This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract.

Purpose The objective of this study was to employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform. Methods Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler. Results For the carrier-free formulation considered, turbulence was determined to be the primary deaggregation mechanism. A strong quantitative correlation was established between the mass median diameter (MMD) and newly proposed non-dimensional specific dissipation (NDSD) factor, which accounts for turbulent energy, inverse of the turbulent length scale, and exposure time. A 3D rod array design with unidirectional elements maximized NDSD and produced the best deaggregation with MMD<1μm. Conclusions The new NDSD parameter can be used to develop highly effective dry powder inhalers like the 3D rod array that can efficiently produce submicrometer aerosols for next-generation respiratory drug delivery applications.

Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.

Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity. Cascade impaction experiments were used to determine the initial mass median aerodynamic diameters of 0.1% albuterol aerosols produced by the AeroNeb commercial (4.69 μm) and lab (3.90 μm) nebulizers and to validate the CFD model in terms of droplet evaporation. Through an appropriate selection of flow rates, nebulizers, and model drug concentrations, submicrometer and nanometer aerosols could be formed with the three devices considered. Based on CFD simulations, a wire heated design was shown to overheat the airstream producing unsafe conditions for inhalation if the aerosol was not uniformly distributed in the tube cross-section or if the nebulizer stopped producing droplets. In comparison, a counter-flow heated design provided sufficient thermal energy to produce submicrometer particles, but also automatically limited the maximum aerosol outlet temperature based on the physics of heat transfer. With the counter-flow design, submicrometer aerosols were produced at flow rates of 5, 15, and 30 LPM, which may be suitable for various forms of oral and nasal aerosol delivery. Thermodynamic conditions of the aerosol stream exiting the counter-flow design were found be in a range of 21-45 °C with relative humidity greater than 40% in some cases, which was considered safe for direct inhalation and advantageous for condensational growth delivery.

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