Abstract
ISAM2025 Congress Abstracts
Invited Speaker Abstracts
Artificial Intelligence (AI) Empowered User-Center Smart Inhaler for Targeted Drug Delivery to Designated Airway Sites
Mohammad Rashedul Islam, Chenang Liu, and
Oklahoma State University, Stillwater, USA.
Conventional inhalation therapies often fail to precisely target diseased airway regions, with a large dose deposited on healthy tissues in human respiratory systems. This inefficiency not only reduces therapeutic effectiveness but also increases side effects. Computational Fluid Particle Dynamics (CFPD) has proven reliable in visualizing patient-specific pulmonary air-particle flow dynamics, which can be employed for personalized targeted drug delivery planning. However, the high computational cost of patient-specific CFPD simulations has hindered its clinical use for targeted drug delivery planning. To address such a challenge, Machine Learning (ML) and Deep Learning (DL) present transformative solutions by leveraging high-fidelity CFPD data to optimize drug delivery efficiency. AI models can learn complex relationships between operational parameters, patient-inhaler coordination, and drug deposition patterns, enabling personalized targeted drug delivery planning. This study will showcase two research efforts to demonstrate how CFPD-AI integration can accelerate the development of personalized targeted drug delivery and advance next-generation smart inhaler designs. Specifically, the two examples are: (1) Targeted drug delivery to larynx and glottis for Juvenile Onset Recurrent Respiratory Papillomatosis (JORRP) treatment, (2) AI-empowered smart inhaler development for personalized targeted drug delivery to the peripheral lung for more effective treatment of COPD/asthma.
EVALUATING CHARCOAL BLOCK PHARMACOKINETICS AS A SURROGATE FOR REGIONAL LUNG DRUG DELIVERY IN ORALLY INHALED DRUG PRODUCTS
U.S. Food and Drug Administration, Silver Spring, USA.
For orally inhaled drug products (OIDPs), observations from in vivo charcoal block pharmacokinetics (PK) studies are expected to reflect total lung drug delivery via co-administration of the drug and activated charcoal, which blocks gut absorption from swallowed drug. While an understanding of total lung drug delivery is important for evaluating OIDP performance, an understanding of regional lung drug delivery is often needed because the effectiveness of a drug may depend on accurate lung targeting. It may be possible to select charcoal block PK metrics that reflect regional lung drug delivery but is unclear what metrics may be appropriate or if such relationships would be drug specific. Computational modeling may be used to evaluate relationships between charcoal block PK metrics and regional drug delivery, using techniques such as regional deposition, physiologically based pharmacokinetic (PBPK), and population PK modeling. Machine learning methods have also been proposed to aid with population PK model selection and to enhance ordinary differential equation solver methods used for PBPK and population PK modeling. For drugs such as fluticasone propionate, PK metrics may serve as indicators of regional lung drug delivery [1]. This presentation covers research aimed at understanding how variations in charcoal block PK metrics may reflect regional lung drug delivery.
References
[1] Hochhaus, G., Chen, M.J., Kurumaddali, A. et al. (2021). AAPS J 23,1–14. doi.org/10.1208/s12248-021-00569-x
DRY POWDER INTRANASAL VACCINES: MANUFACTURABILITY AND FORMULATION CONSIDERATIONS IN AN EMERGING AREA
Lonza, Bend, USA.
Non-invasive mucosal vaccination holds great promise to protect against infection via the respiratory route. In recent years, interest in such vaccines delivered via the nasal route has increased substantially, as the upper respiratory tract is often the point of infection. In addition, intranasal vaccines formulated as dry powders can convey exceptional shelf stability, eliminating the need for cold chain delivery. This is critical to enable global access to vaccines in areas with underdeveloped medical infrastructure.
This talk will focus on dry powder vaccines prepared by spray drying, a scalable and precedented technology for particle engineering of biologic molecules, including proteins, peptides, and nucleic acids. Balancing the formulation and manufacturing needs of intranasal vaccine dry powders remains challenging. A successful product must: maintain the activity of the antigen, include any necessary adjuvants, achieve a nasal-appropriate particle size, remain physically stable as a powder at temperatures of 25°C or above, and redisperse into its primary particle size out of a dry powder device. Case studies will demonstrate the impact of key formulation excipients on yield and stability of dry powder vaccines manufactured by spray drying.
GLP-1: Exploring Respiratory Delivery through the Development of a GLP-1 Analogue Dry Powder
1Harro Hoefliger, Allmersbach im Tal, Germany. 2University of Parma, Parma, Italy. 3DFE Pharma, Goch, Germany. 4Sterling, Corciano, Italy. 5University of Padova, Padova, Italy.
Semaglutide (SMG), a GLP-1 analogue with longer half-life (160h), is marketed for the treatment of type 2 diabetes and weight loss by subcutaneous or oral administration. With the goal to overcome cold-chain storage and poor bioavailability of the commercialized products 1, we started investigating the feasibility of delivering SMG through the lungs.
SMG stability in different feed-stock solutions was investigated by a full factorial design. Six powders were then spray dried screening 2 factors: buffer (2 levels) and bulking agent (3 levels). Assay, physico-chemical characterization and respirability of the powders were tested. Finally, lead formulation impact on A549 metabolic activity was performed by MTT.
SMG was stable in all feed-stocks. Therefore, the highest solid concentration (0.8% w/v) to maximize process outcome and the lowest buffer concentration (5 mM) to reduce salts influence on process yield and respirability were spray dried. Trehalose showed to be the most suitable bulking agent, particularly in presence of phosphate buffer. This lead candidate had no effect on cell viability for SMG content up to 64 µg/mL, an eight times higher concentration than the one expected in the lungs considering powder dosage.
Through this study we identified a lead candidate for respiratory delivery of SMG. Evaluation of the SMG bioavailability in vivo is on-going.
References
[1] Overgaard, R.V.; Hertz, C.L.; Ingwersen, S.H. et al. (2021). Cell Rep Med 2, 100387. 10.1016/j.xcrm.2021.100387.
FORMULATION STRATEGIES FOR LGWP PROPELLANT TRANSITION IN MDI: ENSURING A SMOOTH TRANSITION FOR MULTI-DRUG SOLUTION AND SUSPENSION PRODUCT
Chiesi, Parma, Italy.
The transition to low global warming potential (LGWP) propellants in metered dose inhalers (MDIs) is essential for reducing the environmental impact of pharmaceutical aerosols. This presentation provides a technical overview of formulation strategies to ensure a smooth transition for multi-drug solution and suspension products, focusing on maintaining inhalation performance equivalent to traditional hydrofluoroalkane (HFA) propellants.
The presentation highlights the physicochemical properties of LGWP propellants, such as hydrofluoroolefins (HFO1234ze) and difluoroethane (HFA 152a), and their implications for MDI formulations. Case studies of successful reformulation strategies will be shared. The reformulation of triple API combination products and the importance of applying established formulation technology platforms are discussed. The presentation will focus on the use of in silico mathematical models to predict aerosol performance and ensure bioequivalence of reformulated products and the use of engineered excipient particles co-suspended with APIs for MDI suspension, as tools for a smooth propellant replacement. The presentation aims to convey that transitioning to LGWP propellants with targeted reformulation technologies can be achieved without compromising product performance or altering the safety and efficacy profile of the reference product.
Propellant Manufacturer Perspective: HFO-1234ze(E)
Honeywell International, Morris Plains, USA.
An ideal novel inhalation propellant should meet strict criteria: be a liquified gas, safe, non-flammable, chemically stable, patient-acceptable, with appropriate solvency, density, and meeting past performance standards. Importantly, it must also have a minimal environmental impact. Finding compounds that meet all these requirements is a formidable challenge.
Solstice® Air (HFO-1234ze(E)) has been developed as an ultra-low GWP propellant for pMDIs, designed to significantly reduce environmental impact while maintaining therapeutic efficacy and patient safety. This presentation offers the propellant manufacturer's perspective and a comprehensive overview of HFO-1234ze(E)'s physico-chemical properties, formulation stability, compatibility, and safety profile.
HFO-1234ze(E) exhibits similar density and water solubility to current HFA propellants. Sedimentation and creaming rates of HFO-1234ze(E) formulations match those of HFA-134a formulations. It is compatible with various excipients and APIs commonly used in MDIs. Preclinical safety studies show that HFO-1234ze(E) has no toxicity concerns. LCAs indicate that converting current pMDIs to HFO-1234ze(E) would result in a carbon footprint as low as or lower than that of DPIs.
In conclusion, HFO-1234ze(E) is an ultra-low GWP near drop-in propellant replacement for high-GWP HFA propellants. Regulatory approvals and adoption by industry leaders are critical for a successful transition to low carbon footprint pMDI products.
GLOBAL TRANSITION TO LOWER GLOBAL WARMING POTENTIAL PROPELLANTS - CURRENT CONTEXT
Faegre Drinker Consulting, Washington, USA.
Metered Dose Inhalers (MDIs) remain a valuable therapeutic option for treating asthma, COPD and other respiratory conditions. Responding to the global threat of climate change is a priority for patients, clinicians, and policymakers around the world. MDIs present some unique challenges and opportunities for sustainability. The propellants in existing MDIs are fluorinated gases (F-Gases) with a relatively high global warming potential (GWP). The Kigali Amendment to the Montreal Protocol encourages countries around the world to phase down these gases. MDI companies are innovating to develop lower GWP MDIs. Health regulators will need to review and approve these new MDIs before they can reach patients. Regulatory expectations regarding the range and type of additional studies needed to obtain approval, however, are currently different among European Medicines Agency, Health Canada, UK’s MHRA, and U.S. FDA. There is an opportunity for a strengthened collaboration and mutual education among stakeholders for the benefit of patients to ensure a timely, smooth transition that is supportive of the ongoing patient care.
An overview of FDA’s AI rules and guidance in the combination products space
Faegre Drinker, District of Columbia, USA.
The integration of artificial intelligence (AI) technologies into combination products—therapeutic and diagnostic products that combine drugs, devices, and/or biological products—marks a significant advancement in healthcare innovation. This presentation will provide a high-level overview of the FDA's rules and guidance governing the use of AI within the combination products space, offering essential insights into the current regulatory landscape.
The FDA has developed a series of guidances and frameworks to address the unique challenges posed by AI in combination products. We will see how key AI guidances deliver a structured framework approach for ensuring the safety, effectiveness, and reliability of AI components, including those integrated into combination products like drug delivery systems and diagnostic tools. We will discuss critical considerations for manufacturers, including interoperability, cybersecurity, and data integrity.
Real-world examples will help attendees get a clear understanding of how the FDA's AI rules and guidance are applied in practice. The presentation will also touch on the opportunities and compliance challenges associated with incorporating AI into combination products and potential changes to enforcement priorities under Trump 2.0.
TRANSITION TO LGWP MDIs: A TECHNICAL OVERVIEW
Bespak, Holmes Chapel, United Kingdom.
This talk will cover the technical aspects to be considered when developing a pmdi using low gwp propellants. from formulation to scale up and manufacturing, this will be a ‘level set’ before my colleagues go into detail around each specific section
Probiotic Inhalation Powders for the Management of S. aureus Infection in NCFB
Stefania Glieca,1 Eride Quarta,1 Chiara Schianchi,1 Benedetta Bottari,1 Elena Bancalari,1 Erika Scaltriti,2 Martina Tambassi,2 Laura Mazzera,2 Ruggero Bettini,1 Fabio Sonvico,1 and
1Food and Drug Department, University of Parma, Parma, Italy. 2Risk Analysis and Genomic Epidemiology Unit, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia-Romagna (IZSLER), Parma, Italy.
Non-cystic fibrosis bronchiectasis (NCFB) is characterized by the loss of homeostasis leading to both increased pathogen burden and neutrophilic inflammation. To improve the efficacy of inhaled antimicrobial therapies, probiotics could be administered to the lungs. Previously, we developed a dry powder for inhalation containing viable lactic acid bacteria (LAB) which showed bactericidal activity against P. aeruginosa [1]. The aim of this study was to assess the potential anti-inflammatory and anti-microbial activity on S. aureus of the formulation.
Lpb. plantarum suspension was spray-dried adding lactose and L-leucine with or without raffinose and the respirability of the powders was assessed using a NGI. The anti-inflammatory activity was evaluated on A549 as the ability to reduce IL-6 after inducing inflammation with LPS. A co-culture assay was performed to test the antimicrobial activity of LAB powders on S. aureus.
The two powders embedded 1.5x109 CFU in 40 mg of formulation and showed similar aerodynamic behaviour (MMAD of 4.7 µm).
Only the raffinose-containing powder was able to reduce inflammation both when used as prevention and treatment. In addition, both the powders were able to significantly reduce the growth of the three different strain of S. aureus tested.
Subsequent studies will involve the testing of this promising formulations on the mucus of NCFB patients.
References
[1] Glieca S et al. (2024) Int J Antimicrob Agents. 63(1):107001. 10.1016/j.ijantimicag.2023.107001
An Alternative Approach for Pressurized Metered Dose Inhalers (pMDIs) Manufacturing and its Application in Low Global Warming Potential pMDI Transition
Irene Rossi,1 Sally Stanford,2 Sheryl Johnson,2 James Murray,2 Kris Brosig,1 Tony Clark,3 and
1Harro Hoefliger, Allmersbach im Tal, Germany. 2Orbia Fluor & Energy Materials, Ince, United Kingdom. 3Pharmatec Solutions, Gyfelia, United Kingdom.
In consequence of the Kigali Amendment, two low global warming potential propellants have been identified, with HFA 152a reducing the carbon footprint of pressurized metered dose inhalers (pMDIs) by over 90% than HFA 134a 1. However, 152a flammability is forcing manufacturers to implement additional safety measures which makes traditional processes more challenging. By decoupling the filling of individual ingredients and direct dosing them into the canister, these challenges can be mitigated 1. We have initially explored this approach at a bench top scale for a Salbutamol Sulphate (SS) suspension.
SS (30 mg) was dry filled (RSD 1.7-2.1%) employing the Drum TT or a spatula into canisters. These were then crimped using a manual crimper or a Vacuum Crimper X5004 2 and gassed with 152a. Aerodynamic particle size distribution (APSD) and drug delivered (DD) were tested at time zero and after 3 months at 40°C/75% RH.
DD was not affected by either filling or crimping method. APSD showed also comparable results with a slight decrease in respirability during stability with no clear trending differences.
This manufacturing method would significantly de-risk HFA 152a handling, eliminating the need for mixing vessels and enabling pMDI manufacturing no longer dependent on vessel capacity.
Propellant Manufacturer Perspective: The Widespread Potential of Zephex® 152a
Orbia Fluor & Energy Materials, Chester, United Kingdom.
Orbia Fluor & Energy Materials are the market leaders in the supply of medical propellants. To address increasing environmental, regulatory and stakeholder pressure to reduce the carbon footprint associated with the use of MDIs, Orbia’s F&EM have developed and introduced a new low carbon pMDI propellant Zephex-152a.
Zephex-152a has the potential to be a widely used next generation propellant due to its favorable physical properties, formulation behaviour and 90% lower global warming potential (GWP) than current propellants. To date, research has optimised Zephex-152a’s compatibility with device componentry ensuring it provides reliable performance in MDIs, assuring consistent medication delivery [1].
The inhalation safety of Zephex-152a has been studied for nearly 10 years, showing no acute or chronic toxicity, no genotoxic or carcinogenic activity, no developmental or reproductive toxicity, and no cardiopulmonary or respiratory toxicity, also with evidence supporting its paediatric safety [2]. Zephex-152a offers significant environmental benefits without compromising therapeutic performance or patient safety, ensuring the longevity of an essential dosage form.
References
[1] Stanford, S. Flaherty, S. Johnson, S. Murray, J. (2024). DDL Digital proceedings, Vol. 35 pp 267–270. doi:10.60565/cjpx-1k63
[2] Mohar, I. Lewandowski, T.A. Johnson, S. Corr, S. Leach, C. (2023). DDL Digital proceedings, Vol. 34 pp 260–263. doi:10.60565/rt43-7m33
Imaging, Modeling, and Physiology of Aerosols in the Lung
MODELING AEROSOL BOLUS INHALATIONS WITH THE MULTIPLE PATH PARTICLE DEPOSITION MODEL
Bahman Asgharian,1 Owen Price,1 Azadeh A.T. Borojeni,2 Andrew P. Kuprat,3 Sean Colby,3 Rajesh K. Singh,3 Richard A. Corley,4 and
1Applied Research Associates, Arlington Division, Raleigh, NC, USA. 2Department of Medicine, University of California, San Diego, CA, USA. 3Pacific Northwest National Laboratory, Richland, WA, USA. 4Greek Creek Toxicokinetics Consulting, LLC, Boise, ID, USA.
Most one-dimensional models of aerosol deposition ignore mixing mechanisms of inhaled aerosols during their transport in the lung. In this study, we improved on the multiple path particle dosimetry model (MPPD) to account for flow irreversibility and particle trapping in the alveolar spaces, as well as mixing occurring in the tracheobronchial region. This new version of MPPD was coupled with CFPD-based predictions of aerosol bolus dispersion in the oral airway to model the entire respiratory system. The model was used to predict the deposition, dispersion, and mode shift of 1 µm aerosol bolus inhaled at different penetration depths within the lung for breathing patterns matching experiments [1]. Predictions agreed relatively well with subject-specific experimental values for both aerosol bolus deposition and dispersion, while predictions of mode shift overestimated the mouthward shift of the exhaled bolus for tests performed at large penetration volumes. Of these three parameters, mode shift has been shown to have the greatest intrasubject variability and it is thus not surprising that deviations between experiments and predictions were the greatest for this parameter. Even though a quite simplified approach was used, this new version of MPPD can be a useful tool to provide better insight in targeted drug delivery and its potential benefit in the treatment of lung diseases. This study was funded by NIH/NIEHS 1U01ES028669.
References
[1] Darquenne et al. J Aerosol Sci, 99:27–39, 2016.
High-Flow Nasal Aerosol Therapy; Regional Aerosol Deposition and Airway Responsiveness
Stony Brook University Hospital, Stony Brook, USA.
During tidal breathing, aerosols settle in small airways. In obstructive lung disease (OLD), airway collapse during expiration causes turbulence, increasing central deposition. High-flow nasal cannula (HFNC) therapy, which washes out dead space, may alter deposition and drug delivery. This study compared aerosol deposition and airway responsiveness in OLD following traditional and HFNC nebulization.
12 OLD subjects completed a 2-day study. Spirometry was measured pre- and post-inhalation. On Day 1, subjects inhaled radiolabeled albuterol via AeroTech II. On Day 2, inhalation was via HFNC (60 L/min) using i-AIRE with nebulization at 50 mL/h. Lung deposition mechanisms were analyzed using multiple linear regression (MLR), considering breathing frequency, FEV1, and DLCO.
Albuterol deposition was matched (D1 vs D2, p=0.13) with central/peripheral (sC/P) ratios of 1.99±0.98. HFNC increased peripheral deposition by 31%±33% (sC/P=1.51±0.43, p=0.011). Spirometry showed a 16.1±16.7% increase in FVC (p=0.003). Nasopharyngeal deposition was 333% of lung deposition. Heart rate and O2 saturation were unaffected (p=0.31, p=0.63). MLR analysis differed between D1 (R²=0.82) and D2 (R²=0.12).
HFNC nebulization was well tolerated, improved peripheral drug delivery, and enhanced spirometry without systemic effects, suggesting limited nasal absorption. MLR revealed distinct mechanisms for traditional versus HFNC delivery, supporting HFNC as an effective and controllable therapy for OLD.
PREDICTING PULMONARY ABSORPTION OF INHALED DRUGS USING THE EX VIVO ISOLATED PERFUSED LUNG (IPL) MODEL
1University of Parma, Parma, Italy. 2Chiesi Farmaceutici s.p.a., Parma, Italy.
This study explored the potential of the ex vivo isolated perfused rat lung (IPL) model to predict the lung absorption of inhaled drugs [1]. Unlike in vitro methods, IPL better replicates the physiological environment of the lung, preserving key aspects of lung function and tissue barriers. The focus was on a poorly water-soluble compound in pharmaceutical development, administered in three formulations: free-base powder, compound salt powder, and free-base nanosuspension. The IPL model enabled controlled drug delivery and frequent sampling of the perfusate, facilitating the assessment of pulmonary absorption. This approach aligns with the 3Rs principles by minimizing animal use. The IPL data were compared with in vivo pharmacokinetic profiles from rat studies. Results revealed a strong correlation between ex vivo and in vivo profiles for all formulations, despite differences in the devices used for powder administration in each setting. This study underscores the value of the IPL model in assessing and potentially predicting the pharmacokinetics of inhaled drugs, particularly for poorly water-soluble compounds. Its ability to reduce animal usage and provide frequent sampling makes it a promising tool for preclinical drug development.
References
[1] Eriksson, J., Sjögren, E., Lennernäs, H, (2020). AAPS J 22, 71; DOI: 10.1208/s12248-020-00456-x.
In-silico evaluation of regional lung deposition: the impact of realistic breathing profiles
1PULMOTREE, Munich, Germany. 2Nanopharm, Cwmbran, United Kingdom. 3Ockham Biotech, Portsmouth, United Kingdom.
JET NEBULIZATION DURING MECHANICAL VENTILATION: USING MASS BALANCE
1Stony Brook university Hospital, NY, USA. 2Stony Brook University, NY, USA.
PREDICTIVE MODELING OF PEDIATRIC INTRANASAL DRUG DELIVERY: KEY ANATOMICAL AND ADMINISTRATION PARAMETERS
Virginia Commonwealth University, Richmond, USA.
Predictive models for pediatric in vitro posterior drug delivery (PDD) across 40 pediatric nasal cavities using Nasacort (NC) and Flonase Sensimist (FS) nasal sprays [1] in relation to anatomical dimensions, administration parameters, and airway patency were developed. Stepwise regression method identified key parameters that significantly influence PDD. Our results revealed strong correlations, r2 = 0.802 for NC and r2 = 0.895 for FS, between the three parameters and PDD. Notably, based on the obtained p-values, insertion depth and coronal angle emerged as crucial factors for NC and FS, respectively. Additionally, variable importance assessments revealed the importance of tip-to-INV distance for NC and the cross-sectional area (CSA) of the INV plane for both nasal sprays. These findings underscore the importance of considering anatomical variability in developing targeted intranasal drug delivery systems, and the differences between adult and pediatric populations in terms of the most influential parameters on governing the PDD. We demonstrated that patient-specific administration parameters are crucial for enhancing drug delivery efficacy, but the extent of the enhancement is limited by the airway anatomy [2].
References
[1] Esmaeili AR, Wilkins J V., Hosseini S, et al. (2024). J Aerosol Sci 179:106387. doi:10.1016/J.JAEROSCI.2024.106387
[2] Hejazi M, Alshammary AM, Edwards DJ, et al. (2025). Comput Biol Med 187: 109746. doi:10.1016/j.compbiomed.2025.109746
COMPUTATIONAL FLUID DYNAMICS MODEL VALIDATION OF SPRAY CHARACTERISTICS FROM A SUSPENSION-BASED PRESSURIZED METERED-DOSE INHALER
FDA, Silver Spring, USA.
Pressurized metered dose inhalers (pMDIs) are widely used for delivering aerosolized medications to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The efficiency of drug delivery depends on the characteristics of the emitted spray, including plume width and plume angle, which influence particle transport, deposition patterns, and overall therapeutic effectiveness. Computational fluid dynamics (CFD) models provide a powerful, cost-effective approach for investigating these factors by simulating complex flow and transport phenomena. Understanding how spray characteristics impact drug delivery is essential for optimizing inhaler designs and improving patient outcomes. This study aims to evaluate the effects of plume width and plume angle on drug deposition using CFD models. As a first step, we conducted a validation study to ensure model accuracy. We simulated and analyzed the plume width and plume angle from a suspension-based pMDI, comparing the results with particle image velocimetry (PIV) data of sprayed particles [1]. The validated models establish a basis for improving predictive capabilities, enabling more accurate assessments of drug transport in the respiratory tract, guiding the development of more effective inhaler designs, and aiding with bioequivalence recommendations for generic drug products.
References
[1] Crosland, B.M., Johnson, M.R., Matida, E.A. (2009). J Aerosol Med Pulm Drug Deliv 22, 85–97. doi.org/10.1089/jamp.2008.0687
Regional Nasal Deposition Predictions for Sumatriptan Succinate Nasal Powder
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, USA.
Sumatriptan succinate nasal powder is indicated for treatment of migraine headaches. For nasal administration, the sites of action include the posterior region of the nasal cavity and potentially the olfactory region as well if nose-to-brain drug delivery occurs. Drug delivery to the sites of action may be impacted by factors related to regional deposition within the nasal passage such as flowrate, administration time, and nosepiece insertion angle. This work summarizes the results of a computational fluid dynamics (CFD) model that evaluates these factors for their effect on regional deposition, which is differentiated based on anterior vs. posterior deposition as well as three equally spaced vertical regions. The model is validated against gamma scintigraphy data [1] of radiolabeled lactose particles administered with the Onzetra Xsail® nasal device that is commercially used by the brand name manufacturer to deliver sumatriptan succinate nasal powder. Results show that flowrate and administration time minimally affect regional deposition, but that nosepiece insertion angle is a significant factor. Additional investigation regarding mucociliary clearance and the rate of uptake for sumatriptan succinate is warranted to determine the significance of nosepiece insertion angle on drug delivery to the site of action.
References
[1] Djupesland, P. G. and Skretting, A. (2012). Journal of Aerosol Medicine and Pulmonary Drug Delivery 25, 280–289. doi: 10.1089/jamp.2011.0924
DEVELOPMENT OF A CFPD-BASED VIRTUAL NEXT GENERATION IMPACTOR (VNGI) TO PREDICT THE AERODYNAMIC PARTICLE SIZE DISTRIBUTION (APSD) OF RESPIRATORY DRUG DELIVERY PRODUCTS
1School of Chemical Engineering, Oklahoma State University, Stillwater, USA. 2Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, USA.
Next Generation Impactor (NGI) is widely used to measure the emitted Aerodynamic Particle Size Distribution (APSD) from inhalers at various flow rates. However, air-particle flow dynamics in NGI remain understudied due to the limitations of experimental visualization and operational flexibility. To address the gap, a first-of-its-kind computational fluid particle dynamics (CFPD)-based virtual NGI (vNGI) was developed, replicating the real NGI configuration. The vNGI can enable the visualization of spatiotemporal air-particle flow distributions and would facilitate experimental design by adjusting flow and inhaler design parameters without requiring extensive in vitro tests. For the vNGI, a mesh independence test was conducted to determine the optimal computational mesh, and a particle number independence study was also conducted. The resulting tetrahedron-based mesh with near-wall prism layers contains 17,954,689 cells. The vNGI was validated by comparing deposition efficiencies (DEs) across stages with in vitro NGI test data at 30 L/min. Comparisons show that vNGI accurately predicts DE in each stage up to Stage 3, while noticeable differences in Stages 4 to 7 may stem from unreported experimental errors in particle size and DE. In conclusion, the vNGI has been rigorously validated and is ready to assess the impact of environmental conditions on APSDs. Future work will investigate how relative humidity influences APSDs, which is difficult to quantify using in vitro tests.
Effect of Airflow on Nasal Powder Deposition in Models of the Nasal Cavity
1King's College London, London, United Kingdom. 2University of Parma, Parma, Italy. 3Aptar Pharma, Le Vaudreuil, France. 4Nanopharm Ltd, an Aptar Pharma Company, Cwmbran, United Kingdom.
Nasal casts, particularly segmented models, are widely used in drug deposition studies [1]. This study employed a design of experiments (DOE) approach to evaluate the effects of airflow (no airflow vs. 15 L/min) on regional deposition in two nasal casts, Alberta Idealised Nasal Inlet® (AINI) and Aeronose®, lined with various coating agents.
Sumatriptan micronised powder (ThermoFisher Scientific®) was delivered via a UDSp device (Aptar Pharma), inserted into the nostril at an angle of 45o. In the AINI, turbinate deposition was 76.6 ± 4.2% without airflow, dropping to 20.5 ± 15.1% with airflow (p < 0.001). In the Aeronose, airflow had no significant effect on turbinate deposition, 49.5 ± 21.6% without airflow, but reduced floor and nasal valve deposition by 83.2% and 24.3%, respectively. These reductions corresponded to increased deposition in posterior regions, including the nasopharynx and filter.
These data demonstrate the impact of airflow on nasal powder deposition [2]. The findings show differences in deposition patterns between casts, highlighting the need for standardisation and validation of in vitro drug deposition models before they can be used for in vitro-in vivo correlations.
References
[1] Williams, G. and Suman, J. D. (2022). Pharmaceutics 14, 7. doi: 10.3390/pharmaceutics14071353
[2] Jüptner, A. and Scherließ, R. (2025). European Journal of Pharmaceutics and Biopharmaceutics 209, 114666. doi: https://doi.org/10.1016/j.ejpb.2025.114666
PREDICTION OF TOTAL AND REGIONAL DEPOSITION EFFICIENCY OF SURFACTANT DELIVERY IN THE PRETERM NEONATE RESPIRATORY SYSTEM
1Department of Bioengineering, Northeastern University, Boston, MA, USA. 2Department of Respiratory Care Therapy, Seattle Children’s Hospital, Seattle, WA, USA. 3Center for Respiratory Biology and Therapeutics, Seattle Children’s Research Institute, Seattle, WA, USA.
Neonatal Respiratory Distress Syndrome (NRDS) in preterm infants results from insufficient surfactant production, leading to alveolar collapse and impaired gas exchange. Aerosolized surfactant therapy offers a non-invasive treatment option, but its effectiveness is limited by low delivery efficiency. We have developed 1D and 3D Computational Fluid Dynamics and Particle Deposition (CFPD) models, which incorporate medical image-derived lung geometry. The 1D model, validated with adult lung deposition data, covers the entire respiratory tract, while the 3D model provides detailed upper airway insights. Variability in model inputs (e.g., geometry, tidal volume, respiratory rates) was studied. The 1D and 3D models demonstrated consistent dosimetry for the 1-5 μm diameter particles considered. For 1 μm particles, 73% of the total particles deposit in the respiratory system, with 38% reaching the alveoli, whereas 5 μm particles result in 98% total deposition, but only 19% reach the alveoli. This study highlights that smaller particles achieve better alveolar deposition, while larger particles primarily deposit in the proximal airways. This study pioneers CFPD-based prediction of aerosolized surfactant delivery for treatment in preterm neonates. Future work will focus on incorporation of data from multiple subjects and optimization of device settings to target the deep lung.
Funding Source: Bill and Melinda Gates Foundation INV-018835-5.
BRANCHED PEGYLATION AS A STRATEGY TO OVERCOME THE MUCUS BARRIER TO AEROSOLIZED NANOMEDICINE
University of Maryland, Silver Spring, USA.
Delivery of aerosolized therapeutics to the lungs is severely limited by the mucus barrier. Nanoparticles often get trapped in the mucus mesh and cleared from the airways before they can render therapeutic benefit. To address this, nanoparticles can be coated with polyethylene glycol (PEG) to enhance their penetration through the mucus barrier. While linear PEG is conventional, we have recently investigated how PEG structure and branching impacts nanoparticle mobility through the extracellular matrix[1]. We now turn our focus to the effect of PEG branching on aerosolized nanoparticle delivery. For these studies, we cultured bronchial epithelial cells (BCis) at air liquid interface (ALI) and after fully differentiating, we collected mucus and analyzed nanoparticle mobility using particle tracking. We found that 10 kDa branched PEG coatings enable more efficient nanoparticle mobility in airway mucus as compared to linear PEG types. Building upon these findings, we are investigating how PEG type impacts aerosolized nanoparticle uptake in an in vitro airway model. For these ongoing studies, we are using a VITROCELL in vitro exposure system to aerosolize nanoparticles coated with PEG of varied structure for delivery in fully differentiated ALI cultures. Future studies will evaluate in vivo biodistribution of branched PEGylated nanoparticles delivered locally to the lung.
References
[1] Cahn, D., Stern, A., Buckenmeyer, M et. al (2024). ACS Nano 18, 32045–32055. DOI: 10.1021/acsnano.4c10381
INTEGRATION OF FLEXIBLE COLLAGEN-ELASTIN MEMBRANE FOR MIMICKING BREATHING MECHANISMS IN ALVEOLUS-ON-CHIP MODEL TO STUDY STAPHYLOCOCCUS AUREUS INFECTION
1University Hospital, Jena, Germany. 2FILK Institute gGmbH, Freiberg, Germany. 3Fraunhofer IWS, Dresden, Germany.
References
[1] Kollef, M. H., et al (2005). Epidemiology and Outcomes of Health-care–Associated Pneumonia.Chest,128, 3854–3862. doi:10.1378/chest.128.6.3854.
THE NOVEL MONOCLONAL HUMAN ALVEOLAR EPITHELIAL CELL LINE “ARLO” FOR MODELING THE PULMONARY AIR-BLOOD BARRIER IN VITRO
1Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany. 2Saarland University, Saarbrücken, Germany.
In vitro models of the human deep lung are crucial for studying respiratory health, disease, and drug delivery. Due to their physiological relevance, primary human alveolar epithelial cells (hAEpC) are currently considered the most accurate representation of deep lung cells, but they are limited by their variability and availability. Cell lines, on the other hand, offer accessibility and reproducibility, but often lack the barrier properties needed to model the alveoli. To address the need for a barrier-forming deep lung cell line, we immortalized hAEpC and established the hAELVi cell line, which we further improved via single-cell printing to generate the monoclonal cell line “Arlo” [1, 2]. Arlo exhibits pronounced and reproducible barrier properties, strict monolayer formation, and TEER values of approximately 3000 Ω*cm².
To demonstrate Arlo’s suitability for modeling the air-blood barrier, we investigated alveolar barrier formation, permeability, and performed proteomic and transcriptomic analyses to identify key barrier- and infection-related proteins. In addition to its application in infection research, Arlo’s unique barrier properties enable disease modeling, such as pulmonary edema, providing a platform for drug efficacy testing.
References
[1] Kuehn, A. Kletting, S., de Souza Carvalho-Wodarz, C. et al. (2016). ALTEX, vol. 33, no. 3, pp. 251–260 doi:10.14573/altex.1511131
[2] Carius, P. Jungmann, A. Bechtel, M. et al. (2023). Adv. Sci. 2023, 2207301. doi:10.1002/advs.202207301
UPDATES IN COMPLETE-AIRWAY SIP MODELING OF REGIONAL AEROSOL DEPOSITION: IMPROVEMENTS IN PHYSIOLOGICAL REALISM AND COMPARISONS WITH PATIENT-SPECIFIC 3D SPECT DATA
Virginia Commonwealth University, Richmond, USA.
A clinically relevant complete-airway computational fluid dynamics (CFD) model offers the ability to assess the regional dosages of orally inhaled pharmaceutical aerosol products throughout the airways. Our group has previously developed a Stochastic Individual Path (SIP) approach for implementing complete-airway CFD modeling and assessing respiratory drug delivery across multiple inhaler platforms (MDIs, DPIs, softmist nebulizers). Although this model showed excellent agreement with 2D in vivo data, a limitation was the incomplete mapping of the SIP geometry to the pleural space of each lung lobe. Furthermore, SIP geometries assumed symmetrical bifurcations, which are expected to impact regional aerosol deposition. Recently, we developed and implemented a technique and semi-automated workflow that uses chest CT scans and combines a tracheobronchial lobar tree-filling algorithm and a physiologically realistic bifurcation generation algorithm to improve the physiological realism of the SIP complete-airway modeling approach [1]. The current study focuses on advancing SIP-based complete-airway CFD models by incorporating realistic airway anatomy from patient-specific chest CT scans, a new acinar model, and an exhalation model for validation against carefully controlled in vivo 3D SPECT data of nebulized droplet delivery for a healthy subject [2].
References
[1] Thomas ML, et al. (2024) RDD 2024: 552–556.
[2] Conway, J, et al. (2012) Journal of Aerosol Science 52: 1–17.
PREDICTIVE MODEL FOR PEDIATRIC LUNG DELIVERY: INTEGRATING ANATOMY, AEROSOL DYNAMICS, AIRWAY CONDITIONS, AND TIDAL BREATHING
John Wilkins,
Virginia Commonwealth University, Richmond, USA.
The efficacy of pediatric aerosol delivery has been studied using in vitro and in silico models [1]. However, some in vivo studies highlight limitations in predicting subject-specific lung drug delivery [2]. This study evaluated the suitability of a lung delivery correlation [3], developed using nonvolatile aerosol, in prediction of hygroscopic pharmaceutical aerosol transport through nine pediatric oral airways (6-14 years old) [3]. Aqueous solution of albuterol sulfate (AS, 2 mg/mL) was nebulized and delivered to the models by humidified air at three breathing patterns, while a low-resistance filter at the model’s outlet captured the AS, representing lung delivery. Next, the AS concentrations were assayed via high-performance liquid chromatography. The existing correlation for stable aerosols [3] did not accurately predict lung delivery of hygroscopic droplets, due to size changes by evaporation or hygroscopic growth. To address this, a new correlation incorporating tidal volume, Stokes, Reynolds, and Peclet numbers was developed, achieving an R² = 0.73, while accounting for variations in anatomy and breathing pattern.
References
[1] Carrigy, N., Ruzycki, C., Golshahi, L. et al. (2014) J. Aerosol Med. Pulm. Drug Deliv. 27(3):149-169. DOI: 10.1089/jamp.2013.1075
[2] Yang, M. Y., Ruzycki, C., Verschuer, J. et al. (2017). Aerosol Sci. Tech. 51(3), 363–376. DOI: 10.1080/02786826.2016.1262532
[3] Golshahi, L., Vehring, R., Noga, M. L. et al. (2013) J Aerosol Sci. 57: 14–21. DOI: 10.1007/s10439-013-0747-0
MODELING THE DELIVERY OF ADVAIR-HFA VIA PRESSURIZED METERED DOSE INHALER (PMDI) THROUGH A VALVE HOLDING CHAMBER (VHC) TO MITIGATE HIGH ALTITUDE PULMONARY EDEMA (HAPE)
1Applied Research Associates, Inc., Raleigh, USA. 2Johannes Gutenberg University of Mainz, Maniz, Germany. 3University of Maryland, Baltimore, USA. 4University of Colorado, Denver, USA. 5Lucent, Inc., Denver, USA. 6US Army Military Operational Medicine Research Program, Ft. Detrick, USA.
When ascending to high altitudes without an acclimatization period, individuals may develop potentially lethal HAPE. Inhalation of the β-adrenergic receptor agonist salmeterol has shown potential in preventing HAPE. This study investigated the ability of the FDA approved Advair-HFA (hydrofluoroalkane), which is used to treat asthma, to travel beyond the superficial bronchial regions involved in asthma, to reach the alveolar region. A computational fluid and particle dynamics (CFPD) analysis was conducted to model the transport of drug particles released from a pMDI into a valve holding chamber VHC equipped with a one-way valve for particle conditioning. The drug particles then passed through the oral cavity before reaching the lung airways. A semi-empirical transport model, based on the CFPD analysis, was developed and integrated with a previously established lung deposition model to predict the behavior of Advair-HFA in the lung. Model predictions indicated that the 4-micrometer drug particles reached the deep lung with a 30% delivery efficiency, suggesting the Advair system could be targeted for new applications such as HAPE. At the strategic level, our results show that inhalation modeling could be powerful tool in the discovery of novel applications for existing drugs as well as the development of novel drug and device combinations. This research was supported by the Medical Technology Enterprise Consortium (MTEC) under base agreement number 2018-679.
High-throughput bioinspired 3D cultures capture macrophage responses to pathogenic bacterial invasion in diseased lung microenvironments
University of Delaware, Newark, USA.
Chronic lung diseases are characterized by a dysregulated microenvironment that leads to impaired immune function, increasing susceptibility to persistent and fatal bacterial infections. As the first responders to bacteria, macrophages are a key component of this dysfunction. Microenvironmental changes are known to influence macrophage phenotype, but it remains unclear whether these changes specifically impair their initial response to bacteria. To investigate this, we have established workflows for probing macrophage responses to bacteria in 3D synthetic extracellular matrices (ECMs) using a high-throughput ink-jet bioprinting approach.
Synthetic ECMs were created using PEG-based hydrogels that incorporate integrin-binding peptides, inspired by ECM proteins. Human THP-1 cells were encapsulated within hydrogels and differentiated into macrophages. Viability, morphology, and immunophenotype were assessed within synthetic ECMs with stiffnesses relevant to healthy (storage modulus (G′) ∼ 1.1 kPa) and fibrotic (G′∼4.8 kPa) lung tissues. Imaging, flow cytometry, and ELISA revealed appropriate macrophage responses to bacteria. Notable differences in the characteristics of macrophage response were found between fibrotic and healthy microenvironments. By recreating disease-altered lung environments, this work enables mechanistic studies of host-pathogen interactions and provides a foundation for identifying therapeutic strategies to restore immune function in chronic lung disease.
ENHANCING PULMONARY DRUG DELIVERY WITH THE TIDAL MODEL: A NEW APPROACH TO IN VITRO AEROSOL DOSIMETRY
University of Delaware, Newark, USA.
Understanding where inhaled aerosol drugs are deposited within the lungs is essential to optimizing their efficacy and reducing off target effects. Experimental in vitro deposition assessments are a critical component of the preclinical pipeline, validating computational simulations and providing spatial information in the absence of clinical studies. TIDAL, the Total Inhalable Deposition in an Actuated Lung model, consists of 3D-printed patient-derived upper airways connected to deformable lobe units and lattice filters to provide high-resolution deposition data and customizability to varied patient populations. Our initial TIDAL prototype has demonstrated total lung volume over 7 liters and breathing rates over 30 LPM. Adopting a resting, symmetric breathing profile exchanging ∼600mL of air at a peak inspiratory flow rate of 21.5 ± 1.0LPM, TIDAL was able to generate spatial deposition maps of fluorescence aerosols from an Aerogen Lab Nebulizer (MMAD 6.77µm) with a planar-equivalent central to peripheral ratio (C/P) of 1.08 ± 0.03. This C/P result is in line with analogous human scintigraphy studies, supporting the relevance of our design in generating accurate spatial deposition profiles. Building from these promising results, our on-going efforts include updating the range of breathing profiles and validating the model using a broader range of aerosol sizes to increase the utility of this new in vitro platform.
New Devices and Emerging Therapies
DESIGNING DRUG-DEVICE COMBINATION PRODUCTS COMPRISING PASSIVE DRY POWDER INHALERS TO MAXIMIZE AIRWAY TARGETING AND IMPROVE DOSE CONSISTENCY
AeroFluor Pharma Consulting, Half Moon Bay, USA.
This presentation discloses a human factors strategy around the design of dry powder inhalers (DPIs) to mitigate dose preapation, dose inhalation, and treatment adherence errors. To improve patient outcomes it is critical that the formulation and device work in concert. Designing improved formulations that bypass deposition in the upper respiratory tract is deemed critical, as it improves lung targeting, reduces off-target adverse events, and mitigates critical dose inhalation errors associated with oropharyngeal filtering of particles, variations in inspiratory pressure, and co-formulation effects in fixed dose combinations. More specifically this presentation will describe how to design drug-device combination products that: (1) Minimize variability associated with oropharyngeal filtering of particles by designing spray-dried powders with a monomodal aerodynamic particle size distribution and an impaction parameter of 100-200 μm2 L/min; (2) Target small airways delivery without the risk of particle exhalation in the absence of a breath-hold by designing spray-dried particles with an MMAD of about 3 μm and a mass median impaction parameter (MMIP) of about 200 μm2 L/min. This necessitates dose delivery with a high resistance dry powder inhaler at a flow rate of about 22 L/min; (3) Minimize inspiratory pressure drop dependence with a passive DPI by tuning device resistance.
Comparison of Aerosol Therapy Using High-Pressure Gas vs. Ventilator-Integrated Nebulization Systems
1Chang Gung University, Taoyuan, Taiwan. 2Yuanlin Christian Hospital, Changhua, Taiwan.
A NEW NEBULIZER ARCHITECTURE: EFFICIENT ENERGY TRANSFER INTO COUPLING LAYER-FREE SUPERSTRATES
1Nebu-Flow Limited, Glasgow, United Kingdom. 2University of Glasgow, Glasgow, United Kingdom.
One of the primary issues with any nebulizer device is the burden on the user to clean the device effectively between sessions [1]. User compliance with existing cleaning protocols is typically only partial at best, which can lead to degradation of device performance, as well as microbial growth and cross-contamination [2].
To circumvent this, we propose a novel nebulizer architecture that employs energy transfer from an ultrasonic transducer to a detachable superstrate, which can then be safely disposed of post-nebulization. Superstrates are a popular approach for other microfluidic tasks and have previously been explored for nebulization [3]; however, gel or liquid coupling layers are typically required to mitigate the low coupling efficiency arising from material impedance mismatches. Such coupling strategies are undesirable for a nebulizer device since they create additional cleaning steps for the user.
Here we show that efficient energy transfer is feasible without the use of a coupling layer. This approach overcomes the cleaning issues inherent to the use of a coupling layer and has the potential to facilitate a true plug-and-play experience for the user.
References
[1] Boyter, A.C., Carter, R. (2005). Respir Med 99, 1413–1417. doi:10.1016/j.rmed.2005.03.004
[2] MacFarlane, M., Carson, L., Crossan, A. et al. (2019). J. Infect Prev 21(1), 14–22. doi:10.1177/1757177419855603
[3] Wong KS, Lee L, Hung YM, et al. (2015). Anal Chem 91, 12358–12368. doi:10.1021/acs.analchem.9b02850
Nasal high flow achieved superior deep lung deposition of nebulized albuterol, outperforming the conventional mask in in-vitro model
1Fisher & Paykel healthcare, Auckland, New Zealand. 2Sydney Pharmacy School, The University of Sydney, Sydney, Australia. 3Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
AEROPULSR: A PRECISE HIGH DOSE GENERATION AEROSOL PLATFORM FOR CRITICAL CARE PEDIATRIC AND ADULT PATIENTS
KAER Biotherapeutics Corporation, Escondido, USA.
5.7 Million Americans are admitted to ICU‘s each year, accounting for 13% of hospital costs. Tragically, many of these are children between 6 months to 5 years of age and senior adults who are most susceptible to pneumonia or influenza with high mortality. Current aerosolization techniques are unable to deliver the minimum effective doses of anti-infectives and surfactant to the alveoli necessary to enable positive clinical outcomes. AeroPulsR generates therapeutic aerosols of high payload from liquid drugs of low or high viscosity, while maintaining their complex molecular structures. These drugs include antibiotics, antivirals, surfactants, biologics and oligomeric molecules. AeroPulsR’s mechanism of aerosol generation fundamentally differs from atomizers and mesh nebulizers. Liquid drugs are aerosolized at a precise selectable rate between of 1 to 4 ml/min and delivered as fine respirable aerosols with diameters of 2 - 4 µm. The aerosolization output is 10 times and 4 times higher than existing atomizers and nebulizers, respectively. The aerosol output is delivered either continuously, periodically, or spontaneously with each breath. AeroPulsR delivers 20 mg/kg dose of 10% γ-globulins within 20 min to a simulated adult patient, whereas this dose is delivered in 12 min to a simulated pediatric patient. This rapid delivery rate provides shorter treatment duration, reduced supervision time, improved adherence and promises better clinical outcomes.
BREATHING MANEUVER IMPACT ON A BREATH-ACTUATED NEBULIZER: ASSESSMENT OF AEROSOL PERFORMANCE AND DELIVERY EFFICIENCY UNDER A GUIDING SYSTEM
HCmed Innovations Co., Ltd., Taipei, Taiwan.
References
[1] van Velzen, A. J., Uges J. W., Le Brun P. P. et al. (2015). J Cyst Fibros 14(6): 748–54. doi: 10.1016/j.jcf.2015.01.002
[2] Cuevas Brun, E. H., Richter, J., Grill, M. J. et al. (2024) Proceedings of DDL 35, 345–48. doi.org/10.60565/cjpx-1k63
IMPROVING THE FLEXIBILITY OF A MESH-NEBULIZER-BASED SPRAY DRYING SYSTEM: SCALABLE MULTIPLEXED MESH SOURCES AND INCREASING THE PARTICLE SIZE RANGE
Virginia Commonwealth University, Richmond, USA.
A New Dry Powder Inhaler with Air-jet Multi-Cycle Oscillatory-Jet (MC-OJ) Technology for Targeted Nasal Delivery
1Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, USA. 2Department of Pharmaceutics, Virginia Commonwealth University, Richmond, USA.
DEVELOPMENT OF A NOSE-TO-LUNG AEROSOL DELIVERY PLATFORM FOR ADMINISTERING DRY POWDER AEROSOL SYNTHETIC LUNG SURFACTANT (SLS) THERAPY TO PRETERM INFANTS
1Virginia Commonwealth University Department of Mechanical and Nuclear Engineering, Richmond, VA, USA. 2Virginia Commonwealth University Department of Pharmaceutics, Richmond, VA, USA.
The objective of this study was to develop a device and interface for intranasal delivery of a spray-dried synthetic lung surfactant (SLS) aerosol therapy to the lungs of preterm infants with respiratory distress syndrome. Using the concept of excipient enhanced growth (EEG), the device was intended to produce a small particle (∼1.5 µm) aerosol that efficiently penetrates the upper airways and targets the alveolar region. The efficacy of this SLS-EEG aerosol therapy was recently demonstrated in an infant-size surfactant-washout animal (rabbit) model and found to be superior to liquid bolus instillation of Curosurf when administered intratracheally at a total aerosol device loaded powder dose of 60 mg [1]. An air-jet DPI with a variable-volume aerosolization chamber (D3 device; holding 30 mg powder mass loadings) was coupled with a newly designed rapid-expansion nasal interface, and the device was actuated four times with air volumes of 10 mL each, at a flow rate of 3 L/min. Median volumetric diameter (Dv50) of the aerosol from the device was 1.6 µm. Based on initial testing with a realistic nose-throat model of a preterm infant (1500g), 35% of the loaded dose reached the tracheal filter. In conclusion, the new delivery system formed a small-particle SLS-EEG aerosol with reasonable baseline transmission through the nasal geometry of a preterm infant.
References
[1] Longest, W. et al. (2025). J. Aerosol Med. Pulm. Drug Deliv. (in press).
SUNRISER DRY POWDER INHALER - INNOVATIVE PLATFORM TAILORED FOR EFFICIENT DELIVERY OF DIVERSE FORMULATIONS
1H&T Presspart, Marsberg, Germany. 2H&T Presspart, L’Arboç, Spain. 3H&T Presspart, Blackburn, United Kingdom.
The inhalation route is recognized as an effective method for delivering medications, targeting not only respiratory diseases but also systemic conditions [1]. These advancements have led to new formulation technologies creating novel powders with new challenges and are prompting the development of new devices to achieve reliable and consistent dosing to the patient. The device and formulation are linked, as the device efficiency depends on the characteristics of the formulation [2]. The “Sunriser” is an innovative capsule-based DPI device showing efficient dispersion of different formulations. Its core feature includes a powerful engine with a patented oscillating capsule movement and classification technology. In collaboration with our partner Hovione, we have tested both spray-dried formulations and traditional carrier-based formulations. Initial studies illustrate Sunriser’s high aerosolization capabilities and consistent performance even with cohesive powders and varying flow rates. This highlights the device’s potential as a platform device suitable for diverse inhalation therapies. Its ability to maintain high fine particle fraction across these diverse formulations suggests broad applicability, enabling the delivery of innovative inhalation therapies.
References
[1] Y. Ye, Y. Ma, J. Zhu (2022) Int. J. Pharm 614, doi: 10.1016/j.ijpharm.2022.121457
[2] M. Hoppentocht, P. Hagedoorn, H.W. Frijlink, A.H. de Boer (2014) Adv. Drug Deliv. Rev 75,18-31 doi: 10.1016/j.addr.2014.04.004
AEROSOL CHARACTERISATION AND IN-SILICO LUNG DEPOSITION MODELLING OF A BREATH-ACTIVATED MESH NEBULIZER AS COMPARED WITH A CONTINUOUSLY PRODUCING NEBULIZER
Phillips Medisize, Chippenham, United Kingdom.
Vibrating mesh nebulizers such as the FOX® device are portable drug delivery systems that can facilitate short treatment times, reproducible dosing and targeted pulmonary deposition. The use of breath activation (BA) together with real-time feedback enables precise timing of the aerosol bolus during controlled inhalation. This has been proven in vivo to increase drug deposition in the lung [1], which can prevent local adverse effects in the upper respiratory tract, reduce treatment frequency, and improve clinical outcomes [2,3].
Despite the advantages of BA, the demonstration of the technology in vitro can be challenging. Laboratory evaluation as guided by USP 1601 and Ph. Eur. 2.9.44 provides an important determination of dose and delivery rate, although these evaluations do not sufficiently inform the lung dose and in vivo performance of the device in response to the breath pattern.
This study characterizes the differences between breath activated and continuous devices for the delivery of salbutamol sulphate inhalation solution. In silico lung analysis has been used to expand the relevance of the in vitro data and provide a more comprehensive understanding of nebulizer performance.
References
[1] Corcoran, T, Wesolowski, A, Nagel, M, Suggett, J, et al. (2019). Respiratory Care, 64 (Suppl 10);3235398. Doi:10.4187/respcare.20193235398
[2] Gessler, T. (2019). Therapeutic Advances in Respiratory Disease,13 Doi:10.1177/1753466619835497
[3] Saunders D. (2015). Respiratory Care, 60(10): OF9 Poster.
A NOVEL NEBULIZER SPACER SYSTEM ENSURES CONSISTENT HIGH DOSE INHALED DRUG DELIVERY DESPITE CHANGING BREATH PATTERNS ASSOCIATED WITH INCREASING SEVERITY OF LUNG DISEASE
1Inspiring Pty Ltd, Nedlands, Australia. 2The Kids Research Institute, Nedlands, Australia. 3University of Western Australia, Nedlands, Australia. 4Respidex LLC, San Francisco, USA.
Prolongation of exhalation time relative to inhalation time (I:E ratio) is a feature of respiratory diseases such as Asthma/COPD/CF. With disease progression and particularly during acute exacerbations, I:E ratios decrease, meaning longer exhalation times. Continuous nebulizers lose all aerosol produced while the user is exhaling, meaning as patients become sicker, paradoxically more drug is lost and less is inhaled.
We have developed a novel low-tech low-cost closed-circuit Universal Spacer System (USS) that when used with a standard mesh nebulizer (MN) stores aerosol produced during exhalation and makes it available for the next inhalation. We compared the USS+MN to the MN alone in USP/EMA guided experiments using a breath simulator set to different breath patterns simulating “real-life” clinical scenarios (eg Asthma/COPD). Results show despite lengthening exhalation time periods with a range of I:E ratios, the USS+MN consistently delivered >70% of the total nebulised dose, whereas the MN alone delivers 40% at 1:1 decreasing to 16% at 1:4. Mean aerosol loss across all I:E ratios for the USS was 4% (0-12%) of total nebulised dose versus 68% (56-78%) from the MN alone. Results of varying breath rate and volume are also presented.
These results suggest that the USS’s mechanism for improving consistency of high dose inhaled drug delivery to patients despite worsening symptom and disease severity, has the potential to significantly improve treatment outcomes and even save lives.
ADVANCED ANALYSIS OF VISCOSITY AND FLOW RATE INFLUENCE ON DROPLET SIZE DISTRIBUTION IN ULTRA-SOFT NASAL SPRAY SYSTEMS
Nicolas Buchmann,1 Frank Verhoeven,2 and
1Resyca GmbH, Munich, Netherlands. 2Resyca BV, Enschede, Netherlands. 3Resyca GmbH, Munich, Germany.
References
[1] D’Angelo, D., Kooij, S., Verhoeven, F., et al. (2023). Journal of Advanced Research, 44, 227–232. doi:10.1016/j.jare.2022.04.011
[2] Verhoeven, F., Ravensbergen, P., Sibum, I., et al. (2024). Drug Delivery to the Lungs, Volume 35, 2024, https://doi.org/10.60565/cjpx-1k63
Repurposing Clofazimine for Inhaled Delivery to treat a Rare Cancer of the Lungs’ Pleural Cavity
St. John's University, Jamaica, USA.
Malignant Pleural Mesothelioma (MPM) is an aggressive neoplasm predominantly attributed to asbestos exposure, with <10% 5-year survival. A long latency period of 30-50 years complicates diagnosis and treatment. Treatment options include surgery, radiotherapy, and chemotherapy, each with limitations and side effects. Clofazimine, an FDA-approved anti-leprotic agent, effectively suppresses tumor growth in various cancers by inhibiting Wnt signaling pathways. Our group has recently demonstrated anti-mesothelioma efficacy of CFZ, indicating its potential for repurposing for MPM treatment. Therefore, CFZ PLGA nanoparticles (NPs) were formulated utilizing the probe sonication method and analyzed for various in-vitro characterizations. The resulting nanoparticles demonstrated an average particle size of 217.8±5.1 nm with an encapsulation efficiency of 49.3±3.1%. NPs were stable over two months at 4°C and 25°C. Analysis of lung deposition revealed that these nanoparticles had MMAD of 1.8±0.1 µm with 87.9±1.9% fine particle fraction. In-vitro evaluations confirmed that CFZ nanoparticles exhibited ∼2.1-fold reduction in the IC50 value compared to the plain drug on the H2452 cell line. Significant inhibition of tumor migration was corroborated through scratch assay. Dose-dependent spheroid volume reduction was also observed with 3D spheroid assay. Thus, inhalable polymeric nanoparticles of CFZ represent a novel therapeutic strategy against MPM.
LOCAL TARGETING OF CELASTROL BY INHALATION FOR NON-SMALL CELL LUNG CANCER (NSCLC) THERAPY
St John's University, Queens, USA.
Despite advances in targeted therapies, the five-year survival rate for advanced non-small cell lung cancer (NSCLC) remains approximately 28%. Celastrol (CELA), a bioactive compound from Tripterygium wilfordii, has strong anticancer activity but suffers from poor solubility and bioavailability. Encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles for inhalation delivery offers a promising strategy to enhance its therapeutic potential. CELA-loaded PLGA nanoparticles were formulated via solvent evaporation, achieving an encapsulation efficiency of 54.7±11.8%, a nearly monodispersed particle size of 204.2±1.3 nm. In-vitro studies showed significantly enhanced anticancer efficacy in H1975 NSCLC cells, with PLGA-CELA exhibiting an IC50 of 0.53±0.07 µM versus 1.4 ± 0.07 µM for free CELA (p<0.0001). In 3D spheroid models, PLGA-CELA significantly reduced tumor spheroid volume compared to free celastrol, indicating superior inhibition. Live/dead assay results confirmed these findings, showing increased red fluorescence (RFP) in PLGA-CELA-treated spheroids, indicating enhanced cytotoxicity than free CELA (p < 0.05). 3D viability studies at 1.4 µM revealed significantly lower cell viability in PLGA-CELA-treated spheroids (6.0±0.8%) compared to CELA (59.0±4.0%) (p<0.0001). These findings highlight PLGA-CELA’s potential as an inhalable nanotherapeutic for NSCLC, with ongoing aerosolization and in-vitro studies to further evaluate its efficacy.
AI-Powered Smart Inhaler: A Comprehensive Solution for Optimized Respiratory Care
1Purcell Global, London, United Kingdom. 2Arizona State University, Tempe, USA.
Early & accurate disease detection is critical for improving patient outcomes & reducing healthcare costs. Purcell BioPro+™ is a next-generation, AI-powered point-of-care-test diagnostic device, based on principles of electrochemical sensing in order to enable near real-time disease diagnostics. The device uses an array of electrochemical sensors for identifying volatile organic compound (VOC) concentration patterns associated with respiratory disorders & coupled with a combination of optical & pressure sensors, along with microphones for detecting anomalies in inhalation/exhalation patterns. The information is channelled into a cloud-based AI/ML pipeline analyzing sensor information for the presence of disease markers for COPD & asthma. Support Vector Machines (SVM) & Principal Component Analysis (PCA) are amongst the most efficient models at classifying patients based on breath profile variations and VOC quantification with prediction surpassing 90% accuracy. This is further refined through feature selection techniques, such as Bootstrap Recursive Feature Elimination to enhance the model’s reliability. With in-situ health monitoring becoming more relevant in today's world, this sensor-based breath analysis system provides a promising, non-invasive, low cost, yet reliable solution for early respiratory disease screening & monitoring, potentially saving millions of dollars in treatment costs alone while reducing the national patient economic burden for COPD & asthma.
Electrochemical Sensor-Based Point-of-Use Diagnostic Device for Real-Time Disease Detection and Monitoring
1Purcell Global, London, United Kingdom. 2Arizona State University, Tempe, USA.
Early & accurate disease detection is critical for improving patient outcomes & reducing healthcare costs. Purcell BioPro+™ is a next-generation, AI-powered point-of-care-test diagnostic device, based on principles of electrochemical sensing in order to enable near real-time disease diagnostics. The device uses an array of electrochemical sensors for identifying volatile organic compound (VOC) concentration patterns associated with respiratory disorders & coupled with a combination of optical & pressure sensors, along with microphones for detecting anomalies in inhalation/exhalation patterns. The information is channelled into a cloud-based AI/ML pipeline analyzing sensor information for the presence of disease markers for COPD & asthma. Support Vector Machines (SVM) & Principal Component Analysis (PCA) are amongst the most efficient models at classifying patients based on breath profile variations and VOC quantification with prediction surpassing 90% accuracy. This is further refined through feature selection techniques, such as Bootstrap Recursive Feature Elimination to enhance the model’s reliability. With in-situ health monitoring becoming more relevant in today's world, this sensor-based breath analysis system provides a promising, non-invasive, low cost, yet reliable solution for early respiratory disease screening & monitoring, potentially saving millions of dollars in treatment costs alone while reducing the national patient economic burden for COPD & asthma.
AI-Powered Smart Inhaler: A Comprehensive Solution for Optimized Respiratory Care
Nicholas Purcell,1
1Purcell, London, United Kingdom. 2Arizona State University, San Francisco, USA. 3Arizona State University, Arizona, USA. 4Arizona State University, London, USA.
Around 600 million people are affected annually by asthma and chronic obstructive pulmonary disease (COPD), with poor prescription adherence leading to avoidable hospitalizations. We at Purcell Global, through the use of an AI-powered smart inhaler suite integrated with an AI-SaMD (Software as a Medical Device) platform, aim to revolutionize respiratory care by optimizing drug delivery and user ergonomics. The inhaler suite, Purcell Inhaler Pro™, consists of a reusable smart inhaler, a mobile app, and a cloud-based backend infrastructure. Its multimodal inhalation monitoring system tracks airflow, volume/pressure, & drug deposition via integrated flow sensors & an infrared (IR) camera to locate the back of the throat & optimize when to dose medications. OpenFOAM simulations optimize inhaler placement and dispersion angle for effective drug delivery. Data from sensors is transmitted via Bluetooth low energy (BLE) to provide real-time feedback on inhalation patterns, adherence, dosage, & deposition. Tidal volume, respiratory rates, deposition fraction & clearance rates are noted as some key parameters influencing optimal drug delivery & its variability across age groups. This data, processed by the microcontroller and camera sensor, provides real-time user guidance for optimal positioning, which is the most important factor in optimal drug delivery. By integrating AI-driven analytics & real-time monitoring, Purcell inhalerPro™ aims to personalize respiratory care.
Electrochemical Sensor-Based Point-of-care-test Diagnostic Device for Real-Time Disease Detection and Monitoring
Nicholas Purcell,1
1Purcell, London, United Kingdom. 2Arizona State University, San Francisco, USA. 3Arizona State University, Arizona, USA. 4Arizona State University, New Jersey, USA.
Early & accurate disease detection is critical for improving patient outcomes & reducing healthcare costs. Purcell BioPro+™ is a next-generation, AI-powered point-of-care-test diagnostic device, based on principles of electrochemical sensing in order to enable near real-time disease diagnostics. The device uses an array of electrochemical sensors for identifying volatile organic compound (VOC) concentration patterns associated with respiratory disorders & coupled with a combination of optical & pressure sensors, along with microphones for detecting anomalies in inhalation/exhalation patterns. The information is channelled into a cloud-based AI/ML pipeline analyzing sensor information for the presence of disease markers for COPD & asthma. Support Vector Machines (SVM) & Principal Component Analysis (PCA) are amongst the most efficient models at classifying patients based on breath profile variations and VOC quantification with prediction surpassing 90% accuracy. This is further refined through feature selection techniques, such as Bootstrap Recursive Feature Elimination to enhance the model’s reliability. With in-situ health monitoring becoming more relevant in today's world, this sensor-based breath analysis system provides a promising, non-invasive, low cost, yet reliable solution for early respiratory disease screening & monitoring, potentially saving millions of dollars in treatment costs alone while reducing the national patient economic burden for COPD & asthma.
Pediatrics and Clinical Development
PULMONARY REHABILITATION IN COVID-19 RECOUPING PATIENTS
1Hyderabad, Hyderabad, India. 2AIIMS, Nagpur, India.
Deconstructing Pavlovian Paradigms in Dry Powder Inhaler Technique
1Imperial College London, London, United Kingdom. 2Food and Drug Administration, Maryland, USA. 3University of Hertfordshire, Hatfield, United Kingdom.
Miist: a novel inhaler for rapid treatment
Miist Therapeutics, Alameda, USA.
Rapid treatment has great benefit, for example in addiction, pain and insomnia. The oral, buccal, transdermal and nasal routes have Tmax ³ 20 min. SC is moderately faster, Tmax ³ 10 min. IV injection is fast, but requires a clinician and triggers needle phobia.
Rapid small molecule delivery can be achieved with aerosols of < 3.5 µm MMAD [1]. Existing inhalers require extensive preparation, lack portability, generate large and high velocity particles and/or have formulation and manufacturing challenges.
Miist Therapeutics has developed the Miist inhaler by adapting vibrating mesh technology to rapid delivery. Miist is a small inhaler with prefilled drug cartridges and minimal preparation. Miist delivers hundreds of puffs of aqueous formulations from each cartridge. No heating is required. Optimized aerodynamics yield MMAD < 3 µm. Miist controls dose for weaning, tolerance and mg/kg dosing.
Our pipeline includes nicotine for smoking cessation (MST-01) and sumatriptan for migraine (MST-02). MST-01 has completed a Phase 1 trial, demonstrating delivery of 1.3 mg of nicotine in 7 puffs, Tmax of 30s [2] and 92% craving reduction within 2 min [2,3]. MST-01 achieved significantly shorter Tmax, higher Cmax, and better craving reduction than patches, gums, or lozenges. MST-01 treats nicotine addiction, gradually reducing delivered nicotine to 0 over a 12 week period.
References
[1] Patton, J and Byron, P (2007). Nat Rev Drug Disc 6(1),67-74. doi:10.1038/nrd2153
[2] 1st time point
[3] Measured by VAS
EFFECT OF HYPERTONIC SALINE ON MUCOCILIARY CLEARANCE IN MODERATE TO SEVERE ASTHMA
UNC-Chapel Hill, Chapel Hill, USA.
A SIMPLIFIED SYNTHETIC LUNG SURFACTANT (SLS) EXCIPIENT ENHANCED GROWTH (EEG) DRY POWDER AEROSOL FORMULATION TO TREAT NEONATAL RESPIRATORY DISTRESS SYNDROME
1Virginia Commonwealth University, Richmond, USA. 2Seattle Children’s Research Institute, Seattle, USA.
[1] Longest, W., Hindle, M., Farkas, D et al. (2025). J Aerosol Med Pulm Drug Deliv (in press).
Expression and prognostic value of serum exosome let-7a and miR-155 combined lung function indexes in children with acute asthma attack
Chongqing Liangjiang New District Traditional Chinese Medicine Hospital, Chongqing, China.
BUBBLE PRESSURE SURFACE TENSION FOR SPRAY-DRIED SYNTHETIC LUNG SURFACTANT (SLS) EXCIPIENT ENHANCED GROWTH (EEG) FORMULATIONS
Virginia Commonwealth University, Richmond, USA.
References
[1] Momin M et al. (2024). Pharmaceutical Research 8, 1703–1723. doi: 10.1007/s11095-024-03740-z.
STORAGE STABILITY OF A DRY POWDER SYNTHETIC LUNG SURFACTANT FORMULATION
Virginia Commonwealth University, Richmond, USA.
References
[1] Momin, M. et al. (2024). Pharmaceutical Research 8, 1703–1723. doi:10.1007/s11095-024-03740-z
[2] DiBlasi, R.M. et al. (2024). Pharmaceutical Research 9, 1827–1842. doi: 10.1007/s11095-024-03754-7
DELIVERY OF A DRY POWDER AEROSOL SYNTHETIC LUNG SURFACTANT (SLS) THERAPY THROUGH LARYNGEAL MASK AIRWAY (LMA) INTERFACES TO PRETERM INFANTS
Virginia Commonwealth University, Richmond, USA.
Accessing Nebulizers and Nebulized Medications Guide by the COPD Foundation Nebulizer Consortium
1Lovelace Biomedical, Albuquerque, USA. 2COPD Foundation, Miami, USA. 3Theravance Biopharma, Incance, Atlanta, USA.
The COPD Foundation Nebulizer Consortium (CNC) aims to improve the understanding of risks associated with administration of nebulized therapies and to develop solutions that ensure the safety of patients, caregivers, and healthcare providers. In addition, the CNC works to ensure that patients are supported with clear, scientific based materials around the utilization of nebulizers in management and treatment of their disease. The CNC identified that the differences in nebulizer technologies create confusion within the patients. Therefore, a guidance document was developed to help streamline the process of accessing and using nebulizer. The guide will highlight different types of nebulizers (breath-actuated jet, breath-enhanced jet, standard jet and vibrating mesh) that can be used with prescribed medications and how to use them. When specific combinations of API and nebulizer must be prescribed together (TOBI) this will be highlighted to patients. Additionally, common frequently asked questions are addressed from the prescribing clinician. These questions go beyond typical questions observed by drug development scientists and bridge into the relationship between patients, payers, specialty pharmacy and how to manage timelines. Together the guide for healthcare providers will increase patient understanding of how nebulizer therapies may provide a high quality of care and ensure that common issues around utilization of nebulizers are addressed with the patients themselves.
ACTINOMYCES INFECTION IN A POST-TB CAVITY: A CASE REPORT
1Medical Student, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan. 2House officer, Shifa International Hospital (SIH), Islamabad, Pakistan. 3Consultant Pulmonologist and Critical Care, Department of Pulmonology, Shifa International Hospital (SIH), Islamabad, Pakistan
Actinomyces is a chronic bacterial infection caused by gram positive, anaerobic bacilli, commonly affecting the oral cavity, gastrointestinal, and urogenital tract. Pulmonary actinomycosis is uncommon, compromising only 15% of cases, and is misdiagnosed due to its resemblance to malignancies or fungal infections. Post-Tuberculous (Post-TB) cavities serve as breeding ground for secondary infection, particularly fungal, with bacterial infections being rare. We present a 56 year old male with a history of TB in the right upper lung (RUL), who developed pulmonary actinomyces in a Post-TB cavity. He presented with a complaint of hemoptysis and had comorbidities like poorly controlled diabetes mellitus, hyperlipidemia, and smoking history. Chest CT showed a “tree in bud” appearance in the RUL cavity. Pulmonary functions tests showed obstructive changes. A biopsy was taken which confirmed actinomyces. The patient was treated with IV ceftriaxone for 4-6 weeks, followed by oral Augmentin for 1.5 years. Clinical improvement was noted on followup. This case emphasizes the rare development of actinomyces in a post-TB cavity, highlighting the need of histopathological diagnosis in patients with cavitary lung disease. Due to the risk of misdiagnosis and inappropriate therapy, actinomyces should be considered in chronic lung disease patients presenting with hemoptysis and cavitary lesions, especially in TB endemic areas. A multidisciplinary approach is important for optimal management.
IMPACT OF FLOW RESISTANCE ON INHALATION PATTERNS IN PAH PATIENTS AND HEALTHY SUBJECTS INHALING WITH SOFT MIST INHALERS
Nicolas Buchmann, and
Resyca BV, Enschede, Netherlands.
References
[1] Baloira, A., Abad A., Fuster A., et al. (2021). Int. J. of Chronic Obstructive Pulmonary Disease, 16, 1021–1033. DOI: 10.2147/COPD.S297980
DRY POWDER SYNTHETIC SURFACTANT AEROSOL ACCELERATES WEANING FROM MECHANICAL VENTILATION IN SURFACTANT-DEFICIENT RABBITS
1Seattle Children’s Research Institute, Center for Respiratory Biology and Therapeutics, Seattle, USA. 2Department of Pharmaceutics, Virginia Commonwealth University, Richmond, USA. 3Department of Mechanical & Nuclear Engineering, Virginia Commonwealth University, Richmond, USA.
A NOVEL IN VIVO RABBIT CHIMERA MODEL OF NEONATAL RESPIRATORY DISTRESS SYNDROME (RDS) TO ASSESS THE EFFICACY OF NONINVASIVE RESPIRATORY SUPPORT AND AEROSOL THERAPIES FOR PRETERM INFANTS
1Seattle Children’s Research Institute, Center for Respiratory Biology and Therapeutic, Seattle, USA. 2Department of Mechanical & Nuclear Engineering, Virginia Commonwealth University, Richmond, USA. 3Aerogen Pharma, San Mateo, USA. 4Department of Pharmaceutics, Virginia Commonwealth University, Richmond, USA.
LUNG DELIVERY EFFICIENCY OF A NOVEL BREATH SYNCHRONIZED SURFACTANT AEROSOL SYSTEM FOR USE WITH NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) IN PRETERM INFANTS
Hattie KenKnight,1 Andy Clark,2 Huy Le,1 Narges Mirdamadi,3 David Durand,2 James Fink,2 and
1Seattle Children’s Research Institute, Center for Respiratory Biology and Therapeutics, Seattle, USA. 2Aerogen Pharma, San Mateo, USA. 3Department of Bioengineering, Northeastern University, Boston, USA.
DO PARTICLE SIZE ESTIMATES OF DEOSITION WITH A 28 WEEK GA UPPER AIRWAY MODEL RELATE TO IN VITRO AND IN VIVO DEPOSITION OF AEROSOL SURFACTANT IN PRETERM INFANTS?
1Aerogen Pharma, San Mateo, USA. 2Seattle Children’s Research Institute, Center for Respiratory Biology and Therapeutics, Seattle, USA.
SERIAL IMAGES OF AEROSOL SURFACTANT DELIVERY WITH BREATH SYNCHRONIZED SMALL PARTICLE SURFACTANT AEROSOL SYSTEM VIA NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE (NCPAP) IN RABBIT MODEL OF PRETERM INFANTS
1Seattle Children Research Institute, Center for Respiratory Biology and Therapeutics, Seattle, USA. 2Aerogen Pharma, San Mateo, USA. 3Northeastern Univiery, Depr of Bioengineering, Boston, USA.
Regulatory, CMC and Standardization Issues
Performance Insights from an Anatomical Nasal Inlet of an Intranasal Epinephrine Powder
Matthew Owen,1 Chris Kloc,1 Michael Smalley,1 Blake Poe,1 Colin Patrick,1 Thomas Henry,1 Amr Hefnawy,1 Heli Chauhan,2 David Wilcox,1 Brian Taubenheim,3 and
1Catalent Pharma Solutions, Morrisville, NC, USA. 2MSP, a Division of TSI, Shoreview, MN, USA. 3Belhaven Biopharma, Raleigh, NC, USA.
Two spray-dried (SD) epinephrine powders with different particle size distributions (PSD) were filled into a nasal powder device (Aptar UDSp) and evaluated for performance using laser diffraction and an anatomical nasal inlet, the Alberta Idealized Nasal Inlet (AINI). Bulk powders differed in particle size, where the Dv50 of SD1 was 5.25 µm while the Dv50 of SD2 was 17.9 µm, which is more typical for nasal powder [1]. Aerosol emitted from UDSp devices showed that SD1 powders resulted in more large agglomerates (>100 µm) and contained more fines (<10 µm) than SD2 powders. Evaluation of the effect of drum filling vacuum pressures on the emitted PSD (ePSD) of SD2 powders showed large aggregates were slightly increased with increasing vacuum pressure, likely a result of powder compaction when drawn into the filling bore of the drum [2]. Differences in PSD and ePSD did not result in differences in deposition in the AINI, with both SD1 and SD2 powders having similar distributions within the model and less than 5% depositing past the nasopharynx. This suggests that with the delivery of SD from an active nasal delivery device, such as the UDSp, differences in bulk PSD and ePSD have minimal impact on the regional deposition in an adult upper airway within the ranges studied. The effect of increased fines and larger emitted particles should be studied as it could affect product performance on stability.
EFFECT OF PMDI ORIFICE DIAMETER ON REGIONAL EXTRATHORACIC DEPOSITION IN AN IDEALIZED CHILD AIRWAY
1University of Alberta, Edmonton, Canada. 2Lovelace Biomedical, Albuquerque, USA. 3Kokua Pharma Inc., Richmond, Canada.
We previously demonstrated that the actuator orifice diameter (OD) of a pressurized metered dose inhaler (pMDI) influences in vitro regional deposition in the adult Alberta Idealized Throat (AIT) for a suspension epinephrine formulation [1]. In particular, oral cavity deposition was reduced, and in vitro lung deposition increased when using smaller ODs. Whether these effects persist in the smaller upper airways of school-aged children is unknown.
In the present work, we explored regional extrathoracic deposition of epinephrine pMDI aerosols in an idealized child mouth-throat geometry. A sectioned version of the Alberta Idealized Child Throat (AICT), divided into analogues of the oral cavity, the pharynx/larynx, and the upper trachea, was used to test pMDIs with small and large ODs (0.22 and 0.44 mm) across a range of inhalation flowrates (10, 30, 60, and 100 L/min), with two inhaler insertion angles (transverse and coaxial).
Broadly, similar trends were noted in regional deposition patterns between the adult AIT and the AICT, with the exception of higher deposition in the child oral and laryngeal regions, and corresponding decreases in the in vitro lung region. Overall, actuator orifice diameter strongly influenced in vitro regional extrathoracic deposition in the child model, with smaller ODs decreasing oral cavity deposition, and increasing delivery to the laryngeal region and lungs.
References
[1] Ruzycki et al. (2024). DDL conference proceedings, Vol 35, pg 292–295. doi: 10.60565/cjpx-1k63.
EVOLVING ADVOCACY: A DECADE OF OINDP ENGAGEMENT ON DEVICE REGULATORY REQUIREMENTS
AstraZeneca, Gaithersburg, USA.
In June 2024, the US FDA released draft guidance on “Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biologicals,” introducing new requirements that stirred industry comments, especially from the Orally Inhaled and Nasal Drug Product (OINDP) sector. This abstract outline the evolution of device requirements impacting OINDP, highlighting the importance of advocacy for recognizing the unique designs and benefits of these products.
Historically, OINDP was regulated under drug standards. The 2013 “CGMP Requirements for Combination Products” mandated adherence to both drug and device quality systems, including design controls. However, OINDP was traditionally exempt from these device standards. This discrepancy was noted by IPAC-RS, which advocated against applying these new standards to legacy OINDP devices. The FDA, while acknowledging these concerns, indicated that full exemption from device QS regulations wasn't feasible.
Subsequent guidances and inspection manuals consistently affirmed that MDIs, a common OINDPs, are subject to device QS regulations. This persistent shift necessitates vigilant monitoring and advocacy by OINDP manufacturers to ensure product-specific requirements remain appropriate. Given their differences from parenteral products, the OINDP industry must continue to engage with FDA policies to safeguard their interests.
LASER DIFFRACTION MEASUREMENTS OF PMDI PARTICLE SIZE DISTRIBUTIONS DOWNSTREAM OF EXTRATHORACIC AIRWAYS IN ENVIRONMENTS WITH LOW AND HIGH AMBIENT HUMIDITY
University of Alberta, Edmonton, Canada.
Measuring particle size distributions (PSDs) of aerosols from pressurized metered dose inhalers (pMDIs) can be challenging due to rapid propellant evaporation and potential condensation of water vapor in humid air. In this study we used laser diffraction (LD) to assess PSDs downstream of adult and child extrathoracic (ET) airways in low and high ambient humidity.
The test inhalers included QVAR HFA (100 µg), Ventolin HFA (100 µg), Flovent HFA (50 µg), and Flovent HFA (250 µg). Inhalers were actuated into the Alberta Idealized Throat (AIT) or Alberta Idealized Child Throat (AICT), which were connected in series to a Spraytec LD inhalation cell and a Next Generation Impactor (NGI), with a vacuum pump drawing 30 L/min of air through the system.
Under low humidity conditions (17±8 %RH, 21±1 oC), ET deposition was higher in the AICT than the AIT. The correlation between LD- and NGI-measured PSDs varied between inhalers.
For tests performed at high humidity (85±2 %RH, 21±1 oC), the NGI was replaced with a fine particle filter. Compared to low humidity results, ET deposition increased while filter (lung) dose decreased. The influence of high humidity on PSDs varied by inhaler, due to competing effects of condensational particle growth and deposition of larger particles in the ET airways. Extending humidity exposure by ∼125 ms by adding tubing between the ET model and LD system had minimal impact on PSDs, suggesting relatively stable PSDs in humid air downstream of the ET airways.
AEROSOL PERFORMANCE CHARACTERIZATION FOR DRY POWDER FORMULATION OF MOSLICIGUAT, AN INHALED sGC ACTIVATOR
1Pulmovant, Inc., Waltham, MA, USA. 2Oliyai Consulting, Atherton, CA, USA. 3Pulmovant, Inc., Waltham, MA, United States.
Mosliciguat is an investigational, small-molecule soluble guanylate cyclase (sGC) activator. sGC is a key enzyme in the nitric oxide and cyclic guanosine monophosphate (cGMP) signaling pathway that helps maintain vascular homeostasis. Pulmovant is developing formulations of mosliciguat for the treatment of Pulmonary Hypertension (PH) targeting the lung via dry powder inhalation. In Phase 1, higher dose levels were achieved using multiple capsules. To optimize dosing and improve patient adherence for Phase 2, higher-strength formulations were developed to enable single capsule delivery.
Pulmovant sought to characterize the newly developed optimized dry powder formulations. Delivered Dose (DD) and aerodynamic particle size distribution (APSD) were evaluated by Next Generation Impactor (NGI) per USP <601>.
New formulations were effectively aerosolized with a DD of 50-75% and fine particle fraction (FPF < 5.0µm) of 20-40% relative to capsule strength. Additionally, the MMAD and FPF for mosliciguat remained independent of air flow rate when tested at 2 and 4kPa by NGI. In-use stability data further confirm that performance remains robust over 30 days under simulated patient-use scenarios.
Data suggest that mosliciguat can be effectively administered to patients with different lung pathophysiology, while maintaining consistent aerosol characteristics. This is particularly important for patients with Group 3 PH, who exhibit lung conditions such as ILD and COPD.
PROPELLANT AS A DEVICE COMPONENT IN METERED DOSE INHALERS: IMPLICATIONS FOR PROPELLANT SWITCH PROGRAMS
Lostritto Consulting, LLC, Maitland, USA.
Currently, HFA 134a or HFA-227 are the propellants used in pressurized metered dose inhalers (pMDIs). They have significant global warming potential compared to likely 3rd generation propellents (3GP), HFA 152a and HFO1234ez(E).
pMDI propellants serve as the physical driving force for aerosolization and drug delivery. Propellants act analogously to a spring in an auto-injector combination product, where the spring provides the physical driving force for drug delivery as a device component. Likewise, heparin lock flush solution is regulated by the FDA as a device despite the fact that heparin exerts a pharmacological effect on the body (anticoagulation) at the molecular level.
These and other well established precedents set the stage for pMDI propellants to be regulated as device components and not as formulation components (1). In the US combination product review model for pMDIs, CDER could continue to lead the pMDI review, and CDRH would review the propellents' physical aerosolization function as a device component from an engineering perspective.
This approach is arguably more relevant and more conducive to an engineering and science based assessment of propellant function on aerosolization performance in PMDIs. Further, it may apply particularly well when an applicant for an approved pMDI combination product submits to switch propellant. to a 3GP via the prior approval supplement (PAS) pathway.
References
[1] Lostritto RT., (2024), Respiratory Drug Delivery, Volume 1, 161–176.
Quantitative Studies to Inform PSG Development for Tiotropium Bromide Inhalation Spray, Metered
Food and Drug Administration, Silver Spring, USA.
Drug delivery with inhalation sprays typically involves emission of a slow-moving aerosol, which supports assessing spray velocity as a critical performance metric. Particle image velocimetry (PIV) and high-speed videography data were collected for Tiotropium Bromide Inhalation Spray, Metered (NDA 021936, brand name Spiriva Respimat) to assist the U.S. Food and Drug Administration in developing study design recommendations for an in vitro spray velocity bioequivalence study as part of product-specific guidance (PSG) development. PIV measurements were collected at ambient conditions (20oC, 35% relative humidity) to measure spray velocity. The plume front was tracked from the leading edge of the mouthpiece over time. Plume front velocity was determined from the slope of the distance versus time curve and evaluated at varied measurement distances (20-, 40-, 60-, 80-, 100-, 120-, 140-mm). The distance vs. time curves that were assessed for both PIV and high-speed videography and the plume front velocity data agreed well with literature values. High variability was observed for plume front velocity measurements at distances of 0-60 mm from the mouthpiece. Plume front velocity is best measured 80-120 mm from the nozzle due to relatively low variability in the region beyond 60 mm from the mouthpiece. The current study provided valuable information for the study design recommendations for the spray velocity bioequivalence study that were used to support the development of the PSG.
INVESTIGATING THE IMPACT OF DEVICE AND FORMULATION CHANGES ON PRODUCT PERFORMANCE IN ORALLY INHALED AND NASAL DRUG PRODUCT
Malvern Panalytical, Westborough, USA.
Orally Inhaled and Nasal Drug Products (OINDPs) present a unique set of challenges to drug developers as regulators view them as complex products/complex generics. This classification requires that any potential device(s) and drug product(s) be put through rigorous testing prior to being selected for the final formulation.
Understanding interactions between drug product and device is a key consideration for formulators in the development of OINDPs. Drug deposition targets require that particular droplet sizes be generated by the final product, ensuring the delivery of drug product to proper areas within the body.
Droplet Size Distribution (DSD) via laser diffraction provides unique insight into the effects device and formulation have on the performance of the final product. This study utilizes laser diffraction to show how changes in device have a direct impact on the droplet sizes formed by the final product. The study also highlights how minor formulation changes made during the development of a complex generic impact the droplet size of the final product.
IN VITRO CHARACTERIZATION OF AN IN SITU NASAL GEL FOR CNS DELIVERY
Ana Fortuna,1,2 F Gouveia,1,3 Goncalo Farias,4 and
1University of Coimbra, Coimbra, Portugal. 2Coimbra Institute for Biomedical Imaging and Translational Research, Coimbra, Portugal. 3Coimbra Institute for Biomedical Imaging and Translational Research, Coimbrac, Portugal. 4Aptar Pharma, Le Vaudreuil, France. 5Aptar Pharma, Congers, USA.
[1] Silva S, Fonseca C, Bicker J, Falcaõ A, and Fortuna A (2024). European Journal of Pharmaceutics and Biopharmaceutics 194, 118–130. https://doi.org/10.1016/j.ejpb.2023.12.002
[2] Gouveia, F, Carona A, Lacerda M, Bicker J, Camins A, Cruz MT, Ettcheto M., Falcão A, Fortuna A (2024). Biochem Pharmacol. 230(Pt 3):116616. doi: 10.1016/j.bcp.2024.116616.
VARIABILITY IN VIBRATING MESH NEBULIZER AEROSOL CONCENTRATION DURING NONCLINICAL USE
1Labcorp, Madison, USA. 2Labcorp, Bangalore, India. 3Labcorp, Huntingdon, United Kingdom.
Nonclinical inhalation toxicology studies involve delivering an aerosol to multiple animals simultaneously for up to 6 hours/day. The vibrating mesh nebulizer is well-suited for formulations with fragile active ingredients such as antibodies and lipid nanoparticles. Clinical nebulizer output is commonly directed into a mouthpiece or patient facemask, whereas nonclinical nebulizer output is directed into a stream of carrier air going to the animal breathing zone. Aerosol analysis allows for determination of the delivered dose, which is important for calculating clinical safety margins. Data from 9 studies were analyzed for formulation concentration, number of vibrating mesh nebulizers, airflow rate, exposure duration, aerosol concentration and particle size distribution (PSD). A single nebulizer produced more variable aerosol concentrations than 2-4 nebulizers, independent of airflow rate; however, PSD often exceeded 3 µm with 3-4 nebulizers. An increased formulation concentration produced correlating increased aerosol concentration across test article classes with multiple (R=0.93) but not single (R=0.25) nebulizer usage. The duration of nebulizer usage (30 to 360 minutes) did not consistently affect variability in aerosol concentration. In conclusion, nonclinical aerosols can be generated from multiple vibrating mesh nebulizers to ensure more accurate achieved doses with attention to respirable PSD.
HOW TO QUANTIFY AMORPHOUS MATERIAL IN DPI PRODUCTS
Memory Jiri, Vaishnavi Kapileshwari, Rana Erfan, Jacques Ledru, and
M2M Pharmaceuticals Ltd., Winnersh Triangle, United Kingdom.
This study assesses the ability of analytical techniques to quantify the amorphous content of an inhaled API in an excipient matrix. Extensive research has been carried out for determining the amorphous content individually in an API and a carrier. However, limited work has been carried out on detecting low levels of amorphous content in a DPI formulated product. Two sensitive analytical techniques, Dynamic Vapour Sorption (DVS) and Solution Calorimetry (SolCal) were used. With DVS, the principle of recrystallisation being directly proportional to the presence of amorphous material was used [1], whilst the difference in heat of solution distinguishes responses for different heterogenous samples for SolCal. Four samples were prepared; crystalline lactose, lactose mixed with either crystalline or amorphous API, and a combination of both forms of API with lactose. Each sample was analysed in triplicate, with the sensitivity of both techniques tested by having the quantity of API as 1% w/w of the formulation. Results indicated that DVS could effectively distinguish responses of the API from lactose and API forms from each other, while SolCal was sensitive enough to detect an overall difference between varying samples. Overall, this study establishes the complementary nature of DVS and SolCal for quantifying amorphous content in DPI formulated products.
References
[1] Ticehurst, MD., Basford, PA., Dallman, CI et al. (2000). Int J Pharm 193(2), 247–59. doi:10.1016/s0378-5173(99)00347-6
[2] Sheryl, J., Murray, J., Carr J. et al. (2022). In Drug Delivery to the Lungs, The Aerosol Society 33.
[3] Stanford, S., Johnson, S., Robinson, I. et al. (2024). In Respiratory Drug Delivery, 1, 304–307.
Optimizing Inline Aerosol Delivery of Colistin Methanesulfonate via High-Flow Nasal Cannula
Shih-Yu Chen,1 Kenneth Liew,2 Hui-Ling Lin,3 Jung-Yien Chien,4 Hak-Kim Chan,5 and
1Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan. 2Department of Pharmacy, National Taiwan University Cancer Center, Taipei, Taiwan. 3Department of Respiratory Therapy, Chang Gung University, Taoyuan, Taiwan. 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 5Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. 6National Taiwan University School of Pharmacy, Taipei, Taiwan.
Nebulized colistin methanesulfonate (CMS) is an adjunct therapy for pneumonia, achieving high lung concentrations while limiting systemic toxicity. However, the efficiency of inline CMS delivery via high-flow nasal cannula (HFNC) is uncertain, as high flow rates and humidification can impact aerosol size and deposition. This study assessed the feasibility of administering off-label nebulized CMS (160 mg) via HFNC integrated with a vibrating mesh nebulizer (Aerogen Solo). CMS solutions (26.7–160 mg/mL) were prepared using injectable water or normal saline, with saline selected for final concentrations of 26.7–53.3 mg/mL based on osmolarity, anion content, and viscosity. An in vitro-in vivo correlation setup using a nasal airway replica and two breathing profiles assessed aerosol performance at HFNC flow rates of 10–60 L/min and diluent volumes of 3 or 6 mL. Lower flow rates yielded higher inhaled doses, particularly under distressed breathing (107.4 ± 8.8 mg vs. 3.7 ± 0.4 mg). Larger diluent volumes also enhanced lung deposition (36.0 ± 2.0 mg vs. 71.1 ± 3.1 mg). Estimated fugitive doses peaked at 10–20 L/min and were higher with quiet breathing. These findings highlight the need to optimize CMS solution properties and HFNC settings to improve therapeutic outcomes while managing fugitive emissions.
USING FAST SCREENING IMPACTOR FOR DETERMINING FINE PARTICLE DOSE DURING INHALER FERFORMANCE ASSESSMENT
Jan Olof Svensson,1,2 Patrik Andersson,1 Moltas Olofsgård,1 and
1AstraZeneca, Gothenburg, Sweden. 2Chalmers University, Gothenburg, Sweden. 3AstraZeneca, Durham, USA.
The European Medicines Agency's recent draft quality guideline enables the shift from full-impactor testing using the Next Generation Impactor (NGI) / Andersen Cascade Impactor (ACI) to the Fast Screening Impactor (FSI) for determining the fine particle dose (FPD) during QC testing.
This study explores the effectiveness of the Refined Fast Screening Impactor (R-FSI) and a semi-automated method in evaluating FPD for respiratory products. Equipped with a Respirgard filter, the R-FSI offers a faster alternative to traditional cascade impactors while maintaining accuracy in measuring particles smaller than 5µm.
Comparative analysis with the NGI for a dry powder inhaler (DPI) and the ACI for a pressurized metered dose inhaler (pMDI) demonstrates excellent agreement. Additionally, the MaTilda robot's semi-automated method showed equivalence with traditional manual methods for a DPI, yielding only a 3.9% difference in delivered dose uniformity (DDU) and a 1.0% difference in FPD - both within acceptable limits. The method also provides significant time savings: 65% for DDU and 80% for FPD.
These advancements highlight the potential for automating quality control processes. The FSI and MaTilda emerge as critical components in this shift, supporting the development of fully automated testing platforms. This work marks significant progress towards efficient, automated inhaler performance assessment and lays the groundwork for future innovations in respiratory product testing.
Environmental/Occupational Health/Preclinical
Preclinical Evaluation of Inhaled Spray-Dried Tigecycline Formulations for Pulmonary Mycobacterium abscessus Infection
1CSU, Fort Collins, USA. 2RTI International, Research Triangle Park, NC, Durham, USA. 3Universityof Tennessee Health Science Center, Memphis, TN, Memphis, USA. 42RTI International, Research Triangle Park, NC, durham, USA.
Mycobacterium abscessus pulmonary disease (MAB-PD) presents significant therapeutic challenges due to limited treatment options and systemic side effects. Tigecycline (Tygacil®), a glycylcycline antibiotic, shows promise for MAB-PD but is limited by adverse effects from intravenous (IV) administration. To address this, spray-dried tigecycline powder formulations (DP-TGC) were developed for intratracheal (IT) delivery as a targeted alternative. DP-TGC formulations were optimized for low moisture, high dispersibility, and respirable particle sizes (1–5 μm). In GM-CSF knockout mice infected with M. abscessus, IT delivery reduced lung bacterial burden by over 1,000-fold and decreased bacterial loads in extrapulmonary organs, including the spleen and liver. Safety evaluations confirmed DP-TGC was well-tolerated, with no adverse effects or blood parameter changes. Pharmacokinetic (PK) studies revealed IT delivery achieved 10–50 times higher lung tigecycline exposure than IV administration, with similar plasma levels despite a five-fold higher dose. Lung-to-plasma ratios demonstrated higher lung concentrations. Checkerboard MIC studies confirmed tigecycline’s synergy with clarithromycin and imipenem, supporting its inclusion in multidrug regimens. These findings highlight IT delivery of DP-TGC as a safe, effective treatment for MAB-PD. Further studies are needed to optimize dosing, assess long-term efficacy, and explore combination therapies.
CHARACTERIZING AND DELIVERING AEROSOLIZED AAV IN A MOUSE SNOUT-ONLY INHALATION STUDY
Simon Moore,1
1Labcorp Early Development Laboratories Ltd., Huntingdon, United Kingdom. 2Labcorp Early Development Laboratories Inc., Madison, USA.
Clinical approval of an inhaled drug often requires preclinical evaluation using a small and large animal model. Small animal dosing is undertaken using a snout-only inhalation chamber and specifically for Adeno-associated viruses (AAVs) is contained within an ABSL2 designated area. Male C57BL/6J mice were administered AAV6.2-mCherry aerosol at achieved aerosol concentrations determined by quantitative polymerase chain reaction (qPCR) for low and high doses of 3.2 x 109 viral genome copies (GC)/L and 2.0 x 109 GC/L, respectively. This resulted in delivered doses of 2.0 x 1010 GC/kg and 1.2 x 1011 GC/kg, respectively. The aerosol was generated using an Aeroneb Solo™ nebulizer. The achieved mass median aerodynamic diameter (MMAD) for the low and high groups was 6.0 and 4.7 µm, respectively, in contrast to an MMAD of 4.2 µm during initial aerosol characterization assessment. The achieved MMAD is toward the upper limit of respirable droplet size, but respiratory tract tissue distribution data confirmed animals received an inhaled dose. Swab samples from various locations external to the inhalation exposure system were collected and analyzed using qPCR to test for laboratory contamination. Samples collected gave negligible values of AAV. In conclusion, the data presented demonstrates the feasibility of aerosolizing AAV6.2-mCherry for inhalation exposure and that ABSL2 procedures are required to ensure cleanliness and minimize the risk of cross contamination.
EVIDENCE OF LUNG ABNORMALITIES IN ASYMPTOMATIC VAPERS
Department of Medicine, University of California, San Diego, CA, USA.
Despite many reports of vaping-related lung illness, most vapers are symptom-free. Still, long-term health effects associated with vaping are not established. Unlike spirometry, the lung clearance index (LCI) derived from multiple breath washouts (MBW) is a sensitive measure of early lung disease. In this study, nitrogen MBWs and DLCO tests were performed in triplicate and duplicate, respectively, in 34 healthy non-vaping adults (control, 56% female, age: 21.1±3.4 yr) and 33 asymptomatic vapers with normal spirometry (vaper, 58% female, age: 22.7±3.7 years; 15 THC, 7 nicotine (NIC) and 11 NIC+THC vapers; vaping history: 3.7±2.2 yr) using a commercial device (EasyOne Pro LAB & Wbreath v4.00.14, NDD, Switzerland). Functional residual capacity (FRC) and LCI were calculated from the MBW. LCI was defined as the lung turnover at which mean expired N2 concentration reached 1/40th of its pretest concentration. There was no significant difference in FRC between groups (p=0.36). DLCO was significantly lower and LCI significantly higher in vapers (DLCO: 90±9%pred; LCI: 6.00±0.43) than in controls (DLCO: 98±14%pred, p=0.01; LCI: 5.77±0.32, p=0.01). Using the mean and standard deviation from the control group, z-score for LCI in the vaper group was calculated to be 0.73±1.34. These data suggest a detrimental effect of vaping on lung structure and function in asymptomatic vapers with normal spirometry.
QUANTIFICATION AND CHARACTERIZATION OF MANUFACTURED NANOMATERIALS SHED FROM FACE MASKS
1National Research Council Canada, Ottawa, Canada. 2Health Canada, Ottawa, Canada.
Face masks are an important public health measure whose use became wide-spread during the COVID-19 pandemic. Manufactured nanomaterials (MNMs) have been used in face masks to enhance their anti-microbial and self-cleaning properties. There is currently a gap in the literature on the shedding potential of MNMs as it relates to inhalation uptake.
In this study, three face masks, claiming to contain titanium dioxide (TiO2), were analyzed with regard to their composition and particle shedding. Masks were analyzed with Inductively Coupled Plasma Mass Spectrometry (ICP-MS) to determine the mass fraction of TiO2 and Scanning electron microscopy-energy dispersive X-ray (SEM-EDX) to determine the composition of the particles detected. Masks were then tested in a custom-built system under continuous air flow with and without concurrent mask agitation. Particles were measured via multiple particle counters and sizers to determine particle concentrations and size distributions. Particles were also captured on filters for additional analysis.
The compositional analysis showed that all masks tested contained different levels of Ti, with particles observed at the surface of the fibers. Particle shedding was observed only for masks exposed to continuous airflow with concurrent agitation. Further analysis of the shed particles did not indicate the presence of Ti. This data adds to the body of evidence relating to inhalation uptake from shedding of MNMs and may inform future risk assessments.
INVESTIGATION OF RESPIRATOR FIT PERFORMANCE USING A REFERENCE LABORATORY SYSTEM WITH 3D-PRINTED HEAD FORMS
1National Research Council Canada, Ottawa, Canada. 2McMaster University, Hamilton, Canada.
Respirator fit is of extreme importance for protection and safety for the workers, as ill-fitting respirators could potentially expose them to harmful particles. It is known that anthropometric differences exist based on sex and ethnicity, which has a direct impact on PPE. Limited research has been done to identify the difficulties women and visible minority groups face in finding PPE that has fits, is comfortable and provides protection. This was especially relevant during the pandemic for health care workers but has broader implications in several fields.
This study addresses this challenge by investigating the effect of face size and shape on respirator efficiency and quantify respirator leakage based on anthropometric data. For this purpose, the performance of several types of respirators was evaluated on 3D printed head forms of different sizes (in accordance with the ISO 16976-2 standard) in a custom-built setup. Size-resolved particle filtration efficiencies were determined for charge-neutralized NaCl, to provide a measure of the inward leakage around the edges of the respirators.
We show that the size and type of respirator influence the edge leakage, which we quantify for the different head forms. In future work, findings of this study will be compared to fit tests performed on multiple individuals with a multitude of face sizes and shape to distinguish between the effect of respirator type, shape, size as a function of anthropometric data.
In vitro primary human alveolar epithelium/endothelium and fibroblast model: a tool for investigating IPF and treatment strategies
Maciej Gusciora, Maxim Marfin, An Nguyen, Mireille Caul-Futy, Song Huang, Bernadett Boda, and
Epithelix, Geneva, Switzerland.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. The current paradigm suggests that TGF-β1 plays a crucial role in the initiation of fibrosis by inducing extracellular matrix stiffening through the fibroblast-to-myofibroblast transition (FMT) and epithelial-to-mesenchymal transition (EMT).
This study aims to develop an IPF model using human primary cells. We use AlveolAir™, a tight epithelium composed of type I and II pneumocytes, cultured at the air-liquid interface, along with endothelial cells and fibroblasts.
AlveolAir™ and fibroblasts were stimulated with TGF-β1 and TNF-α for 72 hours. Nintedanib and Pirfenidone, used as reference antifibrotics, were tested concomitantly with the stimulation in the basal culture medium. To monitor FMT, α-SMA was analyzed, while EMT was assessed by measuring multiple cytokines.
The expression of α-SMA in the stress fibers were observed after stimulation, quantified by immunofluorescence, resulting in a significant increase in mean intensity. Following stimulation, the co-culture exhibited a significant increase in the release of MMP1 and MMP3—biomarkers also observed in patients with IPF. Exposing the stimulated model to Nintedanib or Pirfenidone significantly reduced α-SMA expression and cytokine secretion.
This IPF-induced model could improve preclinical antifibrotic screening and deepen the understanding of IPF molecular mechanisms.
A Human Systemic Model for Concurrent Evaluation of Antibody-Drug Conjugates Efficacy and Interstitial Lung Disease Risk
Jimmy Vernaz,1 Simon Latour,2 Xiao-Yann Huang,1 Aurélien Roux,2 Gregory Segala,3 Clélia Bourgoint,3 and
1Epithelix, Geneva, Switzerland. 2University of Geneva, Geneva, Switzerland. 3Fluosphera, Geneva, Switzerland.
Antibody-drug conjugates (ADCs) represent a revolutionary class of targeted anticancer therapies. However, their systemic toxicities, including interstitial lung disease (ILD), pose significant challenges to clinical development. ILD, characterized by inflammation and scarring of the lung interstitium, can impair respiratory function and has become a critical safety concern in ADC therapies.
To address the lack of robust in vitro platforms to assess the systemic effects of ADCs, we propose a new co-culture platform combining an advanced alveolar epithelial model with encapsulated cancer spheroids. The alveolar model, AlveolAir™, includes primary lung epithelial cells (ATI/ATII pneumocytes and endothelial cells) cultured at an air-liquid interface. This system integrates encapsulated SK-BR-3 spheroids, a HER2-positive breast cancer cell line.
This new co-culture model was used to test trastuzumab deruxtecan (T-Dxd) and its payload Dxd (Exatecan derivative). It enables simultaneous assessment of T-Dxd’s anticancer efficacy and lung toxicity, measuring biomarkers such as LDH for cytotoxicity, IL-6/IL-8 for inflammation, TEER for epithelial integrity, and microscopy for T-Dxd’s effects on SK-BR-3 spheroids.
This integrated assay allowed the determination of T-Dxd’s efficacy against cancer cells while assessing its systemic toxicity to alveolar epithelial cells simultaneously. This novel in vitro platform has the potential to de-risk ADC development.
Aligning In Vitro and Animal Models for Lung Inflammation Assessment
1Adolphe Merkle Institute, Fribourg, Switzerland. 2University of Bern, Bern, Switzerland. 3Inselspital, Bern, Switzerland. 4University of Fribourg, Fribourg, Switzerland.
Relevant in vitro models are essential for assessing the safety of inhaled therapeutics, environmental pollutants, and nanomaterials. Improving such models requires more reliable in vitro to in vivo extrapolation (IVIVE). The Adverse Outcome Pathway (AOP) framework links molecular initiating events to adverse pulmonary outcomes supporting extrapolation and helping combine in vitro, in silico, and in vivo data for better risk assessment. Previous studies utilized short-term exposure models, but they may not fully capture chronic inflammation or delayed toxicity, particularly those arising from distinct modes of action of particles compared to soluble chemicals. To address this, we compared in vitro and in vivo inflammatory responses after exposure to crystalline quartz silica (DQ12). By extending the investigation to 7 days post-exposure, we aligned the in vitro timeline with the in vivo rat model suggested by current testing guidelines. Using a harmonized in vitro co-culture model of human bronchial epithelial cells (Calu-3) and monocyte-derived macrophages, we observed no enhanced cytotoxicity or membrane disruption at day 7, whereas in vivo tissue analysis revealed significant damage. However, gene expression of IL-1β, IL-6, and IL-8 correlated between both models. This study showcases AOP’s role in identifying key biomarkers and refined IVIVE through optimized exposure durations to enhance in vitro predictivity.
Biopharmaceutical Evaluation of Excipients Used in Inhalation Drug Delivery
Trinity College Dublin, Dublin, Ireland
This work aims to study the safety and biopharmaceutical evaluation of inhaled excipients. The NCI-H441 cells were used as the in vitro model of choice as they mimic the distal lung epithelium. Cytotoxicity was assessed using the alamarBlue® assay, where cells were treated with excipients at various concentrations for 24 h. Immunoblotting and semi-quantitative real-time PCR were performed to quantify protein and mRNA expression of MRP1/ABCC1 and BCRP/ABCG2 after excipient treatment. Results showed 2-Hydroxy propyl β-cyclodextrin (2-HP β-CD) as the most cytotoxic excipient (IC50 = 2.39% w/v), followed by glycine (3.85% w/v), D-mannitol (4.57% w/v), and lactose monohydrate (8.05% w/v). A significant upregulation of ABCG2 (2.354 ± 0.5368) was observed after 24 h treatment with 2-HP β-CD, while protein expression analysis showed increased BCRP (137 ± 19%) and decreased MRP1 (70 ± 15%) levels after a 5-day treatment. Similarly, D-mannitol and lactose monohydrate treatments increased both BCRP and MRP1 expression. (165 ± 26%, 206 ± 44%, 204 ± 65%, and 223 ± 71%, respectively) The IC50 values obtained can be considered of minimal concern since epithelial lung fluid concentrations of these excipients in-vivo would likely be much lower. In conclusion, the mentioned excipients can be used in future studies at non-cytotoxic ranges, modulating MRP1 and BCRP expression, which demonstrates that the NCI-H441 model is suitable for cytotoxic and biopharmaceutical assessments.
Pharmacokinetics of OHet72 after IV and Pulmonary Administration: Implication of the Differences in Disposition between Species and Predicted Therapeutic Effect
Univ Oklahoma Health Sciences Center, Oklahoma City, USA.
Mucin-Targeted Gene Therapy for Asthma
University of Maryland, College Park, USA.
Asthma is a globally burdensome respiratory disease, affecting millions worldwide. It is characterized by chronic airway inflammation, airway remodeling, and impaired mucociliary clearance (MCC). Mucus comprises gel-forming mucin proteins mucin 5B (MUC5B) and mucin 5AC (MUC5AC), with MUC5B being the predominant mucin. In individuals with asthma, there is a shift from MUC5B to MUC5AC as the predominantly secreted mucin. These changes to mucus composition have been shown to impair MCC and obstruct airways due to increased mucus plugs in asthma patients [1]. Given the overproduction of MUC5AC in the asthmatic airway, we hypothesized that delivery of MUC5AC siRNA to the airway epithelium, could improve MCC, reduce airway hyperreactivity, and improve asthma symptoms in vitro and in vivo. To determine the potential therapeutic benefit of modulating mucus, we assessed adeno-associated virus (AAV6) as a gene delivery vector to deliver MUC5AC-targeting siRNA in vitro and in vivo. We confirmed that AAV6 can transduce airway epithelial cells (AECs) in vivo and in vitro. We also found that prophylactic treatment with AAV6-MUC5AC-siRNA reduced MUC5AC expression and normalized MCC in IL-13 stimulated human AECs in vitro. Future studies will evaluate the therapeutic potential of AAV-mediated MUC5AC siRNA delivery in an allergic asthma mouse model.
References
[1] Lachowicz-Scroggins, M. E.; Yuan, S.; Kerr, S. et al. (2016). Am J Respir Crit Care Med 194, 1296–1299. doi: 10.1164/rccm.201603-0526LE
Rat Precision-cut Lung Slices (PCLS) as a Model for Inhalation Toxicology: Advancing 3Rs Principles to Reduce Animal Use
1Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. 2Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 3Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, Fribourg, Switzerland.
Regulatory inhalation toxicity testing, following OECD guidelines, primarily relies on rats for acute and sub-chronic studies. This study explores the optimization of an ex vivo model—rat precision-cut lung slices (PCLS) —in alignment with the 3Rs principles (Replace, Reduce, Refine) to minimize animal use in regulatory testing.This study employs the Adverse Outcome Pathway (AOP) framework 173 to investigate whether endpoints can be aligned between in vivo data using the OECD-approved rat model and rat PCLS. Using DQ12, a quartz-silicate particle known to induce inflammation and fibrosis in vivo, we aimed to determine appropriate dosimetry for PCLS. We assessed total protein release, cytotoxicity, and viability following DQ12 exposure. Additionally, we analyzed the gene expression of inflammatory markers (IL6, IL1β, and TNFα) alongside fibrosis markers (α-SMA, fibronectin, and collagen), which are typically challenging to evaluate in in vitro models. Preliminary data revealed promising dose-dependent cytokine responses, especially at 7 days post-DQ12 exposure. By integrating this ex vivo approach—offering greater physiological complexity than conventional in vitro models while requiring fewer animals than in vivo studies—we aim to reduce animal use in inhalation toxicology testing and advance the adoption of OECD-compliant alternative models.
PRECLINICAL DEVELOPMENT OF A DRY POWDER FORMULATION FOR LOXAPINE FOR INTRANASAL DELIVERY
Paul Shields,1 Irene Rossi,2 Daniela Schwotzer,3 Philip Kuehl,3
1Enteris Biopharma, Boonton, USA. 2Harro Höfliger, Allmersbach im Tal, Germany. 3Lovelace Biomedical, Albuquerque, USA. 4Nanopharm, Cwmbran, United Kingdom. 5Aptar Pharma, Congers, USA.
[1] Sachs GS (2006). J Clin Psychiatry 67(10), 5-12. 16965190
[2] Wong AH, Crispino L, Parker J, McVaney C, Rosenberg A, Ray JM, Whitfill T, Iennaco JD, Bernstein SL (2019). Am J Emerg Med 37(7),1376-1379. 10.1016/j.ajem.2018.12.027
[3] Alexa Pharmaceuticals: Adasuve Prescribing Information [https://www.adasuve.com/]. Accessed December 28, 2023.
Exhaled Breath Sample Recovery Comparison Between Samplers for SARS-CoV-2 and Influenza Infections
University of Maryland, College Park, USA.
From paired sampling events, this study compared the performance of two exhaled breath (EB) samplers, the established Gesundheidt-II (G-II) and the novel combination of the BioCascade and BioSpot-VIVAS samplers (BC-VIVAS). From recruited participants with SARS-CoV-2 and influenza infections, we collected EB samples in identical sampling events. Using both samplers sequentially, we collected EB for 30 minutes, asking the participants to intermittently recite the alphabet. For both samplers, we measured total viral nucleic acid recovery via qRT-PCR. Due to differing sampling flow rates (125 LPM for G-II, 12 LPM for BC-VIVAS), we hypothesized a significant difference in viral recovery performance between the samplers for both infection types. A paired t-test of COVID-19 sampling events (n=40) showed a significant difference in total RNA collected in the G-II and BC-VIVAS (p=0.002). A Wilcoxon signed-rank test of influenza samples (n=8) found no significant difference in total recovery between the samplers (p=0.31). McNemar’s tests revealed a significant difference exists in frequency of positive and negative samples between systems for COVID-19 sampling events (p=0.013), but not for influenza (p=0.221). Overall agreement of the samplers was 83.7% for COVID-19 and 62.5% for influenza cases. With limited influenza sampling event data, we conclude that the novel BC-VIVAS performs comparably to the established G-II EB sampler for influenza infections, but not for COVID-19.
INACTIVATION MECHANISM OF AIRBORNE φX174 BY NON-THERMAL PLASMA
University of Michigan, Ann Arbor, USA.
Airborne transmission of infectious diseases poses substantial risks for public health, with environmental factors thought to either mitigate or exacerbate these risks. Therefore, there is a need for the development of advanced environmental control methods which can better prevent or reduce the airborne spread of the viruses, bacteria, and spores that are responsible for respiratory infections. Specifically for viral diseases, the structural diversity of airborne viruses demands that environmental control methods that rely on pathogen neutralization or inactivation - rather than airborne particle filtration - be challenged and evaluated against diverse virus topologies. In this study we determine the degree of inactivation of airborne φX174 bacteriophage from exposure to non-thermal plasma (NTP), the first such study to examine NTP inactivation of a DNA virus. Through plaque assays, previous experiments have shown 0.35 log inactivation, 56% inactivation, of φX174 after momentary passage of the aerosols through an NTP reactor. The present study seeks to assess the manner of inactivation. Using qPCR analysis, the genomic damage of φX174 during momentary NTP exposure can be revealed.
Longitudinal changes in the lungs of Apoe-/- mice following exposure to smoldering Douglas Fir smoke
Charbel Yazbeck,1 Matthew Eden,2 Jacqueline Matz,1 Michael Gollner,3 Chiara Bellini,1 and
1Northeastern University, Boston, USA. 2University of Michigan, Ann Arbor, USA. 3University of California Berkeley, Berkeley, USA.
The frequency and severity of wildland fires (WLFs) are on the rise, increasing the risk to wildland firefighters (WLFFs). We model an average career length of 12-28 years by equating surface-area normalized cumulative deposited dose between WLFFs and mice. Particulate concentration was 40 mg/m3 and exposure durations were 8 and 16 weeks. Lung mechanics and morphometry was assessed. Pro-inflammatory cytokines were quantified from bronchoalveolar lavage fluid, and biomarker expression was measured in fluorescent-stained lung sections. Particles had a count median diameter of 110 ± 20 nm and a geometric standard deviation of 1.47 ± 0.03. Following 16 weeks of DFS exposure, static compliance increased, supported by enlarged airspaces. Pro-inflammatory cytokines RANTES and IL-1α were elevated only after 8 weeks; IL-6 was increased at 16 weeks. Mean fluorescent intensity (MFI) of extracellular matrix proteases (neutrophil elastase, macrophage elastase [MMP12], and MMP9) and surfactant protein D was increased after 8 weeks. Xenobiotic response (CYP1A1), oxidative damage (4-HNE), and apoptosis (cleaved caspase-3) were elevated at both time points. The significant decrease in the MFI of tight junction marker ZO-1 in the parenchyma suggested compromised barrier integrity. The decline in lung functions could be attributed to degraded alveolar septa orchestrated by inflammatory and remodeling mediators, along with cellular damage.
NIH/NIEHS R01E5033792 and DHS/FEMA - EMW-2017-FP-00446.
Inhaling Innovation: Application of Isolated Perfused Rat Lung in Preclinical Testing of Novel Inhalational Drug Candidates
Dorothee Winterberg, Helena Obernolte, Phlippe Vollmer Barbosa, Christina Hesse, Horst Windt, Katharina Bluemlein, Katherina Sewald, Armin Braun, and
Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
To support early feasibility assessment and decision-making in the early phase of preclinical development reliable, human-predictive models are of particular importance. The isolated perfused lung (IPL) presents a unique and predictive platform for evaluating key aspects of safety, efficacy, and pharmacokinetics after inhalation including inhalational RNA therapies.
To assess relevant endpoints the IPL model provides a large spectrum of parameters incl. on-line assessment of lung function and viability as well as post-experimental immunological/biochemical analysis or imaging of lung tissue via preparation and re-cultivation of Precision Cut Lung Slices (PCLS) for up to several days.
It has been successfully used to 1) show successful intracellular delivery of functional intact mRNA throughout the respiratory tract of IPLs after inhalation determined by mCherry expression in PCLS, 2) determine human-predictive respiratory pharmacokinetic parameters as input parameter for PK modeling and 3) estimate in vivo NOAELs for acute respiratory toxicity and therefore providing a valuable screening tool prior to guideline studies.
To sum up the IPL model provides a unique combination of in vivo relevance, controlled experimental conditions and a vast spectrum of endpoints on different levels to assess many aspects highly relevant in early drug development, thus supporting early assessment of novel inhalational therapies not only on a qualitative but also a quantitative level.
Formulation
EFFECT OF SURFACE ENRICHMENT OF HYDROPHOBIC AMINO ACIDS IN AEROSOLIZATION, DISSOLUTION, AND CELLULAR TRANSPORT OF SPRAY DRIED DRY POWDERS INHALERS
Purdue University, West Lafayette, USA.
Spray drying generates fine solid particles from a liquid source within seconds. Since dry powder inhalers (DPIs) require fine particles, spray drying has been utilized to produce DPIs. However, spray-dried (SD) DPIs can be hygroscopic and absorb atmospheric moisture over time, which induces particle size growth and deteriorates powder dispersibility. One of strategies to protect SD DPIs against moisture is by inclusion of hydrophobic excipients, which, due to their low water solubility, can enrich on the particle surface. While such excipients have been reported to provide satisfactory moisture protection, it has been less investigated into their impact on dissolution or cellular transport, which contribute to DPI performance. Therefore, in this work, colistin was co-spray dried with leucine or trileucine at various weight ratios. Aerosolization was evaluated before and after exposure to 75% relative humidity. The underlying moisture protective mechanism was also investigated. Furthermore, the dissolution and cellular uptake were also evaluated. Our results indicate that leucine and trileucine could restore the aerosol performance against moisture absorption. Trileucine outperformed leucine due to a better particle surface enrichment efficiency. Importantly, trileucine or leucine did not significantly alter the dissolution or cellular transport, which could be attributed to small particle sizes and incomplete particle coverage by the excipient.
Improved Thermostability of RNA-Lipid Nanoparticles through Electrostatic Interaction
Purdue University, West Lafayette, USA.
Lipid nanoparticles (LNPs) are powerful carriers for RNA vaccines and therapeutics. However, RNA-LNPs exhibit poor thermostability and tend to accumulate in the liver. Ionizable lipids are considered the key component, regulating RNA encapsulation and intracellular delivery. Here, we investigated the effect of pH on stability of spray-dried RNA-LNPs for pulmonary delivery.
The results indicated that the pKa of ionizable lipid (ALC-0315) is 6.09, consistent with previously reported value [1], and the pKa of RNA-LNPs is 6.36. Therefore, pH 5, 6 and 7 were selected for further analysis. When pH was lower than pKa, spray-dried RNA-LNPs exhibited better stability, maintaining ∼95% encapsulation after storage at 40°C for 1 week and 4°C for 1 month. However, when pH was close to or greater than pKa, encapsulation reduced significantly after storage. The enhanced thermostability at low pH was attributed to strengthening the electrostatic interactions between polyanionic RNA and the ionizable lipid, facilitating by the protonation of ionizable lipid, which helps retain RNA within the LNPs under stress. Particle size, PDI and zeta potential also remained stable after spray drying and storage when the pH was below the pKa.
Overall, this study showed the potential of stable pH-modified, spray-dried RNA-LNPs for pulmonary delivery.
References
[1] Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids. WO2017075531A1; 2017
RAPID IN SITU FORMING PEG HYDROGELS FOR NASAL DRUG DELIVERY
University of Maryland, College Park, USA.
Drug delivery through the nasal route is limited by mucociliary clearance (MCC). MCC is a physiological defense mechanism that clears mucus within the nasal cavity every 15 to 20 min and results in rapid clearance of therapeutics which leads to low bioavailability. To address this challenge, we developed a rapid in situ forming polyethylene glycol (PEG) hydrogels [1]. These gels form within 30 seconds under physiological conditions and can adhere to mucosal epithelium, prolonging drug residence time. To synthesize rapid forming PEG gels, 4-arm thiol terminated PEG and 4-arm Ortho pyridyl disulfide terminated PEG solutions in phosphate buffered saline are mixed in equal volumes. We identified 6 lead formulations, which rapidly form disulfide-linked PEG hydrogels in ≤30 seconds and retain stability in PBS for ≥ 24 hours. Pull-apart adhesion tests with porcine intestine tissue showed mucoadhesive strengths >600 Pa. In vitro release studies demonstrated that protein-based cargoes were gradually released from PEG gels over several hours, whereas 40 nm nanoparticle-based cargoes retained for over 24 hours. In vitro biocompatibility tests resulted in >80% viability of HEK 293T cells highlighting their safety. Further in vivo retention studies demonstrated nasal residence for up to seven days in mice, highlighting the potential for clinical development.
References
[1] Yeruva, T.; Morris III, R. J.; Zhao, L. et al. (2024). bioRxiv, 2024–08. doi: 10.1101/2024.08.16.608319
THERMALLY-STABLE COVID-19 VACCINE POWDER
1Global Product Development, AstraZeneca, Durham, USA. 2Biopharmaceutical Development, AstraZeneca, Gaithersburg, USA.
ChAdOx1 nCoV-19 is a recombinant replication-defective simian adenovirus carrying gene encoding spike protein antigen of SARS-CoV-2. This gene induces human cells to produce spike protein, prompting the immune system to produce antibodies and activate T cells and B cells. We aimed to demonstrate the feasibility of removing the refrigeration requirement by spray drying liquid vaccine with stabilizing excipients, producing thermally-stable dry powder.
The adenoviral vector vaccine was spray-dried on custom in-house spray drying equipment to particles in the inhalation size range. The feedstock contained liquid drug substance diluted into trehalose & glycerol solution. Results demonstrate that the spray dried vaccine powder had orders of magnitude improved infectivity on accelerated stability (1mo at 40°C) relative to liquid dosage form. We conclude that thermally-stable COVID-19 vaccine powder can be produced by spray drying. This could aid stockpiling and global distribution, enhancing pandemic preparedness.
THIN-FILM FREEZE-DRIED ANTIBODY FOR INHALATION
1Global Product Development, AstraZeneca, Durham, USA. 2Global Product Development, AstraZeneca, Gothenburg, Sweden. 3Division of Molecular Pharmaceutics and Drug Delivery, University of Texas at Austin, Austin, USA. 4TFF Pharmaceuticals Inc., Fort Worth, USA.
Excipient-Free Inhalable Bedaquiline-Pyrazinamide Powders via Three-Fluid Nozzle Spray Drying for Potential Tuberculosis Treatment
1National Taiwan University School of Pharmacy, Taipei, Taiwan. 2The University of Sydney, School of Pharmacy, Sydney, Australia
Multidrug-resistant tuberculosis (MDR-TB) remains a global health challenge. Bedaquiline (BDQ) is highly effective but expensive MDR-TB drug. Its combination with pyrazinamide (PZA) has shown synergy. Inhalation therapy offers a promising alternative by delivering drugs directly to the lungs, enhancing efficacy while reducing systemic toxicity.
This study aimed to develop an excipient-free inhalable BDQ-PZA dry powder via spray drying with a three-fluid nozzle. A Box-Behnken design optimized three key parameters, including inlet temperature, BDQ-to-PZA feeding rate ratio, and PZA concentration, to maximize yield. Analytical techniques, including dynamic vapor sorption, scanning electron microscopy (SEM), differential scanning calorimetry, X-ray diffraction (XRD), high-performance liquid chromatography, and Next-Generation Impactor, assessed physicochemical properties and aerosol performance.
The optimized formulation achieved a 67.43% yield, with SEM showing spherical, wrinkled particles and XRD confirming amorphous BDQ and crystalline PZA. It exhibited low hygroscopicity (1.34%), good content uniformity, and a median size of 1.75 µm. NGI analysis showed a mass median aerodynamic diameter of 3.03 µm for PZA and 2.55 µm for BDQ, with high fine particle fractions (PZA: 79.8%, BDQ: 88.1%), supporting pulmonary delivery feasibility.
This novel excipient-free BDQ-PZA formulation demonstrates potential for inhaled TB therapy, offering an effective alternative to TB treatment.
ROBUSTNESS OF THE REFORMULATION OF BREZTRI AEROSPHERE® FROM HFA-134a TO THE NEAR ZERO GWP PROPELLANT HFO-1234ze
1AstraZeneca, Durham, USA. 2AstraZeneca, Gothenburg, Sweden.
AstraZeneca fully supports global efforts to achieve carbon emission reduction targets and has committed to net-zero healthcare. As part of this commitment, AstraZeneca proactively initiated the development of next generation MDIs by substituting the current propellant (HFA-134a) with a next generational propellant (HFO-1234ze) that has near-zero global warming potential (GWP).
The next generation Breztri Aerosphere® is fixed-dose combination (FDC) of an inhaled corticosteroid (budesonide, 160 μg per actuation), a long-acting muscarinic antagonist (glycopyrrolate, 9 μg per actuation), and a long-acting β2-agonist (formoterol fumarate 4.8 μg per actuation), formulated using Aerosphere® co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in HFO-1234ze propellant.
The AstraZeneca Aerosphere® platform technology enables the successful reformulation of Breztri Aerosphere® from HFA-134a to the near zero GWP propellant HFO-1234ze such that product labeling may be retained.
The robustness and reliability of the next generation Breztri Aerosphere® is demonstrated through delivered dose and aerodynamic particle size distribution (APSD) characterization designed to inform product labelling such as product handling per the instructions for use, priming prior to first use and after periods of non-use, effect of shake energy, and performance after a drop.
DEVELOPMENT OF SPRAY-DRIED TEDIZOLID PHOSPHATE INHALATION POWDERS FOR TUBERCULOSIS THERAPY
Erik Pena, and
RTI International, Research Triangle Park, USA.
Tuberculosis (TB), the world’s leading cause of death by a single infectious agent, claimed the lives of 1.25 million people in 2023 according to the WHO. Multidrug-resistant TB (MDR-TB) is resistant to the two most effective first-line antibiotics, rifampicin and isoniazid, and remains a threat to global health. In 2019, the BPaL (bedaquiline, pretomanid, and linezolid) regimen was approved by the U.S. FDA for patients with nonresponsive MDR-TB. While effective, linezolid is known for adverse reactions at the required doses, causing patients to reduce their daily dose or stop taking the drug altogether. Tedizolid, a novel oxazolidinone, has come to the forefront as a potentially safer alternative owing to its improved in vitro performance compared to linezolid. In this effort, we developed inhalable tedizolid phosphate (TDZ) dry powders with the future goal of replacing linezolid in the BPaL regimen. In addition to exchanging linezolid for TDZ, incorporating targeted drug delivery to the lungs may reduce required doses and off-target effects. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was incorporated to improve solubility of the water-insoluble TDZ. Initial spray-dried formulations comprised of a 3:1 mass ratio of HP-β-CD:TDZ yielded particles with a mass median aerodynamic diameter of 2.38 ± 0.17 µm (GSD 1.87 ± 0.06) and fine particle fraction of 47.6 ± 1.7% relative to the emitted dose. Further efforts to improve particle deaggregation and maximize TDZ dose are ongoing.
OPTIMIZATION AND CHARACTERIZATION OF INHALABLE ZEIN-ENCAPSULATED HDAC INHIBITOR MICROPARTICLES FOR POTENTIAL TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS
National Taiwan University School of Pharmacy, Taipei, Taiwan.
Idiopathic pulmonary fibrosis is a progressive and irreversible lung disease. Current oral treatments often cause systemic side effects due to high and frequent dosage. On the contrast, inhalable powders can directly deliver drug into the lungs and lower systemic exposure. A novel HDAC inhibitor recently developed shows strong anti-fibrotic efficacy but requires sustained release. Zein, a GRAS and polymeric excipient, is a potential sustained-release carrier but is not approved for inhalation. To minimize this polymer usage, lactose was incorporated as a bulking agent. This study aimed to employ three-fluid nozzle spray drying to encapsulate the HDAC inhibitor and lactose within zein microparticles to produce stable powder for inhalation.
A Box-Behnken design is used to optimize spray drying parameters to achieve the highest zein surface coverage and delaying powder recrystallization humidity. Optimized conditions (spray gas: 1281 L/h, inlet temp.: 92°C, flow rate: 6 mL/min, excipient: 30%) yielded stable zein-coated particles delaying recrystallization from 40% to 60% RH at 25°C. Moreover, although the resultant powder was amorphous, it showed an good aerodynamic performance with MMAD of 1.09 ± 0.01 µm and FPF of 85.4 ± 0.57%.
This study demonstrated that the zein-based microparticle formulation encapsulating an HDAC inhibitor and lactose via three-fluid nozzle spray drying ensured high zein surface coverage, delayed lactose recrystallization, and good aerodynamic properties.
SPRAY DRYING PROCESS OPTIMIZATION AND MODELING FOR AN INHALED DRY POWDER OF 5-AZACYTIDINE FOR LOCAL LUNG CANCER TARGETING
1Bend Bioscience, Bend, USA. 2Lovelace Biomedical Research Institute, Albuquerque, USA. 3Amofor GmbH, Dortmund, Germany.
A dry powder formulation of 5-Azacytidine (5-AZA) recently showed improved tumor reduction and systemic exposure for the local treatment of lung cancer.1 To progress this formulation, the target product profile required doubling the active loading. Here, a series of powders were spray dried to increase 5-AZA loading and process parameters were varied to identify handles controlling powder properties. Formulations were sprayed via in-line mixing, where separate dimethyl sulfoxide (DMSO) and aqueous solutions were mixed immediately upstream of atomization. A core-shell structure was observed matching previous reports of spray dried L-leucine from water and ethanol. Powders with glass transition temperatures (Tg) below room temperature were successfully manufactured, attributed to crystalline L-leucine surrounding the low Tg core. Residual DMSO was primarily controlled by the DMSO:water ratio. Perturbed-Chain Statistical Associating Fluid Theory was employed to understand droplet drying processes by developing ternary phase diagrams and drying trajectories. This work enables the manufacture of both dry inhalable 5-AZA powder for local lung cancer targeting and low Tg materials previously thought to be unmanufacturable via spray drying. It also highlights the importance of aligning experimental data and theoretical models to improve understanding of complex processes.
References
[1] Kuehl, P., Tellez, C., Grimes, M et al. (2020). Br J Cancer 122, 1194–1204. doi:10.1038/s41416-020-0765-2
MINIMISING AGGREGATES WHEN NEBULIZING ANTIBODY FAB FRAGMENTS: HIGH THERMOSTABILITY AND HIGH CONCENTRATION ARE KEY
1Fraunhofer ITEM, Hannover, Germany. 2F. Hoffmann-La Roche Ltd, Basel, Switzerland. 3Roche Innovation Center Munich, Penzberg, Germany.
The treatment of lung diseases by inhaled drugs has enormous potential by maximizing drug concentration in the lung while minimizing systemic toxicity. However, few inhaled proteins are in clinical development, in large part due to formulation challenges: proteins must be protected from shear stress, heat, and partial unfolding at the large air/water interface of the aerosol during nebulization to prevent denaturation and aggregation, which can increase immunogenicity risk.
This study investigates factors affecting Fab stability during nebulization using a vibrating mesh nebulizer. In particular, the effect of Fab thermostability and concentration on the stability in nebulization was evaluated using a series of 14 Fab molecules with melting temperatures (Tm) ranging from 60-90°C and concentrations of 10 and 80 mg/mL. When nebulized, all molecules led to an aerosol displaying an appropriate droplet size <5 µm, suitable for deposition into the human alveolar region. Aggregation of the Fabs due to nebulization, however, varied significantly, and we found two key solutions to minimize aggregation of Fabs during vibrating mesh nebulization: Firstly, increasing the Fab melting temperature, and secondly, using a high Fab concentration. Both solutions work individually but work best in conjunction. These findings have the potential to facilitate and accelerate the development of therapeutic Fabs for inhalation and reduce their immunogenicity risk.
Optimizing the Delivery of a Conjugated Lipopeptide Antibiotic Dry Powder Aerosol
1RTI international, Research Triangle Park, USA. 2University of Southern California, Los Angeles, USA. 3Monash University, Clayton, Australia
Antimicrobial resistance is one of the greatest threats to human health [1]. The depsipeptide teixobactin has been identified as a ‘resistance-resistant’ antibiotic with a novel mechanism of action [2]. We have developed broader-spectrum hybrids of teixobactin conjugated with polymyxin-like lipopeptide antibiotics via labile linker [3]. This conjugation allows for targeted delivery and enhanced permeability into Gram-negative bacteria, and allows the hybrid to dissociate into its constitutive parts at the infection site. To target lung infections caused by drug-resistant bacteria, we have prepared inhalable dry powders of the hybrid using spray drying, optimizing their aerodynamic particle size distributions to maximize efficient delivery. Utilizing a 2-level, 3-factor Design of Experiment, we have optimized the physical characteristics and aerodynamic performances of a dry powder for inhalation. Initial results showed that a teixobactin-lipopeptide hybrid spray dried with mannitol, lactose, or trehalose is thermally stable up to 181, 144, and 195ºC, respectively, with less than 5% moisture content. Key studies are underway to determine how the excipients affect aerosol behavior.
References
[1] IDSA (2010) Clin Infect Dis 50, 1081–1083. doi: 10.1086/652237
[2] Ling, L.L., Schneider, T., Peoples, A.J., et al. (2015) Nature 517, 455–459. doi: 10.1038/nature14098
[3] Hussein, M., Karas J.A., et al. (2020) mSystems, 5(3):e00077-20. doi: 10.1128/mSystems.00077-20
LUNG SURFACTANT-DOPED LIPID NANOPARTICLES FOR ENHANCED PULMONARY DELIVERY OF RNA BASED-THERAPIES
1University of Maryland, College Park, USA. 2Alexandria University, Alexandria, Egypt.
LNPs are currently the gold standard for mRNA delivery. However, its inherent immunogenicity limits therapeutic utility and we need structural modifications to curb it [1] and boost protein expression [2]. Surfactant lung cocktail (Proactant-α) and helper lipid (DSPC) of LNPs are structurally similar, hence we hypothesized incorporating Proactant-α or its components in LNPs can improve performance for pulmonary gene delivery. Thus, LNPs were prepared by mixing ethanolic solution of Dlin-DMC-MC3, Cholesterol, DSPC, and DSPE-PEG2000K (molar ratios 50%, 38.5%,10%,1.5%) with siRNA (NP ratio =10) or mRNA (NP ratio=6) in acetate buffer (100mM, pH=5). Surfactant containing LNPs (Surf-LNPs) were similarly prepared, with full DSPC displacement with Proactant-α. LNP’s Colloidal properties were analysed with nanoparticle tracking analysis, in-vitro transfection and cytotoxicity were assessed in A549 with mEGFP as reporter. We found full DSPC replacement with Proactant-α did not alter colloidal properties or encapsulation efficiency of LNPs. Yet, it significantly enhanced in-vitro transfection efficiency and level of protein expression in A549(∼10X). Both LNPs and Surf-LNPs were cytocompatible. Such results support continued development of Surf-LNPs for inhaled gene delivery.
References
[1] Ndeupen S, Qin Z, Jacobsen S, et al. (2021). J Immunol 206:30.01-30.01. doi: 10.4049/jimmunol.206.supp.30.01
[2] Rohner E, Yang R, Foo KS, et al. (2022). Nat Biotechnol 40:1586–1600. doi: 10.1038/s41587-022-01491-z
IMPROVING STORAGE STABILITY OF ANTIVIRALS VIA SPRAY DRYING
1University of Alberta, Edmonton, Canada. 2Stanford University, Stanford, USA.
Locked nucleic acids (LNAs) are a promising class of programmable antivirals, that can be complexed with the transfection agent JetPEI to facilitate cellular uptake. Several LNA molecules were identified that protected animals from influenza A lethal infection and SARS-CoV-2 respiratory infection when administered intranasally as liquid formulation [1]. The programmable antiviral approach can serve as a platform that enables rapid identification of LNAs that target other viruses with pandemic potential1. In the present work, spray drying of LNA-JetPEI complexes was investigated to improve thermostability and potentially enable alternative powder delivery methods. Trehalose was used as the primary stabilizing and bulking excipient. UV spectroscopy of reconstituted powder formulation confirmed that LNA quantity was conserved. Similarly, dynamic light scattering showed that size of the LNA-JetPEI complexes was maintained. A short term stability study at room and elevated (40 °C) temperatures over three months demonstrated that the resulting dry powder had improved thermostability as compared to the liquid formulation. The dry powder format has the potential to reduce the need for cold chain logistics, lowering distribution costs while preserving antiviral activity. These results demonstrate that spray drying is a viable strategy for enhancing the stability and accessibility of LNA based antivirals.
References
[1] Hagey, R. J., et al. (2022) Nat Med 28, 1944–1955. doi:10.1038/s41591-022-01908-x
LIPOSOMAL ENCAPSULATION OF BACTERIOPHAGES FOR INHALED DELIVERY - FORMULATION DEVELOPMENT AND IN VITRO EVALUATION
Purdue University, West Lafayette, USA.
Bacteriophages (phages), viruses that infect and kill bacteria, are gaining attention as alternatives to antibiotics to treat multidrug resistant respiratory infections. Inhaled delivery of phages provides direct access to infection site; however, loss of phage viability during manufacturing and delivery is a major challenge. Recent studies reveal phages can be uptaken by lung epithelial cells consequently, reducing phages available to act against extracellular bacteria such as Pseudomonas aeruginosa.
To address these challenges, this study investigates phage encapsulation in liposomes. The objectives are to understand: (i) factors influencing phage encapsulation, (ii) the effect on phage nebulization, and (iii) phage cellular uptake in a lung epithelial cell model (H441).
Our results show that phages can be encapsulated with a minimal loss in viability 0.64 ± 0.21 log, and encapsulation efficiency of 58%. Liposomes exhibit slow and complete phage release over 10 hours in simulated lung fluid. Phage loss during nebulization was reduced from 1.55 ± 0.04 log to 1.08 ± 0.05 log on encapsulation. Phage liposomes reduced cellular uptake in H441 lung epithelial cells by 2-fold compared to free phages.
These findings highlight the potential of liposomes for improved inhaled phage delivery. The availability of phages can be improved by encapsulation, as liposomes can control phage release, minimize loss during nebulization, and reduce phage uptake by lung epithelial cells.
LONG-TERM STABILITY OF A SPRAY-DRIED COCKTAIL OF ANTI-TUBERCULOSIS PHAGES FIONNBHARTH, MUDDY, AND D29
1University of Alberta, Edmonton, Canada. 2Université de Sherbrooke, Sherbrooke, Canada. 3Seattle Children's Research Institute, Seattle, USA. 4University of Pittsburgh, Pittsburgh, USA.
As of 2023, tuberculosis (TB) has returned to being the leading cause of death from a single infectious agent globally, with over 10 million new TB cases and 1.25 million deaths each year [1]. Mycobacteriophages have the potential to combat increasing cases of multi-drug-resistant TB. A stable, dry phage powder could improve global availability by reducing dependency on cold-chain infrastructure. This work evaluated the stability of a powder cocktail of anti-Mycobacterium tuberculosis phages Fionnbharth, D29, and Muddy in an accelerated 6-month study. Phages were spray-dried in a solution of 50 mg/mL trehalose and 1 mg/ml trileucine dissolved in standard phage buffer and stored at 4 °C, 25 °C, and 40 °C. Phage activity level was determined via plaque titering against M. smegmatis, a common surrogate for M. tuberculosis, in triplicate. Physical stability was assessed by monitoring particle morphology, moisture content, and solid phase over time. After 6 months, titer reduction of the cocktail stored at 40 °C was less than 0.6 ± 0.1 log (PFU/mL), and negligible for the powder stored at 4 °C and 25 °C. Physical stability was maintained for all temperatures. For comparison, titer reduction over 6 months at 40 °C of a liquid cocktail exceeded 5.0 ± 0.1 log (PFU/mL). Stability of this spray-dried cocktail shows impressive potential for the global distribution of inhalable dry phage powders.
References
[1] World Health Organization (2024). Global Tuberculosis Report 2024. ISBN 978-92-4-010153-1
Best Oral Presentations
INFLUENCE OF OHET72 NANOCRYSTAL (NC) CONCENTRATION ON THE PROPERTIES OF AEROSOLS GENERATED BY NEBULIZATION: EFFECT ON ITS ACTIVITY AGAINST MYCOBACTERIUM TUBERCULOSIS (MTB)
University of Oklahoma Health Sciences Center, Oklahoma City, USA.
MOLECULAR MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF INHALED UC-MSC EXOSOMES IN PULMONARY FIBROSIS
1National Tsing Hua University, Hsinchu City, Taiwan. 2National Taiwan University College of Medicine, Taiepi, Taiwan. 3Chang Gung University, Taoyuan City, Taiwan.
Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disorder with limited therapeutic options, primarily focused on palliative care. This study investigates the therapeutic potential of umbilical cord-derived mesenchymal stem cell (UC-MSC) exosomes administered via inhalation in a bleomycin-induced pulmonary fibrosis model. Compared to conventional intravenous administration, inhaled exosome treatment resulted in significant pathophysiological improvements and lung tissue recovery, including a 105% reduction in hydroxyproline content and decreased collagen deposition. Functional assessment revealed substantial lung function recovery, characterized by a 20% increase in total lung capacity, a 38% reduction in airway resistance, and a 40% improvement in lung compliance. Furthermore, inhaled exosome treatment mitigated severe weight loss associated with fibrosis (-24% in the IPF group vs. -2% in the inhaled exosome group). Gene expression analysis revealed downregulation of MUC5B (mucin causing airway obstruction in IPF), IL-1RN (pro-fibrotic inflammatory mediator), and DSP (marker of epithelial-mesenchymal transition), with concurrent upregulation of SFTPC (surfactant protein C essential for alveolar function), indicating active repair processes. These findings suggest that inhaled UC-MSC exosomes represent a promising therapeutic approach for pulmonary fibrosis, highlighting inhalation as a viable route for clinical translation.
INBRIJA VERSUS LEVODOPA CYCLOPS: AN IN VITRO – IN VIVO COMPARISON OF TWO ORALLY INHALED LEVODOPA DRY POWDER PRODUCTS
1University of Groningen, Groningen, Netherlands. 2PureIMS, Roden, Netherlands.
Inbrija and Levodopa Cyclops are two levodopa dry powder inhalation products for the rapid termination of OFF episodes in Parkinson’s Disease. The two products differ in their inhaler (e.g. resistance to air flow) and formulation properties (e.g. excipients and particle density). The aim of this study is to assess whether these differences reflect in the in vitro dissolution and aerosol characteristics and, subsequently, in the in vivo pharmacokinetics. In vitro aerosol characteristics and dissolution were assessed by (modified) compendial methods. The pharmacokinetics of both products were determined by a randomized crossover study in 26 healthy volunteers. The in vitro experiments demonstrated that both products have a similar emitted dose and fine particle dose, while deep lung deposition of Inbrija is expected to be slightly higher due to its higher resistance to air flow and consequential lower inhalation flow rate at the same pressure drop. Levodopa Cyclops showed substantially faster dissolution than Inbrija: 80% dissolved in 8.3 versus 33.0 minutes. Despite the in vitro differences, the in vivo study revealed no significant differences in the pharmacokinetic profiles of Inbrija (84 mg) and Levodopa Cyclops (90 mg). This indicates that the dissolution rate is not the rate-limiting step for absorption or that the dissolution method lacks physiological relevance. Hence, DPI dissolution testing should always be initiated, performed and interpreted with caution.
A Step Towards Region-Specific In Vitro Deposition and Dissolution: Characterization of an Alveolar Filter Designed for Dissolution Measurements
1Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada. 2Proveris Scientific Corporation, Hudson, MA, USA. 3Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada.
Efficacy of inhaled therapies may be improved by targeting deposition to physiologically relevant regions of the lungs; it follows that local dissolution rates in airway lining fluids could also influence efficacy. Previously we have developed an in vitro method that divides the inhaled dose into tracheobronchial (TB) and alveolar doses using filters. The TB filter is well-suited for studying dissolution of the TB dose [1], however the alveolar dose has to date been collected within a fibrous filter that may not be ideal for such studies.
This work evaluates an alternative filter material (woven stainless steel, ASADA Mesh Co.) intended to capture the alveolar dose while facilitating further dissolution study. The filtration properties of the filter media were characterized using an electrical low-pressure impactor and a neutralized aerosol of salt crystals. Collection of pharmaceutical aerosols (Flovent Diskus) was evaluated using stainless steel filters in place of the fibrous filter and comparing recovered dose.
A two-layer filter was found to capture over 90% of the alveolar dose whereas a single layer captured 70 to 80%. Micrographs of the stainless steel filters show particles distributed atop the tightly packed wire lattice rather than embedded within fibers. These results indicate the two-layer filter can facilitate investigation of dissolution of the captured alveolar dose.
References
[1] Huang et al. (2024). DDL Conference Proceedings, vol 35, pg 503–506. doi: 10.60565/cjpx-1k63
Tuning Hydrogel Nanoparticle Surface Chemistry to Highlight Age-Based Changes in Innate Immune Cells Response to Inhaled Therapeutics
University of Delaware, Newark, USA.
Aged individuals show higher susceptibility to severe respiratory infections due to altered pulmonary immune cell functions that is not well treated with traditional vaccine approaches. Alternatively, pulmonary delivery offers direct targeting to lung immune cells. Highly phagocytic antigen-presenting cells (APCs) are widely abundant in lung tissue and ripe targets for nanoparticle (NP)-based designs. However, design parameters to uniquely capture these aged APCs have yet to be established. Herein, we characterize surface chemistry effects on APC localization and activation using poly(ethylene glycol)-based hydrogel NPs. Thus far, murine studies have demonstrated age-based changes in inhaled, charged NP uptake by APCs. Of note, alveolar macrophages from aged 16-mo mice demonstrate nearly 3-fold decrease in anionic NP uptake, while anionic NP uptake in interstitial macrophages from aged mice increases by nearly 10-fold. Comparatively, conventional dendritic cells preferentially engulf cationic NP at a similar capacity across age. However, all charged NP formulations increased inflammatory responses in aged APCs. From this, we are tuning stimulatory ligand density of NPs to control activation responses for aged APC phenotypes to design better NP vaccines for older individuals. Thus, this work outlines an overall approach to formulate inhalable NP therapeutics for a broad range of immunoengineering applications and highlight the rising need for age-based immunotherapy designs.