Abstracts (DOI: jamp.2021.ab01.abstracts)

01. Surfactant Foam Therapy For Severe Covid‐19 Patients With Acute Respiratory Distress Syndrome (ARDS)

Josué Sznitman, Associate Professor

Director, Norman Seiden Graduate Program in Nanoscience & Nanotechnology

Associate Chair for Undergraduate Studies

Department of Biomedical Engineering

Israel Institute of Technology

The 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 Review

Harish Kumar Jeswani, Research Fellow

Sustainable Industrial Systems, Department of Chemical Engineering and Analytical Science,

The University of Manchester, Manchester M13 9PL, UK

Pressurised 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 Treffler¹

¹Avient Corporation, Performance Masterbatches (DE) GmbH, Kornkamp 50, D‐22926 Ahrensburg, Germany

Introduction: 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 Devices

B.J.A. Thorne¹, S.B. Kirton¹, M. Knowles², K.C. Lee³, D. Murnane¹, A.I. Sapsford², A.D. Wright²

¹The University of Hertfordshire, College Lane, Hatfield, Hertfordshire, AL10 9AB

²Bespak Europe Limited, Bergen Way, King's Lynn, Norfolk, PE30 2JJ

³The University of East London, Docklands Campus, University Way, London, E16 2RD

The 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 Development

Chris Hurlstone¹

¹Team Consulting, Abbey Barns, Duxford Road, Ickleton, Cambridgeshire, CB10 1SX, UK

Mention 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 reprogramming

David K. Lyon, Ph.D.

Sr. Fellow, Global Research & Development

Lonza Pharma & Biotech

Bend, Oregon, USA

Background: 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 Infections

Mengyu Li¹, Rachel Yoon Kyung Chang¹ and Hak‐Kim Chan¹

¹Advanced 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 peptides

Claire Dumont¹, Sandrine Le Guellec^2,3, Maria Cabrera², Mathieu Iampietro¹, Marion Ferren¹, Cyrille Mathieu¹, Matteo Porotto^4,5, Gilles Chantrel⁷, Anne Moscona^4,5,6, Laurent Vecellio² and Branka Horvat¹

¹Immunobiology of viral infections, International Center for Infectiology Research‐CIRI, INSERM U1111, CNRS UMR5308, University Lyon 1, ENS de Lyon, Lyon, France

²INSERM U1100, CEPR, University of Tours, Tours, France

³DTF‐Aerodrug, Aerosoltherapy R&D department of DTFmedical, Faculty of Medicine, Tours, France

⁴Center for Host‐Pathogen Interaction, Columbia University Medical Center, New York, USA

⁵Department of Pediatrics, Columbia University Medical Center, New York, USA

⁶Departments of Pediatrics, Microbiology & Immunology, and Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, 10032, USA

⁷DTF 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 infections

Khaled Almansour¹, Iman M. Alfagih², Tariq J. Almutairi¹, Rakan F. Alshammari¹, Raisuddin Ali², Turki Al Hagbani¹ and Mustafa M.A. Elsayed^1,3

¹Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, Saudi Arabia

²Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

³Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Terbinafine 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 Infections

Qiuying Liao¹, Han Cong SEOW¹, Shuofeng YUAN², and Jenny K.W. LAM¹

¹Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong

²Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong

In 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 device

Christian Etschmann, Regina Scherließ

Department of Pharmaceutics and Biopharmaceutics, Kiel University Grasweg 9a, 24118 Kiel, Germany

Introduction: 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 Blends

Professor Darragh Murnane

University of Hertfordshire, UK

Summary: 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 AstraZeneca

Anders Broo

Director and Head of Data science and Modelling, Pharmaceutical Sciences R&D, AstraZeneca

Artificial 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 approach

Vishal Chaugule¹, Larissa Gomes dos Reis², David F. Fletcher³, Paul M. Young², Daniela Traini² and Julio Soria¹

¹Laboratory for Turbulence Research in Aerospace and Combustion (LTRAC), Department of Mechanical and Aerospace Engineering, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia

²Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2037, Australia

³School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia

Advancement 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 Printing

Kai Berkenfeld¹, Paul Bebernik¹, Jakob Freidel¹, Roman Groß^1,3, Christoph Schulte³, Ameet Sule², Sunita Sule² and Alf Lamprecht¹

¹Department of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, GER

²Inhalation Product Technology Centre, Presspart Manufacturing Ltd., H&T Presspart, Blackburn BB1 5RF, UK

³Presspart GmbH & Co. KG, H&T Presspart, 34431 Marsberg, GER

The 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, DPI_IM) 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 (DPI_3D25), 50 (DPI_3D50), and 100 (DPI_3D100) μm. All models were compared by full resolution aerosol analysis using the Next Generation Impactor, analyzing a spray dried formulation of rifampicin.

Cascade impactor analyses showed relative depositions in the DPI of 0.058 ± 0.006, 0.036 ± 0.003, 0.049 ± 0.003, and 0.066 ± 0.008 and fine particle fractions (cumulative powder mass <5μm) of 44.5 ± 3.0%, 48.0 ± 2.7%, 48.4 ± 2.5%, and 37.5 ± 3.4% for the DPI_IM, DPI_3D25, DPI_3D50, and DPI_3D100, respectively. Differences in deposition and performance can be attributed to the different accuracies of the models.

MSLA 3D printing was found to be a viable option for rapid prototyping of DPI devices, if suitable printing parameters (i.e. LH) are selected.

16. Konjac glucomannan microcarriers and macrophages – a promising interaction in lung diseases treatment

Filipa Guerreiro¹, Ana M. Rosa da Costa² and Ana Grenha¹

¹Centre for Marine Sciences, Drug Delivery Laboratory, Faculty of Sciences and Technology, Universidade do Algarve, Campus de Gambelas, Faro, 8005‐139, Portugal

²Algarve Chemistry Research Centre and Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, Universidade do Algarve, Campus de Gambelas, Faro, 8005‐139, Portugal

While pulmonary drug delivery requires engineering suitable delivery systems, alveolar targeting of drugs has been studied in recent years as an approach to treat some lung diseases. This work explores the potential of konjac glucomannan (KGM) as matrix material of microcarriers targeted to alveolar macrophages, relevant actors in diseases such as tuberculosis, focusing on the analysis of particle‐macrophage interaction. Mannose units composing KGM potentially improve this interaction, fostering the phagocytosis of drug‐loaded particles by pathogen‐infected macrophages. Spherical convoluted KGM microcarriers with geometric diameter around 3 μm were produced by spray‐drying, exhibiting suitable shape and size to be internalised by macrophages. KGM microparticles‐macrophage interaction was analysed by flow cytometry after 2h exposure of macrophage‐like THP‐1 cells to fluorescently‐labelled KGM microparticles. Approximately 100% of the sampled cells were shown to phagocytose KGM particles, which was significantly higher compared with the uptake of poly(vinyl alcohol) microcarriers (62%) of similar characteristics, used as control. Furthermore, polymer‐macrophage interaction (24h) was found to not induce an inflammatory response, as the release of tumour necrosis factor‐α and interleukin‐8 by macrophage‐like THP‐1 cells was significantly lower than that induced upon exposure to lipopolysaccharide. Finally, KGM microparticles at concentrations up to 1 mg/mL demonstrated absence of toxicity in macrophage‐like THP‐1 cells, inducing cell viability of 77‐86% (MTT assay) and minimal release of LDH comparing with the positive control (Triton X‐100). KGM thus appears to be a promising material for alveolar macrophage targeting, potentiating the interaction with these cells through phagocytosis without causing any harm.

17. Inhalable Microparticles Embedding Therapeutic Calcium Phosphate Nanoparticles for Heart Targeting

Eride Quarta^{1 2}, Paolo Colombo², Alessio Alogna³, Daniele Catalucci⁴, Claudio De Luca⁵, Michele Iafisco⁶, Fabio Sonvico², Teresa D. Tetley⁷, Raphaele Audibert ⁸, Vecellio Laurent ⁸, Francesca Buttini²

¹Food and Drug Department, University of Parma, 43124, Parma, Italy

²PlumeStars SRL, 43125, Parma, Italy

³Medizinische Klinik m. S. Kardiologie Charite, Berlin 13353, Germany

⁴Institute of Genetics and Biomedical Research, Milan Unit, National Research Council, Milan 20139, Italy

⁵Fin‐Ceramica Faenza SPA, 48018 Faenza, Italy

⁶Institute of Science and Technology for Ceramics, CNR, 48018 Faenza, Italy

⁷Lung Cell Biology, Airways Disease, National Heart and Lung Institute, Imperial College London, United Kingdom, SW3 6LY

⁸Nemera, La Verpilliere, France

Introduction: The aim of this work was to develop an innovative nanomedicine consisting in highly respirable microparticulate dry powder (dpCaPs) able to embed and release calcium phosphate nanoparticles (CaPs) loaded with Mimetic Peptide (11 aminoacids, 1326 Da), a therapeutic substance selectively targeting the cytosolic Ca_vb2 chaperon subunit of the cardiac L‐type Calcium Channel Complex (LTCC) restoring cardiac function. The embedded therapeutic nanoparticles, released in deep lung by carrier dissolution upon inhalation, can target the hearth by translocation to pulmonary vein blood.

Methods: Spray drying (SD) technique was employed to transform the nanoparticle dispersion in inhalable microparticles. Mannitol as water soluble carrier excipient, was used for microparticle construction. In vitro respirability was assessed in vitro using medium resistance prototype inhaler device from Nemera. Immortalized human alveolar cells TT1 and TT2 and macrophages were exposed to increasing concentrations of microparticles for toxicology investigation. The dry powder formulation was administered in vivo to heart diseased mini pigs.

Results: The powder having the ratio CaPs/mannitol 1:4 exhibited the best aerodynamic performance for CaP lung deposition and release (CaPs size 85.4 nm). The EF was >92% and the FPF >80%. Microparticles had a spherical shape, rough surface and very low density. The high extra‐FPF (<2μm) favours CaP deep lung deposition and translocation to the heart. In vitro evaluation found that dpCaPs were not toxic for human lung alveolar epithelial cells and macrophages and did not induce cytokine release. Finally, the dpCaPs pulmonary administered to diseased mini pigs were able to restore normal heart contractility.

Conclusion: Inhalation of the highly respirable microparticles embedding CaP nanoparticles loaded with Mimetic Peptide were. effective in delivering mimetic peptide from lung to heart.

18. Benchmarking of particle engineering technologies for nasal powder manufacture

Patrícia Henriques^1,2, João Marques³, Maria Paisana³, Ana Fortuna^2,4 and Slavomíra Doktorovová ¹

¹Drug Product Development, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal

²Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000‐548 Coimbra, Portugal

³Analytical Development, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal

⁴CIBIT/ICNAS – Coimbra Institute for Biomedical Imaging and Translational Research of University of Coimbra, University of Coimbra, Edifício do ICNAS, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000‐548, Coimbra, Portugal

Powder formulations of a drug and mucoadhesive polymer have increased residence time in the nasal cavity and can be manufactured by blending, spray‐drying or agglomeration of primary particles into chimeral agglomerates (CA). While spray‐drying allows particle size control and generation of amorphous solid dispersions (ASD), blending is simpler and CA should allow faster dissolution after breakup into smaller particles. Our research hypothesis is whether spray‐dried microparticles (SDM) have significant advantages over blends and CA for a poorly soluble drug (piroxicam).

ASD screening was performed by differential scanning calorimetry and the solvent shift method. SDM and CA primary particles were prepared by spray‐drying, CA by sieve shaker, and corresponding blends by Turbula. Formulations were characterized regarding particle size distribution (PSD), morphology, solid state and water content. In vitro performance was assessed by emitted dose, aerodynamic profile, dissolution (paddle‐over‐disk) and real‐time PSD monitoring (RTPM) in simulated nasal fluid.

Formulations with 20% drug load and PVP/VA or HPMC E3 were selected. CA presented the lowest (∼50%) and most variable (standard deviation >30%) emitted doses. All formulations presented a very high fraction potentially retained in the nasal cavity (<95%). Dissolution testing revealed poor performance of blends and HPMC CA, possibly due to the crystalline content (confirmed by XRPD), and higher performance for SDM and PVPVA CA. RTPM showed prolonged deagglomeration times for PVPVA CA.

SDM provided advantages over CA and blends, which presented challenges on emitted dose and dissolution performance. Spray‐drying generates particles with more predictable performance and highly suitable profile for nasal delivery.

19. Laboratory Study to Evaluate a Pressurized Metered Dose Inhaler with Valved Holding Chamber (pMDI + VHC) Use Scenario in COVID‐19 Situation where pMDIs in Short Supply

Jason A. Suggett¹, Mark W. Nagel¹ and Jolyon P. Mitchell²

¹Trudell Medical International, 725 Baransway Drive, London, Ontario, N65 5G4, Canada

²Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Rd., London, Ontario, N6H 2R1, Canada

Patients infected with COVID‐19 and admitted to hospital often require inhaled bronchodilator therapy to manage breathlessness. US hospitals are considering optimal ways to deliver such medication with pMDIs in short supply; the inhaler segregated from the patient allowing for reuse elsewhere without risk of contamination. In response to questions from hospitals, this laboratory study was undertaken to assess a protocol being considered in a specific facility. The pMDI (Ventolin^†, 100 μg salbutamol) was actuated once into a VHC (AeroChamber Plus* Flow‐Vu*), simulating use at the medication cart in a hospital hallway. The inhaler was removed and the pMDI adapter port of the VHC covered. 10s elapsed before connecting the VHC mouthpiece to a vacuum via an electrostatic filter to collect the suspended aerosol at 28.3 L/min. This delay simulated the time to enter patient room, and have patient inhale the salbutamol. Two, three and four rapid actuations (1‐s apart) into the VHC prior to administration were also simulated. The mass of salbutamol was determined by HPLC‐spectrophotometry. Salbutamol recovered (per actuation) from the filter for one to four actuations was 18 ± 7μg; 13 ± 1μg; 6 ± 1μg; and 5 ± 1μg respectively, confirming that the per‐label practice of actuating and inhaling one puff at a time is the most efficient delivery method. For this specific and off label delivery scenario though, the maximum amount delivered as a single dose was achieved following two rapid actuations and as such can be considered optimal. Less than, or more than two actuations resulted in lower total delivery of salbutamol.

20. High‐fidelity simulations of multi‐component pressurised metered‐dose inhaler sprays

Daniel J Duke¹, David P Schmidt²

¹Laboratory for Turbulence Research in Aerospace & Combustion (LTRAC)

Department of Mechanical & Aerospace Engineering

Monash University, Clayton, Victoria 3800, Australia

²Department of Mechanical & Industrial Engineering

University of Massachusetts, Amherst MA 01003, USA

Accurate predictions of drug delivery from pressurised‐metered dose inhalers (pMDI) require a detailed understanding of the formulation's state when it leaves the nozzle. This is difficult to experimentally determine, but is important as it sets the initial conditions for the formation of inhaled droplets and particles. The aim of this study is to develop an improved computational model to predict the initial state of the droplets produced by pMDIs. The flow inside a pMDI is complex and unsteady. Most existing models ignore the unsteady turbulent flow inside the device and the effects of the internal geometry. Most models also assume that the propellant state is at thermodynamic equilibrium or in a fixed state, while in reality an intermediate state is likely. We present a novel computational framework for multicomponent pMDI formulations that simultaneously addresses all these phenomena. A homogeneous relaxation model allows the formulation to relax toward thermodynamic equilibrium over an empirically determined time scale. Our model assumes that the liquid and vapour are well mixed within each computational cell, and a population balance model is used to simulate droplet formation. Interaction of the formulation with the ambient air is also considered. Results for placebo P‐134a and P‐134a‐ethanol solutions are shown and compared favourably with optical, X‐ray and Malvern measurements of sprays from a conventional Bespak actuator. The model allows us to determine droplet properties (initial D₃₂, temperature and density) and predict the likelihood of water adsorption into the primary droplets due to entrainment of the warmer, humid ambient air.

21. PMDI leakage and ingress algorithm for new lower global warming propellants

William Treneman¹, Mark Knowles²

¹UPC Cambridge Limited, Unit 23, Park Farm Business Park, Bury St Edmunds, IP28 6TS UK

²Bespak Europe Limited, Bergen way, King's Lynn, PE30 2JJ UK

22. Predicting pMDI formulation thermophysical properties using activity coefficient models

Joseph Camm¹, Hendrik Versteeg²

¹School of Engineering, Technology and Design, Canterbury Christ Church University, North Holmes Road, Canterbury, Kent, CT1 1QU, UK

²Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough, Leicestershire, LE11 3TU, UK

The Kigali amendment to Montreal protocol sets the timetable for phasing out of pMDI propellants HFA134a and HFA227ea, creating a requirement for green propellants to take their place. To assist this transition, accurate prediction of thermophysical properties that control aerosol generation of new formulations is crucial. A relevant challenge is how to predict property data such as saturated vapour pressure, surface tension and viscosity of propellant/excipient/drug mixtures using the smallest possible programme of physical testing. It is proposed to use a thermodynamic framework based on activity coefficients to model intermolecular forces between constituents, which are known to control multi‐component thermophysical property behaviour. It is proposed to use the UNIFAC method, which is based on detailed physical understanding of molecular functional groups and their interactions, with the ability to capture azeotropic behaviour. Surface tension, viscosity and vapour pressure measurements of mixtures of HFA134a with ethanol at 20°C have been studied to validate the technique.

Utilizing UNIFAC parameter fitting to the experimental dataset with non‐linear least‐squares optimization, a root mean square deviation (RMSD) of 7% in predicted surface tension, 6% in predicted viscosity and 2% in predicted vapour pressure was obtained. Previously unavailable UNIFAC interaction parameters for HFA‐alcohol mixtures were created.

The capability is highly versatile, accepting various thermophysical property data and giving good agreement with measured values for existing formulation mixtures. The framework can be readily applied to mixtures of green propellants such as HFA152a to extend experimental data when available and support insights into thermophysical properties and aerosol generation.

23. A Dispersible Salbutamol Sulphate Tablet for an Environmentally Sustainable HFC 152a Propellant

Rachael Kay¹, Cuong Tran¹ and Ségolène Sarrailh²

¹i2c Pharma Services, Cardiff Medicentre, Cardiff, CF14 4UJ, UK.

²Aptar Pharma, Route des Falaises, 27100 Le Vaudreuil, France.

Introduction: The switch from hydrofluoroalkanes HFA 134a and 227 to environmentally sustainable HFC 152a presents ongoing challenges for those involved in the manufacture of pressurised metered dose inhalers (pMDIs). Respitab is a propellant dispersible tablet technology designed to overcome manufacturing and formulation challenges such as drug loss and suspension homogeneity and delivered dose uniformity respectively.

Research Hypothesis: Respitab pMDI technology is effectual for salbutamol sulphate (SS) in HFC 152a.

Methods: A powder mixture containing micronized SS with excipients menthol and lactose was blended by low shear mixing, followed by analysis of SS for content uniformity. 100 mg tablets, each sufficient for delivering 200 doses of SS were manufactured using a single punch tablet machine and dispensed into plain 19 mL canisters. After crimping with pMDI valves, HFC 152a was pressure filled. Standard testing of pMDI hardware and pharmaceutical characteristics were conducted and assessed over a period of months at accelerated stability storage conditions to determine quality aspects of the aerosol characteristics.

Results and Discussion: Data collected on Respitab SS pMDI using HFC 152a generated efficient aerosols during characterisation assessment, highlighted with high aerosol characteristics of fine particle fraction (FPF, %<5.0 μm) and uniformity of delivered dose. The use of standard hardware components showed limited effect on the physical stability of the pMDI formulation. Furthermore, aerosol assessment showed possible in‐vitro bioequivalence to marketed product with non‐optimised active pharmaceutical ingredient and excipients.

Conclusion: Respitab SS produces a consistent, uniform and high quality aerosol to assist with the switch to HFC 152a pMDIs.

24. Novel Flow Sensor and Electronic Platform for Smart Metered‐Dose Inhalers

Haykel Ben Jamaa ¹

¹Sensirion, Laubisruetistrasse 50, Staefa, 8712, Switzerland

The growing number of asthma cases is a source of concern due to the increasing burden on healthcare systems. Using metered‐dose inhalers (MDIs) promises many patients a controlled disease course. However, the efficacy of MDIs is limited by the patients' mistakes and the poor adherence to the therapy. Measuring the inhalation flow and the MDI firing timing while following the inspiratory parameters evolution over time provides a data basis to support improved drug delivery and adherence. Our development consists of enabling such measurements without affecting the inhaler performance nor the user experience. Inhalation flow measurement was realized by a miniaturized flow sensor measuring a defined by‐pass flow during inhalation. The system was enhanced by an accelerometer to detect the MDI fire timing and save power consumption. A Bluetooth module enables the data transfer to a mobile app. Tested with a spirometry syringe, the method showed an accurate flow measurement within 3% accuracy of the inhaled volume. Superimposing the drug firing with the flow measurement allows to quickly understand if the drug delivery and inhalation were timed correctly. Inhalation‐related indicators, including peak‐inspiratory flow, inspired volume and airway resistance were extracted and streamed them to a terminal that tracks the patient data and the disease course. In a nutshell, our inhaler clip‐on enables a reliable indication on the efficiency of the MDI usage and an accurate tracking of the inhalation indicators which allow to understand the course of the disease, improve the disease management and possibly prevent the next exacerbation

25. Exploring the potential and practicalities of semi‐automation in inhaler testing

Raquel Borda D'Agua¹, João Pereira¹, Anna Sipitanou² and Mark Copley²

¹R&D Analytical Development, Hovione FarmaCiencia S.A., Lisbon, Portugal

²Copley Scientific Ltd., Colwick Quays Business Park, Road No. 2, Nottingham, NG4 2JY, UK

The ability of cascade impactors to generate drug‐specific aerodynamic particle size distribution data (APSD) for orally inhaled products (OIPs) is central to formulation development and OIPs performance characterization. However, this requires a systematic and laborious drug recovery from each stage of the impactor and from the surfaces of other accessory components that complete the test set‐up. The semi‐automation of cascade impaction has an important role to play in improving the quality of OIP test data while simultaneously reducing health and safety concerns and improving analyst productivity. In this article a comparative study of manual and automated drug recovery was carried out by Hovione showing statistical equivalence between the methods and highlighting a 40% time savings in analyst bench work

26. Indian generic fluticasone/salmeterol dry powder inhalers – An aerodynamic comparison

Waiting Tai¹, Arvind B. Bhome², Patricia Tang¹, Hak‐Kim Chan¹ and Philip Chi Lip Kwok¹

¹Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia

²Proposed PGI, YCM Hospital, PCMC, Pimpri, Pune 411018, India

Introduction: Seretide^® Accuhaler^® is an originator dry powder inhaler containing fluticasone propionate and salmeterol xinafoate. Its generic products have been available in India for many years, but there is no published study comparing them with the originator product.

Aim: The objective of the current study is to compare the in vitro dispersion performance between Accuhaler and two Indian generic products, Esiflo^® Lupihaler^®, and Seroflo^® Revolizer^®.

Methods: Three inhalers of each product from the same batch were tested. Each inhaler underwent 10 dose uniformity runs and three aerodynamic particle size distribution tests in a randomized order. They were conducted with the Dose Uniformity Sampling Apparatus and the Next Generation Impactor, respectively. The drug deposits after dispersion were quantified using high performance liquid chromatography.

Results and discussion: Both generic products emitted 25‐30% less fluticasone propionate and 12‐16% less salmeterol xinafoate than the originator. The mass median aerodynamic diameter of fluticasone propionate was the smallest for Accuhaler (Accuhaler: 3.2 μm; Lupihaler: 4.5 μm; Revolizer: 4.0 μm; p < 0.05). Lupihaler had a significantly lower fine particle fraction <5 μm (Accuhaler: 19.6%; Revolizer: 18.6%; Lupihaler: 11.4%; p < 0.05). Interestingly, the mass median aerodynamic diameter and fine particle fraction of salmeterol xinafoate were similar between the products, at approximately 3.5 μm and 17%, respectively.

Conclusions: The two Indian generics were non‐equivalent to Accuhaler in vitro. Further in vivo studies are necessary to examine the clinical significance of the observed in vitro differences.

27. In vitro comparison of Indian generic fluticasone/salmeterol metered dose inhalers

Tsz Hei Kwong¹, Sarah Clymans¹, Arvind B. Bhome², Patricia Tang¹, Hak‐Kim Chan¹ and Philip Chi Lip Kwok¹

¹Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia

²Proposed PGI, YCM Hospital, PCMC, Pimpri, Pune 411018, India

Introduction: Seretide^® metered dose inhaler (MDI) is a combination product containing fluticasone propionate and salmeterol xinafoate. Although its generic products are commonly used in India, there is yet no published studies comparing them.

Aim: The objective of the study was to compare the in vitro aerosol performance between Seretide, Esiflo^®, and Seroflo^® MDIs.

Methods: Two inhalers of each product were examined. The life of each inhaler was divided into beginning, middle, and end phases. Ten dose uniformity and three aerodynamic particle size measurements were randomly performed on each inhaler in each phase. The tests were measured by the Dose Uniformity Sampling Apparatus and the Next Generation Impactor, respectively. The dispersed drugs were analysed by high performance liquid chromatography.

Results and discussion: There was no significant difference in the delivered dose uniformity and aerodynamic particle size distribution in the beginning phase. In the middle phase, the ex‐actuator fraction of both drugs from Seroflo was significantly higher than those from Seretide. Seroflo emitted 26‐27% more drugs than Seretide but both generic products produced significantly lower fine particle fractions <5 μm. Differences in aerosol performance were more pronounced in the end phase. The ex‐actuator fraction of fluticasone propionate for both generics were significantly lower (Seretide: 88.7%; Esiflo: 62.4%; Seroflo: 68%). Seroflo produced a significantly lower fine particle fraction <5 μm of salmeterol xinafoate (Seretide: 37.6%; Esiflo: 32.0%; Seroflo: 25.3%).

Conclusions: Both generics performed differently to Seretide. In vivo studies are required to test their bioequivalence and compare their therapeutic effects.

28. In‐Vitro Study of Inhaled Iloprost Delivery Using a Modified Deepro Mesh Nebulizer with Breath‐Actuated Function

Edgar Hernan Cuevas Brun, Ciou‐Ting Wang, Jui Shui Chen, Yuan‐Ming Hsu, Yi‐Ying Chen, Huei‐An Tsai and Ke‐Ting Chen

HCmed Innovations Co. Ltd., Rm. B, 10F., No.319, Sec.2, Dunhua S. Rd., Taipei City, 106, Taiwan

Introduction: Pulmonary hypertension is a life‐threatening disease characterized for the narrowing, blockage and destruction of blood vessels in the lungs. Inhaled iloprost has long been used to treat patients suffering from this condition. In order to ensure an effective treatment, breath‐actuated mesh nebulizers are considered as one of the most efficient delivering devices.

Objective: A non‐commercial modified Deepro mesh nebulizer with newly developed breath‐actuated function was used to nebulize iloprost and demonstrate its in‐vitro delivery effectiveness, which adds an alternative for delivering this formulation.

Methods: Iloprost (Ventavis®, Bayer) inhalation solution, 20 μg/2 mL, was tested. Particle size distribution parameters were analysed using a laser diffraction system (Spraytec, Malvern), obtaining volume median diameter (DV50), fine particle fraction (FPF), and geometric standard deviation (GSD). Delivered dose was collected using a breathing simulator (BRS2100, Copley Scientific) and analysed with HPLC. The nebulization time was also computed according to the breathing simulation.

Results: Filled volumes were adjusted to deliver doses of 2.5 and 5.0 μg at the mouthpiece. The mean values of triplicates for DV50, FPF, and GSD were 4.2 μm, 60%, and 1.74, respectively. The nebulization time to deliver 2.5 μg was 4.5 mins, while 5 μg was delivered in 5 mins.

Conclusion: The modified Deepro, equipped with a new pressure sensor for breath actuation, successfully nebulized iloprost within reasonable time to improve patient adherence. Particle size distribution characteristics were aligned with the requirements for proper lung deposition. This new technology could also be used to effectively deliver other types of formulations.

29. New in‐vitro bioequivalence approaches for generic nasal suspension products

Ethan Dixon‐Naish¹, Mark Parry¹, Mervin Ramjeeawon¹ and Jonathan Brazier¹

¹Intertek Melbourn, Ash House, Saxon Way, Melbourn, SG8 6DN, United Kingdom

Since early 2016 there has been significant focus from the generic pharmaceutical industry in pursuing an in‐vitro only approach to bioequivalence for ANDA submissions to the FDA for nasal spray products. This new approach has been triggered by the successful approval of a generic Nasonex® by Apotex Corp, demonstrating Q1/Q2/Q3 equivalence and thus provided a weight of evidence approach that bypassed the traditional in‐vivo clinical endpoint study requirement. Subsequently, the FDA have issued several sets of product specific guidance for nasal products, including the suggestion of an alternative approach to comparative clinical endpoint study.

The principle new technique used was the inclusion of a novel in‐vitro method that utilised Morphologically‐ Directed Raman Spectroscopy (MDRS) technology developed by Malvern Panalytical to chemically identify and characterise the particle size distribution of the API particles within the nasal spray formulation. This technique has opened the possibility to assess and characterise API particle sizes not only from the formulation excipients but also in the size range of <3μm enabling more detailed comparison of the key particle size metrics for test and reference products.

There are limitations to this technique once the size is less than 0.5um which is typically the case for some of the API material present. To address this, orthogonal techniques can be incorporated such as laser diffraction. While it lacks specificity to API particles, using the MDRS data to inform the laser diffraction data interpretation, allows a detailed characterisation of the API within complex formulation types.

30. The relevance of simulated lung fluid composition on the drug solubility and predicted in‐vivo performance of inhaled drug delivery

S. Radivojev¹, G. Luschin‐Ebengreuth¹, J.T. Pinto¹, A. Paudel^1,3 and E. Fröhlich^1,2

¹Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz, 8010, Austria

²Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, Graz, 8010, Austria

³Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, Graz, 8010, Austria

Physiologically based pharmacokinetic modelling (PBPK) can be used to predict the in‐vivo performance of drug products. Drug solubility is one of the crucial parameters for the construction of PBPK models. Currently, solubility of inhaled drugs is studied using simulated lung fluids (SLF) with a variety of compositions. In this work, we aimed to evaluate how different SLF components can impact drug solubility and predicted in‐vivo performance.

The solubility of salbutamol sulphate (SS; logP = 0.44) and budesonide (BUD; logP = 2.52) was investigated in phosphate buffer (PBS, pH 7.0) and SLFs composed of lipids (dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG) and cholesterol; 5.2mg/mL) and/or protein (albumin) in the concentration of 13 (alveolar fluid) or 29.1 mg/mL (bronchiolar fluid). The PBPK models of both drugs were developed using GastroPlus^TM and the impact of the resulting solubilities on the predicted PK parameters was examined.

SS presented similar high solubility values in all the tested media, leading to no differences being found in the predicted PK profiles. For BUD, a notable impact of the media components was observed and its solubility increased in the following order: PBS < PBS + albumin < PBS + lipids < PBS + lipids + albumin. The predicted c_max and t_max of BUD correlated better to the known in‐vivo values when the solubility in SLF + albumin was used, while in case of AUC_0‐∞, the lowest deviation was seen when PBS + lipids were used.

These observations showed the relevance of using biorelevant components to derive solubilities that will be subsequently used for PBPK modelling. Additionally, we highlighted how PBPK modelling can help the development of in‐vitro methods.

31. Comparative Assessment of Pharmacokinetics and Acute Lung Inflammation of Nicotine Dry Powder Aerosols Generated by PreciseInhale^®

Sharon Lam¹, Raymond Ng¹, Blaine Phillips¹, Tan Wei Teck¹, Charles Teng¹, Chris Wong¹, Romain Piault², Celine Merg², Davide Sciuscio², Julia Hoeng² and Patrick Vanscheeuwijck²

¹Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Rd, #02‐07, Singapore, 117406, Singapore

²PMI R&D, Philip Morris Products SA, Quai Jeanrenaud 3, Neuchâtel, 2000, Switzerland

Previous studies by our group investigated the pharmacokinetic (PK) profile of a spray‐dried nicotine dry powder (Batch A) delivered via the PreciseInhale^® dry powder aerosol exposure system. In a new study, Batch B was produced for evaluation against Batch A. Both batches comprised 2% nicotine, and other excipients. Specifically, this work aimed to compare the aerosol characteristics and nicotine PK profiles of both batches and investigate if these batches, when inhaled, would cause acute lung inflammation in rats. Both batches were delivered intratracheally at a dose of 0.1 mg nicotine/kg body weight by using the PreciseInhale^® dry powder aerosol exposure system. Plasma samples for nicotine/cotinine PK analyses were collected by repeated blood sampling via a tail‐vein catheter, while single bronchoalveolar lavage fluid (BALF) samples were collected at different time points post‐exposure for BALF differential cell counting using flow cytometry and inflammatory protein measurements using Luminex^®.

Briefly, both batches showed consistent aerosol yields, had similar mass median aerodynamic diameters and geometric standard deviations (approximately 4 μm and 1.8, respectively), and were delivered within short exposure durations (approximately 3 min per animal to achieve the target dose). It was further observed that both batches showed similar nicotine and cotinine PK profiles and did not cause significant lung inflammation up to 24 h post‐exposure. Based on these results, it can be concluded that the two batches of nicotine dry powder were comparable in terms of aerosol characteristics and nicotine PK profiles, and did not cause significant lung inflammation in rats.

32. In silico and in vitro aerodynamic profile of chitosan/thiolated chitosan and hyaluronic acid hybrid nanoplex based DPIs for tuberculosis

Mahwash Mukhtar¹ and Rita Ambrus¹

¹Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös utca 6, Szeged, H‐6720, Hungary

Tuberculosis (TB) is the infectious disease with highest mortality in the recent times. Conventional dosage forms failed in treatment of TB because of rapid drug clearance and low bioavailability at the target site. Recently, dry powder inhalers (DPIs) have been in focus as they deliver the high concentration of drug directly to the lungs. However, because of low potency antitubercular agents are administered at high doses orally to reach lungs, thereby producing toxicity. To overcome the challenges, nanotechnology based DPIs are being exploited to target the site of action. The rationale of the active targeted delivery in TB is the controlled release of drug in the alveolar macrophages (where the causative agent resides) while minimizing the drug associated toxicity to the healthy pulmonary epithelium. In this study, biocompatible polymers, chitosan (CS)/ thiolated chitosan (TC) and hyaluronic acid (HA), able to target the surface receptors of alveolar macrophage were employed to develop the hybrid nanoplexes by a cost‐effective ionic gelation method and later freeze‐dried to obtain nano‐DPIs. The in‐vitro investigation techniques, FTIR, XRPD and DSC revealed the physicochemical compatibility of components of nanoplexes. Moreover, in‐vitro release profile of isoniazid loaded corresponded nanoplexes was in correspondence to the permeation studies in terms of the pattern of drug content dissolved over time. An in‐vitro aerodynamic study found the fine particle fraction (FPF) <3 μm to be 53.11 % and 46.86 % for TC/HA and CS/HA nanoplexes respectively indicating the high drug deposition in the lower areas of the lungs, particularly in the alveolar region. In‐silico deposition profile was corelated to the aforementioned results. Additionally, the cell viability of A549 cell line was found to be more than 90 % for the nano DPIs. Altogether, the results were optimistic for the delivery of drug in TB.

33. Spray‐dried composite formulation for lung sustained release

Beatriz Noriega Fernandes¹, Bernadett Vlocskó¹, Ruben Chaves², Maria Paisana² and João Henriques¹

¹Drug Product Development, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal

² Analytical Development, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal

Although drug delivery to the lung presents several advantages, its therapeutic efficiency is limited by a rapid clearance, thus the development of sustained release formulations suitable for lung delivery has been studied intensively in recent years. The main goal of the present work was to assess the impact of encapsulating a model drug (fluticasone propionate, FP) in 1,2‐distearoyl‐sn‐glycero‐3‐phosphocholine (DSPC) vesicles prior to spray‐drying (SD) and assess the impact on the final product performance and dissolution.

Two formulation procedures were carried out: Formulation 1 (1% FP, 79% trehalose and 20% L‐leucine) was manufactured by SD; Formulation 2 (1% FP encapsulated in 29% DSPC, 50% trehalose and 20% L‐leucine) was manufactured by (i) liposome formation by ethanol injection; (ii) processing by high pressure homogenization; and (iii) by SD with excipients. The formulations were characterized for particle size distribution, differential scanning calorimetry, X‐ray powder diffraction, aerodynamic performance and biorelevant dissolution using paddle over disk apparatus.

The formulations presented a PSD within the inhalation range and a fine particle fraction (FPF) of 79 ± 2% and 56 ± 5% for formulation 1 and 2, respectively. The FPF could be to be a consequence of the particle size increase, which can be controlled by optimizing the SD process. Lastly, the dissolution results indicated the DSPC had a sustained release effect on the product, with a 50% of dissolution occurring by 30 min and 90 min for formulation 1 and 2, respectively.

Therefore, a standard composite formulation appears to be suitable to manufacture powders containing DSPC as a drug encapsulating agent to achieve a sustained release delivery.

34. Dry Powder Inhaler for lung to heart drug delivery

Gildas Huet¹, Raphaele Audibert¹, Vincey Raphael¹, Myriam Giraud¹, Eride Quarta², Paolo Colombo², Francesca Buttini³, Thadé Penel¹, Asma Aït Sidi Hammou¹, Lilia Petit Ben Saidane¹, Laurent Vecellio¹

¹Nemera, La Verpilliere, France

²PlumeStars ‐ University of Padova, Padova, Italy

³University of Parma, Parma, Italy

Introduction/context: Cardiovascular diseases account for more than 30% of human deaths globally. The field is in urgent need for new patient‐friendly therapies ‐ more efficient and heart‐specific. CUPIDO is an EU‐funded project which aims to hit the “heart” of the cardiovascular disease by inhalation.

Research hypothesis/core question: Within CUPIDO, a Dry Powder Inhaler (DPI) device with good performances in term of Fine Particle Fraction and Emitted Dose has to be developed to ensure the nanoparticle deposition in the deep part of the lungs with a high reproducible dose.

Methods: Nanoparticles loaded with a therapeutic substance restoring cardiac function were embedded into microparticles and were produced by spray drying in order to obtain a size compatible with an alveolar deposition. A prototype inhaler device with a medium resistance was developed, was optimised with design of experiment and was evaluated by in vitro aerosol measurements and user tests.

Results and discussion of results: Based on the pharmacopeia methods using a Next Generation Impactor, we obtained an emitted fraction of 92% and a Fine Particle Fraction (FPF) of 80% at 60l/min. Results obtained in terms of fine particle fraction using a laser diffraction method by Spraytec (Malvern instruments, UK) showed an increase of fine particle fraction from 30L/min to 60L/min and a small decrease from 60L/min to 100L/min. These differences are low (15%) and should not have a high impact in terms of lung deposition variability. Overall, the Cupido device usability was satisfactory for most of the 17 participants (steps, handling…). They appreciated the ergonomic aspect of the Cupido device, with a suitable size and large button to pierce the capsule.

Conclusion: This study has demonstrated the ability to generate an inhalable powder containing nanoparticle with the relevant FPF performance for lung to heart treatment.

35. Integrated Acoustic Actuator for Signalling Inhaler Activity

Mark Sanders¹, Alexander Thomason¹ and Cuong Tran²

¹Clement Clarke International Limited, Edinburgh Way, Harlow, CM20 2TT, United Kingdom

²i2c Pharma Services, Cardiff Medicentre, Cardiff, CF14 4UJ, United Kingdom

Introduction: Integrated pMDI technique‐guidance requires successful manufacturing at scale and suitability for the user. A new guidance tool is part of/adjacent to the pMDI stem block (SB), and is active at 20‐45L.min⁻¹ flow rate (slow, steady inhalation). The audible whistle is distinct from normal background noise and is smartphone‐detectable up to 10m.

Core question: Current research investigated the effect of this new actuator on aerosol particle size distribution (APSD) and delivered dose.

Methods: Two APSD experiments were conducted at 30L.min⁻¹ using standard Next Generation Impactor methodologies. The first compared salbutamol, n = 5, (Ventolin® Evohaler® control, GSK) with Ventolin housed in a substantially similar actuator that incorporated a whistling 0.5mm SB‐orifice (the In‐Tone™ actuator). The second compared, as control, a standard actuator salbutamol‐HFA152a development formulation (Zephex® 152a, Koura Limited, 0.3mm SB‐orifice) with the In‐Tone actuator in three SB‐orifice sizes (0.3mm, 0.4mm, 0.5mm).

Results and discussion: In‐Tone did not affect the APSD profile or key variables of Ventolin Evohaler (FPF‐%<5μm: control 45.7 ± 4.0, +In‐Tone 49.5 ± 2.6; FPD‐μg<5μm: control 40.8 ± 3.6, +In‐Tone 45.7 ± 4.1) or the HFA152a 0.3mm SB‐orifice (FPF: control 53.7 ± 2.6, +In‐Tone 55.9 ± 4.4; FPD: control 69.4 ± 12.2, +In‐Tone 72.5 ± 15.3). The two larger HFA‐152a SB‐orifice diameters resulted in greater induction port deposition and decreased FPFs but were fully functional and proportionate in response.

Conclusion: These early example data suggest that this guidance actuator can deliver the required APSD performance with today's and future formulations. This propounds the possibility of low‐cost non‐Bluetooth® smart inhalers capable of providing user guidance, which could lead to improved inhaler technique

36. Carbon footprint assessment of Breezhaler^® dry powder inhaler.

Aumônier, S.^1,, Whiting, A.¹, Norris, S.¹, Collins, M.¹, Coleman, T.², Fulford, B.³ and Breitmayer, E.²

¹ERM, Eaton House, Wallbrook Court, North Hinksey Lane, Oxford, OX2 0QS, UK

² Resource and Waste Solutions, 302 Cirencester Business Park, Love Lane, Cirencester, GL7 1XD, UK

³Novartis, Novartis Campus, Basel, Switzerland

Delivery of respiratory inhalers makes a significant contribution to the carbon footprint (CFP) of healthcare. Consistent with Novartis' commitment to reduce the environmental impact of its products, the inhaler used in its asthma combinations is available in the hydrofluoroalkane / chlorofluorocarbon (HFA/CFC)‐free Breezhaler^® device.

Cradle to grave CFP studies of two Breezhaler^® inhaled combinations have been completed: one containing indacaterol acetate (IND) and mometasone furoate (MF); and the other IND, MF and glycopyrronium bromide (GLY).

The CFP is verified as compliant with the Greenhouse Gas Protocol Product Life Cycle Accounting and Reporting Standard Sector Guidance for Pharmaceuticals and Medical Devices.

The study boundary excludes the benefits of the drugs and an optional sensor in terms of asthma exacerbations, rescue medication and adherence.

CFPs are appraised for Germany, France, UK and Japan and in 30‐day (both products) and 90‐day packs (IND/GLY/MF).

In Germany, inhaler CFPs range from 0.184 kg CO₂eq per month for IND/GLY/MF (90‐day, no sensor) to (0.481 kg CO₂eq per month) for IND/GLY/MF (30‐day, with sensor). Of the 30‐day devices, IND/GLY/MF (no sensor) has the lowest CFP (0.359 kg CO₂eq per month).

Active pharmaceutical ingredients, inhaler raw materials and packaging make the largest contributions to the CFP, sensor raw materials dominating where used. Excipients, distribution and end of life stages all make minimal contributions to the carbon footprint for all of the device models.

Overall, when considering inhalation therapy environmental impacts, the assessed Breezhaler^® portfolio has a low CFP, consistent with the literature on DPIs.

37. To Connect, or, Not to Connect

Paul Greenhalgh ¹

^TTeam Consulting, Abbey Barns, Duxford Road, Ickleton, Cambridge CB10 1SX, UK

The money wasted each year due to non‐compliance of healthcare solutions is staggering. With the challenges healthcare budgets face (i.e. an ageing population, chronic conditions), how can we get patients to better manage their own health? Whilst making a device connected isn't a magic bullet to improve compliance and health, there are some obvious benefits. How do you decide if a device should be smart, connected or neither?

Three key areas to consider

40. The path to a sustainable future for inhalation products

Dan Cowen¹, Henry Blower¹ and Matt Garwood¹

¹Cambridge Consultants Ltd, 29 Science Park, Milton Road, Cambridge, CB4 0DW, UK

The climate impact of propellants used in pressurised metered‐dose inhalers is well‐documented and has received significant attention in recent years. In response, a number of promising compounds with lower global warming potential are the subject of ongoing research. Whilst propellants represent the largest climate change contributor of inhalation products, many other aspects across all product types affect not only global warming, but also the wider environment. Sustainability is increasingly important to patients and healthcare providers and is a significant driver of product choices. The full product life cycle must be considered, from use of resources through processing of materials, manufacture, qualification, transport, usage and disposal. At all stages environmental harm can and does occur, from climate change to depletion of finite natural resources and aquatic ecotoxicity. As devices become increasingly connected, harmful electronics production processes and waste must also be considered.

We examine routes to achieve sustainability in inhalation products whilst maintaining the safety and efficacy at their core. As product developers we have the power to effect significant change at the design stage through considered architectural choices and careful use and specification of materials. Design decisions are quantified using tools such as life cycle analysis, which allows a holistic view of environmental impact. Other avenues include changing and challenging use paradigms, using materials which are sustainably sourced, and designing for safe disposal and recycling of devices. Finally, investment in developing radical new delivery technologies has the potential to create brand new product categories which can permanently alter the landscape.

41. Computational analysis of helical aerosol streams for controlled micro‐ or nano‐drug delivery in representative human upper lung airways

Adithya Gurumurthy¹ and Clement Kleinstreuer¹

¹North Carolina State University, Raleigh, North Carolina NC‐27606, United States

Pulmonary drug delivery is becoming the preferred route for treating several lung and systemic diseases, ranging from insulin delivery to cancer therapy. It is a non‐invasive procedure where ideally drugs are directly delivered to affected sites. In reality, the efficacy is typically quite limited due to the physiology of human upper lung airways, which function as mechanical barriers to particle transport. For example, medical inhalers may delivery less than 20% of the inhaled drugs to lung regions, which are invariably the target sites. Hence, there is a need to reduce the wastage of inhaled aggressive/expensive drugs in human upper lung airways. In our recent in silico study, we observed up to 70% reduction in the deposition of micron‐size particles in the human oral cavity, while using helical streams, rather than conventional jets generated by pressurized‐metered dose inhalers. We now expanded our work by computationally analyzing helical streams transporting nano‐size drugs in representative human upper lung airways. As expected, helical flows enhance the efficacy of nanodrug streams. However, this consistent trend is not observed at very high swirl numbers, in part due to the influence of Brownian motion. The differences in deposition patterns between micron‐ and nano‐drugs, while using helical aerosol streams at different flowrates, are provided. Results from regional deposition studies are presented to obtain additional physical insight. The findings help to deepen the understanding of inhaled helical aerosol streams, and pave the way towards their successful practical implementation.

42. Exploring In Vitro Equivalence Tests Using a Bayesian Hierarchical Model

William J. Ganley¹, Jagdeep Shur and Robert Price

¹Nanopharm Ltd, an Aptar Pharma Company, Cavendish House Hazell Drive, Newport NP10 8FY

Bayesian methods allow us to learn from data by fitting complex interconnected probability models to a range of predictor and outcome data types. Such models can handle sparse data sets, data following a zoo of probability distributions and can be updated as new information is gathered without fear of biasing results. The methods have been applied to clinical trials and explored by regulatory agencies such as EMA and FDA.

In this study the relationship between flow rate, impactor stage deposition and the certainty of passing the EMA's suggested test for comparing multistage impactor data was modelled. The model relied merely on impactor data and well‐known expressions for impactor stage cut offs and confidence intervals. The connection between variable inhaler performance and uncertainty in the equivalence determination were quantified and used to track the risk of performing in vitro trials at different flow rates.

This study has shown how a Bayesian hierarchical model can be used to identify the relationship between parameters of an impactor study and the probability of determining equivalence of pharmaceutical products. The method allows the maximum insight to be gained from the data we generate, and a more complete understanding of uncertainty has the potential to de‐risk expensive trials.

43. The attitude of UK asthma patients towards ‘smart’ and connected inhaler features

Grace Kane¹, Matthew Jones¹ and Danielle Coffey¹

¹DCA Design International Ltd, 19 Church Street, Warwick, CV34 4AB, UK

‘Smart’ and connected inhaler features have the potential to improve patients' asthma control and their adherence to therapies. It is possible to incorporate a wide variety of different automated functions within an inhaler, but just because it can be done, it doesn't mean that it should. When specifying a new inhaler, it can be challenging for developers to find evidence on the best features to include for a particular patient population.

Much of the data that exists on patient attitudes towards ‘smart’/connected inhalers (and other ‘smart’/connected drug delivery devices) is either focused on a particular commercially available device, or is not current.

This investigation provides current data on the potential electronic features that patients value most. A number of possible features were identified for evaluation with the grounding of DCA's extensive experience in developing connected and ‘smart’ drug delivery devices and through systematic examination of each step in the asthma treatment journey. The features were grouped into the following categories: usage tracking, prescription management, lung health monitoring, HCP interaction, technique monitoring and device location.

A sophisticated online, closed‐response survey captured the priorities and preferences of 166 UK asthma patients aged 18 to 75+ towards these ‘smart’/connected features and the potential trade‐offs that they could introduce. Data was collected for patients of different ages, using different medications and inhaler types, and with varying levels of asthma control. This allowed us to uncover a number of interesting findings regarding the attitudes of different patient groups.

44. Development of chrysin dry powder inhaler formulation for the potential treatment of respiratory‐related diseases

Rahaf Oum¹, Yuosef Al ayoub¹, A. Paradkar¹, Omar Abu Abed² and K.H. Assi¹

¹School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, UK.

² Faculty of Graduate Studies, Arab American University in Palestine, Ramallah, Palestine

Chrysin has been reported by many studies as an anti‐inflammatory agent. However, high doses of flavonoids should be used due to its low bioavailability after oral administration. Therefore, formulating inhalational chrysin, to be delivered directly to the site of action in the lung, may enhance the bioavailability due to the absence of first pass metabolism. The aim of this study is to assess the aerosol performance of the chrysin DPI formulation using two common carriers (lactose and mannitol) and various drug‐carrier's mixing ratios (1/10 and 1/67.5 w/w%). Inhalable chrysin particles were prepared by two different techniques: the sono‐crystallisation and ball‐milling methods. For sono‐crystallisation formulations, the highest FPF% of 27% was obtained with lactose formulation compared to 14% for the mannitol, with MMAD below 2.6μm for both formulations. A similar trend was observed in ball‐milling samples; the highest FPF% of 10.3% when lactose was the carrier, and 8.6% for mannitol, with MMAD below 3.8μm. These results demonstrate that the performance of chrysin DPI formulations produced using a sono‐crystallisation technique was superior to the formulations produced with a mechanical ball‐milling process. This finding agrees with previous studies that found particles produced by ultrasound have an enhanced inhalational application. Besides, all formulations in the current study showed a higher FPF% and lower MMAD when lactose was used as a carrier. It was also found that FPF% of chrysin increases when increasing the carrier concentration. The chrysin formulations produced using sono‐crystallisation are more suitable to be used for further inhalation and animal studies.

45. Methionine offers superior aerosolization stability over leucine for inhalable high‐dose spray‐dried kanamycin formulation

Bishal Raj Adhikari¹, Karlis Berzins², Sara J. Fraser‐Miller², Keith C. Gordon² and Shyamal C. Das¹

¹School of Pharmacy, University of Otago, 18 Frederick Street, Dunedin, 9054, New Zealand

²Department of Chemistry, University of Otago, Union Place West, Dunedin, 9016, New Zealand

Leucine has been widely used to improve aerosolization of high dose spray‐dried formulations for inhalation. However, the use of other amino acids such as methionine for the same purpose has not been well established. The aim of this study was to assess the aerosolization stability offered by methionine inclusive formulation. Inhalable particles of kanamycin‐methionine (KM) and kanamycin‐leucine (KL) were prepared by co‐spray drying of the drug with amino acids in 1:1 molar ratio. Solid state characterization was conducted using thermal techniques, microscopy, and Raman spectroscopy. Stability study was performed at 25 °C/<15% relative humidity (RH) and 25 °C/53% RH over 28 days. The Fine Particle Fraction (FPF), determined by Next Generation Impactor with an aerolizer, of the freshly prepared KM and KL formulations were 84% and 85%. Methionine formed a co‐amorphous system with kanamycin while leucine crystallized in the co‐spray dried in freshly prepared KL. After storage at 25 °C/53% RH for 28 days, the water content of KL and KM were 10.5% and 9.7%, the particles stuck together only in KL, and the methionine in KM crystallized; the FPF of the KL formulation significantly decreased to 79% (p < 0.05) whereas the FPF of the KM formulation remained unchanged. The decrease in FPF of the KL was possibly due to particle sticking as evident from SEM images. This study suggests that methionine offers better aerosolization stability than leucine at high relative humidity (53%) for kanamycin formulation.

46. Comparing the Aerosol In Vitro Performance and Surface Energetics of Dry Powder Inhaler Formulations

A.J. Jamal¹, K.H. Assi¹, V.G. Vangala¹ and Y. Alayoub²

¹School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, UK.

²Eurofins Professional Scientific Services UK Limited, I54 Business Park, Wolverhampton, WV9 5GB, UK

Many studies on lung deposition have failed to include surface energy calculations to help explain the poor performance and efficacy of current market formulations. Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, the surface energies of a set of drug and carrier (budesonide with either mannitol or lactose) in different ratios were measured using Inverse Gas Chromatography. The surface energies of the examined formulations were then compared to their lung deposition performance using a Next Generation Impactor to establish the correlation between them and determine whether it could be used for the estimation of in vitro drug delivery for dry powder inhalers. Different ratios were chosen as current market formulations all have different amounts of carrier. A higher ratio of [work of adhesion/work of cohesion] was associated with a higher FPF for each set of drug and carrier. For example, the 1:10 ratio of budesonide and lactose showed the highest FPF as well as the highest [work of adhesion/work of cohesion] compared to other mixing ratios for this set. The results indicate that by measuring the surface energies of a set of formulations using IGC, and comparing these to their lung deposition performance using an NGI, it is possible to identify best ratio of drug to carrier that will provide the most efficient aerosol performance and lung deposition.

47. Influence of the opening size on the air velocity through the capsule in the capsule based DPI's

Milica Stankovic‐Brandl¹, Dalibor Jajcevic¹, Thomas Wutscher¹, Sarah Zellnitz¹, S. Biserni³, A. Mercandelli³, M. Kobler⁴, F. Buttini⁵, V. Chierici⁵, L. Andrade⁶, V. Daza⁶, S. Ecenarro⁷, L. Canalejas⁷ and Amrit Paudel^1,2

¹Research Center Pharmaceutical Engineering, Inffeldgasse 13, Graz, 8010, Austria

^2:Graz University of Technology, Institute for Process and Particle Engineering, Inffeldgasse 13, 8010 Graz, Austria

^3:MG2, Via del Savena 18, 40065 Pian di Macina di Pianoro, Bologna, Italy

^4:MEGGLE Excipients and Technology, Megglestraße 6‐12, 83512 Wasserburg, Germany

^5:Food and Drug Department, University of Parma, Parco delle Scienze 27, 43121 Parma, Italy

^6:Laboratorios Liconsa, S.A. C/ El tejido 2, 19200 Guadalajara, Spain

^7:Qualicaps Avda. Monte Valdelatas 4, 28108 Alcobendas, Madrid, Spain

A number of single dose capsule‐based dry powder inhaler devices contain prefilled capsules that are perforated by a needle to release powder. The patient breath actuation releases the contained powder through the generated openings. In the current work, we attempt to understand the relation between the air flow, powder emission and opening size of differently lubricated capsules.

To calculate the size of the openings, gelatine capsules (n = 3) with different external lubricants were pierced using Plastiape RS01 device with one needle from each side and assessed using DSLR camera and ImageJ software. The gas flow through the device was simulated using computational fluid dynamics (CFD), at a flow rate of 60 l/min, considering a perfect rotational motion of the capsule. Aerodynamic performance of the capsules filled with 1 wt% Budesonide and 99 wt% Inhalac 230 was assessed using Fast Screening Impactor.

The capsules opening size varied depending on the presence and type of the external lubricant and largely influenced the air velocity within the capsule. Slightly higher powder retention in the capsule with smaller opening size was observed, however, the total emitted dose (ED) for a given blend was not largely influenced by the opening size.

CFD simulation was proven to be a powerful tool to predict changes in air velocity through different opening sizes. Experimentally, these changes did not have a drastic effect on the ED of the formulation studied. However, using carrier free formulations, the ED is expected to be strongly affected by the air velocity inside the capsule.

48. Optimising DPI formulations – The influence of surface energy on the suitability of additional fines

Nicholas Bungert¹, Mirjam Kobler², Regina Scherließ¹

¹Department of Pharmaceutics and Biopharmaceutics, Kiel University Grasweg 9a, 24118 Kiel, Germany

²Meggle GmbH & Co KG, Megglestr. 6‐12, 83512 Wasserburg, Germany

Introduction: A well‐known strategy to optimise interactive blends is the addition of fines, which leads to an increased aerodynamic performance, measured as the fine particle fraction (FPF). This study shows the superiority of milled lactose fines in comparison to sieved fines and the influence of surface energy.

Methods: Preparation of interactive blends: Initially, intrinsic fines of InhaLac^® 230 were removed by sieving (IH230). The mixing process comprises the addition of 7.5% (w/w) lactose fines (different batches of InhaLac 400/IH400 or intrinsic fines of InhaLac 230/IH230F) to IH230 followed by the addition of micronised drug particles (Ipratropium bromide) using the Picomix^® high‐shear blender (Hosokawa Alpine).

Surface energy measurements: The surface energy (SE) was determined with the Surface Energy Analyser (Surface Measurement Systems).

Aerodynamic assessment: Impaction analysis was performed with the Next Generation Impactor (Copley Scientific) utilising the Novolizer^® (MEDA Pharma) at controlled environmental conditions.

Results and Conclusion: IH400 showed highest SEs of the analysed materials. IH400, which exceeded its shelf life showed reduced SE and decreased FPF (41.46%) of the resulting blend compared to new batches (45.69%). IH230F led to lower FPFs (30.57%) than IH400, but to an increase compared to the fine‐free blend (25.15%). It could be assumed, that higher SE of fines leads to stronger adhesion forces, which increases the saturation of active sites, as well as the agglomerate strength.

The SE is one parameter which highlights the differences in adhesion and cohesion properties and is a useful tool for the investigation of the operating principles of lactose fines.

49. Probing the effect of USP induction port geometry on aerodynamic performance of dry powder inhalers

Piyush Pradeep Mehta¹

¹Department of Quality Assurance, Poona College of Pharmacy,

Bharati Vidyapeeth Deemed to be University, Erandwane, Pune, 411038, Maharashtra, India

Introduction: Induction port (IP) geometry play an important role in aerodynamic assessment of dry powder inhalers (DPIs).

Research hypothesis: The present study aims to probe the effect of two different USP IPs on aerosolization performance of fluticasone propionate (FP)‐loaded DPIs.

Methods: Lactose carrier (InhaLac^® 160) and FP particles were thoroughly analyzed for physicochemical properties. Afterward, InhaLac^® 160 and micronized FP were blended using a low shear Alphie^® 3D shaker mixer (80 rpm). The powder blend equal to 100 μg of FP was manually filled in size 3 HPMC capsules and stored in polypropylene containers. The aerodynamic assessment was performed using the Andersen cascade impactor (ACI) equipped with two different USP IP namely, USP standard IP and USP modified IP at steady flow rate of 60 L/min using medium resistance Revolizer^® inhaler.

Results: Tomahawk‐shaped, middle‐sized InhaLac^® 160 particles showed acceptable powder flow properties with particle size and surface roughness of 109.46 and 2.70 μm, respectively. Micronized FP showed particle size (3.35 μm) suitable for pulmonary delivery. During ACI analysis, both IPs showed a significant difference in powder retention within the IP. USP modified IP demonstrates superior % fine particle fraction (p ≤ 0.001) as compared to USP standard IP. Additionally, in stage‐wise grouping USP modified IP showed higher FP deposition in group 3 [Stage 1 to 4 (cut‐off diameter of <5 μm)] as compared to USP standard IP.

Conclusion: USP modified IP showed better aerodynamic performance as compared to USP standard IP however additionally analytical efforts may be required to cross‐examining the reported results.

50. Solid state modification of ciprofloxacin for high dose dry powder inhalation

Thomas Hibbard¹, Hisham Al‐Obaidi¹, Kenneth Shankland¹, and Bildad Nyambura²

¹University of Reading, Whiteknights, Reading, RG6 6AH, UK

²Quotient Sciences, 5 Boulton Road, Reading, RG2 0NH, UK

Introduction: Ciprofloxacin base is a broad‐spectrum fluoroquinolone antibiotic with strong activity against respiratory pathogens. It is used in this study as a model poorly soluble drug with oral and inhaled applications. Current oral formulations record low lung partitioning hence a need for reformulating to a controlled release or repurposing to an inhaled formulation. Tolerability issues associated with large volumes of powder limit the maximum practical inhalation for dry powder inhalers (DPIs). Inhaled antibiotics require high local concentrations therefore current DPI formulations using coarse carriers such as lactose need modifying to account for this.

Research hypothesis/core question: Can solid state modification of ciprofloxacin generate high dose inhalation powders without the need for a carrier?

Methods: Cocrystals/salts of ciprofloxacin and four organic acids were produced through liquid assisted grinding and single crystals grown from solvent. Crystallographic, spectroscopy, and thermal analysis were used to identify and characterize the products. Inhalation properties of powders were measured through Andersen Cascade Impaction (ACI).

Results: All four novel cocrystal/salt formulations of ciprofloxacin showed reduced MMAD compared to ciprofloxacin control (MMAD (μm) = 2.41, 2.54, 2.37, 2.31, 8.05, for succinic, glutaric, adipic, pimelic and control respectively). MMAD between 2 and 3 μm has been shown to correspond to ideal lung deposition for DPI formulations. Differences were also seen in the FPF% corresponding to suitable inhalable fractions for the formulations.

Conclusion: A novel correlation between improved inhalation properties and solid‐state modification has been found. This area should be pursued as a possible route to carrier‐free dry powder inhalation.

51. The Influence of blend composition on the aerodynamic performance of a novel high resistance multi‐dose device

Irene Rossi¹, William J. Ganley¹, Arron Danson¹, Cyrine Mestiri¹, Gonçalo Farias¹, David Farrow¹, Gregoire Deraime², Segolene Serrailh², Rob Price¹ and Jagdeep Shur¹

¹Nanopharm Ltd, An Aptar Pharma Company, Cavendish House Hazell Drive, Newport NP10 8FY

²Aptar Pharma, Route des Falaises, 27100, Le Vaudreuil, France

High resistance multi‐dose inhaler devices are prescribed to Chronic Obstructive Pulmonary Disease (COPD) and asthma patients regardless of the severity of their disease, due to their easier handling and low peak inhalation flow (PIF) required.

The aim of this study was to investigate the influence of different blend composition on the aerodynamic performance of Aptar Prohaler^® (Aptar Pharma, FR), a novel high resistance multi‐dose inhaler.

Fluticasone propionate was blended (0.8% w/w) with lactose (D_v,50 74 μm) to manufacture 8 different formulations comprising different percentages of fine lactose (D_v,50 3 μm, 0 up to 5% w/w) and/or a force control agent (FCA). Strips were filled with 5 mg of formulation using Omnidose TT (Harro Höfliger, DE) and subsequently loaded into Prohaler^®. Aerodynamic performance was tested employing a Next Generation Impactor (Copley Scientific, UK) at 39 L·min⁻¹ for 3.1 seconds. Data analysis was performed using R statistical software.

The presence of FCA significantly increased the Fine Particle Mass (FPM) as well as a higher fine lactose percentage. However, the latter was significant only in the formulations without FCA. Formulations with FCA showed the best performance (Fine Particle Fraction = 45%) overall. Mass Median Aerodynamic Diameter (MMAD) did not change significantly with an increased percentage of fine lactose. However, when FCA was used the lower MMAD was recorded (2.10 ± 0.15 μm).

The study highlighted that the use of a FCA, in a model blend formulation and in Prohaler^® device, positively increased the FPM and produced a lower MMAD.

52. Development of NSAID‐containing dry powder inhalation formulation co‐spray‐dried with sodium stearate

Edit Benke, Piroska Szabó‐Révész and Rita Ambrus

Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös str. 6., Szeged, H‐6720, Hungary

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is well established in local pulmonary therapy, for example in cystic fibrosis. They are able to directly reduce inflammation, even indirectly slowing the progression of this disease. In the case of pulmonary drug delivery, the use of dry powder inhalation (DPI) systems is most common. Spray drying is a popular method for preparing these. The successful use of a number of excipients has already been published, however, there is still little experience with NSAID‐containing DPIs. The aim of the present work was to study DPI formulations prepared by co‐spray‐drying, using meloxicam‐potassium (MXP) and different concentrations of sodium stearate (NaSt). Physicochemical, in vitro drug release and in vitro lung deposition studies, were performed with the prepared microcomposites. Based on the results, it can be stated that the use of NaSt during co‐spray‐drying of MXP has a positive effect on the morphology, particle size and cohesive work of the produced particles, as a result, the in vitro aerodynamic properties were also improved and the dissolution of the drug in simulated lung fluid in the presence of NaSt was improved. Overall, the study of excipients that have already been proven in other pharmacological groups is justified in the case of pulmonary delivery of NSAIDs, and there are still many opportunities for the development of NSAID‐containing DPI formulations.

Supported by the ÚNKP‐20‐3‐SZTE‐308 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund.

53. In Vitro Performance of the Handihaler® and the Respimat® ^{Soft Mist™ Inhaler Under Inhalation Profiles Simulating COPD}

Janelle Soong¹, Ben Forbes¹ and Mark Parry²

¹Department of Pharmacy, King's College London, 150 Stamford Street, London, SE1 9NH, UK

²Intertek‐Melbourn Scientific Limited, Saxon Way, Melbourn, SG8 6DN, UK

Introduction: This study investigates the effects of simulated mild, moderate and severe chronic obstructive pulmonary disease (COPD) inhalation profiles (Global Initiative for Chronic Obstructive Lung Disease guidelines 2019) on tiotropium delivery by the Handihaler® and the Respimat® Soft Mist™ Inhaler.

Research hypothesis: It was hypothesised that the Respimat would demonstrate a higher fine particle fraction and less oropharyngeal impaction than the Handihaler, as well as a more consistent performance across simulated disease severities.

Methods: Inhalation profiles were constructed to simulate typical inhaler use by COPD patients using data from published literature. Emitted Dose (n = 6) and Next Generation Impactor (NGI) analyses (n = 3) were conducted to investigate Total Emitted Dose (TED) and aerodynamic particle size distribution (APSD). APSD data was interpreted in terms of fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD).

Results and Discussion: The Handihaler exhibited TED values that decreased with simulated inspiratory flow rate. However, the Respimat produced similar TED values across disease states. The Respimat generated a higher FPF (60.9%‐72.2%) than the Handihaler (24.4%‐35.9%) under mild and moderate COPD profiles, with greater deposition on later stages of the NGI. Both devices achieved MMAD in the respirable range (1‐5 μm). Analysis of the fine particle dose showed no significant difference between the inhalers for all disease states (p > 0.05), nor between the different severities under each inhaler (p > 0.05).

Conclusion: Both inhalers are capable of meeting the in vitro criteria for successful inhaled drug delivery but the Respimat achieves more efficient drug delivery, independent of disease severity.

54. Efficacy of the PARI Filter/Valve set to prevent environmental contamination with aerosol during nebulizer therapy

Uwe Schuschnig, Rosina Ledermüller and Jens Gramann

PARI GmbH, Lochhamer Schlag 21, Gräfelfing, Germany

Introduction: During aerosol therapy with a PARI jet nebulizer, about two thirds of the aerosolized drug are inhaled while one third is emitted to the environment during exhalation. In order to avoid environmental contamination with aerosols, PARI is marketing a filter set to capture the exhaled fraction.

The purpose of this study was to test the efficacy of the filter system and to determine the aerosol amounts emitted to the environment during nebulizer therapy with PARI nebulizers.

Methods: LC PLUS and LC SPRINT nebulizers were tested (n = 6, each) in breath simulation experiments using an adult breathing pattern. In addition to inspiratory and expiratory filters, nebulizer was placed under an extraction hood with a third particle filter to capture the aerosol emitted through leakages or at the inhalation valve. In order to validate the experiments, mass recovery rate was also determined.

Summary: With the PARI filter set attached to the nebulizers, the aerosol amounts emitted to the environment are below 1% of the total aerosolized drug amount. The mean values ranged from 0.4% for the LC PLUS to 0.6% for the LC SPRINT. The highest value found in a single experiment was 0.82%. The mean recovery rate in the experiments was 99.7%.

In absolute amounts, of 2.5 ml liquid initially filled into the nebulizer, 0.006 ml liquid was emitted to the environment instead of 0.36 ml without expiratory filter. This corresponds to a 98.4% reduction of aerosol contamination by the expiratory filter set.

55. Formulation and characterization of spray‐dried budesonide in organic solvent suspensions for aerosol delivery to the lungs

Wei‐Ren Ke¹, Philip Chi Lip Kwok¹ and Hak‐Kim Chan¹

¹ Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, Pharmacy and Bank Building A15, The University of Sydney, NSW 2006, Australia

Spray drying technique is a rapid method for converting a liquid feed into dried particles. However, spray‐dried powders produced from solutions are mostly amorphous. The amorphous lactose is particularly unstable when exposed to moisture. To avoid this problem, a suspension containing crystalline lactose particles and dissolved BUD in an organic solvent was spray dried. In the present study, the powder generated from this suspension were characterised. The solution formulation using a cosolvent system was spray dried as a control.

The suspension formulation contained 0.77 mg/mL dissolved BUD and 12 mg/mL suspended lactose in isopropanol alcohol. The solution formulation contained 3.39 mg/mL BUD and 49.57 mg/mL lactose in 50:50 IPA/water. Both spray‐dried powders were stored at 25°C/60% RH for three months. The particle properties and in vitro dispersion performance were examined at different storage time points.

The powder generated from solution showed rapid recrystallization. Its volumetric median diameter (VMD) was significantly increased from 4.2 to 24.4 μm after 1‐week storage. Although the crystallinity of the powder spray dried from suspension measured by XRD remained the same after three‐months storage, SEM indicated that interparticulate solid bridges started to form after 1‐month storage. The VMD of the particles changed from 4.22 μm to a maximum of 4.37 μm after one month and 4.28 μm after three months, with the change in the fine particle fraction (FPF) from 51.4% to 25.1%. In conclusion, spray‐dried powder obtained from suspension was more stable than the formulation spray‐dried from solution. However, the powder still deteriorated, even though more gradually.

56. Use of A Sectional Adult Nasal Airway Model for the Evaluation of Nasal Delivery Devices and Administration Techniques

Mark W. Nagel ¹, Jason A. Suggett¹ and Jolyon P. Mitchell²

¹Trudell Medical International, 725 Baransway Drive, London, Ontario, N65 5G4, Canada

²Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Rd., London, Ontario, N6H 2R1, Canada

The nasal cavity is a target for both locally and systemically acting medications. However, it is difficult to evaluate drug deposition in the nasal passageways, and in particular the olfactory region where there is the potential to bypass the blood‐brain barrier, with different nasal devices and administration techniques. Two variants of a sectional nasal airway model were developed based on an adult MRI nasal scan (Guilmette and Gagliano,1994) to visualize deposition patterns and measure regional dosages from a nasal nebulizer (NasoNeb*, Nasoneb Inc., Plattsburgh, NY). Using a longitudinally segmented transparent version of the model a colour‐presenting water‐finding product (Sar‐Gel*, Sartomer Americas, Exton, PA) was used to qualitatively assess deposition. The second model was segmented horizontally (anterior, middle and posterior sections) and made from sintered nylon to allow for chemical compatibility and drug assay. Laser diffraction was used to characterize volume mean diameters ((VMDs), n = 3 replicates at 6‐cm working distance) at Dv₁₀ (21.0 ± 1.1μm), Dv₅₀ (56.1 ± 4.0μm) and Dv₉₀ (231.5 ± 32.9μm) respectively. The mass of budesonide was determined by HPLC‐spectrophotometry. Using Pulmicort* Nebuamp* (500μg/2ml, AstraZeneca, Canada Inc.) as test formulation, budesonide recoveries (mean ± SD) from the anterior, middle and posterior portion of the model were 81 ± 16, 173 ± 58 and 39 ± 29 μg respectively. These analytical results helped confirm the visual observations with the transparent model that showed the bulk of the deposition occurred in the middle/turbinate region of the nose model.

Guilmette, R.A. Gagliano, T.1.(1994) Construction of a model of human nasal airways using in vivo morphometric data, Ann OccHyg.1994;38(Suppl. 1):69‐75.

57. Fucoidan‐coated lipid nanocapsules encapsulating a model drug for lung drug delivery

Jorge F. Pontes¹, Emanuel Duarte², Noelia Flórez‐Fernandez^1,2,3, João Rico², Joana Cruz², Giovanna Lollo⁴, and Ana Grenha^1,2

¹Centre for Marine Sciences, Drug Delivery Laboratory, Universidade do Algarve, Campus de Gambelas, Faro, 8005‐139, Portugal

²Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus Gambelas, Faro, 8005‐139, Portugal

³Faculty of Sciences, University of Vigo, Campus As Lagoas, Ourense, Spain

⁴University of Lyon, Université Claude Bernard Lyon 1, LAGEPP CNRS, UMR 5007, Villeurbanne, France

Lipid nanocapsules (LNC), comprised of an oily core and an outer polymeric shell, have been proposed for the delivery of hydrophobic drug molecules. LNC can be formed almost instantaneously by solvent displacement technique, a method involving the mixture of two phases of opposite polarities. This work proposes LNC comprised of an oily core of positively charged lecithin (1,2‐dioleoyloxy‐3‐trimethylammoniumpropanchloride, DOTAP) and medium chain triglycerides (Miglyol^® 812), coated with fucoidan (FUC), a sulphated polysaccharide of marine origin, as drug carriers. The selection of the formulation of FUC/DOTAP = 0.5/0.1 (% m/v, total 10 mL) was based on previous studies of stability, excipient concentration, and drug encapsulation capacity. Curcumin (0.75 mg) was associated as model hydrophobic drug. Sizes around 200 nm and strong negative zeta potential (ca. ‐70 mV) were obtained for unloaded and drug‐loaded LNC, no significant changes being observed upon drug association. The LNC revealed stability of the physicochemical parameters when stored at 4 °C for 30 days. Moreover, a 24 h exposure of alveolar epithelial (A549) cells to curcumin‐loaded nanocapsules at curcumin concentrations up to 20 μg/mL did not induce cell toxicity (cell viability >70%) and demonstrated the capacity of LNC to mitigate the cytotoxicity of the drug. In fact, free curcumin induced cell viability below 70% and resulted in half maximal inhibitory concentration (IC₅₀) of 3.59 μg/mL. Envisaging an application in lung delivery, LNC were microencapsulated by spray‐drying, using mannitol as matrix material (Mannitol/LNC = 85/15 (w/w)), a process under optimisation to attain adequate aerodynamic characteristics.

58. 4 steps to selecting the ‘right’ delivery device for your inhaled therapy.

Charlotte Harris¹

Team Consulting, Abbey Barns, Duxford Road, Ickleton, Cambridge CB10 1SX,

When developing a new inhaled therapy – the device you develop or select to deliver it, will be key to the overall product success.

If you don't wish to develop your own device from scratch – how do you decide which of the many inhalation technologies on the market or in development, will be optimum for your therapy?

These four steps taken early in the process ensure you're on the path to selecting the ‘right’ device!

61. Increased Sustainability Via the Use of Abbreviated Impactor Measurements (AIM) for Aerodynamic Particle Size Distribution (APSD) of Oral Pressurised Metered Dose Inhalers (pMDIs).

Jim Clay¹ and Andy Cooper¹

¹Kindeva Drug Delivery Limited, Derby Road, Loughborough, Leicestershire, LE11 5SF, UK

Determination of Aerodynamic Particle Size Distribution (APSD) is one of the most significant tests within an inhaler laboratory and the preferred instrument of choice for this test is the multistage full resolution Cascade Impactor (CI). Abbreviated Impactor Measurements (AIM) are a possible alternative with numerous benefits including a reduction in carbon footprint, reducing analysis times and solvent usage.

A key attraction of the AIM approach undertaken here is the simple addition of a filter paper on to an existing stage of a Next Generation Impactor (NGI) to provide product optimised reduced Next Generation Impactor (rNGI) configurations. A combination pMDI containing an ethanol free suspension formulation of Salbutamol Sulphate and Ipratropium Bromide Monohydrate was assessed.

The impactor mass (IM), impactor sized mass (ISM), fine particle mass (FPM) and ratio of large particle mass (LPM) and small particle mass (SPM) were compared for both active pharmaceutical ingredients (APIs) by both the full NGI and rNGI and were shown to be in very close agreement (less than 10% difference), with no statistical difference for all four parameters (p > 0.05).

Mass Median Aerodynamic Diameter (MMAD) was also determined for both the full NGI and rNGI and were shown to be in very close agreement (less than 5% difference). For the rNGI, an appropriate size fractionation stage had been chosen to allow this to be determined by interpolation.

62. Quantification of Surface Composition and Distribution of Inhalation Powders using TOF‐SIMS

Mark Nicholas, Mats Josefson, Magnus Fransson, Jonas Wilbs, Carl Roos, Catherine Boissier and Kyrre Thalberg

Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden

Surface properties are often critical to the behaviour of powder formulations, especially in the case of dry powders for inhalation, as surface properties directly affect inter‐particulate forces and, hence, the dispersibility of the formulation.

A multivariate TOF‐SIMS (time‐of‐flight secondary‐ion mass spectrometry) methodology has been developed and applied to quantify surface composition and chemical distribution for dry powder blends.

The mass spectrum at each pixel was fitted to a linear combination of reference spectra obtained by non‐negatively constrained alternating least squares. From the pixel compositions, average surface coverage and a range of other image features were calculated.

Two kinds of blended systems have been examined:

64. Plume temperatures of current and future low GWP pMDI propellants measured in an anatomical throat geometry

Ben Myatt¹, Stephen Stein² and Barzin Gavtash¹

¹Kindeva Drug Delivery, Charnwood Campus, 10 Bakewell Road, Loughborough, United Kingdom, LE11 5RB

²Kindeva Drug Delivery, 3M Center, St. Paul, MN, US, 55144‐1000

The EMMACE throat is widely used for in‐vitro testing of inhalation products. A novel instrumented EMMACE throat has been developed as a diagnostic tool enabling measurement of temperatures within the oral cavity. Plume temperature is an important factor in patient acceptability of a product, as was seen during the CFC to HFA transition. Plume temperature should therefore be considered when developing future pMDI products with new low GWP propellants, as plume temperature of these propellants and their effect on patient ‘feel’ is currently unknown.

The instrumented EMMACE throat was produced using SLA 3D printing incorporating small holes to allow instrumentation with fine wire thermocouples in the oral cavity. Placebo pMDIs of various current and potential future propellants were fired using an actuator with 0.3 mm diameter spray orifice into the instrumented throat with 30 lpm air co‐flow. The thermocouple voltages were amplified with bespoke equipment and digitised and logged using a Kistler 5165A LabAmp.

Temperature profiles measured in the oral cavity were very similar in trend showing a sharp reduction in temperature as the cold spray plume passed over the thermocouple followed by a temperature recovery to ambient conditions. Liquid propellent evaporation during the actuation causes self‐cooling of the propellant and produces cold vapour. For a given device and metered dose, the temperature drop and therefore minimum temperature observed varies according to the thermodynamic properties of each propellant. We found that HFA227ea had the overall warmest spray plume, followed by HFO1234ze, HFA134a and the coldest was HFA152a.

65. Challenging the Challenges of Nanoparticle Testing Using In Vitro Methods

Nashwa Osman¹, Darren Sexton¹ and Imran Saleem¹

¹Liverpool John Moores University, School of Pharmacy and Biomolecular Sciences

Byrom Street, Liverpool, L3 3AF, UK

Introduction: In vitro testing using cell cultures are the cornerstone standard methods for the initial screen of nanoparticles (NPs) providing many valuable mechanistic evaluations for NPs interactions with the target tissues. For example, Alamar Blue (AB), Lactate Dehydrogenase assay (LDH), Reactive Oxygen Species (ROS) assays are widely used assays for evaluating NP toxicity testing. However, these methods were adopted from the conventional chemical materials toxicology testing where these materials are soluble in the testing medium. The particulate nature and the exceptional NP physicochemical characteristics influence completely their behaviour under in vitro testing that render false positive or false negative results. Our study will illustrate technical issues that can be seen in in vitro testing in commonly used assays such as AB, LDH, and ROS.

Methods: Assays were performed according to standard protocols or adapted by applying procedures to minimize the NPs‐interactions with the assays.

Results and Discussions: Assay adaptations such as wash steps, using different procedures for the same assay, using alternative reagents, are providing better results that ensures the endpoints measured are due to genuine effects of NPs on the cells and minimise NPs‐interactions with the assays.

Conclusion: In vitro cell cultures‐based assays require optimization to overcome major challenges with assay interference when it comes to in vitro NP toxicology testing.