Airway Deposition of Extrafine Inhaled Triple Therapy in Patients with COPD: A Model Approach Based on Functional Respiratory Imaging Computer Simulations.

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting ß2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs. Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients' high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition. Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively). Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.

Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages.

Raman spectroscopy has been positively evaluated as a tool for the in-line and real-time monitoring of powder blending processes and it has been proved to be effective in the determination of the endpoint of the mixing, showing its potential role as process analytical technology (PAT). The aim of this study is to show advantages and disadvantages of Raman spectroscopy with respect to the most traditional HPLC analysis. The spectroscopic results, obtained directly on raw powders, sampled from a two-axis blender in real case conditions, were compared with the chromatographic data obtained on the same samples. The formulation blend used for the experiment consists of active pharmaceutical ingredient (API, concentrations 6.0% and 0.5%), lactose and magnesium stearate (as excipients). The first step of the monitoring process was selecting the appropriate wavenumber region where the Raman signal of API is maximal and interference from the spectral features of excipients is minimal. Blend profiles were created by plotting the area ratios of the Raman peak of API (AAPI) at 1598cm-1 and the Raman bands of excipients (AEXC), in the spectral range between 1560 and 1630cm-1, as a function of mixing time: the API content can be considered homogeneous when the time-dependent dispersion of the area ratio is minimized. In order to achieve a representative sampling with Raman spectroscopy, each sample was mapped in a motorized XY stage by a defocused laser beam of a micro-Raman apparatus. Good correlation between the two techniques has been found only for the composition at 6.0% (w/w). However, standard deviation analysis, applied to both HPLC and Raman data, showed that Raman results are more substantial than HPLC ones, since Raman spectroscopy enables generating data rich blend profiles. In addition, the relative standard deviation calculated from a single map (30 points) turned out to be representative of the degree of homogeneity for that blend time.

Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the long-acting muscarinic antagonist glycopyrronium.

OBJECTIVES: The long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237) has recently been approved as a once-daily treatment for COPD. The objectives of this study were to determine the dose delivery characteristics of glycopyrronium and compare them with those of the LAMA tiotropium, both delivered by their respective capsule-based dry-powder inhalers (DPIs). RESEARCH DESIGN AND METHODS: Seven inhalation profiles derived from patients with moderate and severe COPD were reproduced to determine the aerodynamic particle size distribution of glycopyrronium delivered by the Breezhaler device, a low-resistance DPI†. Theoretical respiratory tract deposition was estimated using a semi-empirical model for healthy lungs. These results were compared with those of tiotropium delivered by the high-resistance HandiHaler‡ device obtained in a previous study using the same set of inhalation profiles. Study limitations are that fine particle fraction (FPF) and particle size are generated by the inhalers are not a direct measure of lung deposition, and the bronchodilator effect of inhaled drugs does not depend solely upon the percentage of the total dose that reaches the lung. RESULTS: The mean FPF (≤4.7 µm) was 42.6% of the nominal dose (which refers to the content of the capsule) for glycopyrronium and 9.8% for tiotropium while the mass median aerodynamic diameter (MMAD) was 2.8 µm and 3.9 µm for glycopyrronium and tiotropium, respectively. The mean estimated intrathoracic drug deposition as a percentage of the mean dose delivered to the Next Generation Impactor was 39% for glycopyrronium and 22% for tiotropium. CONCLUSIONS: The glycopyrronium capsule-based DPI delivered a higher FPF and greater and more consistent intrathoracic deposition irrespective of age and disease severity compared to the tiotropium capsule-based DPI, suggesting that it may be suitable for use by patients with a wide range of COPD severities.