Pharma & drug development

Elegant Simplicity

Single-dose disposable inhalers (SDDIs) represent the cutting edge of inhalation drug delivery, having been indicated for emergency therapies and vaccines as well as chronic pulmonary diseases. Unfortunately, they have yet to become a commercial reality. Philippe Rogueda, R&D executive director at Actavis, explains why the industry is failing to embrace this technology, and asks whether that is set to change.

Single-dose disposable inhalers (SDDIs) have long been billed as the future of aerosol science. Beguilingly straightforward, not to mention cheap to produce, this method of drug delivery holds promise for a vast array of health conditions across the world. Unfortunately, over the last few years, commercial success has been slow coming.

SDDIs in themselves are nothing new. In fact, the concept came into being as early as the 1970s, when the liquid inhaler Penthrox was used as an emergency analgesic. Since then, the technology has found various applications ranging from the pharmaceutical to the recreational.

But, while more than 800 patents have been filed, peaking in 2007, there has recently been a slowdown in activity. More disappointingly, the possibilities have failed to translate into practice, with very few fully fledged examples on the market. According to Philippe Rogueda, R&D executive director at Actavis, something is amiss.

“SDDIs are in my view a cut above the rest,” he says. “They’re extremely simple, perform very well, and are as efficient as the inhalers that everybody uses. So why isn’t this elegant technology being used?”

Rogueda has spent much his career pondering such questions. As an expert in inhalation drug delivery, he is the founder of Inhalation Asia and has worked extensively in the field of pharmaceutical formulation and powder flow. SDDIs remain a major area of interest.

“The technology is proven. It works. It’s available,” he explains. “But, curiously enough, there is no large Western company that has taken up those patents. When it comes to single-dose disposable inhalers, there is a whole range of technologies that nobody is using.”

Breakthroughs in inhalation science

Inhalation science has never been static; ever since the inhaler was invented in 1858, this has been a fertile ground for research. The oldest variants were nebulisers, which worked in a broadly similar manner to a bicycle pump. Atomised liquid medication was dispersed into the mouth using compressed gas, a high-frequency ultrasound or a vibrating mesh. These technologies are still in existence, albeit in a more sophisticated form.

The first real alternative arrived in 1956, in the form of the metered dose inhaler (MDI). This delivered a dose suspended in a propellant, administering a spray whenever the canister was pressed. It was followed by the dry powder inhaler (DPI) in 1973, which places the drug inside a capsule or powder reservoir and makes coordination easier for the patient.

Subsequent breakthroughs have mostly been variations on a theme. In 1995, harmful CFC propellants were replaced by hydrofluoroalkane for the first time. The first systemic inhaler, Relenza, was developed in 1999. Then, in 2006, the industry exalted at the arrival of Exubera, the first inhalable insulin product. This was pegged to revolutionise diabetes treatment, as well as including powder engineering in a DPI.

Unfortunately, the fanfare didn’t last: a year after being launched, Exubera was quietly shelved. Beset by safety concerns, the sector grew cautious; enthusiasm was dampened, the R&D spike tapered down. Since then, the gap between technological possibility and commercial reality has come to seem very broad.

In truth, the lack of SDDIs cannot be pinned on a failure of research and development. There are prototypes in abundance, each of which is based on the same straightforward idea.

“You take your inhaler and the dose is already in it,” explains Rogueda. “You have no manipulation, you open the blister package, and there you are: you have the dose. You put the little disposable device in your mouth and the drug ends up in your lungs.”

It is important to differentiate here between the single-dose disposable inhaler and single-dose inhalers per se. In the latter case, there are plentiful examples. The Spiriva HandiHaler, for instance, is a single-dose dry-powder inhaler for the treatment of chronic obstructive pulmonary disorder (COPD).

“Capsule systems like these are single dose in a way,” says Rogueda. “You have a device and every time you want to take a dose or treatment you put what we would describe as a capsule inside the device and inhale whatever comes out of it.”

Clearly, the HandiHaler is a long way removed from the likes of Diskus and Turbohaler, which can hold 60 doses at a time. This said, because it is reusable, not disposable, it lacks some of the benefits that SDDIs can bring.

One of these is sheer stylistic elegance; a whittling away of unnecessary extras to incorporate the minimum of components. While GSK’s Diskus has 14 parts, and Boehringer Ingelheim’s Respimat has 32, a typical SDDI gadget will comprise only two or three. They are simpler even than the HandiHaler with eight – and the pricing implications are significant. With so little assembly required, production costs can plummet.

The advantages do not stop there. SDDIs are also smaller and less bulky than your standard inhaler. You don’t risk cross-dose contamination. And because they remain in their packaging until the point of use, they are insulated against moisture and wear and tear.

“Let’s think about the example of a swimmer with asthma,” says Rogueda. “You need to take your medication next to the swimming pool where it’s highly humid, and this is bad news, as usually inhalers are very sensitive to humidity. But if you have it prepackaged as a single dose that protects against humidity, then you have no problem. Your dose is not going to be contaminated and your inhaler is going to behave precisely as you expect.”

Where SDDIs really come up trumps, however, is their suitability as one-off rescue remedies. The list is extensive: pain management, analgesics, emergency therapies and antihistamines, among others. They are also ideal for vaccinations, inoculating against measles or tuberculosis without recourse to a needle. Most recently, Team Consulting designed an SDDI, Occoris, which could vaccinate whole populations in the case of natural disasters and bioterrorism.

“If you have a chronic disease, then a 60-dose device is probably on average better, but there is a space for SDDIs that is not taken by any other inhaler,” points out Rogueda.

 

[Subhead] IP issues

Considering their versatility and low cost, SDDIs are particularly suited for use in the developing world. They don’t require intensive cold chain, which is critical in countries beset by war or lacking a cohesive infrastructure. And because of their resistance to environmental conditions, they could easily be preserved in hot or humid climates.

The case for SDDIs would appear to be overwhelming. Why, then, have we failed to see any uptake? Rogueda thinks it partially comes down to acceptance, both by practitioners and patients.

“When you’re chronically ill, you want to be stablised with a particular technology,” he says. “So if you’re using a Diskus or Breezhaler, and you know it controls your asthma or COPD, the placebo effect is very important. People are going to want to use what they have; they don’t want to move.”

Perhaps more intractably, there is a reluctance on the part of pharmaceutical companies to create something so easy to copy. Ironically enough, the very simplicity of the SDDIs could turn out to be their undoing; while they may be easy to use and to assemble, they are near-impossible to safeguard in terms of intellectual property rights.

“There must be an interest from the big pharma companies not to pursue these technologies, because they are protected by very simple patents,” says Rogueda. “You can’t have multiple patent protections on them because you only have three parts. And so the economics probably do not work out in their favour.”

The key issue here is a lack of new molecules: an issue that has stymied the development of many a new device. As Rogueda describes, there are numerous formulation technologies in existence, each of them just as exciting and effective as the SDDIs, which have yet to see the light of day.

“The way inhalation works is people create devices, have ideas, and then they try to look around for new molecules to put in them,” he explains. “When you’re a technology supplier, you want to aim for high rewards associated with a new molecule, so they’ll wait for new molecules and then the investment will be worthwhile. There haven’t been any new molecules recently to speak of, and if there are, they belong to AstraZeneca, they belong to Pfizer, they belong to GSK. And they already have device platforms that they want to keep because they’re complex with multilayer IP protections.”

So is this the final word for single-dose disposable inhalers: just another clever gizmo designed with no mind for market realities? A cynic might say so; after all, any pharma company worth its salt is anxious to fence off the entry of generics. Complex device platforms are an established means of doing so, once the patent on their molecule runs out.

Rogueda, however, believes there is hope for the SDDI yet; a situation borne out by the steady trickle of patent applications. Commercial progress is slow, for sure, but the topic of SDDIs has not yet been quashed.

“The technologies are not dead, and investors are paying for the patents to be maintained,” he points out. “So there’s an interest there, and investors think there’s something behind it.”

He thinks pulmonary conditions like asthma and COPD are unlikely to represent the point of breakthrough. Rather, the fate of SDDIs is most likely tethered to how they fare outside the US and the EU; specifically, whether other economies are happy to accept products that haven’t had commercial success elsewhere.

It will also depend on the success or failure of the various inhaled vaccine programmes in development. If these take off in terms of molecules for the lungs, Rogueda suspects there will be a colossal market for SDDIs, potentially paving the way for mainstream acceptance. For now, though, the future of the technology remains open to question.

“I don’t think it’s going to die just yet,” says Rogueda. “SDDIs have strong advantages: breath actuated, in-built dose counter, no cross-contamination, easy to carry, cheap manufacturing; a range of application for vaccines, rescue therapies, one-off uses, emergency treatments and lifestyle needs. But it’s a mystery why it keeps going and where it’s going at the moment, and that’s why I follow the field with such keen interest.”

This article appears in the 2014 vol 1 edition of World Pharmaceutical Frontiers

 

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