Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model

Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation–inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI–mouth–lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth–throat, and lung. Concerning the device–patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth–throat loss and increased lung doses in both the central and peripheral regions.

Evaluating the technique of using MDI and DPI in patients with respiratory disease

Inhalation therapy plays a major role in treatment of respiratory diseases. Correct inhalation technique is crucial for effective clinical outcomes. The aim of this study was to evaluate and analyse technique of use of Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) in patients with respiratory disease. This observational study was conducted at pulmonary outpatient department of a tertiary care hospital. 30 patients were enrolled using convenience sampling. Participants’ demographic and disease specific data was recorded. Participants were asked to use their inhaler just as they would at home. The technique of device use was observed and recorded using inhaler specific checklists. Data collected was analyzed using descriptive statistics. Out of 30 patients 26 were using MDI, 23 of which (92%) performed at least 1 error. Among 4 patients using DPI, 3 (75%) performed at least 1 error. Patients using MDI for more than 1 year performed less errors compared to those who had been using MDI for less than 1 year, however the difference observed was not significant (n=26, p= 0.304). 29 patients (96%) received education about inhaler device use. The most common incorrectly performed steps were “complete exhalation” and “breath hold.” 92% of MDI and 75% of DPI users made at least one error during the inhalation maneuver despite majority being educated about inhaler technique. The most frequently performed incorrect steps for MDI and DPI were “Complete exhalation” and “Breath hold”.

Correlation of Metered Dose Inhaler Use Technique and Asthma Control Level in Asthma Patients at a Hospital in Bandung, West Java, Indonesia.

Background: Asthma is still a major health problem in global population, including Indonesia. Antiasthma drugs available in various dosage forms, including inhaler. However, several problems related to inhalation route were found due to its unique device form and spesific use technique. One of the major problems related to inhalation route is inappropriate use technique of inhaler device, which could lead to treatment failure. Therapy outcome can be measured through Asthma Control Test (ACT). Objectives: This study was aimed to evaluate correlation between metered dose inhaler (MDI) use technique and asthma control level in patients. Material and Methods: A cross-sectional analytic study was conducted in May - June 2021. Thirty patients who met inclusion criteria were enrolled in this study. Patients’ MDI use technique and asthma control level were evaluated using a valid and standardized questionnaire. Statistics analysis was performed to determine the correlation between MDI use technique and asthma control level. Results: This study showed that most of asthmatic patients were women in older age, with mild asthma severity for more than 10 years. The most prevalent medication used was Fenoterol HBr, followed by salbutamol, and salmeterol/fluticasone combination. Inappropriate MDI use was found in 70,0% patients, with major problem found in patients’ breathing technique before and during MDI use. Asthma control test was performed and showed that 90,0% of asthmatic patients involved in this study have an uncontrolled asthma. Statistical analysis using Pearson product-moment correlation test showed a positive correlation between proper use of MDI and asthma control level (r=0.425, p<0.05). Conclusions: Patient who properly use MDI may have a higher score in asthma control test, thus have a better control of asthma. This study emphasized pharmacist role as patient educator in ensuring appropriate inhaler use in order to achieve therapeutic goals.

The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered-Dose Inhaler in the Treatment of COVID-19 Patients

Introduction: Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help prevent these respiratory complications. Method: A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with a low melting point were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors. Results : There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has been started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals. Conclusion: Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.

Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial

Objective To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. Design Randomised, double blind, placebo controlled trial. Setting Three Canadian provinces (Quebec, Ontario, and British Columbia). Participants 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. Intervention Participants were randomised to receive either inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily) or metered dose inhaler and nasal saline placebos for 14 days. Main outcome measures The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. Results The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval −7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. Conclusion Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. Trial registration ClinicalTrials.gov NCT04435795 .

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease

Background Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. Methods This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. Results The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). Conclusions Radiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

Evaluation of Aerosol Drug Delivery Options during Adult Mechanical Ventilation in the COVID-19 Era

Drug delivery devices used for aerosol therapy during mechanical ventilation to ease the symptoms of respiratory diseases provide beneficial treatment but can also pose challenges. Reflecting the significant changes in global guidance around aerosol usage and lung-protective ventilation strategies, seen in response to the COVID-19 pandemic, for the first time, we describe the drug delivery performance of commonly used devices under these conditions. Here, vibrating mesh nebuliser (VMN), jet nebuliser (JN) and pressurised metered-dose inhaler (pMDI) performance was assessed during simulated adult mechanical ventilation. Both standard test breathing patterns and those representatives of low tidal volume (LTV) ventilation with concurrent active and passive humidification were investigated. Drug delivery using a VMN was significantly greater than that with a JN and pMDI for both standard and LTV ventilation. Humidification type did not affect the delivered dose across all device types for standard ventilation. Significant variability in the pMDI dosing was evident, depending on the timing of actuation and the adapter type used. pMDI actuation synchronised with inspiration resulted in a higher delivered drug dose. The type of adapter used for pMDI actuation influenced drug delivery, with the highest dose observed using the CombiHaler.