Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C / 15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.

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In vivo carbon dioxide clearance of a low-flow extracorporeal carbon dioxide removal circuit in patients with acute exacerbations of chronic obstructive pulmonary disease

Perfusion ◽

10.1177/0267659119896531 ◽

2020 ◽

Vol 35 (5) ◽

pp. 436-441 ◽

Cited By ~ 1

Author(s):

Nicholas A Barrett ◽

Nicholas Hart ◽

Luigi Camporota

Keyword(s):

Carbon Dioxide ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Gas Flow ◽

Carbon Dioxide Removal ◽

Chronic Obstructive ◽

Extracorporeal Carbon Dioxide Removal ◽

Obstructive Pulmonary Disease ◽

Acute Exacerbations

Background: Veno-venous extracorporeal carbon dioxide removal allows clearance of CO2 from the blood and is becoming popular to enhance protective mechanical ventilation and assist in the management of acute exacerbations of chronic obstructive pulmonary disease, including the prevention of intubation. The main factor determining CO2 transfer across a membrane lung for any given blood flow rate and venous CO2 content is the sweep gas flow rate. The in vivo characteristics of CO2 clearance using ultra-low blood flow devices in patients with acute exacerbations of chronic obstructive pulmonary disease has not been previously described. Methods: Patients commenced on extracorporeal carbon dioxide removal for acute exacerbations of chronic obstructive pulmonary disease recruited to a randomized controlled trial of non-invasive ventilation versus extracorporeal carbon dioxide removal had pre- and post-membrane circuit gases measured after each increment of sweep gas flow to allow calculation of the transmembrane CO2 clearance. This was compared with the clearance reported by the device and also corrected to inlet PCO2 to allow characterization of the CO2 clearance of the device at different sweep gas flow rates. Results: CO2 clearance was calculated using both the transmembrane CO2 whole-blood content difference and CO2 clearance reported by the device. The two methods demonstrated a linear relationship and agreement with a bias of 14 mL/minute (SD = ±10) and an R2 of 0.92. The membrane CO2 clearance was non-linear with nearly two thirds of total clearance achieved with sweep gas flow below 2 L/minute (VCO2 of 40 ± 16.7 mL/minute) and a plateau above 5 L/minute sweep gas flow (VCO2 64 ± 1 2.4 mL/minute). Conclusion: The extracorporeal carbon dioxide removal device used in the study provides efficient clearance of CO2 at low sweep flow rates which then plateaus. This has implications for how the device may be used in clinical practice, particularly during the weaning phase where the final discontinuation of the device may take longer than anticipated. (ClinicalTrials.gov: NCT02086084, registered 13 March 2014, https://clinicaltrials.gov/ct2/show/NCT02086084 )

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A generic fluticasone propionate and salmeterol dry powder inhaler: Evidence of usability, function, and robustness

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.200112 ◽

2021 ◽

Vol 42 (1) ◽

pp. 30-35 ◽

Cited By ~ 1

Author(s):

Donald P. Tashkin ◽

Arkady Koltun ◽

Róisín Wallace

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Fluticasone Propionate ◽

Healthy Volunteers ◽

Pulmonary Disease ◽

Dry Powder Inhaler ◽

Chemical Degradation ◽

Chronic Obstructive ◽

Dry Powder ◽

Obstructive Pulmonary Disease ◽

Flow Rates

Background: A generic combination of fluticasone propionate and salmeterol xinafoate inhalation powder in a premetered, multidose, nonreusable inhaler was recently approved. Objective: To assess the performance of the generic device. Methods: Findings from three studies with regard to device usability, function, and robustness were reviewed. Results: In a study to assess device function in patients and healthy volunteers, the generic device was successfully used by patients with asthma and chronic obstructive pulmonary disease who were either dry powder inhaler users or dry powder inhaler‐naive, even though they were not trained beyond being provided the instructions for use. In a study to measure inhaled flow rates generated by patients and healthy volunteers, the generic device consistently simulated the delivery of a full dose of drug, even to patients with severe respiratory disease and reduced inspiratory flow rates. Although the generic device had a slightly higher airflow resistance, this study demonstrated that this difference did not result in any clinically meaningful differences in terms of drug delivery. Pressure drop, a key parameter that drives the fluidization and aerosolization of the powder dose, was found to be comparable between the devices. In an open-label study, the generic device met all U.S. Food and Drug Administration specifications for device robustness after 21.5 days of twice-daily dosing via oral inhalation among 111 participants with asthma or chronic obstructive pulmonary disease. All inhalers tested demonstrated conformity with a pharmacopeia with respect to key quality parameters (assay, delivered dose uniformity, aerodynamic size distribution). There was no evidence of chemical degradation of the active ingredients, nor of microbial or water ingress into the powder, as a result of inhaler use.

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