Historically, inhaled drugs have been used to deliver medicines targeted at the main respiratory diseases, namely asthma and chronic obstructive pulmonary disease (COPD). Current estimates suggest that as many as 235 million people worldwide have asthma and over 200 million people have COPD, with rates set to increase in developing countries (see Graphic 1).¹ The need for efficacious medications for these incurable diseases is still a major focus for research, and off-patent drugs are able to bring in large revenues. In the U.S., for example, GSK’s Advair (seretide) came off patent in 2010 but still generated revenues of >$8 billion per annum in 2012 and $5.5 billion in 2015.²

The combined drugs market for asthma, COPD, cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF) alone was $28.1 billion in 2015 and is predicted to expand by more than 50% by 2022 (see Graphic 1).⁴

Other respiratory diseases, such as infections, tuberculosis, and lung cancer, are also a large worldwide health burden, and there is no quick or easy solution to meet this future global challenge.

Delivering respiratory medications directly to their site of action in the respiratory system is an obvious advantage of inhalation formulations, but there are other benefits too, and it is these additional benefits (see Graphic 2) that are driving research into inhalation treatments for systemic diseases.

One of the first well-publicized inhalation products for treating a systemic disease was Pfizer’s Exubera. An inhaled form of insulin for treating diabetes, Exubera was withdrawn in 2008 due to poor sales blamed, in part, on the bulky and inconvenient inhaler. Initially a setback to innovation in this sector, the failure of Exubera resulted in other companies reconsidering similar product developments. However, in June 2014 the U.S. Food and Drug Administration (FDA) approved Mannkind’s Afrezza, an inhaled insulin product.⁷ The current market success of this product appears limited, but may relate to the need for specific patient screening and product pricing rather than the efficacy of, or preferences for, the inhaled medication.⁸

Exubera’s withdrawal has certainly not hindered the interest in inhalation delivery, quite the opposite in fact. In the last four years, 1,350 active inhalation studies—for new, combination, and existing products, encompassing 802 different diseases and 105 rare diseases—have been logged with the U.S. FDA clinical trial register. More than half of these inhalation studies are for systemic conditions.⁷

Inhalation devices and formulations
As previously indicated with the Exubera inhaled insulin device, the success of inhaled medications depends on two key considerations: drug formulation and the inhaler device itself. Innovations in both these aspects of design are leading to more effective drugs—new, combination, and generic—although improved powder formulations may be developed more cost-effectively than new, sophisticated inhalers.⁹

Inhalation devices
A considerable amount of development time, effort, and money goes into the production of any inhalation device as it can contribute to the drug’s success, irrespective of how effective and beneficial the drug may be to the patient. Inhalation delivery offers something that is unique compared to other routes of administration. When used in combination, it provides extended patent protection. In the U.S., for example, GSK’s Advair (seretide) came off patent in 2010, although the Diskus delivery device remained in patent through 2016.¹⁰ To be effective, an inhalation device must be matched to the patient, easy to use, forgiving of poor technique, and able to provide feedback to the user about dose emission and technique (see Table 1).

The size of the market for respiratory inhaler devices continues to expand, with estimates suggesting it will reach $43 billion by the end 2025—a compound annual growth (CAGR) of 4.3%.¹²

Formulations for inhalation
Traditionally, the fine drug particles required for delivery in dry powder inhaler (DPI) devices have been produced by mechanical micronization using air jet mills. These fine particles are then often combined with a lactose carrier to improve drug stability and dose control, depending on the drug type or compound class. More recently, however, particle engineering techniques look poised to transform future drug formulations (see Box 1).⁹ These new techniques have the potential to provide a more efficacious drug, allowing lower doses to be used and reducing the potential for side effects.

Nanotechnology
Nanotechnology needs special mention. Clearly the size of the particle is pivotal for inhalation studies in ensuring effective lung deposition. However, nano-sized materials are broadening the options for development. Nanomaterials are defined as particles that have oneor more external dimensions 1–100 nm in size.

The market for nanotechnology usage in medicine is huge, with applications in diagnosis, prevention, and treatment.¹³ It is predicted that by 2021, the nanotechnology-enabled drug delivery market will be worth $136 billion, which would represent 15% of nanomedicines globally.¹³

Despite this exciting prospect, there are still public concerns about the safety of nanomaterials, particularly for engineered materials, because the long-term effects of these materials is still unknown.

Inhalation technology strategy through discovery and regulatory non-clinical development
Of the various considerations when planning efficacy and toxicology studies using inhalation technologies, regardless of formulation, dose delivery methodology and the reproducibility of effective dosing are two of the most important. The main methodologies for drug delivery in non-clinical studies are intratracheal and inhalation dosing. Intratracheal dosing involves anesthesia and intubation, with the drug delivered via bolus through the intubation tube, and is principally used for early screening studies. This method is simple, uses minimal amounts of drug, and the delivered dose is easily quantified. However, it is prone to artefactual toxicological and pharmacological results, and the particle size used in testing often differs from that which will be used non-clinically.

Inhalation dosing, on the other hand, delivers compound to conscious animals by the clinical route of administration—that is, the lung—removing the risk of intratracheal artefacts. The essential aspect of this method is the necessity for specialist inhalation technology capabilities and experience. Having the ability to reproducibly control the aerosol during both intra- and inter-exposures is pivotal in ensuring study integrity is maintained; failure to achieve reproducible control may compromise study endpoints, allowing poorer data interpretation and reducing the scientific impact of the study. At worst, the study may need to be repeated if the aerosol is not controlled effectively.

Envigo has conducted nearly 2,000 inhalation studies in the last nine years and more than 100 inhalation studies on drugs formulated using new, novel formulation techniques. Our experience with these formulations is that the aerosol concentration is more consistent, reproducible, and aerostable than standard, lactose-based carrier formulations, which improves study conduct, decreases potential animal-to-animal variation, and reduces the overall amount of drug required to conduct the study.

Compound requirements is always a topic for discussion with inhalation studies as it requires larger amounts of drug than other routes of administration do, although a considerable number of practical techniques can be employed to minimize the dose.¹⁴ We have worked collaboratively with a number of clients to develop more efficient methods for inhalation delivery of powders, including developing a capsule-based aerosol generator (CBAG) with GSK that offers significant cost savings over commercially available instruments.¹⁵

It is also important to consider that the FDA assumes 100% deposition of a delivered dose in humans, 10% in rodents, and 25% in non-rodents.¹⁴ When planning dosing experiments, it is important to take this into account in order to ensure adequate dose coverage.

Conclusions
In seeking competitive advantage, companies are increasingly considering alternative solutions to the historic method of drug discovery. These include route switching of established products to extend the product’s value proposition, de-risking drugs earlier in the product-development timescale by incorporating additional endpoints into early in vivo studies, and further innovative reformulations and particle engineering.

Inhalation delivery will continue to be utilized for drugs targeted at both respiratory and systemic diseases, which will continue to grow, even when cures for all of these diseases can
be found. 

References

1. Forum of International Respiratory Societies. Respiratory diseases in the world. Realities of Today – Opportunities for Tomorrow. Sheffield, UK: European Respiratory Society, 2013. https://www.ersnet.org/pdf/publications/firs-world-report.pdf (last accessed September, 2016).
2. Statista. Revenue of GlaxoSmithKline’s Seretide/Advair worldwide from 2012 to 2015, by region (in million British pounds). https://www.statista.com/statistics/312366/revenue-of-seretide-advair-worldwide-by-region/ (last accessed October, 2016).
3. World Health Organization (WHO). World Health Statistics. 2008. http://www.who.int/whosis/whostat/2008/en/ (last accessed October, 2016)
4. GBI Research. Cystic fibrosis therapies will push Vertex ahead of GSK in $46.6 billion respiratory market by 2022, says GBI Research. http://www.gbiresearch.com/media-center/press-releases/cystic-fibrosis-therapies-will-push-vertex-ahead-of-gsk-in-466-billion-respiratory-market-by-2022-says-gbi-research (last accessed October, 2016).
5. Health Research Funding. 17 Amazing Cystic Fibrosis Life Expectancy Statistics. http://www.gbiresearch.com/media- center/press-releases/cystic-fibrosis-therapies-will-push-vertex-a head-of-gsk-in-466-billion-respiratory-market-by-2022-says-gbi-research (last accessed October, 2016).
6. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J 2015; 46: 795-806.
7. Moore S. What is the future of inhalation delivery? Envigo, 2016. http://landing.envigo.com/inhalation-white-paper (last accessed October, 2016).
8. Staton T. Sanofi tried and failed with Afrezza. Why does MannKind still think it can win? http://www.fiercepharma.com/pharma/sanofi-tried-and-failed-afrezza-why-does-mannkind-still-think-it-can-win (last accessed October, 2016)
9. Moore S. Is micronisation the way forward for inhaled delivery? – the changing shape of test article powder formulations. Developments in Life Sciences in press.
10. Kelley T KM. Glaxo Declines as FDA Clears Path for Advair Rivals. http://www.bloomberg.com/news/articles/2013-09-10/glaxo-falls-most-in-20-months-on-fda-generic-rules (last accessed October, 2016).
11. Schmierer. T and Malica. C. Inhalation Technology: A breath of fresh air in drug delivery! 2011. http://www.oindpnews.com/ wp-content/uploads/2014/10/Capsugel-Inhalation-Technology- %E2%80%93-A-breath-of-fresh-air-in-drug-delivery.pdf (last accessed October, 2016).
12. Future Market Insights. Respiratory Inhaler Devices Market: Increasing Prevalence of Asthma and COPD to drive the Global market for Respiratory Inhalers Devices; Global Industry Analysis and Opportunity Assessment, 2015 – 2025.  2015. http://www.futuremarketinsights.com/reports/respiratory-inhaler-devices-market (last accessed October, 2016).
13. Nanoscientium. UK Nanomedicine Market, Current Status and Future Prospects. 2014.
14. Moore S. Inhalation Study Design: 20 critical questions you should ask before planning your inhalation study. Envigo, 2015. http://landing.envigo.com/20-critical-questions-inhalation-webinar (last accessed October, 2016).
15. Rodgers D GC, Paul G, Moore S, Meecham K, Jordan S,. Efficacy of an inhaled PFE4 inhibitor, GSK256066, delivered by a novel dry powder pre-clinical inhalation delivery system in the acute cigarette smoke induced pulmonary inflammation model. 2015.
16. Pulmatrix. Pulmatrix Highlights Recent Report Predicting Rapid Growth for Inhaled Drug Delivery Methods. 2016. http://ir.pulmatrix.com/2016-09-23-Pulmatrix-Highlights-Recent- Report-Predicting-Rapid-Growth-for-Inhaled-Drug-Delivery-Methods (last accessed October, 2016).

---

Simon Moore is Director of Inhalation Science and Engineering at Envigo. He joined Huntingdon Life Sciences in 1999 as an inhalation study analyst. In 2016 he was promoted to his current position with managerial responsibility for the inhalation engineering services and aerosol technologist groups. In this role, Simon is responsible for all aspects of aerosol technology, including the overall interpretation and reporting of the inhalation studies at the Huntingdon site. The inhalation engineering services group designs, prototypes, and manufactures custom-made inhalation equipment for all inhalation sites within the Envigo organization.