Why pulmonary medications and inhalation technology are more relevant than ever in tackling worldwide health crises

With over half a billion people worldwide suffering from a chronic respiratory condition and cases of COVID-19 climbing above 25 million globally, pulmonary drug delivery via specialist inhalation devices is more relevant than ever. Pulmonary drugs offer the best potential for optimal delivery to the lungs while minimizing systemic side effects–properties that have made pulmonary drugs the main treatment for asthma and chronic obstructive pulmonary disease (COPD) for decades. Pulmonary drug delivery may also be the most appropriate treatment for other serious conditions, including COVID-19.

We’ll explore the current status of pulmonary drug delivery and possible future opportunities in pulmonary drug development in this article.

Pulmonary drugs have a long track record in effectively treating common respiratory diseases such as asthma and COPD

Historically pulmonary drugs have been used to target medicines to the lungs for main respiratory diseases such as asthma and COPD. Current estimates suggest that as many as 272 million people worldwide have asthma and almost 300 million people have COPD (Box 1).1

In many countries these rates are set to increase in the coming years owing to higher smoking prevalence and ageing populations.2 Indeed, the World Health Organization predicts that COPD will become the world’s third largest health threat by 2030.

First-line treatment for asthma and COPD has been dominated historically by short-acting β2 agonists (SABA). Then came corticosteroids, initially formulated individually, but more recently as combinations with long-acting muscarinic antagonists (LAMA) and long-acting β2 agonists (LABA). This is known as “triple therapy” in a single device.3, 4

In the United States and in Western Europe, dry powder inhalers (DPIs) are common, while pressurized metered-dose inhalers (pMDI) of inhaled corticosteroids and SABA are most commonly used in developing countries, owing to price concerns.

Pulmonary drugs are also used to treat idiopathic pulmonary fibrosis (IPF) and cystic fibrosis; both are chronic lung conditions characterized by progressive lung damage, and for which improved treatments are greatly needed.5, 6

Specifically, nebulized pulmonary treatments are sometimes used for patients with COPD, if distressing or disabling breathlessness persists despite the use of inhalers.4

Other respiratory disease targets for pulmonary drug development include COVID-19, tuberculosis and lung infections

Other respiratory diseases such as tuberculosis, lung cancer and other more general (and usually unspecified) respiratory infections are also a large worldwide health burden,1 and there is no quick or easy solution to meet this global challenge.

In addition, COVID-19, is sweeping across every continent7 creating a deep need for efficacious medications with industry and academic research bodies around the world seeking to develop pulmonary drugs for COVID-19.10-12

BOX 1: Respiratory disease facts

In 2017, chronic respiratory diseases affected nearly 545 million people worldwide (an increase of 23% since 2007) and caused the deaths of nearly 4 million people.1, 8

Asthma1, 8 272.7 million people affected worldwide Causes nearly half a million deaths per yearCOPD1, 8 Nearly 300 million people affected worldwide 18.5 million new cases diagnosed every yearCystic fibrosis (CF)5 In the EU, around 2000 – 3000 children born with CF per yearIdiopathic pulmonary fibrosis (IPF)6 Occurs at a rate of 3,000 – 9,000 cases per 100,000 persons in Europe and North America

In 2017, the world saw 17.9 billion new acute respiratory infections, which caused the deaths of 3.8 million people.1, 8

Lower respiratory tract infections1, 8 10.6 million cases in total 2.6 million deathsPneumococcal
pneumonia
1, 8 This is the leading cause of death due to a lower respiratory tract infection in children aged <5 years
Tuberculosis1, 8 1.9 billion cases worldwide with 9 million new cases diagnosed in 2017. Responsible for 1.2 million deaths

Lung cancer is the most diagnosed cancer, accounting for 11.6% of the total, and the most common cause of cancer death (18.4% of the total).9 Lung cancer claimed the lives of 1.9 million people in 2017.8

To expedite development, companies are using either intratracheal or intranasal administration routes for early screening studies as an alternative to inhalation before commencing first-in-human studies.

Pulmonary delivery has multiple benefits for respiratory and systemic diseases

Delivering respiratory medications directly to their site of action in the respiratory system is an obvious advantage of pulmonary formulations, but there are other benefits too.

Pulmonary delivery also avoids the first-pass metabolism that can limit oral bioavailability for some drugs, thus encouraging lower dosages, which in turn might cause fewer systemic side effects. For instance, protein and peptide drugs can be more stable when delivered via inhalation because these drugs are typically degraded by the GI tract before they can reach their target organs.13-16

Pulmonary drug delivery for systemic conditions

The above benefits are partly responsible for driving research into pulmonary treatments for systemic diseases. One of the first well publicized pulmonary products for treating a systemic disease was Pfizer’s Exubera®. An inhaled form of insulin for treating diabetes, Exubera® was withdrawn in 2007 due to poor sales, blamed in part on the bulky and inconvenient inhaler. This drug created an initial setback to pulmonary delivery innovation with other companies reconsidering similar product developments.

In June 2014, however, the United States Food and Drug Administration (U.S. FDA) approved Mannkind’s Afrezza®, an inhaled insulin product. Initial sales of Afrezza® were also slow ,17 but by January of 2020, revenue had more than doubled, 18 providing a clearer picture to sponsors that inhaled delivery for systemic diseases could be a possibility.

In the long run, Exubera’s® withdrawal has not hindered the interest in pulmonary delivery. In the last 2 years, more than 2,000 active inhalation studies – for new, combination and existing products as well as pulmonary delivery methods and techniques – have been registered with Clinical Trials.gov. These studies span nearly 1,500 indications, both respiratory and systemic, and more than 200 trials involve patients with COVID-19.19

Particle engineering techniques have transformed drug formulations

The success of inhaled medications depends on many factors but primary ones include how the drug is formulated and the inhaler used to deliver it. The latter consideration is unique to pulmonary delivery, compared to other delivery routes.20

The key facets of an inhaled medication are the active ingredient and its formulation. Traditionally, the fine drug particles required for delivery in 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 (Box 2) have transformed inhaled drug formulations so more effective formulations can be devised, allowing for lower doses, which often correlate to a lower potential for side effects.

BOX 2: Examples of some particle engineering techniques

‘Drying’ techniques This is the most common particle engineering technique. Examples include spray drying, freeze drying and vacuum foam drying

Supercritical fluid technology The drug is dissolved in a supercritical fluid; particles form due to rapid expansion of the fluid or by precipitation from the fluid

Sonocrystallization Uses an ultrasound-controlled crystallization technique. For example, the Prosonix platform from Circassia Pharmaceuticals Plc—its fluticasone propionate pressurized metered-dose inhaler (pMDI) has been approved as the generic equivalent of GlaxoSmithKline’s Flixotide® pMDI by European decentralized procedure, following a filing to the UK Medicines and Healthcare Products Regulatory Agency

Proprietary techniques Examples include: Pulmatrix’s iSPERSE® platform—their PUR1900 drug (for fungal infections in the lungs of patients with cystic fibrosis) is currently in clinical testingLiquidia’s PRINT® (Particle Replication In Non-Wetting Templates) platformMannkind’s Technosphere® Technology—used in their insulin product, Afrezza®

Devices are vital to the clinical success of pulmonary delivery and can extend patent life too

The properties of a delivery device can contribute significantly to the drug’s success, irrespective of how effective and beneficial the drug itself may be to the patient.

The unique benefits that occur when an effective drug formulation is combined with an efficient delivery device explain why considerable development time, effort and money is dedicated to the production of any inhalation device.20

To put this importance into context, GSK’s Adavair® (Seretide) came off patent in the U.S. in 2010, but when combined with the Diskus® delivery device, Adavair remained patented through 2016. As a result, Adavair still generated revenues of over USD 5.5 billion in 2015 and around USD 2.1 billion in 2019.21

While some early delivery devices may be coming off patent, the size of the market for respiratory inhaler devices is considerable and continues to expand with estimates suggesting it will reach 48 billion USD by the end of 2029 – a CAGR of 4.2%.22

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 Box 3 for an overview of the desired physical characteristics of an inhalation device.

Box 3: Desired physical characteristics of devices

PRIMARYSECONDARY
Easy to use
  • To avoid additional stress during an acute attack
  • Simple treatment implies a less ‘serious’ disease that is under control
Discreet
  • The device should not attract attention during administration
  • Small — it should fit into the palm of the hand
  • Unobtrusive style without bright colors to avoid appealing to children
Portable
  • Should fit easily into a trouser or jacket pocket
Visible dosing
  • Remaining doses should be visible to allow the patient to anticipate when a new prescription will be required
Easy dose loading
  • Should be possible to load dose into the device quickly and hygienically
Clean and hygienic
  • Should be simple to protect and clean the mouthpiece
Separate device and doses
  • To avoid additional costs and wastage

The already huge respiratory market is set for continued growth

The value of the global respiratory drug delivery market is projected to reach USD 52.37 billion by 2021, which was an increase from USD 36.10 billion in 2016, compounding at an annual growth rate (CAGR) of 6.5% during the forecast period.

Growth in this market is mainly being driven by increasing preference of pulmonary route of drug delivery, increasing technological developments in the form of smart/digital inhalers, and rising incidences of respiratory diseases such as COPD, asthma and cystic fibrosis.23 The asthma segment accounts for the major share in the market during the forecast period due to increasing prevalence of this disease across the globe.

On a side note, the Asian market is expected to register the highest CAGR during this forecast period due to its rapidly increasing geriatric population, adoption of unhealthy lifestyles, urbanization, exposure to air pollution and prevalence of COPD in the region.

Conclusions

The fact that some 2,000 active inhalation studies – including over 220 for COVID-19 at last count – are ongoing, demonstrates the interest in and pace of research into pulmonary drug delivery.

Covance is at the forefront of nonclinical, clinical, regulatory and medical device evaluation with these cutting-edge technologies. In particular, we have extensive experience testing drugs for pulmonary delivery, performing more than 150 nonclinical inhalation studies each year.

We are consistently optimizing study techniques, pulmonary drug formulations and devices, and are at the forefront of testing the novel formulation techniques that are transforming the precision of aerosol delivery. This focus is leading to more reliable study results and reductions in the drug quantities needed for pulmonary testing. Most importantly, this advanced engineering and constant advancement in aerosol and inhalation technology translates to patient benefits also: more efficient dosing and easier to use devices, thus helping reach better compliance.

Contact us to learn more about inhalation & pulmonary testing

References

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16.         Moore S. Is micronization the way forward for inhaled delivery? – The changing shape of test article powder formulations.  2016.

17.         Oleck J, Kassam S, Goldman JD. Commentary: Why Was Inhaled Insulin a Failure in the Market? Diabetes Spectr. 2016;29(3):180-4.

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