Journal of Aerosol Medicine and Pulmonary Drug Delivery

Understanding the geometries of the human upper airway and their impact on drug particle transport is important. This study investigates the impact of inhaler mouthpiece size on extrathoracic airway geometry across a diverse body mass index (BMI) range.

Magnetic resonance imaging (MRI) was performed on 28 participants. Subjects were asked to bite on replicas of inhaler mouthpieces with incisal openings of 13.5 mm and 27 mm, and the effects of mouthpiece size on upper airway geometry were analysed.

Mouthpiece size affects the oral space, and the results show a significant linear correlation between oral space and BMI, with a reduction in the cross-sectional area (CSA) between the soft palate and the tongue of approximately 0.08 cm² per BMI unit increase. This trend contrasts with an increase in anterior-posterior (AP) length across three other pharyngeal regions of interest, with the largest increase observed in the oropharynx, where AP length increased by approximately 0.042 cm/(kg·m²). While the impact of device size was significant in the oral space across all participants, its effect in the oropharynx was significant only in the high BMI cohort. This group exhibited an expansion in the oropharynx when using the larger mouthpiece compared to the smaller one.

These findings may have implications for inhaler design and prescription. The knowledge presented has the potential to improve inhaler efficacy in high BMI populations when accounting for mouthpiece size.

Proper inhaler use is critical to the management of chronic obstructive pulmonary disease (COPD), and age plays a significant role in determining the appropriate device. This study evaluated inhaler technique, critical errors, and peak inspiratory flow (PIF) required to activate the inhaler in elderly patients with COPD.

A total of 81 patients with COPD, 41 aged ≤65 years and 40 aged >65 years, using at least one pressurized metered-dose inhaler (pMDI), dry powder inhaler (DPI), or soft mist inhaler (SMI) were included in the study. Inhaler technique was assessed using a checklist and critical errors were identified. PIF was measured with the In-Check DIAL device and compared with the optimal reference value for each type of inhaler.

Patients over 65 years of age had lower technique scores (p < 0.001) and a higher incidence of critical errors (p < 0.001) compared with younger patients. Older patients using three inhalers had lower technique scores than those using one or two inhalers (p < 0.001) and had five times more critical errors than younger patients (p < 0.02). A strong correlation between the number of critical errors and technique score was observed in the older group (r = 0.74; p < 0.001). In both groups, critical errors were identified in patients with good or high technical score. With the exception of four older patients, all participants, regardless of age or obstruction severity, achieved the required PIF for proper inhaler activation.

In conclusion, patients over 65 years of age with COPD showed a tendency to misuse inhalers, especially pMDIs and multiple inhalers. Patients with adequate or high technique scores in both age groups made critical errors highlighting the importance of investigating the nature of the error regardless of the technique score. By considering the minimum flow value for each inhaler, almost all patients were able to achieve an effective PIF for inhaler activation.

Pressurized metered dose inhalers (pMDIs) currently contain propellants with relatively high global warming potential (GWP), such as hydrofluoroalkane-134a (HFA-134a). Hyrofluoroolefin-1234ze (HFO-1234ze) is a near-zero GWP propellant in development for use in future pMDIs.

This Phase IIIb, multicenter, randomized, double-blind, single-dose crossover study aimed to assess post-dose lung function and clinical manifestations of bronchospasm following single doses of HFA-134a and HFO-1234ze via pMDI (four inhalations with no active drugs) in participants with well or partially controlled asthma. The primary endpoint was change from baseline in forced expiratory volume in one second area under the curve from 0 to 15 minutes (FEV₁ AUC_{0–15 minutes}) post-dose and was assessed using a linear mixed-effect model. Secondary endpoints included cumulative incidence of bronchospasm events (reduction in FEV₁ of >15% from baseline at 5 or 15 minutes post-dose with associated wheezing, shortness of breath, or cough). Safety and tolerability were also assessed.

Among 52 participants randomized to treatment, noninferiority of HFO-1234ze pMDI versus HFA-134a was established for change from baseline in FEV₁ AUC_{0–15 minutes} post-dose between treatments (least squares mean [LSM]; 95% confidence intervals [CI] change: HFO-1234ze pMDI, –0.014 [–0.033, 0.006] L; HFA-134a, –0.004 [–0.024, 0.015] L; LSM [95% CI] difference: –0.009 [–0.037, 0.018; p = 0.492]). No bronchospasm events were reported. Two patients (3.8%) in each group experienced ≥1 adverse event (AE). No serious AEs, AEs of special interest, or AEs leading to discontinuation were reported.

HFO-1234ze pMDI was well tolerated in participants with well or partially controlled asthma. As with HFA-134a pMDI, no significant effects on lung function or bronchospasm events were observed. As HFO-1234ze pMDI has a near-zero GWP, it represents a compelling, environmentally conscious alternative propellant for use in pMDI devices for treatment of chronic respiratory disease.

NCT05850494.

Delivering large molecules and biologics via inhalation or intranasal routes allows these innovative therapies to directly target the respiratory tract, access the richly vascularized lymphatic tissue in the nose for vaccination, bypass gastro-intestinal and first-pass hepatic metabolism for systemically active drugs, and provide a convenient alternative to injections. These advantages are driving significant growth in research and development within this field. However, before such products can reach the market, they must undergo rigorous nonclinical studies and clinical trials and address challenges related to formulation, manufacturing, analytical testing, quality standards, and regulatory review.

This report summarizes discussions among leading experts from industry, academia, and regulatory bodies on how to apply general Chemistry, Manufacturing, and Controls (CMC) principles, alongside bioequivalence (BE) considerations, to the development of inhalable and nasal biologics (INBs). It also explores the balance between these requirements and the established techniques for medical aerosols. In the absence of explicit regulatory guidelines for the development of INBs, this article reviews applicable literature, including guidelines from the US FDA and EMA for biologics, on the one hand, and for small-molecule inhalation and nasal drug products, devices, and combination products, on the other. The original discussions reflected here took place at the 2023 workshop co-organized by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). Subsequent recent developments have also been added. The article describes regulatory expectations, the selection of delivery systems and formulation types, and analytical techniques for assessing product quality attributes of INBs. Several specific cases are presented in detail, including regulatory considerations for generic peptides, the approval package for one of the first marketed biologics for inhalation, and analytical detection strategies for viral-based products delivered to the lungs.

Looking ahead, the future of INBs includes opportunities to treat and potentially cure diseases that currently have no effective treatment or that require repeated injections. Continued collaboration among researchers, developers and regulators will be key to advancing these therapies, ultimately benefiting patients and improving health outcomes. The future of INBs looks promising!.