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This consensus document addresses the reduction of the environmental impact of inhalers in Portugal. It was prepared by the Portuguese Council for Health and the Environment and the societies representing the specialties that account for these drugs' largest volume of prescriptions, namely the Portuguese Society of Pulmonology, the Portuguese Society of Allergology and Clinical Immunology, the Portuguese Society of Pediatrics, the Portuguese Society of Internal Medicine, the Portuguese Association of General and Family Medicine and also a patient association, the Respira Association. The document acknowledges the significant impact of pressurized metered-dose inhalers on greenhouse gas emissions and highlights the need to transition to more sustainable alternatives. The carbon footprint of pressurized metered-dose inhalers and dry powder inhalers in Portugal was calculated, and the level of awareness among prescribing physicians on this topic was also estimated. Finally, recommendations were developed to accelerate the reduction of the ecological footprint of inhalers.

Este documento de consenso aborda a redução do impacto ambiental dos inaladores em Portugal. Foi elaborado pelo Conselho Português para a Saúde e Ambiente e pelas sociedades que representam as especialidades com maior volume de prescrição destes medicamentos, nomeadamente a Sociedade Portuguesa de Pneumologia, a Sociedade Portuguesa de Alergologia e Imunologia Clínica, a Sociedade Portuguesa de Pediatria, a Sociedade Portuguesa de Medicina Interna e a Associação Portuguesa de Medicina Geral e Familiar em conjunto com uma associação de doentes, a Associação Respira. Reconhece-se o impacto significativo dos inaladores pressurizados doseáveis nas emissões de gases com efeito de estufa e a necessidade de transição para alternativas mais sustentáveis. Calculou-se a pegada de carbono dos inaladores pressurizados doseáveis e dos inaladores de pó seco em Portugal e estimou-se o nível de literacia dos médicos prescritores relativamente a este tema. Finalmente, foram elaboradas recomendações com o objetivo de acelerar a redução da pegada ecológica dos inaladores.

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Inhalation systems, mostly metered dose inhalers (MDIs) and dry powder inhalers (DPIs), are currently submitted to a critical assessment for their carbon footprint (CF) and environmental impact. They are related to greenhouse gas (GHG) emissions and they produce waste of used devices with withheld drug residues and unused doses. However, with estimated contributions to anthropogenic GHG-emissions of 0.03% for MDIs and 0.0012% for DPIs globally, it may not be expected that mitigating the GHG emissions from inhalers will have a meaningful effect on the current climate change and global warming, notwithstanding that nationally these percentages may be somewhat higher, depending on the ratio of MDIs to DPIs and the total national CF. MDIs are particularly the preferred type of inhalers over DPIs in the USA and UK with ratios of 9: 1 and 7: 3 respectively. In such countries, a partial switch from MDIs to DPIs is to be recommended, providing that such a switch does not jeopardize the therapy. Using renewable energy only for the production and waste management of DPIs will make this type of inhaler almost climate neutral. A greater concern exists about inhaler waste, more particularly about the residual drug and unused doses in discarded devices. Inhalers contribute less than 0.02% to global plastic waste annually and most plastic inhalers end in the domestic waste bin and not as litter polluting the environment with plastic. However, they do contain retained drug and unused doses, whereas even full inhalers are disposed. Because globally most municipal waste (70%) ends up in dumps and landfills, leakage of the drugs into the soil and surface waters is a serious problem. It pollutes drinking water and endangers species and biodiversity. Therefore, a good collection system and an adequate waste management program for used inhalers seems to be the most meaningful measure to take for the environment, as this will stop inhalers and drugs from putting ecosystems at risk.

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Background Chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma significantly impair quality of life and impose a substantial burden on healthcare systems. Proper inhalation technique is important for effective management of these diseases, yet remains poorly performed by many patients. This study evaluated the impact of structured counseling and training sessions on inhaler use among patients with COPD and asthma, aiming to enhance technique correctness and disease control. Methodology This cross-sectional study analyzed 150 patients with asthma and COPD who fulfilled the inclusion criteria for inhalation techniques. Patients were counseled regarding the proper seven-step inhalation technique for each inhaler type [metered-dose inhaler (MDI), MDI with spacer, and dry powder inhaler (DPI)] through practical demonstration at baseline visits. Correct use of inhalers was assessed by a predefined checklist for each inhaler device at the baseline visit and after three months. The correctness of the inhalation technique was evaluated by scoring each of the seven steps. The disease control assessment was done using the COPD assessment test (CAT) and asthma control test (ACT) at the baseline visit and after three months. Results In this study of 150 patients, there were 97 (64.7%) males and 53 (35.3%) females. In total, 67 (44.7%) were diagnosed with asthma and 83 (55.3%) with COPD. The mean age was 45.33 ± 12.62 years. Post-counseling improvements in inhaler technique were marked, with MDI users enhancing their technique score from an average of 4.4 to 6.1, MDI with spacer from 4.56 to 6.26, and DPI from 4.92 to 6.24 (p < 0.001 for all). Disease control also showed significant gains; CAT scores decreased for MDI users from 23.4 to 20.5, MDI with spacer from 23.92 to 20.96, and DPI from 24.89 to 21.96. Concurrently, ACT scores increased for MDI users from 16.4 to 18.0 (p = 0.002), MDI with spacer from 17.29 to 19.04, and DPI from 16.42 to 18.37 (p < 0.001 for both), reflecting substantive advances in managing COPD and asthma symptoms. Furthermore, patients with primary education exhibited a significant boost in technique mastery post-counseling (p < 0.001), underscoring the potential of well-crafted counseling to transcend educational barriers in promoting effective inhaler use. Conclusions Post-counseling, inhaler technique improved significantly across all types, with MDI with spacer users demonstrating the most progress. Technique scores increased notably (p < 0.001), and disease control scores for COPD and asthma, measured by CAT and ACT, also showed significant improvements (p < 0.001). Remarkably, primary education level participants exhibited substantial technique gains post-intervention, emphasizing the effectiveness of counseling irrespective of initial educational status in enhancing inhaler use and disease management.

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Introduction: Nanoparticles have the advantages of improving the solubility of poorly water-soluble drugs, facilitating the drug across biological barriers, and reducing macrophage phagocytosis in pulmonary drug delivery. However, nanoparticles have a small aerodynamic particle size, which makes it difficult to achieve optimal deposition when delivered directly to the lungs. Therefore, delivering nanoparticles to the lungs effectively has become a popular research topic. Methods: Nanoaggregate microparticles were used as a pulmonary drug delivery strategy for the improvement of the bioavailability of cyclosporine A (CsA). The nanoaggregate microparticles were prepared with polyvinyl pyrrolidone (PVP) as the excipient by combining the anti-solvent method and spray drying process. The physicochemical properties, aerodynamic properties, in vivo pharmacokinetics and inhalation toxicity of nanoaggregate microparticles were systematically evaluated. Results: The optimal nanoparticles exhibited mainly spherical shapes with the particle size and zeta potential of 180.52 nm and -19.8 mV. The nanoaggregate microparticles exhibited irregular shapes with the particle sizes of less than 1.6 µm and drug loading (DL) values higher than 70%. Formulation NM-2 as the optimal nanoaggregate microparticles was suitable for pulmonary drug delivery and probably deposited in the bronchiole and alveolar region, with FPF and MMAD values of 89.62% and 1.74 µm. In addition, inhaled NM-2 had C max and AUC0-∞ values approximately 1.7-fold and 1.8-fold higher than oral cyclosporine soft capsules (Neoral®). The inhalation toxicity study suggested that pulmonary delivery of NM-2 did not result in lung function damage, inflammatory responses, or tissue lesions. Conclusion: The novel nanoaggregate microparticles for pulmonary drug delivery could effectively enhance the relative bioavailability of CsA and had great potential for clinical application.

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In this work, feasibility of injection molding was demonstrated for manufacturing capsule shells. 600 µm-thick prototypes were successfully molded with pharmaceutical-grade low-viscosity polyvinyl alcohols (PVAs), possibly added with a range of different fillers. They showed reproducible weight and thickness (CV < 2 and 5, respectively), compliant behavior upon piercing (holes diameter analogous to the reference), tunable release performance (immediate and pulsatile), and moisture protection capability. To assess the latter, an on-line method relying on near infrared spectroscopy measurements was set-up and validated. Based on the data collected and considering the versatility IM would provide for product shape/thickness/composition, PVA-based molded shells could help widening the portfolio of ready-to-use capsules, representing an interesting alternative to those commercially available. Indeed, these capsules could be filled with various formulations, even those with stability issues, and intended either for oral administration or for pulmonary delivery via single-dose dry powder inhalers.

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Pulmonary delivery of drugs has emerged as a promising approach for the treatment of both lung and systemic diseases. Compared to other drug delivery routes, inhalation offers numerous advantages including high targeting, fewer side effects, and a huge surface area for drug absorption. However, the deposition of drugs in the lungs can be limited by lung defence mechanisms such as mucociliary and macrophages' clearance. Among the delivery devices, dry powder inhalers represent the optimal choice due to their stability, ease of use, and absence of propellants. In the last decades, several bottom-up techniques have emerged over traditional milling to produce inhalable powders. Among these techniques, the most employed ones are spray drying, supercritical fluid technology, spray freeze-drying, and thin film freezing. Inhalable dry powders can be constituted by micronized drugs attached to a coarse carrier (e.g., lactose) or drugs embedded into a micro- or nanoparticle. Particulate-based formulations are commonly composed of polymeric micro- and nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, nanocrystals, extracellular vesicles, and inorganic nanoparticles. Moreover, engineered formulations including large porous particles, swellable microparticles, nano-in-microparticles, and effervescent nanoparticles have been developed. Particle engineering has also a crucial role in tuning the physical-chemical properties of both carrier-based and carrier-free inhalable powders. This approach can increase powder flowability, deposition, and targeting by customising particle surface features.

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This section aims to provide a concise and contemporary technical perspective and reference resource covering dry powder inhaler (DPI) formulations. While DPI products are currently the leading inhaled products in terms of sales value, a number of confounding perspectives are presented to illustrate why they are considered surprisingly, and often frustratingly, poorly understood on a fundamental scientific level, and most challenging to design from first principles. At the core of this issue is the immense complexity of fine cohesive powder systems. This review emphasizes that the difficulty of successful DPI product development should not be underestimated and is best achieved with a well-coordinated team who respect the challenges and who work in parallel on device and formulation and with an appreciation of the handling environment faced by the patient. The general different DPI formulation types, which have evolved to address the challenges of aerosolizing fine cohesive drug-containing particles to create consistent and effective DPI products, are described. This section reviews the range of particle engineering processes that may produce micron-sized drug-containing particles and their subsequent assembly as either carrier-based or carrier-free compositions. The creation of such formulations is then discussed in the context of the material, bulk, interfacial and ultimately drug-delivery properties that are considered to affect formulation performance. A brief conclusion then considers the future DPI product choices, notably the issue of technology versus affordability in the evolving inhaler market.

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γ-Cyclodextrin metal-organic frameworks (CD-MOFs) are considered as a green and biocompatible material with great potential in drug delivery systems. Original CD-MOFs show the poor aerosol properties, which limit the application in pulmonary drug delivery. To improve the in vitro deposition properties, herein, we synthesized CD-MOFs by the vapor diffusion method using a series of modulators to achieve better pulmonary delivery of cyclosporine A (CsA). The results showed that blank CD-MOFs and drug loaded CD-MOFs prepared with different modulators all preserved the cubical shape, and exhibited the similar crystal form, structural characteristics, thermal behaviors and release properties. In addition, drug loaded CD-MOFs prepared with polyethylene glycol 10000 (PEG 10000) as a modulator exhibited better in vitro aerosol performance than those of synthesized using other modulators, and the in vivo pharmacokinetics data demonstrated that the bioavailability of CsA could be significantly enhanced by inhalation administration of drug loaded CD-MOFs compared with oral administration of Neoral®. The repeated dose inhalation toxicity also confirmed the fine biocompatibility of CD-MOFs as the carrier for pulmonary drug delivery. Therefore, the results demonstrated CD-MOFs as the promising carrier could be used for pulmonary drug delivery.

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Background: We examined the effect of physical position on peak inspiratory flow (PIF) in patients with chronic obstructive pulmonary disease (COPD) using dry-powder inhalers (DPIs) with low­medium internal resistance (R2) and/or high internal resistance (R5). Methods: This prospective study in stable, ambulatory patients with spirometry-confirmed COPD evaluated the effect of 3 physical positions on maximal PIF achieved. Participants had PIFs of 30-90L/min (R5) or 60-90L/min (R2 DPIs) using the In-Check™ DIAL. PIF was measured in triplicate randomly in 3 positions that patients might be in while using their inhaler (standing, sitting, and semi-upright [supine position with the head of the bed at 45°, neck flexed forward]) against prescribed DPI resistance (R2/R5/both). Correlations between PIF and percentage decline in PIF between positions and differences in participant characteristics with >10% versus ≤10% PIF decline standing to semi-upright were calculated. Results: A total of 76 participants (mean age, 65.2 years) had positional measurements; 59% reported seated DPI use at home. The mean (standard deviation) PIF standing, sitting, and semi-upright was 80.7 (13.4), 77.8 (14.3), and 74.0 (14.5) L/min, respectively, for R2 and 51.1 (9.52), 48.6 (9.84), and 45.8 (7.69) L/min, respectively, for R5 DPIs. PIF semi-upright was significantly lower than sitting and standing (R2; P < 0.0001) and standing (R5; P= 0.002). Approximately half of the participants had >10% decline in PIF from standing to semi-upright. Patient characteristics exceeding the 0.10 absolute standardized difference threshold with the decline in PIF for both the R2 and R5 DPIs were waist-to-hip ratio, modified Medical Research Council dyspnea score, and postbronchodilator percentage predicted forced vital capacity and PIF by spirometry. Conclusions: PIF was significantly affected by physical position regardless of DPI resistance. PIF was highest when standing and lowest when semi-upright. We recommend that patients with COPD stand while using an R2 or R5 DPI. Where unfeasible, the position should be sitting rather than semi-upright. ClinicalTrials.gov identifier NCT04168775.

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In this review, an extensive analysis of dry powder inhalers (DPIs) is offered, focusing on their characteristics, formulation, stability, and manufacturing. The advantages of pulmonary delivery were investigated, as well as the significance of the particle size in drug deposition. The preparation of DPI formulations was also comprehensively explored, including physico-chemical characterization of powders, powder processing techniques, and formulation considerations. In addition to manufacturing procedures, testing methods were also discussed, providing insights into the development and evaluation of DPI formulations. This review also explores the design basics and critical attributes specific to DPIs, highlighting the significance of their optimization to achieve an effective inhalation therapy. Additionally, the morphology and stability of 3 DPI capsules (Spiriva, Braltus, and Onbrez) were investigated, offering valuable insights into the properties of these formulations. Altogether, these findings contribute to a deeper understanding of DPIs and their development, performance, and optimization of inhalation dosage forms.

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Introducción: En Colombia son escasos los datos sobre el uso de los inhaladores en pacientes con EPOC. Objetivo: Describir la técnica de uso de inhaladores de dosis medida y polvo seco en pacientes de un hospital colombiano. Materiales y métodos: Estudio descriptivo en pacientes mayores de 40 años con EPOC atendidos en un hospital en La Virginia, Risaralda, Colombia, entre el 1 de septiembre de 2019 al 31 de enero de 2020. La unidad de análisis fueron los pacientes. Se incluyeron variables sociodemográficas, clínicas y lista de chequeo para uso de inhaladores. Se aplicaron frecuencias y proporciones para variables discretas, estadísticas de tendencia central y dispersión para variables continuas. Resultados: Se incluyeron 104 pacientes con edad media de 73,6 ± 10,1 años; 57 eran mujeres (54,8 %). Además, 48 pacientes estaban clasificados como GOLD-D (46,2 %). Igualmente, 89 pacientes manifestaron haber recibido educación sobre el uso de broncodilatadores (85,6 %). Los más frecuentes fueron los inhaladores de dosis medida (DM) en 95 casos (91,3 %), seguido de los de polvo seco unidosis (7,7 %). Así mismo, 37 pacientes que usaron DM sin inhalocámara (35,6 %) no cumplieron los pasos de la lista de chequeo. En el sistema multidosis, el más realizado fue cerrar de manera adecuada el inhalador y el menos ejecutado, expulsar el aire lentamente evitando hacerlo cerca del inhalador (n = 6; 5,7 %). Discusión: Se lograron describir las características de la técnica de uso de los inhaladores en pacientes con EPOC. A pesar de que ningún paciente logró utilizar el inhalador de forma "perfecta", la mayoría han recibido educación por parte de los profesionales de la salud. Conclusión: Un alto porcentaje de pacientes usa inadecuadamente los dispositivos para suministrar los broncodilatadores. Esto puede impactar negativamente en el control de la enfermedad.

Introduction: In Colombia, there is limited data on the use of inhalers in patients with COPD. Objective: The objective was to describe the technique of using metered-dose inhalers and dry powder in patients in a Colombian hospital. Methods: Observational, descriptive study of patients over 40 years of age with COPD, treated in a hospital in La Virginia, Risaralda, Colombia, between September 1st, 2019 and January 31st, 2020. The unit of analysis were patients in consultation. Sociodemographic and clinical variables, and a checklist for use of inhalers were included. Frequencies and proportions were applied for discrete variables, statistics of central tendency and dispersion for continuous variables. Results: A total of 104 patients with an average age of 73.6 ± 10.1 years were included; 57 were women (54.8%). In addition, 48 patients were classified as GOLD-D (46.2%). Similarly, 89 patients reported having received education on the use of bronchodilators (85.6%). The most common were metered-dose (MD) inhalers in 95 cases (91.3%), followed by single-dose dry powder inhalers in eight patients (7.7%). Likewise, 37 patients who used DM without inhalochamber (35.6%) did not comply with the steps of the checklist. In the multidose system, the most performed was to properly close the inhaler and the least performed was to expel the air slowly, avoiding doing so near the inhaler (n=6; 5.7%). Discussion: The characteristics of the technique of using inhalers in patients with COPD were described. Although no patient was able to use the inhaler "perfectly", most have received education from health professionals. Conclusion: A high percentage of patients misuse the devices to deliver bronchodilators. This can negatively impact the control of the disease.

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BACKGROUND AND OBJECTIVE: Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD). METHOD: Magnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPa0.5minL-1, 0.035 kPa0.5minL-1 and 0.05 kPa0.5 minL-1, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances. RESULT: The results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region. CONCLUSION: Results from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.

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INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder that affects millions of people worldwide and inhalation therapy is central to the symptomatic management of the disease. Therefore, knowledge of the minimum Peak inspiratory flow (PIF) requirements for specific inhalers especially dry powder inhalers (DPI's) is necessary when prescribing inhalation therapy. The purpose of this study is to assess the effect of COPD severity on PIF in patients with COPD. METHODOLOGY: A total of 150 subjects (75 patients with stable COPD, and 75 apparently healthy subjects) participated in the study. PIF was assessed using the In-check Inhaler Assessment Kit (manufactured by Clement Clarke International Ltd, Harlow, UK). Lung function was assessed by spirometry with subjects divided into four groups based on the severity of their airway obstruction using the GOLD criteria. The Modified Medical Research Council (MMRC) dyspnea scale was used to assess dyspnea severity. Exercise capacity was assessed using the 6-minute walk test. Statistical analysis was performed with SPSS 23.0 software. In all the statistical tests, a p value of <0.05 was considered significant. RESULTS: The mean age for the COPD patient and control population are 72.48 ± 8.01 and 70.69 ± 5.82 respectively. The control group had higher PIF than COPD group; however, only the clickhler and pMDI had statistically significant difference between the mean PIF of the patients compared with the control group. Generally, there was an observed trend of a decrease in mean PIF as the COPD stage progresses with a statistically significant difference observed for Easibreathe (F= 3.52, p= 0.019) and pressurized Metered dose inhaler (pMDI) (F= 4.26, p= 0.008). There was a significant positive correlation between FEV1%, FVC, Exercise capacity (6-minute walk distance) and PIF for Clickhaler, Autohaler, Easybreathe and pMDI. For pMDI, there was a statistically significant difference between means of PIF across the MMRC dyspnea scale with PIF decreasing with increasing severity of dyspnea (F= 2.85, p= 0.033). CONCLUSION: COPD patients have slightly lower PIF than controls. Poor exercise tolerance and lower spirometric pulmonary function parameters may contribute to low PIF.

INTRODUCTION: La bronchopneumopathie chronique obstructive (BPCO) est un trouble respiratoire chronique qui touche des millions de personnes dans le monde et la thérapie par inhalation est essentielle à la gestion symptomatique de la maladie. Par conséquent, il est nécessaire de connaître les exigences minimales en matière de débit inspiratoire de pointe (DIP) pour certains inhalateurs, en particulier les inhalateurs de poudre sèche (IPS), lors de la prescription d'un traitement par inhalation. L'objectif de cette étude est d'évaluer l'effet de la gravité de la BPCO sur le débit de pointe inspiratoire chez les patients atteints de BPCO. MÉTHODOLOGIES: Un total de 150 sujets (75 patients atteints de BPCO stable et 75 sujets apparemment sains) ont participé à l'étude. Le PIF a été évalué à l'aide du kit d'évaluation In-check Inhaler (fabriqué par Clement Clarke International Ltd, Harlow, UK). La fonction pulmonaire a été évaluée par spirométrie, les sujets étant répartis en quatre groupes en fonction de la gravité de l'obstruction des voies respiratoires selon les critères GOLD. L'échelle de dyspnée modifiée du Medical Research Council (MMRC) a été utilisée pour évaluer la sévérité de la dyspnée. La capacité d'exercice a été évaluée à l'aide du test de marche de 6 minutes. L'analyse statistique a été réalisée avec le logiciel SPSS 23.0. Dans tous les tests statistiques, une valeur p de <0,05 a été considérée comme significative. RÉSULTATS: L'âge moyen des patients atteints de BPCO et de la population de contrôle est respectivement de 72,48 ± 8,01 et 70,69 ± 5,82. Le groupe de contrôle avait un PIF plus élevé que le groupe BPCO; cependant, seuls le clickhler et le pMDI présentaient une différence statistiquement significative entre le PIF moyen des patients et celui du groupe de contrôle. D'une manière générale, on a observé une tendance à la diminution du FRP moyen au fur et à mesure de l'évolution de la BPCO, avec une différence statistiquement significative pour l'Easibreathe (F= 3,52, p= 0,019) et l'aérosol-doseur pressurisé (pMDI) (F= 4,26, p= 0,008). Il existe une corrélation positive significative entre le VEMS, la CVF, la capacité d'exercice (distance de marche de 6 minutes) et le PIF pour Clickhaler, Autohaler, Easybreathe et pMDI. Pour le pMDI, il y avait une différence statistiquement significative entre les moyennes de PIF sur l'échelle de dyspnée du MMRC, le PIF diminuant avec l'augmentation de la sévérité de la dyspnée (F= 2,85, p= 0,033). CONCLUSION: Les patients atteints de BPCO ont un PIF légèrement inférieur à celui des témoins. Une mauvaise tolérance à l'exercice et des paramètres spirométriques de la fonction pulmonaire plus faibles peuvent contribuer à la faiblesse du PIF. Mots clés: Maladie pulmonaire obstructive chronique, Inhalateurs de poudre sèche, Débit inspiratoire de pointe, Aérosol-doseur pressurisé.

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Fibrosing interstitial lung disease (ILD) is a pathological condition that is highly heterogeneous and lethal, and has few effective treatment choices. Other than pirfenidone and nintedanib for the therapy of idiopathic pulmonary fibrosis, no medications are currently licensed for the treatment of ILD. Luteolin is a common flavonoid with multiple biological effects such as anti-inflammation but with poor solubility and absorption. In this study, we loaded luteolin into γ-cyclodextrin metal-organic frameworks (CD-MOFs) to deliver the medicine to the lungs using dry powder inhalers; in vitro pulmonary deposition results showed LUT@CDMOF had a high fine particle fraction (FPF) (59.77 ± 3.48%). LUT@CDMOF effectively inhibited ILD progression in the BLM-induced fibrosing ILD model rats. When compared to oral administration, the inhalation of LUT@CDMOF dry powder in rats showed considerable improvements in absorption and bioavailability, with a tmax of 0.08 h and a high absolute bioavailability (82%) of LUT (The AUC(0-t) and Cmax of inhal. LUT@CDMOF respectively increased about 4.03 times and 9.11 times, when compared with the i.g. LUT group). These studies demonstrate the potent anti-inflammatory activities of LUT@CDMOF. The inhaled LUT@CDMOF might be considered as a promising new strategy in the treatment of fibrosing ILD.

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In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 µm and 1.94 ± 0.02 µm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 µm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.

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Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with âˆ¼ 50-60% of respirable fraction and fine particle fraction 55-70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance.

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The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

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Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.

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Dry powder inhalers (DPIs) are essential in treating patients with pulmonary diseases. Since DPIs were introduced in the 1960s, a remarkable improvement has been made in their technology, dose delivery, efficiency, reproducibility, stability, and performance based on safety and efficacy. While there are many DPIs on the market and several more under development, it is vital to evaluate the performance of DPIs for effective aerosol drug delivery to patients with respiratory disorders. Their performance evaluation includes the physicochemical properties of the drug powder formulation, metering system, device design, dose preparation, inhalation technique, and patient-device integration. The purpose of this paper is to review current literature evaluating DPIs through in vitro studies, computational fluid models, and in vivo/clinical studies. We will also explain how mobile health applications are used to monitor and evaluate patients' adherence to prescribed medications.

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AIM: Investigate inhalation techniques using different inhalers types and their effect on the course of disease. MATERIALS AND METHODS: This cross-sectional study included 110 patients with asthma, chronic obstructive pulmonary disease using the inhaler at least one month. Inhaler errors performed during demonstration were evaluated for each patient and entered in the check-lists. We also collected information about co-morbidities, education, mMRC dyspnea score, rate of exacerbations, and performed spirometry. RESULTS: 80.9% of patients used metered-dose inhaler, 20.9% - single-dose and 21.8% - multiple-dose dry powder inhaler, 22.7% - soft-mist inhaler. Inhaler errors were made by 80.9% patients. The mean number of mistakes in metered-dose inhaler use was 2±1.6, single-dose powder inhaler -1.5±1.3, multiple-dose dry powder inhaler - 1.25±1.4, soft-mist inhaler - 0.68±0.7 (р=0.003). Age, diagnosis, duration of disease, education level, inhalers usage by relatives have no influence on the inhalation technique. A number of errors was related to female gender (р=0.007) and usage of more than 2 inhalers (r=0.3, p=0.002), previous instruction about inhalation technique (r=0.3, p=0.001). On the other hand, there were correlations between the number of errors and degree of bronchial obstruction, asthma control, severity of dyspnea by mMRC score, exacerbation rate. CONCLUSION: Patients with bronchoobstructive diseases perform many inhaler errors, that substantially influences the severity and course of asthma and chronic obstructive pulmonary disease.

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