Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Background: Intranasal corticosteroids (INCSs) are widely prescribed for allergic and nonallergic rhinitis and chronic rhinosinusitis, frequent causes of upper airway cough syndrome (UACS). In UACS, adherence is strongly influenced not only on pharmacological efficacy but also on device performance and sensory tolerability. Despite this, few studies have linked in vitro spray characteristics with patient-reported outcomes.

Objective: To evaluate the technological characteristics and clinical acceptability of mometasone furoate administered via the liquid VP3 nasal spray device by integrating in vitro performance testing and in vivo patient-reported outcomes in individuals with chronic cough and UACS.

Methods: In vitro experiments assessed deposition patterns in a silicone nasal cast, dripping behavior on inclined gel surfaces, viscosity, and spray plume geometry. An observational study enrolled 10 patients (80% female, mean age 56 ± 8.4 years) referred to a tertiary cough clinic for chronic cough (mean duration 3.5 years) associated with postnasal drip. Patients switched from conventional mometasone sprays to the device and completed Anchored Best-Worst Scaling evaluations of 11 sensory and treatment-related attributes. Global satisfaction was rated using a visual analog scale (VAS) and Treatment Satisfaction Index (TSI).

Results: Deposition was reproducible (27.9 ± 1.7% of cast surface) with distribution into middle and lower turbinates. Moderate viscosity (14.4 ± 3.2 mPa·s) and stable plume geometry supported retention. In vivo, overall satisfaction scores remained stable following switching (TSI: 64.3 ± 3.4 vs 63.8 ± 4.6; VAS: 6.8 ± 3.2 vs 6.1 ± 1.6). However, patients reported significantly greater satisfaction in two sensory domains and rated three domains as more important (p < 0.05). No deterioration in any attribute was observed.

Conclusion: The liquid VP3 nasal spray device delivering mometasone furoate demonstrated reliable in vitro performance and favorable patient acceptability in UACS. The correspondence between deposition behavior and patient-reported tolerability supports its suitability for INCS delivery and warrants further evaluation in larger, longer-term studies.

This article provides a high-level overview of regulatory considerations for medicinal aerosol products around the world. It builds on our previous review and reflects developments related to more recent trends and innovations in science, business, technology, and regulation. All medicines, including medicinal aerosol products, must be approved by an appropriate government agency prior to marketing authorization. Knowing and complying with the requirements of an appropriate regulatory agency (or agencies) is a prerequisite to successful commercialization of any aerosol therapy. The range of governmental regulatory oversight is broad, including inspections of manufacturing sites, evaluations of preliminary data and study protocols before the start of trials in human subjects, evaluations of the sponsor's clinical and in vitro data for the proposed product, approval of final labeling and of postapproval changes to any aspect of the product or manufacturing process, monitoring of adverse event reports, and other areas. The specific regulatory requirements vary by the product type and by country, and they also change over time as the science and technology involved in the development, manufacture, and characterization of pharmaceutical and biological products evolve. In general, in order to obtain marketing authorization, the sponsor must demonstrate to regulators, using data from appropriately designed studies and other relevant documentation, (1) that the product is safe and efficacious for the proposed therapeutic indication in the target patient population, (2) that the product's manufacturing facility follows current good manufacturing practice^2-4 and/or quality management systems,^5,6 and (3) that appropriate quality control and quality assurance programs are in place, including programs to verify that the product released to the market, as well as product kept in stability-testing environmental chambers, complies with preset quality specifications. For aerosol delivery devices and drug-device or biological-device combination products, the sponsor must also assess the influence of human factors, device robustness, and materials' (bio)compatibility. The sponsor's responsibility to regulators continues after a product's approval in the form of, for example, required compliance with ongoing quality testing, pharmacovigilance monitoring, any postapproval commitments, and qualification of any postapproval changes. This article provides an overview of the regulatory considerations for inhaled and nasal products.

Background: Pulmonary dysfunction in individuals with post-coronavirus disease-2019 (COVID-19) syndrome may impair aerosol deposition and pulmonary perfusion, compromising respiratory efficiency. Inspiratory muscle training (IMT) has been proposed as a strategy to improve respiratory mechanics and lung function.

Objective: To compare aerosol deposition and pulmonary perfusion in individuals with post-COVID-19 syndrome before and after 8 weeks of IMT.

Methods: This was a randomized controlled clinical trial involving 19 participants, divided into an IMT group (n = 10) and a control group (n = 9). The IMT group performed training with a load adjusted to 50% of maximal inspiratory pressure, while the control group used a device without resistance. Aerosol deposition and pulmonary perfusion were evaluated by gamma scintigraphy using the radioisotopes technetium-labeled diethylene-triamine-pentaacetic acid and technetium99-labeled macroaggregated human serum albumin, respectively. Total radiopharmaceutical activity in both lungs, as well as in the right and left lungs separately, was quantified pre- and post-intervention.

Results: After 8 weeks, the IMT group showed a significant increase in total lung activity for both aerosol deposition (p = 0.028) and perfusion (p = 0.013). In the right lung, activity increased significantly for aerosol deposition (p = 0.005) and perfusion (p = 0.005). In the left lung, significant increases were also observed for perfusion (p = 0.007). No significant increases were observed in the control group. In the between-group analysis, the IMT group showed higher activity in both lungs combined and separately, compared with controls, for aerosol deposition (all p < 0.05) and in the right lung for perfusion (p = 0.010).

Conclusion: IMT improved total aerosol deposition and perfusion in individuals with post-COVID-19 syndrome. These findings support the use of IMT as a rehabilitation strategy to enhance pulmonary deposition of inhaled agents and increase pulmonary perfusion in this population.

Introduction: Inhaled medication delivered through a pressurized metered dose inhaler (pMDI) with a valved holding chamber (VHC) is the optimal treatment for asthma. The best technique is the breath-holding (BH) technique. Tidal breathing (TB) technique is also recommended by Global Initiative for Asthma (GINA) as an alternative. Clinical studies have shown variable results, but the scintigraphy study shows better lung deposition with the BH technique. The present study was designed to address the shortcomings in previous studies and to confirm the scintigraphy study findings by comparing the two techniques.

Methods: This randomized controlled trial included children aged 5-14 years with nonsevere asthma not taking inhaled medications on entry to the study, but during the study, they were given inhaled medications by pMDI + VHC (according to GINA guidelines) over an 8-week period. Demography, clinical details, spirometry parameters, and asthma control were recorded/assessed. The primary outcome was change in spirometry parameters at 2 and 8 weeks.

Results: Eighty-two children (mean age: 8.64 years, 46 boys) were included. There was no intergroup difference in the spirometry parameters and asthma control scores at any point in time (p > 0.05). A significant intragroup improvement was noted only for forced expiratory volume in the first second at 8 weeks (p < 0.05). Similarly, a significant intragroup improvement in asthma control score was noted at 8 weeks (p < 0.05). No adverse event was noted in either of the groups.

Conclusions: The present study found no difference between the BH and the TB techniques while delivering aerosols through a pMDI with a VHC. Either the BH or the TB technique may be used in children (5-14 years) with nonsevere asthma.

Clinical trial registration number: CTRI/2020/12/030078.

Asthma and chronic obstructive pulmonary disease are prevalent conditions associated with sudden, symptomatic decline in respiratory function requiring urgent treatment. Management of acute airflow obstruction includes frequent, thorough assessments as well as timely administration of supplemental oxygen, corticosteroids and inhalational drug delivery of short acting bronchodilators. The benefits of inhaled administration of aerosolized short-acting bronchodilators include rapid symptom relief and improvements in lung function with fewer side effects. To optimize these benefits requires an understanding of the factors concerning aerosol delivery in the acute care setting that include patient age, severity of airway obstruction, aerosol generating device and the patient and device interface. Treatment strategies have been developed that include increased dosing of short-acting bronchodilators, combined administration of β-agonist and anticholinergic bronchodilators, continuous drug delivery and the use of helium to enhance lower respiratory tract drug deposition and improve patient outcomes.

Background: In spite of efforts to eradicate tuberculosis (TB), TB remains the deadliest infectious disease in the world; there is an urgent need for a thermostable, noninvasive TB vaccine suitable for distribution in the developing world. Spray-dried versions of a clinical-stage TB vaccine, ID93 + GLA-SE, are currently undergoing testing in baboons in both pulmonary and intranasal versions. We developed manufacturing processes and delivery systems to achieve delivery of each version to its intended site of action while avoiding off-target deposition.

Methods: Pulmonary ID93 + GLA-SE was manufactured in a custom research-scale spray dryer. Delivery efficiency using a custom intratracheal insufflator was measured gravimetrically, and aerodynamic performance was evaluated via cascade impaction. Intranasal ID93 + GLA-SE was manufactured in a pilot-scale spray dryer. In vitro regional deposition in the Alberta Idealized Nasal Inlet, measured by LC-MS/MS, was used as a surrogate for aerodynamic performance; total deposition was used to calculate a total delivered dose. For both powders, ID93 antigen content was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and GLA-SE adjuvant content was assessed via HPLC.

Results: No substantial processing losses of the antigen or adjuvant were observed after spray drying in either formulation. For the pulmonary powder, the emitted dose exiting the endotracheal tube across three tube sizes ranged from 15.9% to 21.4% of the nominal dose; for the 8 mm tube size, the emitted dose mass median aerodynamic diameter was 5.3 µm, which was deemed suitable for pulmonary administration. For the intranasal powder, the delivered dose was 88% ± 2% of nominal, and in vitro deposition in the posterior nasal cavity was 63% ± 10% of the emitted dose, with minimal anticipated lung deposition.

Conclusions: Pulmonary and intranasal spray-dried ID93 + GLA-SE powders were successfully manufactured. The proposed dosing systems are expected to achieve exclusive pulmonary or intranasal delivery to nonhuman primates while requiring only a moderate amount of powder.

Background: We aimed to assess the knowledge of health care professionals regarding inhaled therapy devices and techniques and to evaluate the effectiveness of a targeted educational intervention.

Methods: An educational program designed to update the knowledge and improve the technical skills of these professionals in the use of different types of inhalers was developed. Before and after each training session, we applied an ad hoc questionnaire that consisted of 15 multiple-choice questions on inhaled therapy grouped into three sections, including knowledge about devices used for inhaled therapy, knowledge about inhaler techniques, and knowledge about adherence to inhaled therapy, as well as the Test of the Adherence to Inhalers. The questionnaire also included a summary question. We calculated the mean score and the standard deviation for the pre- and postevaluations, compared the mean scores using Student's t-test, and evaluated the relevance of the changes using Cohen's d.

Results: During the 23 meetings held throughout Spain, 267 participants completed the pretraining questionnaire, including 105 primary care physicians, 90 nurses of specialized care, 41 nurses working in primary care, and 31 health care professionals of various origins. Overall, the mean (SD) total score (i.e., number of correct answers out of a maximum of 15; range 0-15) significantly increased from 8.99 (2.26) to 11.46 (2.50) points, for a mean pre-post difference of 2.5 (p < 0.001). Notable issues included the misidentification of device types and confusion between inhalation techniques for pressurized metered-dose inhalers and dry powder inhalers. The mean total scores significantly increased across the three main specialties, with large effect sizes in all cases.

Conclusion: Our study suggests that both primary care physicians and nurses have relevant gaps in knowledge- and technique-related issues regarding the use of inhalation devices that could be improved using a brief educational intervention.

Background: Oral administration of clofazimine, an antimicrobial agent with demonstrated in vitro efficacy against nontuberculous mycobacteria (NTM), including Mycobacterium avium complex, requires high dosages to reach minimum inhibitory concentration in the lungs. Clofazimine Inhalation Suspension is a novel formulation designed to offer rapid, targeted drug delivery with prolonged half-life in lung tissues while minimizing systemic toxicities. The objective of this study was to evaluate the pharmacokinetic and safety profiles and proposed dosing regimen of Clofazimine Inhalation Suspension for adjuvant treatment of pulmonary NTM disease.

Methods: A proposed dosing regimen consisting of 28 days of once-daily 4 mL Clofazimine Inhalation Suspension (nominal 80 mg clofazimine) via jet nebulizer followed by a 56-day drug-intake holiday was evaluated using: (1) a first-in-human phase 1 study examining safety, tolerability, and plasma pharmacokinetics of single and multiple ascending doses across 30-90 mg of clofazimine, (2) a physiology-based pharmacokinetic model establishing human equivalent dosing based on preclinical, and phase 1 human Clofazimine Inhalation Suspension data along with published oral clofazimine data and generated human lung pharmacokinetic estimates.

Results: Human studies showed no safety issues at any dose. In healthy volunteers, treatment was well tolerated, with mild adverse events and no signs of systemic clofazimine deposition in the skin or sclera. Plasma drug levels are anticipated to remain below the previously established safe levels for oral clofazimine.

Discussion: Clofazimine Inhalation Suspension demonstrated effective antimicrobial lung concentrations and achievable long-term coverage with potential for less systemic toxicity than oral clofazimine. This novel formulation is an alternative delivery strategy to oral ingestion for pulmonary NTM disease. Further evaluation in the phase 3 ICoN-1 global clinical trial is underway.

Background: The optimal management of chronic obstructive pulmonary disease (COPD) requires effective drug delivery through dry powder inhalers (DPIs). Maximum forced inspiratory flow (FIFmax), easily obtained from routine spirometry, can reflect inspiratory capacity and serve as a physiological marker associated with exacerbation risk. However, its clinical implications have not been fully established. Methods: This retrospective cohort study analyzed COPD patients treated with DPIs over a 5-year observational period. Baseline and follow-up FIFmax values were measured through repeated spirometric evaluations. The primary outcome was the incidence of moderate-to-severe exacerbations. The optimal cutoff of FIFmax for minimizing the risk of moderate-to-severe exacerbations was calculated, and the clinical factors associated with maintaining FIFmax above this optimal cutoff were explored. Results: A FIFmax threshold of 220 L/min was identified as the most optimal cutoff for lowering the risk of moderate-to-severe exacerbations. Patients who maintained FIFmax above this threshold over 5 years showed a significantly reduced risk of moderate-to-severe exacerbation (adjusted hazard ratio = 0.722 [95% confidence interval = 0.546-0.953], p = 0.022). Factors such as younger age, lower comorbidity burden, and better baseline lung function were linked to a higher FIFmax. In contrast, advanced age, severe comorbidities, and poor inhaler technique were associated with a rapid decline in FIFmax. Conclusion: FIFmax can be a promising physiological marker that reflects inspiratory capacity and stratifies exacerbation risk in COPD patients using DPIs. Regular assessment and patient education to maintain adequate inspiratory flow could support more effective disease management and stable long-term outcomes in this population.