Nipah virus (NiV) is a lethal zoonotic paramyxovirus that can be transmitted from person to person through the respiratory route. There are currently no licensed vaccines or therapeutics. A lipopeptide-based fusion inhibitor was developed and previously evaluated for efficacy against the NiV-Malaysia strain. Intraperitoneal administration in hamsters showed superb prophylactic activity and promising efficacy, however the intratracheal delivery mode in non-human primates proved intractable and spurred the development of an aerosolized delivery route that could be clinically applicable. We developed an aerosol delivery system in an artificial respiratory 3D model and optimized the combinations of flow rate and particle size for lung deposition. We characterized the nebulizer device and assessed the safety of lipopeptide nebulization in an African green monkey model that mimics human NiV infection. Three nebulized doses of fusion-inhibitory lipopeptide were administered every 24 h, resulting in peptide deposition across multiple regions of both lungs without causing toxicity or adverse hematological and biochemical effects. In peptide-treated monkeys challenged with a lethal dose of NiV-Bangladesh, animals retained robust levels of T and B-lymphocytes in the blood, infection-induced lethality was significantly delayed, and 2 out of 5 monkeys were protected from NiV infection. The present study establishes the safety and feasibility of the nebulizer delivery method for AGM studies. Future studies will compare delivery methods using next-generation fusion-inhibitory anti-NiV lipopeptides to evaluate the potential role of this aerosol delivery approach in achieving a rapid antiviral response.

Non-Human Primates (NHPs) are particularly relevant for preclinical studies during the development of inhaled biologics. However, aerosol inhalation in NHPs is difficult to evaluate due to a low lung deposition fraction and high variability. The objective of this study was to evaluate the influence of mesh nebulizer parameters to improve lung deposition in macaques. We developed a humidified heated and ventilated anatomical 3D printed macaque model of the upper respiratory tract to reduce experiments with animals. The model was compared to in vivo deposition using 2D planar scintigraphy imaging in NHPs and demonstrated good predictivity. Next, the anatomical model was used to evaluate the position of the nebulizer on the mask, the aerosol particle size and the aerosol flow rate on the lung deposition. We showed that placing the mesh-nebulizer in the upper part of the mask and in proximal position to the NHP improved lung delivery prediction. The lower the aerosol size and the lower the aerosol flow rate, the better the predicted aerosol deposition. In particular, for 4.3 +/- 0.1 mu m in terms of volume mean diameter, we obtained 5.6 % +/- 0.2 % % vs 19.2 % +/- 2.5 % deposition in the lung model for an aerosol flow rate of 0.4 mL/min vs 0.03 mL/min and achieved 16 % of the nebulizer charge deposited in the lungs of macaques. Despite the improvement of lung deposition efficiency in macaques, its variability remained high (6-21 %).

IntroductionBacterial pneumonia is a major cause of morbidity and mortality worldwide. Antibiotics constitute the standard of care but face the emergence of antimicrobial resistance and curative failure. Moreover, antimicrobial agents are often administered orally or intravenously (I.V.) regardless the site of infection, as they are expected to distribute to this site. Inhalation is the obvious way of matching the delivery route to the target's location to treat pneumonia. It is suitable for protein therapeutics [1], and usually improves the therapeutic index of drugs. Here, we investigated inhalation of FLAMOD, a Toll-Like receptor 5 agonist, which enhances airway innate immune defenses. It improves the therapeutic outcome relative to antibiotic alone [2] and has synergic effect when combined with antibiotics, in pneumonia. Evidences showing that the FLAMOD-mediated immune protective effectors are regionally compartmentalized in the lungs further support the relevance of developing inhalation.MethodsFLAMOD has been delivered either by nebulization into the lungs of macaques (Aerogen Solo®) or I.V. blood and bronchoalveolar lavages were collected to analyze innate immune response induced by the FLAMOD, in the systemic and local compartments and assess the potential immunogenicity of the inhaled formulation.ResultsOur results demonstrate that inhalation resulted in a local response, associated with a transient peak in cytokine secretion 2 to 70-fold lower than systemic response, as compared to the I.V. route. Moreover, the inhalation route led to lower anti-drug antibody (ADA) production than I.V. route.ConclusionOverall, our findings indicate that inhalation is better to achieve and restrict the immunomodulatory activity of FLAMOD into the lung compartment.

Preclinical aerosol studies using animals are essential for evaluating toxic or therapeutic effects on human respiratory tract. Macaques are relevant animal models for respiratory studies, but they are sensitive, expensive and difficult-to-access. In the context of preliminary studies before animal experiments, we set up an alternative in vitro anatomical model of macaque airways to reduce, refine and replace (3Rs) the animals. We printed an in vitro anatomical cast until the third bronchial division from X-ray computed tomography data of a healthy cynomolgus macaque. This in vitro model was then connected to a respiratory pump to mimic macaque’s breathing. We assessed the relevance of this in vitro model, by comparing aerosol deposition patterns obtained with the anatomical model and in three macaques using planar gamma camera imaging. DTPA-99mTechnetium aerosols were produced using three jet nebulizers, generating three different particle sizes: 13.1, 3.2 and 0.93 µm in terms of the mass median aerodynamic diameter (MMAD). The data showed no statistical differences between the animal and anatomical in vitro models in terms of total aerosol deposited in the airways. However, the distribution of the deposition in the airways showed a higher deposited fraction in the upper respiratory tract in the animals than the in vitro model for all particle sizes. The anatomical printed model appears to be a relevant in vitro tool to predict total aerosol deposition in macaque airways.

Background and Purpose. Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of VAP caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. Experimental Approach. (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa. Key Results. By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p<0.001). No phage was detected in the sera and urines throughout the experiment. Conclusion and Implications. Our findings demonstrated: (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation, (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of VAP with high translational value.

Journal of Aerosol Medicine and Pulmonary Drug DeliveryVol. 34, No. 3 Abstracts fromThe Aerosol Society Drug Delivery to the Lungs 31 Virtual Online Conference December 9–11, 2020Free AccessAbstracts (DOI: jamp.2021.ab01.abstracts)Published Online:14 Jun 2021https://doi.org/10.1089/jamp.2021.ab01.abstractsAboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Abstracts: Drug Delivery to the Lungs 3101. Surfactant Foam Therapy For Severe Covid‐19 Patients With Acute Respiratory Distress Syndrome (ARDS)Josué Sznitman, Associate ProfessorDirector, Norman Seiden Graduate Program in Nanoscience & NanotechnologyAssociate Chair for Undergraduate StudiesDepartment of Biomedical EngineeringIsrael Institute of TechnologyThe SARS‐CoV‐2 virus enters primarily through the respiratory tract and penetrates epithelial cells. In severe cases, the disease deteriorates to a form of acute respiratory distress syndrome (ARDS) and is accountable for most deaths. To date, there is no effective pharmacological treatment in ARDS in adults with mortality rates around 40%. One of the hallmarks of ARDS is damage to pulmonary surfactant. Although COVID‐19 pathophysiology is not thoroughly understood, the virus kills surfactant secreting alveolar cells. Surfactant Replacement Therapy (SRT) is a life‐saving clinical procedure in treating preterm neonates, whose immature lungs lack pulmonary surfactant. SRT is based on endotracheal administration of liquid surfactant instillations. Due to differences in lung size, this strategy is ineffective in adults. Instillations are strongly affected by gravity drowning some lung regions while leaving others untreated. We present a novel method to improve alveolar availability by foaming surfactant prior to intratracheal administration. Unlike liquid, foam “defies gravity” and distributes homogeneously with doses >100 ml to each lung. Homogenous distribution of LIFT was demonstrated ex vivo in porcine lungs with striking quantitative differences between liquid instillations and LIFT. Next, we tested the safety and efficacy of foamed calf lung extracted surfactant (Infasurf) in an in vivo rat model of ARDS induced by repeated whole lung lavage. Following such preclinical experiments, we have developed a functional prototype of the delivery device and are conducting in vivo experiments in models of ARDS in adult pigs. Successful results in pigs will fast‐track the chances of deploying LIFT towards phase I clinical trials in severe COVID‐19 patients.02. Environmental Impacts of Inhalers‐ a Cradle to Grave ReviewHarish Kumar Jeswani, Research FellowSustainable Industrial Systems, Department of Chemical Engineering and Analytical Science,The University of Manchester, Manchester M13 9PL, UKPressurised metered dose inhalers (pMDIs) have played a vital role in the delivery of a number of medications through the inhalation route and continue to be the major method of choice for the delivery of drugs for treatment of asthma and chronic obstructive pulmonary disease (COPD) across the globe. Originally formulated using chlorofluorocarbon propellants, particularly CFC‐12 and CFC‐11, the adoption of the Montreal Protocol initiated an industry‐wide transition to hydrofluorocarbon (HFC) to reduce the impact on the ozone layer. However, HFC‐134a and HFC‐227ea propellants, which are currently used in these inhalers, have significantly high global warming potentials. To reduce the climate change impact of inhalers, several options are available to the industry, including alternative devices, such as dry powder inhalers and nebulisers and modification of pMDI devices to reduce the propellant quantity per dose. In addition, the manufacturers can use a different propellant with a lower global warming potential, such as HFC‐152a. This talk will focus on the cradle‐to‐grave life cycle environmental impacts of different types of inhaler and discuss various options to reduce their impacts.03. How to design materials for inhalation devices to be more sustainable?Beate Treffler11Avient Corporation, Performance Masterbatches (DE) GmbH, Kornkamp 50, D‐22926 Ahrensburg, GermanyIntroduction: Today, one unpleasant effect of the wide use of plastics is the increase in waste leading to marine littering, micro‐plastics... Although the Healthcare market is a minor contributor, first steps can be taken. Medical devices producers take actions to develop more sustainable solutions. What are benefits of using a bio‐based material rather than fossil‐fuel based plastics? What are the current solutions offered to reduce the carbon footprint of your pulmonary and nasal drug delivery devices?I / Carbon footprint reduction: Carbon footprint reduction can be achieved by using biobased polymers from renewable feedstock. These resins are displayed to consume CO2 and not generate CO2 (defined until the factory gate).II / Weight reduction via chemical foaming agents: Chemical foaming agents are substances which are activated at typical thermoplastic polymer processing temperatures, generating a foamed structure. A weight reduction of 20% can be achieved in parts with wall thicknesses of 2 mm.III / Outlook for “greener” inhalers: It is possible to design material solutions in compounded form where the fossil fuel‐based content is reduced to approximately 50%. Thus, carbon footprint is reduced by modifying these resins with a combination of raw materials such as: non fossil fuel‐based resins/additives, natural and synthetic mineral fillers.Conclusion: Healthcare plastic waste is less significant, but it cannot be ignored. Solutions exist to make your devices ‘greener’: from designing devices using bio‐based polymers or chemical foaming agents for light weighting to designing materials where fossil fuel‐based content is reduced. With these possibilities you can make inhalation devices more sustainable!04. The Application of Thermofluid Mechanic Modelling to the Development of Novel pMDI DevicesB.J.A. Thorne1, S.B. Kirton1, M. Knowles2, K.C. Lee3, D. Murnane1, A.I. Sapsford2, A.D. Wright21The University of Hertfordshire, College Lane, Hatfield, Hertfordshire, AL10 9AB2Bespak Europe Limited, Bergen Way, King's Lynn, Norfolk, PE30 2JJ3The University of East London, Docklands Campus, University Way, London, E16 2RDThe performance of highly effective new pressurised metered dose inhaler (pMDI) devices is strongly dependent on the complex interplay between the pMDI valve, actuator and the pharmaceutical formulation. This is a particularly important area of study with the transition to propellants with a low global warming potential (GWP). The present study developed a 1‐dimensional model to describe the aerosolisation behaviour of placebo formulations, based on previous studies by Harang (PhD Thesis 2013), Clark (PhD Thesis 1991) and Gavtash et al. (2017). The resulting model allows droplet sizes, liquid and gas exit velocities and dose discharge times to be estimated for placebo formulations with varying fractions of ethanol, whilst also taking into account the valve opening process. The pMDI metering chamber volume, valve orifice diameter, actuator sump volume and nozzle orifice diameter were varied as part of a Taguchi Orthogonal Array Design of Experiments study to ascertain the effects of these on device performance. A partial least squares regression (PLSR) study was then applied to the model results using the Unscrambler X. This identified the actuator orifice diameter and ethanol fraction as having the largest impact on predicted minimum pre‐flashing, post‐orifice droplet size where increasing either of these parameters led to an increase in this response. In the present study, this was found to range between 32.1 and 75.3 μm, where subsequent flashing has not yet been considered. The metering chamber and actuator sump volumes were found, statistically, to have a less significant effect, but still contributed to the variation observed.05. Systems Engineering Approaches to Device DevelopmentChris Hurlstone11Team Consulting, Abbey Barns, Duxford Road, Ickleton, Cambridgeshire, CB10 1SX, UKMention of “Systems Engineering” often brings to mind images of large scale products, such as radar installations, airliners or information networks. But Systems Engineering is just as applicable in the development of medical devices, large and small. Unfortunately, it is often ignored as not required for ‘device level’ development programmes, until its importance is realised at later stages of a project.By describing Systems Engineering as applied to a number of respiratory devices the paper will describe the advantages of applying these tools and techniques and describe potential pitfalls of not adopting a ‘system mindset.’Examples will include the breaking down of product requirements across individual sub‐systems, the need to establish a system integration plan together with robust system architecture prior to starting detailed design, and the use of model‐based engineering. By considering the product as a combination of discrete sub‐systems ‐ each specified, designed, iterated and verified separately prior to final integration ‐ the paper will illustrate how numerous technical challenges can be tackled and resolved in parallel. The importance of defining and managing effective interfaces, at device level and across the different disciplines involved, will also be highlighted.The objectives of the presentation will be to describe key elements of Systems Engineering approaches. It will also seek to illustrate how these approaches, tools and techniques can be applied to the development of inhalers. It will include some examples of what can happen if a systems engineering mindset is not applied during a development.06. 5‐Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogrammingDavid K. Lyon, Ph.D.Sr. Fellow, Global Research & DevelopmentLonza Pharma & BiotechBend, Oregon, USABackground: Epigenetic therapy through demethylation of 5‐methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5‐azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed.Methods: Pharmacokinetics of inhaled spray‐dried dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations.Results: Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (∼4‐h half‐life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumor burden 70–95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signaling and immune pathways.Conclusions: These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival.07. Pseudomonas Phage Cocktail Powders for Respiratory InfectionsMengyu Li1, Rachel Yoon Kyung Chang1 and Hak‐Kim Chan11Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.Respiratory infections caused by Pseudomonas aeruginosa are highly problematic due to intrinsic and acquired resistance to multiple antibiotics. Inhaled phage therapy is reconsidered as a promising supplement to antibiotics. Since phages are specific to the bacterial hosts, cocktails containing multiple types of phages are used to maximize the therapeutic outcome by broadening the host range. Inhalation dry powders provide a fast and convenient way to administer therapeutic agents directly to the lungs. This study aimed to produce phage cocktail powders for treatment of bacterial infections caused by P. aeruginosa. Spray‐drying was used to produce a three‐phage cocktail formulation targeting specific bacterial hosts. The formulation contained PEV20 and PEV1 (both long‐tailed myovirus phages), PEV2 (a short‐tailed podovirus phage), with leucine (20 wt. %) and lactose (80 wt.%) as excipients. The phages were reasonably robust to spray‐drying, showing a titre reduction of 0.11‐1.3 logs in the cocktail powder. The powder contained mostly small, spherical amorphous particles (volume median diameter of 1.9 μm) with weak crystallinity due to leucine as shown by the X‐ray diffraction. Dispersion of the powder using the high‐ and low‐resistance Osmohalers produced fine particle fraction (wt. % of particles <5 μm in the aerosols related to the loaded dose) values of 62.7 ± 2.1% and 45.4 ± 0.27% at 60 and 100 L/min, respectively. To conclude, the inhalable cocktail formulation showed powder properties and in vitro phage activity suitable to combat drug resistant P. aeruginosa in respiratory infections.08. Development of airways protection against respiratory Nipah virus infection by inhalation of antiviral peptidesClaire Dumont1, Sandrine Le Guellec2,3, Maria Cabrera2, Mathieu Iampietro1, Marion Ferren1, Cyrille Mathieu1, Matteo Porotto4,5, Gilles Chantrel7, Anne Moscona4,5,6, Laurent Vecellio2 and Branka Horvat11Immunobiology of viral infections, International Center for Infectiology Research‐CIRI, INSERM U1111, CNRS UMR5308, University Lyon 1, ENS de Lyon, Lyon, France2INSERM U1100, CEPR, University of Tours, Tours, France3DTF‐Aerodrug, Aerosoltherapy R&D department of DTFmedical, Faculty of Medicine, Tours, France4Center for Host‐Pathogen Interaction, Columbia University Medical Center, New York, USA5Department of Pediatrics, Columbia University Medical Center, New York, USA6Departments of Pediatrics, Microbiology & Immunology, and Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, 10032, USA7DTF medical, Saint Etienne, France.Introduction: Nipah virus (NiV) is a recently emerged zoonotic paramyxovirus, capable of inter‐human transmission and listed by WHO among the top eight emerging pathogens, based on the probability of causing severe outbreaks and a pandemic potential. In humans, NiV induces acute respiratory distress and encephalitis with a lethality of 40‐100%. A novel antiviral approach, based on peptides which interfere with the fusion of NiV with host cells has been recently developed.Research hypothesis: The project aims to develop a new approach to administer aerosolized peptides capable of inhibiting respiratory NiV infection, which may be applied to the other respiratory viruses using similar fusion mechanism for viral entry.Methods: We have developed an inhalation strategy using nebulized antiviral peptide in African Green Monkey (AGM), an animal model shown to well reproduce human NiV infection.Results and discussion: A customized nebuliser with a specific mesh size and interface to produce an aerosol of peptides while ensuring the upkeep of >90% of antiviral activity after nebulisation was assessed. Lung deposition was measured by in vivo scintigraphy (8‐16% in terms of nebulizer charge). Toxicology analysis in AGM demonstrated the absence of adverse lung findings from nebulised peptides after several consecutive administrations of 10 min. Immunofluorescence assays, using peptide specific antibodies on lung slices, revealed the presence of peptides along the respiratory tract 24 h after administration.Conclusion: Developed nebulisers are now ready for the first proof‐of‐concept study with the infectious NiV in a Biosafety level 4 laboratory. The results may open new perspectives for antiviral prevention against respiratory viruses and the strategy could be further extended to the ongoing SARS‐CoV‐2 outbreak (funded by DGA‐ANR‐Astrid‐Maturation).09. Engineering of inhalable microparticles containing terbinafine for management of pulmonary fungal infectionsKhaled Almansour1, Iman M. Alfagih2, Tariq J. Almutairi1, Rakan F. Alshammari1, Raisuddin Ali2, Turki Al Hagbani1 and Mustafa M.A. Elsayed1,31Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, Saudi Arabia2Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia3Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptTerbinafine is a broad‐spectrum antifungal agent with potential therapeutic value in management of pulmonary aspergillosis. The aim of this work was to engineer a dry powder inhalation formulation of terbinafine hydrochloride by nano spray drying. A factorial experimental design was constructed to study factors influencing characteristics of formulations prepared by nano spray drying. The experimental design involved two excipients (mannitol and lactose), different spray solvents (hydroethanolic and aqueous), different spray nozzles, and different drying gas inlet temperatures. The nano spray drying products were characterized mainly in terms of the yield, the crystallinity using differential scanning calorimetry, the disintegration/dissolution behaviour in a bronchial/alveolar fluid surrogate, and the aerodynamic performance using a Next Generation Impactor with Cyclohaler® as an inhalation device at 100 L/min. Factors influencing characteristics of nano spray drying products were identified. The influence of the spray solvent was most interesting: a spray solvent composed of 50.5 % w/w ethanol in water was found, compared to water, to result in smaller particles with up to 3.5‐fold higher respirability, i.e. higher fine particle fractions. The influence is attributed to the dependence of the size of spray droplets generated by the vibrating‐mesh atomizer on the spray solution viscosity. The formulations exhibited partial (< 40 %) drug dissolution within 2 minutes of dispersion in a bronchial/alveolar fluid surrogate. Undissolved drug particles were smaller than 160 nm in diameter, suggesting they have potential to avoid clearance by alveolar macrophages and mucociliary escalation and to thus provide prolonged local action.10. Development of Inhalable Powder Formulation of Broad‐Spectrum Antiviral Agent for Respiratory Viral InfectionsQiuying Liao1, Han Cong SEOW1, Shuofeng YUAN2, and Jenny K.W. LAM11Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong2Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong KongIn response to emerging and re‐emerging respiratory viral infections with high morbidity and mortality such as Coronavirus Disease 2019 (COVID‐19), Middle East respiratory syndrome coronavirus (MERS‐CoV), and influenza, early administration of broad‐spectrum antivirals can facilitate pandemic control and improve patient outcomes. This provides empiric therapeutic options during the time‐lag for developing specific drug/vaccine. AM80 (tamibarotene), an orally active retinoid, was demonstrated with broad‐spectrum antiviral efficacy in a recent study. To maximise antiviral efficacy in respiratory tract, an inhalable powder formulation of AM80 was developed by spray freeze drying (SFD) technology with hydroxypropyl‐b‐cyclodextrin (HPbCD) as solubiliser. The formulation showed good aerosol performance, as evaluated by Next Generation Impactor, with a fine particle fraction of 65.1 ± 7.9% and an emitted fraction of 95.1 ± 1.7%. The sublimation of solvent crystal led to the formation of porous particles, which was visualised by scanning electron microscopy. In contrast to the slow‐dissolving unformulated AM80, the SFD AM80 powder displayed a burst‐release dissolution, which is postulated to be a combined result of enhanced solubility by HPbCD and increased surface area of porous structure. The in vivo pharmacokinetics of the SFD AM80 powder after intratracheal administration was investigated in mice. With the same dose given, inhaled AM80 powder resulted in higher bioavailability in both lungs and plasma than intraperitoneally injected unformulated AM80 in 0.1% DMSO solution. This study demonstrated a strategy to develop an inhaled formulation for a broad‐spectrum antiviral agent, which could be a strong candidate in clinical applications for various respiratory viral infections.11. High dose antibiotic therapy – Sweeper crystals to enhance fine particle dose in the Twister deviceChristian Etschmann, Regina ScherließDepartment of Pharmaceutics and Biopharmaceutics, Kiel University Grasweg 9a, 24118 Kiel, GermanyIntroduction: For local treatment of lung infections, high doses of antibiotics can be administered by inhalation as dry powder softpellets. However, when large doses are needed, a lot of the active pharmaceutical ingredient (API) is retained in the inhaler. This study evaluates the applicability of the sweeper crystal concept as used in the Twincer (University of Groningen) for a capsule inhaler.Methods:Softpellet production: Micronised rifampicin was agglomerated to softpellets by a vibration process (500 μm sieved starting agglomerates, sinus wave shape, 100 Hz frequency, 0.7 mm amplitude).Impaction analysis: Impaction analysis was performed with the Fast Screening Impactor (Copley Scientific) utilising the Twister (Aptar Pharma) device. Capsules were filled with 20 mg ±0.5 mg softpellets and 10 mg ±0.5 mg lactose crystals (Inhalac 70, x50 215 μm, or Inhalac 120, x50 129 μm, both Meggle). Reported data is average of three runs.Results and Conclusion: Loading the Twister with three capsules, each filled with 20 mg softpellets, generated an FPD of 20 mg and an emitted dose of 65%. Filling the capsules with additional 10 mg of InhaLac 70 significantly increased the FPD to 24 mg and the emitted dose to 74% (no statistical difference using InhaLac 120). The sweeper crystal concept can be applied to the Twister. During inhalation, the large InhaLac 70 particles get to the inner wall by centrifugal forces and detach adhering API. It is possible to maximise emitted dose using sweeper crystals, which is a typical issue in high dose delivery.12. Powder Microstructural Analysis for Inhalation BlendsProfessor Darragh MurnaneUniversity of Hertfordshire, UKSummary: Formulation microstructure has emerged as an important topic of consideration for the demonstration of equivalence between different product batches or between branded and generic medicinal products. In the case of dry powder inhalation products, the formulation performance depends on the structuring of the component materials within the powder bed, because it is this structuring which determines the geometries of interparticulate cohesion forces, as well as the permeability of the powder bed to fluidizing airflow. Understanding the link between microstructure, processing, input material properties and product performance is crucial, but a central part of this is the microstructural characterisation. X‐ray computed tomography (XCT), a form of x‐ray microscopy (XRM), has emerged as invaluable, non‐destructive tool for the characterisation in materials science field as diverse as metallurgy to catalysis. XCT is well‐known in pharmaceutical sciences for its biological applications, but advances in x‐ray optical technologies has resulted in the availability of laboratory instruments with resolution scales suitable for the analysis of inhalation powders. In this lecture, the technology and application of three distinct XRM techniques will be introduced: X‐ray attenuation CT; phase‐contrast attenuation XCT; and diffraction contrast tomography. Specifically, the ability of XRM to provide microstructural insight at nano‐ and micro‐scales when assessing the distribution of active pharmaceutical ingredients within pharmaceutical blends will be presented. Additionally, the links between powder processing and powder microstructure will be discussed, highlighting the powerful ability of XRM as a non‐destructive technology to characterise particle and powder properties, that determine the interactions between formulation components.13. Data Science and AI in drug development– challenges and case studies from AstraZenecaAnders BrooDirector and Head of Data science and Modelling, Pharmaceutical Sciences R&D, AstraZenecaArtificial Intelligence (AI) is a very broad term, originally defined by Allan Turing in the early 1950's as “a machine that can perform tasks commonly being performed by intelligent beings”. AI is about the ability to reason, discover meaning, generalize, or learn from past experience. In the pharma industry we have for long time used computer models to learn from small datasets to predict what to do next in designing new active molecules, so called Machine Learning (ML) models. We have used advanced statistical analysis methods to interpret outcome from clinical trials and pre‐clinical testing. The advances of compute power, algorithm and access to large datasets has started a new wave of interest to the field of AI.In this talk I will review the external trends in AI/ML and how they have been adopted to the pharma industry. I will show a few use cases from AstraZeneca on how we have used AI and ML to accelerate our discovery and development programs. I will also discuss the challenges we have in creating the datasets needed for efficient implementation of AI empowered tools. I will also describe how we in Sweden have created a cross different industries, academia and the healthcare providers echo system for AI called “AI Innovation of Sweden” aimed to cross‐fertilize and increase innovation in the AI space.14. Improving dry powder inhaler performance: An integrated approachVishal Chaugule1, Larissa Gomes dos Reis2, David F. Fletcher3, Paul M. Young2, Daniela Traini2 and Julio Soria11Laboratory for Turbulence Research in Aerospace and Combustion (LTRAC), Department of Mechanical and Aerospace Engineering, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia2Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2037, Australia3School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, AustraliaAdvancement of dry powder inhalers (DPIs) is hindered by the limited understanding and control of de‐agglomeration mechanisms and flow characteristics, which affect aerosol performance. These complex and intertwined phenomena are contingent to device design, inhalation flow, and formulation properties. To study these processes, an integrated approach is presented, combining three complementary methods: in‐vitro deposition by cascade‐impactor, computational fluid dynamics (CFD), and particle image velocimetry (PIV).The impact of device design on its performance was assessed using 3D‐printed DPI models with modified tangential inlets and the addition of a grid. Aerosol performance was investigated via a cascade‐impactor (NGI‐Copley), using a 1% w/w beclomethasone dipropionate‐loaded lactose formulation, at 60 l/min. CFD was used to simulate the flow in the device and downstream region using a novel Scale‐Resolving‐Simulation approach to capture the turbulence structure and study particle behaviour (carrier and drug) via Lagrangian tracking. PIV measurements were performed using water‐based experiments under geometrically and dynamically similar conditions to DPIs operating in air.Inlets' modification did not affect fine particle dose assessed in‐vitro. The grid inclusion decreased throat deposition due to a straightened outflow without lateral spreading, as observed from the PIV, which also showed a high‐swirling and recirculating jet‐flow emerging from DPIs without the grid. The CFD results showed close agreement with PIV data, validating the simulations, and providing detailed information on the flow and particle‐dynamics.Overall, this work demonstrates the correlation of fluid‐ and particle‐dynamics with aerosol dispersion and particle deposition, within and from a DPI, that can be achieved.15. Impact of Layer Height on the Quality of DPI Prototypes Prepared by Masked Stereolithography 3D PrintingKai Berkenfeld1, Paul Bebernik1, Jakob Freidel1, Roman Groß1,3, Christoph Schulte3, Ameet Sule2, Sunita Sule2 and Alf Lamprecht11Department of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, GER2Inhalation Product Technology Centre, Presspart Manufacturing Ltd., H&T Presspart, Blackburn BB1 5RF, UK3Presspart GmbH & Co. KG, H&T Presspart, 34431 Marsberg, GERThe delivery of therapeutic aerosols via dry powder inhalation devices (DPI) is used for drug application via the lungs and the performance of the device used is an integral part of the performance of a given product. Typically, DPIs are manufactured through injection molding, but in DPI development, the use of rapid prototyping techniques is desirable. Recently, masked stereolithography (MSLA) 3D printing has become very affordable, making this technique an excellent candidate for rapid prototyping in this context. The aim of this study was to assess the applicability of MSLA 3D printing for DPI prototyping.A 3D representation of a commercial DPI (RS01 equivalent, DPIIM) was obtained by imaging the device with a micro computer‐tomographic system. Based on this, a printable 3D model was generated and 3D printed on a Prusa SL1 using Prusa tough resin at three different layer heights (LH) i.e. 25 (DPI3D25), 50 (DPI3D50), and 100 (DPI3D100) μm. All models were compared by full resolut

Background: Obstructive patients may benefit from nasal high-flow (NHF) therapy, but the use of pressurized metered-dose inhalers (pMDIs) has not been evaluated in this situation. Methods: Using an adult circuit and medium-sized cannula, we have tested different NHF rates, pMDI positions, breathing patterns, spacers, and spacer orientation. First, we evaluated albuterol delivery at the nasal cannula outlet. The second set of experiments made use of a nasopharyngeal cast to estimate the mass of albuterol potentially reaching the lungs. Albuterol was caught on filters placed at the cannula outlet and downstream of the nasal cast, and albuterol was quantified by spectrophotometry. Results: The highest amounts of albuterol delivered at the cannula outlet were observed with a 30 L/min flow rate (vs. 45 and 60 L/min) and placing the device close to the nasal cannula (in comparison with a position on the dry side of the humidification chamber). The use of a spacer was associated with higher delivery. The highest albuterol delivery was observed placing the spacer close to the nasal cannula, oriented for aerosol delivery following the gas flow and a 30 L/min NHF rate. Using this optimal setting, activating the pMDI at the beginning of inspiration (compared to expiration) increased albuterol delivery downstream of the nasopharyngeal cast. Whether in a quiet- or distress-breathing pattern, our measurements showed an amount of albuterol potentially delivered to the lungs exceeding 10% of the actuated dose in optimal conditions. Conclusions: The use of pMDIs is feasible to deliver albuterol within a NHF circuit. Using a spacer placed just upstream from the nasal cannulas, a low NHF rate and activating the pMDI at the beginning of inspiration was associated with drug delivery susceptible to induce bronchodilation, which will require to be tested in the clinical setting.

Introduction: Nipah virus (NiV) is a recently emerged zoonotic paramyxovirus, capable of inter-human transmission and listed byWHO among the top eight emerging pathogens, based on the probability of causing severe outbreaks and a pandemic potential. In humans, NiV induces acute respiratory distress and encephalitis with a lethality of 40-100%.Anovel antiviral approach, based on peptideswhich interferewith the fusion of NiV with host cells has been recently developed. Research hypothesis: The project aims to develop a new approach to administer aerosolized peptides capable of inhibiting respiratory NiV infection, which may be applied to the other respiratory viruses using similar fusion mechanism for viral entry. Methods: We have developed an inhalation strategy using nebulized antiviral peptide in African Green Monkey (AGM), an animal model shown to well reproduce human NiV infection. Results and discussion: A customized nebuliser with a specific mesh size and interface to produce an aerosol of peptides while ensuring the upkeep of >90% of antiviral activity after nebulisation was assessed. Lung deposition was measured by in vivo scintigraphy (8-16% in terms of nebulizer charge). Toxicology analysis in AGM demonstrated the absence of adverse lung findings from nebulised peptides after several consecutive administrations of 10 min. Immunofluorescence assays, using peptide specific antibodies on lung slices, revealed the presence of peptides along the respiratory tract 24 h after administration. Conclusion: Developed nebulisers are now ready for the first proof-of-concept study with the infectious NiV in a Biosafety level 4 laboratory. The results may open new perspectives for antiviral prevention against respiratory viruses and the strategy could be further extended to the ongoing SARS-CoV-2 outbreak (funded by DGAANR-Astrid-Maturation).

In patients with fibrotic pulmonary disease such as idiopathic pulmonary fibrosis (IPF), inhaled aerosols deposit mostly in the less affected region of the lungs, resulting in suboptimal pharmacokinetics of airway-delivered treatments. Refinement of aerosol delivery technique requires new models to simulate the major alterations of lung physiology associated with IPF, i.e., heterogeneously reduced lung compliance and increased airway caliber. A novel physical model of the respiratory system was constructed to simulate aerosol drug delivery in spontaneously breathing (negative pressure ventilation) IPF patients. The model comprises upper (Alberta ideal throat) and lower airway (plastic tubing) models and branches into two compartments (Michigan lung models) which differ in compliance and caliber of conducting airway. The model was able to reproduce the heterogeneous, compliance-dependent reduction in ventilation and aerosol penetration (using NaF as a model aerosol) seen in fibrotic lung regions in IPF. Of note, intrapulmonary percussive ventilation induced a 2-3-fold increase in aerosol penetration in the low-compliance/high airway caliber compartment of the model, demonstrating the responsiveness of the model to therapeutic intervention.

There is an absence of controlled clinical data showing bronchodilation effectiveness after nebulization via nasal high-flow therapy circuits.

Background: Albeit not recommended because of contradictory results, nebulized 3% hypertonic saline is widely used for treating acute viral bronchiolitis. Whether clinical differences may be attributed to the type of nebulizer used has never been studied. Objectives: By modifying the amount of salt deposited into the airways, the nebulizer characteristics might influence clinical response. Methods: A prospective, randomized, controlled trial included infants hospitalized in a French university hospital for a first episode of bronchiolitis. Each child received 6 nebulizations of 3% hypertonic saline during 48 h delivered with 1 of the 3 following nebulizers: 2 jet nebulizers delivering large or small particles, with a low aerosol output, and 1 mesh nebulizer delivering small particles, with a high aerosol output. The primary endpoint was the difference in the Wang score at 48 h. Results: Only 61 children of 168 were recruited before stopping this study because of severe adverse events (n = 4) or parental requests for discontinuation due to discomfort to their child during nebulization (n = 2). One minor adverse event was noted in 91.8% (n = 56/61) of children. A high aerosol output induced 75% of the severe adverse events; it was significantly associated with the nebulization-induced cough between 24 and 48 h (p = 0.036). Decreases in Wang scores were not significantly different between the groups at 48 h, 9 recoveries out of 10 being obtained with small particles. Conclusion: No beneficial effects and possibly severe adverse events are observed with 3% hypertonic saline in the treatment of bronchiolitis.

BACKGROUND:The delivery profile of Aztreonam lysine (AZLI) during mechanical ventilation (MV) is unknown. We evaluated the amount of AZLI drug delivered using an in vitro model of adult MV. METHODS:An adult lung model designed to mimic current clinical practice was used. Both nebulizers were placed before a Y-piece and 4 settings were tested: A) Aeroneb solo® [AS] with a t-piece; B) AS with the spacer; C) M-Neb® [MN] with a t-piece and D) MN with the spacer. Performance was evaluated in terms of: 1) Mass median aerodynamic diameter (MMAD); 2) Geometric standard deviation (GSD), 3) Fine particle dose (FPD), 4) Fine particle fraction (FPF), 5) Inhalable mass (IM), and 6) Recovery rate (RR). RESULTS:Both devices showed an adequate delivery of AZLI during MV, with MMAD between 2.4-2.5 µm and 87% of FPF. The FPD (38.8 and 31.7), IM (44.8 and 36.1) and RR (30 and 24) were similar for AS and MN respectively. Nebulizer aerosol delivery increased (50 and 70% respectively) for both nebulizers when using the spacer. CONCLUSION:Both AS and MN showed a good aerosol delivery profile for AZLI during in vitro mechanical ventilation. Better aerosol delivery performance was obtained using the spacer.

SummaryAerosol therapy in infants and toddlers is challenging. Nebulization within a nasal high flow (NHF) circuit is attractive. The aim of this study was to quantify aerosol lung deposition when combined with NHF as compared with standard practice. Lung doses were measured scintigraphically after nebulization with jet and mesh nebulizer placed within a NHF circuit in a spontaneously breathing non‐human primate model (macaque) and in the anatomical bench SAINT model, respectively representing a full‐term newborn and a 9‐month‐old toddler. In the SAINT model, lung depositions observed with the mesh nebulizer placed in the NHF circuit set at 2 and 4 L/min were 3.3% and 4.2% of the nebulizer charge, respectively, and similar to the 1.70% observed with the control standard facemask jet nebulization (6 L/min flow). In the macaque model, the depositions observed with the mesh nebulizer in the NHF circuit set at 2 and 4 L/min were 0.49% and 0.85%, respectively, also similar to the control measurement (0.71%). Mesh nebulization within a NHF circuit set at 8 L/min and jet nebulization either within a NHF circuit or placed on top of the cannula (NHF set at 2 L/min; total flow of 8 L/min), resulted in a significantly lower lung depositions. Mesh nebulization within a NHF circuit delivering up to 4 L/min gas is likely to be at least as effective than jet nebulization with a facemask in infants and toddlers. Aerosol facemask placement on top of cannulas or jet nebulization within the NHF circuit may be less effective. Pediatr Pulmonol. 2017;52:337–344. © 2016 Wiley Periodicals, Inc.