Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler® Device in Healthy Subjects, Asthmatic Patients, and COPD Patients

Johann Christian Virchow, Gianluigi Poli, Christiane Herpich, Claudius Kietzig, Hilke Ehlich, Daniela Braeutigam, Knut Sommerer, Sabine Häussermann, Fabrizia Mariotti, Johann Christian Virchow, Gianluigi Poli, Christiane Herpich, Claudius Kietzig, Hilke Ehlich, Daniela Braeutigam, Knut Sommerer, Sabine Häussermann, Fabrizia Mariotti

Abstract

Background: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) (100/6 μg) delivered as an extrafine dry powder formulation (mass median aerodynamic diameter, MMAD (μm) BDP = 1.5; FF = 1.4) through the NEXThaler® device in healthy subjects, asthmatics, and patients with COPD.

Methods: Healthy subjects (n = 10), asthmatic patients (n = 9; 30%≤FEV1 < 80%), and COPD patients (n = 9; FEV1/FVC ≤70%, 30%≤FEV1 < 50%) completed this open-label, single administration (inhalation of four actuations) parallel group study. After inhalation of 99mTc-radiolabeled BDP/FF combination (radiolabeled BDP + unlabeled FF), the drug deposition was assessed using a gamma-scintigraphy technique. Patients' lung function was assessed.

Results: No significant difference in drug deposition was observed between the three study groups. Mean lung deposition, extrathoracic deposition, and amount exhaled ranged, respectively, between 54.9% and 56.2%, between 41.8% and 43.2%, and between 1.6% and 3.3% of BDP emitted dose (71.7 ± 2.5 μg) for the three study groups. The central to peripheral ratio (reflecting the lung distribution pattern) ranged between 1.23 and 2.02 for the three study groups, indicating a distribution of the drug throughout the airways, including periphery. The study treatment produced a forced expiratory volume in one second (FEV1) increase over time, reaching a maximum improvement generally within 1-4 hours.

Conclusions: The fixed extrafine dry powder combination BDP/FF (100/6 μg) administered through the DPI NEXThaler® achieved similar intrapulmonary deposition in healthy subjects, in asthmatic patients, and COPD patients (approximately 55% of emitted dose) irrespective of the underlying lung disease with a negligible amount of exhaled particles. The study showed high reliability of the device, reproducible dosing, and distribution throughout the lungs. The results supported the concept of efficient delivery of the combination to the target pulmonary regions, thanks to the extrafine formulation. FEV1 profile confirmed a relevant pharmacodynamic effect of the product.

Keywords: BDP/formoterol combination; COPD; NEXThaler® DPI; asthma; inhaled drug; lung deposition.

Conflict of interest statement

Johann Christian Virchow has served as Coordinating Investigator for another clinical study from Chiesi. Gianluigi Poli and Fabrizia Mariotti are employees at Chiesi Farmaceutici SpA, which sponsored the study. Christiane Herpich, Claudius Kietzig, Hilke Ehlich, Daniela Zanker, and Knut Sommerer are employees at Inamed GmbH, the Contract Research Organization, employed by Chiesi, responsible for coordinating the study. Sabine Häussermann was employee at Inamed GmbH at the time of study execution.

Figures

FIG. 1.
FIG. 1.
Definition of central, intermediate, and peripheral regions of interest relative to the total lung.
FIG. 2.
FIG. 2.
Particle size distribution of unlabeled BDP (reference) and radiolabeled BDP. Radiolabeled BDP measured by radioactivity and by ACI and HPLC (mean ± SD of three batches). Unlabeled BDP (reference) measured by ACI and HPLC only (mean ± SD of three inhalers from one batch). ACI, Andersen Cascade Impactor; BDP, beclometasone dipropionate; HPLC, high-performance liquid chromatography.
FIG. 3.
FIG. 3.
Log-probability plot of cumulative particle size distribution of unlabeled BDP (reference) and radiolabeled BDP. Radiolabeled BDP measured by radioactivity and by ACI and HPLC (mean of three batches). Unlabeled BDP (reference) measured by ACI and HPLC only (mean of three inhalers from one batch).
FIG. 4.
FIG. 4.
Particle size distribution of Formoterol in the formulation containing unlabeled BDP (reference) and in the formulation containing radiolabeled BDP. Formoterol measured by ACI and HPLC in both formulations (mean ± SD of three radiolabeled batches and of three inhalers from one unlabeled batch).
FIG. 5.
FIG. 5.
Histogram showing mean (±SD) drug deposition in healthy subjects (n = 10), asthma patients (n = 9), and COPD patients (n = 9), after inhalation of four actuations of BDP/FF (100/6 μg) NEXThaler®. FF, formoterol fumarate.
FIG. 6.
FIG. 6.
Central to peripheral deposition (C/P) in healthy subjects (n = 10), asthmatic patients (n = 9), and COPD patients (n = 9) after inhalation of four actuations of BDP/FF (100/6 μg) NEXThaler®.
FIG. 7.
FIG. 7.
Scintigraphy in individual subject (healthy subject no. 13: DL 55.2%, DE 42.2%, C/P 1.12; asthmatic patient no. 15: DL 57.4%, DE 41.3%, C/P 2.01; COPD patient no. 16: DL 53.6%, DE 42.8%, C/P 1.40%).
FIG. 8.
FIG. 8.
Definition of central, intermediate, and peripheral regions of interest relative to the total lung in individual subject (healthy subject no. 13; asthmatic patient no. 15; COPD patient no. 16).
FIG. 9.
FIG. 9.
81mKrypton-ventilation scan in individual subject (healthy subject no. 13; asthmatic patient no. 15; COPD patient no. 16).
FIG. 10.
FIG. 10.
Mean (±SD) forced expiratory volume in 1 second (FEV1) over time in asthmatic patients (n = 9) and COPD patients (n = 9) after inhalation of four actuations of BDP/FF (100/6 μg) NEXThaler®. FEV1, forced expiratory volume in one second.

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