Effect of Flow Rate on In Vitro Aerodynamic Performance of NEXThaler(®) in Comparison with Diskus(®) and Turbohaler(®) Dry Powder Inhalers

Francesca Buttini, Gaetano Brambilla, Diego Copelli, Viviana Sisti, Anna Giulia Balducci, Ruggero Bettini, Irene Pasquali, Francesca Buttini, Gaetano Brambilla, Diego Copelli, Viviana Sisti, Anna Giulia Balducci, Ruggero Bettini, Irene Pasquali

Abstract

Background: European and United States Pharmacopoeia compendial procedures for assessing the in vitro emitted dose and aerodynamic size distribution of a dry powder inhaler require that 4.0 L of air at a pressure drop of 4 kPa be drawn through the inhaler. However, the product performance should be investigated using conditions more representative of what is achievable by the patient population. This work compares the delivered dose and the drug deposition profile at different flow rates (30, 40, 60, and 90 L/min) of Foster NEXThaler(®) (beclomethasone dipropionate/formoterol fumarate), Seretide(®) Diskus(®) (fluticasone propionate/salmeterol xinafoate), and Symbicort(®) Turbohaler(®) (budesonide/formoterol fumarate).

Methods: The delivered dose uniformity was tested using a dose unit sampling apparatus (DUSA) at inhalation volumes either 2.0 or 4.0 L and flow rates 30, 40, 60, or 90 L/min. The aerodynamic assessment was carried out using a Next Generation Impactor by discharging each inhaler at 30, 40, 60, or 90 L/min for a time sufficient to obtain an air volume of 4 L.

Results: Foster(®) NEXThaler(®) and Seretide(®) Diskus(®) showed a consistent dose delivery for both the drugs included in the formulation, independently of the applied flow rate. Contrary, Symbicort(®) Turbohaler(®) showed a high decrease of the emitted dose for both budesonide and formoterol fumarate when the device was operated at airflow rate lower that 60 L/min. The aerosolizing performance of NEXThaler(®) and Diskus(®) was unaffected by the flow rate applied. Turbohaler(®) proved to be the inhaler most sensitive to changes in flow rate in terms of fine particle fraction (FPF) for both components. Among the combinations tested, Foster NEXThaler(®) was the only one capable to deliver around 50% of extra-fine particles relative to delivered dose.

Conclusions: NEXThaler(®) and Diskus(®) were substantially unaffected by flow rate through the inhaler in terms of both delivered dose and fine particle mass.

Keywords: Diskus®; NEXThaler®; NGI flow rate; Turbohaler®; aerodynamic assessment; extra-fine particle mass.

Figures

FIG. 1.
FIG. 1.
Delivered dose (% of the label claim) performance of the NEXThaler (A), Diskus (B), and Turbohaler (C) at different flow rates; inhalation volume 4L. Error bars represent standard deviations (n=6).
FIG. 2.
FIG. 2.
Delivered dose of formoterol fumarate (A) and beclomethasone dipropionate (B) from NEXThaler as a function of inhalation volume (2L and 4L) and different air flow rates (values are mean (SD), n=10).
FIG. 3.
FIG. 3.
Fine particle mass expressed as amount of formoterol (FF) (A) and beclometasone dipropionate (BDP) (B) below 2 μm and below 5 μm when NEXThaler was activated at different flow rates, inhalation volume 4L (n=6).
FIG. 4.
FIG. 4.
Fine particle mass expressed as amount of salmeterol (as xinafoate) (SX) (A) and fluticasone propionate (FP) (B) below 2 μm and below 5 μm when Diskus was activated at different flow rates, inhalation volume 4L (n=6).
FIG. 5.
FIG. 5.
Fine particle mass expressed as amount of formoterol (FF) (A) and budesonide (BD) (B) below 2 μm and below 5 μm when Turbohaler was activated at different flow rates, inhalation volume 4L (n=6).
FIG. 6.
FIG. 6.
Extrafine particle fraction (0–2 μm) expressed as percentage of dose delivered of the long-acting beta agonist (LABA) and corticosteroid released from products at 60 L/min, inhalation volume 4L (n=6).
FIG. 7.
FIG. 7.
Stage by stage deposition profiles of formoterol fumarate (A) and beclomethasone dipropionate (B) inside the Andersen Cascade Impactor and Next Generation Impactor after NEXThaler aerosolization at 60 L/min, inhalation volume 2 and 4L (values are mean (SD), n=3).

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