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

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.

The Relevance of Targeting Treatment to Small Airways in Asthma and COPD

“…3 Compared with nonextrafine formulations, the intrapulmonary deposition of extrafine particles studied with the gamma scintigraphy technique, multi-slice CT scans, and computational fluid dynamics in subjects with moderate and severe COPD exhibited better regional lung deposition as well as significant improvements in static lung volumes and a reduction in extrathoracic drug deposition. 147,150,189 This observation supports other results indicating that exposure to lower doses of ICS with the administration of an extrafine formulation of beclomethasone dipropionate yielded comparable results in preventing exacerbations and better odds of treatment stability at 2 y compared with nonextrafine fluticasone in subjects with moderate to very severe air-flow obstruction. 190 In subjects with COPD, the administration of extrafine beclomethasone dipropionate/formoterol significantly improved FVC, 191 air trapping, 192,193 dyspnea 193 and quality of life.…”

An innovative corticosteroid/long-acting β2-agonist breath-triggered inhaler: facilitating lung delivery of fluticasone propionate/formoterol fumarate for the treatment of asthma

“…The mean penetration index (the ratio of peripheral to central lung deposition) with the k-haler was 0.31, demonstrating that FP and FORM were deposited in both central and peripheral regions of the lung (Figure 3(a-c)), suggesting that FP/FORM delivered by the k-haler effectively reaches small-caliber bronchi [48]. The 43.0% lung deposition, as a percentage of metered or nominal dose, of the FP/FORM k-haler compares well with that of other ICS/LABA inhalers in patients with asthma, with a higher deposition than that reported for the FP/SAL pMDI (14.7% of nominal dose) [52], beclometasone dipropionate [BDP]/FORM pMDI (30.9% of nominal dose) [53], and BDP/FORM NEXThaler ® (Chiesi Farmaceutici, Parma, Italy) (40.3% of nominal dose) [54]. Thus, the promising in vitro characteristics seem to translate to high levels of lung deposition.…”

Lung Deposition and Inspiratory Flow Rate in Patients with Chronic Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review and Expert Opinion

“… 69 Furthermore, clear differences in lung deposition were not observed when patients performed inhalation correctly. 68 For the main DPI devices, the published lung deposition rates from individual studies (without direct comparisons) are as follows: Accuhaler ® 7.6%, 70 Aerolizer ® 13%–20%, 34 , 71 Breezhaler ® 26.8%–39%, 24 , 29 Easyhaler ® 18.5%–31%, 71 , 72 Genuair ® 30.1%–51.1%, 27 , 73 , 74 Handihaler ® 9.8%–46.7%, 19 , 24 , 71 Ingelheim inhaler ® 16%–59%, 75 NEXThaler ® 39.4%–56%, 11 , 76 Spinhaler ® 11.5%, 75 Turbuhaler ® 14.2%–69.3%, 21 , 42 , 77–79 and Twisthaler ® 36%–37%. 80 Similarly to all inhaler devices, other factors are probably influencing the lung deposition rate.…”