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.

Development of a High-Dose Infant Air-Jet Dry Powder Inhaler (DPI) with Passive Cyclic Loading of the Formulation.

PURPOSE: The objective of this study was to incorporate a passive cyclic loading strategy into the infant air-jet dry powder inhaler (DPI) in a manner that provides high efficiency aerosol lung delivery and is insensitive to powder mass loadings and the presence of downstream pulmonary mechanics. METHODS: Four unique air-jet DPIs were initially compared and the best performing passive design (PD) was selected for sensitivity analyses. A single preterm in vitro nose-throat (NT) model, air source, and nasal interface were utilized throughout. While the majority of analyses were evaluated with a model spray-dried excipient enhanced growth (EEG) formulation, performance of a Surfactant-EEG formulation was also explored for the lead DPI design. RESULTS: Two devices, PD-2 and PD-3, evaluated in the preterm model achieved an estimated lung delivery efficiency of 60% with the model EEG formulation, and were not sensitive to the loaded dose (10-30 mg of powder). The PD-3 device was also unaffected by the presence of downstream pulmonary mechanics (infant lung model) and had only a minor sensitivity to tripling the volume of the powder reservoir. When using the Surfactant-EEG formulation, increasing the actuation flow rate from 1.7 to 4.0 L/min improved lung delivery by nearly 10%. CONCLUSIONS: The infant air-jet DPI platform was successfully modified with a passive cyclic loading strategy and capable of providing an estimated > 60% lung delivery efficiency of a model spray-dried formulation with negligible sensitivity to powder mass loading in the range of 10-30 mg and could be scaled to deliver much higher doses.

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.

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.