In previous blog posts, we described how carrier-based Quattrii uses a carefully controlled airflow regime within the dose blister itself to deagglomerate and classify the formulation, preferentially emitting the fine, respirable API while retaining most of the much larger carrier fraction. This is quite different from the way we traditionally think about dry powder inhalers, where a high emitted dose – and therefore an almost empty dose container after inhalation – is generally regarded as a good thing. However, if most of the material in the formulation is only there to aid manufacture, and handle a very small quantity of API, it is worth asking the obvious question: why do we need to deliver all of that carrier to the patient at all?
Carrier particles, usually lactose, have been extraordinarily useful in respiratory drug delivery. A few micrograms of micronised API can be difficult – if not impossible – to meter, fill and handle reproducibly, so blending those tiny particles with a much larger quantity of free-flowing, coarse carrier particles creates a formulation that can be manufactured and dosed far more reliably. During inhalation, the API is detached from the carrier and, ideally, travels into the lungs. The much larger lactose particles cannot penetrate deeply into the respiratory tract, so most deposit in the mouth and throat and are subsequently swallowed or ideally rinsed away. For conventional asthma and COPD medicines, where the quantity of API is small and the overall formulation mass is modest, this approach has worked extremely well for decades.
The problem becomes more interesting as the required API dose increases. Imagine that we want to deliver milligrams rather than micrograms of drug using a carrier-based formulation. If the API represents only a small proportion of the total blend, increasing the amount of drug can rapidly result in a very large overall powder mass. Most of that additional material will still be carrier (typically 85%+ is carrier w/w), which ultimately has no therapeutic purpose once the formulation has left the inhaler. The patient wants the drug in their lungs; they do not particularly benefit from receiving a correspondingly large quantity of lactose in their mouth and throat.
Selective emission in action. The carrier remains largely in the blister; the fine API mimic is emitted and collected across the NGI stages.
This is one of the reasons we became interested in selective emission, rather than simply maximising total emitted mass. In carrier-based Quattrii, the large carrier particles circulate within the blister while the much finer API is progressively detached and preferentially carried out with the airflow. Most of the carrier remains behind and is then discarded with the used blister. Consequently, the aerosol leaving the device can contain a much higher proportion of the material that we actually want the patient to inhale.
That distinction becomes particularly important for higher-dose medicines. If we can retain most of the carrier within the device, then increasing formulation payload does not necessarily have to translate directly into increasing the mass deposited in the patient’s mouth and throat. It also means that the engineering objective changes slightly. We are no longer trying to achieve the highest possible total emitted dose; we are trying to achieve the highest useful emitted dose. Those are not necessarily the same thing.
We are no longer trying to achieve the highest possible total emitted dose; we are trying to achieve the highest useful emitted dose.
There is another consequence that is particularly interesting here. In many reusable inhalers, deliberately retaining a large quantity of powder somewhere within the device would create an obvious problem: it could accumulate from dose to dose, alter the airflow, contaminate subsequent doses, and eventually interfere with device performance. Quattrii avoids this because the classification chamber is also the disposable primary package. Each dose begins with a new blister, and the retained carrier leaves the inhaler when that used blister is removed. The part of the system in which we deliberately allow powder to remain is effectively renewed for every dose.
This opens up some interesting possibilities for carrier-based formulations that sit outside the traditional highly potent asthma and COPD model. A formulation scientist might wish to use a relatively coarse carrier because it provides excellent flowability and manufacturing robustness, while still needing to deliver a considerably larger API dose than would normally be associated with a conventional DPI. Ordinarily, increasing the amount of carrier to accommodate that dose might create an undesirable patient burden. If the inhaler can separate those two functions – using the carrier to make a good pharmaceutical formulation, but then preventing most of it from being delivered to the patient – the formulation scientist has substantially more design freedom.
None of this means that carrier retention is automatically beneficial for every formulation, of course. The interaction between API and carrier, drug loading, carrier morphology, fines content, surface properties and many other variables all influence aerosol performance. The important point is that complete emptying of the dose container does not have to be the objective. For some formulations, leaving most of the carrier behind may be precisely what an efficient inhaler should do.
Complete emptying of the dose container does not have to be the objective
This also returns us to a theme running through this series: the inhaler, formulation and primary package should not necessarily be treated as three independent components. In Quattrii, the blister protects the formulation, contains a relatively large dose, becomes the aerosolisation and classification chamber during inhalation, and then conveniently takes the unwanted carrier away when it is discarded.
This blog post was originally published as part of a series of LinkedIn articles, written by David Harris.