The ideal situation is that all types of patient gain an effective dose; but if dose delivery is highly dependent on the flow profile applied – a particular problem with dry powder inhalers – then this may not be the case.
Furthermore, since in vitro testing is carried out under standardized conditions for all orally inhaled products (OIPs), flow rate dependent performance inevitably compromises in vitro and in vivo correlations for certain patient groups. Developing DPIs with drug delivery characteristics that are more independent of flow rate would tackle both of these issues.
Q: So, how exactly are you defining “extrafine” particles?
A: With an increasing body of research referencing extrafine and sub-micron aerosols, the term is now routinely used to describe inhaled particles, but an absolute definition hasn’t yet been formally agreed on. The general consensus seems to be that particles less than 1-2 µm are referred to as extrafine, although some papers use the same term to reference particles less than 0.1 µm in diameter, an extremely fine particle size for our field.
Chiesi’s preferred approach, in line with the definition most commonly used by the scientific community, is to reflect clinical definitions based on the extremities of the lung and the ability of the particle to reach the small airways, so we set the upper limit for extrafine particles as 2 µm. Defining “extrafine” as everything less than 2 µm means overlap with the traditional 1-5 µm range but re-focuses to the finer end of this range, with an extension of interest to even finer particles.
Q: Are there existing formulations with a significant proportion of ‘‘extrafine’’ already commercialized? Do they demonstrate enhanced performance?
A: Our Fostair product was one of the first to be designed specifically to deliver extrafine particles, and it demonstrates high drug delivery efficiency. It is reasonable to suggest that there is also likely to be an extrafine fraction in many other existing formulations, though that fraction may be small.
This is because in DPI formulations a geometric standard deviation of around 2 is typical for the particle size distribution. So, although the MMAD of the product may be 3 µm – outside the extrafine range – the particle size distribution will run from 1-5 µm. That said, the amount of material in the extra fine region is of course far higher in a product specifically designed to deliver finer particles, as evidenced from work reported by Buttini.
