Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Background: Inhalation errors are a common source of underdosing in asthma therapy, leading to poor asthma control. Therefore, regular inhalation training is recommended. The Kata® app is a digital inhalation coach that provides step-by-step guidance on how to inhale effectively. This analysis evaluated the effect of the app on inhalation technique and clinical endpoints (fractional exhaled nitric oxide [FeNO]; Asthma Control Questionnaire [ACQ-5]) in a clinical trial. Methods: This post hoc analysis of app data collected during a phase-II randomized controlled trial, included adult patients with moderate-to-severe, uncontrolled type-2 high asthma (N = 78). A smartphone with the study-specific app version was provided and patients' usual asthma maintenance treatment entered. Inhalations were video recorded whenever the inhalation coach was used. Inhalation errors were scored by trained experts according to predefined criteria. Rates for total and critical errors (significantly affecting drug delivery) were calculated as the number of errors per inhalation. Analysis of clinical endpoints used data from the run-in phase only to avoid interference with study interventions. Results: Univariate regression analysis showed a significant decrease of the total error rate of 1.4% per study day (p < 0.001; 95% CI: 0.8-1.9) and of the critical error rate (1.8% per study day; p < 0.001; 95% CI: 1.0-2.6). A significant reduction of the ACQ-5 score was found for the run-in phase (p = 0.036; N = 59). The mean (SD) ACQ-5 change (V2-V0) was -0.2 (0.7), reflecting a small improvement of asthma control. A clinically relevant improvement of the ACQ-5 score was found in 18 of 59 patients (31%). No significant improvement of FeNO was found (p = 0.170; N = 60). However, 26 of 60 patients (43%) showed a clinically relevant decrease (>20%) of FeNO. Conclusions: The Kata app improved inhalation technique and this was accompanied by a small improvement of asthma control. The Kata app is a useful tool for patients using inhalers to treat their asthma.

Background: Aerosol delivery via high-flow nasal cannula (HFNC) with an inspiration-synchronized vibrating mesh nebulizer (VMN) yielded higher inhaled doses than with a continuous VMN. Recently, a prototype VMN generating aerosol particles <3 µm improved aerosol delivery during invasive ventilation in adult and pediatric models, outperforming the conventional VMN. However, the effects of inspiration-synchronized small-particle VMN during HFNC remain unknown. Methods: An adult manikin was connected to a dual-chamber lung model driven by a ventilator to simulate spontaneous breathing. An HFNC system was utilized with gas flows at 15, 30, and 60 L/min with temperature at 37°C. Both small-particle and conventional VMNs were tested in inspiration-synchronized and continuous modes, with placements at the humidifier inlet and near the nasal cannula. Each experiment involved delivering 1 mL of albuterol (2.5 mg/mL) and was repeated five times. A collecting filter placed at the trachea captured aerosol, which was then eluted and assayed with UV spectrophotometry (276 nm). Results: When VMN was placed near the nasal cannula, inspiration-synchronized VMN consistently delivered greater inhaled doses compared with continuous VMN, regardless of aerosol particle sizes or HFNC flows (all p < 0.05). When positioned at the humidifier inlet, continuous VMN yielded higher inhaled doses than inspiration-synchronized VMN at 30 and 60 L/min but lower inhaled doses at 15 L/min (all p < 0.05). In the inspiration-synchronized mode, the small-particle VMN delivered greater inhaled doses at HFNC flows of 15 and 30 L/min than the conventional VMN, independent of nebulizer placements (all p < 0.05). The highest inhaled dose was observed with the inspiration-synchronized VMN placed near the nasal cannula and the continuous VMN placed at the humidifier inlet. Conclusions: In a model of adult transnasal aerosol delivery, the inspiration-synchronized VMN delivered a higher inhaled dose than the continuous VMN when placed near the nasal cannula. The small-particle VMN offers potential for further improvement in aerosol delivery.

Background: The "Miller" design of mixing inlet (MI) enables a cascade impactor to operate at a constant flow rate while the orally inhaled product-on-test is evaluated at varying flow rates by controlling the flow of air via its side-arm. Study Purpose: As part of the European Pharmaceutical Aerosol Group (EPAG) Impactor subgroup, we report a cross-industry experimental investigation by five organizations to determine internal losses of different inhaler-generated aerosolized medications within commercially available MIs, focusing on pharmacopeial methods for product testing. Methods: Evaluations were undertaken of solution and suspension formulations delivered by pressurized metered dose inhalers (pMDIs), passive dry powder inhalers (DPIs), and compressed air-jet and vibrating mesh nebulizers. Four different apparatuses were evaluated at different constant air flow rates entering the MI side arm. The nebulizers were tested utilizing a variable adult flow profile generated by a breathing simulator. Results: Losses within the MI were generally <5%, expressed as a percentage of the delivered mass of active pharmaceutical ingredient (API) ex-inhaler. These losses were sufficiently small that they can in most cases be accommodated within the allowance of ±5% OIP label claim emitted mass/actuation in the pharmacopeial compendia for total internal losses for aerodynamic particle size distribution (APSD) determination. However, corresponding average losses were between 2.8% and 5.2% of the mass of API presented to the MI for the blister-based DPIs. APSD-derived measures were largely unaffected by the magnitude of pressurized air flow up to 60 L/min to the side-arm of the MI, except for the solution-formulated pMDI, where increasing flow rate was associated with reduced mass median aerodynamic diameter and increased geometric standard deviation, suggestive of a dependency related to ethanol co-solvent evaporation rate. Conclusions: MI loss evaluation should be considered an important part of method development to minimize internal losses of the aerosolized medication being sampled.

Inhaler-based digital biomarkers can be objectively evaluated to indicate changes in response to therapeutic interventions. In chronic respiratory disease (CRD), measures of exhaled airflow play a central role in diagnosis and management, yet inhaled measures have not. Digital inhalers can passively collect inspiratory parameters such as inhaled volume (InhV) and peak inspiratory flow (PIF) during real-life patient use. Emphasis has been directed to the PIF, but little is known about the role of the InhV. InhV has now been observed to decrease prior to an exacerbation of asthma or chronic obstructive pulmonary disease and increase afterwards and be lower in uncontrolled asthma patients. These observations are consistent with the current understanding of the pathophysiology of CRD, whereby a strong correlation between InhV and forced expiratory volume in one second has been observed. Measurement of InhV has demonstrated accuracy and low variability, supporting the validity of interpreting individualized trends over time. After counseling, patient inhalation technique decays over time, and it is InhV that decreases more than PIF. Together, these findings suggest that InhV, captured by a digital inhaler, has utility as an effective digital biomarker to aid management of patients with CRD, with InhV being a major factor in the predictive value with respect to acute exacerbations.

Introduction: Receiving wrong health education from health care professionals (HCPs) might contribute to patients' poor inhaler technique. We set out to investigate HCPs' knowledge on asthma and metered-dose inhaler technique in selected health facilities in Dar es Salaam, Tanzania. Methods: In a cross-sectional study done from August 2020 to February 2021, participant's demographics were recorded. The inhaler technique was assessed using a 12-step checklist. Participants had correct inhaler technique when all the steps were performed correctly; otherwise, the technique was poor. An 18-question questionnaire for health care professional knowledge was used to assess asthma knowledge. One point was awarded to each correctly answered question, whereas a zero point was given to a wrongly answered or unanswered question. Knowledge was adequate if the score was 13/18 or higher. Chi-square was used to compare categorical data, while analysis of variance was used for comparison of mean scores for asthma knowledge and inhaler technique. A p value ≤0.05 was considered significant. Results: A total of 114 participants were enrolled; 57% were medical officers, and 59.6% had work experience of <5 years. The majority (53.5%) had no training on inhaler technique, and 75% had inadequate knowledge on asthma. Good asthma knowledge was associated with age ≥40 years (p = 0.039) and being a medical specialist (p = 0.002). Only 4.4% of the participants did all the steps of inhaler technique correctly. Conclusion: Knowledge on asthma and inhaler use technique is generally lacking among health care professionals. In-service training on asthma and inhaler demonstration should be considered for HCPs in asthma clinics.

Background: Sarcoidosis is a multisystem granulomatous disease that often impacts the lungs with mucosal inflammation, cobblestoning of the central airways, obstruction, and small airway disease. Airway involvement is often under-reported and not well understood, despite likely having implications for the work of breathing and particle dosimetry. Methods: To shed light on sarcoidosis disease with airway involvement, we performed patient-specific computational fluid dynamics and particle transport simulations in three subjects, for a few generations of the large conducting airways, with various presentations of airway disease. While Patient A had peripheral obstruction as identified from pulmonary function tests (PFTs), airway models created from computed tomography (CT) scans highlighted lower left lobe central airway abnormalities. Patient B presented with airway obstruction and diffusive stenosis throughout all five lobes while Patient C had normal PFTs and CT scans. Results: Localized central airway remodeling in Patient A resulted in localized elevation in dosimetry but no changes in total dosimetry or airway resistances, as also seen in Patient C. The subject with diffusive remodeling had abnormally high airway resistances and central airway deposition within the 3D-modeled airways. Conclusions: Results from this pilot study suggest that patients with diffuse remodeling may have enhanced susceptibility to environmental pollutants due to increased aerosol dosimetry. For aerosol medication treatment, the subject with diffusive airway remodeling may not receive adequate therapeutic dose if the goal is to deliver medication to the lung periphery. This study provides the first glimpse of airflow, resistances, and particle dosimetry in sarcoidosis subjects. Future studies should focus on phenotyping airway abnormalities in a larger sarcoidosis cohort and performing whole lung dosimetry modeling.

Background: Tanimilast is a novel phosphodiesterase-4 inhibitor under clinical development for the maintenance therapy of asthma and chronic obstructive pulmonary disease (COPD). Since tanimilast is inhaled, it is important to evaluate lung deposition as part of its clinical development. The current study, therefore, used functional respiratory imaging, a validated, noninvasive quantification imaging methodology, to evaluate the lung deposition of tanimilast in patients with asthma or COPD. Methods: This retrospective study used data from 12 patients with asthma and 12 patients with COPD, primarily selected based on disease severity. Patients with COPD had chronic bronchitis, with minimal high-resolution computerized tomography evidence of emphysema. Total intrathoracic, central, distal, peripheral, and extrathoracic deposition of tanimilast 400 µg and 800 µg was evaluated using three inhalation profiles-inhalation durations of 1, 2, and 3 seconds, with associated peak flows of 100, 60, and 45 L/min, respectively. Results: Intrathoracic deposition as a percentage of the delivered dose was similar in asthma and COPD, with mean ± SD varying between 34.6 ± 8.5% and 44.9 ± 5.9%, increasing slightly with increasing inhalation duration (i.e., from 1 to 3 seconds), whereas extrathoracic deposition decreased progressively. Central deposition was low (<5%) regardless of inhalation duration (2.7 ± 0.9% to 4.4 ± 1.6%). Distal deposition was similar with the two tanimilast doses and although not impacted by inhalation duration was slightly higher in COPD than asthma. Peripheral deposition increased with increasing inhalation duration (e.g., in asthma for tanimilast 400 µg, from 14.1 ± 3.6% for a duration of 1 second to 19.9 ± 4.0% for a duration of 3 seconds) and was higher in asthma than in COPD. Conclusions: Tanimilast effectively reached all levels of the airway in patients with asthma or COPD. Peripheral deposition was enhanced by lower inspiratory flows (i.e., longer inhalation durations), suggesting that specific inhalation strategies may have the potential to improve therapeutic outcomes in obstructive lung diseases.

Background: Clofazimine inhalation suspension is a novel formulation of clofazimine developed as a potential lung-targeted treatment for pulmonary nontuberculous mycobacteria disease. Methods: Safety and toxicokinetic parameters were assessed in 28-day, repeat-dose studies of up to 3.59 mg/kg/day clofazimine inhalation suspension in 8-week-old Sprague Dawley rats and up to 2.72 mg/kg/day in 5-7-month-old beagle dogs with 56-day recovery periods. A 6-month inhalation toxicity study without recovery was also conducted in beagle dogs, with daily doses up to 2.95 mg/kg for 182 days. Results: No adverse effects were observed, but minimal to mild nonadverse pulmonary changes were observed in high-dose treatment groups. The no-observed-adverse-effect levels were a sex-averaged 1.78 mg/kg in rats (28 days) and 2.73/2.95 mg/kg in male/female dogs (182 days). Median time to maximum concentration ranged from 6 to 12 hours and 0.5 to 6 hours in the rat and dog studies, respectively. Plasma area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased dose-dependently and exhibited accumulation ratios ≥∼2 in both 28-day studies. Clofazimine concentrations in lung tissue were dose-dependent in all 3. Discussion: Clofazimine inhalation suspension was well tolerated at doses supporting multifold safety margins for the ongoing phase 3 ICoN-1 study. Lung concentrations exceeded the estimated minimum inhibitory concentration against Mycobacterium avium complex, even after 56 days of recovery.