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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
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Tuberculosis (TB) remains a major cause of morbidity and mortality, particularly in low- and middle-income countries where access to health care workers, cold-chain storage, and sterile water sources may be limited. Inhaled drug delivery is a promising alternative to systemic delivery of antimycobacterial drugs, as it enables rapid achievement of high infection-site drug concentrations. The off-patent drug clofazimine (CFZ) may be particularly suitable for this route, given its known systemic toxicities. In this study, micronized CFZ particles produced by air jet milling were assessed for shelf-stability, pharmacokinetics, and anti-TB efficacy by the oral and pulmonary routes in BALB/c mice. Intratracheal instillation of micronized CFZ particles produced several-fold higher lung concentrations after a single 30 mg/kg dose compared to delivery via oral gavage, and faster onset of bactericidal activity was observed in lungs of mice with chronic Mycobacterium tuberculosis infection compared to the oral route. Both infection status and administration route affected the multidose pharmacokinetics (PK) of micronized CFZ. Increased lung and spleen accumulation of the drug after pulmonary administration was noted in infected mice compared to naive mice, while the opposite trend was noted in the oral dosing groups. The infection-dependent PK of inhaled micronized CFZ may point to a role of macrophage trafficking in drug distribution, given the intracellular-targeting nature of the formulation. Lastly, air jet milled CFZ exhibited robustness to storage-induced chemical degradation and changes in aerosol performance, thereby indicating the suitability of the formulation for treatment of TB in regions with limited cold chain supply.
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Mycobacterium tuberculosis , Tuberculosis , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Clofazimina/farmacología , Ratones , Ratones Endogámicos BALB C , Tuberculosis/tratamiento farmacológico , AguaRESUMEN
PURPOSE: To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids. METHODS: A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated. RESULTS: Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures. CONCLUSIONS: Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.
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Sistemas de Liberación de Medicamentos , Fosforilcolina , Administración por Inhalación , Aerosoles , Tamaño de la Partícula , Fosfolípidos , PolvosRESUMEN
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.
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Antibacterianos/química , Modelos Químicos , Secado por Pulverización , Tobramicina/química , Administración por Inhalación , Aerosoles , Antibacterianos/administración & dosificación , Antibacterianos/metabolismo , Preescolar , Simulación por Computador , Composición de Medicamentos , Humanos , Hidrodinámica , Pulmón/metabolismo , Nebulizadores y Vaporizadores , Análisis Numérico Asistido por Computador , Tamaño de la Partícula , Polvos , Distribución Tisular , Tobramicina/administración & dosificación , Tobramicina/metabolismoRESUMEN
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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Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors' knowledge, there are no reports using L-Car or L-Car HCl as an inhaled aerosol through the respiratory route in a targeted manner either from dry powder inhaler (DPI) or liquid delivery system. The purpose of the comprehensive and systematic comparative study between L-Car and L-Car HCl salt was to design and develop dry powder inhalers (DPIs) of each. This was followed by comprehensive physicochemical characterization, in vitro cell viability as a function of dose on 2D human pulmonary cell lines from different lung regions and in vitro cell viability on 3D small airway epithelia human primary cells at the air-liquid interface (ALI). In addition in vitro transepithelial electrical resistance (TEER) in air-interface culture (AIC) conditions on 2D human pulmonary cell line and 3D small airway epithelia human primary cells was carried out. In vitro aerosol dispersion performance using three FDA-approved human DPI devices with different device properties was also examined. Following advanced spray drying under various conditions, two spray drying pump rates (low and medium) were found to successfully produce spray-dried L-Car powders while four spray drying pump rates (low, medium, medium-high, and high) all resulted in the production of spray-dried L-Car HCl powders. Raw L-Car and L-Car HCl were found to be crystalline. All SD powders retained crystallinity following spray drying and polymorphic interconversion in the solid-state was identified as the mechanism for retaining crystallinity after the advanced spray drying process. All SD powders aerosolized readily with all three human DPI devices. However, the in vitro dispersion parameters for the SD powders was not conducive for in vivo administration to rats in DPIs due to hygroscopicity and nanoaggreation. In vivo rat studies were successfully accomplished using inhaled liquid aerosols. Safety was successfully demonstrated in vivo in healthy Sprague Dawley rats. Furthermore, therapeutic efficacy was successfully demonstrated in vivo in the monocrotaline (MCT)-rat model of PH after two weeks of daily L-Car inhalation aerosol treatment.
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Hipertensión Pulmonar , Monocrotalina , Administración por Inhalación , Aerosoles , Animales , Carnitina , Técnicas de Cultivo de Célula , Inhaladores de Polvo Seco , Hipertensión Pulmonar/tratamiento farmacológico , Pulmón , Tamaño de la Partícula , Polvos , Ratas , Ratas Sprague-DawleyRESUMEN
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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Composición de Medicamentos/métodos , Excipientes/química , Modelos Químicos , Secado por Pulverización , Administración por Inhalación , Aerosoles , Química Farmacéutica , Simulación por Computador , Inhaladores de Polvo Seco , Hidrodinámica , Tamaño de la PartículaRESUMEN
To ensure consistency of clinical outcomes, orally inhaled therapies must exhibit consistent delivered dose and aerosol properties at the time of manufacturing, throughout storage, and during various patient-use conditions. Achieving consistency across these scenarios has presented a significant challenge, especially for combination products that contain more than one drug. This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI; Bevespi Aerosphere™). GFF MDI, a fixed-dose combination (FDC) of a long-acting muscarinic antagonist, glycopyrrolate (18 µg, equivalent to glycopyrronium 14.4 µg), and a long-acting ß2-agonist, formoterol fumarate (9.6 µg; equivalent to formoterol fumarate dihydrate 10 µg), is formulated using innovative co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. In this study, delivered dose uniformity was assessed through the labeled number of doses, and aerosol properties, such as percent fine particle fraction (FPF) and mass median aerodynamic diameter, were determined by cascade impaction. GFF MDI achieved reproducible dose delivery and an FPF greater than 55%, whether formulated and delivered as a monocomponent or dual FDC. The performance of GFF MDI was maintained across various manufacturing batches, under extended storage, and with variations in flow rate. Furthermore, unlike a GFF drug crystal-only suspension, drug delivery remained consistent for GFF MDI when simulated patient-handling errors were applied, such as reduced shake energy and delays between shaking and actuation. These results demonstrate that co-suspension delivery technology overcomes well-known sources of variability in MDI drug delivery.
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Broncodilatadores/farmacocinética , Sistemas de Liberación de Medicamentos/normas , Fumarato de Formoterol/farmacocinética , Glicopirrolato/farmacocinética , Invenciones/normas , Inhaladores de Dosis Medida/normas , Administración por Inhalación , Aerosoles/administración & dosificación , Aerosoles/farmacocinética , Broncodilatadores/administración & dosificación , Método Doble Ciego , Sistemas de Liberación de Medicamentos/métodos , Fumarato de Formoterol/administración & dosificación , Glicopirrolato/administración & dosificación , Humanos , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Reproducibilidad de los Resultados , SuspensionesRESUMEN
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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The purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. The results revealed that the apical to basolateral transport of DNCs across polarized Calu-3 monolayers increases with an increase in PEG surface density. DNC having the greatest number of PEG groups (n = 25) on their surface traversed at a rate 10-fold greater than its non-PEGylated counterpart, in spite of their larger size. This behavior was attributed to a significant reduction in charge density upon PEGylation. We also observed that PEGylation can be used to modulate cellular internalization. The total uptake of PEG-free DNC into polarized Calu-3 monolayers was 12% (w/w) vs 2% (w/w) for that with 25 PEGs. Polarization is also shown to be of great relevance in studying this in vitro model of the lung epithelium. The rate of absorption of DNCs administered to mice lungs increased dramatically when conjugated with 25 PEG groups, thus supporting the in vitro results. The exposure obtained for the DNC with 25PEG was determined to be very high, with peak plasma concentrations reaching 5 µg·mL(-1) within 3 h. The combined in vitro and in vivo results shown here demonstrate that PEGylation can be potentially used to modulate the internalization and transport of DNCs across the pulmonary epithelium. Modified dendrimers thereby may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lung as pathway to the bloodstream, for systemic delivery.
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Dendrímeros/química , Portadores de Fármacos/química , Pulmón/metabolismo , Mucosa Respiratoria/metabolismo , Animales , Transporte Biológico Activo , Biofarmacia , Línea Celular , Dendrímeros/administración & dosificación , Dendrímeros/farmacocinética , Sistemas de Liberación de Medicamentos , Fluoresceína-5-Isotiocianato , Colorantes Fluorescentes , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Biológicos , Nanoestructuras/química , Polietilenglicoles/química , Propiedades de SuperficieRESUMEN
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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Aerosoles/metabolismo , Aerosoles/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Administración por Inhalación , Simulación por Computador , Sistemas de Liberación de Medicamentos/métodos , Inhaladores de Polvo Seco/métodos , Humanos , Modelos Anatómicos , Modelos Teóricos , Tamaño de la Partícula , Distribución Tisular/fisiologíaRESUMEN
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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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.
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The bioaerogel microparticles have been recently developed for respiratory drug delivery and attract fast increasing interests. These highly porous microparticles have ultralow density and hence possess much reduced aerodynamic diameter, which favour them with greatly enhanced dispersibility and improved aerosolisation behaviour. The adjustable particle geometric dimensions by varying preparation methods and controlling operation parameters make it possible to fabricate bioaerogel microparticles with accurate sizes for efficient delivery to the targeted regions of respiratory tract (i.e. intranasal and pulmonary). Additionally, the technical process can provide bioaerogel microparticles with the opportunities of accommodating polar, weak polar and non-polar drugs at sufficient amount to satisfy clinical needs, and the adsorbed drugs are primarily in the amorphous form that potentially can facilitate drug dissolution and improve bioavailability. Finally, the nature of biopolymers can further offer additional advantageous characteristics of improved mucoadhesion, sustained drug release and subsequently elongated time for continuous treatment on-site. These fascinating features strongly support bioaerogel microparticles to become a novel platform for effective delivery of a wide range of drugs to the targeted respiratory regions, with increased drug residence time on-site, sustained drug release, constant treatment for local and systemic diseases and anticipated better-quality of therapeutic effects.
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Sistemas de Liberación de Medicamentos , Geles , Humanos , Animales , Aerosoles , Administración por Inhalación , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/químicaRESUMEN
The demand for a more efficient and targeted method for intranasal drug delivery has led to sophisticated device design, delivery methods, and aerosol properties. Due to the complex nasal geometry and measurement limitations, numerical modeling is an appropriate approach to simulate the airflow, aerosol dispersion, and deposition for the initial assessment of novel methodologies for better drug delivery. In this study, a CT-based, 3D-printed model of a realistic nasal airway was reconstructed, and airflow pressure, velocity, turbulent kinetic energy (TKE), and aerosol deposition patterns were simultaneously investigated. Different inhalation flowrates (5, 10, 15, 30, and 45 L/min) and aerosol sizes (1, 1.5, 2.5, 3, 6, 15, and 30 µm) were simulated using laminar and SST viscous models, with the results compared and verified by experimental data. The results revealed that from the vestibule to the nasopharynx, the pressure drop was negligible for flow rates of 5, 10, and 15 L/min, while for flow rates of 30 and 40 L/min, a considerable pressure drop was observed by approximately 14 and 10%, respectively. However, from the nasopharynx and trachea, this reduction was approximately 70%. The aerosol deposition fraction alongside the nasal cavities and upper airway showed a significant difference in pattern, dependent on particle size. More than 90% of the initiated particles were deposited in the anterior region, while just under 20% of the injected ultrafine particles were deposited in this area. The turbulent and laminar models showed slightly different values for the deposition fraction and efficiency of drug delivery for ultrafine particles (about 5%); however, the deposition pattern for ultrafine particles was very different.
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One of the key challenges in developing a dry powder inhaler (DPI) of an inhalable potent fixed-dose combination (FDC) is the ability of the formulation to generate an effective and reproducible aerosol able to reach the lower parts of the lungs. Herein, a one-step approach is presented to expedite the synthesis of nanoaggregates made from a biocompatible and biodegradable polyamide based on L-lysine amino acid employing market-leading active pharmaceutical ingredients (fluticasone propionate (FP) and salmeterol xinafoate (SAL)) for the management of asthma. The nanoaggregates were synthesized using interfacial polycondensation that produced nanocapsules with an average particle size of 226.7 ± 35.3 nm and zeta potential of -30.6 ± 4.2 mV. Differential scanning calorimetric analysis and x-ray diffraction, as well as scanning electron microscopy of the produced FDC, revealed the ability of the produced nanocapsules to encapsulate the two actives and display the best aerodynamic performance. The FDC nanocapsules displayed 88.5% and 98.5% of the emitted dose for FP and SAL, respectively. The fine particle fraction of the nominated dose was superior to the marketed product (Seretide Diskus®, Brentford, United Kingdom). The in-vitro release study showed an extended drug release profile. Our findings suggest that nanoaggregates using polyamides based on L-lysine and interfacial polycondensation can serve as a good platform for pulmonary drug delivery of FDC systems.
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The aim of this study was to evaluate the device performance of a new design by comparing with a typical commercial DPI. Computational fluid dynamics (CFD) coupled with the discrete element method (DEM) collision has been utilized in this study to characterize and examine the flow field and particle transportation, respectively. A typical commercial DPI and an in-house designed novel DPI with distinct design features were compared to explore their dispersion capabilities and suitability for delivery to the respiratory tract. For this exploration, realistic oral to larynx and tracheobronchial airway models consisting of bio-relevant features were adopted to enhance practical feasibility. Distinct aerosol performances were observed between the two DPIs in the respiratory tract, where the in-house DPI, in comparison with the commercial DPI, has shown approximately 30% lower deposition fraction in the mouth-throat region with approximately 7% higher escape rate in the tracheobronchial region under the identical inhalation condition. This observation demonstrates that a novel in-house designed DPI provides higher device efficiency over the selected typical commercial DPI.
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Inhaladores de Polvo Seco , Sistema Respiratorio , Administración por Inhalación , Aerosoles , Simulación por Computador , Diseño de Equipo , Hidrodinámica , Tamaño de la Partícula , PolvosRESUMEN
Thymoquinone (TQ), the main active constituent of Nigella sativa, has demonstrated broad-spectrum antimicrobial, antioxidant, and anti-inflammatory effects, which suggest its potential use in secondary infections caused by COVID-19. However, clinical deployment has been hindered due to its limited aqueous solubility and poor bioavailability. Therefore, a targeted delivery system to the lungs using nanotechnology is needed to overcome limitations encountered with TQ. In this project, a novel TQ-loaded poly(ester amide) based on L-arginine nanoparticles was prepared using the interfacial polycondensation method for a dry powder inhaler targeting delivery of TQ to the lungs. The nanoparticles were characterized by FTIR and NMR to confirm the structure. Transmission electron microscopy and Zetasizer results confirmed the particle diameter of 52 nm. The high-dose formulation showed the entrapment efficiency and loading capacity values of TQ to be 99.77% and 35.56%, respectively. An XRD study proved that TQ did not change its crystallinity, which was further confirmed by the DSC study. Optimized nanoparticles were evaluated for their in vitro aerodynamic performance, which demonstrated an effective delivery of 22.7-23.7% of the nominal dose into the lower parts of the lungs. The high drug-targeting potential and efficiency demonstrates the significant role of the TQ nanoparticles for potential application in COVID-19 and other respiratory conditions.
RESUMEN
Inhalation therapy plays an important role in management or treatment of respiratory diseases such asthma and chronic obstructive pulmonary diseases (COPDs). For decades, pressurized metered dose inhalers (pMDIs) have been the most popular and prescribed drug delivery devices for inhalation therapy. The main objectives of the present computational work are to study flow structure inside a pMDI, as well as transport and deposition of micron-sized particles in a model of human tracheobronchial airways and their dependence on inhalation air flow rate and characteristic pMDI parameters. The upper airway geometry, which includes the extrathoracic region, trachea, and bronchial airways up to the fourth generation in some branches, was constructed based on computed tomography (CT) images of an adult healthy female. Computational fluid dynamics (CFD) simulation was employed using the k-ω model with low-Reynolds number (LRN) corrections to accomplish the objectives. The deposition results of the present study were verified with the in vitro deposition data of our previous investigation on pulmonary drug delivery using a hollow replica of the same airway geometry as used for CFD modeling. It was found that the flow structure inside the pMDI and extrathoracic region strongly depends on inhalation flow rate and geometry of the inhaler. In addition, regional aerosol deposition patterns were investigated at four inhalation flow rates between 30 and 120 L/min and for 60 L/min yielding highest deposition fractions of 24.4% and 3.1% for the extrathoracic region (EX) and the trachea, respectively. It was also revealed that particle deposition was larger in the right branches of the bronchial airways (right lung) than the left branches (left lung) for all of the considered cases. Also, optimization of spray characteristics showed that the optimum values for initial spray velocity, spray cone angle and spray duration were 100 m/s, 10° and 0.1 sec, respectively. Moreover, spray cone angle, more than any other of the investigated pMDI parameters can change the deposition pattern of inhaled particles in the airway model. In conclusion, the present investigation provides a validated CFD model for particle deposition and new insights into the relevance of flow structure for deposition of pMDI-emitted pharmaceutical aerosols in the upper respiratory tract.