Development of an effective two-equation turbulence modeling approach for simulating aerosol deposition across a range of turbulence levels.

Pharmaceutical aerosol systems present a significant challenge to computational fluid dynamics (CFD) modeling based on the need to capture multiple levels of turbulence, frequent transition between laminar and turbulent flows, anisotropic turbulent particle dispersion, and near-wall particle transport phenomena often within geometrically complex systems over multiple time scales. Two-equation turbulence models, such as the k-ω family of approximations, offer a computationally efficient solution approach, but are known to require the use of near-wall (NW) corrections and eddy interaction model (EIM) modifications for accurate predictions of aerosol deposition. The objective of this study was to develop an efficient and effective two-equation turbulence modeling approach that enables accurate predictions of pharmaceutical aerosol deposition across a range of turbulence levels. Key systems considered were the traditional aerosol deposition benchmark cases of a 90-degree bend (Re=6,000) and a vertical straight section of pipe (Re=10,000), as well as a highly complex case of direct-to-infant (D2I) nose-to-lung pharmaceutical aerosol delivery from an air-jet dry powder inhaler (DPI) including a patient interface and infant nasal geometry through mid-trachea (500

Advancement of a high-dose infant air-jet dry powder inhaler (DPI) with passive cyclic loading: Performance tuning for different formulations.

There is a current medical need for a dry powder aerosol delivery device that can be used to efficiently and consistently administer high dose therapeutics, such as inhaled antibiotics, surfactants and antivirals, to the lungs of infants. This study considered an infant air-jet dry powder inhaler (DPI) that could be actuated multiple times with minimal user interaction (i.e., a passive cyclic loading strategy) and focused on the development of a metering system that could be tuned for individual powder formulations to maintain high efficiency lung delivery. The metering system consisted of a powder delivery tube (PDT) connecting a powder reservoir with an aerosolization chamber and a powder supporting shelf that held a defined formulation volume. Results indicated that the metering system could administer a consistent dose per actuation after reaching a steady state condition. Modifications of the PDT diameter and shelf volume provided a controllable approach that could be tuned to maximize lung delivery efficiency for three different formulations. Using optimized metering system conditions for each formulation, the infant air-jet DPI was found to provide efficient and consistent lung delivery of aerosols (∼45% of loaded dose) based on in vitro testing with a preterm nose-throat model and limited dose/actuation to <5 mg.

Effects of different mesh nebulizer sources on the dispersion of powder formulations produced with a new small-particle spray dryer.

The objective of this study was to explore the aerosolization performance of powders produced with different mesh nebulizer sources in the initial design of a new small-particle spray dryer system. An aqueous excipient enhanced growth (EEG) model formulation was spray dried using different mesh sources and the resulting powders were characterized based on (i) laser diffraction, (ii) aerosolization with a new infant air-jet dry powder inhaler, and (iii) aerosol transport through an infant nose-throat (NT) model ending with a tracheal filter. While few differences were observed among the powders, the medical-grade Aerogen Solo (with custom holder) and Aerogen Pro mesh sources were selected as lead candidates that produced mean fine particle fractions <5 µm and <1 µm in ranges of 80.6-77.4% and 13.1-16.0%, respectively. Improved aerosolization performance was achieved at a lower spray drying temperature. Lung delivery efficiencies through the NT model were in the range of 42.5-45.8% for powders from the Aerogen mesh sources, which were very similar to previous results with a commercial spray dryer. Ultimately, a custom spray dryer that can accept meshes with different characteristics (e.g., pore sizes and liquid flow rates) will provide particle engineers greater flexibility in producing highly dispersible powders with unique characteristics.

New Air-Jet Dry Powder Insufflator for High-Efficiency Aerosol Delivery to Rats.

Pulmonary deposition of lung-targeted therapeutic aerosols can achieve direct drug delivery to the site of action, thereby enhancing the efficacy and reducing systemic exposure. In this study, we investigated the in vitro and in vivo aerosol performance of the novel small animal air-jet dry powder insufflator (Rat AJ DPI) using spray-dried albuterol excipient-enhanced-growth (EEG) powder as a model formulation. The in vitro aerosolization performance of the optimized albuterol EEG powder was first assessed using the Rat AJ DPI. The performance of Rat AJ DPI to deliver albuterol EEG aerosol to rat lungs was then compared to that of the Penn-Century Insufflator. Albuterol EEG powders dispersed using the Rat AJ DPI demonstrated narrow unimodal aerosol size distribution profiles, which were independent of the loaded powder dose (1, 2, and 5 mg). In addition, the span value for Rat AJ DPI (5 mg powder mass) was 1.32, which was 4.2-fold lower than that for Penn-Century insufflator (5 mg powder mass). At a higher loaded mass of 5 mg, the Rat AJ DPI delivered significantly larger doses to rat lungs compared with the Penn-Century DPI. The Rat AJ DPI with hand actuation delivered approximately 85% of the total emitted dose (2 and 5 mg loadings), which was comparatively higher than that for Penn-Century DPI (approximately 75%). In addition, percentage deposition in each of the lung lobes for the Rat AJ DPI was observed to be independent of the administration dose (2 and 5 mg loadings) with coefficients of variation below 12%, except in the right middle lobe. Automatic actuation of a 5 mg powder mass using the Rat AJ DPI demonstrated a similar delivered dose compared to manual actuation of the same dose, with 82% of the total emitted dose reaching the lung lobes. High-efficiency delivery of the aerosol to the lobar lung region and low sensitivity of the interlobar delivery efficiency to the loaded dose highlight the suitability of the new air-jet DPI for administering therapeutic pharmaceutical aerosols to small test animals.

Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers.

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.

Establishing quantitative relationships between changes in nasal spray in vitro metrics and drug delivery to the posterior nasal region.

Nasal sprays are typically characterized using in vitro spray metrics such as spray cone angle and droplet size distribution. It is currently not clear how these in vitro metrics correlate with regional nasal deposition, and these relationships could help explain the impact of product differences. In this study, the effects of changes in spray cone angle, spray velocity, spray ovality and droplet size distribution on regional nasal deposition were analyzed using a validated computational fluid dynamics model in recently developed adult characteristic nasal airway anatomies. The impact of the spray on the surrounding air phase was included. Results indicated that changes in spray cone angle largely influenced the nasal posterior deposition (PD) of the drug. Changes in the plume ovality and characteristic droplet size moderately influenced PD, but the results were dependent on the insertion conditions and nasal geometry. Changes in spray velocity and uniformity constant of the droplet size distribution had only minimal influence on PD. The rank order of metrics having the greatest to least impact on PD was cone angle ≫ plume ovality ≫ characteristic droplet size ≫ velocity ≫ size distribution uniformity constant. Overall, results from this study established quantitative relationships for predicting expected changes in PD.

Near Elimination of In Vitro Predicted Extrathoracic Aerosol Deposition in Children Using a Spray-Dried Antibiotic Formulation and Pediatric Air-Jet DPI.

PURPOSE: This study evaluated the in vitro aerosol performance of a dry powder antibiotic product that combined a highly dispersible tobramycin powder with a previously optimized pediatric air-jet dry powder inhaler (DPI) across a subject age range of 2-10 years. METHODS: An excipient enhanced growth (EEG) formulation of the antibiotic tobramycin (Tobi) was prepared using a small particle spray drying technique that included mannitol as the hygroscopic excipient and trileucine as the dispersion enhancer. The Tobi-EEG formulation was aerosolized using a positive-pressure pediatric air-jet DPI that included a 3D rod array. Realistic in vitro experiments were conducted in representative airway models consistent with children in the age ranges of 2-3, 5-6 and 9-10 years using oral or nose-to-lung administration, non-humidified or humidified airway conditions, and constant or age-specific air volumes. RESULTS: Across all conditions tested, mouth-throat depositional loss was < 1% and nose-throat depositional loss was < 3% of loaded dose. Lung delivery efficiency was in the range of 77.3-85.1% of loaded dose with minor variations based on subject age (~ 8% absolute difference), oral or nasal administration (< 2%), and delivered air volume (< 2%). Humidified airway conditions had an insignificant impact on extrathoracic depositional loss and significantly increased aerosol size at the exit of a representative lung chamber. CONCLUSIONS: In conclusion, the inhaled antibiotic product nearly eliminated extrathoracic depositional loss, demonstrated high efficiency nose-to-lung antibiotic aerosol delivery in pediatric airway models for the first time, and provided ~ 80% lung delivery efficiency with little variability across subject age and administered air volume.

In Vitro Evaluation of Nebulized Pharmaceutical Aerosol Delivery to the Lungs Using a New Heated Dryer System (HDS).

The objective of this study was to develop a new heated dryer system (HDS) for high efficiency lung delivery of nebulized aerosol and demonstrate performance with realistic in vitro testing for trans-nasal aerosol administration simultaneously with high-flow nasal cannula (HFNC) therapy and separately for direct oral inhalation (OI) of the aerosol. With the HDS-HFNC and HDS-OI platforms, new active synchronization control routines were developed to sense subject inhalation and coordinate drug aerosol delivery. In vitro experiments were conducted to predict regional drug loss and lung delivery efficiency in systems that included the HDS with various patient interfaces, realistic airway models, and simulated breathing waveforms. For the HDS-HFNC platform and a repeating breathing waveform, total system loss was < 10%, extrathoracic deposition was approximately 6%, and best-case lung delivery efficiency was 75-78% of nebulized dose. Inclusion of randomized breathing with the HFNC system decreased lung delivery efficiency by ~ 10% and had no impact on nasal depositional loss. For the HDS-OI platform and best-case mouthpiece, total system loss was < 8%, extrathoracic deposition was < 1%, and lung delivery efficiency was > 90% of nebulized dose. Normal vs. deep randomized oral inhalation had little impact on performance of the HDS-OI platform and environmental aerosol loss was negligible. In conclusion, both platforms demonstrated the potential for high efficiency lung delivery of the aerosol with the HDS-OI platform having the added advantages of nearly eliminating extrathoracic deposition, being insensitive to breathing waveform, and preventing environmental aerosol loss.

Recent developments in the computational simulation of dry powder inhalers.

This article reviews recent developments in computational modeling of dry powder inhalers (DPIs). DPIs deliver drug formulations (sometimes blended with larger carrier particles) to a patient's lungs via inhalation. Inhaler design is complicated by the need for maximum aerosolization efficiency, which is favored by high levels of turbulence near the mouthpiece, with low extrathoracic depositional loss, which requires low turbulence levels near the mouth-throat region. In this article, we review the physical processes contributing to aerosolization and subsequent dispersion and deposition. We assess the performance characteristics of DPIs using existing simulation techniques and offer a perspective on how such simulations can be improved to capture the physical processes occurring over a wide range of length- and timescales more efficiently.

Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults.

To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.

Importance of Spray-Wall Interaction and Post-Deposition Liquid Motion in the Transport and Delivery of Pharmaceutical Nasal Sprays.

Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways that creates complex droplet-wall interactions followed by significant liquid motion after initial wall contact. Additionally, liquid motion can occur after deposition as the spray liquid moves in bulk along the nasal surface. It is difficult or impossible to capture these conditions with commonly used computational fluid dynamics (CFD) models of spray droplet transport that typically employ a deposit-on-touch boundary condition. Hence, an updated CFD framework with a new spray-wall interaction (SWI) model in tandem with a post-deposition liquid motion (PDLM) model was developed and applied to evaluate nasal spray delivery for Flonase and Flonase Sensimist products. For both nasal spray products, CFD revealed significant effects of the spray momentum on surface liquid motion, as well as motion of the surface film due to airflow generated shear stress and gravity. With Flonase, these factors substantially influenced the final resting place of the liquid. For Flonase Sensimist, anterior and posterior liquid movements were approximately balanced over time. As a result, comparisons with concurrent in vitro experimental results were substantially improved for Flonase compared with the traditional deposit-on-touch boundary condition. The new SWI-PDLM model highlights the dynamicenvironment that occurs when a nasal spray interacts with a nasal wall surface and can be used to better understand the delivery of current nasal spray products as well as to develop new nasal drug delivery strategies with improved regional targeting.

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.

Computational Fluid Dynamics (CFD) Guided Spray Drying Recommendations for Improved Aerosol Performance of a Small-Particle Antibiotic Formulation.

PURPOSE: The objective of this study was to implement computational fluid dynamics (CFD) simulations and aerosol characterization experiments to determine best-case spray drying conditions of a tobramycin excipient enhanced growth (Tobi-EEG) formulation for use in a pediatric air-jet dry powder inhaler (DPI). METHODS: An iterative approach was implemented in which sets of spray drying conditions were explored using CFD simulations followed by lead candidate selection, powder production and in vitro aerosol testing. CFD simulations of a small-particle spray dryer were performed to capture droplet drying parameters and surface-averaged temperature and relative humidity (RH) conditions in the powder collection region. In vitro aerosol testing was performed for the selected powders using the pediatric air-jet DPI, cascade impaction, and aerosol transport through a pediatric mouth-throat (MT) model to a tracheal filter. RESULTS: Based on comparisons of CFD simulations and in vitro powder performance, recommended drying conditions for small-particle powders with electrostatic collection include: (i) reducing the CFD-predicted drying parameters of κavg and κmax to values below 3 µm2/ms and 114 µm2/ms, respectively; (ii) maintaining the Collector Surface RH within an elevated range, which for the Tobi-EEG formulation with l-leucine was 20-30 %RH; and (iii) ensuring that particles reaching the collector were fully dried, based on a mass fraction of solute CFD parameter. CONCLUSIONS: Based on the newly recommended spray dryer conditions for small particle aerosols, delivery performance of the lead Tobi-EEG formulation was improved resulting in >60% of the DPI loaded dose passing through the pediatric MT model.

Performance of Low Air Volume Dry Powder Inhalers (LV-DPI) when Aerosolizing Excipient Enhanced Growth (EEG) Surfactant Powder Formulations.

Efficient delivery of dry powder aerosols dispersed with low volumes of air is challenging. This study aims to develop an efficient dry powder inhaler (DPI) capable of delivering spray-dried Survanta-EEG powders (3-10 mg) with a low volume (3 mL) of dispersion air. A series of iterative design modifications were made to a base low air volume actuated DPI. The modifications included the replacement of the original capsule chamber with an integral dose containment chamber, alteration of the entrainment air flow path through the device (from single-sided (SS) to straight through (ST)), change in the number of air inlet holes (from one to three), varying the outlet delivery tube length (45, 55, and 90 mm) and internal diameter (0.60, 0.89, and 1.17 mm). The modified devices were evaluated by determining the influence of the modifications and powder fill mass on aerosol performance of spray-dried Survanta-EEG powders. The optimal DPI was also evaluated for its ability to aerosolize a micronized powder. The optimized dose containment unit DPI had a 0.21 mL powder chamber, ST airflow path, three-0.60 mm air inlet holes, and 90 mm outlet delivery tube with 0.89 mm internal diameter. The powder dispersion characteristics of the optimal device were independent of fill mass with good powder emptying in one 3 mL actuation. At 10 mg fill mass, this device had an emitted mass of 5.3 mg with an aerosol Dv50 of 2.7 µm. After three 3 mL actuations, >85% of the spray-dried powder was emitted from the device. The emitted mass of the optimal device with micronized albuterol sulfate was >72% of the nominal fill mass of 10 mg in one 3 mL actuation. Design optimization produced a DPI capable of efficient performance with a dispersion air volume of 3 mL to aerosolize Survanta-EEG powders.

Development and Characterization of Excipient Enhanced Growth (EEG) Surfactant Powder Formulations for Treating Neonatal Respiratory Distress Syndrome.

This study aimed to develop and characterize a spray-dried powder aerosol formulation of a commercially available surfactant formulation, Survanta® intratracheal suspension, using the excipient enhanced growth (EEG) approach. Survanta EEG powders were prepared by spray drying of the feed dispersions containing Survanta® (beractant) intratracheal suspension, hygroscopic excipients (mannitol and sodium chloride), and a dispersion enhancer (l-leucine or trileucine) in 5 or 20% v/v ethanol in water using the Buchi Nano Spray Dryer B-90 HP. Powders were characterized for primary particle size, morphology, phospholipid content, moisture content, thermal properties, moisture sorption, and surface activity. The aerosol performance of the powders was assessed using a novel low-volume dry powder inhaler (LV-DPI) device operated with 3-mL volume of dispersion air. At both ethanol concentrations, in comparison to trileucine, l-leucine significantly reduced the primary particle size and span and increased the fraction of submicrometer particles of the Survanta EEG powders. The l-leucine-containing Survanta EEG powders exhibited good aerosolization performance with ≥ 88% of the mass emitted (% nominal) after 3 actuations from the modified LV-DPI device. In addition, l-leucine-containing powders had a low moisture content (< 3% w/w) with transition temperatures close to the commercial surfactant formulation and retained their surface tension reducing activity after formulation processing. A Survanta EEG powder containing l-leucine was developed which showed efficient aerosol delivery from the modified LV-DPI device using a low dispersion air volume.

Characterization of excipient enhanced growth (EEG) tobramycin dry powder aerosol formulations.

Spray drying can be utilized to produce highly dispersible powder aerosol formulations. However, these formulations are known to be hygroscopic, leading to potential solid-state stability and aerosol performance issues. This study aims to investigate if control of the spray drying particle formation conditions could be employed to improve the solid-state stability and alter the aerosol performance of tobramycin EEG formulations. Eight formulations were prepared, each had the same drug:excipient ratio of 60%w/w tobramycin, 20% w/w l-leucine, 18% w/w mannitol, and 2% w/w poloxamer 188. An experimental design matrix was performed with drying air water content of 1 or 10 g/m3 and spray drying solution l-leucine concentrations of 4.6, 7.6, 15.2 or 23.0 mmol/L. The particle size, morphology and crystallinity of spray dried formulations were characterized together with their dynamic moisture vapor sorption and aerosol performance. Higher crystallization and glass transition %RH were observed for the formulations spray dried using drying air with higher water content indicating more stable characteristics. Initial screening using a handheld dry powder inhaler of the realistic aerosol performance revealed that neither changing l-leucine concentration nor the drying gas water content affect the in-vitro expected lung dose. However, using a novel positive pressure inhaler, formulations produced using spray drying solutions with lower l-leucine concentrations showed better aerosol performance with MMAD around 2 µm and FPF < 5 µm around 80%.

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.

Devices for Improved Delivery of Nebulized Pharmaceutical Aerosols to the Lungs.

Nebulizers have a number of advantages for the delivery of inhaled pharmaceutical aerosols, including the use of aqueous formulations and the ability to deliver process-sensitive proteins, peptides, and biological medications. A frequent disadvantage of nebulized aerosols is poor lung delivery efficiency, which wastes valuable medications, increases delivery times, and may increase side effects of the medication. A focus of previous development efforts and previous nebulizer reviews, has been an improvement of the underlying nebulization technology controlling the breakup of a liquid into droplets. However, for a given nebulization technology, a wide range of secondary devices and strategies can be implemented to significantly improve lung delivery efficiency of the aerosol. This review focuses on secondary devices and technologies that can be implemented to improve the lung delivery efficiency of nebulized aerosols and potentially target the region of drug delivery within the lungs. These secondary devices may (1) modify the aerosol size distribution, (2) synchronize aerosol delivery with inhalation, (3) reduce system depositional losses at connection points, (4) improve the patient interface, or (5) guide patient inhalation. The development of these devices and technologies is also discussed, which often includes the use of computational fluid dynamic simulations, three-dimensional printing and rapid prototype device and airway model construction, realistic in vitro experiments, and in vivo analysis. Of the devices reviewed, the implementation of streamlined components may be the most direct and lowest cost approach to enhance aerosol delivery efficiency within nonambulatory nebulizer systems. For applications involving high-dose medications or precise dose administration, the inclusion of active devices to control aerosol size, guide inhalation, and synchronize delivery with inhalation hold considerable promise.