In respiratory medicine there is a growing demand to deliver higher payloads (for example, over 50 mg) to the lung, driven by an increasing number of lower potency molecules for treating conditions beyond asthma and COPD [1][2]. The higher payloads present significant challenges for the current delivery technology, resulting in variability in the delivered dose and an undesirably low respirable fraction. [3]
One challenge limiting the maximum dose that can be inhaled in a single inhalation is the “cough reflex”. This is a reflexive reaction of the throat and upper airways which triggers a cough when inhaling a large dose of powder. There are conflicting myths in the inhalation field about what is the maximum dose that can be inhaled before cough is induced. In reality, there is no definitive number because the maximum inhalable dose is formulation dependent: for example, a user may be able to inhale 80 mg of mannitol, but only a few mg of chilli powder!
Traditionally, due to the tiny quantity of highly potent drug required for a dose, drugs delivered by DPIs are diluted with the inert sugar lactose, commonly referred to as the “carrier fraction” and typically making up at least 95% of the “fill mass”. A typical fill mass (the total mass of formulation filled for a single dose) for the treatment of respiratory illnesses such as asthma and COPD is approximately 10 mg. However, for many new molecules doses can be higher than 50 mg, which exceeds the limit of tolerability for many patients, and presents significant challenges for the current delivery technology, resulting in variability in the delivered dose and an undesirably low respirable fraction.
Our Quattrii and Aeolus inhalers offer an innovative solution to this problem: separate (or “classify”) the API from the carrier particles within the blister and retain the large, inert carrier particles in the blister. This significantly reduces the mouth and throat deposition, allowing for much higher doses to be delivered in a single inhalation. We call this “classification”.
Figure 1 shows performance comparison data between Quattrii and RS01 for the same fill mass (75 mg). With RS01, nearly all of the 75 mg dose is emitted from the device, including 65 mg of large, inert carrier fraction, which will land in the throat, potentially inducing cough. The Fine Particle Dose (FPD) emitted by Quattrii is as high as (or better than) RS01, but only a total mass of less than 15 mg is emitted from the device, the rest of the carrier fraction is retained in the blister.
|
Figure 1: Comparison of total emitted mass for 75 mg fill mass between RS01 and Quattrii at 4 kPa pressure drop (NGI results) |
|
If a patient’s inhalation tolerance limit is 30 mg, for example, then a dose of 75 mg would need to be delivered in 3 separate inhalation shots in RS01, to avoid cough. However, in Quattrii the entire dose could be delivered in a single inhalation, because the majority of the inert carrier fraction is retained in the blister.
Novel engineered spray-dried particles are growing in popularity, which allow primary packaging to be filled with API-only formulations, with zero carrier fraction. Whilst these novel formulations are designed to have better flowability than traditional micronised API formulations, they still pose substantially greater handling and filling challenges than carrier-based formulations.
API-only formulations may be the right choice for some applications, for which we also have API-only variants of both Aelous and Quattrii.
Our classifying DPIs, Aeolus and Quattrii, allow existing and new carrier-based formulations to be delivered to the lung in much higher single-shot inhalations, potentially eliminating the need to transition to API-only formulations.
[1] Claus S, Weiler C, Schiewe J, Friess W, How can we bring high drug doses to the lung?, European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik 86(1) 2013
[2] Hickey A, Why we need to deliver large amounts of powder to the lungs and the concurrent challenges, Drug Delivery to the Lungs, Volume 30, 2019
[3] Sibum I, Hagedoorn P, Boer A H, Frijlink H W, Grasmeijer F: Challenges for pulmonary delivery of high powder doses, International Journal of Pharmaceutics 2018 ;Volume 48, 1: pp 325 – 336.