Development of a self-microemulsifying drug delivery system to deliver delamanid via a pressurized metered dose inhaler for treatment of multi-drug resistant pulmonary tuberculosis.

Tuberculosis (TB) is a serious health issue that contributes to millions of deaths throughout the world and increases the threat of serious pulmonary infections in patients with respiratory illness. Delamanid is a novel drug approved in 2014 to deal with multi-drug resistant TB (MDR-TB). Despite its high efficiency in TB treatment, delamanid poses delivery challenges due to poor water solubility leading to inadequate absorption upon oral administration. This study involves the development of novel formulation-based pressurized metered dose inhalers (pMDIs) containing self-microemulsifying mixtures of delamanid for efficient delivery to the lungs. To identify the appropriate self-microemulsifying formulations, ternary diagrams were plotted using different combinations of surfactant to co-surfactant ratios (1:1, 2:1, and 3:1). The combinations used Cremophor RH40, Poly Ethylene Glycol 400 (PEG 400), and peppermint oil, and those that showed the maximum microemulsion region and rapid and stable emulsification were selected for further characterization. The diluted self-microemulsifying mixtures underwent evaluation of dose uniformity, droplet size, zeta potential, and transmission electron microscopy. The selected formulations exhibited uniform delivery of the dose throughout the canister life, along with droplet sizes and zeta potentials that ranged from 24.74 to 88.99 nm and - 19.27 to - 10.00 mV, respectively. The aerosol performance of each self-microemulsifying drug delivery system (SMEDDS)-pMDI was assessed using the Next Generation Impactor, which indicated their capability to deliver the drug to the deeper areas of the lungs. In vitro cytotoxicity testing on A549 and NCI-H358 cells revealed no significant signs of toxicity up to a concentration of 1.56 µg/mL. The antimycobacterial activity of the formulations was evaluated against Mycobacterium bovis using flow cytometry analysis, which showed complete inhibition by day 5 with a minimum bactericidal concentration of 0.313 µg/mL. Moreover, the cellular uptake studies showed efficient delivery of the formulations inside macrophage cells, which indicated the potential for intracellular antimycobacterial activity. These findings demonstrated the potential of the Delamanid-SMEDDS-pMDI for efficient pulmonary delivery of delamanid to improve its effectiveness in the treatment of multi-drug resistant pulmonary TB.

Application of different counseling strategies for better adult asthma control.

OBJECTIVE: We aimed to compare the effectiveness of three distinct counseling methods to determine the most effective approach. METHODS: In this prospective cohort study with a two-month follow-up, A group of non-smoking adults, aged 19-60 years, were randomly collected at outpatients clinic with prior asthma diagnosis, based on the forced expiratory volume in one seconds to forced vital capacity ratio (FEV1/FVC) and the guidelines outlined by the Global Initiative for Asthma (GINA), At the baseline assessment, all patients, underwent FEV1/FVC measurements, asthma symptom evaluations using Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), and GINA symptoms control assessment questionnaire, and assessment of pressurized metered-dose inhaler (pMDI) usage. The patients were divided into three groups, each assigned a distinct counseling strategy: traditional verbal counseling, advanced counseling utilizing the Asthma smartphone-application, and a combination of advanced-verbal counseling. We conducted a two-month monitoring period for all three groups. RESULTS: Significant differences (p < .001) were observed among the three counseling groups in ACT, FEV1/FVC ratio, and GINA symptoms control assessment scores from the first month to the second month visit. Regarding ACQ, the study unveiled a noteworthy disparity in ACQ scores during the second week, with a significant difference (p = .025) observed between the verbal and advanced-verbal counseling groups. Similarly, a significant difference (p = .016) was noted between the advanced counseling group and the advanced-verbal counseling groups. CONCLUSION: The study findings indicate that the combining advanced-verbal counseling by incorporating the Asthma smartphone-application alongside traditional verbal counseling is a more effective approach for improving asthma control in adults.

Canister valve and actuator deposition in metered dose inhalers formulated with low-GWP propellants.

A challenge in pressurised metered-dose inhaler (pMDI) formulation design is management of adhesion of the drug to the canister wall, valve and actuator internal components and surfaces. Wall-material interactions differ between transparent vials used for visual inspection and metal canister pMDI systems. This is of particular concern for low greenhouse warming potential (GWP) formulations where propellant chemistry and solubility with many drugs are not well understood. In this study, we demonstrate a novel application of X-ray fluorescence spectroscopy using synchrotron radiation to assay the contents of surrogate solution and suspension pMDI formulations of potassium iodide and barium sulphate in propellants HFA134a, HFA152a and HFO1234ze(E) using aluminium canisters and standard components. Preliminary results indicate that through unit life drug distribution in the canister valve closure region and actuator can vary significantly with new propellants. For solution formulations HFO1234ze(E) propellant shows the greatest increase in local deposition inside the canister valve closure region as compared to HFA134a and HFA152a, with correspondingly reduced actuator deposition. This is likely driven by chemistry changes. For suspension formulations HFA152a shows the greatest differences, due to its low specific gravity. These changes must be taken into consideration in the development of products utilising low-GWP propellants.

Uncapped Metered-Dose Inhalers: A Risk for Foreign Body Aspiration. A Case Report and Review of the Literature.

The risk of foreign body aspiration associated with uncapped handheld metered-dose inhalers (MDIs) is underestimated. We report a case in which a plastic cable clip accidentally lodged in the mouthpiece of an uncapped pressurized MDI was aspirated during its use. A literature search revealed 16 other cases of foreign body aspiration associated with uncapped handheld inhalers, all but one of which were pressurized inhalers. Patients should be informed of the risk of foreign body aspiration associated with uncapped pocket inhalers. The use of an uncuffed armoured tracheal tube with a separate oxygen tubing during flexible bronchoscopy for foreign body removal ensures a safe airway. Foreign bodies that exceed the lumen size of the tracheal tube can be pulled to the distal opening with forceps and removed when the tube is withdrawn.

Evaluación e impacto de la educación de la técnica inhalatoria en pacientes adultos que usan inhalador de dosis medida / Evaluation and Impact of Education on the Inhalation Technique in Adults who Use a Metered Dose Inhaler

Introducción: los inhaladores de dosis medida (MDI) ocupan un lugar fundamental en el tratamiento de las enfermedades obstructivas. Sin embargo, existe evidencia de su in-correcta utilización y, por consiguiente, limitados beneficios. El objetivo de este traba-jo es evaluar el uso de los MDI y conocer el impacto que tiene la educación en la técnica inhalatoria. Método: estudio prospectivo, antes-después realizado en pacientes hos-pitalizados y ambulatorios. Se registraron datos demográficos y sobre el uso del MDI. Posteriormente, se pidió al paciente que realizara dos inhalaciones con su MDI y aero-cámara, se otorgó un puntaje según la escala ESTI y se educó en forma oral, visual y con folleto explicativo. Los pacientes fueron reevaluados antes de cumplir un mes de la primera evaluación. Resultados: se incluyeron 119 pacientes, 53,8% masculinos, con edad media de 60,6 (± 16) años. El 60,5% utilizaba aerocámara siempre y el 19,3% casi siempre. El 65% tenía la percepción de que su técnica inhalatoria era buena o muy bue-na. El 32% no sabía identificar su inhalador de rescate. El puntaje en la escala ESTI ba-sal fue de 6,8 (± 2,3) ptos. el que mejoró en la reevaluación, 8,7 (± 1,5) ptos.; p<0,0001. La técnica inhalatoria calificada de muy buena o buena mejoró de un 24,4% a un 63%; p<0.0001. Conclusión: nuestros resultados muestran que la técnica de inhalación con MDI es deficiente y una educación activa evidencia un impacto significativo en el co-rrecto uso de estos dispositivos. (AU)

Introduction: metered dose inhalers (MDI) are fundamental in treating obstructive dis-eases. However, there is evidence of its incorrect use and therefore limited benefits. This work aims to evaluate the use of MDIs and to know the impact of education on the cor-rect inhalation technique. Method: prospective, before-after study, carried out in hospitalized and outpatients. Demographic data and data on the use of the MDI are re-corded. Subsequently, the patient was asked to take 2 inhalations with his MDI and valved-holding chamber, a score was given according to the ESTI score and he was ed-ucated orally, visually, and with an explanatory brochure. The patients were reassessed within 1 month of the first evaluation. Results: 119 patients were included, 53.8% male, with a mean age of 60.6 (±16) years. 60.5% always used an aero chamber and 19.3% almost always. 65% had the perception that their inhalation technique was good or very good. 32% did not know how to identify their rescue inhaler. The score on the base-line ESTI scale was 6.8 (± 2.3) points, which improved in the reassessment, 8.7 (± 1.5) points; p<0.0001. The inhalation technique rated as very good or good improved from 24.4% to 63%; p<0.0001. Conclusion: our results show that the inhalation technique with MDI is deficient and active education demonstrates a significant impact on the cor-rect use of these devices. (AU)

Assessing of low-tech solutions for aerosol delivery: Comparative performance study of manufactured versus homemade spacers.

PURPOSE: This study aims to evaluate the performance of low-cost homemade spacers compared with manufactured valved holding chambers (VHCs) for fluticasone propionate delivery via a pMDI (pressurized Metered Dose Inhaler). METHODS: The Total Emitted Dose (TED) and particle size distribution were measured for pMDI alone or connected to the different spacers, according to CAN/CSA-Z264.1-02 standard. Two types of low-cost alternative and manufactured spacers were investigated: 500 mL plastic bottle and 553 mL aluminium can; non-antistatic plastic VHCs and aluminium antistatic VHCs. RESULTS: The TED of homemade plastic bottle vs plastic VHC were similar in the 20-23% range. In contrast, the TED of homemade aluminium can was higher compared to aluminium VHC (83% vs 68%). The Fine Particle Fraction (FPF) was similar for the two plastic-based spacers (in the 12.68-17.60% range), although it was greater for the aluminium can compared to aluminium VHC (51% vs 42%). However, all spacers have limited large particles fraction, mainly deposited in the oropharyngeal tract, potentially decreasing side effects. CONCLUSION: We demonstrated that low-tech solutions as homemade spacers have at least similar performances to VHC medical devices composed of same material (aluminium or plastic). Thus, low-cost homemade spacers represent alternatives in case of emergency and without VHCs nearby.

[Endobronchial Foreign Bodies Telling Readable Stories]. / Endobronchiale Fremdkörper, die lesbare Geschichten erzählen.

We present two case reports in which, in a surprising way, readable writing or numbers on the aspirated material provided useful information about the more detailed circumstances of the aspiration.In the first case, the patient complained of foreign body sensation after using a metered dose inhaler. A few hours later, the initially unknown aspirated material was recovered by flexible bronchoscopy. With the help of the text fragment on the material, it could be concluded that it was the packaging foil of a candy, which had entered the mouthpiece of the metered dose inhaler while stored in the patient's jacket pocket.In the second case, the patient experienced recurrent pneumonia over a period of years. With the help of the serial number on the bronchoscopically recovered plastic material, the exact time and place of aspiration could be determined. The patient had aspirated the plastic label of a spare part during his occupational activity in a car repair shop.

Assessment of vaping devices as an alternative respiratory drug delivery system.

The respiratory system has generated significant interest as an alternative drug delivery route. However, because of the limitations encountered with the present inhalation devices, alternative options could present an ideal opportunity to enhance therapeutic effectiveness and patient compliance. Vaping devices have been extensively used to deliver nicotine. This manuscript aimed to conduct an in vitro evaluation of the performance of commonly used vaping devices to assess their effectiveness in delivering fluticasone propionate (FP) to the lungs. Vaping devices were assessed for aerodynamic performance using the NGI. The e-liquid containing FP was made using glycerin and propylene glycol. The results showed the superiority of the vape-tank and vape-coil over the vape-pod. The vape-tank delivered the highest amount of nicotine. The e-liquid containing the FP was assessed and the results were compared with a marketed FP pressurized metered-dose inhaler (pMDI). The results of the respirable dose (RD) ranged from 22.10 µg for the vape pod, to 50.38 µg for the vape-tank; whereas the marketed pMDI value was 44.54 µg despite the lower content of FP per actuation in the vaping devices (100 µg versus 125 µg). Interestingly, the vaping devices showed a significantly lower level of oropharyngeal deposition than the pMDI (10% versus 50%), and hence, the potential for fewer side effects than those encountered with the chronic use of inhalers. Despite the effectiveness of the vape tank and coil in delivering a high percentage of FP, which makes them a promising alternative for delivering an effective yet user-friendly dosage of respiratory drugs, their safety and toxicity need to be established.

Nanotechnology-Assisted Metered-Dose Inhalers (MDIs) for High-Performance Pulmonary Drug Delivery Applications.

PURPOSE: Respiratory disorders pose a major threat to the morbidity and mortality to public health. Here we reviewed the nanotechnology based pulmonary drug delivery using metered dose inhalers. METHODS: Major respiratory diseases such as chronic obstructive pulmonary diseases (COPD), asthma, acute lower respiratory tract infections, tuberculosis (TB) and lung cancer. At present, common treatments for respiratory disorders include surgery, radiation, immunotherapy, and chemotherapy or a combination. The major challenge is development of systemic delivery of the chemotherapeutic agents to the respiratory system. Conventional delivery of chemotherapy has various limitation and adverse side effected. Hence, targeted, and systemic delivery need to be developed. Towards this direction nanotechnology, based controlled, targeted, and systemic drug delivery systems are potential candidate to enhance therapeutic efficacy with minimum side effect. Among different route of administration, pulmonary delivery has unique benefits such as circumvents first pass hepatic metabolism and reduces dose and side effects. RESULTS: Respiratory disorders pose a major threat to the morbidity and mortality to public health globally. Pulmonary delivery can be achieved through various drug delivery devices such as nebulizers, dry powder inhalers, and metered dose inhalers. Among them, metered dose inhalers are the most interesting and first choice of clinician over others. This review focused on nanotechnology based pulmonary drug delivery using metered dose inhalers. This report focused on delivery of various types of therapeutics using nanocarriers such as polymeric nanoparticles and micelles, dendrimers, lipid nanocarriers such as liposomes, solid lipid nanostructures and nanostructured lipid carriers, and other using metered dose inhalers discussed comprehensively. This report provides insight about the effect of parameters of MDI such as co-solvent, propellants, actuators shape, nozzle diameters, and jet lengths, and respiratory flow rate, and particle size of co-suspension of drug on aerodynamics and lung deposition of formulation. This review also provided the insight about various metered dose inhalers market scenario and digital metered dose inhalers. CONCLUSION: This report concluded the clinical potential of metered dose inhalers, summary of current progress and future perspectives towards the smart digital metered dose inhalers development.

[Reduction of greenhouse gas emissions by inhaler choice in the therapy of asthma and COPD patients]. / Reduktion klimaschädlicher Treibhausgase durch Auswahl der Inhalatoren in der Therapie von Patienten mit Asthma und COPD.

BACKGROUND: The global warming potential of inhaled medication depends on the applied inhaler. Pressurised metered dose inhalers (pMDI) contain green-house gases (GHG) and are associated with a 10 to 40 times higher CO2-footprint than GHG-free dry-powder inhalers (DPI). AIM: Feasibility and relevance of prescription conversion from pMDI to DPI were investigated in a pulmonology outpatient clinic regarding the CO2-footprint and the economic costs under real-world conditions. METHODS: Based on exemplary therapy regimens of different intensity for three patients, the annual CO2-footprint and daily therapy costs were investigated. The effect of converting from pMDI to DPI on CO2-footprint and economic costs were calculated on the basis of prescriptions during the first quarter of 2020 compared to the first quarter of 2021. RESULTS: Conversion of a pMDI-based inhalative therapy of exemplary asthma and COPD patients to a DPI-based therapy saved between 115 and 480 kg CO2 equivalents (CO2e) per year and patient depending on intensity of therapy and GHG used. A total of 184,297 and 164,165 defined daily doses (DDD) were prescribed by the clinic for 2,610 (January-March 2020) and 2,693 (January-March 2021) patients, respectively. The proportion of DPI prescribed increased from 49 to 78% of total inhaler prescriptions. The increase in prescriptions for single-agent inhaled corticosteroids from 19.8 to 74.1% of total inhaler prescriptions was particularly striking. Due to the conversion, emissions were reduced by 35,000 to 40,000 kg CO2e between January-March 2020 and January-March 2021 in our clinic. During the same period, there was no increase in costs compared to nationwide costs. The relation of prescribed DPI and pMDI in the same period did not change among the pulmonologists in Saxony nor nationwide in Germany. If all ambulant pulmonologists in Germany would prescribe 75% DPI, CO2-emissions could be reduced by 11,650 tonnes CO2e per quarter and 46,600 tonnes CO2e per year, respectively. CONCLUSION: The type of inhalers can be converted from pMDI to DPI in a real-world setting. Thereby, a significant reduction of GHG emissions is possible without increased costs.

Prevalence of chronic respiratory diseases and medication use among children and adolescents in Brazil - a population based cross-sectional study / Prevalência de doenças respiratórias crônicas e uso de medicamentos entre crianças e adolescentes no Brasil - um estudo transversal de base populacional

Abstract Objectives: to describe the prevalence of chronic respiratory diseases and their pharmacological management in children and adolescents in Brazil. Methods: data from the Pesquisa Nacional de Acesso, Uso e Promoção do Uso Racional de Medicamentos no Brasil (PNAUM)(National Access Survey, Use and Promotion of Rational Use of Medicines in Brazil),a population-based cross-sectional study, were analyzed. Household surveys were conducted between September 2013 and February 2014. We included the population under 20 years of age with chronic respiratory diseases. Prevalence of disease, indication of pharmacological treatment, and their use were assessed. Results: the prevalence of chronic respiratory diseases in children aged less than 6 years old was 6.1% (CI95%= 5.0-7.4), 4.7% (CI95%= 3.4-6.4) in those 6-12 years, and 3.9% (CI95%= 2.8-5.4) in children 13 years and older. Children under 6 showed a higher prevalence of pharmacological treatment indication (74.6%; CI95%= 66.0-81.7), as well as medication use (72.6%; CI95%= 62.8-80.7). Of those using inhalers, 56.6% reported using it with a spacer. The most frequent pharmacologic classes reported were short-acting β2 agonists (19.0%), followed by antihistamines (17.2%). Conclusion: children and adolescents who report chronic respiratory diseases living in urban areas in Brazil seem to be undertreated for their chronic conditions. Pharmacological treatment, even if indicated, was not used, an important finding for decision-making in this population.

Resumo Objetivos: descrever a prevalência de doenças respiratórias crônicas e seu manejo farmacológico em crianças e adolescentes no Brasil. Métodos: foram analisados os dados da Pesquisa Nacional de Acesso, Uso e Promoção do Uso Racional de Medicamentos no Brasil (PNAUM), um estudo transversal de base populacional. As pesquisas domiciliares foram realizadas entre setembro de 2013 e fevereiro de 2014. Incluímos a população com menos de 20 anos de idade com doenças respiratórias crônicas. Foi avaliada a prevalência de doença, indicação de tratamento farmacológico e seu uso. Resultados: a prevalência de doenças respiratórias crônicas em menores de 6 anos foi de 6,1% (IC95%= 5,0-7,4), 4,7% (IC95%= 3,4-6,4) naqueles 6-12 anos e 3,9% (IC95%= 2,8-5,4) em crianças com 13 anos ou mais. Crianças menores de 6 anos apresentaram uma maior prevalência de indicação de tratamento farmacológico (74,6%; IC95%= 66,0-81,7), assim como uso de medicamentos (72,6%; IC95%= 62,8-80,7). Dos usuários de inaladores, 56,6% relataram o uso com espaçador. As classes farmacológicas mais frequentemente relatadas foram β2 agonistas de curta ação (19,0%), seguidos por anti-histamínicos (17,2%). Conclusão: crianças e adolescentes que relatam doenças respiratórias crônicas residentes em áreas urbanas no Brasil parecem ser subtratados para suas condições crônicas. O tratamento farmacológico, mesmo quando indicado, não foi utilizado em sua totalidade, um achado importante para a tomada de decisão nessa população.

Comparison of Sinus Deposition from an Aqueous Nasal Spray and Pressurised MDI in a Post-Endoscopic Sinus Surgery Nasal Replica.

BACKGROUND: Optimising intranasal distribution and retention of topical therapy is essential for effectively managing patients with chronic rhinosinusitis, including those that have had functional endoscopic sinus surgery (FESS). This study presents a new technique for quantifying in vitro experiments of fluticasone propionate deposition within the sinuses of a 3D-printed model from a post-FESS patient. METHODS: Circular filter papers were placed on the sinus surfaces of the model. Deposition of fluticasone on the filter paper was quantified using high-performance liquid chromatography (HPLC) assay-based techniques. The deposition patterns of two nasal drug delivery devices, an aqueous nasal spray (Flixonase) and metered dose inhaler (Flixotide), were compared. The effects of airflow (0 L/min vs. 12 L/min) and administration angle (30° vs. and 45°) were evaluated. RESULTS: Inhaled airflow made little difference to sinus deposition for either device. A 45° administration angle improved frontal sinus deposition with the nasal spray and both ethmoidal and sphenoidal deposition with the inhaler. The inhaler provided significantly better deposition within the ethmoid sinuses (8.5x) and within the maxillary sinuses (3.9x) compared with the nasal spray under the same conditions. CONCLUSION: In the post-FESS model analysed, the inhaler produced better sinus deposition overall compared with the nasal spray. The techniques described can be used and adapted for in vitro performance testing of different drug formulations and intranasal devices under different experimental conditions. They can also help validate computational fluid dynamics modelling and in vivo studies.

Secondary asthma prevention measures are not adequately addressed prior to emergency department discharge!

BACKGROUND: Exacerbations of acute asthma are frequent presentations to the Emergency Department (ED) and contribute to ED overcrowding and healthcare cost. The purpose of this study was to evaluate whether ED clinicians are implementing secondary asthma prevention measures prior to discharging patients after an acute asthma exacerbation and also to determine whether ED clinicians are able to correctly demonstrate how to use an asthma metered dose inhaler (MDI) device. METHODS: Consenting doctors employed at four EDs situated in the Gauteng province of South Africa were asked to complete a questionnaire and thereafter demonstrate the technique of using an MDI device. Collected data was presented using descriptive statistics. RESULTS: Eighty-six doctors were included in the study. Of these, 18 (20.9%) routinely checked that inhaler technique was correct, 50 (58.1%) routinely enquired regarding adherence to their asthma treatment, 8 (9.3%) routinely informed patients of the side effects of asthma medication, 16 (18.6%) routinely provided patients with a written asthma action plan, 7 (8.1%) routinely evaluated for the presence of concurrent allergic rhinitis and 53 (61.6%) routinely counselled patients regarding smoking cessation. With regards to correctly demonstrating how to use an MDI device, only 23 (26.74%) physician participants performed all eight steps correctly. CONCLUSION: This study indicates that secondary asthma prevention measures are not adequately addressed by clinicians prior to discharging patients from the ED after an acute asthma attack. It is recommended that ED clinicians are educated with regards to the importance of these measures.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts.

BACKGROUND: In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. METHODS: KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 µg, GFF 14.4/10 µg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 µg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 µg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12-24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. RESULTS: Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. CONCLUSIONS: In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001.

Dose-Ranging and Cumulative Dose Studies of Albuterol Sulfate MDI in Co-Suspension Delivery™ Technology (AS MDI; PT007) in Patients with Asthma: the ASPEN and ANTORA Trials.

BACKGROUND AND OBJECTIVES: Co-suspension Delivery™ Technology has been developed for the administration of albuterol sulfate pressurised inhalation suspension via metered-dose inhaler (AS MDI, PT007). We assessed the efficacy and safety of AS MDI versus Proventil® in order to determine the optimal dose of AS MDI to take to Phase III clinical trials. METHODS: ASPEN (NCT03371459) and ANTORA (NCT03364608) were Phase II, randomised, crossover, multicentre studies of AS MDI versus Proventil® in patients with persistent asthma. In ASPEN, 46 patients received cumulative-dose treatments (90 µg/inhalation using 1 + 1 + 2 + 4 + 8 inhalations at 30-minute intervals) in 1 of 2 possible sequences: AS MDI/Proventil or Proventil/AS MDI. In ANTORA, 86 patients were randomised to one of 10 treatment sequences of AS MDI (90 µg or 180 µg), placebo MDI, or Proventil (90 µg or 180 µg). The primary endpoints were baseline-adjusted forced expiratory volume in 1 second (FEV1) 30 minutes after each cumulative dose (ASPEN) and change from baseline in FEV1 area under the curve from 0 to 6 h (ANTORA). Safety was assessed in both studies. RESULTS: In ASPEN, AS MDI was equivalent to Proventil (within pre-specified bounds of ± 200 mL) following cumulative doses of albuterol up to 1440 µg for the primary endpoint. In ANTORA, 90 µg and 180 µg doses of AS MDI and Proventil were significantly superior to placebo MDI (p < 0.0001), and AS MDI was non-inferior to Proventil at both doses, based on a margin of 100 mL. No new safety concerns were identified. CONCLUSION: The effects of albuterol delivered via AS MDI and Proventil on bronchodilation were equivalent, supporting the selection of AS MDI 180 µg to be taken into Phase III clinical trials, either alone or in combination with an inhaled corticosteroid. TRIAL REGISTRATION NUMBER: ASPEN (NCT03371459); Date of registration: 29/12/2017. ANTORA (NCT03364608); Date of registration: 15/12/2017.

The Impact of Budesonide/Formoterol pMDI Medication Reminders on Adherence in Chronic Obstructive Pulmonary Disease (COPD) Patients: Results of a Randomized, Phase 4, Clinical Study.

PURPOSE: Among patients with chronic obstructive pulmonary disease (COPD), adherence to inhaled medication leads to fewer exacerbations and improved health status. The goal of the present study was to evaluate the effects of medication reminders via the BreatheMate device on adherence in patients with COPD. PATIENTS AND METHODS: A 6-month, phase 4, randomized, multicenter, open-label US study (NCT02864342) enrolled 138 patients aged ≥40 years with moderate to very severe COPD and ≥10 pack-year smoking history. Patients in the intervention (n = 68) and control (n = 70) groups received the BreatheMate device, smartphone application, and vouchers to redeem pressurized metered-dose inhalers (pMDIs) for the prescribed 2 puffs of budesonide/formoterol 160/4.5 µg twice daily. The intervention group also received twice-daily electronic reminders to take budesonide/formoterol. The primary endpoint was the mean number of sets of adherent puffs/day (4 puffs: 2 puffs within 60 minutes, twice daily) over 6 months. Secondary endpoints included adherence by three 60-day intervals, usage days, prescription refills, and Clinical COPD Questionnaire (CCQ) score. Study enrollment terminated early due to issues with inconsistent syncing. RESULTS: A higher mean proportion of adherent days (77.6% vs 60.2%; P <0.001) and sets of adherent puffs/day (1.61 vs 1.33; P <0.001) were recorded for the intervention group versus the control group. Intervention group adherence was higher than that of the control group for each 60-day interval (P <0.001); the intervention group was 3.07 (95% confidence interval: 1.49-6.52) times more likely than the control group to be adherent for ≥80% of study days. Overuse (>2 sets of 2 puffs/day), underuse (<2 sets of 2 puffs/day), and no use days were lower in the intervention group versus control (P <0.05). Patients aged ≥65 years had higher adherence (P <0.001). CONCLUSION: Medication reminders through the BreatheMate device and application produced greater adherence to inhaled therapy in patients with COPD.

Device use errors among patients with asthma and COPD and the role of training: a real-life study.

Background and objectives: Administration of inhaled medication for asthma and COPD is often difficult and incorrect device use is associated with unfavorable outcomes. We aimed to evaluate device use errors in asthma and COPD patients and to associate incorrect use with the patient's characteristics and medical history.Methods: Demographics and medical history were recorded. The use of each prescribed device was evaluated according to predefined steps.Results: 607 patients (49.9% male, median age (IQR) 63 (51, 70) years performed 663 demonstrations (56 patients were using 2 different types of devices). 51.4% were treated for asthma and 48.6% for COPD. 79.6% of demonstrations were performed using DPIs. Errors were documented on 41.2% of demonstrations and were associated with the type of device, p < 0.001. Elderly patients were less frequently using their devices correctly compared to younger patients, 50.8% vs 62.2%, respectively, p = 0.007. Correct demonstrations were more among asthmatics compared to COPD patients 63.1% vs 54.5%, p = 0.024. Incorrect use was associated with more acute exacerbations in the preceding year [median(IQR), 1(0, 2) vs 1(0, 1)], for incorrect and correct use, respectively, p < 0.001. Upon demonstration, 15.5% of patients have never been trained (i.e., undergone actual demonstrations and observation while using their device) by anyone. Errors occurred more frequently among patients who reported not to be trained compared to those who were trained, 67.0% vs 14.6%, respectively, p < 0.001. The commonest error was associated with the inspiration maneuver and accounted for the 48.3% of errors in the DPIs and 53.0% of errors in the MDIs.Conclusion: Device use errors are common and associated with unfavorable outcomes. Trained patients were more likely to use the device correctly.

Development and in vitro characterization of a novel pMDI diclofenac formulation as an inhalable anti-inflammatory therapy for cystic fibrosis.

Anti-inflammatory treatment options for cystic fibrosis (CF) patients are currently limited and as such, there is an imperative need to develop new anti-inflammatory agents to reduce the persistent inflammation present within CF lungs. This study explored the potential of Diclofenac (DICLO) as a novel inhaled anti-inflammatory drug for CF treatment. The anti-inflammatory activity of DICLO on an air-liquid interface (ALI) cell culture model of healthy (NuLi-1) and CF (CuFi-1) airways showed a significant reduction in the secretion of pro-inflammatory cytokines, IL-6 and IL-8. Therefore, pressurized metered dose inhaler (pMDI) DICLO formulations were developed to allow targeted DICLO delivery to CF airways. As such, two pMDI DICLO formulations with varying ethanol concentrations: 5% (w/w) equating to 150 µg of DICLO per dose (Low dose), and 15% (w/w) equating to 430 µg of DICLO per dose (High dose) were developed and characterized to determine the optimum formulation. The Low dose pMDI DICLO formulation showed a significantly smaller particle diameter with uniform distribution resulting in a greater aerosol performance when compared to High dose formulation. Consequently, the Low dose pMDI DICLO formulation was further evaluated in terms of in vitro transport characteristics and anti-inflammatory activity. Importantly, the DICLO pMDI displayed anti-inflammatory activity in both healthy and CF in vitro models, highlighting the potential of an aerosolized low-dose DICLO formulation as a promising inhaled anti-inflammatory therapy for CF treatment.