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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.
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Inaladores de Pó Seco , Excipientes , Recém-Nascido , Humanos , Lactente , Pós , Desenho de Equipamento , Tamanho da Partícula , Administração por Inalação , Aerossóis , TensoativosRESUMO
A critical factor affecting the accuracy of Computational Fluid Dynamic (CFD) simulations and the time required to conduct them is construction of the computational mesh. This study aimed to evaluate the relatively new polyhedral mesh style for simulating aerosol deposition in the upper conducting airways compared with established meshing techniques and experimental data. Hexahedral and polyhedral mesh solutions were compared in two benchmark geometries: 1) a 90°-bend with flow characteristics similar to the extrathoracic airways of an adolescent child, and 2) a double bifurcation representing bifurcations B3-B5 in an adult. Both 4-block and 5-block hexahedral meshes were used in the 90°-bend to capture the potential of fully-structured hexahedral meshes. In the 90°-bend, polyhedral elements matched polydisperse in vitro deposition data with 20% relative error (RE; averaged across the particle sizes considered), which is an improvement on the accuracy of the 4-block hexahedral mesh (35% RE) and is similar to the accuracy of the 5-block hexahedral mesh (19% RE). In the double bifurcation, deposition fraction relative differences evaluated between polyhedral and hexahedral meshes ranged from 0.3% to 28.6% for the different particle sizes assessed, which is an order of magnitude improvement compared with previous studies that considered hexahedral vs. hybrid tetrahedral-prism meshes for the same flow field. Solution convergence time with polyhedral elements was found to be 50% to 140% higher than with hexahedral meshes of comparable size. While application dependent, the increase in simulation time observed with polyhedral meshes will likely be outweighed by the ease and convenience of polyhedral mesh construction. It was concluded that the polyhedral mesh style, with sufficient resolution especially near the walls, is an excellent alternative to the highly regarded hexahedral mesh style for predicting upper airway aerosol transport and deposition and provides a powerful new tool in the assessment of respiratory aerosol dosimetry.
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PURPOSE: In order to improve the delivery of dry powder aerosol formulations to the lungs of infants, this study implemented an infant air-jet platform and explored the effects of different air sources, flow rates, and pulmonary mechanics on aerosolization performance and aerosol delivery through a preterm nose-throat (NT) in vitro model. METHODS: The infant air-jet platform was actuated with a positive-pressure air source that delivered the aerosol and provided a full inhalation breath. Three different air sources were developed to provide highly controllable positive-pressure air actuations (using actuation volumes of ~10 mL for the preterm model). While providing different flow waveform shapes, the three air sources were calibrated to produce the same flow rate magnitude (Q90: 90th percentile of flow rate). Multiple air-jet DPI designs were coupled with the air sources and evaluated with a model spray-dried excipient enhanced growth formulation. RESULTS: Compared to other designs, the D1-Single air-jet DPI provided improved performance with low variability across all three air sources. With the tested D1-Single air-jet and Timer air source, reducing the flow rate from 4 to 1.7 L/min marginally decreased the aerosol size and significantly increased the lung delivery efficiency above 50% of the loaded dose. These results were not impacted by the presence of downstream pulmonary mechanics (resistance and compliance model). CONCLUSIONS: The selected design was capable of providing an estimated >50% lung delivery efficiency of a model spray-dried formulation and was not influenced by the air source, thereby enabling greater flexibility for platform deployment in different environments.
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Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Pós/química , Administração por Inalação , Aerossóis/química , Desenho de Equipamento/métodos , Excipientes/química , Humanos , Lactente , Pulmão/metabolismo , Nariz/efeitos dos fármacos , Tamanho da PartículaRESUMO
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.
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PURPOSE: The purpose of this study was to develop a new computational fluid dynamics (CFD)-based model of the complex transport and droplet drying kinetics within a laboratory-scale spray dryer, and relate CFD-predicted drying parameters to powder aerosolization metrics from a reference dry powder inhaler (DPI). METHODS: A CFD model of the Buchi Nano Spray Dryer B-90 was developed that captured spray dryer conditions from a previous experimental study producing excipient enhanced growth powders with L-leucine as a dispersion enhancer. The CFD model accounted for two-way heat and mass transfer coupling between the phases and turbulent flow created by acoustic streaming from the mesh nebulizer. CFD-based drying parameters were averaged across all droplets in each spray dryer case and included droplet time-averaged drying rate (κavg), maximum instantaneous drying rate (κmax) and precipitation window. RESULTS: CFD results highlighted a chaotic drying environment in which time-averaged droplet drying rates (κavg) for each spray dryer case had high variability with coefficients of variation in the range of 60-70%. Maximum instantaneous droplet drying rates (κmax) were discovered that were two orders of magnitude above time-averaged drying rates. Comparing CFD-predicted drying parameters with experimentally determined mass median aerodynamic diameters (MMAD) and emitted doses (ED) from a reference DPI produced strong linear correlations with coefficients of determination as high as R2 = 0.98. CONCLUSIONS: For the spray dryer system and conditions considered, reducing the CFD-predicted maximum drying rate experienced by droplets improved the aerosolization performance (both MMAD and ED) when the powders were aerosolized with a reference DPI.
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Composição de Medicamentos/métodos , Excipientes/química , Modelos Químicos , Secagem por Atomização , Administração por Inalação , Aerossóis , Química Farmacêutica , Simulação por Computador , Inaladores de Pó Seco , Hidrodinâmica , Tamanho da PartículaRESUMO
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.
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Broncodilatadores/administração & dosagem , Inaladores de Pó Seco/instrumentação , Pulmão/efeitos dos fármacos , Administração por Inalação , Aerossóis , Broncodilatadores/farmacocinética , Criança , Pré-Escolar , Sistemas de Liberação de Medicamentos/métodos , Desenho de Equipamento , Humanos , Hidrodinâmica , Boca , Tamanho da Partícula , Pós , Distribuição TecidualRESUMO
PURPOSE: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments. METHODS: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate. RESULTS: The low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size. CONCLUSIONS: The combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.
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Administração Intranasal/instrumentação , Administração Intranasal/métodos , Aerossóis/administração & dosagem , Simulação por Computador , Hidrodinâmica , Administração por Inalação , Adulto , Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos , Desenho de Equipamento , Humanos , Pulmão , Sprays Nasais , Nariz , Tamanho da PartículaRESUMO
Tenacious sputum poses a critical diffusion barrier for aerosol antibiotics used to treat cystic fibrosis (CF) lung infection. We conducted a proof-of-concept study using dense poly(ethylene glycol) coated polystyrene nanoparticles (PS-PEG NPs) as model muco-inert particles (MIPs) formulated as a powder using an excipient enhanced growth (EEG) strategy, aiming to minimize extrathoracic airway loss, maximize deposition in the airway and further overcome the sputum barrier in the CF lungs. The EEG aerosol formulation containing PS-PEG MIPs was prepared by spray drying and produced discrete spherical particles with geometric diameter of approximately 2 µm; and >80% of the powder dose was delivered from a new small-animal dry powder inhaler (DPI). The MIPs released from the EEG aerosol had human airway mucus and CF sputum diffusion properties comparable to the suspension formulation. These properties make this formulation a promising pulmonary drug delivery system for CF lung infections.
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Fibrose Cística/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Pneumopatias/tratamento farmacológico , Pulmão/efeitos dos fármacos , Nanopartículas/química , Administração por Inalação , Fibrose Cística/patologia , Inaladores de Pó Seco/métodos , Excipientes/química , Humanos , Pulmão/crescimento & desenvolvimento , Pneumopatias/patologia , Muco/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Poliestirenos/química , Poliestirenos/farmacologiaRESUMO
PURPOSE: To demonstrate efficient aerosol delivery through an in vitro nasal model using a dry powder inhaler (DPI) requiring low actuation air volumes (LV) applied during low-flow nasal cannula (LFNC) therapy. METHODS: A previously developed LV-DPI was connected to a LFNC system with 4 mm diameter tubing. System connections and the nasal cannula interface were replaced with streamlined components. To simulate nasal respiration, an in vitro nasal model was connected to a downstream lung simulator that produced either passive or deep nasal respiration. Performance of a commercial mesh nebulizer system was also considered. RESULTS: For the optimized system, steady state cannula emitted dose was 75% of the capsule loaded dose. With cyclic nasal breathing, delivery efficiency to the tracheal filter was 53-55% of the loaded dose, which was just under the design target of 60%. Compared with a commercially available mesh nebulizer, the optimal LV-DPI was 40-fold more efficient and 150 times faster in terms of delivering aerosol to the lungs. CONCLUSIONS: The optimized LV-DPI system is capable of high efficiency lung delivery of powder aerosols through a challenging nasal cannula interface.
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Inaladores de Pó Seco/instrumentação , Sprays Nasais , Administração por Inalação , Química Farmacêutica , Desenho de Equipamento , Espaçadores de Inalação , Pulmão/anatomia & histologia , Nariz/anatomia & histologia , Oxigênio/química , Tamanho da Partícula , Pós/químicaRESUMO
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.
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PURPOSE: To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. METHODS: A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. RESULTS: Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells. CONCLUSIONS: Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.
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Corticosteroides/farmacologia , Antiasmáticos/farmacologia , Broncodilatadores/farmacologia , Nanopartículas/química , Traqueia/efeitos dos fármacos , Administração por Inalação , Corticosteroides/administração & dosagem , Aerossóis , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Transporte Biológico/fisiologia , Broncodilatadores/administração & dosagem , Budesonida/farmacologia , Biologia Computacional , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Fluticasona/farmacologia , Humanos , Simulação de Dinâmica Molecular , Terapia Respiratória , Propriedades de SuperfícieRESUMO
Aerosolized medications may benefit infants receiving mechanical ventilation; however, the lung delivery efficiency of these aerosols is unacceptably low. In vitro experiments were conducted to evaluate aerosol delivery through conventional and modified ventilation systems to the end of a 3mm endotracheal tube (ETT) under steady state and realistic cyclic flow conditions. System modifications were employed to investigate the use of small charged particles and included streamlined components, a reduction in nebulizer liquid flow rate, synchronization with inspiration, and implementation of a previously designed low-flow induction charger (LF-IC), which was further modified in this study. Cyclic flow experiments implemented a modern ventilator with bias airflow and an inline flow meter, both of which are frequently excluded from in vitro tests but included in clinical practice. The modified LF-IC system demonstrated superior delivery efficiency to the end of the ETT (34%) compared with the commercial system (~1.3%) operating under cyclic ventilation conditions. These findings indicate that commercial systems still provide very low lung delivery efficiencies despite decades of innovation. In contrast, the modified system increased dose delivery to the end of the ETT by 26-fold. Despite initial concerns, the charged aerosol could be efficiently delivered through the small diameter ETT and reach the lungs. Future studies will be required to determine if the applied particle charge can eliminate expected high exhalation aerosol loss and will require the development of a realistic lung model.
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PURPOSE: The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product. METHODS: Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated. RESULTS: Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 µm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions. CONCLUSIONS: The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.
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Aerossóis/farmacocinética , Antialérgicos/farmacocinética , Furoato de Mometasona/farmacocinética , Cavidade Nasal/metabolismo , Mucosa Respiratória/metabolismo , Administração Intranasal , Aerossóis/administração & dosagem , Antialérgicos/administração & dosagem , Simulação por Computador , Humanos , Modelos Biológicos , Furoato de Mometasona/administração & dosagem , Sprays Nasais , Tamanho da Partícula , SolubilidadeRESUMO
PURPOSE: 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. METHODS: A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9 µm) 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. RESULTS: Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9 µm 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. CONCLUSIONS: 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.
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Aerossóis/administração & dosagem , Sistemas de Liberação de Medicamentos , Desenho de Equipamento , Respiração Artificial , Aerossóis/química , Aerossóis/farmacocinética , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Humanos , Lactente , Inalação/fisiologia , Intubação Intratraqueal , Pulmão/metabolismo , Masculino , Tamanho da Partícula , Distribuição TecidualRESUMO
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Aerossóis/metabolismo , Aerossóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Administração por Inalação , Simulação por Computador , Sistemas de Liberação de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Humanos , Modelos Anatômicos , Modelos Teóricos , Tamanho da Partícula , Distribuição Tecidual/fisiologiaRESUMO
PURPOSE: Properly charged particles can be used for effective lung targeting of pharmaceutical aerosols. The objective of this study was to characterize the performance of a new induction charger that operates with a mesh nebulizer for the production of highly charged submicrometer aerosols to bypass the mouth-throat and deliver clinically relevant doses of medications to the lungs. METHODS: Variables of interest included combinations of model drug (albuterol sulfate) and charging excipient (NaCl) as well as strength of the charging field (1-5 kV/cm). Aerosol charge and size were measured using a modified electrical low pressure impactor system combined with high performance liquid chromatography. RESULTS: At the approximate mass median aerodynamic diameter (MMAD) of the aerosol (~0.4 µm), the induction charge on the particles was an order of magnitude above the field and diffusion charge limit. The nebulization rate was 439.3 ± 42.9 µl/min, which with a 0.1% w/v solution delivered 419.5 ± 34.2 µg of medication per minute. A new correlation was developed to predict particle charge produced by the induction charger. CONCLUSIONS: The combination of the aerosol induction charger and predictive correlations will allow for the practical generation and control of charged submicrometer aerosols for targeting deposition within the lungs.
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Aerossóis/química , Albuterol/química , Broncodilatadores/química , Administração por Inalação , Excipientes/química , Pulmão/efeitos dos fármacos , Nebulizadores e Vaporizadores , Tamanho da PartículaRESUMO
The delivery of pharmaceutical aerosols to infants receiving mechanical ventilation is extremely challenging due to small diameter flow passages, low tidal volumes, and frequent exhalation of the aerosol. The use of small charged particles is proposed as a novel method to prevent deposition in ventilator components and foster deposition in the lower infant airways. The objective of this study was to compare the performance of multiple new devices for generating small charged particles that are expected to maximize respiratory drug delivery in ventilated infants. Criteria used to select a leading device included production of a charged aerosol with a mass median aerodynamic diameter (MMAD) ≤ approximately 1.8 µm; low device depositional loss of the aerosol (<20%); particle charge in the range of the Rayleigh limit/100; and high drug output with low performance variability. Proposed new devices were a wick electrospray (WES) system with accelerated cross-flow air; a condensational vapor (CV) system with a charged solution and strong field gradient; and a low flow - induction charger (LF-IC) designed to operate with a modified commercial mesh nebulizer. Based on infant ventilation conditions, flow rates through the devices were in a range of 2-5 L/min and the devices were assessed in terms of depositional drug loss and emitted drug mass; droplet size distribution (DSD) using a Mini-MOUDI; and DSD and net charge with a modified ELPI. Considering the WES, primary limitations were (i) low and variable aerosol production rates and (ii) high device depositional losses. The CV device produced a high quality aerosol with a MMAD of 0.14 µm and a drug delivery rate of 25 µg/min. However, the device was excluded because it failed to produce a charged aerosol. In contrast, the LF-IC produced a 1.6 µm aerosol with high net charge, low device depositional loss (<15% based on recovery), and low variability. In the ELPI size fraction bin nearest the MMAD, the LF-IC produced >100 elementary charges per particle, which was an order of magnitude increase compared to the case of zero charging voltage. In conclusion, the LF-IC was selected as a leading system that is expected to improve aerosol delivery efficiency in ventilated infants through the use of small charged particles.
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Previous studies have demonstrated that factors such as airway wall motion, inhalation waveform, and geometric complexity influence the deposition of aerosols in the alveolar airways. However, deposition fraction correlations are not available that account for these factors in determining alveolar deposition. The objective of this study was to generate a new space-filling model of the pulmonary acinus region and implement this model to develop correlations of aerosol deposition that can be used to predict the alveolar dose of inhaled pharmaceutical products. A series of acinar models was constructed containing different numbers of alveolar duct generations based on space-filling 14-hedron elements. Selected ventilation waveforms were quick-and-deep and slow-and-deep inhalation consistent with the use of most pharmaceutical aerosol inhalers. Computational fluid dynamics simulations were used to predict aerosol transport and deposition in the series of acinar models across various orientations with gravity where ventilation was driven by wall motion. Primary findings indicated that increasing the number of alveolar duct generations beyond 3 had a negligible impact on total acinar deposition, and total acinar deposition was not affected by gravity orientation angle. A characteristic model containing three alveolar duct generations (D3) was then used to develop correlations of aerosol deposition in the alveolar airways as a function of particle size and particle residence time in the geometry. An alveolar deposition parameter was determined in which deposition correlated with d2t over the first half of inhalation followed by correlation with dt2, where d is the aerodynamic diameter of the particles and t is the potential particle residence time in the alveolar model. Optimal breath-hold times to allow 95% deposition of inhaled 1, 2, and 3 µm particles once inside the alveolar region were approximately >10, 2.7, and 1.2 s, respectively. Coupling of the deposition correlations with previous stochastic individual path (SIP) model predictions of tracheobronchial deposition was demonstrated to predict alveolar dose of commercial pharmaceutical products. In conclusion, this study completes an initiative to determine the fate of inhaled pharmaceutical aerosols throughout the respiratory airways using CFD simulations.
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PURPOSE: The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device. METHODS: DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices. RESULTS: The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI. CONCLUSIONS: High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD < 1.5 µm, FPF<5 µm/ED > 90%, and ED > 80%.
Assuntos
Aerossóis/química , Cápsulas/química , Preparações Farmacêuticas/química , Pós/química , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Excipientes/química , Tamanho da PartículaRESUMO
Nasal delivery of lung targeted pharmaceutical aerosols is ideal for drugs that need to be administered during high flow nasal cannula (HFNC) gas delivery, but based on previous studies losses and variability through both the delivery system and nasal cavity are expected to be high. The objective of this study was to assess the variability in aerosol delivery through the nose to the lungs with a nasal cannula interface for conventional and excipient enhanced growth (EEG) delivery techniques. A database of nasal cavity computed tomography (CT) scans was collected and analyzed, from which four models were selected to represent a wide range of adult anatomies, quantified based on the nasal surface area-to-volume ratio (SA/V). Computational fluid dynamics (CFD) methods were validated with existing in vitro data and used to predict aerosol delivery through a streamlined nasal cannula and the four nasal models at a steady state flow rate of 30 L/min. Aerosols considered were solid particles for EEG delivery (initial 0.9 µm and 1.5 µm aerodynamic diameters) and conventional droplets (5 µm) for a control case. Use of the EEG approach was found to reduce depositional losses in the nasal cavity by an order of magnitude and substantially reduce variability. Specifically, for aerosol deposition efficiency in the four geometries, the 95% confidence intervals (CI) for 0.9 and 5 µm aerosols were 2.3-3.1 and 15.5-66.3%, respectively. Simulations showed that the use of EEG as opposed to conventional methods improved delivered dose of aerosols through the nasopharynx, expressed as penetration fraction (PF), by approximately a factor of four. Variability of PF, expressed by the coefficient of variation (CV), was reduced by a factor of four with EEG delivery compared with the control case. Penetration fraction correlated well with SA/V for larger aerosols, but smaller aerosols showed some dependence on nasopharyngeal exit hydraulic diameter. In conclusion, results indicated that the EEG technique not only improved lung aerosol delivery, but largely eliminated variability in both nasal depositional loss and lung PF in a newly developed set of nasal airway models.