Comparison of peak inspiratory flow rate via the Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very severe COPD: a randomized cross-over trial.

BACKGROUND: The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. METHODS: This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. RESULTS: In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. CONCLUSIONS: Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients' COPD severity, age or gender. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.

Inhalation of tobramycin using simulated cystic fibrosis patient profiles.

INTRODUCTION: TOBI® Podhaler™ is a capsule-based drug-device combination (tobramycin inhalation powder [TIP] 28 mg capsules via unit-dose dry powder T-326 Inhaler [Podhaler™]) developed for treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF). We explored how inspiratory flow profiles and mouth-throat geometries affect drug delivery with the T-326 Inhaler. METHODS: Inspiratory flow profiles were recorded from 38 subjects aged 6-71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDin vitro ) was measured using four anatomical throat models, ranging from a child to a large adult. RESULTS: Aerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDin vitro ranged from 54.8% to 72.4% of capsule content between the flow profile/throat options tested, and the mean TLDin vitro across the range of flow profiles and anatomical throats tested was 63 ± 5%. CONCLUSIONS: Our findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLDin vitro . Pediatr Pulmonol. 2016;51:1159-1167. © 2016 Wiley Periodicals, Inc.

Dose emission characteristics of placebo PulmoSphere® particles are unaffected by a subject's inhalation maneuver.

BACKGROUND: Good compliance to the prescribed dosing regimen and inhaler instructions for use are critical for asthma/chronic obstructive pulmonary disease (COPD) patients to achieve good control of their disease. We investigated the extent to which a system comprising porous particles delivered with a passive dry powder inhaler could be designed to achieve significant reductions in dose inhalation errors. METHODS: Porous placebo particles were prepared by an emulsion-based spray-drying method (PulmoSphere® technology). The formulations were administered as dry powders with a portable, blister-based dry powder inhaler (Simoon Inhaler). The inhalation profiles of 69 asthma/COPD subjects were determined with an inhaler simulator with resistance comparable to that of the Simoon Inhaler. Powder emptying from the device was assessed by laser photometry. Aerosol performance was assessed on a Next Generation Impactor, and with the idealized Alberta mouth-throat model using both square-wave and subject-inhalation profiles generated in the breathing study. RESULTS: Virtually all subjects could achieve a pressure drop of at least 1 kPa and an inhaled volume of at least 500 mL with the Simoon Inhaler. In vitro measures of particle deposition were found to be largely independent of the inhalation maneuver (flow rate, inhaled volume, ramp time) across the broad range of inhalation profiles observed in the breathing study. The rapid emptying of powder from the Simoon Inhaler minimizes the impact of dose-related errors, such as failure to exhale before inhalation and failure to breath-hold post inhalation. CONCLUSIONS: Inertial impaction that is largely independent of a subject's inhalation maneuver can be achieved with a drug/device combination product comprising a porous particle formulation and blister-based inhaler.

Application of a droplet evaporation model to aerodynamic size measurement of drug aerosols generated by a vibrating mesh nebulizer.

BACKGROUND: Droplet evaporation has been known to bias cascade impactor measurement of aerosols generated by jet nebulizers. Previous work suggests that vibrating mesh nebulizers behave differently from jet nebulizers. Unlike jet nebulizers, vibrating mesh nebulizers do not rely on compressed air to generate droplets. However, entrained air is still required to transport the generated droplets through the cascade impactor during measurement. The mixing of the droplet and entrained air streams, and heat and mass transfer occurring downstream determines the final aerosol size distribution actually measured by the cascade impactor. This study is aimed at quantifying the effect of these factors on droplet size measurements for the case of vibrating mesh nebulizers. METHODS: A simple droplet evaporation model has been applied to investigate aerodynamic size measurement of drug aerosol droplets produced by a proprietary vibrating mesh nebulizer. The droplet size measurement system used in this study is the Next Generation Impactor (NGI) cascade impactor. Comparison of modeling results with experiment indicates that droplet evaporation remains a significant effect when sizing aerosol generated by a vibrating mesh nebulizer. RESULTS AND CONCLUSIONS: Results from the droplet evaporation model shows that the mass median aerodynamic diameter (MMAD) measured by the NGI is strongly influenced not only by the initial droplet size, but also by factors such as the temperature and humidity of entrained air, the nebulizer output rate, and the entrained air flow rate. The modeling and experimental results indicate that the influence of these variables on size measurements may be reduced significantly by refrigerating the impactor down to 5°C prior to measurement. The same data also support the conclusion that for the case of nebulized drug solutions, laser diffraction spectrometry provides a meaningful droplet sizing approach, that is simpler and less susceptible to such droplet evaporation artifacts.