Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.

Characteristics of initiators of budesonide/glycopyrrolate/formoterol for treatment of chronic obstructive pulmonary disease (COPD) in the United States: the AURA study.

INTRODUCTION: A twice-daily single inhaler triple therapy consisting of budesonide/glycopyrrolate/formoterol fumarate (BGF) was approved by the US Food and Drug Administration (FDA) in July 2020 as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The objective of this AURA study is to describe patient characteristics, exacerbation and treatment history, and healthcare resource utilization (HCRU) before BGF initiation to better inform treatment decisions for prescribers. METHODS: This retrospective cohort study leveraged data of all payer types from IQVIA's Longitudinal Prescription Data (LRx) linked to Medical Data (Dx). Patients with COPD who had ⩾1 LRx claim for BGF between 1 October 2020 and 30 September 2021 were included. The date of first BGF claim was the index date. Patient demographic and clinical characteristics, history of COPD exacerbation or related event, treatment history, and HCRU were assessed during the 12 months before index (baseline). RESULTS: We identified 30,339 patients with COPD initiating BGF (mean age: 68.2 years; 57.1% female; 67.6% Medicare). Unspecified COPD (J44.9; 74.0%) was the most commonly coded COPD phenotype. The most prevalent respiratory conditions/symptoms were dyspnea (50.8%), lower respiratory tract infection (25.3%), and sleep apnea (19.0%). Uncomplicated hypertension (58.8%), dyslipidemia (43.9%), cardiovascular disease (41.4%), and heart failure (19.9%) were the most prevalent nonrespiratory conditions. During the 12-month baseline, 57.9% of patients had evidence of a COPD exacerbation or related event, and 14.9% had ⩾1 COPD-related emergency department (ED) visit; 21.0% of patients had evidence of prior triple therapy use, while 54.3% had ⩾1 oral corticosteroid (OCS) fill. Among OCS users, 29.9% had cumulative exposures >1000 mg [median [Q1-Q3] exposure: 520 (260-1183) mg]. CONCLUSION: This real-world data analysis indicates that BGF is being initiated in patients with COPD experiencing symptoms and exacerbations despite current therapy, and among patients who have various chronic comorbidities, most often cardiopulmonary-related.

Cognitive impairment according to Montreal Cognitive Assessment independently predicts the ability of chronic obstructive pulmonary disease patients to maintain proper inhaler technique.

BACKGROUND: Maintaining correct inhaler technique is crucial in the management of chronic obstructive pulmonary disease (COPD). We aimed to investigate the inhaler technique in patients with COPD, to compare it immediately after and at 1 month after training, and to identify the predictors of incorrect inhaler use at 1 month after training. METHODS: This prospective study was conducted at the COPD clinic of Siriraj Hospital (Bangkok, Thailand). Patients demonstrating improper inhaler use were trained face-to-face by pharmacists. Inhaler technique was re-assessed immediately after and at 1 month after training. The Montreal Cognitive Assessment (MoCA) score, pulmonary function tests, 6-min walk distance (6 MWD), modified Medical Research Council scale score, and COPD Assessment Test (CAT) score were evaluated. RESULTS: Sixty-six patients with COPD who demonstrated at least one critical error during the use of any controller inhaler were enrolled. The mean age was 73.0 ± 9.0 years, and 75.8% patients had moderate/severe COPD. Immediately after training, all patients used dry powder inhalers correctly and 88.1% used pressurized metered-dose inhalers correctly. At 1 month, the number of patients demonstrating the correct technique decreased across all devices. Multivariable analysis revealed that MoCA score ≤ 16 was independently associated with a critical error at 1 month after training (adjusted odds ratio: 12.7, 95% confidence interval: 1.8-88.2, p = 0.010). At 1 month, CAT score (11.4 ± 8.9 vs. 8.4 ± 5.5, p = 0.018) and 6 MWD (351 ± 93 m vs. 372 ± 92 m, p = 0.009) had significantly improved in patients demonstrating the correct technique, and CAT score met the minimal clinically important difference. CONCLUSIONS: Face-to-face training by pharmacists improved patient performance. However, the number of patients following proper technique had decreased at 1 month after training. Cognitive impairment (MoCA score ≤ 16) independently predicted the ability of COPD patients to maintain proper inhaler technique. Assessment of cognitive function combined with technical re-assessment and repeated training should improve COPD management.

Assessment and management of asthma exacerbations in an emergency department unit.

BACKGROUND: The Pediatric Respiratory Assessment Measure (PRAM) score is a useful tool for the assessment of asthma exacerbations in children. This study aimed to estimate the risk of hospitalization in children, assessed with the PRAM score and having mild-moderate asthma exacerbation, who were treated with salbutamol delivered via a metered-dose inhaler and spacer (MDI/S). METHODS: The study population consisted of children aged 3-16 years with mild-moderate asthma exacerbations. All children received 1mg/kg prednisolone p.o. (max 40 mg) and 4-6 puffs of salbutamol via MDI/S. RESULTS: Fifty patients participated in the study. Admission was associated positively with the initial PRAM score (OR: 18.91, CI: 2.42-123.12, P = 0.005) and negatively with the improvement in PRAM score (OR: 0.52, CI: 0.01-0.78, P = 0.032). CONCLUSION: PRAM is a reliable tool that can be used effectively to estimate the asthma exacerbation severity.

Estimated cost-savings from optimizing use of inhaled medications for inpatients with obstructive lung disease.

CONCLUSIONS: Models representing transitions from all-nebulized to nebulizer-plus-MDI respiratory medications resulted in cost savings, largely from the reduction of labor cost of nebulizer administration with nebs-only treatment. Therefore, transitioning from nebs to MDIs can lead to cost savings and could allow greater opportunities for inhaler education.

An aerosol inhalation monitor would improve the accuracy of checklist assessment in drug inhalation techniques.

BACKGROUND: Checklists are usually employed to assess the inhalation techniques in patients, but partial techniques are difficult to evaluate visually. This study aimed to assess the checklist validity and an agreement between checklists and an aerosol inhalation monitor (AIM) assessments. METHODS: This study used a checklist and an AIM to evaluate the participants' inhalation techniques with a pressurized metered-dose inhaler (MDI) and two dry powder inhalers (DPIs). The kappa (κ) coefficient, prevalence-adjusted and bias-adjusted κ (PABAK), sensitivity, specificity, positive predictive value, and negative predictive value were all calculated to determine the agreement between the checklist and AIM in an MDI and DPIs with different inhalation technique steps. RESULTS: The checklist and AIM exhibited poor agreement in the MDI for actuation and inhalation time, and a moderate agreement for inspiratory flow. The fair agreement was observed in DPIs for inspiratory flow between the checklist and AIM. The steps of holding breath in MDI and DPIs were highly correlated between both assessments. The lowest accuracy evaluated with an AIM was found in the step of actuation and inhalation time in the MDI and in the inspiratory flow step in DPIs. CONCLUSION: The checklist tended to overestimate the accuracy of critical techniques including the actuation and inhalation time in MDIs and the inspiratory flow in DPIs. Thus, the AIM device can be used as an objective auxiliary tool to assess and quantify the specific steps of inhalation technique for the users with MDI and DPIs.

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.

Impact of choice of inhalers for asthma care on global carbon footprint and societal costs: a long-term economic evaluation.

BACKGROUND: While effective asthma control medications reduce the burden of asthma, a significant subgroup of these treatments, namely metered-dose inhalers (MDIs), produce substantial greenhouse gas (GHG) emissions, thus contributing to climate change. This study quantified the global climate impact (i.e. carbon dioxide equivalent [CO2e] emissions) and costs of long-term status quo asthma inhaler use versus alternative scenarios substituting MDIs with propellant-free dry powder inhalers (DPIs). METHODS: Three scenarios were evaluated across 10-year (2020-2030) and 50-year (2020-2070) time horizons: A (status quo inhaler use), B and C (2% and 5% year-over-year substitution of MDIs with DPIs, respectively). Global inhaler volumes and costs at baseline were sourced from IQVIA, then projected using UN and WHO trends in per capita GDP, urbanization, and asthma population growth. Inhaler spending was assumed to fall by 90% following generic entry in 2030. The carbon footprint per inhaler and health damage factors for disability-adjusted life years (DALYs) were derived from literature. The US government's central and high-impact estimates for the social cost of carbon (SCC) were used to calculate emissions costs. RESULTS: Over 50 years, scenario A resulted in 826 million tonnes of CO2e emissions globally, with an associated SCC between 21% and 65% of the projected global spending on asthma inhalers. In comparison, CO2e emissions were reduced by 38% and 58% in Scenarios B and C, respectively, and DALYs improved by 33 and 51%. Depending on SCC estimates, Scenarios B and C increased global costs by 7.3% and 16.5%, respectively (central SCC), or decreased costs by 4.2% and 2.6% (high-impact SCC) versus Scenario A. Over 10 years, Scenario A resulted in 97 million tonnes of CO2e emissions globally, with an associated SCC between 4.4% and 12.2% of projected spending. In comparison, Scenarios B and C were associated with 12% and 24% reductions in CO2e emissions and improvements in DALYs by 11.5% and 22.7%, respectively. CONCLUSIONS: Global efforts by environmental and health-policy decision-makers to substitute currently available MDIs with DPIs for asthma control would result in substantial reductions in GHG emissions with manageable costs, or potential cost savings, depending on the SCC. Policies that decrease use of MDIs warrant global attention.

Economic Evaluation of Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate for the Treatment of Moderate to Very Severe Chronic Obstructive Pulmonary Disease in China Using a Semi-Markov Model.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease with considerable clinical and socioeconomic impact. Budesonide/glycopyrrolate/formoterol fumarate (BGF) is a newly approved pharmacotherapy for COPD in China that has been shown to improve lung function and reduce the risk of exacerbations, but the cost-effectiveness of BGF remains unknown. The objective of this study was to evaluate the cost-effectiveness of BGF in patients with moderate to very severe COPD from a Chinese healthcare system perspective. METHODS: A semi-Markov model was developed to compare the costs and benefit of treatment with BGF versus a composite comparator of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) therapies. Clinical inputs for BGF and the composite comparator were based on the KRONOS study (NCT02497001) and a network meta-analysis. Cost inputs were derived from published literature and Chinese government documents, supplemented by expert opinion where necessary. Health-related quality-of-life inputs were also obtained based on the KRONOS study. Lifetime costs, number of exacerbations, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. Costs were measured in 2020 Chinese Yuan (CN¥) and converted into US dollars (US$). Scenario analyses and sensitivity analyses were conducted. RESULTS: Over the lifetime horizon, BGF treatment led to fewer moderate and severe exacerbations (4.01 and 0.87, respectively) versus the composite comparator (8.42 and 2.04, respectively), with a base-case ICER of CN¥13,685.94 (US$1983.47) per QALY gained. Scenario analyses considering different population and utilities resulted in ICERs ranging from dominant to CN¥13,673.91 (US$1981.73). Extensive sensitivity analyses indicated robust base-case results since all analyses yielded ICERs below the conservative cost-effectiveness threshold of one times the Chinese per capita gross domestic product (CN¥72,447.00 [US$10,499.57], 2020). CONCLUSION: Triple therapy with BGF was predicted to improve outcomes and be a cost-effective treatment option compared with LAMA/LABA therapies for patients with moderate to very severe COPD in China.

[Assessment of general practitioners' knowledge of inhalers]. / Évaluation des connaissances des médecins généralistes sur les inhalateurs. Les médecins généralistes savent-ils utiliser les inhalateurs qu'ils prescrivent dans le traitement de l'asthme ?

INTRODUCTION: Inhaled drug delivery is the cornerstone treatment for asthma. General practitioners (GPs) have a key role for educating patient about how to use their inhalers. The purpose of this study was to find out whether GPs know how to use the inhalers they usually prescribe. METHOD: This was a descriptive and analytical cross-sectional study among GPs from the Paris metropolitan area. GPs had to choose the inhalers they usually prescribe and then demonstrate their use. The technique of use was assessed using a scale specific to each type of inhaler. Overall success was defined by the use of prescribed inhalers without critical errors. RESULTS: Thirty-seven GPs were recruited between July 2018 and July 2019. Nineteen GPs (51.4%) were able to use the inhalers they prescribed without critical errors. The success rate without critical error was better with the pressurized metered dose inhalers with spacer than with other inhalers. The overall success rate was better among GPs who had previously used an inhaler on a personal basis (OR 7.58 95%CI [1.86, 37.02]) or who had prescribed only one type of inhaler (OR 4,8 95%CI [1.21, 22.41]). CONCLUSION: Half of the GPs in our study did not know how to use the inhalers they prescribe and therefore may have difficulty educating their patients.

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.

An in vitro visual study of fugitive aerosols released during aerosol therapy to an invasively ventilated simulated patient.

COVID-19 can cause serious respiratory complications resulting in the need for invasive ventilatory support and concurrent aerosol therapy. Aerosol therapy is considered a high risk procedure for the transmission of patient derived infectious aerosol droplets. Critical-care workers are considered to be at a high risk of inhaling such infectious droplets. The objective of this work was to use noninvasive optical methods to visualize the potential release of aerosol droplets during aerosol therapy in a model of an invasively ventilated adult patient. The noninvasive Schlieren imaging technique was used to visualize the movement of air and aerosol. Three different aerosol delivery devices: (i) a pressurized metered dose inhaler (pMDI), (ii) a compressed air driven jet nebulizer (JN), and (iii) a vibrating mesh nebulizer (VMN), were used to deliver an aerosolized therapeutic at two different positions: (i) on the inspiratory limb at the wye and (ii) on the patient side of the wye, between the wye and endotracheal tube, to a simulated intubated adult patient. Irrespective of position, there was a significant release of air and aerosol from the ventilator circuit during aerosol delivery with the pMDI and the compressed air driven JN. There was no such release when aerosol therapy was delivered with a closed-circuit VMN. Selection of aerosol delivery device is a major determining factor in the release of infectious patient derived bioaerosol from an invasively mechanically ventilated patient receiving aerosol therapy.

Global Quality Statements on Reliever Use in Asthma in Adults and Children Older than 5 Years of Age.

INTRODUCTION: Widespread misuse of short-acting beta-agonists (SABAs) may contribute to asthma-related morbidity and mortality. Recognizing this, the Global Initiative for Asthma neither recommends SABA monotherapy nor regards this formulation as a preferred reliever. Many health systems and healthcare professionals (HCPs) experience practical issues in implementing guidelines. Clear quality standards can drive improvements in asthma care and encourage implementation of global and national medical guidelines. METHODS: A steering group of global asthma experts came together between May and September 2019 to develop quality statements codifying the minimum elements of good quality asthma care. These statements were either evidence based (when robust evidence was available) or reflected a consensus based on clinical expertise and experience of the group. RESULTS: The quality statements (and associated essential criteria) developed emphasize key elements concerning (1) objective diagnosis specific to individual symptoms, (2) treatment appropriate to the long-term management of asthma as an inflammatory disease, consistent with evidence-based recommendations, (3) controlled dispensing of SABA canisters and monitoring to prevent overuse, (4) regular review of patients after treatment initiation or change, and (5) follow-up of patients in primary care after treatment for an exacerbation in a hospital or an emergency department. CONCLUSIONS: The steering group proposes quality statements that national and local clinical groups can implement as quantitative quality standards that are appropriate to their local circumstances, including during the coronavirus disease 2019 (Covid-19) pandemic. By translating these statements into locally relevant quality standards, primary care physicians and HCPs can encourage optimal management and reduce preventable healthcare interactions. The evidence-based evolution of care encapsulated in these statements will further engender high-quality, patient-centered holistic management that addresses asthma as an inflammatory disease. In particular, the statements empower self-management by patients and encourage health-promoting behaviors, which are essential to reduce exacerbations, the primary goal of asthma management.

Economic and workload impact of therapeutic interchange of inhaler medications and nebulizer solutions.

PURPOSE: To examine the financial impact of automatic formulary substitution of nebulization solutions for pressurized metered dose inhalers and dry powder inhalers and the effect of the automatic substitution initiative on respiratory care practitioner (RCP) workload at a community hospital. METHODS: A retrospective observational study was conducted in a 326-bed nonacademic community hospital. Adult patients who received respiratory medications and had an inpatient stay, were admitted for observation, or had an emergency room visit from December 2016 through February 2017 (the control group) or from December 2017 through February 2018 (the study group) were included in the analysis. The primary outcomes were the cost of respiratory medications per hospital stay and the number of RCP visits per hospital stay. The secondary outcome was the cost of wasted doses per hospital stay. RESULTS: A total of 3,766 patients were included in the study: 2,030 in the study group and 1,736 in the control group. The mean cost of respiratory medications per hospital stay was significantly lower in the study group vs the control group ($13.29 vs $36.48, P < 0.001). The mean number of RCP visits per hospital stay was also statistically lower in the study group vs the control group (11.6 vs 12.9, P = 0.04). The mean cost of wasted doses was significantly lower in study group vs the control group ($0.25 vs $22.91, P < 0.001). CONCLUSION: Automatic formulary substitution of nebulization solutions for inhaler medications significantly decreased medication costs without increasing the average number of RCP visits per hospital stay.

Commercial valved spacers versus home-made spacers for delivering bronchodilator therapy in pediatric acute asthma: a cost-effectiveness analysis.

OBJECTIVE: Although valved spacers are the preferred method for administering metered-dose inhaler bronchodilators such as albuterol in pediatric acute asthma, their high cost and their lack of availability have limited their use, especially in low- and middle-income countries (LMICs). Because of this, it is a common practice to use home-made spacers, although a formal analysis evaluating their cost-effectiveness is lacking. Therefore, the objective of this study was to analyze the cost-effectiveness of home-made spacers compared to commercial valved spacers for delivering bronchodilator therapy in pediatric acute asthma. METHODS: A decision-analysis model was used to estimate health outcomes and costs of a simulated cohort of pediatric patients treated for acute asthma. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from hospital bills and from the national manual of drug prices in Colombia. The study was carried out from the perspective of the national healthcare system in Colombia, a middle-income country (MIC). The main outcome of the model was avoidance of hospital admission. RESULTS: Base-case analysis showed that compared to commercial valved spacers, administering bronchodilators with home-made spacers results in lower overall treatment costs (US$126.75 vs. US$128.59 average cost per patient) without a significant difference in the probability of hospitalization avoided (0.8500 vs. 0.8500). CONCLUSIONS: The present study shows that in Colombia, an MIC, compared with commercial valved spacers, the use of home-made spacers for administering bronchodilator therapy is more cost-effective because it yields a similar probability of hospital admission at lower overall treatment costs.

Assessment of different techniques for the administration of inhaled salbutamol in children breathing spontaneously via tracheal tubes, supraglottic airway devices, and tracheostomies.

BACKGROUND: Perioperative respiratory adverse events account for a third of all perioperative cardiac arrests, with bronchospasm and laryngospasm being most common. Standard treatment for bronchospasm is administration of inhaled salbutamol, via pressurized metered dose inhaler. There is little evidence on the best method of attaching the pressurized metered dose inhaler to the artificial airway during general anesthesia. AIM: The aim of this study is to investigate the best method to deliver aerosolized salbutamol via pressurized metered dose inhaler to the lungs of an anesthetized child. METHODS: We measured salbutamol delivered by pressurized metered dose inhaler through different sized tracheal tubes, supraglottic airway devices, and tracheostomies in vitro for methods commonly employed for connecting the pressurized metered dose inhaler to the artificial airway. Breathing was simulated for patients weighing 3, 16, 50, and 75 kg. Pressurized metered dose inhaler actuation coincided with inspiration. RESULTS: A pressurized metered dose inhaler combined with an in-line non-valved or valved spacer, or the direct method, when delivered via tracheal tube, was linked with improved delivered dose of salbutamol, compared to all other methods for 3 or 50 kg simulated patients weights. The delivered dose when using a non-valved spacer was greater than all methods for 16 and 75 kg patient weights. A spacer improved delivery for the flexible supraglottic airway device type, and there was no difference with or without a spacer for remaining types. CONCLUSION: Via tracheal tube and non-valved spacer, the following doses should be delivered after single actuation of a 100 µg labeled-claim salbutamol dose: ~2 µg kg-1 per actuation to a 3 kg neonate, ~1 µg kg-1 per actuation to a 16 kg child, and ~ 0.5 µg kg-1 per actuation for a 50-75 kg child. The least effective methods were the syringe, and the uni- and bidirectional adaptor methods, which require replacement by the direct method if a spacer is unavailable.

Addressing the Need for Controls on Particle Bounce and Re-entrainment in the Cascade Impactor and for the Mitigation of Electrostatic Charge for Aerodynamic Particle Size Assessment of Orally Inhaled Products: an Assessment by the International Consortium on Regulation and Science (IPAC-RS).

Multi-stage cascade impactors (CI) are accepted for the determination of metrics of the drug mass aerodynamic particle size distributions (APSD) of aerosols emitted from orally inhaled products (OIPs). This is particularly important for products where the drug to excipient ratio or particle density may not be the same in each aerodynamic size fraction; examples of such products are carrier-containing dry powder inhalers (DPIs) and suspension pressurized metered-dose inhalers (pMDIs). CI measurements have been used as the "gold standard" for acceptance of alternative methods of APSD assessment, such as laser diffraction for nebulized solutions. Although these apparatus are labor-intensive, they are accepted in regulatory submissions and quality control assessments because the mass of active pharmaceutical ingredient(s) in the aerosol can be quantified by chemical assay and measured particle size is based on the aerodynamic diameter scale that is predictive of deposition in the respiratory tract. Two of the most important factors that modify the ideal operation of an impactor are "particle bounce," that is often accompanied by re-entrainment in the air flow passing the stage of interest, and electrostatic charge acquired by the particles during the preparation and aerosolization of the formulation when the inhaler is actuated. This article reviews how both factors can lead to biased APSD measurements, focusing on measurements involving pMDIs and DPIs, where these sources of error are most likely to be encountered. Recommendations are provided for the mitigation of both factors to assist the practitioner of these measurements.

Sustainability in Inhaled Drug Delivery.

Asthma and chronic obstructive pulmonary disease (COPD) are amongst the most common chronic diseases worldwide, and are largely preventable by improving the quality of the air we breathe. The most commonly deployed treatment, the metered dose inhaler (MDI), uses hydrofluorocarbon propellants, which are powerful greenhouse gases that contribute disproportionately to the climate crisis. Alternative treatment strategies are required if we are to avoid contributing to the worst effects of climate change. These strategies include promoting non-pharmacological therapies like smoking cessation and pulmonary rehabilitation; empowering patients to gain better disease control through written management plans and encouraging preventer, rather than reliever therapies. Pharmacological strategies include: improving inhaler technique and spacer use; minimising propellant release by using smaller volume MDIs and simpler dosing regimes; dose counters to prevent waste; switching to low global warming potential inhalers; and inhaler recycling. There are also opportunities to improve disease control alongside reduced greenhouse gas emissions, including better matching of patients' devices to inhaler technique rather than defaulting to MDIs, stopping unnecessary inhaled steroids in COPD and maintenance and reliever therapy in asthma. New, lower global warming potential propellants are on the horizon, and their introduction could offer a golden opportunity to enhance MDIs usability and sustainability by making them refillable, integrating whistles to optimise inhalation technique, adding integrated caps, optimising materials for recycling and adding dose counters to all MDIs.

Functional respiratory imaging assessment of glycopyrrolate and formoterol fumarate metered dose inhalers formulated using co-suspension delivery technology in patients with COPD.

BACKGROUND: Functional respiratory imaging (FRI) is a quantitative postprocessing imaging technique used to assess changes in the respiratory system. Using FRI, we characterized the effects of the long-acting muscarinic antagonist (LAMA), glycopyrrolate metered dose inhaler (GP MDI), and the long-acting ß2-agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease. METHODS: Patients in this phase IIIb, randomized, double-blind crossover study received twice-daily GP MDI (18 µg) and FF MDI (9.6 µg). Primary endpoints were specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and specific image-based airway resistance (siRaw), measured using FRI. Secondary and other endpoints included additional FRI, spirometry, and body plethysmography parameters. Postdose efficacy assessments were performed within 60-150 min of dosing on day 15. RESULTS: A total of 23 patients were randomized and 19 completed both treatment periods. GP MDI and FF MDI both achieved significant improvements from baseline to day 15 in siVaw [11% (p = 0.0187) and 23% (p < 0.0001) increases, respectively] and siRaw [25% (p = 0.0219) and 44% (p < 0.0001) reductions, respectively]. Although, on average, improvements were larger for FF MDI than GP MDI, some individuals displayed greater responses with each of the two treatments. These within-patient differences increased with airway generation number. Spirometry and body plethysmography endpoints showed significant improvements from baseline in inspiratory capacity for both treatments, and numeric improvements for other endpoints. CONCLUSION: Both GP MDI and FF MDI significantly improved siRaw and siVaw at day 15 versus baseline. FRI endpoints demonstrated increased sensitivity relative to spirometry and body plethysmography in detecting differences between treatments in a small number of patients. Intra-patient differences in treatment response between the LAMA and the LABA provide further support for the benefit of dual bronchodilator therapies. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT02937584 The reviews of this paper are available via the supplemental material section.