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Asthma is a common chronic disease affecting the airways in the lungs. The receptors of allergic cytokines, including interleukin (IL)-4, IL-5, and IL-13, trigger the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which involves the pathogenesis of asthma. GDC-0214 is a JAK inhibitor that was developed as a potent and selective target for the treatment of asthma, specifically targeting the lungs. While inhaled GDC-0214 is a promising novel treatment option against asthma, improvement is still needed to achieve increased potency of the powder formulation and a reduced number of capsules containing powder to be inhaled. In this study, high-potency amorphous powder formulations containing GDC-0214 nanoaggregates for dry powder inhalation were developed using particle engineering technology, thin film freezing (TFF). A high dose per capsule was successfully achieved by enhancing the solubility of GDC-0214 and powder conditioning. Lactose and/or leucine as excipients exhibited optimum stability and aerosolization of GDC-0214 nanoaggregates, and aerosolization of the dose was independent of air flow through the device between 2 and 6 kPa pressure drops. In the rat PK study, formulation F20, which contains 80% GDC-0214 and 20% lactose, resulted in the highest AUC0-24h in the lungs with the lowest AUC0-24h in the plasma that corresponds to a 4.8-fold higher ratio of the lung-to-plasma exposures compared to micronized crystalline GDC-0214 powder administered by dry powder inhalation. Therefore, GDC-0214 nanoaggregates produced by TFF provided an improved dry powder for inhalation that can lead to enhanced therapeutic efficacy with a lower risk of systemic toxicity.
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Asma , Inibidores de Janus Quinases , Ratos , Animais , Pós/química , Congelamento , Lactose , Administração por Inalação , Asma/tratamento farmacológico , Inaladores de Pó Seco , Tamanho da Partícula , Aerossóis e Gotículas RespiratóriosRESUMO
Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.
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Asma , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/tratamento farmacológico , Administração por Inalação , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Asma/tratamento farmacológico , Terapia RespiratóriaRESUMO
There is a pressing need for efficacious therapies in the field of respiratory diseases and infections. Lipid nanocarriers, administered through aerosols, represent a promising tool for maximizing therapeutic concentration in targeted cells and minimizing systemic exposure. However, this approach requires the application of efficient and safe nanomaterials. Palmitoylethanolamide (PEA), an endocannabinoid-like endogenous lipid, plays a crucial role in providing protective mechanisms during inflammation, making it an interesting material for preparing inhalable lipid nanoparticles (LNPs). This report aims to preliminarily explore the in vitro behavior of LNPs prepared with PEA (PEA-LNPs), a new inhalable inflammatory-targeted nanoparticulate drug carrier. PEA-LNPs exhibited a size of about 250 nm, a rounded shape, and an marked improvement in PEA solubility in comparison to naked PEA, indicative of easily disassembled nanoparticles. A twin glass impinger instrument was used to screen the aerosol performance of PEA-LNP powders, obtained via freeze-drying in the presence of two quantities of mannose as a cryoprotectant. Results indicated that a higher amount of mannose improved the emitted dose (ED), and in particular, the fine particle fraction (FPF). A cytotoxicity assay was performed and indicated that PEA-LNPs are not toxic towards the MH-S alveolar macrophage cell line up to concentrations of 0.64 mg/mL, and using coumarin-6 labelled particles, a rapid internalization into the macrophage was confirmed. This study demonstrates that PEA could represent a suitable material for preparing inhalable lipid nanocarrier-based dry powders, which signify a promising tool for the transport of drugs employed to treat respiratory diseases and infections.
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Nanoestruturas , Doenças Respiratórias , Humanos , Manose , Sistemas de Liberação de Medicamentos , EndocanabinoidesRESUMO
Ultrafine KAl(OH)2CO3 dry powder (UDWP), as a novel high-temperature-resistant ultrafine dry powder fire extinguishing agent, has garnered significant attention in the field of aviation fire protection. However, its development has been hindered by its hydrophilicity, which leads to hygroscopicity, and its tendency for re-ignition due to oil deposition. Therefore, this study employs perfluorodecyltrimethoxysilane (PFDTMS) to modify the surface of UDWP, resulting in hydrophobic and oleophobic M-UDWP. The thermal stability and hydrophobicity of M-UDWP ensure its long-term stable storage in aircraft equipment compartments, thereby reducing aircraft maintenance costs. Additionally, its oleophobicity provides excellent anti-re-ignition performance, protecting aircraft power compartments from secondary fire damage. Energy-dispersive X-ray spectroscopy (EDS), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) analyses indicate that the PFDTMS modifier was successfully grafted onto KAl(OH)2CO3. Furthermore, M-UDWP exhibits a three-stage thermal decomposition process. The first-stage decomposition can be regarded as a single-step reaction, and the calculated kinetic parameters provide accurate predictions. Thermogravimetric analysis-Fourier transform infrared spectroscopy-mass spectrometry (TG-FTIR-MS) results reveal that M-UDWP significantly produces H2O and CO2 during thermal decomposition, which is one of its core fire extinguishing mechanisms. For the combustion of #RP-3 and #RP-5 aviation kerosene, commonly found in aircraft engine nacelles, the extinguishing times required by M-UDWP are 243 ms and 224 ms, respectively, with minimum extinguishing concentrations (MEC) of 25.9 g/m3 and 23.4 g/m3, respectively. The study of M-UDWP's thermal stability aids in understanding its storage stability under high-temperature conditions and its fire extinguishing mechanisms in fire zones. Moreover, the research findings suggest that M-UDWP has the potential to replace Halon 1301 in aircraft engine nacelles.
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Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.
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Sistemas de Liberação de Medicamentos , Inaladores de Pó Seco , Inaladores de Pó Seco/métodos , Humanos , Administração por Inalação , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Nanomedicina/métodos , Tamanho da Partícula , Nanotecnologia/métodosRESUMO
Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.
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Inaladores de Pó Seco , Pulmão , Tamanho da Partícula , Inaladores de Pó Seco/métodos , Pulmão/metabolismo , Administração por Inalação , Sistemas de Liberação de Medicamentos/métodos , Aerossóis , Pós , Liberação Controlada de FármacosRESUMO
In this study, dry dispersion laser diffraction was used to study the dispersibility of spheronized agglomerate formulations and identify geometric particle size metrics that correlated well with aerodynamic particle size distribution (APSD). Eleven unique batches of agglomerates were prepared for both laser diffraction and cascade impaction testing. Correlations between the particle size distribution (PSD) and aerodynamic particle size distribution (APSD) metrics for the eleven agglomerate batches were determined in a semi-empirical manner. The strongest correlation between APSD and PSD was observed between the impactor-sized mass (%ISM) and the cumulative PSD fraction <14.5 µm. The strongest correlation with fine particle fraction (FPF) was observed with the cumulative PSD fraction <0.99 micron (R-squared = 0.974). In contrast to the other APSD metrics, good correlations were not found between the mass median aerodynamic diameter (MMAD) and the cumulative PSD fractions. Overall, the implementation of laser diffraction as a surrogate for cascade impaction has the potential to streamline product development. Laser diffraction measurements offer savings in labor and turnaround time compared to cascade impaction.
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Inaladores de Pó Seco , Lasers , Aerossóis , Composição de Medicamentos , Tamanho da Partícula , Administração por Inalação , PósRESUMO
Dry powder inhaler (DPI) products are commonly formulated as a mixture of micronized drug particles and large carrier particles, with or without additional fine particle excipients, followed by final powder filling into dose containment systems such as capsules, blisters, or reservoirs. DPI product manufacturing consists of a series of unit operations, including particle size reduction, blending, and filling. This review provides an overview of the relevant critical process parameters used for jet milling, high-shear blending, and dosator/drum capsule filling operations across commonly utilized instruments. Further, this review describes the recent achievements regarding the application of empirical and mechanistic models, especially discrete element method (DEM) simulation, in DPI process development. Although to date only limited modeling/simulation work has been accomplished, in the authors' perspective, process design and development are destined to be more modeling/simulation driven with the emphasis on evaluating the impact of material attributes/process parameters on process performance. The advancement of computational power is expected to enable modeling/simulation approaches to tackle more complex problems with better accuracy when dealing with real-world DPI process operations.
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Portadores de Fármacos , Inaladores de Pó Seco , Pós , Composição de Medicamentos/métodos , Administração por Inalação , Simulação por Computador , Tamanho da Partícula , AerossóisRESUMO
Pulmonary deposition of lung-targeted therapeutic aerosols can achieve direct drug delivery to the site of action, thereby enhancing the efficacy and reducing systemic exposure. In this study, we investigated the in vitro and in vivo aerosol performance of the novel small animal air-jet dry powder insufflator (Rat AJ DPI) using spray-dried albuterol excipient-enhanced-growth (EEG) powder as a model formulation. The in vitro aerosolization performance of the optimized albuterol EEG powder was first assessed using the Rat AJ DPI. The performance of Rat AJ DPI to deliver albuterol EEG aerosol to rat lungs was then compared to that of the Penn-Century Insufflator. Albuterol EEG powders dispersed using the Rat AJ DPI demonstrated narrow unimodal aerosol size distribution profiles, which were independent of the loaded powder dose (1, 2, and 5 mg). In addition, the span value for Rat AJ DPI (5 mg powder mass) was 1.32, which was 4.2-fold lower than that for Penn-Century insufflator (5 mg powder mass). At a higher loaded mass of 5 mg, the Rat AJ DPI delivered significantly larger doses to rat lungs compared with the Penn-Century DPI. The Rat AJ DPI with hand actuation delivered approximately 85% of the total emitted dose (2 and 5 mg loadings), which was comparatively higher than that for Penn-Century DPI (approximately 75%). In addition, percentage deposition in each of the lung lobes for the Rat AJ DPI was observed to be independent of the administration dose (2 and 5 mg loadings) with coefficients of variation below 12%, except in the right middle lobe. Automatic actuation of a 5 mg powder mass using the Rat AJ DPI demonstrated a similar delivered dose compared to manual actuation of the same dose, with 82% of the total emitted dose reaching the lung lobes. High-efficiency delivery of the aerosol to the lobar lung region and low sensitivity of the interlobar delivery efficiency to the loaded dose highlight the suitability of the new air-jet DPI for administering therapeutic pharmaceutical aerosols to small test animals.
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Albuterol , Inaladores de Pó Seco , Animais , Ratos , Pós , Aerossóis , Administração por Inalação , Excipientes , Tamanho da Partícula , PulmãoRESUMO
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death with 1.6 million deaths worldwide reported in 2021. Oral pyrazinamide (PZA) is an integral part of anti-TB regimens, but its prolonged use has the potential to drive the development of PZA-resistant Mtb. PZA is converted to the active moiety pyrazinoic acid (POA) by the Mtb pyrazinamidase encoded by pncA, and mutations in pncA are associated with the majority of PZA resistance. Conventional oral and parenteral therapies may result in subtherapeutic exposure in the lung; hence, direct pulmonary administration of POA may provide an approach to rescue PZA efficacy for treating pncA-mutant PZA-resistant Mtb. The objectives of the current study were to (i) develop novel dry powder POA formulations, (ii) assess their feasibility for pulmonary delivery using physicochemical characterization, (iii) evaluate their pharmacokinetics (PK) in the guinea pig model, and (iv) develop a mechanism-based pharmacokinetic model (MBM) using in vivo PK data to select a formulation providing adequate exposure in epithelial lining fluid (ELF) and lung tissue. We developed three POA formulations for pulmonary delivery and characterized their PK in plasma, ELF, and lung tissue following passive inhalation in guinea pigs. Additionally, the PK of POA following oral, intravenous, and intratracheal administration was characterized in guinea pigs. The MBM was used to simultaneously model PK data following administration of POA and its formulations via the different routes. The MBM described POA PK well in plasma, ELF, and lung tissue. Physicochemical analyses and MBM predictions suggested that POA maltodextrin was the best among the three formulations and an excellent candidate for further development as it has: (i) the highest ELF-to-plasma exposure ratio (203) and lung tissue-to-plasma exposure ratio (30.4) compared with POA maltodextrin and leucine (75.7/16.2) and POA leucine salt (64.2/19.3) and (ii) the highest concentration in ELF (CmaxELF: 171 nM) within 15.5 min, correlating with a fast transfer into ELF after pulmonary administration (KPM: 22.6 1/h). The data from the guinea pig allowed scaling, using the MBM to a human dose of POA maltodextrin powder demonstrating the potential feasibility of an inhaled product.
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Líquidos Corporais , Pirazinamida , Humanos , Animais , Cobaias , Leucina , PósRESUMO
BACKGROUND: Several clinical guidelines recommend chronic inhaled therapy for pwCF (people with cystic fibrosis) and chronic Pseudomonas aeruginosa infection of the lungs. METHODS: To demonstrate what kind of therapy regimens are used in Germany, we retrospectively analysed chronic inhaled antibiotic therapy within the cohort of the German CF Registry in 2020. For comparison we also analysed the use of inhaled antibiotics in pwCF with intermittent Pseudomonas or without Pseudomonas infection. RESULTS: A total of 1960 pwCF had chronic P. aeruginosa infection and were retrospectively evaluated. Almost 90% (n = 1751) received at least one inhaled antibiotic. The most commonly used inhaled antibiotic was colistin solution for inhalation (55.2%), followed by aztreonam solution for inhalation (32.6%) and tobramycin solution for Inhalation (30%). Almost 56% of adults and 44% of children alternated two antibiotics for inhalation. In children, alternating colistin + tobramycin was the most often used regimen. In adults, only 23% used colistin + tobramycin; there was a wide range of treatment regimens among adults using two inhaled antibiotics alternately. 2456 pwCF had no Pseudomonas infection, but almost 24% had a chronic inhaled antibiotic therapy, while 56% of 361 pwCF and intermittent chronic Pseudomonas infection had a chronic inhaled antibiotic therapy. CONCLUSION: In all three groups the most commonly used inhaled antibiotic was colistin solution for inhalation. Almost 56% of adults and 44% of children with chronic Pseudomonas infection alternated two antibiotics for inhalation. It will be interesting to see how the introduction of the highly effective modulator elexacaftor/tezacaftor/ivacaftor will change the use of inhaled antibiotics.
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Fibrose Cística , Infecções por Pseudomonas , Adulto , Criança , Humanos , Antibacterianos , Infecções por Pseudomonas/tratamento farmacológico , Estudos Retrospectivos , Colistina/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Pseudomonas aeruginosa , Tobramicina , Administração por Inalação , AlemanhaRESUMO
PURPOSE: The probability of agglomerate-to-wall collision was quantified using a unique image processing technique applied to high-speed microscopic images. The study aimed to investigate the effects of flow rate and particle size on the percentage of colliding agglomerates detected within an in-house powder dispersion device. METHOD: The device consists of a swirl chamber and two tangential inlets in various configurations, designed to emulate the geometric features of commercial devices such as the Aerolizer® and Osmohaler®. The test cases were conducted with constant flow rates of 30 SLPM and 60 SLPM. Four powder samples were tested, including carrier Respitose® SV010 (median volume diameter 104 µm, span 1.7) and mannitol of three constituent primary particle sizes (3 µm, 5 µm and 7 µm; span 1.6 - 1.9). RESULTS: At the lower flow rate of 30 SLPM, collision frequencies were significantly different between powders of different constituent particle sizes, but the effects of powder properties diminished on increasing the flow rate to 60 SLPM. At the higher flow rate, all powders experienced a significant increase in the proportion of colliding particles. CONCLUSION: Analysis of collision events showed that the probability of collision for each agglomerate increased with agglomerate diameter and velocity. Experimental data of agglomerate-to-wall collision were utilised to develop a logistic regression model that can accurately predict collisions with various powders and flow rates.
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Inaladores de Pó Seco , Manitol , Aerossóis , Pós , Tamanho da Partícula , Administração por InalaçãoRESUMO
PURPOSE: The purpose of this study was to evaluate the in vitro lung dissolution of amorphous and crystalline powder formulations of rifampicin in polyethylene oxide (PEO) and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), and to predict the in vivo plasma concentration-time profiles using the in vitro data. METHODS: The in vitro dissolution and permeation profiles of respirable rifampicin particles were studied using a custom-made dissolution apparatus. Data from the in vitro dissolution test were used to estimate the parameters to be used as the input for the simulation of in vivo plasma concentration-time profiles using STELLA® software. For prediction of in vivo profiles, a one-compartment model either with a first order elimination or with a Michaelis-Menten kinetics-based elimination was used. RESULTS: Compared to the crystalline formulation, the amorphous formulation showed rapid in vitro dissolution suggesting their possible faster in vivo absorption and higher plasma concentrations of rifampicin following lung delivery. However, the simulations suggested that both powder formulations would result in similar plasma-concentration time profiles of rifampicin. CONCLUSIONS: Use of an in vitro dissolution test coupled with a simulation model for prediction of plasma-concentration time profiles of an inhaled drug was demonstrated in this work. These models can also be used in the design of inhaled formulations by controlling their release and dissolution properties to achieve desired lung retention or systemic absorption following delivery to the lungs.
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Rifampina , Rifampina/química , Pós/química , Solubilidade , Fenômenos Químicos , Simulação por ComputadorRESUMO
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
INTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria. AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying. METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%. CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Capreomicina/química , Capreomicina/uso terapêutico , Pós/química , Peptídeos Antimicrobianos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Aerossóis/química , Peptídeos/farmacologia , Inaladores de Pó Seco/métodos , Tamanho da Partícula , Administração por InalaçãoRESUMO
PURPOSE: Intratracheal delivery and consistent dosing of dry powder vaccines is especially challenging in mice. To address this issue, device design of positive pressure dosators and actuation parameters were assessed for their impacts on powder flowability and in vivo dry powder delivery. METHODS: A chamber-loading dosator assembled with stainless-steel, polypropylene or polytetrafluoroethylene needle-tips was used to determine optimal actuation parameters. Powder loading methods including tamp-loading, chamber-loading and pipette tip-loading were compared to assess performance of the dosator delivery device in mice. RESULTS: Available dose was highest (45%) with a stainless-steel tip loaded with an optimal mass and syringe air volume, primarily due to the ability of this configuration to dissipate static charge. However, this tip encouraged more agglomeration along its flow path in the presence of humidity and was too rigid for intubation of mice compared to a more flexible polypropylene tip. Using optimized actuation parameters, the polypropylene pipette tip-loading dosator achieved an acceptable in vivo emitted dose of 50% in mice. After administering two doses of a spray dried adenovirus encapsulated in mannitol-dextran, high bioactivity was observed in excised mouse lung tissue three days post-infection. CONCLUSIONS: This proof-of-concept study demonstrates for the first time that intratracheal delivery of a thermally stable, viral-vectored dry powder can achieve equivalent bioactivity to the same powder, reconstituted and delivered intratracheally. This work may guide the design and device selection process for murine intratracheal delivery of dry powder vaccines to help progress this promising area of inhalable therapeutics.
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Produtos Biológicos , Animais , Camundongos , Administração por Inalação , Pós , Polipropilenos , Aço , Inaladores de Pó Seco , Tamanho da Partícula , AerossóisRESUMO
OBJECTIVE: Breath-actuated inhalers (BAIs) are gaining attention in the management of obstructive airway diseases (OADs). In Nepal, a BAI containing fluticasone propionate/salmeterol (FPS) has been available for a year. This survey is aimed at determining the perception and experience of physicians in Nepal concerning BAIs. METHODS: A cross-sectional, questionnaire-based survey was conducted. A total of 141 physicians participated and filled the survey. RESULTS: Most physicians felt that the right device should be easy to teach, learn and remember. They considered coordination and multiple steps as the primary challenges with pressurized metered-dose inhalers and dry powder inhalers, respectively. Most of them agreed that BAIs could address these challenges. BAIs were not only preferred by most of the physicians for asthma and chronic obstructive pulmonary disease but were also the preferred choice in newly diagnosed patients. Physicians believed that if current patients were shifted to BAIs, it could improve inhalation technique (88%) and compliance/adherence (81%). Almost all of them (92-97%) agreed that teaching the breathing technique and the cleaning process was easier and faster in BAIs. BAIs were considered easy and simple to use. Also, BAI's dose-counter helps patients to increase adherence to inhalation therapy. CONCLUSIONS: In this INTROSPECT survey, physicians in Nepal believed that BAIs could address the key challenges faced with using pMDIs and DPIs in asthma and COPD patients.
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Asma , Médicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Asma/tratamento farmacológico , Estudos Transversais , Nepal , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Terapia Respiratória , Inaladores Dosimetrados , Inaladores de Pó Seco , Inquéritos e Questionários , Percepção , Administração por InalaçãoRESUMO
Aim: Inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) combination therapy is used for the effective control of asthma. Aim of this study was to collect data on the effectiveness, safety, quality of life, and patient satisfaction from a fixed dose combination of budesonide/formoterol administered with the Elpenhaler® device following 3-months' treatment.Methods: A 3-month real-life, multicentre, one-arm, prospective observational study (SKIRON study-NCT03055793) was conducted, using the following questionnaires: Asthma Control Questionnaire (ACQ-6) for asthma control assessment, MiniAQLQ questionnaire for QoL assessment, and Feeling of Satisfaction with Inhaler questionnaire (FSI-10) for patients' satisfaction with the inhaler device. Comorbidities and safety data were also recorded during the study.Results: We enrolled 1,174 asthmatic patients following standard clinical practice in primary care from 126 sites in urban and rural areas of Greece. The majority of patients (71.5%) had at least one comorbidity. A statistically significant improvement in the ACQ-6 score was noted at 3 months compared to the baseline evaluation (mean ± SD 2.19 ± 0.97 at baseline vs. 0.55 ± 0.56 at 3 months; mean change -1.64 (95%CI -1.69, -1.57), p < 0.0001). MiniAQLQ score was statistically and clinically significantly improved, compared to baseline, (4.55 ± 1.04 at baseline vs. 6.37 ± 0.64 at 3 months; mean change 1.82 (95%CI 1.75, 1.87), p < 0.0001). The mean FSI-10 score of 44.2 ± 5.4 indicated patient satisfaction and ease-of-use of the Elpenhaler® device.Conclusions: In this large real-world study of inadequately-controlled asthma patients in primary care settings, the treatment with budesonide/formoterol FDC with the Elpenhaler® device was associated with significant improvement in patients' asthma control and quality of life.
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Asma , Humanos , Asma/tratamento farmacológico , Asma/induzido quimicamente , Qualidade de Vida , Fumarato de Formoterol/uso terapêutico , Budesonida/uso terapêutico , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Atenção Primária à Saúde , Administração por Inalação , Combinação de Medicamentos , Resultado do Tratamento , Etanolaminas/uso terapêuticoRESUMO
BACKGROUND: Gene therapy for lung cancer has emerged as a novel tumor-combating strategy for its superior tumor specificity, low systematical toxicity and huge clinical translation potential. Especially, the applications of microRNA shed led on effective tumor ablation by directly interfering with the crucial gene expression, making it one of the most promising gene therapy agents. However, for lung cancer therapy, the microRNA treatment confronted three bottlenecks, the poor tumor tissue penetration effect, the insufficient lung drug accumulation and unsatisfied gene transfection efficiency. To address these issues, an inhalable RGD-TAT dual peptides-modified cationic liposomes loaded with microRNA miR-34a and gap junction (GJ) regulation agent all-trans retinoic acid (ATRA) was proposed, which was further engineered into dry powder inhalers (DPIs). RESULTS: Equipped with a rough particle surface and appropriate aerodynamic size, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs were expected to deposit into the deep lung and reach lung tumor lesions guided by targeting peptide RGD. Assisted by cellular transmembrane peptides TAT, the RGD-TAT-CLPs/ARTA@miR-34a was proven to be effectively internalized by cancer cells, enhancing gene transfection efficiency. Then, the GJ between tumor cells was upregulated by ARTA, facilitating the intercellular transport of miR-34a and boosting the gene expression in the deep tumor. CONCLUSION: Overall, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could enhance tumor tissue penetration, elevate lung drug accumulation and boost gene transfection efficiency, breaking the three bottlenecks to enhancing tumor elimination in vitro and in vivo. We believe that the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could serve as a promising pulmonary gene delivery platform for multiple lung local disease treatments.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Humanos , Lipossomos , Neoplasias Pulmonares/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Pulmão/metabolismo , Oligopeptídeos , Junções Comunicantes/metabolismo , Genes Neoplásicos , Linhagem Celular TumoralRESUMO
Azithromycin is an antibiotic proposed as a treatment for the coronavirus disease 2019 (COVID-19) due to its immunomodulatory activity. The aim of this study is to develop dry powder formulations of azithromycin-loaded poly(lactic-co-glycolic acid) (PLGA) nanocomposite microparticles for pulmonary delivery to improve the low bioavailability of azithromycin. Double emulsion method was used to produce nanoparticles, which were then spray dried to form nanocomposite microparticles. Encapsulation efficiency and drug loading were analysed, and formulations were characterised by particle size, zeta potential, morphology, crystallinity and in-vitro aerosol dispersion performance. The addition of chitosan changed the neutrally-charged azithromycin only formulation to positively-charged nanoparticles. However, the addition of chitosan also increased the particle size of the formulations. It was observed in the NGI® data that there was an improvement in dispersibility of the chitosan-related formulations. It was demonstrated in this study that all dry powder formulations were able to deliver azithromycin to the deep lung regions, which suggested the potential of using azithromycin via pulmonary drug delivery as an effective method to treat COVID-19.