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/longacting b 2-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/ FORM pMDI (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

Fluticasone propionate/formoterol: A fixed-combination therapy with flexible dosage

“…At 60 lpm, the optimal inhalation flow with both DPIs, the MMAD, GSD and FPF of labeled dose were, respectively, 4.0, 2.0 and 15% for salmeterol and 3.7, 1.8 and 18% with fluticasone propionate. The MMAD, GSD and FPF of labeled dose were 2.5, 1.9 and 30% with formoterol and 2.5, 1.9 and 35% with budesonide [59]. These results are substantially in accordance with other previously known, where the average MMAD, GSD and Fine Particle Dose of labeled dose were, respectively, 3.5, 1.5 and 18% for salmeterol and 3.6, 1.5 and 20% with fluticasone propionate using the Diskus; and 3.3, 1.6 and 11% with formoterol and 3.1, 1.6 and 13% with budesonide using the Turbuhaler [61].…”

“…It has been demonstrated that the percentage of respirable fraction contained in the aerosol (defined as drug particles with the diameter range between 2 and 5 μm) correlates with the drug deposition in lung tissues [57,58]. The inhaler used for the administration of the fluticasone propionate/ formoterol combination ensures the distribution of an aerosol with a respirable fraction of 40% of the inhaled dose [59], which is consistent at different inspiratory flows, with a plume value of 168 ms [60]. These characteristics facilitate drug deposition throughout the airways.…”

“…The DIFFUSE study has extensively evaluated the particle size distribution of the aerosol delivered by the fluticasone/formoterol combination inhaler at the strength of 5/125 μg in accordance with the European Pharmacopeia [59]. The mean (±SD) Median Mass Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) were respectively 3.52 (±1.59) for the LABA and 3.52 (±1.56) for the ICS at a flow of 28.3 lpm; the Fine Particle Fraction (FPF) of the labeled dose was, respectively, 39% and 41%.…”

Letter in Response to the Review by De Maria et al. 2014

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We would like to clarify some points about the DIFFUSE (Defining fluticasone propionate/ formoterol particulate size) study (December 2013, p 39) [1] in light of the recent review by De Maria and colleagues [2]. Our in vitro study assessed the effects of inhalation flow rate on the aerodynamic particle size distribution Hence, the flow rate dependency of inhalers is of interest to physicians as well as regulators.

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“…Hence, the plates were coated with surfactant when testing the two DPIs [1], as recommended by the European Pharmacopoeia. Coating may be not necessary for testing pMDIs [16,17] Moreover, the total amount of drug recovered from all stages, including from the ACI induction port, was within USP limits.…”