Pharmaceutical Aerosol Deposition Research Articles

Pharmaceutical aerosol transport in airways: A combined machine learning (ML) and discrete element model (DEM) approach

The continuum and discrete phase interaction could significantly affect the inhaled particle's transport behaviour. The accurate analysis of continuum and discrete phase interaction needs computational fluid dynamics (CFD) and Discrete Element Method (DEM) simulation, which is computationally expensive. Therefore, this study aims to develop a novel machine learning (ML) prediction model from CFD-DEM data to predict pharmaceutical aerosol transport in airways accurately. This study uses the CFD model for the continuum and DEM for the discrete phases. A soft sphere approach was used to calculate the overlap of the colliding particles. Proper validation was performed to ensure the accuracy of the present model. The CFD-DEM model analysed the particle transport in an idealised and realistic airway model, and different methods were used to analyse the transport behaviour. As the flow rate increased from 15 to 60 lpm, the deposition efficiency (DE) significantly improved due to particle interaction, rising from 20 % to 42 % without interaction and from 50 % to a remarkable 76 % with interaction, demonstrating the critical role of particle interaction in enhancing DE across varying flow rates. During the particle-particle interaction, a stagnation point and a high-pressure zone were observed at the airway model's carinal angle. Finally, a ML prediction model is developed from CFD-DEM data, which accurately predicts the pharmaceutical aerosol deposition in airways. The ML prediction model predicts the deposition pattern for different flow rates and particle sizes without CFD-DEM simulations. The present findings and more case-specific investigation would advance the knowledge of aerosol transport in airways and benefit more efficient targeted drug delivery devices.

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<Re<7,000). Of the k−ω family of models, the low Reynolds number (LRN) shear stress transport (SST) approach was determined to provide the best agreement with experimental aerosol deposition data in the D2I system, based on an improved simulation of turbulent jet flow that frequently occurs in DPIs. Considering NW corrections, a new correlation was developed to quantitatively predict best regional values of the y+limit, within which anisotropic NW turbulence is approximated. Considering EIM modifications, a previously described drift correction approach was implemented in pharmaceutical aerosol simulations for the first time. Considering all model corrections and modifications applied to the D2I system, regional relative errors in deposition fractions between CFD predictions and new experimental data were improved from 19–207% (no modifications) to 2–15% (all modifications) with a notable decrease in computational time (up to ∼15%). In conclusion, the highly efficient two-equation k−ω models with physically realistic corrections and modifications provided a viable, efficient and accurate approach to simulate the transport and deposition of pharmaceutical aerosols in complex airway systems that include laminar, turbulent and transitional flows.

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers

To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition estimates. We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. The two methods were shown to provide similar estimates of extrathoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients. Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods.

Simulations of the deposition of pharmaceutical aerosols in the human respiratory tract by dry powder inhalers (DPIs)

Investigation of pharmaceutical aerosol deposition in the human respiratory tract is an important topic because it enhances knowledge regarding the effective treatment of lung diseases. Herein, deposition in the human respiratory tract produced by the use of Dry Powder Inhalers (DPIs) was modeled for an adult male. A modified version of the model named Exposure Dose Model 2 (ExDoM2) was used where simulations incorporated both monodisperse and polydisperse aerosols. The impact of breath holding and mouthpiece diameter was also examined. The results revealed that the larger the aerodynamic diameter, the greater the deposition in the extrathoracic region. On the contrary, higher deposition of polydisperse particles in the tracheobronchial and alveolar-interstitial region was observed for particles with aerodynamic diameter 2–4 μm. In the extrathoracic region, deposition increased with a decrease in the mouthpiece diameter. However, its effect is negligible for particles approximately <1 μm in the tracheobronchial and alveolar-interstitial regions. For bigger particles, an increase in mouthpiece diameter resulted in an increase of the deposition. Similar findings were obtained for monodisperse particles. In addition, the results showed that breath holding increases the deposition in the lungs for all mouthpiece diameters and Mass Median Aerodynamic Diameters (MMADs), which confirms the medical recommendations of breath holding after inhalation of pharmaceutical aerosols through DPIs for more effective treatment of lung diseases. Finally, the user of the modified version of ExDoM2 has the capability to modify the parameters of the model for a more representative/realistic scenario. Future objectives include simulations that adopt the effect of particle properties (density and shape factor) and other parameters (such as the tidal volume), as well as simulations incorporating deposition using realistic input data (MMAD and standard deviation sg).

In vitro-in vivo correlations (IVIVCs) of deposition for drugs given by oral inhalation.

Conventional in vitro tests to assess the aerodynamic particle size distribution (APSD) from inhaler devices use simple right-angle inlets ("mouth-throats", MTs) to cascade impactors, and air is drawn through the system at a fixed flow for a fixed time. Since this arrangement differs substantially from both human oropharyngeal airway anatomy and the patterns of air flow when patients use inhalers, the ability of in vitro tests to predict in vivo deposition of pharmaceutical aerosols has been limited. MTs that mimic the human anatomy, coupled with simulated breathing patterns, have yielded estimates of lung dose from in vitro data that closely match those from in vivo gamma scintigraphic or pharmacokinetic studies. However, different models of MTs do not always yield identical data, and selection of an anatomical MT and representative inhalation profiles remains challenging. Improved in vitro - in vivo correlations (IVIVCs) for inhaled drug products could permit increased reliance on in vitro data when developing new inhaled drug products, and could ultimately result in accelerated drug product development, together with reduced research and development spending.

Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part II: Evaluation of IL-10-loaded Microparticles for the Treatment of Lung Inflammation

Acute respiratory distress syndrome is linked to inflammatory processes in the human lung. The aim of this study was to mimic in vitro the treatment of lung inflammation by using a cell-based human autologous co-culture model. As a potential trial medication, we developed a pulmonary dry powder formulation loaded with interleukin-10 (IL-10), a potent anti-inflammatory cytokine. The inflammatory immune response was stimulated by lipopolysaccharide. The co-culture was combined with the Pharmaceutical Aerosol Deposition Device on Cell Cultures )PADDOCC), to deposit the IL-10-loaded microparticles on the inflamed co-culture model at the air-liquid interface. This treatment significantly reduced the secretion of interleukin-6 and tumour necrosis factor, as compared to the deposition of placebo (unloaded) particles. Our results show that the alveolar co-culture model, in combination with a deposition device such as the PADDOCC, may serve as a powerful tool for testing the safety and efficacy of dry powder formulations for pulmonary drug delivery.

Autologous co-culture of primary human alveolar macrophages and epithelial cells for investigating aerosol medicines. Part I: model characterisation.

The development of new formulations for pulmonary drug delivery is a challenge on its own. New in vitro models which address the lung are aimed at predicting and optimising the quality, efficacy and safety of inhaled drugs, to facilitate the more rapid translation of such products into the clinic. Reducing the complexity of the in vivo situation requires that such models reproducibly reflect essential physiological factors in vitro. The choice of cell types, culture conditions and the experimental set-up, can affect the outcome and the relevance of a study. In the alveolar space of the lung, epithelial cells and alveolar macrophages are the most important cell types, forming an efficient cellular barrier to aerosols. Our aim was to mimic this barrier with primary human alveolar cells. Cell densities of alveolar macrophages and epithelial cells, isolated from the same human donor, were optimised, with a focus on barrier properties. The combination of 300,000 epithelial cells/cm² together with 100,000 macrophages/cm² showed a functional barrier (transepithelial electrical resistance > 500Ω.cm²). This cell model was combined with the Pharmaceutical Aerosol Deposition Device on Cell Cultures. The functionality of the in vitro system was investigated with spray-dried fluorescently labelled poly(lactic-co-glycolic) acid particles loaded with ovalbumin as a model drug.

Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections.

The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy. Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. Microparticles were of spherical shape, smooth surface and size of about 765nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8μm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7μg/cm(2) of deposited powder were transported to the basolateral compartment after 24h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria. The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.

Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data

CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data. The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways. For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7 μm. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error <10% for each inhaler. CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods.

Development of a new technique for the efficient delivery of aerosolized medications to infants on mechanical ventilation.

To evaluate the efficiency of a new technique for delivering aerosols to intubated infants that employs a new Y-connector, access port administration of a dry powder, and excipient enhanced growth (EEG) formulation particles that change size in the airways. A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9μm) and EEG dry powder aerosols. The delivery system consisted of a Y-connector [commercial (CM); streamlined (SL); or streamlined with access port (SL-port)] attached to a 4-mm diameter endotracheal tube leading to the airways of a 6-month-old infant. Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9μm aerosol combined with the SL and SL-port geometries reduced device depositional losses by factors of 3-fold and >10-fold, respectively. With EEG powder aerosols, the SL geometry provided the maximum tracheobronchial deposition fraction (55.7%), whereas the SL-port geometry provided the maximum alveolar (67.6%) and total lung (95.7%) deposition fractions, respectively. Provided the aerosol can be administered in the first portion of the inspiration cycle, the proposed new method can significantly improve the deposition of pharmaceutical aerosols in the lungs of intubated infants.

Mechanisms of Pharmaceutical Aerosol Deposition in the Respiratory Tract

Aerosol delivery is noninvasive and is effective in much lower doses than required for oral administration. Currently, there are several types of therapeutic aerosol delivery systems, including the pressurized metered-dose inhaler, the dry powder inhaler, the medical nebulizer, the solution mist inhaler, and the nasal sprays. Both oral and nasal inhalation routes are used for the delivery of therapeutic aerosols. Following inhalation therapy, only a fraction of the dose reaches the expected target area. Knowledge of the amount of drug actually deposited is essential in designing the delivery system or devices to optimize the delivery efficiency to the targeted region of the respiratory tract. Aerosol deposition mechanisms in the human respiratory tract have been well studied. Prediction of pharmaceutical aerosol deposition using established lung deposition models has limited success primarily because they underestimated oropharyngeal deposition. Recent studies of oropharyngeal deposition of several drug delivery systems identify other factors associated with the delivery system that dominates the transport and deposition of the oropharyngeal region. Computational fluid dynamic simulation of the aerosol transport and deposition in the respiratory tract has provided important insight into these processes. Investigation of nasal spray deposition mechanisms is also discussed.

Comparison of In Vitro Deposition of Pharmaceutical Aerosols in an Idealized Child Throat with In Vivo Deposition in the Upper Respiratory Tract of Children

Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition. In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered. In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2 ± 2.3% of delivered dose) compared well (p>0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8 ± 12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0 ± 1.5%) matched in vivo extrathoracic deposition (p>0.05) in 6 to 16 year old children with cystic fibrosis (70.4 ± 21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR. The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.

Development of Characteristic Upper Tracheobronchial Airway Models for Testing Pharmaceutical Aerosol Delivery

Characteristic models of the upper conducting airways are needed to evaluate the performance of existing pharmaceutical inhalers and to develop new respiratory drug delivery strategies. Previous studies have focused on the development of characteristic mouth-throat (MT) geometries for orally inhaled products; however, characteristic upper tracheobronchial (TB) geometries are currently not available. In this study, a new characteristic model of the upper TB airways for an average adult male was developed based on an analysis of new and existing anatomical data. Validated computational fluid dynamics (CFD) simulations were used to evaluate the deposition of monodisperse and realistic polydisperse aerosols from multiple inhalers. Comparisons of deposition results between the new model and a simpler geometry were used to identify the effects of different anatomical features on aerosol deposition. The CFD simulations demonstrated a good match to regional pharmaceutical aerosol deposition from in vitro experiments in the same geometry. The deposition of both monodisperse and pharmaceutical aerosols was increased in the new TB geometry as a result of additional anatomical detail on a regional and highly localized basis. Tracheal features including an accurate coronal angle, asymmetry, and curvature produced a skewed laryngeal jet and significantly increased regional deposition. Branch curvature and realistic cross-sections increased deposition in the remainder of the TB model. A hexahedral mesh style was utilized to provide the best solution. In conclusion, a number of physiological features in the upper TB region were shown to influence deposition and should be included in a characteristic model of respiratory drug delivery.

Development of a Stochastic Individual Path (SIP) Model for Predicting the Deposition of Pharmaceutical Aerosols: Effects of Turbulence, Polydisperse Aerosol Size, and Evaluation of Multiple Lung Lobes

In this study, a new computational fluid dynamics (CFD) modeling approach for pharmaceutical aerosols is further developed by evaluating the effects of turbulence, polydisperse aerosol size distribution, and multiple lung lobes on deposition in the mouth–throat (MT) and entire tracheobronchial (TB) airways. To evaluate a range of respiratory drug delivery conditions, a model dry powder inhaler (DPI; NovolizerTM) and a model spray soft-mist inhaler (SMI; RespimatTM) were considered. The respiratory geometry consisted of a previously developed characteristic MT and complete upper TB geometry through the third bifurcation (B3). More distal TB airways were simulated using stochastic individual path (SIP) models extending into each of the five lung lobes through bifurcation B15. Based on comparisons with new in vitro deposition data, results indicated that the low Reynolds number (LRN) k–ω turbulence model with near-wall corrections for anisotropic turbulence and velocity conditions accurately predicted deposi...

Development of a stochastic individual path (SIP) model for predicting the tracheobronchial deposition of pharmaceutical aerosols: Effects of transient inhalation and sampling the airways

While a number of studies have considered the dynamics of ambient or environmental particles in the respiratory tract, far fewer have evaluated the transport and deposition of pharmaceutical aerosols from inhalers in the mouth-throat (MT) and tracheobronchial (TB) airways. The objective of this study was to develop a new stochastic individual path (SIP) modeling approach for simulating the MT and TB deposition of a pharmaceutical aerosol from a dry powder inhaler and to evaluate the effects of transient vs. steady state conditions and sampling of the airways. In the SIP approach, representative models of the MT and upper TB geometries are considered through the third respiratory bifurcation (B3; approximately lobar bronchi). Stochastic individual paths are then evaluated extending from B4 to the terminal bronchioles (B15) in which one branch of each bifurcation is continued and one is not. Three SIP geometries were considered extending into the lower right lung lobe through the end of the conducting airways. A commonly prescribed dry powder inhaler (DPI) was connected to the MT geometry and the deposition of drug mass from a realistic polydisperse pharmaceutical aerosol was evaluated. Predictions of deposited drug mass in the MT and upper TB geometries were found to be in good agreement with concurrent experimental results. Transient inhalation was shown to influence the deposition of particles in the MT and upper TB airways through B3, where the Womersley number is greater than 1. In contrast, transient conditions were found to have little influence on deposition in the TB region starting with B4, where steady state simulations provided a good representation of total, regional, bifurcation-averaged, and localized deposition. Furthermore, a single SIP model was shown to characterize both regional and highly localized deposition within a lung lobe assuming mean airway dimensions. The resulting SIP model provides a highly efficient method to simulate the regional and local deposition of pharmaceutical aerosols throughout the conducting airways. In comparison with performing fully transient simulations of all branches in the regions considered, the SIP modeling approach reduces computational effort by a factor of approximately 3×10 5 while predicting regional and local deposition values to within approximately 5%.

Challenges in assessing regional distribution of inhaled drug in the human lungs

Introduction: Both the total amount of drug deposited in the lungs (whole lung deposition) and the amount deposited in different lung regions (regional lung deposition) are potentially important factors that determine the safety and efficacy of inhaled drugs. Radionuclide imaging is well established for quantifying the whole lung deposition of inhaled drugs, but the assessment of regional lung deposition is less straightforward, because of the complex nature of the lung anatomy.Areas covered: This review describes the challenges and problems associated with quantifying regional lung deposition by the two-dimensional (2D) radionuclide imaging method of gamma scintigraphy, and by the three-dimensional (3D) radionuclide imaging methods of single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET). The advantages and disadvantages of each method for assessing regional lung deposition are discussed.Expert opinion: Owing to its 2D nature, gamma scintigraphy provides limited information about regional lung deposition. SPECT provides regional lung deposition data in three dimensions, but usually involves a 99mTc radiolabel. PET enables the regional lung deposition of radiolabeled drug molecules to be quantified in three dimensions, but poses the greatest logistical and technical difficulties. Despite their more challenging nature, 3D imaging methods should be considered as an alternative to gamma scintigraphy whenever the determination of regional lung deposition of pharmaceutical aerosols is a major study objective.

In Vivo–In VitroCorrelations: Predicting Pulmonary Drug Deposition from Pharmaceutical Aerosols

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.

A new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to evaluate pulmonary drug absorption for metered dose dry powder formulations

Absorption studies with aerosol formulation delivered by metered dose inhalers across cell- and tissue-based in vitro models of the pulmonary epithelia are not trivial due to the complexity of the processes involved: (i) aerosol generation and deposition, (ii) drug release from the carrier, and (iii) absorption across the epithelial air–blood barrier. In contrast to the intestinal mucosa, pulmonary epithelia are only covered by a thin film of lining fluid. Submersed cell culture systems would not allow to studying the deposition of aerosol particles and their effects on this delicate epithelial tissue. We developed a new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to mimic the inhalation of a single metered aerosol dose and its subsequent deposition on filter-grown pulmonary epithelial cell monolayers exposed to an air–liquid interface. The reproducibility of deposition of these dry powder aerosols and subsequent drug transport across Calu-3 monolayers with commercially available dry powder inhalers containing salbutamol sulphate or budesonide could be demonstrated. In the context of developing new dry powder aerosol formulations, PADDOCC appears as a useful tool, allowing reducing animal testing and faster translation into clinical trials.

The Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) In Vitro System: Design and Experimental Protocol

The development of aerosol medicines typically involves numerous tests on animals, due to the lack of adequate in vitro models. A new in vitro method for testing pharmaceutical aerosol formulations on cell cultures was developed, consisting of an aerosolisation unit fitting a commercial dry powder inhaler (HandiHaler(c), Boehringer Ingelheim, Germany), an air-flow control unit (Akita(c), Activaero, Germany) and a custom-made sedimentation chamber. This chamber holds three Snapwell(c) inserts with monolayers of pulmonary epithelial cells. The whole set-up, referred to as the Pharmaceutical Aerosol Deposition Device On Cell Cultures (PADDOCC) system, aims to mimic the complete process of aerosol drug delivery, encompassing aerosol generation, aerosol deposition onto pulmonary epithelial cells and subsequent drug transport across this biological barrier, to facilitate the investigation of new aerosol formulations in the early stages of development. We describe here, the development of the design and the protocol for this device. By testing aerosol formulations of budesonide and salbutamol sulphate, respectively, reproducible deposition of aerosol particles on, and the integrity of, the pulmonary cell monolayer could be demonstrated.

Prediction of aerosol deposition in [formula omitted] bends using LES and an efficient Lagrangian tracking method

Aiming at the better prediction of pharmaceutical aerosol deposition in extrathoracic airways, a simpler test case, namely a 90 ∘ bend flow (tubular cross-section) laden with monodisperse particles, is adopted here and studied numerically. The continuous phase is calculated using a large-eddy simulation technique along with a finite-volume method for block-structured curvilinear grids. The particulate phase is simulated using a Lagrangian approach where hundred thousands of individual monodisperse particles with varying particle diameters are released and tracked throughout the computational domain. To allow such a large number of particles, a highly efficient tracking algorithm is applied, where particle paths are predicted in an orthogonal computational domain, avoiding time-consuming search algorithm, normally required when particles are tracked in the actual physical domain of a curvilinear body-fitted block-structured grid. Both simulation algorithms, for the continuous and particulate phases, are completely parallelized using domain decomposition. Additionally, the in-house code applied supports vector processing allowing efficient usage of nearly all kinds of high-performance architectures. Two different Reynolds numbers Re D are considered where Re D is based on the bend diameter and mean flow velocity. The first case is within the laminar regime at Re D = 1000 and serves for the purpose of verification and validation. The second, more challenging case comprises the turbulent regime at Re D = 10 , 000 , which is the intrinsic objective of the present study. Depending on the Stokes number of the particles, 0.001 ⩽ St ⩽ 1.5 , and the releasing locations at the entrance of the bend, the particles will either deposit on the wall or penetrate and exit the computational domain. Simulation results of aerosol deposition efficiency, over the entire range of particle diameters considered here, show an excellent agreement when compared to experimental values obtained by Pui, Romay-Novas, and Liu [(1987). Experimental study of particle deposition in bends of circular cross-section. Aerosol Science and Technology, 7, 301].