Let’s face it – capsule dry powder inhalers (cDPIs) have stood the test of time. From the original Fisons Spinhaler (launched in the 1960s) to the Novartis Onbrez Breezhaler (FDA approved in 2012) – they’re still going strong. And still they use Standard Size 3 capsules. Which are pretty small, and which some people find hard to pick up – and when they do pick them up, they often swallow them with a glass of water… Actually, why on earth are cDPIs ‘still going strong’? Why aren’t more innovations in the pipeline – and if we are to innovate, what would we change?
First and foremost, the cDPI is a mature technology and platform which can be bought more or less ready to go (certainly compared to other candidate devices). In fact, Plastiape proudly claims on its website: ‘The RS01 Monodose dry powder inhaler patented, manufactured and marketed by Plastiape has several appealing features, the first and quite relevant one being that it does exist.’ Enough said.
‘The RS01 Monodose dry powder inhaler patented, manufactured and marketed by Plastiape has several appealing features, the first and quite relevant one being that it does exist.’
If you’re a pharmaco with an NCE (new chemical entity) that needs to be delivered to the lungs, a cDPI has numerous advantages. The filling technology is pretty much off the shelf and proven, as is the primary pack and the capsule which is also known and mature so you can begin stability programmes very early on, almost as soon as your formulation is ready.
Contrast this with the alternatives: pMDIs (pressurized metered dose inhalers) require a liquid formulation and are more difficult for the patient to use correctly; reservoir DPIs are more complex and best suited to routine therapies; and multi-unit dose DPIs offer better moisture protection, but as they are not a standard platform they require bespoke filling equipment. As a result, cDPIs look like a relatively simple, low cost and mature technology that is already accepted by regulators in various guises – so, what’s not to like?
Well… they’re not perfect.
Small capsules are difficult to handle
The size 3 capsules which feature in the large majority of marketed cDPIs are pretty small, at about 15.9 mm in length and just 5.8 mm in diameter, with a volume of 0.27 ml (although they can still hold over 100 mg of typical lactose based formulation, which is much higher than most blister or reservoir devices).
Internal piercing elements are expensive
Another challenge facing most current cDPIs is that they employ metal piercing elements. These have to be very carefully designed so that they pierce the gelatin or HPMC (HydroxyPropylMethylCellulose) material in a controlled and repeatable manner.
If the piercer is too blunt, or has the wrong geometry, there’s a chance that gelatin / HPMC fragments will be created during piercing – not great for inhalation therapies, so metal piercing elements are typically cut, ground, and then flame polished in order to achieve a robust piercing mechanism. This not only requires substantial upfront investment, but also results in a relatively high cost for the end product.
A second limitation of using piercing elements is that you inevitably end up with two or more small holes in the capsule – this makes it difficult, even with good airflow design, to get large quantities of powder formulation out of the capsule within the typically short duration of a single inhalation. In fact, almost all cDPI instructions advise checking for any remaining powder within the capsule and to repeat the inhalation a second time if required. Boehringer Ingelheim’s market leading HandiHaler® even instructs patients to inhale twice with each capsule, in order to ensure that a full dose is delivered.
There’s a lot of waste
As cDPIs are passive devices they have to harvest energy from the patient’s inhalation in order to i) empty the capsule and ii) deagglomerate the fine API particles from the lactose carrier fraction.
This is actually done in a single process by shaking, spinning or rattling the pierced capsule so that its contents are dispersed into the airflow – any detachment of fine API from the carrier fraction is simply a bonus. No cDPI that I’m aware of actually puts energy directly into the formulation in order to promote high efficiency aerosolisation. Consequently, most cDPIs achieve fine particle fractions of 20 to 30%, and only slightly higher with carefully engineered formulations. The remainder (the majority) is, rather wastefully, deposited in the user’s mouth and throat (assuming it’s not left in the capsule), but apart from the undesirable side effects that may result from this, the user probably doesn’t care if the device is 20% or 90% efficient. As long as they receive the right quantity of therapeutic dose each time they use their inhaler, it’s not their problem.
Consider, however, the perspective of a pharmaco desperate to get an NCE through Phase 1 clinical trials. Poor efficiency, combined with a dependency on the inspiratory energy provided by the patient, is likely to lead to variable dose delivery and inconsistency in the therapeutic effect. This means that the statistical power of the study will be weak in comparison to a device that delivers with greater consistency and less dependency on inspiratory effort, and more data will be required to achieve sufficient statistical significance. Despite this, in almost all cases cDPIs remain the first choice for delivering NCEs in early clinical studies.
What innovations can we make?
Although cDPIs are currently far from perfect, they are still used around the world for the effective treatment of asthma and COPD. But with just a few small changes, they could be improved significantly – with important implications for clinical studies, as the combination of these improvements could give the candidate NCE a better chance of a successful outcome, saving time and cost. So what could we consider?:
1. Use bigger capsules
There’s no reason why cDPIs couldn’t be developed to work with much larger capsules. A size 0 capsule, for example, is almost 22 mm long with a diameter of 7.7 mm – most people would be less inclined to swallow it, and with a volume of 0.67 ml it has the potential to hold up to 300 mg of lactose based dry powder formulation.
Moving up a few capsule sizes enables much higher quantities of drug to be delivered for each single inhalation – and makes the capsules easier to handle. This could be of particular interest to patients who suffer from diseases that require large quantities of drug to be inhaled for effective relief, such as cystic fibrosis.
2. Open, not pierce
Opening, rather than piercing, the capsule – by pulling the two halves apart (such as in the Rotahaler® and Aptar’s Twisthaler®) minimises the chance of creating fragments and improves capsule emptying during inhalation.
3. Employ a two-stage engine
If you shake, spin or rattle the capsule within the inhaler, it’s difficult to effectively transfer this energy into the formulation, although surprisingly little energy is required to disperse the contents of a fully opened capsule into the airflow. A two-stage system can divert a major proportion of the available energy and use it to disperse the formulation. With good design, this can result in notable improvements in the overall fine particle efficiency of the system, less dependency upon inspiratory effort, and greater consistency in the delivered dose.
What’s next for cDPIs?
cDPIs are here to stay, not least because of their many advantages over other inhaler technologies, but the fact that they have barely changed in six decades should cause some concern. Many of the ongoing issues affecting cDPI performance are actually quite straightforward to resolve.
Perhaps now is a good time to think about the future of the humble cDPI and to proactively explore its potential to deliver higher payloads, with increased efficiency – as may be demanded by future therapies beyond asthma and COPD. These changes would benefit patients by reducing the number of doses required, and reduce the side effects caused by drug deposition in the mouth and throat. And Pharmacos could benefit hugely – improved cDPIs could deliver better and more consistent results in clinical studies, saving time and money, and enabling NCEs to get to market faster.