Targeting the Small Airways with Inhaled Corticosteroid/Long-Acting Beta Agonist Dry Powder Inhalers: A Functional Respiratory Imaging Study

Abstract

Background: Peripheral deposition of inhaled medication is important as small airway disease has a key role in asthma. In this study, we compared the lung deposition at different mean flow rates of three inhaled corticosteroid (ICS)/long-acting beta 2 -agonist (LABA) combinations delivered by dry powder inhaler (DPI), that is, Foster NEXThaler Ò (extrafine formulation of beclomethasone/formoterol), Relvar Ellipta Ò (fluticasone furoate/vilanterol trifenatate), and Symbicort Turbohaler Ò (budesonide/formoterol). Materials and Methods: In vitro drug delivery parameters were applied to lung computerized tomography (CT) scans of 20 asthma patients by functional respiratory imaging (FRI). Aerosol airway deposition patterns were calculated as percentage (standard deviation) intrathoracic versus extrathoracic deposition, percentage peripheral deposition, and central-to-peripheral (C/P) ratio at different inspiratory mean flow rates. Results: At 60 and 40 L/min, intrathoracic deposition of ICS/LABA was significantly higher with NEXThaler versus Ellipta. Peripheral deposition (60 L/min) with NEXThaler was higher than Ellipta for ICS (24.7% [3.5%] vs. 5.0% [2.0%]; p < 0.001) and LABA (25.3% [3.5%] vs. 13.0% [3.0%]; p < 0.001). C/P ratio with NEXThaler was lower (indicating higher peripheral deposition) than Ellipta (ICS: 0.63 vs. 1.63; LABA: 0.63 vs. 0.99). Inspiratory flow rate did not impact lung deposition with NEXThaler or Ellipta. In contrast, Turbohaler performance was negatively impacted by decreasing inspiratory flow rate. In fact, although lung deposition with Turbohaler was similar to that of NEXThaler at 60 L/min, lung deposition with Turbohaler was significantly lower than NEXThaler at both 40 L/min (*30%) and 30 L/min (*50%). Conclusions: Using FRI, we demonstrated better peripheral deposition and C/P ratios of ICS/LABA with NEXThaler versus Ellipta. NEXThaler demonstrated inspiratory flow rate independency of lung deposition versus Turbohaler. These findings suggest that the extrafine formulation is superior to large particle formulations in delivering ICS/LABA consistently both to the large and small airways.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions

“…Right upper panel of Fig. 2 demonstrates the MMAD of Symbicort® Turbuhaler® as a function of inhalation flow rate, while the lower panels illustrate the fine particle fraction (left) and the aerosolized fraction (right) of the same drug derived from the works of Tarsin et al (2004) , Johal et al (2013) , Watz et al (2021) , Chrystyn et al (2015) , Buttini et al (2016) , Bagherisadegi et al (2017) , de Boer et al (2015) , Haikarainen et al (2017) and Assi et al (2006) . It is worth noting that the aerosolized fractions are not measured values, but they were calculated assuming lognormal size distribution with the help of the formula where erf is the error function.…”

“…These relationships are presented in Table 3 . The presented functions are based on the results of impactor measurements on Seebri® Breezhaler® retrieved in Chapman et al (2011) and Colthorpe et al (2013) , Bufomix® Easyhaler® available in Malmberg et al (2014) , Lahelma et al (2015) , Janson et al (2017) and Haikarainen et al (2017) , Relvar® Ellipta® published in Hamilton et al (2015) , Grant et al (2015) and Saeed et al (2019) , Bretaris® Genuair® published in Block et al (2010) and Newman et al (2009) , and on Foster® NEXThaler® published by Buttini et al (2016) , Corradi et al (2014) , Mariotti et al (2011) , de Boer et al (2015) and Watz et al (2021) .…”

BDP/FF NEXThaler to Improve Asthma Control Status in the Real World: The NEWTON Study

“…[9][10][11] The extrafine formulation of BDP/FF also helps to increase the deposition of the active principles into the peripheral airways compared with non-extrafine formulations, allowing a greater proportion of the inhaled drug to reach its pharmacological target in the small airways and reducing systemic exposure. [12][13][14] Multiple devices, such as pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPI), have been developed to administer inhaled therapy. The characteristics of these inhalers, such as the method of powder aerosolization, the minimum and optimum inspiratory flow, the characteristics of the aerosol cloud formed, the method of use, and feedback on the inhalation procedure, play an important role in determining drug delivery and distribution, thus influencing, together with the chosen drug and patient characteristics, the overall effectiveness of the pharmacological treatment.…”

Determination of 18 β-Agonists in Aquatic Products Using High-Performance Liquid Chromatography Tandem Mass Spectrometry

“…However, their excellent function in promoting the lipolysis in animal muscle tissue and further modulate nutrient repartitioning by enhancing protein synthesis in the organism was demonstrated. 2,3 Thus, these compounds, typically clenbuterol, salbutamol, and ractopamine, are widely applied in livestock industry, especially swine and cattle, 4,5 to improve the feed conversion and growth rate. Moreover, previous reports have shown the accumulation of βagonists in different tissues of food animals.…”

“…These compounds are initially designed for therapeutic use in the treatment of asthma and preterm labor in humans. However, their excellent function in promoting the lipolysis in animal muscle tissue and further modulate nutrient repartitioning by enhancing protein synthesis in the organism was demonstrated. , Thus, these compounds, typically clenbuterol, salbutamol, and ractopamine, are widely applied in livestock industry, especially swine and cattle, , to improve the feed conversion and growth rate. Moreover, previous reports have shown the accumulation of β-agonists in different tissues of food animals. , The uncontrolled use of β-agonists can cause dangerous poisoning accidents in the liver and cardiovascular and central nervous diseases in meat consumers.…”