In the previous blog, we looked at what can happen to an inhalation powder during the months or years before a patient ever uses it, and why protecting the formulation from the environment forms part of the drug-delivery challenge. Once that powder has survived storage – and the patient finally inhales – a different source of variability appears. The energy available to aerosolise the dose now depends on the patient.
A passive dry powder inhaler has no motor, pump or compressed-gas supply. All of the energy needed to fluidise, deagglomerate and aerosolise the formulation has to come from the inspiratory manoeuvre. Patients make somewhat poor standardised power supplies, because both the magnitude and timing of that energy input can vary substantially between people, and even between successive inhalations by the same person. Through all of that variation, however, the pharmaceutical requirement remains essentially unchanged. We still need the inhaler to generate a consistent fine particle dose (FPD) across the intended patient population.
Through all of that variation, however, the pharmaceutical requirement remains essentially unchanged. We still need the inhaler to generate a consistent fine particle dose…
This is something I became particularly interested in some years ago. In work presented at DDL in 2010, we measured inspiratory behaviour in more than 90 healthy subjects, and examined how changing the device resistance affected the characteristics of the manoeuvre, including inhaled volume, peak mouth pressure and the rate at which pressure developed, dP/dt. Pressure is particularly useful here because flow through an inhaler is directly coupled to the resistance of that device; simply quoting a flow rate without considering resistance tells us little about what the patient is actually capable of achieving.
Figure 1: Healthy-adult data showing how device resistance influences inhaled volume, peak mouth pressure and rate of pressure development.
The three resistance plots in Figure 1 come from those data. They show clear relationships between device resistance and inhaled volume, peak pressure and dP/dt, together with the mean, 10th-percentile and 90th-percentile responses. Once a device resistance is selected, those relationships give us a much more useful description of the range of inspiratory inputs that real people can generate through that device. The data are from healthy adults, so they should not be interpreted as defining the performance of a particular respiratory-disease population, but they provide an excellent basis for understanding the coupled behaviour of patient and inhaler.
Using those measured relationships, we can construct representative inspiratory profiles for a chosen device resistance. Figure 2 shows the 10th-percentile, mean and 90th-percentile profiles derived in this way. They differ substantially in peak flow rate, the rate at which flow develops and the duration of the inhalation. Reducing each of those profiles to a single peak-flow number would throw away much of the information describing how energy is actually supplied to the powder.
Figure 1: Representative Quattrii inspiratory profiles from healthy adults, showing differences in peak flow, rise time and inhalation duration.
Routine laboratory testing can make this easy to overlook. Standard DPI test systems commonly use a vacuum source and a rapidly opening valve to establish the required pressure drop through an inhaler. The resulting onset of flow can be extremely sharp, much closer to a square-wave input than the majority of patient-generated inhalations. That’s perfectly useful for standardised and comparative testing, but an aerosolisation mechanism that benefits disproportionately from a very aggressive initial transient may experience a more favourable input on the test bench than it receives from a patient.
Reducing each of those profiles to a single peak-flow number would throw away much of the information describing how energy is actually supplied to the powder.
The same peak flow can also be reached through quite different inspiratory histories. One person may generate pressure rapidly, another may build towards the same peak more gradually, while somebody else may generate a lower peak but sustain the inhalation for longer. All three manoeuvres can provide enough energy to operate a DPI, although the way that energy reaches the formulation is different.
For drug delivery, those differences only become a problem if they materially change the emitted aerosol. If a strong or rapidly accelerating inhalation produces a substantially greater FPD than a weaker or more gradual one, patient physiology has started to influence the respirable dose generated from the same nominal formulation dose. For a medicine intended for people whose respiratory function may already be compromised, that is clearly undesirable.
We therefore put a lot of effort into understanding how our DPI platforms behave when they are driven by realistic inspiratory profiles, instead of relying solely on one nominal laboratory condition. What we want to know is how much the resulting FPD changes as inhaled volume, peak pressure, dP/dt, flow rate and inhalation duration vary across a realistic patient range – ideally, very little.
We also test this directly by varying the pressure available to drive the device. The results shown in Figure 3 are from the current Quattrii Clinical device at pressure drops from 1 to 8 kPa. Between 2 and 8 kPa, the fine particle dose remains remarkably consistent despite a fourfold change in driving pressure, while the fine particle fraction remains within a narrow range. Even at just 1 kPa, where the available aerosolisation energy is extremely low, Quattrii continues to generate a substantial respirable aerosol.
Figure 3: Current Quattrii performance from 1–8 kPa driving pressure with spray-dried model drug. FPD remains highly consistent from 2‑8 kPa, with useful aerosolisation even down to 1 kPa.
Quattrii is deliberately a high-resistance platform, and the resistance has been considered as part of the coupled patient-device system. At a higher device resistance, useful pressure drops can be generated without requiring exceptionally high volumetric flow through the mouthpiece, while small, purpose-designed internal passages can still generate high local velocities, shear and turbulence where they are needed. The resistance plots illustrate that changing this one device characteristic also changes the inhaled volume, peak pressure and pressure-development rate that the patient is likely to produce, so it cannot sensibly be treated as an isolated design parameter.
What we want to know is how much the resulting FPD changes as inhaled volume, peak pressure, dP/dt, flow rate and inhalation duration vary across a realistic patient range – ideally, very little.
Carrier-based Quattrii gains another useful characteristic from the duration of its aerosolisation event. The carrier particles continue to circulate within the blister while API is progressively detached and preferentially emitted, allowing useful energy transfer to continue as the inhalation develops. The process is therefore less reliant on one short, intense event immediately after airflow begins, which helps when the real patient input has a slower rise or a different overall shape.
Carrier-free formulations present a different aerosolisation problem and use a correspondingly different Quattrii engine, as discussed earlier in this series. Several of the patents covering that technology remain unpublished, so we cannot yet describe much of the underlying architecture. We apply the same patient-centred requirement to it, though. Realistic differences in inspiratory input should produce as little variation as practicable in the resulting respirable dose.
There will always be a lower limit with a passive DPI. Below some level of patient-generated pressure and inhaled volume, insufficient energy will eventually be available to fluidise and deagglomerate the formulation effectively. When we talk about inspiratory-flow independence, we therefore mean robust aerosol performance across the clinically relevant range of inspiratory profiles expected from the intended patient population, with FPD being one of the most useful measures of that robustness.
Patients will never all inhale in exactly the same way, and designing an inhaler around the assumption that they will makes little sense. The patient may supply the aerosolisation energy differently from one inhalation to the next, but the pharmaceutical job of the device remains the same.
The patient’s inspiratory flow profile may vary considerably, but their fine particle dose should vary as little as we can reasonably engineer it to.
This blog post was originally published as part of a series of LinkedIn articles, written by David Harris.