Innovation in inhalation

Inhaling drugs is not a new concept. Historical records and artefacts show examples of several ancient civilisations using inhaled vapours for a perceived medicinal benefit. In China, wars were fought to maintain the supply of opium, a Buddhist decoction used as a panacea for medical conditions. Another example can be seen in countries of the Middle East, where the smoking of shisha is still associated with a reduction in stress and anxiety.

Of course, with a comprehensive library of scientific literature to draw upon now, it’s well-known that both substances can cause harm. But advancements in medical science are also broadening the way medications can be delivered to the body, and there is a growing interest in how inhalable drugs might be used to treat conditions outside of common pulmonary diseases, like asthma, where they’re most often applied. Ben Forbes is professor of pharmaceutics at the Institute of Pharmaceutical Science at King’s College London, and he believes we’ll see more and more drugs taken through inhalation over the next few decades.

“Going forward, a lot of the interest is around biologic drugs, and inhalation as a route for things that have to be injected at the moment,” he says. “There are also all the nucleic acid therapeutics and the follow on from the excitement generated by the success of some of the covid vaccines, which are now being repurposed and looked at for inhaled applications.” This is certainly reflected in the vaccine marketplace, with two nasal Covid-19 vaccines given approval in 2022, one in China, the other in India, and many more in clinical trials seeking approval in different regions.

“There are also some potential novel applications that have been proposed,” says Forbes. “Here, you could improve the mucosal barrier function of the lung, to almost trap and remove infection or negate either bacterial or viral infection before it actually engages through its entry point to the body mechanisms.” At the more ambitious end of the research and development spectrum, there are teams looking at the potential for inhalable therapies that can potentially correct innate disease-causing errors of genes, bringing new hope to those suffering from respiratory diseases like cystic fibrosis.

A promising development

The promise of inhalation as a route for drug delivery is significant, but all of it begs the question: Why are the lungs a potentially effective route for drug delivery? “You get instantaneous deposition to the mucosal surface, where you have a huge surface area, relatively low pre-systemic metabolism and extremely high blood flow,” explains Forbes. “It is also one of the few organs in the body, maybe the only organ in the body, that receives the entire cardiac output, and it has an extremely thin air to blood barrier because of its physiological function – which is to oxygenate the blood as it passes.” In layman’s terms, all of this means that inhaled drugs get absorbed into the bloodstream quicker, and because they avoid the GI tract, they aren’t broken down by enzymes that reduce the amount of active pharmaceutical ingredient that reaches its target.

“If you go via the oral route, you are going via an environment that is designed to digest peptides, proteins, carbohydrates and anything else, so going via the lungs, you can avoid that degradation and you can start to achieve better bioavailability,” explains Forbes.

It’s not all advantages though, and there’s a reason the market hasn’t been flooded with inhalable options for therapeutic drugs. “They are much more expensive than a tablet,” says Forbes. “It is the cost of developing something quite so complex and the cost of producing something that has got multiple parts. It has a device and it has a specially formulated medication that requires a particular fine particle size, that is reproducible. Additionally, the drugs themselves can be expensive.”

On the formulation side, another obstacle is the use of excipients – components included in drug formulations to assist in their stability or shelf life, as well as producing immune reactions that can make them work more effectively inside the body. Unlike with parenteral delivery, only a small number of excipients are approved for inhaled drugs. Outside of formulation, Forbes says the barriers are more to do with how environmentally friendly devices are – unsurprising when you’re talking about propelling a gas. “We have already had one reformulation of all the metred-dose inhalers to replace propellants with lower global warming potential alternatives, and that is starting to happen again with even more environmentally friendly options,” he explains. “But there are new devices coming along and new technologies so things will probably change there.”

What the customer wants

One of the most important factors in drug delivery, and something pharmaceutical companies are appreciating more and more, is how the end-user – the patient – interacts with their products. Nélio Drumond, associate director of manufacturing sciences at Takeda, is a frequent keynote speaker on patient-centric drug product design, and he stresses the importance of making things easy for patients. “We should ensure that when we are developing and designing devices, like inhalers, we are thinking about the patient in the very end,” he says. “You need to build a holistic perspective and understand that the device you are engineering must fit the specific needs of the target patient population. Inhaler devices are particularly challenging, because you must consider the whole spectrum of patients, from young children to the very old and frail.”

Both of these patient populations share individual needs that will be distinct from those of healthy adults, and Drumond believes those developing inhalable drugs need to increase their efforts to understand patient language by asking the following questions: “How do they perceive the drug product? How do they intend to use it? And how appropriate is the design being proposed? Generating this knowledge early into the development process will likely increase the chances of commercialising a highly effective drug therapy with strong patient acceptability and compliance.”

So, what are the physical attributes that matter when designing such a product? Drumond says usability factors, such as inhaler size and available grip, must be taken into account during the design process, and that considerations should also be made for patients with visual acuity problems, who may not be able to read dose indicators or instructions for use. Other factors are related to complexity of use, employing a correct administration technique and a patient’s individual capacity to fully inhale the required dose. Device intuitiveness, he adds, is often a “huge limitation” in product design.

“When designing an inhalation device, you need to make sure the required administration technique becomes intuitive for the patient,” says Drumond. “Unfortunately, the majority of devices available on the market do not provide that. If you give a tablet to a patient, the patient understands they will need to swallow it – it is very intuitive. For inhalation devices, this is obviously more challenging.” Designing an inhaler device that patients clearly understand how to use just by looking at it is very difficult to achieve, due to the natural complexity involved in pulmonary drug delivery. “If companies first reach out to patients to gain knowledge on their perspectives, perceptions, and critical usability needs, the chances of developing a prototype that is more intuitive to the patient’s eye will increase exponentially,” Drumond says.

Smart technologies

There’s one key technological development that could be instrumental in the design of more patientfriendly inhalation devices, and it follows a trend seen elsewhere in drug delivery. “Smart inhalers are devices with in-built sensors that can be linked to your smartphone via digital technology, and not only provide valuable information on the accuracy of your inhalation technique and your total inspiratory flow, but also remind you to take your dose on time and alert you if you are missing or repeating a dose,” says Drumond. “I understand that for older patients, this technology might become more difficult to navigate, but I still think having access to it is a game-changer, because patients are given the opportunity to educate themselves from the information being received on their smartphone. Simultaneously, they rely less on their healthcare provider and will reduce the burden on healthcare systems.”

It’s hard to argue with any technological development that takes the pressure off healthcare systems, and smart drug delivery is a concept already explored for the management of long-term conditions like diabetes. But the evidence supporting a beneficial impact on patients is scarce. One recent paper titled ‘The effectiveness of digital health technologies for patients with diabetes mellitus: A systematic review’, concluded after examining outcomes from a total of 3,360 participants across 25 randomised controlled trials, that digital health interventions for those with diabetes mellitus can improve glycaemic control, but there was no consistent clinical impact identified due to a wide variety of options on the market.

There’s also the question of cost, which Forbes identified as a barrier even without the inclusion of sensor technology. Given the cost barrier, along with the research and development hurdles that must be overcome to bring inhalable drug delivery devices to market, Forbes expects to see a trickle rather than a flood of such products hitting the market in the near future. “I think there will be an increase of the more expensive biologic drugs which are getting closer to the market,” he says. “It is the cost of development as much as anything else. Inhalables are a complex drug development route compared to oral development, which is much more straightforward and much better understood.”