Characterisation of Nanomaterial in Nebulised Formulations for Clinical Products: Impact of Particle Size on Dissolution and Predicted Deposition Pattern

 Carolyn Stevenson¹, Henrik Kristensson¹, Karin Carlsson¹, Pia Mattsson¹, John Salomonsson¹, Jan Olof Svensson¹ and Ulrika Tehler¹

¹ Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Sweden

Summary

Selection of a poorly soluble active pharmaceutical ingredient (API) for clinical development can be a strategic decision to achieve lung retention. To attain desirable exposure for these types of APIs, it is possible to optimise the particle size to modify the retention in the lung.

We have investigated three different suspension formulations with different API particle size (d50 of 0.13, 0.23 and 2.2 µm) to be delivered by nebulisation. For the different nanosized products, no significant difference was observed in output rate or mass median aerodynamic diameter, (MMAD). However, for microsized particles a lower output rate and higher MMAD was observed in comparison to the nanoproducts using an experimental inhalation flow rate of 15 L/min. It was found that dissolution rate was altered by modification of the particle size. Prediction of the lung deposition however, suggested no difference between the particle sizes investigated. From a drug product development perspective this means that the particle size of the API can be optimised to achieve the desired exposure of a dissolved API. Additionally, knowledge of the manufacturing window, i.e. the limit of particle size that will achieve desirable exposure, can be gained by evaluating differences in particle sizes.

Key Message

Predicted lung deposition is not changed when altering particle size of a poorly soluble API in nebulised suspensions but the dissolution profile can be manipulated. From a development perspective, this means that the API particle size could be optimised to achieve the desired exposure of a dissolved API.