Innovative Drug Development Approach to Address the Transition to Low Global Warming Potential Propellant Using Hydrofluoroalkane-152a, for Triple Combination Pressurized Metered-Dose Inhaler Products Targeting Small Airways

Abstract Recent and emerging environmental policies have boosted the investigation of pressurized metered-dose inhalers (pMDI) that have a minimal impact on climate change. There is a current move away from existing hydrofluorocarbon (HFC)-based propellants, specifically the hydrofluoroalkane (HFA)-134a and HFA-227ea based pMDI products that are approved for the treatment of asthma and chronic obstructive pulmonary disease (COPD), towards those that use low global warming potential (LGWP) propellants. Changing the propellant to, for example, the less environmentally-damaging HFA-152a, is a focus for many manufacturers. In this paper, we report an innovative approach to developing new pMDI drug products with a LGWP propellant. Moreover, proof of the hypothesis that products containing the current propellant and those using a LGWP propellant can achieve equivalent performance is reported, by showing comparability of a triple combination pMDI (Trimbow®) formulated using the LGWP HFA-152a propellant compared with HFA-134a. This paper will present the use of in silico mathematical modelling, leveraging on Chiesi proprietary Modulite® principles to predict and validate in vitro performances of the drug product under development. Validation is carried out using realistic aerodynamic particle size distribution (rAPSD), a novel approach that offers a more accurate prediction of aerosol distribution by incorporating variations compared to the standard aerodynamic particle size distribution (APSD). Additional in vitro testing validates the prediction of in silico models and confirms good comparability in terms of aerodynamic performance between HFA-152a and HFA-134a, which translates in vivo as evidenced by the preliminary pharmacokinetics (PK) in animal models and the formal clinical PK bioequivalence (BE) studies. (Rony et al. in Pulm Pharmacol Ther 85, 2024). Graphical Abstract