición de micropartículas inhaladas. La dinámica de fluidos computacional a gran escala de alta precisión permite resolver todas las escalas espaciales y temporales gracias al uso de recursos computacionales masivos. Un código de elementos finitos paralelos que se ejecuta en supercomputadoras puede resolver las ecuaciones transitorias e incompresibles de Navier-Stokes. Considerando que la malla más fina contiene 350 millones de elementos, cabe señalar que el presente estudio establece un precedente para simulaciones a gran escala de las vías respiratorias, proponiendo una estrategia de análisis para flujo medio, fluctuaciones, tensiones de corte de pared, espectro de energía y deposición de partículas en el contexto de una inhalación rápida y corta. Una vez realizado el analisis anterior, propondremos un estudio de administración de fármacos con un spray nasal en una cavidad nasal humana bajo diferentes condiciones de inhalación; sniff, caudal constante y respiración sostenida. Las partículas se introdujeron en el fluido con condiciones iniciales de pulverización, incluido el ángulo del cono de pulverización, el ángulo de inserción y la velocidad inicial. El diseño del atomizador del spray nasal determina las condiciones de partículas, entonces se utilizaron quince distribuciones de tamaño de partícula, cada uno definido por una distribución logarítmica normal con una media de volumen diferente. Esta tesis demuestra el potencial de las simulaciones a gran escala para una mejor comprensión de los mecanismos fisiológicos de las vías respiratorias. Gracias a estas herramientas se podrá mejorar el diagnóstico y sus respectivos tratamientos ya que con ellas se profundizará en la comprensión del flujo que recorre las vías aereas así como el transporte de aerosoles terapéuticos

Modeling of Transport in Anatomic Respiratory Airways: Applications in Targeted Drug Delivery and Airborne Pathogenic Transmissions

This thesis aims to explore the potential of improving the efficacy of drugs for treatment of viral infections by targeting the nasopharynx, which is commonly the first site of infection for many viral pathogens. Currently, intranasal sprays are used, but the standard protocol (“Current Use” or CU) results in suboptimal drug deposition at the nasopharynx. To address this issue, an “Improved Use” or, IU protocol has been proposed, which involves pointing the spray bottle at a shallower angle and aiming slightly towards the cheeks. The IU delivery is also robust to perturbations in spray direction, which highlights the practical utility of this new drug administration protocol. The results of the simulation are experimentally verified using a 3D-printed airway cavity of a different subject. Next with the smallpox virus as an example pathogen, a numerical modeling framework for airborne respiratory diseases has been made. This modeling framework shows that the regional deposition of virus-laden inhaled droplets at the initial infection site (for smallpox, this is the oropharynx and the lungs) peaks for the droplet size range (8–27 μm for oropharyngeal deposition, and ≤ 14 μm for lungs) and can be used to determine the number of virions required to launch the infection in a subject. Subsequently, to explore the mechanics of lower airway disease progression, we have considered SARS-CoV-2. We have investigated the spread of SARS-CoV-2 from the nasopharynx to the lower airway. Using computational models, the inhalation process has been tracked with quantification for the volume of nasopharyngeal liquid transmitted to the lower airspace during each aspiration. The results suggest that a significant amount of liquid may be aspirated each day, which could lead to an increased risk of aggressive and accelerated lung infections in individuals with conditions like dysphagia. Finally, in view of the high cost and time required for conducting numerous numerical simulations, we have checked Machine Learning platforms as an alternative method for predicting regional deposition at various anatomical regions based on the geometric features of the anatomic flow domains in respiratory physiology. As an ancillary topic, the thesis also explores the morphological characteristics of the nose and their influence on airflow patterns and heat transfer dynamics inside the nasal cavity of a pig’s nose. The findings indicate that tortuosity has a crucial role in particle capture efficiency, particularly in high-olfactory mammalian species such as pigs and opossums. Understanding the fluid-particle interactions in nasal cavities could lead to the development of nature-inspired designs for various engineering processes, such as the creation of novel filtration devices. Therefore, it is essential to continue investigating the significance of heat management and particle screening in nasal structures to reveal their mechanistic functions and translate this information into practical applications

Numerical analysis of airflow and particle deposition in multi-fidelity designs of nasal replicas following nasal administration

Background and Objective: An improved understanding of flow behaviour and particle deposition in the human nasal airway is useful for optimising drug delivery and assessing the implications of pollutants and toxin inhalation. The geometry of the human nasal cavity is inherently complex and presents challenges and manufacturing constraints in creating a geometrically realistic replica. Understanding how anatomical structures of the nasal airway affect flow will shed light on the mechanics underpinning flow regulation in the nasal pharynx and provide a means to interpret flow and particle deposition data conducted in a nasal replica or model that has reduced complexity in terms of their geometries. This study aims to elucidate the effects of sinus and reduced turbinate length on nasal flow and particle deposition efficiencies. Methods: A complete nasal airway with maxillary sinus was first reconstructed using magnetic resonance imaging (MRI) scans obtained from a healthy human volunteer. The basic model was then modified to produce a model without the sinus, and another with reduced turbinate length. Computational fluid dynamics (CFD) was used to simulate flow in the nasal cavity using transient flow profiles with peak flow rates of 15 L/min, 35 L/min and 55 L/min. Particle deposition was investigated using discrete phase modelling (DPM). Results: Results from this study show that simplifying the nasal cavity by removing the maxillary sinus and curved sections of the meatus only has a minor effect on airflow. By mapping the spatial distribution of monodisperse particles (10 μm) in the three models using a grid map that consists of 30 grids, this work highlights the specific nasal airway locations where deposition efficiencies are highest, as observed within a single grid. It also shows that lower peak flow rates result in higher deposition differences in terms of location and deposition quantity, among the models. The highest difference in particle deposition among the three nasal models is ∼10%, and this is observed at the beginning of the middle meatus and the end of the pharynx, but is only limited to the 15 L/min peak flow rate case. Further work demonstrating how the outcome may be affected by a wider range of particle sizes, less specific to the pharmaceutical industries, is warranted. Conclusion: A physical replica manufactured without sections of the middle meatus could still be adequate in producing useful data on the deposition efficiencies associated with an intranasal drug formulation and its delivery device

Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review

Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. In addition, nasal delivery may help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events in the gastrointestinal tract and avoids the first-pass metabolism in the liver. However, when considering nasal delivery devices and mechanisms, it is important to keep in mind that the prime purpose of the nasal airway is to protect the delicate lungs from hazardous exposures, not to serve as a delivery route for drugs and vaccines. The narrow nasal valve and the complex convoluted nasal geometry with its dynamic cyclic physiological changes provide efficient filtration and conditioning of the inspired air, enhance olfaction, and optimize gas exchange and fluid retention during exhalation. However, the potential hurdles these functional features impose on efficient nasal drug delivery are often ignored. With this background, the advantages and limitations of existing and emerging nasal delivery devices and dispersion technologies are reviewed with focus on their clinical performance. The role and limitations of the in vitro testing in the FDA guidance for nasal spray pumps and pressurized aerosols (pressurized metered-dose inhalers) with local action are discussed. Moreover, the predictive value and clinical utility of nasal cast studies and computer simulations of nasal airflow and deposition with computer fluid dynamics software are briefly discussed. New and emerging delivery technologies and devices with emphasis on Bi-Directional™ delivery, a novel concept for nasal delivery that can be adapted to a variety of dispersion technologies, are described in more depth

Computed intranasal spray penetration: comparisons before and after nasal surgery

Quantitative methods for comparing intranasal drug delivery efficiencies pre- and postoperatively have not been fully utilized. The objective of this study is to use computational fluid dynamics techniques to evaluate aqueous nasal spray penetration efficiencies before and after surgical correction of intranasal anatomic deformities

On a model-based approach to improve intranasal spray targeting for respiratory viral infections

The nasopharynx, at the back of the nose, constitutes the dominant initial viral infection trigger zone along the upper respiratory tract. However, as per the standard recommended usage protocol (“Current Use”, or CU) for intranasal sprays, the nozzle should enter the nose almost vertically, resulting in sub-optimal nasopharyngeal drug deposition. Through the Large Eddy Simulation technique, this study has replicated airflow under standard breathing conditions with 15 and 30 L/min inhalation rates, passing through medical scan-based anatomically accurate human airway cavities. The small-scale airflow fluctuations were resolved through use of a sub-grid scale Kinetic Energy Transport Model. Intranasally sprayed droplet trajectories for different spray axis placement and orientation conditions were subsequently tracked via Lagrangian-based inert discrete phase simulations against the ambient inhaled airflow field. Finally, this study verified the computational projections for the upper airway drug deposition trends against representative physical experiments on sprayed delivery performed in a 3D-printed anatomic replica. The model-based exercise has revealed a new “Improved Use” (or, IU) spray usage protocol for viral infections. It entails pointing the spray bottle at a shallower angle (with an almost horizontal placement at the nostril), aiming slightly toward the cheeks. From the conically injected spray droplet simulations, we have summarily derived the following inferences: (a) droplets sized between 7–17 μm are relatively more efficient at directly reaching the nasopharynx via inhaled transport; and (b) with realistic droplet size distributions, as found in current over-the-counter spray products, the targeted drug delivery through the IU protocol outperforms CU by a remarkable 2 orders-of-magnitude

On a model-based approach to improve intranasal spray targeting for respiratory viral infections

The nasopharynx, at the back of the nose, constitutes the dominant initial viral infection trigger zone along the upper respiratory tract. However, as per the standard recommended usage protocol (“Current Use”, or CU) for intranasal sprays, the nozzle should enter the nose almost vertically, resulting in sub-optimal nasopharyngeal drug deposition. Through the Large Eddy Simulation technique, this study has replicated airflow under standard breathing conditions with 15 and 30 L/min inhalation rates, passing through medical scan-based anatomically accurate human airway cavities. The small-scale airflow fluctuations were resolved through use of a sub-grid scale Kinetic Energy Transport Model. Intranasally sprayed droplet trajectories for different spray axis placement and orientation conditions were subsequently tracked via Lagrangian-based inert discrete phase simulations against the ambient inhaled airflow field. Finally, this study verified the computational projections for the upper airway drug deposition trends against representative physical experiments on sprayed delivery performed in a 3D-printed anatomic replica. The model-based exercise has revealed a new “Improved Use” (or, IU) spray usage protocol for viral infections. It entails pointing the spray bottle at a shallower angle (with an almost horizontal placement at the nostril), aiming slightly toward the cheeks. From the conically injected spray droplet simulations, we have summarily derived the following inferences: (a) droplets sized between 7–17 μm are relatively more efficient at directly reaching the nasopharynx via inhaled transport; and (b) with realistic droplet size distributions, as found in current over-the-counter spray products, the targeted drug delivery through the IU protocol outperforms CU by a remarkable 2 orders-of-magnitude