It has been proven that delivering Viagra through the lungs has an equally good effect as the pill," Dr Philippe Rogueda assures me, somewhat abruptly, in the middle of our conversation. "This is always a nice story to tell. Pfizer discovered that if you take the pill version, your erection will happen in about 20 minutes. If you inhale Viagra, it’s eight minutes. And it’s safe!" World Pharmaceutical Frontiers is ready to take his word on that.

The science, after all, is perfectly sound. When drugs are taken in pill form, the medication has to navigate the full length of the body’s digestive system, which means that there remains a lower limit on the amount of time it takes for the pill to be fully absorbed into the bloodstream. Meanwhile, inhalation through the lungs – insofar as the surface area within the organs is large and possesses a low enzymatic count relative to other parts of the body – allows the quick and systematic absorption of drugs into the bloodstream.

"The onset of action [with inhaled drug delivery] is much faster," says Rogueda. "You incur reduced side effects and a smaller dose when you deliver a drug through the lungs. But it does come with its own problems: you need a huge amount of testing to deliver a drug through the respiratory system and many cannot be delivered in this way because of their levels of toxicity."

It remains somewhat surprising, then, that inhalers are not more widely appreciated as a drug delivery system. Notwithstanding Pfizer’s errant research on their potential in enhancing the male libido, inhalers’ uses remain largely confined to the treatment of asthma and chronic obstructive pulmonary disease (COPD), with the devices coming in three distinct forms: the pressurised metered-dose inhaler, dry powder inhalers and nebulisers. However, research into new molecule formulations and delivery mechanisms has led to growing interest in the technology’s potential in treating diabetes and even forms of lung cancer.

As executive director of inhalable-drug-delivery consultant firm Aedestra, Rogueda is at the forefront of the science. When World Pharmaceutical Frontiers last spoke to him in 2014, the former research scientist was extolling the benefits of single-dose disposable inhalers. His confidence in the wider niche of inhalable medicine remains undimmed. The area Rogueda does seem less sure of is whether his colleagues in big pharma will ever choose to make the leap of faith away from pill delivery. There is, after all, some history to consider.

Airs of investment

When asked about how he began his career in inhalable drug delivery, Rogueda’s answer is reassuringly down to earth. He did not, it turns out, emerge from the womb with an unquenchable thirst to research the finer points of nebuliser technology. "[My interest in the field] originated because I needed a job when I finished my PhD," he laughs.

"I’d finished my thesis in chemistry and physics at Bristol University. Astra had merged with Zeneca at the time and was looking to expand its research site at Charnwood, near Loughborough. When I arrived, the formulating of inhalation products was very empirical. They needed someone who could bring more science and rigour to what was going on, and that’s what I brought.

"At the time, the inhalers they were producing were essentially product-formulated with non-aqueous pressurised liquid, and there was little science in that field from chemistry to understand how the suspension of the solution was taking place. Nobody was really playing with non-aqueous liquids, and that’s what I thought was very exciting, because it was like opening a new door in the field of physical chemistry."

Rogueda spent four years at AstraZeneca before moving to Novartis to work with dry particle inhalers, nebulisers and nasal powder systems. After a career working with major pharmaceutical companies, mixed with stints in academia, he founded Aedestra in 2014. It has granted him a privileged overview of a pharmaceutical sector that’s simultaneously regarded as brimming with potential while remaining largely static when it comes to new inhaler roll-outs.

"The inhaled-drug-delivery sector is in a funny state, in fairness, and it’s owing to the fact that no one is coming up with any new molecules," says Rogueda. "So, when it comes to the brands and big pharma – the ones who want to deliver blockbuster drug systems – they’re selling on the success of inhalers such as the Advair Diskus, the Symbicort, Spiriva or Nasonex."

It’s no accident that all but one of the inhalers Rogueda lists treat asthma and COPD – Nasonex treats symptoms of rhinitus – with some of the largest pharmaceutical companies making bulk sales on drug delivery systems based on big molecules, with no real incentive to diversify their product range. For a long time, that has painted any meaningful innovation within the sector into a corner but, with many of the complex patents on some of the most famous inhalers set to expire in the next few years, that could be about to change.

"The inhalation world, so to speak, has been able to sell these blockbusters and sail the wind on generic applications," explains Rogueda. "The question remains, what is going to happen next? The generic pipeline is going to run out. Once you’ve made them all, what are you going to do next?"

The door, it seems, is set to be opened on a new wave of innovation in the provision of generic inhalers. "As soon as someone is able to deliver a very large molecule, like a biomolecule, through the lungs, that will automatically lead to a large number of possibilities," says Rogueda. "Insulin was one of those hopes, but then, of course, it was never a commercial success, even if it was a clinical one."

Needless needles?

The development of inhalable insulin serves as a cautionary lesson for those pharmaceutical companies eager to exploit the gradual opening of the sector to greater competition – an episode that has recently come back to the fore with the death of Alfred E Mann, the businessman behind the development and promotion of the Afrezza insulin inhaler. Mann’s enthusiasm for a treatment that would cut out the need for daily injections remained strong even after Pfizer developed a similar inhaler – the Exubera – only to withdraw it from circulation after notably poor sales.

"I thought the device was particularly cumbersome and ugly; some people called it ‘the bong’," recalls Rogueda. "So I thought the Exubera was completely wrong. The investment in its manufacture was massive – that was foolish and meant Pfizer needed huge sales to recoup its costs in a suitable way. But they didn’t materialise, so people were disappointed. When Pfizer needed to make cutbacks, it was an obvious target."

While the Afrezza was notably smaller, it largely experienced the same fate. The device was supposed to revolutionise diabetes care but only succeeded in eating away at most of Mann’s estate. Rogueda considers the whole episode a tragic missed opportunity.

"It’s a shame because, when you think of the technological advances that were made in getting the Afrezza to handle the new formulation and the patents that had to be approved to get there, it’s huge, huge technology," he says. "It’s a beautiful idea that they managed to make work, but I think there is a lot to piggy-back on in terms of new ideas and technological prowess."

Back to the well

If inhalable drug delivery is going to push past its reputation of expensive development costs and lacklustre research agendas, Rogueda believes one is going to have to look beyond North America and Europe. "Asia is a huge, huge market," he says. "There are about two billion people living there, and recurrence of conditions like COPD and other lung infections is huge. You could argue that maybe our medications are overpriced, but they’re certainly not priced properly enough for patients in China, India, Pakistan and Indonesia."

And if Western pharmaceutical companies do not get there first, Rogueda earnestly believes that indigenous producers, particularly those operating out of Taiwan and South Korea – which are unfortunately likely to be less regulated, and more susceptible to counterfeit and low-quality ingredients – could seize the opportunity to supply that collective market and experiment with molecules in ways hitherto thought to be impossible in the West.

"There are a lot of players growing in those countries that want to supply their own market," says Rogueda. "From there, they’re able to enter the Western market and start selling something that may be poor quality but cheaper."

This is not, of course, to say that the field of research in inhalable drug delivery is not a vibrant one. In February, the University of Arizona College of Pharmacy received significant publicity for its work on exploring new inhalable drug delivery methods for pulmonary diseases, and there is also ongoing research into inhalable oxytocin, funded in part by the Bill & Melinda Gates Foundation.

Major pharmaceutical companies are also exploring the potential for ‘triple combination therapy’, wherein the patient is treated with a dose mixture made up of three molecules instead of the conventional one or two, potentially enabling the daily treatment of acute respiratory conditions and concomitant increases in patient compliance.

"Combination therapy is very much the byword for brand companies," says Rogueda. It’s one area of progression,
among many, that instils in him the confidence that, despite the current barriers to mass adoption, the ultimate benefits of inhalable drug delivery will be recognised on a much wider scale.

"I do share the optimism for the inhaled-delivery route because it has demonstrated such huge potential," he concludes.