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The Aerosol Society

DDL â&#x20AC;&#x201C; Shaping the next 25 years of nasal and pulmonary Drug Delivery

7th, 8th & 9th December 2016 Proceedings

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Drug Delivery to the Lungs 27

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Wednesday 7th - Friday 9th December 2016 Edinburgh International Conference Centre, Scotland, UK Drug Delivery to the Lungs 27 - Friday 9 December 2016 Wednesday Thank you to7 our Platinum Sponsors th

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About DDL Drug Delivery to the Lungs (DDL) is Europe's premier conference and exhibition dedicated to pulmonary and nasal drug delivery. DDL is organised by a voluntary sub committee of the Aerosol Society and aims to provide a conference dedicated to those with an interest in drug delivery to the airways. The DDL scientific organising committee is made up of members representing industry and academia.

Scientific Organising Committee DDL27 The DDL committee is made up of members representing industry and academia. The current members are: Gary Pitcairn Omar Usmani Sheila Coates Nikki Evans Nick Childerhouse Michelle Dawson Ben Forbes Mark Hammond David Harris Phil Haywood Yorick Kamlag Regina ScherlieĂ&#x; Alex Slowey Geralt Williams

AstraZeneca Imperial College London Vectura Limited GlaxoSmithKline King's College London Aesica Pharma PA Consulting Group OINDP Consultant Zentiva Inhalationsprodukte GmbH Kiel University 3M Health Care Limited Aptar Pharma

Conference Chair Conference Vice-Chair Conference Organiser Conference Organiser

The Aerosol Society is a member based organisation that exists to promote the science of particle distribution and its application in aerosols. Membership is wide reaching and includes scientists and researchers in the fields of climate engineering, environmental pollution, atmospheric health, nano-technology as well as those from the pharmaceutical and healthcare industries.

Conference Abstracts Review Panel To enhance the scientific quality of the meeting and published proceedings, expert reviewers were invited to assist the scientific organising committee in reviewing abstracts submitted to the conference. Many thanks to: Francesca Buttini Shyamal Das Jolyon Mitchell Darragh Murnane Steve Newman Steven Nichols Jag Shur Jason McConville Janet Maas Sarah Zellnitz

University of Parma, Italy University of Otago, New Zealand Jolyon Mitchell, Inhaler Consulting Services Inc, Canada University of Hertfordshire, UK Consultant, UK OINDP Consultant, UK University of Bath, UK University of New Mexico Consultant Research Center Pharmaceutical Engineering, GmbH

CONTENTS Page Nos: DDL27 Programme

1-4

Conference Opening Plenary

5-6

Session 1 Presentations

7 - 19

Inhalers â&#x20AC;&#x201C; Were They Really Meant For Humans? The Annual DDL Lecture Plenary Lecture Session 2 Presentations

20 - 23 24 25 - 40

Beyond Asthma And COPD Session 3 Presentations

41 - 60

The Pat Burnell New Investigator Award Session 4 Presentations

61 - 76

60 Years Of The pMDI Session 5 Presentations

77 - 92

Innovations In Aerosol Delivery Summary of Posters

93 - 101

Posters

102 - 380

WEDNESDAY 7TH DECEMBER

11.00

Registration & Refreshments

12.00

Networking Buffet Lunch in the Exhibition Hall

13.30

Welcome & Opening Remarks Gary Pitcairn, Chair, DDL Committee

13.45

Conference Opening Plenary The European Asthma Research & Innovation Partnership - tackling Europe’s high asthma prevalence and death rates Dr Samantha Walker, Director, Research & Policy and Deputy Chief Executive, Asthma UK

Page Nos 5-6

SESSION 1 INHALERS – WERE THEY REALLY MEANT FOR HUMANS? 14.15

7 - 10 Inhaler device and errors Professor Henry Chrystyn, Emeritus Professor, Inhalation Consultancy

14.45

Manned Posters (1 – 36), Exhibition and Refreshments

16.15

Human factor considerations in inhaler innovation Mr Julian Dixon, Director of Human Factors, Team Consulting Ltd

16.45

Clinically relevant in vitro tests for the assessment of innovator and generic nasal spray products Mrs Mandana Azimi, Virginia Commonwealth University

12 -15

17.05

Innovations in nebulized delivery Dr John N Pritchard, Respironics Respiratory Drug Delivery (UK) Ltd

16 - 19

17.30 – 20.00

17.30 - 20.00

Exhibitor Drinks Reception

Exhibitor Drinks Reception Exhibition hall hall Exhibition Drinks all attendees attendees Drinks&&Canapes Canapés for for all Sponsored by Sponsored by (Add Vectura logo)

THURSDAY 8TH DECEMBER :AM

08.00

Registration & Refreshments Exhibition Hall & Poster Viewing

08.55

Opening of Conference

09.00

ANNUAL DDL LECTURE The challenge of delivering drugs to the lungs Dr Stephen P. Newman, Scientific Consultant

09.45

PLENARY LECTURE Biologics in Asthma – are we turning the corner Professor Roland Buhl, Mainz University Hospital

10.15

20 - 23

Manned Posters (37 - 76), Exhibition and Refreshments

SESSION 2 BEYOND ASTHMA AND COPD

25 - 28

11.30

Development to approval of NARCAN® nasal spray Mr Fintan Keegan, Head of Technical Operations, Adapt Pharma Ltd

12.00

New lung-tumour-penetrating nanocarrier designed for aerosolized chemotherapy Dr Rémi Rosière, Université Libre de Bruxelles

29 - 33

12.15

Oxytocin receptor expression but a lack of response to oxytocin in airway tissues Mr Jibriil Ibrahim, Monash Institute of Pharmaceutical Sciences

34 - 36

12.30

Anti-inflammatory activity of novel trans-stilbene sulfonamide analogues as 37 - 40 potential novel therapeutic agents for lung disease Mrs Rhamiya Mahendran, University of Hertfordshire

12.45

Networking Buffet Lunch in the Exhibition Hall & Poster Viewing

THURSDAY 8TH DECEMBER : PM

SESSION 3 THE PAT BURNELL NEW INVESTIGATOR AWARD 14.00

Characterisation of MRP1 in human distal lung epithelial cells in vitro Mr Mohammed Ali Selo, Trinity College Dublin

41 - 44

14.15

Carrier microstructure and performance of dry powder inhalation mixtures: A step towards universal performance prediction model Mr Ahmed O. Shalash, European Egyptian Pharmaceutical Industries

45 - 48

14.30

Development of inhalable drug formulations for idiopathic pulmonary fibrosis Mr Ville Vartiainen, University of Helsinki

49 - 52

14.45

Investigating the effect of the force control agent magnesium stearate in fluticasone propionate dry powder inhaled formulations with single particle aerosol mass spectrometry (SPAMS) Mr Martin Jetzer, Novartis Pharma AG

53 - 56

15.00

Influence of blender type on the performance of ternary dry powder inhaler formulations Mr Mats Hertel, Kiel University

57 - 60

15.15

Posters, Exhibition and Refreshments

SESSION 4 60 YEARS OF pMDI 16.00

The Future of Propellants for pMDIs Dr Tim Noakes, Medical Products Technical Associate, Mexichem & Stuart Corr, Mexichem

61 - 64

16.30

Next generation formulations for pMDIs Professor Glyn Taylor, Director of Research, i2c Pharmaceutical Services

65 - 68

17.00

Novel techniques for characterising inhalers Dr Alan McKiernan, Prior PLM Medical

69 - 72

17.20

Multi-physics theoretical approach to predict pMDI spray characteristics Dr Barzin Gavtash, Loughborough University

73 - 76

17.45 20.00 17.45 â&#x20AC;&#x201C;- 20.00 Entertainment Evening, Cromdale Hall, Conference Centre Poster Awards & Prize Giving Entertainment Evening by Centre Cromdale Sponsored Hall, Conference Poster Awards & Prize Giving Sponsored by (Add 3M Logo) 3

FRIDAY 9TH DECEMBER

08.00

Registration & Refreshments Exhibition Hall & Poster Viewing

SESSION 5 INNOVATIONS IN AEROSOL DELIVERY 09.00

Innovations in formulations to improve aerosol delivery Professor Peter York, Chairman and Chief Scientist, CrystecPharma

09.30

Aspergillus fumigatus in valved holding chambers: use of silver ion additive 78 - 81 technology on fungal activity and aerosol delivery characteristics Mr Mark Sanders, Clement Clarke International Ltd

09.50

In-silico lung modeling platform for inhaled drug delivery Dr Antonio Cabal, Merck & Co

10.10

Posters, Exhibition and Refreshments

11.20

m-health on asthma â&#x20AC;&#x201C; friend or foe Dr Stephen Fowler, The University of Manchester

11.50

Polymer-protein-based dry powder for efficient pulmonary protein delivery Mr Alejandro Nieto-Orellana, University of Nottingham

88 - 91

12.10

Multiplexed optical molecular sensing and imaging in the lungs Dr Kev Dhaliwal, University of Edinburgh

12.40

Concluding Remarks and Conference Close Gary Pitcairn, Chair, DDL Committee

82 - 86

Drug Delivery to the Lungs 27, 2016 – Samantha Walker, Asthma UK

The European Asthma Research & Innovation Partnership - tackling Europe’s high asthma prevalence and death rates Samantha Walker, Director, Research & Policy and Deputy Chief Executive, Asthma UK Abstract Asthma is highly prevalent and associated with high morbidity and mortality. It affects 30-50 million people in Europe1, often starting in infancy and persisting throughout the lifetime. Asthma is a major global health challenge with growing impact, affecting more than 300 million people worldwide and at least 10% of all Europeans. People with both severe and mild asthma live at risk of life-threatening asthma attacks, leading to at least 500,000 hospitalisations each year2. Approximately 5-10% of asthma cases are so severe that current treatments do not work. 3 people die of asthma every day in the UK. Despite the fact that the direct and indirect costs of asthma are high and continue rising, asthma remains underprioritised in the EU research agenda. Only 0.5% of the FP7 Health research budget was devoted to asthma and COPD (€30m)3. For comparison, over €163m were spent for cardiovascular conditions (5.4 times bigger), and over €618m for brain research (20.6 times bigger). This means that asthma presents a real opportunity for the EU to address a major societal challenge whilst driving substantial economic growth. The high global prevalence of asthma, with an equivalent multibillion global market for asthma drugs, it’s historical underfunding, and the unmet need for new treatments and diagnostics represents an enormous business opportunity. We recognise that a lot of excellent work and partnerships have been developed to tackle asthma. But it’s important to recognise also that Europe’s asthma research communities are still considered fragmented, typically working at a national level on discrete and complex sub-areas of the disease, and that there is an urgent need to develop better medicines, diagnostic methods and effective self-management tools. To capitalise on this opportunity, Asthma UK was commissioned by the European Commission Framework Programme 7 to define the research priorities for asthma through coordination of the European Asthma Research and Innovation Partnership (EARIP: www.earip.eu) EARIP has brought together researchers, industry representatives, patient groups and policymakers to undertake a comprehensive analysis of asthma research, including basic biology, new treatments, health and care systems, self-management and diagnostic tools, to develop a ‘roadmap’ for investment based on unmet need in asthma. Eight expert working groups comprising of world-leading researchers, clinicians, pharmaceutical company personnel and people with asthma carried out reviews of the scientific literature and identified research priorities in key areas of basic, translational and applied asthma science through large scale surveys and pan-European eDelphi consensus-building exercises. Representatives from each group then met to agree a single, coordinated agenda for asthma research and development (R&D). Fifteen over-arching research priorities were agreed which fall into four broad priority areas; personalised medicine, triggers and risk factors for asthma and exacerbations, self-management and adherence and primary care and public health4. Underpinning this is an urgent need for greater understanding of basic asthma mechanisms to drive the development of new treatments in the ~50% people who respond poorly to steroids 5; development of novel diagnostic technologies to allow the development of personalised intervention strategies; and to maximise the potential of digital platforms to transform problems associated with adherence and self-management. This R&D ‘roadmap’ forms the basis of plans to revolutionise the way that asthma is investigated and treated in Europe by attracting significant public and private investment as well as prioritising asthma research in the European medical research agenda. With targeted and focussed investment, this research would have dramatic implications for the lives of over 30million people living with asthma in Europe, whilst reducing healthcare costs, improving competitiveness, and providing a framework through which to solve other long term conditions.

Global Initiative for Asthma (GINA), 2004 Asthma Network (2014), The Global Asthma Report. 3 Decramer M, Sibille Y, eds. European Respiratory Roadmap. Sheffield, European Respiratory Society, 2011. 4 S. C. Masefield, (Sheffield, United Kingdom) et al. , Driving Investment in Asthma Research in Europe: Priorities to Prevent, Cure and Manage Asthma More Effectively. In: American Thoracic Society conference; 2016 May 1318; San Francisco, USA. A2668 1

2 Global

McGrath KW et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012 Mar 15;185(6):612-9. Epub 2012 Jan 20. 5

Drug Delivery to the Lungs 27, 2016 - The European Asthma Research & Innovation Partnership - tackling Europe’s high asthma prevalence and death rates

Having established the research gaps and priority areas for investment, it is vital that an integrated approach is taken to deliver these in order to maximise resource, and achieve the biggest impact for people with asthma, in the shortest space of time. Understanding how breakthroughs in one area will open the door to new developments in another is key to this; similarly, understanding who is best placed to fund and carry out R&D will enable the most coordinated approach to be adopted. Asthma UK is continuing to drive this integrated approach and through our soon-to-be launched 2016-21 research strategy will:    



Strive to fund a balanced mix of types of research. By doing this we link basic and applied science to create a pipeline of research innovation that speeds up the process through which new interventions reach people with asthma. Fund two Research Centres in the UK to develop a critical mass of researchers to collaborate, grow talent, build networks and act as hubs from which to lever greater research activity. Invest to expand the pipeline of world class asthma scientists and equip researchers across all disciplines to build more compelling asthma research applications by sharing our case for investment Actively promote collaborative working and patient and public involvement in asthma research. We will explore opportunities to organise ‘sandpit’ events with the aim of connecting researchers to write collaborative bids for funding for a specific priority research area. Patient and public involvement in research increases the quality and relevance of research and Asthma UK is committed to the promotion of this at all stages of research. Invest our funding where we think this will leverage additional financial support from other funders, and actively pursue different types of research funding partnership models to increase funding available for asthma research, subject to these meeting the same standards of governance as our existing funding.

However wisely Asthma UK directs its own limited research funding, to truly deliver better outcomes for people with asthma we must also be more active in driving European investment in asthma R&D. In the last 5 years there have been more calls on the limited research funds available globally, and we believe asthma has often been overlooked. We are proposing to make the case for asthma research as strongly as possible in the UK and internationally, to ensure asthma research receives a greater share of available research funding. We will be asking funders, institutions, researchers and academics to adopt and address the fifteen research priorities. This will improve collaboration and help us work more effectively towards common goals to improve the lives of the 300 million people living with asthma in Europe. We will be working with funders to adopt the roadmap in their funding decisions, and encouraging researchers to address the specific priorities using the funding offered in line with the priorities from the roadmap. Over the coming years we will also explore how best to encourage collaboration between researchers in the UK and across Europe to address these priorities. We will continue to work with the European Federation of Allergy and Airways Diseases Patients' Associations (EFA) to encourage organisations to adopt the Malaga-London declaration [http://www.efanet.org/malaga-londondeclaration] which is a call for the establishment of strategic framework for asthma research and for the provision of specific funding for asthma within the EU research and innovation funding programmes, as well as through specific initiatives at national level. It makes these calls for specific funding in line with the roadmap’s objectives and pulls together funder-researcher focus on to these areas. EFA will be asking its 28 members to write to members of the European Parliament and the relevant members of the council of ministers calling for EU support in the adoption of the patient declaration. Our engagement will continue with strategic partners in industry and in the Directorate-General responsible for Science, Research and Development in order to secure more investment through one of the European Commissions’ funding streams along the lines outlined in the research roadmap. Specifically, we are exploring the opportunity for a new public-private partnership between industry and the Commission that would drive the development of new therapeutic targets linked to emerging asthma phenotypes. We hope that if funding frameworks are set out alongside the roadmap we will not only see more investment, but also increased European collaboration. It is hoped that EARIP will also lay a stronger foundation for Europe's individual pharmaceutical and healthcare technology companies to grow, and create jobs, through the better identification of new therapeutic targets that will help boost competitiveness and accelerate innovations in healthcare systems and services. Lastly, for true innovation and better drug delivery to work the European Union and member nations also need to be ready for change. There is work to be done around a better regulatory framework for new or innovative treatments. National healthcare systems will have to find ways to fund drugs aimed at small patient cohorts and embrace technology to help managing ageing populations with chronic comorbidities. In summary, the identification of and cross-disciplinary agreement on the 15 most important priorities for investment in asthma R&D gives everyone the opportunity to work together across Europe to transform outcomes for people with asthma and drive growth and jobs. The development of new drugs and better diagnostic tools linked to biomarkers and a greater understanding of asthma mechanisms are fundamental to ensuring that everyone with asthma receives the medicine that works best for them and that asthma deaths are a thing of the past.

Drug Delivery to the Lungs 27, 2016 – Chrystyn H. Inhaler device and errors Chrystyn H Inhalation Consultancy Ltd, Tarn House, 77 High Street, Yeadon Leeds, LS19 7SP and RiRL, 5 Coles Lane, Oakington, Cambridge, CB24 3BA. Summary Inhalation errors have a significant impact on the disease control of asthma and chronic obstructive pulmonary disease (Melani AS et al. Respir Med. 2011;105(6):930-8; Al-Jahdali H et al; Allergy Asthma Clin Immunol. 2013;9(1):8. Westerik JA et al; J Asthma. 2016;53(3):321-329) with resultant economic burdens on the health care costs (Lewis A et al. BMC Health Serv Res. 2016; Jul 12, 16:251). The type and incidence of these errors has not changed over the past 40 years (Sanchis J et al. Chest. 2016;150(2):394-406). Analysis of published inhaler errors highlights that these can be categorised into dose preparation and inhalation manoeuvre errors. These categories are all generic for metered dose inhalers. Inhalation manoeuvre procedures are also generic errors when using dry powder inhalers whereas dose preparation steps are device specific. The CritiKal study, carried out throughout Western Europe and in Australia, examined inhaler errors and the level of asthma control in 3660 patients. This study has identified which inhalation technique errors are clinically significant. Also new invitro methods of identifying dose emission using patient inhalation profiles (Chrystyn H et al. Int J Pharm. 2015;491(12):268-76) are providing useful information about formulations that are not affected by how the patient inhales. Furthermore newer inhalers are now designed so that they are more intuitive to use. These latest contributions to the literature should direct healthcare professionals' counselling sessions when choosing an inhaler for a patient and training them how to use it. Introduction Problems using the correct inhaler technique have been reported to be associated with poor disease control in the management of asthma and chronic obstructive pulmonary disease [1] [2] [3]. It has been reported that errors when using either a metered dose inhaler (MDI) or dry powder inhaler (DPI) are significantly associated with an increased risk of hospitalisations, emergency room visits, increased antibiotic prescribing and increased prescribing of short course of oral prednisolone [1] as well as education level, the patient's age and follow up after inhaler training [1] [2] [3]. These studies have also shown that no previous inhaler technique training is significantly associated with errors. An economic costing model has identified the burden of poor inhaler technique in Spain, Sweden and the UK [4]. Taking into account hospitalisations, emergency room visits, increased antibiotic prescribing and oral prednisolone courses the annual cost of poor inhaler technique was €109, €55 and €21 per patient. Projecting these direct costs and adding indirect costs (such as lost productivity) revealed that the overall cost to each country was considerable. It is important that the clinical significance of inhaler errors is identified and steps are taken to focus on these because there has been no improvement with inhaler technique over the past 40 years [5] from when they were first identified [6]. Inhaler technique - scale of the problem and general classification of errors Recent systemic reviews [5] [7] and a meta-analysis [7] have shown that there are large number of patients that make errors when using their inhalers. The pooled estimate for the percentage of patients with a least one overall and one critical inhaler technique error when using MDIs was found to be 86.8% [95% confidence interval (CI) 79.4–91.9] and 45.6% [95% CI 26.0–66.6], respectively [7]. Similar error rates for DPIs were 60.9% [95% CI 39.4– 79.0] and 28.4% [95% CI 22.0–35.8], respectively [7]. Table 1 highlights that the problems when inhalers are used can be divided into dose emission, dose preparation and the inhalation manoeuvre. For MDIs all the problems shown in Table 1 are generic whereas for DPIs dose emission and dose preparation are unique to the DPI, hence they are device specific. Errors associated with the DPI inhalation manoeuvre are generic. The most common inhalation manoeuvre errors are no exhalation, not sealing the lips round the mouthpiece and not using a fast and deep inhalation as well as no breath hold. Table 1. Problems associated with inhaler use MDI devices Dose emission Consistent Dose preparation Errors are common: shake, upright Inhalation manoeuvre Errors are common: exhale, coordination, slow and deep inhalation, breath hold

DPI devices Ranges from consistent to erratic Errors are device specific Errors are common: exhale, seal lips, fast and deep inhalation, breath hold

Inhaler use problems (a) Dose emission One advantage of MDIs is that dose emission is always consistent whether this is at the beginning (BOL), middle (MOL) and end (EOL) of life for the doses available in the device [8]. In contrast dose emission from DPIs ranges from consistent [9] at BOl, MOL and EOL [10] to large inter- and intra- inhaler variability in the emitted dose [9] [11].

Drug Delivery to the Lungs 27, 2016 - Inhaler device and errors This DPI dose emission variability occurs despite preparing the dose according to the manufacturer's recommended dose preparation procedures in the Patient Information Leaflet. (b) Dose preparation Not shaking before actuating a dose and not holding the device upright are the common errors made by patients when using their MDIs [1]. Shaking the MDI is required because some formulations are a suspension of drug particles in the propellant while not holding the canister upright means that the next dose is not extracted from the formulation [12]. Many MDI formulations are now solutions so shaking before use may not be important but data about this is not available. Incorrect orientation of the DPI when preparing the dose is a very common error made by patients [1] [13]. Other issues during DPI dose preparation are shaking the device after the dose has been prepared [14] and exhaling into the device [1) [13]. Shaking a DPI after the dose has been metered reduces the dose available for inhalation whilst exhaling into the device introduces moisture to the formulation and thus affects dose emission [15]. These shaking and exhaling issues can only be solved by inhaler training whereas correct dose preparation can be solved by DPIs that are not dependent on the inhaler's orientation when the dose is metered [10]. Reducing the number of dose preparation steps and making DPIs more intuitive to use reduces the incidence of these dose preparation errors [14] [16]. (c) Inhalation manoeuvre Not using a slow inhalation and poor co-ordination when using a MDI are the two most common errors made by patients [17] [18]. When patients use a slow inhalation co-ordination is not important as long as the dose is actuated after the start of the inhalation [19]. Using a slow inhalation flow with a MDI improves asthma quality of life [17]. MDIs formulated so that the emitted dose emits extra-fine particles improves lung deposition and reduces the effect of the inhalation flow [20] as well as reducing the effect of poor co-ordination [21]. The generic instruction to use a 'slow and deep' inhalation is not clear and open to mis-interpretation. It has been recommended to replace this with an instruction to use an inhalation that lasts 5 seconds in an adult and 2-3 seconds in a child [22]. This objective instruction has been shown to slow down inhalation flows when patients use their MDI and during real-life use they maintain using a slow flow over the next 4 weeks [23]. Two large studies of real life inhaler technique have reported that almost a third of patients made inhalation manoeuvre errors when using their DPI [1] [13]. These common errors were not exhaling, not inhaling with a forceful and deep inhalation as well as not holding the breath at the end of each inhalation [1] [13]. A recent systematic review [5] has shown that 46% of patients[95% CI of 42%-50%] did not exhale before making an inhalation. Thirty seven percentage of patient [95% CI of 33%-40%] did not hold their breath after an inhalation. Not using a deep and forceful inhalation occurred in 16% [95% CI, of 13-20%] [5]. Another systematic review and meta analysis [7] has also revealed that the most common errors when using a DPI were no exhalation, no breath hold and not sealing the lips. What is the solution to the problems patients have using inhalers? It is essential to prescribe an inhaler that a patient can and will use [22]. A recently completed study, CritiKal [24], which is part of the iHARP asthma review service, involved 3660 adults with asthma throughout West Europe and in Australia. This study has identified which inhaler technique errors are associated with poorer asthma control. CritiKal has identified that the generic inhalation manoeuvre errors, identified above, are all related to poorer asthma control. Furthermore some clinically significant dose preparation errors have been identified [24]. The CritiKal study has, therefore, identified which clinically important (hence critical) errors to focus on during inhalation technique training. Novel in-vitro dose emission methodology which uses patient inhalation profiles to identify the type of dose the patient would have inhaled during real life use has been pioneered [25]. This method replaces the vacuum pumps traditionally used to measure dose emission. Vacuum pumps can only produce a square wave inhalation profile that no human can replicate. Using this new and novel methodology it has been shown that the dose emitted from some DPIs is not dependent on the speed of the inhalation [25]. Hence. if a patient uses a weak inhalation when using certain DPIs the emitted dose is the same as the emitted dose when using a strong inhalation [25]. Using devices that are intuitive to use [14[ [16] will reduce the incidence of dose preparation errors and help to maintain the trained inhalation technique during real life use [14] while patient satisfaction with the device improves patient compliance [26]. Wherever possible patients should be prescribed the same type of device for their medications (either all MDIs or all DPIs). It has recently been reported that patients with COPD who mix devices (MDI and DPI) have more exacerbations than those that use similar devices [27]. The cost of producing most salbutamol DPIs compared to the much lower remuneration that would be received for these salbutamol devices limits their availability. Summary The problems that patients have using their inhalers are common and result in poorer disease control and increased healthcare costs. The Critikal study has identified the clinically significant inhaler technique errors made by patients and these should be the focus during inhaler technique training. Mixing devices should be minimised but this may not be easy because of the limited availability of salbutamol DPIs. Using devices that are more intuitive, easy to use and preferred by patients as well as using devices whose emitted dose is not dependent on the inhalation flow and focusing training on the potential errors that give rise to poor disease control will help to solve the problems patients have using their inhalers.

Drug Delivery to the Lungs 27, 2016 – Chrystyn H.

References [1]. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, Serra M, Scichilone N, Sestini P, Aliani M, Neri M; Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011; 105(6): pp930-938. [2]. Al-Jahdali H, Ahmed A, Al-Harbi A, Khan M, Baharoon S, Bin Salih S, Halwani R, Al-Muhsen S. Improper inhaler technique is associated with poor asthma control and frequent emergency department visits. Allergy Asthma Clin Immunol. 2013; 9(1):8. [3]. Westerik JA, Carter V, Chrystyn H, Burden A, Thompson SL, Ryan D, Gruffydd-Jones K, Haughney J, Roche N, Lavorini F, Papi A, Infantino A, Roman-Rodriguez M, Bosnic-Anticevich S, Lisspers K, Ställberg B, Henrichsen SH, van der Molen T, Hutton C, Price DB. Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting. J Asthma. 2016; 53(3): pp321-329. [4]. Lewis A, Torvinen S, Dekhuijzen PN, Chrystyn H, Watson AT, Blackney M, Plich A. The economic burden of asthma and chronic obstructive pulmonary disease and the impact of poor inhalation technique with commonly prescribed dry powder inhalers in three European countries. BMC Health Serv Res. 2016; 6: 251. [5]. Sanchis J, Gich I, Pedersen S; Aerosol Drug Management Improvement Team (ADMIT). Systematic Review of Errors in Inhaler Use: Has Patient Technique Improved Over Time? Chest. 2016; 150(2): pp394-406. [6]. Paterson IC, Crompton GK. Use of pressurised aerosols by asthmatic patients. Brit Med J. 1976; 10th January: pp76-77. [7]. Chrystyn H, van der Palen J, Sharma R, Barnes N, Delafont B, Mahajan A, Thomas M. Device errors in COPD and asthma: systematic literature review and meta-analysis. (manuscript submitted). [8]. Cripps A, Riebe M, Schulze M, Woodhouse R. Pharmaceutical transition to non-CFC pressurised metered dose inhalers. Respir Med 2000; 94 (Suppl B): ppS3-S9. [9]. Palander A, Mattila T, Karhu M, Muttonen E. In-vtro comparison of three salbutamol containing multidose dry powder inhalers. Clin Drug Invest. 2000; 20: pp25-33. [10]. Canonica GW, Arp J, Keegstra JR, Chrystyn H. Spiromax, a New Dry Powder Inhaler: Dose Consistency under Simulated Real-World Conditions. J Aerosol Med Pulm Drug Deliv. 2015; 28(5): pp309-19. [11]. Tarsin W, Assi KH, Chrystyn H. In-vitro intra- and inter-inhaler flow rate-dependent dosage emission from a combination of budesonide and eformoterol in a dry powder inhaler. J Aerosol Med. 2004;17(1): pp25-32. [12]. Byron P. Performance Characteristics of Pressurized Metered Dose Inhalers in Vitro. J Aerosol Med 1997; 10(1): pp S3-S6. [13]. Molimard M, Raherison C, Lignot M, Depont F, Abouelfath A, Moore N. Assessment of handling of inhaler devices in real life: An observational study in 3811 patients in primary care. J Aerosol Med 2003; 16: 249254. [14]. Chrystyn H, Dekhuijzen R, Rand C, Bosnic-Anticevich S, Roche N, Lavorini F, Thomas V, Steele J, Raju P, Freeman D, Small IR, Canvin J, Price DB. Evaluation of Inhaler Technique Mastery for Budesonide Formoterol Spiromax® Compared with Symbicort Turbohaler® in Adult Patients with Asthma Primary Results From the Easy Low Instruction Over Time [ELIOT] Study. Thorax. 2015 ;70 (Suppl 3): ppA154. [15]. Holmes MS, Seheult JN, O'Connell P, D'Arcy S, Ehrhardt C, Healy AM, Costello RW, Reilly RB. An Acoustic-Based Method to Detect and Quantify the Effect of Exhalation into a Dry Powder Inhaler. J Aerosol Med Pulm Drug Deliv. 2015; 28(4): pp247-53. [16]. van der Palen J, Thomas M, Chrystyn H, Sharma RK, van der Valk PDLPM, Goosens M, Wilkinson T, Stonham C, Chauhan AG, Imber V, Zhu C-Q, Svedsater H, Barnes NC. An open label crossover study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA® with other inhaler devices. NPJ Prim Care Resp Med. in press. [17]. Al-Showair RA, Pearson SB, Chrystyn H. The potential of a 2Tone Trainer to help patients use their metered-dose inhalers. Chest. 2007; 131(6): pp1776-82. [18]. Levy ML, Hardwell A, McKnight E, Holmes J. Asthma patients' inability to use a pressurised metered-dose inhaler (pMDI) correctly correlates with poor asthma control as defined by the global initiative for asthma (GINA) strategy: a retrospective analysis. Prim Care Respir J. 2013; 22(4): pp406-411. [19]. Newman SP, Pavia D, Garland N, Clarke SW. Effect of various inhalation modes on the deposition of radioactive pressurized aerosols. Eur J Respir Dis 1982; 63 (Suppl 119): pp57-65. [20]. Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of beta-2 agonist particle size. Am J Respir Crit Care Med 2005; 172: pp1497-1504. [21]. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler. J Aerosol Med. 2005; 18(4): pp379-85. [22]. Laube BL1, Janssens HM, de Jongh FH, Devadason SG, Dhand R, Diot P, Everard ML, Horvath I, Navalesi P, Voshaar T, Chrystyn H; European Respiratory Society; International Society for Aerosols in Medicine. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011; 37(6): pp1308-31. [23]. El Larhrib, Jones H, Rawson S, Chrystyn H. Train patients to prolong their inhalation manoeuvre when using a metered dose inhaler (MDI). J Aerosol Med Pulm Drug Del. 2015; 28(3): A11.

Drug Delivery to the Lungs 27, 2016 - Inhaler device and errors [24]. Price DB, Roman-Rodriguez M, McQueen RB, Bosnic-Anticevich S, Carter V, Gryffud-Jones K, Harris M, Haughney J, Henrichsen S, Infantino A, Lavorini F, Lisspers K, Papi A, Ryan D, Stallberg B, van der Molen T, Chrystyn H. Inhaler errors in the CRITIKAL study: type, frequency and association with asthma control . Manuscript in preparation. [25]. Chrystyn H, Safioti G, Keegstra JR, Gopalan G. Effect of inhalation profile and throat geometry on predicted lung deposition of budesonide and formoterol (BF) in COPD: An in-vitro comparison of Spiromax with Turbuhaler. Int J Pharm. 2015: 491(1-2): pp268-276. [26]. Chrystyn H, Small M, Milligan G, Higgins V, Gil EG, Estruch J. Impact of patientsâ&#x20AC;&#x2122; satisfaction with their inhalers on treatment compliance and health status in COPD. Respir Medi. 2014; 108, pp358-365. [27]. Bosnic Anticevich S, Chrystyn H, Costello R, Dolovich M, Fletcher M, Lavorini F, RodrĂguez-Roisin R, Ryan D, Wan Yau Ming S, Skinner D, Earnest A, Law LM, Price DP. Impact of using multiple devices with mixed inhalation techniques on COPD outcomes: an observational study. Int J Chron Obstruct Pulmon Dis (in press)

Drug Delivery to the Lungs 27, 2016 - Julian Dixon Human Factor Considerations in Inhaler Innovation Julian Dixon1 1

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

Summary A human factors perspective on inhaled drug products illuminates a range of opportunities for meeting user needs. This paper will review and outline this range. Introduction Over recent years there has been considerable growth in the attention paid to human factors engineering/usability engineering (HFE/UE) on drug/device combination product developments, including OINDPs. This has primarily been focused on ensuring regulatory requirements regarding HFE objectives and process are met. The potential of the HFE/UE perspective for future inhaler device design, of course, goes beyond this focus on user error, patient safety and regulatory approval. This paper reviews and outlines this broader potential: the different ways in which human factors illuminates opportunities for innovation and improvement of inhaler device design. Improving the ‘human fit’ of inhalers The opportunities suggested by a focus on the human factors of inhaled products range in scale, from small readily achievable incremental improvements (‘low hanging fruit’) to those which would involve major long term technology development programmes and which might even be disruptive. Low hanging fruit will be exposed simply by engaging seriously with the HFE process throughout a development project. Better HFE will, at the very least, eliminate avoidably poor interface design decisions. Best practice HFE process is fundamental to achieving better detailed embodiment design. Sufficient and iterative formative research is key. Similarly, challenging and testing the real world effectiveness of instructional materials, including instructions for use (IFUs), will yield small improvements that benefit our users. A broader engagement with how these materials are experienced by users suggests opportunities for improvements. Industry engagement with regulatory agencies is likely to be needed to ensure that these improvements can be realised. A natural extension of this engagement with user experience is the increased and joined-up use of diverse technologies and media for training support and training aids. The established discipline of Inclusive Design focuses attention on the range of capabilities of our intended user populations and of designing interfaces that fall within the capabilities of as many individuals as possible. The drive to expand the inclusivity or universality of a general platform product design can be contrasted with the development of devices tailored or targeted to specific uses. Both represent opportunities. The HF validation study can, too readily, become the sole emphasis of HFE. Proper engagement with HFE will shift attention to its role earlier in development. Attention to preparatory HFE analysis has great potential to influence the clarity of the product concept / vision. And as device design progresses, early HF studies should be formative in terms of impact not just in name. The perspectives described above can be fruitfully applied to inhalers employing standard platform technologies. The platform technologies have well understood limitations that impact on their usability, but this does not mean that HFE cannot minimise or address many of them. High quality HF analysis at the earliest stages of development can direct effort effectively in this regard, including the choice of which platform technology to select at the outset. Giving proper weight to human factors considerations will also influence the trade-offs made between technical device performance and usability, between in-vitro performance under standardised conditions and real world performance in the hands of users. When considering potential new platform technologies, HF will again offer a different perspective on what counts as a good, or as the best, inhaler design. It will suggest different goals. HF will have important inputs to make to the direction and development of ‘connected’ inhalers, for example. In summary, human factors will be a key voice in future inhaler device development. It will carry weight alongside technical performance considerations.

Drug Delivery to the Lungs 27, 2016 – Mandana Azimi et al. Clinically relevant in vitro tests for the assessment of innovator and generic nasal spray products 1

Mandana Azimi , P. Worth Longest

1, 2

, Jag Shur , Robert Price & Michael Hindle

Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, USA Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, 23298, USA 3 Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK

Summary In order to establish equivalence between innovator and generic nasal spray suspension products, similar regional drug deposition at their site of action in the nasal cavity needs to be ensured. The use of realistic models of the nasal airways together with testing using simulated patient use conditions may provide a rapid and inexpensive in vitro assessment of these nasal spray products. The regional deposition of an “in house” mometasone furoate nasal spray and a commercially available generic fluticasone propionate nasal spray test products were compared with their respective innovator products using realistic in vitro testing methods. Three sets of simulated patient use experimental conditions were chosen to compare regional deposition in two realistic nasal airways models (VCU models 1 and 2) in an attempt to simulate in vivo variability and to provide a range of expected middle passage nasal depositions. Based on the in vitro experiments, the middle passage and nasopharynx drug deposition of the “in house” mometasone furoate and fluticasone propionate generic nasal ® ® sprays were not significantly different than their respective innovator products, Nasonex and Flonase across the three different experimental conditions in the two nasal airway models. The developed in vitro test methods may offer a useful, and realistic way to differentiate nasal spray products. Future studies will evaluate the effect of nasal spray plume characteristics (droplet size, plume geometry) on the regional nasal drug deposition to assess the sensitivity of these methods to detect differences in nasal sprays. Introduction The use of realistic physical nasal airway models has become an emerging tool to investigate and compare locally acting nasal spray products. In order to establish equivalence between innovator and generic nasal spray suspension products, similar regional drug deposition at their site of action in the posterior part of the nose or [1, 2] . Realistic in vitro testing methods may offer a rapid and nasal middle passages needs to be ensured inexpensive means of screening nasal spray products compared to radiolabelled imaging and clinical studies. Furthermore, compared to the currently employed in vitro nasal spray product characterization methods which focus on the device and formulation performance, realistic in vitro test methods may also consider the interplay [3] between device, formulation, patient use variables and the resulting nasal drug deposition . Previously, an in vitro regional deposition testing method was described that revealed the importance of patient use factors and the ® geometry of the nasal cavity in determining the in vitro regional nasal deposition of the Nasonex nasal spray product. A full factorial design of experiment approach was used to assess the effects of patient related factors, including nasal spray position in the nose, head angle, the nasal spray actuation-nasal inhalation timing and applied actuation force and their interactions, together with the influence of nasal airway geometry on regional [4, 5] . Nasal middle passage deposition was observed to vary from 16.6 to 57.1% in VCU nasal drug deposition ® model 1 and 46.6 to 77.4% in VCU model 2 when tested in this realistic manner for the Nasonex nasal spray product. The utility of this realistic in vitro nasal deposition method will now be investigated using an “in house” and a commercially available generic nasal spray product, that have similar droplet size and plume characteristics compared to their respective innovator products. Therefore, the objective of this study is to compare the regional nasal drug deposition of these generic and innovator nasal spray products using previously developed realistic in vitro testing methods with a series of realistic experimental conditions in two nasal airways. Materials and Methods The regional nasal deposition of an “in house” mometasone furoate nasal spray, 50 μg (University of Bath, Bath, ® UK BN# MFM11T F9) was characterized and compared with the innovator product, Nasonex ,50 μg (Merck & Co. Inc., Whitehouse Station, NJ, USA) in the VCU nasal models 1 and 2. The “in house” formulation was designed for experimental purposes to be a generic copy of the innovator product with respect to droplet size and plume characteristics. The regional nasal deposition was tested using the experimental set-up shown in Figure 1, that includes an automated nasal spray actuator (Mighty Runt, InnovaSystems Inc., Moorestown, NJ, USA), the VCU nasal model (VCU model 1 or 2) and a programmable breath simulator (ASL 5000-XL, IngMar Medical, Pittsburgh, PA). The VCU nasal model 2 has a larger nasal vestibule surface area compared to VCU model 1 2 2 (14.94 cm vs 11.52 cm ), and the overall surface area/volume ratio for VCU model 2 was also larger than -1 -1 [5] observed in VCU model 1 (1.33 mm vs 0.74 mm ) . Based on previous studies, test conditions for VCU nasal model 1 and 2 were selected to produce low, intermediate and high combined middle passage and nasopharynx [4, 5] . For VCU model 2, only one nasal spray position was identified for testing due to its drug deposition (Table1) smaller nostril hydraulic diameter.

Drug Delivery to the Lungs 27, 2016 – Clinically relevant in vitro tests for the assessment of innovator and generic nasal spray products Similarly, the regional nasal deposition of fluticasone propionate nasal spray 50 μg (Roxane Laboratory, Ohio, ® USA) was characterized and compared with Flonase Nasal Spray, 50 μg, (GlaxoSmithKline, Research Triangle Park, NC, USA) using the experimental conditions and models described in Table 1, with only a single actuation [6] force of 5.8kg employed which was derived from the studies of Doughty et al . For each in vitro deposition experiment, 2 actuations of the nasal spray were delivered into a single nostril, the regional deposition of the drug was measured at four locations, (i) the nasal spray device, (ii) the anterior nose region + the amount of formulation dripped from the nose, (iii) middle passages + nasopharynx and (iv) throat + low resistant inspiratory filter at the exit of the throat. Validated HPLC assays were employed to determine the amount of drug deposited at each location and results were expressed as a percentage of recovered dose. Student t-test was used to compare the regional drug deposition of the “in house” mometasone furoate nasal spray with its innovator product and the generic fluticasone propionate with its innovator nasal spray product across the range of experimental conditions in the two nasal models (JMP Pro 12 software; p-value < 0.05).

Figure 1. Schematic diagram of experimental setup for the realistic in vitro nasal deposition studies Table 1. Experimental conditions for testing of nasal spray products using VCU nasal models 1 and 2.

Expected combined middle passage and nasopharynx regions drug deposition

Actuation force (kg)

Nasal spray a position (mm)

Head angle

Inhalation and b actuation timing

VCU Model 1 Level 1- Low (~ 20%) Level 2- Intermediate (~40%) Level 3- High (~60%)

7.5 7.5 7.5

9 5 5

50° 30° 50°

E D D

VCU Model 2 Level 1- Low (~ 50%) Level 2- Intermediate (~60%) Level 3- High (~77%)

7.5 4.5 4.5

NA NA NA

30° 30° 50°

E D D

a b

Distance between nasal spray applicator and the tip of the nose[4] Inhalation-actuation timing: E - inhalation started at the end of actuation, D - actuation during inhalation[5]

Results and Discussion ®

Middle passage and nasopharynx nasal drug deposition for the “in house” mometasone furoate and Nasonex nasal spray products in the VCU nasal models are summarized in Table 2 for low, intermediate and high, deposition conditions. The total drug recovery for these experiments ranged from 85.0 to 100.8%. The amount of drug deposited on the nasal spray device was lower than 3.0% and no drug recovered from filter positioned at the end of the nasal model. As shown in Table 2, there were no statistical differences for the amount of drug that deposited in the middle passage + nasopharynx region for paired experiments with the “in house” mometasone furoate and innovator product using the three different experimental conditions performed with VCU nasal models 1 and 2. Depending upon the experimental conditions, drug delivery to the middle passages varied from 20.2% to 59.1% (2.9-fold change) for the “in house” product and 16.6% to 57.1% (3.4-fold change) for the innovator product using VCU nasal model 1. Similar values in VCU nasal model 2 were 49.6-70.9% (1.4-fold change) and 46.677.4% (1.7-fold change), respectively. For comparison, conventional in vitro characterization of the spray droplet particle size distribution showed mean (SD) median volume droplet diameters of 47.2 (1.7) m and 44.5 (2.7) m, respectively, for the “in house” mometasone furoate and innovator nasal spray products while measured at actuation force of 7.5kg.

Drug Delivery to the Lungs 27, 2016 – Mandana Azimi et al. Table 2. Mean (standard deviation) in vitro middle passage and nasopharynx nasal drug deposition (expressed as a percentage of recovered dose) for the “in house” mometasone furoate and its innovator nasal spray product in VCU models 1 and 2.

Expected middle passage + nasopharynx drug deposition

Level 1-Low Level 2-Intermediate Level 3-High

Model 1 “In house” mometasone furoate 20.2 (3.2) % 37.0. (9.9) % 59.1 (6.8) %

Model 2 Nasonex

16.6 (2.4) % 34.1 (3.1) % 57.1 (9.4) %

“In house” mometasone furoate 49.6 (10.7) % 62.1 (13.8) % 70.9 (6.5) %

Nasonex

46.6(10.0) % 61.6 (9.6) % 77.4 (8.5) %

The regional drug deposition for the generic fluticasone propionate and innovator nasal spray products are summarized in Table 3. There were no statistical differences found in the amount of drug delivered to the middle passage and nasopharynx in paired experiments for these two nasal spray products using three different experimental conditions performed in VCU nasal models 1 and 2. Depending upon the experimental conditions, drug delivery to the middle passages varied from 17.5% to 39.5% (2.2-fold change) for the generic product and 21.0% to 47.2% (2.2-fold change) for the innovator product using VCU nasal model 1. Similar values in VCU nasal model 2 were 64.6-78.6% (1.2-fold change) and 55.6-79.6% (1.4-fold change), respectively. For comparison, conventional in vitro characterization of the spray droplet particle size distribution showed mean (SD) median volume droplet diameters of 69.4 (2.1) m and 70.8 (1.4) m, respectively, for the generic and innovator fluticasone propionate spray products at actuation force of 5.8kg. Comparing all the nasal spray products, there were no statistical differences in the recovered drug dose when tested using the low, intermediate and high deposition conditions in VCU models 1 and 2. Across both drug products, the variability in drug deposition in the middle passages appears more sensitive to the patient use testing parameters in VCU model 1, and overall there was a trend towards higher middle passage drug deposition observed in VCU model 2, both of which may be reflective of in vivo variability. Table 3. Mean (standard deviation) in vitro middle passage and nasopharynx nasal drug deposition (expressed as a percentage of recovered dose) for the generic fluticasone propionate and its innovator nasal spray product in VCU models 1 and 2.

Expected middle passage + nasopharynx drug deposition

Level 1-Low Level 2-Intermediate Level 3-High

Model 1 Generic fluticasone propionate 17.5 (1.0) % 42.7 (4.1) % 39.5 (5.9) %

Model 2 Flonase

21.0 (3.8) % 41.7 (8.4) % 47.2 (10.4) %

Generic fluticasone propionate 64.6 (4.8) % 74.5 (3.3) % 78.6 (5.6) %

Flonase

55.6 (7.3) % 68.1 (10.8) % 79.6 (0.3) %

Conclusions The regional drug deposition of innovator and generic nasal spray products of two drugs, mometasone furoate and fluticasone propionate, were characterized using realistic in vitro test methods. An ‘in house’ mometasone furoate nasal spray product was not significantly different from its innovator product with respect to drug deposition at the local sites of action within the middle passages of two realistic nasal airway geometries. Similarly, there was no deposition differences observed for a generic fluticasone propionate nasal spray product and its innovator using the realistic in vitro testing method. The range of local deposition observed using the patient use testing parameters and the two nasal models may be reflective of potential in vivo variability in nasal deposition. These realistic testing methods could have utility as an inexpensive tool for early evaluation of regional nasal deposition and with future in vivo validation may offer an efficient means of evaluating equivalence of nasal spray products. Acknowledgments Funding was provided by Contract # HHSF223201310220C, from the Department of Health and Human Services (DHHS), Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily reflect the official policies of the DHHS; nor does any mention of trade names, commercial practices or organizations imply endorsement by the United States Government. The technical support of IngMar Medical (ASL 5000-XL Breath Simulator) and InnovaSystems Inc (Mighty Runt Actuator Station) is gratefully acknowledged. The authors wish to thank Guenther Hochhaus, Renish Delvadia, Bhawana Saluja and Mohammad Absar for their assistance and useful discussions during the planning of this study.

Drug Delivery to the Lungs 27, 2016 â&#x20AC;&#x201C; Clinically relevant in vitro tests for the assessment of innovator and generic nasal spray products

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Shah S A, Berger R L, McDermott J, Gupta P, Monteith D, Connor A, Lin W: Regional deposition of mometasone furoate nasal spray suspension in humans, Allergy Asthma Proc 2015; 36: pp48-57. Djupesland P G: Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review, Drug Deliv Transl Res 2013; 3: pp42-62. FDA Draft Guidance (2003) Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action. Azimi M, Longest P W, Hindle M: Towards clinically relevant in vitro testing of locally acting nasal spray suspension products. In: R N Dalby, P R Byron, J Peart, J Suman, P Young and D Traini (eds): Respiratory Drug Delivery Europe 2015. DHI Publisher, River Grove, IL; pp121-130, 2015. Azimi M, Longest P W, Hindle M, Walenga R L: Comparison of the in vitro deposition of nasonex nasal spray product in two realistic nasal airway models. In: R N Dalby, P R Byron, J Peart, J Suman, P Young and D Traini (eds): Respiratory Drug Delivery 2016. DHI Publishing, River Grove, IL; pp617-622, 2016. Doughty D V, Vibbert C, Kewalramani A, Bollinger M E, Dalby R N: Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings, Drug Dev Ind Pharm 2011; 37: pp359- 366.

Drug Delivery to the Lungs 27, 2016 â&#x20AC;&#x201C; John N Pritchard Innovations in nebulized delivery John N Pritchard Respironics Respiratory Drug Delivery (UK) Ltd, a business of Philips Electronics UK Limited, Chichester, PO20 2FT, UK. Summary In recent years, much of the focus of novel treatments for respiratory diseases has been in the development of inhalers containing new, longer-acting compounds in established drug classes, either alone or in combination. However, there remain patients who are unable to use such devices properly, who rely upon nebulized therapy, yet there have been few new drugs marketed in nebulized form in the last 30 years. This undoubtedly has had a negative impact on disease control. A novel approach to development is to focus first on bringing the nebulized formulation to market, and only to start development of the inhaler once the new drug candidate has successfully demonstrated safety and efficacy. Not only does this mitigate the risks associated with developing an inhaler formulation only for the drug to fail in the clinic, it also studies drug outcomes in the most severe group of patients, in whom a positive effect should be easiest to demonstrate. This can reduce the commercial barriers to the introduction of new nebulized drugs, thereby ensuring such patients have access to the latest innovations in drug development. Parallel device developments will ensure this market continues to grow at a faster rate than that of the overall inhaler market. Innovations such as small volume, breath activated mesh nebulizers are likely to see the gap narrow between the treatment times for inhaler and nebulizer use, whilst the added benefits of an electronic-based technology will lead to adoption of patient monitoring approaches in inherently more at-risk patient populations. Introduction

Estimated number of doses (Millions)

In recent years, much of the focus of novel treatments for respiratory diseases has been in the development of inhalers containing new, longer-acting compounds in the classes of ď ˘-agonists, muscarinics and combinations, either together or with a corticosteroid [1]. Accompanying this has been the introduction of new dry power inhalers and/or engineered particle formulations. These are suitable for the vast majority of patients. Nonetheless, there remain classes of patient, notably the very young, very old and very sick, who are unable to use such devices properly. These patients rely upon nebulized therapy, a delivery system that has been in existence for over 150 years. Yet there have been very few new drugs marketed in nebulized form in the last 30 years. Despite this lack of new product introductions, nebulized treatments are still estimated to be growing faster than those delivered by inhalers (Figure 1 [2]). Globally, this may in part be due to increasing longevity in the general population. However, this is also being driven by increasing access to medicines in developing economies, to the extent that nebulized treatments are now the largest value segment in China [3].

40000

MDI (+2.7% p.a.)

35000

DPI (+1.8% p.a.)

30000

Nebs (+3.3% p.a.)

25000 20000 15000 10000 5000 0 1995

2000

2005

2010

2015

Year

Figure 1 - Estimated global number of inhaled doses of medication by delivery system (adapted from [1]).

Drug Delivery to the Lungs 27, 2016 – Innovations in nebulized delivery Nevertheless, patients on nebulized therapy are unable to access the latest drug developments. This undoubtedly has had a negative impact on disease control. Take for example, the case of a COPD patient who exacerbates and is hospitalized in the US. Upon discharge, 50% are prescribed a nebulized treatment [4], most commonly a combination of short-acting -agonist and muscarinic drugs. Thus, their burden of disease can shift from taking treatment from an inhaler once or twice per day, to a series of 4 nebulized treatments, each lasting several minutes. It is well documented that increased treatment burden adversely affects adherence [5] and it has been estimated that a reduction in adherence of 20% leads to an increase in adverse events in COPD patients of over 10% [6]. It is not surprising, therefore, that once-daily nebulized bronchodilators have been described as a “compelling market opportunity” [4]. However, to date, this opportunity has been largely overlooked; this paper looks at key barriers to the introduction of new nebulized therapies and current initiatives to overcome them. Changing the development paradigm Pharmaceutical companies often begin inhalation drug developments with nebulizers in the early stages, to provide cheaper and faster drug development, but then switch to inhaler devices in later clinical trials to address the majority of patients. Typically it can take 10 to 12 years to launch the new drug onto the market. As a completely different delivery system and formulation, nebulized products will require fresh dose-ranging and pivotal Phase III studies, which will again take some 5 years or more to gain marketing approval. This means that there is little of the original drug patent life left by the time the nebulized formulation reaches the market. As a consequence, unless formulation patents can be obtained on the nebulized formulation, there is insufficient time left to recover the investment in developing this product before generic copies enter the market. Thus, by leaving nebulized development until late in the drug’s life-cycle makes the development of a new drug in nebulized form commercially unattractive. In order to overcome this problem, one company (Mylan) has decided to go straight to market with a new long-acting muscarinic (LAMA) drug moiety in nebulized form [7], despite having previously successfully developed a different LAMA for use in inhalers [8]. Building on this, a novel approach to development is to focus first on bringing the nebulized formulation to market, and only to start development of the inhaler once the new drug candidate has successfully demonstrated safety and efficacy. Not only does this mitigate the costs associated with developing an inhaler formulation only for the drug to fail in the clinic, it also studies drug outcomes in the most severe group of patients, in whom a positive effect should be easiest to demonstrate. This has also been modelled from a financial perspective, calculating the expected Net Present Value (eNPV, the value in today’s terms of cash flows expected from the project in the future, scaled down by the likelihood of success) under varying conditions of peak annual sales for the drug, and interest on the cash equivalent (Discount rate). This is shown in Figure 2 [9].

Figure 2 - Financial returns improve if developing a nebulized formulation before an inhaler (blue), rather than as lifecycle management (green) or an inhaler alone (red) (adapted from [9]).

Drug Delivery to the Lungs 27, 2016 – John N Pritchard It transpires that there is likely to be a much greater financial return than that from adopting a traditional approach to development of the inhaler first. Additionally, nebulized products can command a higher price per dose, and whilst device costs for nebulized products are higher as an initial outlay, they can be amortized over months or years of treatment, making them similar overall to those of a portable inhaler. Furthermore, the capital investment in device production is borne by the nebulizer manufacturer; it does not require an often lengthy development of a bespoke inhaler, and some nebulizers are available immediately with medical device market authorization. If this novel approach to development is adopted moving forward, then the commercial barriers to the introduction of nebulized drugs are significantly reduced, thereby ensuring patients requiring nebulized therapy have access to the latest innovations in drug development. Improving the usability of nebulizers Nebulizers are inherently relatively simple to use, in that the patient is only required to put the formulation into the device and then breathe through it using their natural tidal breathing pattern until delivery is complete. However, for jet nebulizers, there are drawbacks to the patient, including the noise of the compressor, lack of portability, treatment time and cleaning regimen. As a consequence, vibrating mesh nebulizers are gaining increasing popularity, as they address many of the above limitations [10]. As may be seen from Figure 3, they are capable of delivering a wide variety of formulations, so are suited to the delivery of most drugs. Indeed for drugs with low potency, nebulizers may be the only suitable delivery system. Mesh nebulizers are also assuming increasing use in a hospital setting, and with new developments such as mesh nebulizer systems for use in the emergency room (Aerogen UltraTM, Aerogen, Galway, Ireland), it is possible to have a single droplet generation system that can be bridged from in-line ventilator use right through to home use. If new drugs are forthcoming, then using state-of-the-art nebulizers will become increasingly important, as regulatory authorities expect a new drug only to be promoted with nebulizers for which the developer has clinical experience. Increasingly, the drug market authorization will be as a specific drug-device combination product. New, breathactivated mesh nebulizers with low residual volumes, mean that the dose from 2.5 mL of a current nebulizer formulation can be delivered in as little as 0.25 mL. Indeed, there is a novel nebulizer in development for the delivery of inhaled insulin that is capable of delivering doses as low as 50 µL with residual volumes less than 20% [11]. Such small volumes reduce treatment times to one or two breaths. The diameter of the apertures in the mesh can also be controlled to sub-micron tolerances [12], enabling the droplet size to be optimized for a particular mechanism of action. High efficiency may be particularly important in the development of treatments involving macromolecules. Not only are such drugs expensive to manufacture, they are inherently less potent, thereby requiring doses beyond those for which conventional inhalers are capable of delivering, not to mention any additional excipients required to enhance cell penetration. Furthermore, large doses will drive the development of faster output nebulizers in order to maintain an acceptable treatment time. Due to their inherently efficient use of energy, mesh nebulizers are likely to lead the way. This might be through increased hole density, larger aperture plates, or higher vibration frequencies.

Figure 3 - Variation in physicochemical properties of formulations successfully delivered using a vibrating mesh nebulizer (reproduced with permission from Respiratory Drug Delivery 2014, Virginia Commonwealth University and RDD Online [13]). Small molecules (●), proteins/peptides (●), liposomes (●), suspensions (●), and surfactants (●). Bars represent a range of values measured over a range of concentrations.

Improving adherence to therapy However good the device and drug, a therapy will be ineffective unless the patient is motivated to take their medication. Many factors influence this, so feedback from the device on correct operation can be important [14]. With

Drug Delivery to the Lungs 27, 2016 â&#x20AC;&#x201C; Innovations in nebulized delivery a breath-activated mesh nebulizer, it is possible to log when and how the device has been used and upload the information to a server [15]. This information is helpful in understanding the challenging nature of true adherence, and may be crucial to the development and assessment of interventions to promote adherence; it allows patient, physician or support personnel such as relatives to monitor, provide feedback or coach the patient to improve adherence and technique. In the future, monitoring symptoms and capturing the data in the same system may offer even greater benefits, both by ensuring there is optimum treatment and by providing positive feedback to the patient to encourage proper adherence and manage their disease. Concluding remarks Patients requiring nebulized therapy have not benefitted from the recent spate of new products launched in inhaler format for the treatment of asthma and COPD. This situation is changing, as companies begin to recognize this unmet need. Parallel developments in the device technology will ensure this market continues to grow at a faster rate than that of the overall inhaler market. Innovations in nebulized delivery are likely to see the gap narrow between the treatment times for inhaler and nebulizer use, whilst the added benefits of an electronic-based technology will lead to rapid adoption of patient monitoring approaches in what are inherently more at-risk patient populations. References 1

Pritchard J N: Industry guidance for the selection of a delivery system for the development of novel respiratory products. Expert Opin Drug Deliv 2015; 12:11; pp1755-1765.

United Nations Environmental Programme: Report of the Technology and Economic Assessment Panel Volume 1. June 2015. Available at http://ozone.unep.org/en/teap-june-2015-progress-report-volume-1

Shen A: Market analysis of inhalation products for asthma and COPD in China. Presented at: Management Forum Inhaled Drug Delivery. London, 5-6 November 2014.

Winningham R E: Theravance Biopharma. Presented at: 14th annual Needham Healthcare Conference, New York, April 2015, available at https://www.sec.gov/Archives/edgar/data/1583107/000110465915027343/a15-9036_1ex99d1.htm

World Health Organisation: Adherence to Long-Term Therapies: Evidence for action. World Health Organisation, Geneva, Switzerland, 2003.

Mularksi R, McBurnie M A, Donovan J R, Walker K L, Gillespie S E, Vollmer W M: Adherence with inhaled respiratory therapeutics is associated with reduced acute exacerbations of chronic obstructive pulmonary disease. Eur Respir J 2011; 38:Suppl 55; pp4868.

Theravance Biopharma and Mylan Initiate Phase 3 Program for Revefenacin (TD-4208) for Treatment of Chronic Obstructive Pulmonary Disease (COPD), available at http://newsroom.mylan.com/2015-09-14-Theravance-Biopharma-andMylan-Initiate-Phase-3-Program-for-Revefenacin-TD-4208-for-Treatment-of-Chronic-Obstructive-Pulmonary-Disease-COPD

Mylan Announces Acquisition of Rights to Novel LAMA Respiratory Compound from Pfizer, available at http://newsroom.mylan.com/press-releases?item=123190

Pritchard J N: Maximizing the Effectiveness of the Inhaled Drug Development Process. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, Traini D, (eds): Respiratory Drug Delivery 2016, Vol. 3. Virginia Commonwealth University, Richmond; pp 497-502, 2016.

Ari A: Jet, Ultrasonic, and Mesh Nebulizers: An Evaluation of Nebulizers for Better Clinical Outcomes. Eurasian J Pulmon 2014; 16:1; pp1-7.

Degtyareva Y, Metcalf A, Hardaker L E A, Pritchard J N, Hatley R M H: Efficiency of the Micro mesh nebulizer tested with Three different fill volumes. Dalby RN, Byron PR, Peart J, Suman JD, Young PM, Traini D, (eds): Respiratory Drug Delivery Europe 2015, Vol 2. Virginia Commonwealth University, Richmond; pp401-404, 2015.

Hatley R, Hardaker L, Zarins-Tutt J, Quadrelli F, Hogan B, MacLoughlan R, Pritchard J N: Investigation of Optical Density for the Characterization of Nebulizer Meshes. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, Traini D (eds): Respiratory Drug Delivery 2016, Vol 3. Virginia Commonwealth University, Richmond; pp489-492, 2016.

Von Hollen D, Hatley R, Pritchard J N, Nikander K, Hardaker L, Elphick M: Factors to Consider When Selecting a Nebulizer in Drug Development. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, Traini D (eds): Respiratory Drug Delivery 2014, Vol 2: Virginia Commonwealth University, Richmond; pp 539-544, 2014.

Pritchard J N, Nikander K: Impact of Intervention and Feedback on Adherence to Treatment. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, (eds) Respiratory Drug Delivery 2012, Vol 1. Virginia Commonwealth University, Richmond; pp271-282, 2012.

Pritchard J N, Nichols C: Emerging Technologies for Electronic Monitoring of Adherence, Inhaler Competence, and True Adherence. J Aerosol Med Pulm Drug Deliv 2015; 28:2; pp69-81.

Drug Delivery to the Lungs 27, 2016 - Newman

The challenge of delivering drugs to the lungs Stephen P Newman Scientific Consultant, Norfolk, UK Summary The pulmonary route has an established role in the treatment of asthma and chronic obstructive pulmonary disease (COPD), and has a number of other topical and systemic applications. Successful pulmonary drug delivery requires a predictable, reproducible lung dose and clinical effect with each treatment, while minimising unwanted sideeffects, and achieving these objectives at reasonable cost. The patient presents a major barrier to achieving these goals, first because of natural lung defence mechanisms, and second because of the need to use, and to master the use of, an inhaler device. The respiratory tract has evolved in such a way as to prevent the ingress of particles and droplets, and to remove inhaled materials once deposited. Formulators strive to ensure that an adequate fraction of the delivered dose consists of particles within the fine particle range (< 5 µm) for whole lung deposition, and < 3 µm for peripheral lung deposition. Once deposited, drugs may be removed from the lungs by mucociliary clearance or by phagocytosis, or may be degraded by the action of proteases. Each patient must use an inhaler as prescribed (i.e. be adherent to the treatment regimen), and must use it correctly (i.e. prepare the device for inhalation, and then inhale from it in an appropriate way). Poor adherence and inhaler misuse are widespread problems, which can be addressed via appropriate selection of an inhaler, via use of other technology, and via education. Selection of an inhaler also needs to take into account the mass of drug to be delivered; pressurized metered dose inhalers (pMDIs) and many dry powder inhalers (DPIs) are unsuitable for delivering drug doses > 1 mg. Efficient inhalers delivering a high percentage of the drug dose to the lungs generally provide the most reproducible lung dose. The pulmonary route is a relatively complex one, but the advantages it offers justify its use for a range of treatment indications. Introduction The inhaled route is best known as a means of delivering drugs for treatment of asthma and COPD, but it can also be used to deliver a wide range of other drugs intended to achieve either a topical effect in the lungs, or a systemic effect elsewhere in the body. Topical treatment indications include use in several “orphan” diseases, such as cystic fibrosis (CF) and pulmonary arterial hypertension (PAH). The inhaled route has several advantages that derive from drug being delivered direct to its site of action (for a topically acting drug) or site of absorption (for a systemically acting drug). [1] Relatively small drug doses are often sufficient, there is generally a low incidence of systemic sideeffects, and at least for some drugs, the onset of action is rapid. Inhalation provides a way of avoiding injections for biopharmaceuticals with low oral bioavailability, and the huge alveolar surface area (> 100 m2) is an attractive target for such drugs. Several distinct types of inhaler device are used to deliver drugs to the lungs, consisting of pMDIs, DPIs and nebulizers, as well as some novel technologies that do not fit into any of the three previous categories. [2] Each of these major types of inhaler has its own advantages and limitations. Drug delivery to the lungs presents many challenges, but some of the most important of these can perhaps be summarised as trying to ensure a predictable, reproducible lung dose and clinical effect with each treatment, while minimising unwanted side-effects, and achieving these objectives at reasonable cost. Mechanical, chemical and immunological barriers Unfortunately, delivering drugs by inhalation is significantly more complicated than simply taking a tablet or capsule by mouth. The respiratory tract has evolved to prevent the entry of particles and droplets, and to remove them from the body once deposited (Figure 1). The complex anatomy of the upper airways acts as a filter for all but the smallest particles. The nose is a particularly efficient filter, and is not an ideal entry point for drugs intended to reach the lungs. The filtering effect of the oropharyngeal airways has led to definition of the “fine particle fraction” (once called the “respirable fraction”) in terms of particles having an aerodynamic diameter < about 5 µm. Any particle with an aerodynamic diameter > 5 µm is more likely to deposit in the upper airways than in the lungs. Even smaller particles (e.g. aerodynamic diameter < 3 µm) are required to target the most peripheral airways and alveoli. The inhalation mode (e.g. inhaled flow rate and volume) also has a profound effect on the amount of drug entering the lungs and its distribution within the airways. Once deposited on the airway surface, drugs can be removed from the lungs by mucociliary clearance, be acted upon by metabolic enzymes, or be engulfed by alveolar macrophages (phagocytosis). [3] Small molecules (MW < 1000 Da, e.g. analgesics) tend to have systemic bioavailability close to unity, but larger molecules (e.g. insulin) often have systemic bioavailability much less than unity, and which shows a broadly inverse correlation with molecular weight. It may be difficult to deliver an adequate amount of drug to the areas of the lung where it is most needed. The ability of aerosol particles to penetrate deep into the lung is reduced in the presence of airway narrowing in asthma and COPD. Some patients with cystic fibrosis and other conditions may have airways which are completely blocked with

Drug Delivery to the Lungs 27, 2016 – The challenge of delivering drugs to the lungs mucus, and beyond which it is impossible for aerosol to penetrate. Although not caused by mucus blockage, inadequate delivery to lung apices has been one factor explaining the relative failure of inhaled pentamidine in the treatment of human immunodeficiency virus (HIV) infection.

Figure 1 - Barriers to successful pulmonary drug delivery.

Inhaler misuse The patient’s behaviour presents arguably the biggest challenge to delivering inhaled drugs to the lungs. Successful pulmonary drug delivery requires a patient to use, and ideally to master the use of, an inhaler device. [4] Information about how to prepare an inhaler device for use, and then how to inhale from it, is usually presented to patients in a written package insert. Unfortunately, inhaler misuse is common, leading to a sub-optimal and potentially highly variable lung dose, or even zero lung dose. It is widely believed that pMDIs are misused to a greater degree than DPIs, but in practice this belief seems to be a myth. An increasing number of DPI devices is now available, with device-specific instructions, which could contribute to inhaler misuse by causing confusion. Inhaler misuse has clinical consequences: patients taking inhaled corticosteroids were shown to have more poorly controlled asthma if they could not use a pMDI properly, and especially if they could not coordinate actuating the pMDI with inhalation. [5] There are also financial consequences, because patients with poorly controlled asthma are likely to require more expensive treatment options. Any patient can misuse an inhaler but there are several well-recognised risk factors, including socio-economic issues, older age, severity of airway obstruction, lack of training in inhaler use, and using more than one inhaler device. Not surprisingly, young children are particularly prone to poor inhaler technique. Correct device use is now considered to be an essential factor in successful disease management. [6] Poor adherence An inhaler can only be effective if the patient takes the medication as prescribed. Poor adherence (compliance) to the treatment regimen is a separate, although related, problem to inhaler misuse. Poor adherence can involve not collecting (filling) a prescription, taking too few doses, or taking too many doses. One analysis showed that inhaled corticosteroids were underused on 24 to 69 % of days across a series of studies, compared with 2 to 23 % of days on which overuse occurred. [7] In practice, non-adherence can be either intentional or non-intentional; patients can choose not to take their medication, or can simply forget because they are too busy. The highest rates of nonadherence are often found in adolescents and young adults [8]. Poor adherence to an inhaler regimen has both clinical and financial consequences which are similar to those resulting from inhaler misuse. Several devices are available to monitor adherence objectively, and some are used to download adherence data to a computer or mobile phone. [9] Adherence monitoring systems are often incorporated into so-called “intelligent” inhaler systems. [10] The effects of poor inhaler technique and non-adherence are multiplicative, and their combination is sometimes caused “true adherence”. Addressing inhaler misuse and poor adherence The challenges of inhaler misuse and poor adherence can be tackled via both technology and education. Patients unable to use a pMDI correctly may benefit from a breath-actuated pMDI, or from the addition of a spacer device. DPIs with very simple instructions (e.g. open, inhale, close) may be used more successfully than those with more

Drug Delivery to the Lungs 27, 2016 - Newman complex instructions. Patients should not be switched from one DPI brand to another without adequate instruction about how to use the new inhaler. [6] Training aids are available to help patients “press and breathe” simultaneously when using a pMDI, and to adopt an inhaled flow rate appropriate to the type of inhaler. [11] Combining a bronchodilator and corticosteroid within a single inhaler may improve adherence compared with delivering the two drug classes by separate inhalers. Data logging devices that monitor adherence objectively can provide useful feedback to patients. [9] Education is a key issue in addressing problems of inhaler misuse and poor adherence. Management of chronic respiratory diseases has been described as “10 % medication, 90 % education”. [12] Education can take the form of one-on-one sessions between patient and care-giver, written treatment action plans, group training sessions, or instruction via the internet. Undertaking one-on-one sessions may be a challenge for doctors, nurses, pharmacists and other care-givers, who may have difficulty finding time in their busy schedules to meet with individual patients regularly. Unfortunately, many healthcare professionals do not understand inhaled drug delivery any better than their patients. [13] Influencing patterns of adherence has proved difficult. Overcoming the problems of non-adherence involves understanding and influencing patient behaviour. [8] This may need to take into account their concerns about the effectiveness and safety of inhaled medications, their trust in the medical profession, and factors such as family dysfunction. Conveying positive messages to patients about their disease and its treatment, including the need to take inhaled corticosteroids on a regular basis, is critical to the success of inhalation therapy. These messages need to be reinforced regularly. Choosing inhalers for different drugs Choice of inhaler is important because the patient needs to have an inhaler that he or she will use, and can use correctly, in day to day clinical practice. pMDIs and DPIs are ideal for delivering small doses of potent drugs used for asthma and COPD maintenance therapy. Ideally, the same inhaler should be used to deliver multiple drugs where this is feasible, and it should be the inhaler that a patient prefers. An inhaler must of course be affordable, but it should also be cost-effective; there is no value in a very cheap inhaler that doesn’t work. Special considerations apply to the youngest and oldest patients; in both groups delivery of drugs from nebulizers, or from pMDIs plus spacer devices, is often the best option. DPI systems should be designed to achieve a lung dose that is relatively independent of inspiratory effort. Historically, most inhalers delivered no more than 10 – 20 % of the nominal dose to the lungs; fortunately, we now have inhaler devices or device / formulation combinations capable of delivering drug to the lungs with much greater efficiency. A meta-analysis involving almost 200 data sets showed an inverse correlation between the mean value of lung deposition and its coefficient of variation. [14] Inhalers achieving a lung deposition of only c.10 % of the exvalve dose had the highest variability, and inhalers achieving a lung deposition > 30% of the ex-valve dose had the lowest variability, the latter being virtually guaranteed to have a coefficient of variation of lung deposition < 30 %, assuming the inhaler is used correctly. Inhalers delivering drug efficiently to the lungs, while also achieving a reproducible lung dose, are needed for drugs such as insulin, where pulmonary bioavailability may be limited by the action of proteases, and where the therapeutic window is narrow. The first marketed insulin product (Exubera ®, Pfizer) utilised a large “active” dry powder device, in which a novel formulation was aerosolized into a chamber above the device prior to inhalation. The device delivered insulin efficiently and reproducibly to the lungs, but its large size may have contributed to the subsequent withdrawal of the product from the market. The second marketed insulin product (Afrezza®, MannKind) utilises a simple “passive” DPI, but containing an engineered particle formulation that ensures efficient pulmonary delivery. This product is claimed to have a higher bioavailability than other inhaled insulins, and to achieve peak plasma levels more rapidly [15]. These features may result in greater acceptance by patients and physicians. Inhaled antibiotics require the delivery of very large doses that traditionally were the province of nebulizers. For instance, the dose of inhaled tobramycin (TOBI ®, Novartis) is 300 mg, delivered by specific jet nebulizers and compressors. This was the first inhaled antibiotic approved for use in patients with CF, whose lungs are colonised with Pseudomonas aeruginosa. It is also possible to deliver inhaled antibiotics by single dose DPIs where the formulation is contained within capsules or blisters. Formulation of drug powder as engineered particles can ensure that a high percentage of the nominal dose is deposited in the lungs; this in turn reduces the nominal dose required, the likely variability of the lung dose, and treatment time. A reduction in treatment time is considered likely to improve adherence. Such thinking lay behind the development of a dry powder product (TOBITM PodhalerTM, Novartis) to deliver inhaled tobramycin (Figure 2), as an alternative to nebulization. [16] The use of sophisticated nebulizer systems that control both particle size and mode of inhalation is useful for targeting some drugs reproducibly to specific sites in the lungs, e.g. the use of the AKITA® nebulizer system (Vectura) to deliver inhaled alpha-1 anti-trypsin to the alveoli of patients having a deficiency of this enzyme. [17]

Drug Delivery to the Lungs 27, 2016 – The challenge of delivering drugs to the lungs

Figure 2 – Mean deposition of tobramycin by DPI and by nebulizer. Delivery as PulmoSphere particles from a Podhaler DPI can achieve the same lung dose as a jet nebulizer, despite requiring a much smaller nominal dose. [16]

Concluding remarks Successful pulmonary drug delivery requires meeting a variety of challenges, which span scientific, medical, commercial and regulatory issues. Although the pulmonary route has been used for millennia, the scientific and medical issues have only been properly understood in the last few decades. Pulmonary drug delivery remains the cornerstone of asthma and COPD maintenance therapy and is becoming established and accepted for a range of other topical and systemic treatment indications, often fulfilling an unmet need. For these applications, the potential advantages offered by the pulmonary route is currently considered to justify the additional complexity. Judging by attendance at this and other conferences, interest in pulmonary drug delivery seems to be greater than ever. References 1

Rau JL: The inhalation of drugs: advantages and problems, Respir Care 2005; 50: pp367-382.

Dolovich MB, Dhand R: Aerosol drug delivery: developments in device design and clinical use, Lancet 2010; 377: pp10321045.

Clark AR: Limitations of pulmonary drug delivery. In: R Dhand, (ed): ISAM Textbook of Aerosol Medicine. On-line publication, International Society for Aerosols in Medicine, Chapter 14, 2015.

Newman SP: Improving inhaler technique, adherence to therapy and precision of dosing: major challenges for pulmonary drug delivery, Expert Opin Drug Deliv 2014; 11: pp365-378.

Giraud V, Roche N: Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability, Eur Respir J 2002; 19: pp246-251.

Thomas M, Price D, Chrystyn H, Lloyd A, Williams AE, von Ziegenweidt J: Inhaled corticosteroids for asthma: impact of practice level device switching on asthma control, BMC Pulm Med 2009; 9: article 1.

Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH: Inhaled corticosteroids for asthma therapy: patient compliance, devices and inhalation technique, Chest 2000; 117: pp542-550.

Morton RW, Everard ML: Adherence to aerosol medication. In: R Dhand, (ed): ISAM Textbook of Aerosol Medicine. Online publication, International Society for Aerosols in Medicine, Chapter 12, 2015.

Kikidis D, Konstantinos V, Tzovaras D, Usmani OS: The digital asthma patient: the history and future of inhaler based health monitoring devices, J Aerosol Med Pulm Drug Deliv 2016; 29: pp219-232.

Denyer J, Dyche T: The adaptive aerosol delivery (AAD) technology: past, present and future, J Aerosol Med Pulm Drug Deliv 2010; 23 (Supplement 1): ppS1-S10.

Sanders M, Bruin RL: Effect of a new training device on pMDI technique and aerosol performance, In: Drug Delivery to the Lungs 24. Portishead: The Aerosol Society, 2013, pp86-88.

Fink JB: Inhalers in asthma management: is demonstration the key to compliance? Respir Care 2005; 50: pp598-600.

Pritchard JN, Nicholls C: Emerging technologies for electronic monitoring of adherence, inhaler competence and true adherence, J Aerosol Med Pulm Drug Deliv 2015; 28: pp69-81.

Borgström L Olsson B, Thorsson L: Degree of throat deposition can explain the variability in lung deposition of inhaled drugs, J Aerosol Med 2006; 19: pp473-483.

Pfützner A, Forst T: Pulmonary insulin delivery by means of the Technosphere drug carrier mechanism, Expert Opin Drug Deliv 2005; 2: pp1097-1106.

Geller DE, Weers J, Heuerding S: Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology, J Aerosol Med Pulm Drug Deliv 2011; 24: pp175-182.

Bennett WD: Controlled inhalation of aerosolised therapeutics, Expert Opin Drug Deliv 2005; 2: pp763-767.

Biologics in Asthma â&#x20AC;&#x201C; are we turning the corner Professor Roland Buhl, Mainz University Hospital

ABSTRACT UNAVAILABLE AT TIME OF PRINTING www.ddl-conference.com

Drug Delivery to the Lungs 27, 2016 –Fintan Keegan et al. ®

Development to Approval of NARCAN Nasal Spray 1

Fintan Keegan , Michael Dey 1

ADAPT PHARMA Ltd., 45 Fitzwilliam Square, Dublin 2, Ireland Claidmhor Pharma Ltd, Linden Lea, Crewe Road, Sandbach, CW11 4RE, UK

Summary Opioid overdose is a major public health crisis in the United States. Treatment with naloxone has expanded, beyond use by clinicians in the hospital setting, but also beyond pre-hospital emergency medical services (EMS), into the general community. It is critical that the available naloxone dose is consistently adequate for the emergency treatment of an opioid overdose and can be readily and rapidly administered by a first responder ® without exposure to needle-stick injury. Adapt Pharma has developed NARCAN Nasal Spray supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray. Each Narcan 4 mg dose delivered by intranasal administration is approximately equivalent to a 2 mg dose of naloxone hydrochloride delivered by intramuscular injection (IM). Narcan Nasal Spray is for intranasal administration only, in the treatment of suspected or known opioid overdose and frequently must be administered by someone other than a medically trained person. This requires a simple, robust and easy to operate device. The simplicity of the nasal spray was critical in device selection. Selection of the chosen device was based on the small volume of liquid sprayed which remained in the nostril, 100 µL(microliters), regarded as the optimal for nasal administration and the higher naloxone concentration (40 mg/mL) which is optimal for nasal absorption. It is a single dose device that does not require priming before use and gives an orientation independent fine spray adhering to the nasal cavity wall, without the patient being alert. This presentation briefly describes, the rationale and stages in developing Narcan Nasal Spray to achieve these needs. Introduction Naloxone hydrochloride is an opioid antagonist developed in the 1960’s and first approved by FDA in 1971. While the mechanism of action is not fully understood it is thought that it competes for opioid receptor sites in the central nervous system (CNS), blocking the opioid effect caused by drugs such as oxycodone or heroin, reversing respiratory depression and prevention of prolonged hypoxia, organ damage and mortality. Naloxone has been used in the hospital and pre-hospital setting successfully with a wide therapeutic index of safety; initial dose of 0.4 mg to 2 mg intravenous (IV) administration, with repeated doses up to 10mg. The clinical setting, hospital, and EMS, allows for IV administration, but for many years there has been increase use of naloxone in the non clinical setting, mainly by IM injection but also by improvised intranasal administration. Opioid overdose is a critical health matter in many countries and at epidemic proportion in the US. Overdose is not confined to those people with opioid addiction and dependence, it is now the single largest cause of accidental death in the US; with over 28000 1 deaths in 2014 , and representing a 200% increase in opioid overdose related deaths since 2000. Over 60 percent of those deaths are associated with individuals taking prescription opioids. The epidemic has taken a twist in the last couple of years as illicit manufactured fentanyl (IMF) have entered the illegal opioid and counterfeit prescription opioid markets. In British Columbia, the government has declared a public health 2 emergency in response to the rise in illicit drug overdose deaths. Most deaths due to overdose are in the home, and IV and IM treatments are not always appropriate. Adapt Pharma (with our partner Opiant Pharma) and the National Institute of Drug Abuse undertook a development program for an intranasal formulation. It was approved by FDA in November 2015, for use in the non clinical community setting, and launched in February 2016. Patient Profile and Target Product Profile Narcan Nasal Spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or CNS depression. Narcan nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. The product requires a simple, robust and easy to operate and understand administration device. One single dose of Naloxone nasal solution delivers 4 mg naloxone, which achieves exposure 5 times greater than 0.4 mg injected by IM, or 47% relative bioavailability. As the duration (naloxone plasma half-life) is longer for certain opioids compared to naloxone, and respiratory depression can reoccur, a window of 60-90 minutes is provided to obtain medical treatment. The therapeutic window of naloxone is high, IM injection repeated doses up to 10 mg can be given, and an immediate second intranasal dose of 4 mg was safe and efficacious in patients studied. Based on the use of Narcan Nasal spray for this indication, patient profile and the required product profile a high level risk assessment using a Potential Medical Harm List was carried out. This list using a severity ratings for the product risk management assessment as follows: Disastrous (D) Results in patient death, Critical (C) Results in permanent impairment or life-threatening injury, Important (I) Results in injury or impairment requiring professional medical intervention, Slight (S) Results in temporary injury or impairment not requiring professional medical intervention, Negligible (N) Inconvenience or temporary discomfort. The occurrence of the event are rated in the range, very high to very low. The severity rating along with occurrence is tabulated into an overall rating as: Acceptable, As Low as Reasonably Possible, or Unacceptable. Examples are given in Table 1

Drug Delivery to the Lungs 27, 2016 – Development to Approval of NARCAN Nasal Spray Table 1. Potential Medical Harm List and Overall Assessment of Naloxone Nasal Spray Severity Rating

Harm

Single “No dose” Critical delivered by device

Multiple “No dose” Critical delivered by device

Occurrence

Overall Rating

Comments

Low

Unacceptable requires mitigation

Potential life-critical administration; even at 1 in 50,000 defect level assumed to high; requires to be very low

Negligible

Acceptable

Second device failing at 1 in 50,000100,000 rate would be 1 in 2,500,000,000 – 10,000,000,000

A similar approach of risk assessment given in Table 2 was applied to development based on the ideal product formulation and device attributes Table 2 Target Product Profile and High Level Risks and Mitigation for Important Product Attributes for Naloxone Nasal Administration Attribute

Rationale

Risk if defective

Mitigate Risk by

easily

Must be available for immediate use

Delay in treatment may be harmful or fatal

Small discreet, package which is easily portable

Product is easy to open and make ready for use

Must be available for immediate use

Delay in treatment may be harmful or fatal

Easily opened secondary packaging (still providing adequate protection). Device ready for use.

Product must be easily non-tamper evident

Must be available for immediate use and be correct quality product

Administration of Incorrect/forged product may be harmful or fatal

Integral seals easily recognised. Quality product easily recognised.

Product portable

Rationale for Product Design Intranasal administration is an attractive option for local and systemic delivery of therapeutic agents. The nasal mucosa is easily accessible, administration is non-invasive, does not require needles or other penetrating devices, is essentially painless and can be performed easily by a witness/first responder, or by physicians/professionals in emergency settings, including to unconscious, or semi-conscious patients. The drug delivery offers a rapid onset of therapeutic effects, circumventing gastrointestinal degradation and hepatic firstpass metabolism of the drug. However, drug concentration and delivered volume, physical properties of drug like 3 molecular weight and lipophilicity need to be within specific ranges for the drug to be absorbed . In addition 4 Lipinski et al developed a rule of 5s for nasal delivery to be effective based on: •

Drug characteristics: molecular weight <500 Da and Log P < 5



Potency required to be high: < 5 mg per dose



Solubility need to be high: > 50 mg/mL to achieve dose in maximal nasal spray volume of 100 μL/spray

•

pH of solution: approximately 5.5,

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Osmolality: <500 mosm/kg.

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Both recognised the physical size of the nasal cavity required a small volume of maximally 100 μL with 0.2 mL divided between two nostrils to achieve effective delivery, and avoid run off beyond the nasal cavity.

Development started with laboratory bench top batches, the main objective to assess formulations with a stable high concentration of naloxone. With a stable formulation candidate a number of container closure and devices were studied. Again based on stability study data, a pilot clinical study was initiated. In parallel, spray characterisation studies were carried out. Based on optimisation of the formulation, discussion with regulatory authorities, and significantly scaled up and characterised manufacturing process, a subsequent pivotal pharmacokinetics study was initiated. The clinical report and stability from registration batches form a key part of pre-NDA meeting with the FDA. The reference product, agreed with the agency, in the PK studies, was chosen based on the lowest approved effective naloxone dose. The approved route of administration was IM injection at an approved dose of 0.4 mg naloxone.

Drug Delivery to the Lungs 27, 2016 –Fintan Keegan et al. PK evaluation was completed for exposure, (AUC) maximum concentration, Cmax, time to maximum concentration tmax, and initial naloxone plasma concentration. Table 3 gives examples of product attributes measured in the final product configuration. Table 3 Target Product Profile and High Level Risks and Mitigation for Important Product Attributes for Naloxone Nasal Administration – Results for Selected Formulation Attribute

Rationale

Risk if defective

Formulation Achieved

Product formulation must be delivered in volume which remains in nostril

Avoids excessive solution from being swallowed which has much lower oral bioavailability. Avoids excessive solution being inhaled and coughing/choking in nonalert or unconscious patient.

Concentration and volume of spray to be optimised including use in supine position.

Solution of 4 mg in 100 µL; retained in nostril; full dose administered easily in nasal spray.

Product must be robust and reliable when carried around in normal use

Police and first responders to emergency calls or use by members of public would require device to be carried by patient or person administering

Stable at room temperature, but also cover summer/winter use,

Stability data shows 10 to 40 mg/mL o solution stable at 25 C for 24 o months and 6 months at 40 C, o confirming excursions to 40 C in routine use would not affect the product.

Not effected by defects from walking, driving, normal work

Relative bioavailability at 47% Vs IM injection Clinical studies included supine patients with no issues of excess solution being or reported or observed.

The spray is formed by the liquid exiting the device spray orifice and has been characterised by a number of techniques such as Spray Pattern, Plume geometry and Dose Delivered. These attributes are critical to ensure the correct dose volume of solution (100 μL) is delivered from each sprayer, and that the actuator also forms the required shape and pattern for liquid spray, including limits on % < 10 μm, which is the largest droplet size which can be inhaled into the upper regions of the lung. Human Factor Usability and Label Comprehension Testing A number of studies were completed. Firstly qualitative studies were carried out to refine and improve the product label to a point where quantitative studies were initiated. An Accelerated and Compressed Evaluation (ACE), which consisted of 3 consecutive and iterative Human Factors/ Label Comprehension Pre-Tests, was conducted to assess the ability of subjects to understand the labelling, Patient Insert (PI), including a quick start guide (QSG), and to demonstrate simulated use of a naloxone nasal prototype device. The purpose of this testing schedule was to learn and adjust the labelling and materials in an iterative and accelerated manner. The objectives of the study were: (1) To evaluate the subject’s ability to correctly demonstrate the steps for evaluating a patient for the medication, administering the medication, monitoring the patient and, if appropriate, giving a second dose, as instructed in the QSG (Human Factors); (2) To evaluate the subject’s ability to comprehend key messages in the PI (Comprehension); Two Human Factor and Label Comprehension Validation Studies were conducted with the final draft Nasal Spray packaged configuration, in subjects over 12 years of age. Two subgroups were recruited within the general population sample, including Low Literacy and Adolescent (12-17 years of age) subgroups. Primary, Secondary and Exploratory Objectives were collected. In all studies subjects were not trained in the use of the device or explanation of label instructions presented. Both studies were similar but in Study 1 –one device was used, whereas in Study 2-two devices were presented in the packaging configuration. Study 2 was also differentiated by two sub sections; one cohort was given the Patient User section of product labelling and allowed to read in real time. The second cohort were not give any instructions to read, which simulates a real emergency situation. In all cases subjects were presented with a scenario of an unconscious overdose victim simulated by a life-sized mannequin similar to those used for cardiopulmonary resuscitation training. Subjects were given the product with labeling and asked to proceed as they would in a real-life emergency; no training or coaching was provided either prior to or during the simulation. Background noise, in the form of TV and radio, was introduced into the scenario to simulate voices and noise from onlookers. The primary objectives were selected because of the critical impact on delivering care to the victim of an overdose. These included the ability to demonstrate administration of the medication and to comprehend key messages in the labeling. In the Human Factors, subjects correctly completed the critical tasks in the human factors simulated use by 1) Inserting nozzle into nostril, 2) Pressing plunger to release dose into nose. The secondary objectives were important, but of lesser critical impact to the urgent administration of the medication. Subjects correctly completed the secondary tasks in the human factors simulated use: Check for response, Call 911, Move to Recovery Position after administering the dose.

Drug Delivery to the Lungs 27, 2016 – Development to Approval of NARCAN Nasal Spray

In the Comprehension section, subjects responded to the following comprehension questions from the Patient Information such as; Product Indication (product use), Product Indication (medical treatment), How Narcan Nasal Spray should be used, Necessary to get emergency medical help after using Narcan Nasal Spray, Signs of opioid overdose, Potential withdrawal symptoms after use of Narcan Nasal Spray. The primary analysis for human factors was the correct demonstration of 2 critical tasks (insert the nozzle in the nose and depress the plunger to release a dose). Subjects demonstrated the ability to correctly perform both critical tasks, meeting the success threshold in studies using either 1 or 2 devices. Using 1 device, 90.6% of subjects (n = 48 of 53) were able to correctly perform both critical tasks. Similar results were obtained in the study 2, using 2 devices: in arm 1, which included a review of the QSG, 90.6% (n =29 of 32) of subjects correctly performed both critical tasks, while in arm 2, 90.3% (n = 28 of 31) of subjects correctly performed both critical tasks without reviewing the QSG. Device History File and Reliability The device history file (DHF) is initiated at the early stages of development and maintained throughout the life of the product. Based on the FDA medical devices guidelines it uses a traditional waterfall model design process 5 Those products comprised of two or more and became applicable to Combination Products in January 2015 regulated components, as naloxone drug product and a uni-dose nasal sprayer which is physically combined and produced as a single entity, Narcan is classified as a Combination Product. As sponsor and manufacturer, one must implement a streamlined approach, demonstrating compliance with the drug CGMPs (21 CFR part 211) and selected parts of the quality system (QS) regulation (21 CFR part 820) rather than demonstrating full compliance with both. One significant QS which can catch drug product manufacturer unawares, is Design Controls (21 CFR 820.30). This system outlines the design outputs that have been established for all design inputs, design verification and validation activities must be performed to ensure that the combination product design output meets design input requirements, including user needs and intended uses. These activities must be documented in the design history file and must be subjected to design reviews. The design history file for a combination product should address all design issues relating to the combined use of the constituent parts. The file is maintained by quality department and the basis for maintenance of the file is the change control systems. As owner of the file you are responsible for all aspects. As Narcan is used in a lifesaving, emergency setting then, from both design and product control strategy perspectives, the importance and data required to prove reliability of the product, including its use in conditions which were much more demanding than normal room temperature required additional consideration of all stages of product manufacture from components, device sub-assemblies, filled and final packaged product. At each stage structured reviews including Fault Tree Analysis was used to identify and implement additional controls which increased the levels of reliability to assure patient received a full spray on device operation. Since Narcan US launch almost 300,000 doses of Nasal Spray have been dispensed. The product has been well received with no product complaints or devices failures confirming the ease and reliability in actual use. References 1

CDC Morbidity and Mortality Weekly Report (MMWR) “Increases in Drug and Opioid Overdose Deaths — United States, 2000–2014”http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6450a3.htm?s_cid=mm6450a3_w

Province of British Columbia [CA]. BC Gov News; https://news.gov.bc.ca/releases/2016HLTH0026-000568

Bitter C, Zimmermann KS, Surber C (2011). Nasal Drug Delivery in Humans; Surber C, Elsner P, Farage MA (eds) (2011). Topical Applications and the Mucosa. Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 20–35

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23:3– 25. Lipinski et al (1997)

Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products. (January 2015) U.S. Department of Health and Human Services, Food and Drug Administration Office of Combination Products (OCP) in the Office of the Commissioner

Drug Delivery to the Lungs 27, 2016 – Rémi Rosière et al. New lung-tumour-penetrating nanocarrier designed for aerosolized chemotherapy 1

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