Toward Next-Generation Propellants: Assessing Lung Deposition of Beclometasone Dipropionate,Formoterol,and Glycopyrrolate Formulated with HFA-152a Using Functional Respiratory Imaging

Introduction

Inhalation therapy remains a cornerstone in the management of asthma and chronic obstructive pulmonary disease (COPD), owing to its capacity to deliver medications directly to the lungs, achieving high local drug concentrations while minimizing systemic side effects. ¹ Clinical evidence increasingly underscores the importance of targeting the small airways, which are often the initial and persistent sites of inflammation in both diseases. ¹ For instance, Skloot et al. ² demonstrated that inhalers generating extrafine particles (mass median aerodynamic diameter [MMAD] < 2 µm) significantly improve drug deposition in the peripheral lung and, thereby, the small airways, as confirmed through functional respiratory imaging (FRI).

Pressurized metered-dose inhalers (pMDIs) are widely used for inhaled drug delivery in COPD and asthma. pMDIs rely on the driving force of the propellant, which comprises the bulk of the MDI formulation, to atomize droplets containing the drug and excipients and allow them to reach the lungs. Today, pMDIs typically utilize hydrofluoroalkane-134a (HFA-134a) or hydrofluoroalkane-227ea (HFA-227ea) as propellants—both of which have a high global warming potential (GWP) therefore contributing to climate change. ³ In response to mounting climate concerns and regulatory mandates—including the Kigali Amendment ⁴ and recent EU F-gas regulations, ⁵ industry and regulators alike are prioritizing the development of next-generation propellant alternatives. One such candidate, hydrofluoroalkane-152a (HFA-152a), offers over a 90% reduction in GWP compared to HFA-134a, ⁶ which in turn allows reducing the product carbon footprint by up to 90% in line with dry powder inhaler products while maintaining favorable physicochemical characteristics for inhaler use. ⁷

However, replacing the propellant in a pMDI is not a simple substitution. Even when the active pharmaceutical ingredients (APIs), inhaler device, and actuation mechanics remain unchanged, a change in propellant can alter aerosol characteristics—such as MMAD, fine particle fraction, plume velocity, plume angle, and plume duration—all of which can influence lung deposition and therapeutic performance. ⁸ To ensure clinical consistency, regulatory agencies such as the European Medicines Agency and the U.S. Food and Drug Administration require rigorous demonstration of bioequivalence (BE) between reformulated and original inhaled products, typically via in vitro studies and pharmacokinetic assessments. Recent guidance documents,^9,10 also allows in silico evidence to support BE where appropriate.

Matturro et al. ⁶ recently reported that the triple-combination pMDI containing beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB)—hereafter referred to as BDP/FF/GB pMDI—could be successfully reformulated with HFA-152a without compromising the aerodynamic performance. Additionally, recent clinical pharmacokinetic evaluations by Rony et al. ¹¹ and Fioni et al. ¹² demonstrated that the systemic exposure and lung availability of BDP/FF/GB are bioequivalent between HFA-152a and HFA-134a pMDIs, confirming that therapeutic equivalence can be ensured through reformulation.

Within the in silico space, FRI combines high-resolution computed tomography (HRCT) scans with computational fluid dynamic (CFD) to provide patient-specific estimates of airflow and aerosol deposition. This method has been validated against clinical imaging data, such as those from single-photon emission computed tomography studies.^13,14 This validated technique has been widely applied to assess aerosol deposition across different inhalers/formulations, ¹⁵ and patient breathing profiles, ¹⁶ demonstrating its sensitivity to the factors known to influence regional lung deposition.

In the present study, FRI has been implemented to quantitatively compare the lung deposition patterns of the BDP/FF/GB pMDI formulated with either HFA-134a ¹⁶ or HFA-152a. The goal is to determine whether the shift to a next-generation, low-GWP propellant maintains the regional deposition characteristics, further supporting demonstration of therapeutic equivalence to allow a seamless transition for patients suffering from asthma and COPD.

Materials and Methods

Deposition of BDP/FF/GB containing either HFA-134a (Reference) or the low-GWP propellant HFA-152a (Test) was evaluated using FRI in patients with COPD, representing population with small airway disease. As this was a computational study, no patient dosing, spirometric assessments, or spacer use were involved.

The CFD simulations, as part of FRI, incorporated patient-specific airway geometries, inhaler models, an idealized inhalation profile, and device-specific particle and plume characteristics (plume velocity, angle, and duration) Patient-specific digital lung models were extracted from computed tomography (CT) scans, and the inhaler model was digitally coupled to the mouth region.

A total of 10 patients diagnosed with COPD and classified as global initiative for chronic obstructive lung disease (GOLD) stages 2–4 were selected from FLUIDDA’s existing digital database. No patients were recruited, and only pre-existing HRCT scans from selected patients were utilized. The selected cohort consisted of five males and five females, aged 54–70 years (mean age: 63.5 years), with heights ranging from 158 to 176 cm (mean: 167 cm) and a broad spectrum of lung function impairment (forced expiratory volume in 1 second [FEV₁]: 22.0%–70.6% predicted). Summary demographics are provided in Table 1.

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Table 1.

Baseline Demographic and Pulmonary Function Characteristics of Chronic Obstructive Pulmonary Disease Patients Included in the Study

COPD (N = 10)
Parameter	Mean	Range
Sex, male	50%	—
Age (years)	63.5	54–70
Height (cm)	167.0	158–176
Weight (kg)	73.4	45.3–91.4
BMI (kg/m²)	26.05	18.15–29.58
FEV1 (L)	1.04	0.52–2.18
FEV1 (% predicted)	39.38	22.00–70.64
FVC (L)	2.77	1.57–4.25
FEV1/FVC	0.37	0.27–0.51

Values Are Presented as Mean and Range.

BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

The HRCT scans were segmented using an automated algorithm that delineated both parenchymal tissue and the bronchial tree to the point at which intraluminal air could no longer be distinguished from alveolar air. Manual corrections were applied to remove imaging artifacts, and the resulting three-dimensional models were smoothed and trimmed at the terminal bronchi. Airway regions were classified as extrathoracic (mouth and upper airway) or intrathoracic (tracheobronchial tree). Intrathoracic airways were further subdivided into central (trachea and mainstem bronchi), distal (airways beyond the mainstem bronchi and visible on CT), and peripheral (small airways beyond CT resolution, typically ≤1–2 mm). Because the peripheral airways are not visible on CT and therefore cannot be reconstructed, peripheral deposition was defined as the fraction of particles reaching the outlets of the distal visible airways. Although some modeling approaches attempt to extend airway geometries beyond CT-visible regions using idealized algorithms (e.g., space-filling growth), such extensions are not applied in FRI. These methods have not been validated and often fail to represent diseased lungs accurately due to substantial anatomical variability. ¹⁷ At present, no reliable methodology exists for artificially extending airway branches to the alveolar level, which limits the robustness of explicit deep-lung deposition predictions. Nevertheless, in FRI, although peripheral airways are not geometrically resolved, their functional contribution was accounted for through subject-specific lobar ventilation distributions derived from paired inspiratory and expiratory scans and applied as boundary conditions at the distal outlets.

An idealized inhalation profile, characterized by a mean inspiratory flow rate of 30 L/min, an inhalation duration of 5 seconds, and a total inhaled volume of 2.5 L, was applied uniformly across all subjects.

The aerodynamic particle size distribution and plume characteristics of the Test and Reference BDP/FF/GB pMDI formulations were utilized as inputs for the computational modeling performed in this study.

These parameters include the MMAD (<2 µm), geometric standard deviation (GSD), delivered dose (DD), fine particle mass (FPM), plume exit velocity, plume angle, and plume duration—all of which, as previously shown by Matturro et al., ⁶ confirm the comparability of the Test formulation to the Reference (see Table 2; GSD not reported).

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Table 2.

Comparison of Particle and Plume Characteristics between Test (HFA-152a) and Reference (HFA-134a) Triple-Combination (Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium Bromide Pressurized Metered-Dose Inhalers, Reporting the Delivered Dose, Fine Particle Mass, Plume Angle, Exit Velocity and Duration

Propellant	Test (HFA-152a)			Reference (HFA-134a)
	Particle characteristics
API	BDP	FF	GB	BDP	FF	GB
DD (µg)	75–89	4.4–5.4	9.2–10.9	75–89	4.5–5.3	9.3–11.0
MMAD (µm)	1.2–1.5			1.0–1.4
FPM (µg)	35–49	2.1–2.7	4.3–5.6	35–48	2.2–3.0	4.4–6.1
	Plume characteristics
Angle (°)	24.2			21.8
Exit velocity (m/s)	35			33
Duration (s)	0.183			0.251

API, active pharmaceutical ingredient; BDP, beclometasone dipropionate; DD, delivered dose; FF, formoterol fumarate; FPM, fine particle mass; GB, glycopyrronium bromide; MMAD, Mass median aerodynamic diameter.

All three active substances (BDP/FF/GB) were delivered as a fixed-dose triple combination solution pMDI in both Test (HFA-152a) and Reference (HFA-134a) formulations.

As all three APIs are fully dissolved in the ethanolic solution, no inter-drug interactions affecting aerosol generation or lung deposition patterns are expected.

This analysis focused on comparing regional deposition outcomes between the Test and Reference formulations. Key metrics included intrathoracic (total lung), central + distal (large airways), and peripheral (small airway) depositions, along with the central-to-peripheral ([C + D]/P) deposition ratio. Differences in aerosol distribution were assessed at both the population and individual-subject levels.

Results

The deposition of inhaled compounds across the intrathoracic (Fig. 1), central + distal (C + D; Fig. 2), and peripheral (Fig. 3) lung regions was assessed for both the Reference (HFA-134a) and Test (HFA-152a) pMDI formulations. Deposition values are reported as a percentage of the DD (% DD). Results are presented as box plots (N = 10 COPD), showing the median (central line), interquartile range (box), and full range (whiskers). Mean ± standard deviation values are displayed below each x-axis label.

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FIG. 1.

Intrathoracic deposition of BDP, FF, GB, and their average as percentage of the delivered dose for the Reference (HFA-134a) and Test (HFA-152a) formulations. BDP, beclometasone dipropionate; FF, formoterol fumarate; GB, glycopyrronium bromide.

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FIG. 2.

Central + distal (C + D) deposition as percentage of the delivered dose, for Reference and Test formulations.

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FIG. 3.

Peripheral deposition as percentage of the delivered dose, for Reference and Test formulations.

Across all compounds (BDP, FF, GB), intrathoracic deposition (Fig. 1) was comparable between the two formulations, with mean values ranging from 45.95% to 46.88%. The Reference showed an overall deposition of 46.71% ± 2.85%, and the Test averaged 46.05% ± 2.34%, confirming consistent overall lung deposition. This similarity in intrathoracic deposition is particularly relevant from a therapeutic perspective, as it indicates that both formulations achieve equivalent delivery to the target lung regions.

Deposition in the visible (large) airways (>1–2 mm), encompassing the central and distal conducting regions, is illustrated in Figure 2. The mean deposition of each compound and their overall average accounted for 12% of the DD for both formulations, demonstrating a consistent distribution pattern in the large airways irrespective of the propellant used.

More importantly, deposition in the small airways (peripheral; <1–2 mm) accounted for 33.7% and 34.5% of the DD for the Test and Reference formulations, respectively (Fig. 3). The higher peripheral deposition compared with the (C + D) region may reflect the extrafine nature of the BDP/FF/GB aerosol, which facilitates penetration beyond the CT-resolved distal airways into the small-airway regions, ¹⁶ a key therapeutic target in COPD. ¹⁸ Furthermore, as airflow progresses distally, velocities decrease and flow becomes less dominated by inertial impaction and turbulence, favoring the continued transport of small particles toward the peripheral lung. The close agreement between formulations confirms that both propellants achieved comparable deposition performance in the small airways, regardless of propellant type. This was also supported across the studied FEV1/FVC range, where the Test and Reference formulations remained closely aligned (Supplementary Fig. S1).

The (C + D)/P ratio (see Fig. 4) provides a useful indicator of how aerosol deposition is distributed between the central + distal and peripheral regions of the lungs. A ratio below unity denotes a greater proportion of particles depositing in the peripheral airways relative to the central and distal ones, which is desirable for targeting the small conducting and bronchiolar regions in COPD. In this study, the (C + D)/P ratios were similar across all active components and propellants, averaging 0.35 for the Reference (HFA-134a) formulation and 0.37 for the Test (HFA-152a) formulation. These comparable values indicate that both formulations achieved a balanced and consistent deposition pattern, with predominance deposition in the peripheral lung regions. In summary, both pMDI formulations demonstrated comparable intrathoracic and regional deposition. As expected, interpatient variability was observed for each formulation; ¹⁹ however, the low intrasubject variability—calculated for the same subjects receiving both formulations and reflected by the narrow interquartile ranges—suggests good consistency and supports the reliability of these findings.

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FIG. 4.

(Central + distal)/peripheral ([C + D]/P), for Reference and Test formulations.

Agreement between the Reference and Test formulations was further examined using Bland–Altman analysis. The compound-averaged regional deposition endpoints are demonstrated in Figure 5. Mean bias was small across all regions: +0.19% for C + D, −0.85% for Peripheral, and −0.66% for Intrathoracic deposition. The corresponding limits of agreement were also minimal, ranging from −0.53% to + 0.92% for C + D, from −2.28% to + 0.58% for Peripheral, and from −1.79% to + 0.48% for Intrathoracic deposition.

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FIG. 5.

Bland–Altman analysis of the compound-averaged deposition values for intrathoracic, central + distal (C + D), and peripheral endpoints, comparing Test (HFA-152a) and Reference (HFA-134a). All values are expressed as % of delivered dose. Solid lines indicate mean bias and dashed lines the upper limits of agreement and lower limits of agreement (ULOA and LLOA).

The distribution of data points showed no clear dependence of interformulation differences on deposition magnitude, indicating consistent agreement across the observed range. These results show that differences between the Reference and Test formulations were minor relative to the absolute regional deposition levels and did not indicate any meaningful shift in regional lung deposition.

Per-compound Bland–Altman analyses showed a very similar pattern (Supplementary Table S1). This similarity is also visually supported by the representative images shown in Figure 6, where both formulations exhibit nearly identical regional deposition patterns across the airways and lung lobes.

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FIG. 6.

Scintigraphy-like visualizations derived from CFD simulations, comparing regional lung deposition for the Reference (HFA-134a) and Test (HFA-152a) formulations in a subject whose intrathoracic deposition was closest to the cohort mean. CFD, computational fluid dynamic.

Discussion

Across all three active pharmaceutical ingredients (BDP, FF, GB), regional deposition was comparable between the HFA-152a (Test) and HFA-134a (Reference) formulations. Intrathoracic delivery patterns overlapped closely, with regional differences within ≤1%. Notably, the central-plus-distal-to-peripheral (C + D/P) distribution was effectively unchanged, with between-product differences < 0.5%, indicating similar partitioning of the drug between the larger and smaller airways. These negligible variations are consistent with a balanced interplay of aerosol and spray characteristics and, within the context of this study, did not influence total or regional lung delivery.

The in silico findings from the present study align with clinical observations from a randomized crossover study in humans. ¹¹ For the same triple therapy, overall drug exposure and lung availability were broadly similar with HFA-152a and HFA-134a, and occasional early differences were not considered clinically meaningful once the full exposure profile was evaluated. A complementary preclinical study ¹² in rats reported a similar outcome, with comparable exposure to each component under both propellants. Across development and regulatory reports, ²⁰ these results have been interpreted within a totality-of-evidence framework that weighs formulation quality, safety, device performance, and environmental considerations when transitioning to the next-generation propellant, HFA-152a.

The simulations used an idealized inhalation profile with perfect actuation–inhalation coordination. This may not reflect real-world use, where inhaler technique and inspiratory flow vary, especially in groups with coordination or breath-hold challenges. ²¹ Standardizing the maneuver, however, reduces interpatient variability and isolates the influence of the propellant on regional deposition.

Conclusion

This study demonstrates that transitioning from the current HFA-134a propellant to the next-generation propellant HFA-152a in pMDIs maintains deposition characteristics and overall aerosol performance in COPD patients. FRI showed comparable regional deposition for the BDP/FF/GB formulations using the next-generation and current propellants, with high total lung deposition in both. Deposition profiles for each active ingredient overlapped across propellants. The (C + D)/P ratios were similarly low (i.e., peripheral-leaning), consistent with small-airway targeting. The computational analysis using CFD and FRI highlighted minimal differences in regional lung deposition between the two formulations. These subtle variations in aerosol deposition are predominantly influenced by specific particle and plume characteristics, which are expected even between different batches of the same formulation, rather than by the propellant itself. This finding underscores the potential for adopting HFA-152a broadly while maintaining the same efficacy and safety, as supported by clinical pharmacology evidence. The adoption of the next-generation propellant HFA-152a represents a significant step toward carbon minimal pMDI therapies, guaranteeing continuity and flexibility for individualized patient care while reducing the climate impact.

Ethics Approval and Consent to Participate

All data were collected under prior informed consent and ethical approval from the University Hospital Antwerp’s Ethics Committee. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Authors’ Contributions

A.M.: Conceptualization, and writing—review and editing; N.M.T.: Methodology, formal analysis, investigation, visualization, and writing—review and editing; H.S.: Methodology, formal analysis, investigation, visualization, and writing—review and editing; E.C.: Conceptualization and writing—review and editing; S.P.: Conceptualization and writing—review and editing; D.G-.S.: Supervision and writing—review and editing; G.P.: Methodology and writing—review and editing; and F.S.: Review and editing.

Supplemental Material