Pressurized Metered-dose Inhaler Research Articles

Dual-combination maintenance inhaler preferences in asthma and chronic obstructive pulmonary disease: A patient-centered benefit-risk assessment

BackgroundA variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective. MethodsPatient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD. ResultsFor all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 μg/5 μg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 μg/2.5 μg) soft mist inhaler had the highest PrCP (42.3%). ConclusionsPatient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes.

Multidisciplinary consensus on inhaled therapy in asthma

ABSTRACT Background Asthma is managed by health professionals from different specialties. We aim to reach a consensus on the optimal use of inhaled therapy and the initial steps of asthma treatment, taking into account the opinions of the involved specialists. Methods A modified Delphi approach was used. A scientific committee provided 52 controversial statements, which were submitted to primary care physicians, allergists, and pulmonologists. Discrepancies among specialties were evaluated. Results A total of 209 specialists completed the questionnaire (20.2 ± 9.3 years of asthma management experience). A consensus was reached on 37 statements (71.1%), discrepancies among specialties were found in 14. The most recommended maintenance treatment for mild persistent asthma in adults/adolescents was low-dose-inhaled corticosteroids daily. MART (Maintenance and Reliever Therapy) was recommended as salvage treatment for moderate persistent asthma. Panelists agreed on the most frequent critical errors with pressurized Metered-Dose Inhalers or Dry-Powder Inhalers, and considered that Breath-Actuated Inhalers are a suitable option for all patients with the ability to inhale voluntarily. Conclusions The experts endorse the main guidelines recommendations; however, do not fully agree on recent GINA recommendations about the treatment of the initial steps of the disease. The experts value positively the differential characteristics of BAI over other devices.

In Vitro Measurements of Spiriva Respimat Dose Delivery in Mechanically Ventilated Tracheostomy Patients.

Background: For patients with severe chronic obstructive pulmonary disease under invasive mechanical ventilation, medication for aerosol therapy is delivered through tracheostomy or endotracheal airways. Typically, these medications (such as bronchodilators) are long-acting formulations that are delivered through Soft Mist™ Inhalers (SMI), or Pressurized Metered-Dose Inhalers. The Respimat® SMI has been shown to have increased efficiency because of its slow and prolonged aerosol mist and has gained popularity in clinical settings. However, the Respimat was not designed for drug delivery through artificial airways. Therefore, there is a need for SMI adapters in intensive care for use in mechanical ventilator circuits. The purpose of this study was to evaluate the performance of a new Respimat adapter (ODAPT™ for mechanical ventilator [ODAPT MV]) for use in mechanical ventilator circuits which, in combination with a Pulmodyne T-piece adapter, allows use without interruption of the circuit in case of medication replacement. Methods: Tiotropium delivery to the lungs, using Respimat, was assessed using the ODAPT MV adapter within an in vitro setup, including a three-dimensional printed trachea model and a mechanical ventilator. Medication deposition and losses were investigated using two commonly used tracheostomy tube (TT) sizes (6 and 8 mm inner canula) for two flow rates (45 and 60 L/min) under different conditions (30%-50%. and 100% relative humidity [RH]). Medication delivery using the ODAPT MV adapter was compared with the RTC-26C in-line adapter under similar conditions (8 mm TT size, 100% RH at 45 L/min). Results: It was found that 7.1%-13.4% of the nominal dose (ND) was lost in the ODAPT MV adapter for different TT size, RH, and flow rates used. Higher losses were found in the inhaler's mouthpiece ranging from 15.7% to 29.1% ND. The percentage of the delivered medication reaching the lungs was determined to be 13.7%-18.5% ND delivered without significant differences between the experimental conditions tested. The ODAPT MV performed well compared with the RTC-26C under similar conditions (17.9% and 16.6% ND, respectively). Conclusion: The medication delivered through mechanical ventilation using the ODAPT MV adapter represents about one third the dose delivered directly through the Respimat SMI in vivo.

Climate change in healthcare: Exploring the potential role of inhaler prescribing.

Climate change has been described as the biggest global health threat of the 21st century. As a result, governments around the world are committing to legislative change in order to reduce greenhouse gas emissions (GHGEs). The healthcare sector makes a significant contribution to GHGEs and in line with national legislation in the UK, the NHS has recently committed to achieving net zero emissions by 2050. The management of asthma and COPD largely depends on the prescribing of medications that are delivered through inhalers. In the UK, the use of pressurized metered dose inhalers (pMDIs), which rely on hydrofluorocarbon (HFC) propellants accounts for 3.5% of the NHS’s total carbon footprint. In contrast, dry powder inhalers (DPIs) have a much lower carbon footprint due to the absence of a HFC propellant. Here we review evidence of the impact of inhaler choices across four domains: environmental impact, clinical effectiveness, cost effectiveness and patient preferences. We find that as well as a lower global‐warming potential, DPIs have additional benefits over pMDIs in other domains and should be considered first line where clinically appropriate.

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

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. 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. 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). Automatic formulary substitution of nebulization solutions for inhaler medications significantly decreased medication costs without increasing the average number of RCP visits per hospital stay.

Effect of different connection adapters on aerosol delivery in invasive ventilation setting; an in-vitro study

IntroductionDifferent aerosol generators are used during mechanical ventilation connected to spacers or adapters. The design and volume of these connections can significantly affect aerosol delivery. This study aimed to evaluate the impact of a variety of connections on aerosol delivery in invasive mechanical ventilation (IMV) setting. MethodsA ventilator was set at volume-controlled mode (Vt = 500 ml, f = 15/min, PEEP = 5 cm H20), and connected to a test lung model to simulate intubated mechanically ventilated adults with a 1:3 ratio of inspiratory to expiratory phase. An endotracheal tube of 8 mm inner diameter was used in this model, inserted between Y-piece and the breathing simulator. Ventilator settings were selected typically as those indicated for COPD patients in the intensive care unit when IMV is prescribed during acute exacerbations. Aerosol-generator was placed in dual limb IMV at Y-piece in the inspiratory limb.For nebulizer delivery; 1 ml respirable solution was nebulized using vibrating mesh nebulizer with three connection settings; I: T-piece, II: Combihaler (new and old version), and III: Combihaler with a pressurized metered-dose inhaler (pMDI). Only with connection III, two pMDI puffs, 100 μg salbutamol each, were actuated before nebulization of 1 ml of salbutamol solution.For pMDI delivery; pMDI puffs (100 μg per puff) were delivered using two connection settings I: pMDI T-piece adapter (2 and 5 pMDI salbutamol puffs), and II: Combihaler (2 pMDI salbutamol puffs only). 2 and 5 pMDI salbutamol puffs were delivered by pMDI T-piece adapter to determine the possible effect of aerosolized drug condensation on the T-piece. Fates of nebulized, and actuated-doses were determined. ResultsNo significant difference was observed between old and new Combihalers used to deliver nebulized doses with and without pMDI. The pMDI T-piece adapter delivered significantly higher pMDI aerosol than Combihaler (p < 0.05). The new Combihaler delivered a slightly higher pMDI dose than the old Combihaler. ConclusionsThe antistatic property of the new Combihaler affected pMDI delivered dose similar to conventional spacer but does not affect the nebulized dose. Further clinical studies are needed to determine the bronchodilator effect of the pre-nebulization pMDI puffs on the nebulized dose.

Development of Aggregation-Caused Quenching Probe-Loaded Pressurized Metered-Dose Inhalers with Fluorescence Tracking Potentials.

Recently, pressurized metered-dose inhalers (pMDIs) are getting more attention as an effective approach of pulmonary drug delivery, and nanoparticle-based formulations have become a new generation of pMDIs, especially for water insoluble drugs. Up until now, there is no clinical application of nanoparticle-based pMDIs. The main hurdle remains in the lack of knowledge of the in vivo fate of those systems. In this study, a fluorescent probe named P4 with aggregation-caused quenching (ACQ) effect was loaded in the nanoparticle-based pMDIs to track the in vivo fate. P4 probe expressed strong fluorescence when distributed in intact nanoparticles, but quenched in the in vivo aqueous environment due to molecular aggregation. Experimentally, P4 probe was encapsulated into solid lipid nanoparticles (SLN) as P4-SLN, and then, the formulation of pMDIs was optimized. The content (w/w) of the optimal formulation (P4-SLN-pMDIs) was as follows: 6.02% Pluronic® L64, 12.03% ethanol, 0.46% P4-SLN, and 81.49% 1,1,1,2-tetrafluoroethane (HFA-134a). P4-SLN-pMDI was transparent in appearance, possessed a particle size of 132.07 ± 3.56nm, and the fine particle fraction (FPF) was 39.53 ± 1.94%, as well good stability was shown within 10days. The results indicated P4-SLN-pMDI was successfully prepared. Moreover, the ACQ property of P4-SLN-pMDIs was verified, which ensured the fluorescence property as a credible tool for in vivo fate study. Taken together, this work established a platform that could provide a firm theoretical support for exploration of the in vivo fate of nanoparticle-based pMDIs in subsequent studies. Grapical abstract.

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

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. 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. 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 75kg. Pressurized metered dose inhaler actuation coincided with inspiration. 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 50kg simulated patients weights. The delivered dose when using a non-valved spacer was greater than all methods for 16 and 75kg 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. Via tracheal tube and non-valved spacer, the following doses should be delivered after single actuation of a 100µg labeled-claim salbutamol dose: ~2µgkg-1 per actuation to a 3kg neonate, ~1µgkg-1 per actuation to a 16kg child, and~0.5µgkg-1 per actuation for a 50-75kg 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.

Predicting Lung Deposition of Extrafine Inhaled Corticosteroid-Containing Fixed Combinations in Patients with Chronic Obstructive Pulmonary Disease Using Functional Respiratory Imaging: An In Silico Study.

Background: Functional respiratory imaging (FRI) is a computational fluid dynamics-based technique using three-dimensional models of human lungs and formulation profiles to simulate aerosol deposition.Methods: FRI was used to evaluate lung deposition of extrafine beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) and extrafine BDP/FF delivered through pressurized metered dose inhalers and to compare results with reference gamma scintigraphy data. FRI combined high-resolution computed tomography scans of 20 patients with moderate-to-severe chronic obstructive pulmonary disease (mean forced expiratory volume in 1 second 42% predicted) with in silico computational flow simulations, and incorporated drug delivery parameters to calculate aerosol airway deposition. Inhalation was simulated using profiles obtained from real-life measurements.Results: Total lung deposition (proportion deposited in intrathoracic region) was similarly high for both products, with mean ± standard deviation (SD) values of 31.0% ± 5.7% and 28.1% ± 5.2% (relative to nominal dose) for BDP/FF/GB and BDP/FF, respectively. Pairwise comparison of the deposition of BDP and FF gave a mean intrathoracic BDP/FF/GB:BDP/FF deposition ratio of 1.10 (p = 0.0405). Mean intrathoracic, central and peripheral deposition ratios for BDP were 1.09 (95% confidence interval [CI]: 1.05–1.14), 0.92 (95% CI: 0.89–0.96), and 1.20 (95% CI: 1.15–1.26), respectively, and for FF were 1.11 (95% CI: 1.07–1.15), 0.94 (95% CI: 0.91–0.98), and 1.21 (95% CI: 1.15–1.27), within the bioequivalence range (0.80–1.25) for intrathoracic and central regions, and slightly exceeding the upper boundary in the peripheral region. Mean ± SD central:peripheral deposition (C:P) was 0.48 ± 0.13 for BDP/FF/GB and 0.62 ± 0.17 for BDP/FF, indicating a higher proportion of drug deposition in the small airways than in the large airways.Conclusion: FRI demonstrated similar deposition patterns for extrafine BDP/FF/GB and BDP/FF, with both having a high lung deposition. Moreover, the deposition patterns of BDP and FF were similar in both products. Furthermore, the C:P ratios of both products indicated a high peripheral deposition, supporting small airway targeting and delivery of these two extrafine fixed combinations, with a small difference in ratios potentially due to mass median aerodynamic diameters.

EFFECT OF SWITCHING FROM MULTI-INHALER NON-EXTRA FINE TO SINGLE-INHALER EXTRA FINE TRIPLE THERAPHY ON REGIONAL BRONCHODILATION AND VENTILATION IN PATIENTS WITH SEVERE COPD

EFFECT OF SWITCHING FROM MULTI-INHALER NON-EXTRA FINE TO SINGLE-INHALER EXTRA FINE TRIPLE THERAPHY ON REGIONAL BRONCHODILATION AND VENTILATION IN PATIENTS WITH SEVERE COPD

Comparison between traditional and nontraditional add-on devices used with pressurised metered-dose inhalers.

Add-on devices that are attached to metered-dose inhalers (MDIs) were introduced to improve aerosol delivery. The objective of this study was to determine the efficacy of drug delivery from an MDI when attached to different add-on devices at different inhalation volumes.The total emitted dose (TED) of salbutamol was estimated for the MDI alone and the MDI connected to five different add-on devices (Able valved holding chamber, Tips-haler valved holding chamber, Aerochamber plus flow Vu valved holding chamber, Dolphin chamber, and a handmade water bottle spacer), at inhalation flow of 28.3 L·min−1 with flow volume of 1, 2 and 4 L, assuming young child (aged <6 years), old child (>6 years) and adult inhalation volumes, respectively.The TED% ranged between 84.1% and 87.2% at all inhalation volumes from the MDI alone, which was significantly greater than all MDI add-on device combinations (p<0.05). The TED% delivered to MDI sampling apparatus by a homemade water bottle spacer and Dolphin chamber, as non-antistatic add-on devices, ranged between 30.5% and 35.3%. However, washing these non-antistatic add-on devices with a light detergent before use improved their TED to range between 47.6% and 51.2%. Non-antistatic add-on devices had significantly lower TED (p<0.05) than that delivered by most antistatic add-on devices, which ranged from 51.3% to 71.6%.This study suggests that antistatic add-on devices delivered much more aerosol than non-antistatic add-on devices. However, it may be advised to still use a non-antistatic add-on device, for the sake of solving the coordination problem, and wash it with light detergent before use to improve TED.

Comparing Inhaler Use Technique Based on Inhaler Type in Elderly Patients with Respiratory Disease

BackgroundThe aim of this study was to investigate inhaler device handling in elderly patients. Inhaler devices with respect to misuse and error correction were also compared.MethodsInhaler use technique was assessed using standardized checklists at the first visit and 3-month follow-up visit after retraining. The primary outcome was difference in the acceptable use ratio among inhaler devices. Secondary outcomes included differences in error correction, the most common step of misuse, and factors affecting the accuracy of inhaler use.ResultsA total of 251 patients (mean age, 76.4 years) were included. The handling of 320 devices was assessed in the study. All patients had been trained before. However, only 24.7% of them used inhalers correctly. Proportions of acceptable use for Evohaler, Respimat, Turbuhaler, Ellipta, and Breezhaler/Handihaler were 38.7%, 50.0%, 61.4%, 60.8%, and 43.2%, respectively (p=0.026). At the second visit, the acceptable use ratio had increased. There were no significant differences among inhaler types (Evohaler, 63.9%; Respimat, 86.1%; Turbuhaler, 74.3%; Ellipta, 64.6%; and Breezhaler/Handihaler, 65.3% [p=0.129]). In multivariate analysis, body mass index, Turbuhaler, and Ellipta showed positive correlations with acceptable use of inhalers, whereas Chronic Obstructive Pulmonary Disease Assessment Test score showed a negative correlation.ConclusionAlthough new inhalers have been developed, the accuracy of inhaler use remains low. Elderly patients showed more errors when using pressurized metered-dose inhalers than using dry powder inhalers and soft-mist inhalers. However, there were no significant differences in misuse among inhaler devices after individual training. Results of this study suggests that repeat training is more important than inhaler type.

Fluticasone Particles Bind to Motile Respiratory Cilia: A Mechanism for Enhanced Lung and Systemic Exposure?

Background: Inhaled corticosteroids (ICSs) are the main prophylactic treatment for asthma and are used in other diseases, including chronic pulmonary obstructive disease, yet the interaction of ICS particles with the ciliated epithelium remains unclear. The aim of this study was to investigate the earliest interaction of aerosolized fluticasone propionate (FP) particles with human ciliated respiratory epithelium. Methods: A bespoke system was developed to allow aerosolized FP particles to be delivered to ciliated epithelial cultures by nebulization and from a pressurized metered-dose inhaler (pMDI) through a spacer with interactions observed in real time using high-speed video microscopy. Interaction with nonrespiratory cilia was investigated using steroids on brain ependymal ciliary cultures. The dissolution rate of steroid particles was determined. Results: FP particles delivered by aerosol attached to the tips of rapidly beating cilia. Within 2 hours, 8.7% ± 1.8% (nebulization) and 12.1% ± 2.1% (pMDI through spacer) of ciliated cells had one or more particles attached to motile cilia. These levels decreased to 5.8% ± 1.6% (p = 0.59; nebulization) and 5.3% ± 2.2% (p = 0.14; pMDI through spacer) at 24 hours. Particle attachment did not affect ciliary beat frequency (p > 0.05) but significantly (p < 0.001) reduced ciliary beat amplitude. Steroid particles also attached to the tips of motile ependymal brain cilia and also reduced beat amplitude (24 hours: >2 particles bound p < 0.001). Dissolution of FP particles was slow with only 22.8% ± 1.3% of nebulized and 12.8% ± 0.5% of pMDI-delivered drug dissolving by 24 hours. Conclusions: FP particles adhere to the tips of rapidly moving cilia with significant numbers remaining bound at 24 hours, resisting the shear stress generated by ciliary beating. In vivo, this mechanism may predispose to high local drug concentrations and enhance respiratory and systemic corticosteroid exposure.

Comparison of tiotropium delivery with the ODAPT adapter and a valved holding chamber

RATIONALE: Facemasks are commonly used by certain patients requiring assistance for aerosol medication delivery. Adapters are used as connectors between facemasks and inhalers. The valved holding chamber (VHC) is commonly prescribed with pressurized metered dose inhalers (pMDIs) to improve medication delivery. Recently, the VHC has been used with the Respimat Soft Mist Inhaler (SMI), which is a propellant-free inhaler. The ODAPT soft mist adapter was previously designed to serve as a connector for facemasks used with the Respimat SMI. OBJECTIVE The purpose of this in vitro study is to compare the Respimat medication delivery and losses using facemasks when connected separately to 1) the VHC and 2) the ODAPT adapter. METHODS Tiotropium was delivered via the Spiriva Respimat SMI with add-ons (either ODAPT adapter or VHC) and without add-ons under different humidity levels (40–50% and >90%) at 28.3 L/min using an 8-stage Andersen cascade impactor. The particle deposition was assessed via UV-visible spectrophotometry. MEASUREMENTS AND MAIN RESULTS: Under ambient humidity conditions, 7.39% and 19.10% loss of fine particle fraction (FPF) were found using the ODAPT adapter and VHC, respectively. However, for higher humidity, mimicking humidity levels in the lungs, a loss of medication of 16.74% and 30.20% was found using the ODAPT adapter and VHC, respectively. Significant differences were found in medication delivery using the two different connectors, where higher medication losses were found using the VHC. CONCLUSION The ODAPT adapter connected to the Respimat SMI was shown to provide higher medication deposition and to minimize drug losses.

What Makes Flunisolide Different Among Inhaled Corticosteroids Used for Nebulization

Objective: Evidence-based management of bronchial asthma and wheezing in children and adults recommend the employment of inhaled corticosteroids (ICS). Difficulty in using some inhalation devices for ICS delivery such as pressurized metered-dose and dry-powder inhalers are common in young children and in the elderly, and for that reason they are replaced with nebulizers. Methods: We reviewed literature with comparative studies that evaluated funisolide with other ICS currently available on the market, including beclomethasone dipropionate, fluticasone propionate, and budesonide. Moreover, we assessed the role physico-chemical properties of these ICS in determining the drug fate in lung. Results: Data indicate that flunisolide output in respirable particles by any type of pneumatic nebulizer (traditional, open breath or breath-enhanced) is superior to other ICS. This is principally attributed to the higher water solubility of flunisolide. Furthermore, in vivo simulation studies demonstrate that the inter-subject variability of the inhaled dose by asthmatic children was much greater for suspensions of fluticasone propionate and beclomethasone dipropionate than for that of flunisolide. Conclusion: The physicochemical properties and pharmacokinetic profile of flunisolide favor its employment in nebulization.

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.

Strategies to conserve salbutamol pressurized metered-dose inhaler stock levels amid COVID-19 drug shortage.

Essential inhaler medications for patients with respiratory diseases are backordered due to the coronavirus disease of 2019 (COVID-19). In hospitals, there has been a drastic increase in the use of salbutamol pressurized metered-dose inhalers (pMDIs), as well as salbutamol Diskus, leading to a decline in availability and causing interruptions in the supply chain. Patients with asthma are at higher risk of respiratory complications if they are infected with COVID-19. Salbutamol, a short-acting β-agonist (SABA), could be a life-saving medication during critical conditions. Other short-acting muscarinic antagonists (SAMAs), such as ipratropium pMDI, and combinations of SABA/SAMA, such as Combivent Respimat, are also starting to have supply issues. With the ongoing pandemic, hospitals need to consider conservation strategies to facilitate resource-efficient salbutamol delivery and reduce their waste. In this current opinion, we demonstrate several strategies for avoiding pMDI wastage that can be adopted in both the hospital and community settings. These strategies include reprocessing used or expired pMDIs, using intravenous salbutamol and other short acting inhalers when available, and prescribing maintenance inhalers to prevent over usage of salbutamol pMDIs. We also highlight the important role of physicians and pharmacists in optimizing medication therapies to ensure adequate supplies.

Pulmonary deposition of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler formulated using co-suspension delivery technology in healthy male subjects

This gamma scintigraphy imaging study assessed pulmonary, extrathoracic and regional lung deposition patterns of a radiolabelled inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist triple fixed-dose combination budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF 320/14.4/10 μg), delivered by pressurised metered dose inhaler (pMDI) using innovative co-suspension delivery technology (Aerosphere™). In this Phase I, randomised, single-centre, single-dose, two-period, crossover study (NCT03740373), 10 healthy male adults received two actuations of BGF MDI (160/7.2/4.8 μg per actuation) radiolabelled with 99mTc, not exceeding 5 MBq per actuation. Immediately following each inhalation, subjects performed a 10- or 3-second breath-hold, then exhaled into an exhalation filter. The primary objective was to assess the pulmonary deposition of BGF MDI following the 10-second breath-hold. The secondary objectives were to assess deposition after the 3-second breath-hold and lung regional and extrathoracic deposition after each breath-hold length. Imaging of the lungs, stomach, head and neck was recorded by gamma scintigraphy immediately after exhalation. The mean BGF MDI emitted dose deposited in the lungs was 37.7% for the 10-second breath-hold and 34.5% for the 3-second breath-hold. Emitted dose detected in the exhalation filter was ≤0.4% for both breath-hold lengths. The mean normalised peripheral/central ratio was 0.65 and 0.75 for the 10- and 3-second breath-holds, respectively, while the standardised central/peripheral ratios were 1.79 and 1.40, respectively. There were no new or unexpected safety findings. In conclusion, BGF MDI was efficiently deposited in the central and the peripheral regions of the lungs, with similar regional deposition patterns following a 10- and 3-second breath-hold.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial

IntroductionMost guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. MethodsThis was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 μg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. ResultsA total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0–6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. ConclusionAmong patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Inhaled therapy for asthma

Andrew Booth explains why this is the preferred − and more successful − method when managing asthmaInhaled therapy is key to the successful treatment of asthma. National guidelines provide us with the aim of asthma management, which is to maintain control of the disease. The correct combination of drug and device can be individually tailored to the patient. Drugs consist of bronchodilators and anti-inflammatories. Devices consist of aerosol inhalers, also known as pressurised metered dose inhalers, and dry powder inhalers. Both the drug and the device need to be prescribed if the treatment is to be clinically effective. A combination of inhaled steroid with long-acting B2 agonist is one of the most clinically effective ways of delivering asthma treatment. This can be prescribed either as a fixed daily dose with a concomitant short-acting B2 agonist as a reliever, or as maintenance and reliever therapy, which has been shown to improve asthma control and reduce exacerbations.