Characterizing the Effects of Nasal Prong Interfaces on Aerosol Deposition in a Preterm Infant Nasal Model.

The objective of this study was to characterize the effects of multiple nasal prong interface configurations on nasal depositional loss of pharmaceutical aerosols in a preterm infant nose-throat (NT) airway model. Benchmark in vitro experiments were performed in which a spray-dried powder formulation was delivered to a new preterm NT model with a positive-pressure infant air-jet dry powder inhaler using single- and dual-prong interfaces. These results were used to develop and validate a computational fluid dynamics (CFD) model of aerosol transport and deposition in the NT geometry. The validated CFD model was then used to explore the NT depositional characteristic of multiple prong types and configurations. The CFD model highlighted a turbulent jet effect emanating from the prong(s). Analysis of NT aerosol deposition efficiency curves for a characteristic particle size and delivery flowrate (3 µm and 1.4 L/min (LPM)) revealed little difference in NT aerosol deposition fraction (DF) across the prong insertion depths of 2-5 mm (DF = 16-24%) with the exception of a single prong with 5-mm insertion (DF = 36%). Dual prongs provided a modest reduction in deposition vs. a single aerosol delivery prong at the same flow for insertion depths < 5 mm. The presence of the prongs increased nasal depositional loss by absolute differences in the range of 20-70% compared with existing correlations for ambient aerosols. In conclusion, the use of nasal prongs was shown to have a significant impact on infant NT aerosol depositional loss prompting the need for prong design alterations to improve lung delivery efficiency.

In Vitro Analysis of Nasal Interface Options for High-Efficiency Aerosol Administration to Preterm Infants.

Background: An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Methods: Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two in vitro preterm infant NT models. Two excipient-enhanced growth (EEG) dry powder formulations were explored containing either l-leucine or trileucine as the dispersion enhancer. Performance metrics included aerosol depositional loss in the nasal interface, deposition in the NT models, and tracheal filter deposition, which was used to estimate lung delivery efficiency. Results: The best performing nasal interface replaced the straight flexible prong of the original gradual expansion design with a rigid curved prong (∼20° curvature). The prong modification increased the lung delivery efficiency by 5%-10% (absolute difference) depending on the powder formulation. Adding a metal mesh to the flow pathway, to dissipate the turbulent jet, also improved lung delivery efficiency by ∼5%, while reducing the NT depositional loss by a factor of over twofold compared with the original nasal interface. The platform was also found to perform similarly in two different preterm NT models, with no statistically significant difference between any of the performance metrics. Conclusions: Modifications to the nasal interface of an infant air-jet DPI improved the aerosol delivery through multiple infant NT models, providing up to an additional 10% lung delivery efficiency (absolute difference) with the lead design delivering ∼57% of the loaded dose to the tracheal filter, while performance in two unique preterm airway geometries remained similar.

High-Efficiency Dry Powder Aerosol Delivery to Children: Review and Application of New Technologies.

While dry powder aerosol formulations offer a number of advantages, their use in children is often limited due to poor lung delivery efficiency and difficulties with consistent dry powder inhaler (DPI) usage. Both of these challenges can be attributed to the typical use of adult devices in pediatric subjects and a lack of pediatric-specific DPI development. In contrast, a number of technologies have recently been developed or progressed that can substantially improve the efficiency and reproducibility of DPI use in children including: (i) nose-to-lung administration with small particles, (ii) active positive-pressure devices, (iii) structures to reduce turbulence and jet momentum, and (iv) highly dispersible excipient enhanced growth particle formulations. In this study, these technologies and their recent development are first reviewed in depth. A case study is then considered in which these technologies are simultaneously applied in order to enable the nose-to-lung administration of dry powder aerosol to children with cystic fibrosis (CF). Using a combination of computational fluid dynamics (CFD) analysis and realistic in vitro experiments, device performance, aerosol size increases and lung delivery efficiency are considered for pediatric-CF subjects in the age ranges of 2-3, 5-6 and 9-10 years old. Results indicate that a new 3D rod array structure significantly improves performance of a nasal cannula reducing interface loss by a factor of 1.5-fold and produces a device emitted mass median aerodynamic diameter (MMAD) of 1.67 µm. For all ages considered, approximately 70% of the loaded dose reaches the lower lung beyond the lobar bronchi. Moreover, significant and rapid size increase of the aerosol is observed beyond the larynx and illustrates the potential for targeting lower airway deposition. In conclusion, concurrent CFD and realistic in vitro analysis indicates that a combination of multiple new technologies can be implemented to overcome obstacles that currently limit the use of DPIs in children as young as two years of age.

Advancement of a Positive-Pressure Dry Powder Inhaler for Children: Use of a Vertical Aerosolization Chamber and Three-Dimensional Rod Array Interface.

PURPOSE: Available dry powder inhalers (DPIs) have very poor lung delivery efficiencies in children. The objective of this study was to advance and experimentally test a positive-pressure air-jet DPI for children based on the use of a vertical aerosolization chamber and new patient interfaces that contain a three-dimensional (3D) rod array structure. METHODS: Aerosolization performance of different air-jet DPI designs was first evaluated based on a 10 mg powder fill mass of a spray-dried excipient enhanced growth (EEG) formulation. Devices were actuated with positive pressure using flow rate (10-20 L/min) and inhaled volume (750 ml) conditions consistent with a 5-year-old child. Devices with best performance were connected to different mouthpiece designs to determine the effect on aerosolization and tested for aerosol penetration through a realistic pediatric in vitro mouth-throat model. RESULTS: Use of the new vertical aerosolization chamber resulted in high quality aerosol formation. Inclusion of a 3D rod array structure in the mouthpiece further reduced aerosol size by approximately 20% compared to conditions without a rod array, and effectively dissipated the turbulent jet leaving the device. Best case device and mouthpiece combinations produced < 2% mouth-throat depositional loss and > 70% lung delivery efficiency based on loaded dose. CONCLUSIONS: In conclusion, use of a 3D rod array in the MP of a positive-pressure air-jet DPI was found to reduce aerosol size by 20%, not significantly increase MP depositional loss, reduce mouth-throat deposition by 6.4-fold and enable lung delivery efficiency as high as 73.4% of loaded dose based on pediatric test conditions.

Development of Dry Powder Inhaler Patient Interfaces for Improved Aerosol Delivery to Children.

The objective of this study was to explore different internal flow passages in the patient interface region of a new air-jet-based dry powder inhaler (DPI) in order to minimize device and extrathoracic aerosol depositional losses using computational fluid dynamics (CFD) simulations. The best-performing flow passages were used for oral and nose-to-lung (N2L) aerosol delivery in pediatric extrathoracic airway geometries consistent with a 5-year-old child. Aerosol delivery conditions were based on a previously developed and tested air-jet DPI device and included a base flow rate of 13.3 LPM (delivered from a small ventilation bag) and an inhaled air volume of 750 mL. Initial CFD models of the system clearly established that deposition on either the back of the throat or nasal cannula bifurcation was strongly correlated with the maximum velocity exiting the flow passage. Of all designs tested, the combination of a 3D rod array and rapid expansion of the flow passage side walls was found to dramatically reduce interface and device deposition and improve lung delivery of the aerosol. For oral aerosol administration, the optimal flow passage compared with a base case reduced device, mouthpiece, and mouth-throat deposition efficiencies by factors of 8-, 3-, and 2-fold, respectively. For N2L aerosol administration, the optimal flow pathway compared with a base case reduced device, nasal cannula, and nose-throat deposition by 16-, 6-, and 1.3-fold, respectively. In conclusion, a new patient interface design including a 3D rod array and rapid expansion dramatically improved transmission efficiency of a dry powder aerosol.

Development of an Inline Dry Powder Inhaler for Oral or Trans-Nasal Aerosol Administration to Children.

Background: Dry powder inhalers (DPIs) offer a number of advantages, such as rapid delivery of high-dose inhaled medications; however, DPI use in children is often avoided due to low lung delivery efficiency and difficulty in operating the device. The objective of this study was to develop a high-efficiency inline DPI for administering aerosol therapy to children with the option of using either an oral or trans-nasal approach. Methods: An inline DPI was developed that consisted of hollow inlet and outlet capillaries, a powder chamber, and a nasal or oral interface. A ventilation bag or compressed air was used to actuate the device and simultaneously provide a full deep inspiration consistent with a 5-year-old child. The powder chamber was partially filled with a model spray-dried excipient enhanced growth powder formulation with a mass of 10 mg. Device aerosolization was characterized with cascade impaction, and aerosol transmissions through oral and nasal in vitro models were assessed. Results: Best device performance was achieved when all actuation air passed through the powder chamber (no bypass flow) resulting in an aerosol mean mass median aerodynamic diameter (MMAD) <1.75 µm and a fine particle fraction (<5 µm) ≥90% based on emitted dose. Actuation with the ventilation bag enabled lung delivery efficiency through the nasal and oral interfaces to a tracheal filter of 60% or greater, based on loaded dose. In both oral and nose-to-lung (N2L) administrations, extrathoracic depositional losses were <10%. Conclusion: In conclusion, this study has proposed and initially developed an efficient inline DPI for delivering spray-dried formulations to children using positive pressure operation. Actuation of the device with positive pressure enabled effective N2L aerosol administration with a DPI, which may be beneficial for subjects who are too young to use a mouthpiece or to simultaneously treat the nasal and lung airways of older children.

Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler.

The objective of this study was to optimize the performance of a high-efficiency pediatric inhaler, referred to as the pediatric air-jet DPI, using computational fluid dynamics (CFD) simulations with supporting experimental analysis of aerosol formation. The pediatric air-jet DPI forms an internal flow pathway consisting of an inlet jet of high-speed air, capsule chamber containing a powder formulation, and outlet orifice. Instead of simulating full breakup of the powder bed to an aerosol in this complex flow system, which is computationally expensive, flow-field-based dispersion parameters were sought that correlated with experimentally determined aerosolization metrics. For the pediatric air-jet DPI configuration that was considered, mass median aerodynamic diameter (MMAD) directly correlated with input turbulent kinetic energy normalized by actuation pressure and flow kinetic energy. Emitted dose (ED) correlated best with input flow rate multiplied by the ratio of capillary diameters. Based on these dispersion parameters, an automated CFD process was used over multiple iterations of over 100 designs to identify optimal inlet and outlet capillary diameters, which affected system performance in complex and unexpected ways. Experimental verification of the optimized designs indicated an MMAD < 1.6 µm and an ED > 90% of loaded dose. While extrathoracic depositional loss will be determined in future studies, at an operating flow rate of 15 L/min, it is expected that pediatric mouth-throat or even nose-throat aerosol deposition fractions will be below 10% and potentially less than 5% representing a significant improvement in the delivery efficiency of dry powder pharmaceutical aerosols to children.

Use of Computational Fluid Dynamics (CFD) Dispersion Parameters in the Development of a New DPI Actuated with Low Air Volumes.

PURPOSE: To determine the predictive power of computational fluid dynamics (CFD)-based dispersion parameters in the development of a new inline DPI that is actuated with low volumes of air. METHODS: Four new versions of a dose aerosolization and containment (DAC)-unit DPI were created with varying inlet and outlet orifice sizes and analyzed with results from five previous designs. A concurrent in vitro and CFD analysis was conducted to predict the emitted dose (ED; as a % of loaded dose) and aerosol mass median aerodynamic diameter (MMAD) produced by each device when actuated with 10 ml air bursts. CFD simulations of device operation were used to predict flow field and particle-based dispersion parameters. RESULTS: Comparisons of experimental and CFD results indicated that multiple flow field and particle-based dispersion parameters could be used to predict ED (minimum RMS Error = 4.9%) and MMAD (minimum RMS Error = 0.04 µm) to a high degree of accuracy. Based on experiments, the best overall device produced mean (standard deviation; SD) ED = 82.9(4.3)% and mean MMAD (SD) = 1.73(0.07)µm, which were in close agreement with the CFD predictions. CONCLUSIONS: A unique relationship was identified in the DAC-unit DPI in which reducing turbulence also reduced the MMAD.

Use of computational fluid dynamics deposition modeling in respiratory drug delivery.

INTRODUCTION: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption. AREAS COVERED: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols. Areas covered include the development of new complete-airway CFD deposition models and the application of these models to develop a next-generation of respiratory drug delivery strategies. EXPERT OPINION: Complete-airway deposition modeling is a valuable research tool that can improve our understanding of pharmaceutical aerosol delivery and is already supporting medical hypotheses, such as the expected under-treatment of the small airways in asthma. These complete-airway models are also being used to advance next-generation aerosol delivery strategies, like controlled condensational growth. We envision future applications of CFD deposition modeling to reduce the need for human subject testing in developing new devices and formulations, to help establish bioequivalence for the accelerated approval of generic inhalers, and to provide valuable new insights related to drug dissolution and clearance leading to microdosimetry maps of drug absorption.

High-Efficiency Nose-to-Lung Aerosol Delivery in an Infant: Development of a Validated Computational Fluid Dynamics Method.

Background: Computational fluid dynamics (CFD) provides a powerful tool for developing new high-efficiency aerosol delivery strategies, such as nose-to-lung (N2L) aerosol administration to infants and children using correctly sized aerosols. The objective of this study was to establish numerically efficient CFD solution methods and guidelines for simulating N2L aerosol administration to an infant based on comparisons with concurrent in vitro experiments. Materials and Methods: N2L administration of a micrometer-sized aerosol (mass median aerodynamic diameter [MMAD] = 1.4 µm) was evaluated using concurrent CFD simulations and in vitro experiments. Aerosol transport and deposition was assessed in a new nasal airway geometry of a 6-month-old infant with a streamlined nasal cannula interface, which was constructed as a CFD mesh and three-dimensionally printed to form an identical physical prototype. CFD meshes explored were a conventional tetrahedral approach with near-wall (NW) prism elements and a new polyhedral mesh style with an equally refined NW layer. The presence of turbulence in the model was evaluated using a highly efficient low-Reynolds number (LRN) k-ω turbulence model, with previously established NW corrections that accounted for anisotropic wall-normal turbulence as well as improved NW velocity interpolations and hydrodynamic particle damping. Results: Use of the new polyhedral mesh was found to improve numerical efficiency by providing more rapid convergence and requiring fewer control volumes. Turbulent flow was found in the nasal geometry, generated by the inlet jets from the nasal cannula interface. However, due to the small particle size, turbulent dispersion was shown to have little effect on deposition. Good agreement was established between the CFD predictions using the numerically efficient LRN k-ω model with appropriate NW corrections and in vitro deposition data. Aerosol transmission efficiencies through the delivery tube, nasal cannula, and infant nasal model, based on experimental and CFD predictions, were 93.0% and 91.5%, respectively. Conclusions: A numerically efficient CFD approach was established to develop transnasal aerosol administration to infants and children. Small particle aerosols with aerodynamic diameters of ∼1.5 µm were confirmed to have low inertial depositional loss, and have low deposition from turbulent dispersion, making them ideal for high-efficiency lung delivery through an infant nasal cannula interface.

Recommendations for Simulating Microparticle Deposition at Conditions Similar to the Upper Airways with Two-Equation Turbulence Models.

The development of a CFD model, from initial geometry to experimentally validated result with engineering insight, can be a time-consuming process that often requires several iterations of meshing and solver set-up. Applying a set of guidelines in the early stages can help to streamline the process and improve consistency between different models. The objective of this study was to determine both mesh and CFD solution parameters that enable the accurate simulation of microparticle deposition under flow conditions consistent with the upper respiratory airways including turbulent flow. A 90° bend geometry was used as a characteristic model that occurs throughout the airways and for which high-quality experimental aerosol deposition data is available in the transitional and turbulent flow regimes. Four meshes with varying degrees of near-wall resolution were compared, and key solver settings were applied to determine the parameters that minimize sensitivity to the near-wall (NW) mesh. The Low Reynolds number (LRN) k-ω model was used to resolve the turbulence field, which is a numerically efficient two-equation turbulence model, but has recently been considered overly simplistic. Some recent studies have used more complex turbulence models, such as Large Eddy Simulation (LES), to overcome the perceived weaknesses of two-equation models. Therefore, the secondary objective was to determine whether the more computationally efficient LRN k-ω model was capable of providing deposition results that were comparable to LES. Results show how NW mesh sensitivity is reduced through application of the Green-Gauss Node-based gradient discretization scheme and physically realistic near-wall corrections. Using the newly recommended meshing parameters and solution guidelines gives an excellent match to experimental data. Furthermore, deposition data from the LRN k-ω model compares favorably with LES results for the same characteristic geometry. In summary, this study provides a set of meshing and solution guidelines for simulating aerosol deposition in transitional and turbulent flows found in the upper respiratory airways using the numerically efficient LRN k-ω approach.

Development of an infant complete-airway in vitro model for evaluating aerosol deposition.

A complete-airway in vitro model would be very useful for toxicological dosimetry testing and for developing targeted inhaled medications in cases where conducting in vivo experiments are exceedingly difficult, as with infants. The objective of this study was to determine whether packed bed in vitro models, which contain spheres as the primary repeating unit, provide a realistic representation of aerosol deposition in the tracheobronchial region of infant lungs based on computational fluid dynamics (CFD) predictions. The packed bed (PB) CFD model contained an inlet consistent with airway bifurcation B3 (∼lobar bronchi) leading to a spherical array with voids between the spheres forming a divided flow pathway. The hydrodynamic diameter of the voids was approximately matched to the diameter of bifurcations in various lung regions. For comparison, a CFD stochastic individual pathway (SIP) geometry with realistic bifurcations extending from B4-B15 (terminal bronchioles) was selected as an anatomically accurate model. The CFD-SIP model predictions were benchmarked with existing algebraic correlations for aerosol deposition in the lungs and found to be reasonable. Unfortunately, the CFD-PB model did not provide a good representation of aerosol deposition in the tracheobronchial region of human lungs. Through careful selection of the PB sphere size and inlet conditions, total deposition in the CFD-PB model matched CFD-SIP deposition within 10% absolute error across a range of relevant aerosol sizes. However, regional deposition within the CFD-PB model was very different from the CFD-SIP case. Therefore, the PB approach cannot be recommended for determining spatial or temporal distribution of aerosol transport and impaction deposition through the lungs.