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PURPOSE: This study evaluated the in vitro aerosol performance of a dry powder antibiotic product that combined a highly dispersible tobramycin powder with a previously optimized pediatric air-jet dry powder inhaler (DPI) across a subject age range of 2-10 years. METHODS: An excipient enhanced growth (EEG) formulation of the antibiotic tobramycin (Tobi) was prepared using a small particle spray drying technique that included mannitol as the hygroscopic excipient and trileucine as the dispersion enhancer. The Tobi-EEG formulation was aerosolized using a positive-pressure pediatric air-jet DPI that included a 3D rod array. Realistic in vitro experiments were conducted in representative airway models consistent with children in the age ranges of 2-3, 5-6 and 9-10 years using oral or nose-to-lung administration, non-humidified or humidified airway conditions, and constant or age-specific air volumes. RESULTS: Across all conditions tested, mouth-throat depositional loss was < 1% and nose-throat depositional loss was < 3% of loaded dose. Lung delivery efficiency was in the range of 77.3-85.1% of loaded dose with minor variations based on subject age (~ 8% absolute difference), oral or nasal administration (< 2%), and delivered air volume (< 2%). Humidified airway conditions had an insignificant impact on extrathoracic depositional loss and significantly increased aerosol size at the exit of a representative lung chamber. CONCLUSIONS: In conclusion, the inhaled antibiotic product nearly eliminated extrathoracic depositional loss, demonstrated high efficiency nose-to-lung antibiotic aerosol delivery in pediatric airway models for the first time, and provided ~ 80% lung delivery efficiency with little variability across subject age and administered air volume.
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Antibacterianos , Inaladores de Pó Seco , Criança , Humanos , Pré-Escolar , Pós , Excipientes , Desenho de Equipamento , Tamanho da Partícula , Administração por Inalação , Aerossóis , Sprays Nasais , TobramicinaRESUMO
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.
Assuntos
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: 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
The aim of this work was to investigate the phytochemical profile and biological properties of different colours of betalain cactus pear extracts, evaluating their antioxidant, cytoprotective, and anti-angiogenic properties by cell-free, cell-based, and in vivo assays. A QuEChERS extraction method followed by RP-LC-DAD-MS/MS analysis showed that indicaxanthin and betanin were the main compounds (≥94.32% and ≥96.95%, respectively). Orange cactus pear extracts exert the best antioxidant activity in all assays carried out, in particular into ORAC (17,352.55 ± 987.407 mg trolox equivalents/100 g dry weight) and ß-carotene bleaching (60.35%) assays. The red ones, instead, showed the best cytoprotective activity decreasing the cell mortality, LDH, and Caspase-3 release ranging from 4.0 to 55%. According to antioxidant results, the orange cactus pear extracts showing also the highest anti-angiogenic activity (IC50 19.31 µg/ml), followed by the red (IC50 23.55 µg/ml) and the yellow ones (IC50 33.97 µg/ml). In light of the results and correlation analysis, the behaviour of these molecules varies a lot according to their structure and physicochemical features and synergistic activity between betalain classes may be postulated; so the plant complex could be of greater interest compared with the isolated molecules for potential nutraceutical and pharmaceutical uses.
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Antioxidantes/química , Betalaínas/química , Frutas/química , Opuntia/química , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/química , Compostos Fitoquímicos/farmacologiaRESUMO
The objective of this study was to explore the aerosolization performance of powders produced with different mesh nebulizer sources in the initial design of a new small-particle spray dryer system. An aqueous excipient enhanced growth (EEG) model formulation was spray dried using different mesh sources and the resulting powders were characterized based on (i) laser diffraction, (ii) aerosolization with a new infant air-jet dry powder inhaler, and (iii) aerosol transport through an infant nose-throat (NT) model ending with a tracheal filter. While few differences were observed among the powders, the medical-grade Aerogen Solo (with custom holder) and Aerogen Pro mesh sources were selected as lead candidates that produced mean fine particle fractions <5⯵m and <1⯵m in ranges of 80.6-77.4% and 13.1-16.0%, respectively. Improved aerosolization performance was achieved at a lower spray drying temperature. Lung delivery efficiencies through the NT model were in the range of 42.5-45.8% for powders from the Aerogen mesh sources, which were very similar to previous results with a commercial spray dryer. Ultimately, a custom spray dryer that can accept meshes with different characteristics (e.g., pore sizes and liquid flow rates) will provide particle engineers greater flexibility in producing highly dispersible powders with unique characteristics.
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Química Farmacêutica , Telas Cirúrgicas , Humanos , Pós , Química Farmacêutica/métodos , Tamanho da Partícula , Aerossóis , Administração por Inalação , Inaladores de Pó Seco/métodosRESUMO
Background: An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Methods: Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two in vitro preterm infant NT models. Two excipient-enhanced growth (EEG) dry powder formulations were explored containing either l-leucine or trileucine as the dispersion enhancer. Performance metrics included aerosol depositional loss in the nasal interface, deposition in the NT models, and tracheal filter deposition, which was used to estimate lung delivery efficiency. Results: The best performing nasal interface replaced the straight flexible prong of the original gradual expansion design with a rigid curved prong (â¼20° curvature). The prong modification increased the lung delivery efficiency by 5%-10% (absolute difference) depending on the powder formulation. Adding a metal mesh to the flow pathway, to dissipate the turbulent jet, also improved lung delivery efficiency by â¼5%, while reducing the NT depositional loss by a factor of over twofold compared with the original nasal interface. The platform was also found to perform similarly in two different preterm NT models, with no statistically significant difference between any of the performance metrics. Conclusions: Modifications to the nasal interface of an infant air-jet DPI improved the aerosol delivery through multiple infant NT models, providing up to an additional 10% lung delivery efficiency (absolute difference) with the lead design delivering â¼57% of the loaded dose to the tracheal filter, while performance in two unique preterm airway geometries remained similar.
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Inaladores de Pó Seco , Recém-Nascido Prematuro , Administração por Inalação , Aerossóis , Desenho de Equipamento , Humanos , Lactente , Recém-Nascido , Tamanho da Partícula , PósRESUMO
Background: Positive-pressure dry powder inhalers (DPIs) have recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high efficiency aerosolization with low actuation air-volumes (AAVs). The objective of this study was to initially develop the positive-pressure air-jet DPI platform for high efficiency aerosol delivery to newborn infants by using the nose-to-lung route. Methods: Aerosolization performance metrics of six air-jet DPIs were first assessed at AAVs that were consistent with full-term (30 mL) and preterm (10 mL) neonates. Designs of the air-jet DPIs varied based on geometry of the inlet and outlet flow passages and shape of the aerosolization chamber. Aerosolization metrics evaluated at the device outlet were emitted dose (ED) and mass median aerodynamic diameter (MMAD). Designs with the best aerosolization performance were connected to a smoothly expanding nasal interface and full-term infant (3550 g) nose-throat (NT) model with tracheal filter. Results: The three best performing devices had characteristics of a cylindrical and horizontal aerosolization chamber with a flush or protruding outlet orifice. Including multiple air inlets resulted in meeting the aerosolization targets of >80% ED (based on loaded dose) and MMAD <1.8 µm. Reducing the AAV by a factor of threefold from 30 to 10 mL had little effect on aerosol formation. The three leading devices all delivered â¼50% of the loaded dose through a full-term NT in vitro model by using an AAV of 30 mL. Conclusion: With careful selection of design attributes, the air-jet DPI platform is capable of high-efficiency aerosolization of a 10 mg powder mass by using AAVs that are consistent with infant inhalation. The associated infant air-jet DPI system, which forms a seal at the nostril(s) and delivers both the aerosol and a complete inhalation, is capable of rapid and efficient aerosol administration to infant lungs, based on initial testing in a full-term in vitro NT model.
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Inaladores de Pó Seco , Administração por Inalação , Aerossóis , Desenho de Equipamento , Humanos , Lactente , Recém-Nascido , Tamanho da Partícula , PósRESUMO
Background: Dry powder inhalers (DPIs) offer a number of advantages, such as rapid delivery of high-dose inhaled medications; however, DPI use in children is often avoided due to low lung delivery efficiency and difficulty in operating the device. The objective of this study was to develop a high-efficiency inline DPI for administering aerosol therapy to children with the option of using either an oral or trans-nasal approach. Methods: An inline DPI was developed that consisted of hollow inlet and outlet capillaries, a powder chamber, and a nasal or oral interface. A ventilation bag or compressed air was used to actuate the device and simultaneously provide a full deep inspiration consistent with a 5-year-old child. The powder chamber was partially filled with a model spray-dried excipient enhanced growth powder formulation with a mass of 10 mg. Device aerosolization was characterized with cascade impaction, and aerosol transmissions through oral and nasal in vitro models were assessed. Results: Best device performance was achieved when all actuation air passed through the powder chamber (no bypass flow) resulting in an aerosol mean mass median aerodynamic diameter (MMAD) <1.75 µm and a fine particle fraction (<5 µm) ≥90% based on emitted dose. Actuation with the ventilation bag enabled lung delivery efficiency through the nasal and oral interfaces to a tracheal filter of 60% or greater, based on loaded dose. In both oral and nose-to-lung (N2L) administrations, extrathoracic depositional losses were <10%. Conclusion: In conclusion, this study has proposed and initially developed an efficient inline DPI for delivering spray-dried formulations to children using positive pressure operation. Actuation of the device with positive pressure enabled effective N2L aerosol administration with a DPI, which may be beneficial for subjects who are too young to use a mouthpiece or to simultaneously treat the nasal and lung airways of older children.