Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus Other Combination Products: the DIFFUSE Study

Abstract

Introduction: The efficacy of inhaled products is affected by the degree, and potentially the site, of drug particle deposition in the lungs. Lung deposition correlates with the fine particle fraction (FPF; the proportion of dose containing particles\5 lm in aerodynamic diameter). This in vitro study (defining fluticasone propionate/ formoterol particulate size [DIFFUSE]) examined the effects of inhalation flow rate on the FPF of the fluticasone propionate/formoterol (FP/FORM) pMDI aerosol compared with three other inhaled corticosteroids/long- acting b2-agonist (ICS/LABA) combination therapies administered by either DPI or pMDI [fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (BUD/FORM) and beclometasone dipropionate/formoterol (BDP/ FORM)].Methods: Aerodynamic particle size distribution was determined for each product using an 8-stage Andersen Cascade Impactor at two inhalation flow rates: 28.3 and 60.0 L/min. Fine particle dose (mass of dose\5.0 lm) and FPF were calculated as a percentage of the labeled dose for the LABA and ICS of each product at both flow rates. Results: FP/FORM suspension aerosol provided a high and consistent FPF of approximately 40% for the ICS and LABA components at both flow rates. At 28.3 L/min, the FPF of each component of FP/FORM (41.2% and 39.2%) was greater than that of FP/SAL DPI (12.5% and 11.3%), BUD/FORM DPI (8.2% and 6.6%) and BDP/ FORMpMDI (28.5% and 26.0%). At 60.0 L/min, the FPFs of the FP/FORM components (43.7% and 42.1%) were greater than those of FP/SAL (17.8% and 14.8%) and BUD/FORM (35.0% and 30.1%), and similar to those of BDP/FORM (43.0% and 39.5%). Discussion: The FP/FORM suspension aerosol produced a high and consistent FPF of approximately 40% across both flow rates. The consistent FPF in vitro may be predictive of FP/ FORM providing more consistent drug dosing in vivo, helping to counteract variable lung dose due to variation in inspiratory flow rate among patients and between a patient’s day-to- day or successive inhalation maneuvers. Keywords: Aerodynamic particle size distribution; Andersen Cascade Impactor; Bronchodilators; Fine particle fraction; Flow rate dependency; Inhaled corticosteroids/long- acting b2-agonist combination products; Pressurized metered-dose inhalers; Respiratory