Dry powder inhalers have been enormously successful. They are compact, convenient, propellant-free, and have delivered billions of doses for the treatment of asthma and COPD, improving the lives of patients around the world for several decades. However, most of today’s DPIs were developed around a particular type of medicine: potent, small-molecule drugs required in relatively small quantities. The next generation of inhaled medicines can be quite different. Biologics, peptides, vaccines, diagnostics and other emerging therapies may require much larger lung doses to be effective; they can also be very expensive to manufacture, highly sensitive to moisture and difficult to formulate. Some may need tens of milligrams of powder to be delivered in a single treatment. The molecules have changed considerably. The inhalers, for the most part, have not.
The entire contents of a GSK Ellipta in a CHI Quattrii blister.
The above photograph illustrates this point visually. It shows the entire powder contents of a GSK Ellipta inhaler placed inside a single Quattrii blister. To be clear, this is not intended as a criticism of Ellipta, which is an extremely successful inhaler platform, and does the job it was designed to do very well. Nor is it intended as a direct comparison of aerosol performance between the two devices. Ellipta was developed for highly potent respiratory medicines, where each individual dose is relatively small; Quattrii was developed with much larger and more demanding payloads in mind. What the photograph illustrates clearly is the difference in scale. A complete multidose inhaler’s worth of conventional formulation fits into one Quattrii dose blister – with room to spare.
Ellipta was developed for highly potent respiratory medicines, where each individual dose is relatively small; Quattrii was developed with much larger and more demanding payloads in mind.
For a conventional asthma medicine, limited payload capacity may not be a significant problem. A small quantity of respirable API — active pharmaceutical ingredient — is often blended with much larger carrier particles, usually lactose, to make the formulation easier to handle during manufacture. When the patient inhales, some of the API detaches from the carrier and reaches the lungs, while much of the larger carrier fraction deposits in the mouth and throat, with API still attached to it. When the drug is potent and the required lung dose is small, this can work perfectly well. It becomes less attractive when the formulation contains an expensive biologic, or when a much larger dose is required. A relatively inefficient inhaler may then need a substantially greater fill mass, resulting in more drug being wasted, potentially intolerable mouth and throat deposition, and possibly several inhalations necessary for a single treatment.
Simply enlarging the dose container is not enough to overcome these issues, of course. The device must still entrain, disperse and deliver the additional powder efficiently during the patient’s inhalation. Cohesive spray-dried formulations do not necessarily behave like conventional carrier-based blends, either; their performance may depend on particle morphology, density, surface chemistry, electrostatic behaviour and sensitivity to humidity. An inhaler that works well with one formulation may behave very differently with another. The device therefore needs to provide useful payload capacity, but also a means of aerosolising that payload efficiently. One without the other is not particularly helpful.
There is also the question of protection. Many of the molecules now being considered for inhalation are highly sensitive to moisture, which makes primary packaging an important part of the product rather than a secondary consideration. It is not enough for a formulation to perform optimally when freshly prepared in the laboratory; it must remain stable during manufacture, storage, transport and patient use. An aluminium-laminate coldform blister can provide excellent protection for an individual dose, keeping it sealed until the moment of use. In most DPIs, however, the dose container is treated as something separate from the aerosolisation system: it protects the formulation but contributes relatively little once the dose is opened. We wondered whether it could do more.
Passive DPIs use only the energy supplied by the patient, but patients vary considerably in their inhalation strength.
There is a further complication. Passive DPIs use only the energy supplied by the patient, but patients vary considerably in their inhalation strength. A healthy adult, a young child and someone with significant respiratory disease are unlikely to produce identical inhalation profiles, and even the same patient will not inhale in precisely the same way every time. If device performance changes substantially with inspiratory effort, variability is introduced before the biology of the drug has even been considered. That matters during normal use, but it can be particularly problematic during clinical development, where device-related variability makes it harder to establish whether differences in outcome are caused by the molecule, the patient or the inhaler. For a pharmaceutical company investing heavily in a new inhaled therapy, the device should ideally reduce uncertainty rather than add to it.
For a pharmaceutical company investing heavily in a new inhaled therapy, the device should ideally reduce uncertainty rather than add to it.
When we began developing Quattrii, we decided not to start with an existing inhaler architecture and ask how it might be enlarged or modified to accommodate new, lower-potency molecules. Instead, we asked what a DPI would look like if it were designed from the outset specifically for larger, more valuable and more demanding formulations. How could a large quantity of powder be aerosolised efficiently using only the patient’s inhalation energy? How could a sensitive formulation be protected within a robust primary package? How could unnecessary mouth and throat deposition be minimised? How could the device accommodate both carrier-based and carrier-free powders, while recognising that their aerosolisation requirements are fundamentally different? And how could useful performance be maintained across a broad range of patient inhalation strengths?
In Quattrii, the dose blister becomes an active and integral part of the complete aerosolisation system.
Those questions led us away from the conventional relationship between the dose container and the inhaler. In most DPIs, the dose container holds the powder, and the inhaler aerosolises it elsewhere. In Quattrii, the dose blister becomes an active and integral part of the complete aerosolisation system. The photograph shows just how much formulation the blister can contain; the more interesting part is what happens to the powder once the patient begins to inhale. This will be the subject of the next article...
This blog post was originally published as one of a series of LinkedIn articles, written by David Harris.