(162p) A Molecular Approach for the Development of Hydrofluoroalkane-Based Pressurized Metered-Dose Inhaler Formulations

Pressurized metered-dose inhalers (pMDIs) are the least expensive inhalation therapy devices available. pMDIs are, therefore, potentially attractive vehicles for the systemic delivery of drugs, including biomolecules, to and through the lungs. The phase-out of chlorofluorocarbons (CFCs) due to their ozone depleting nature has given rise to a new class of environmentally friendlier propellants, the hydrofluoroalkanes (HFAs). However, HFAs have different solvent properties compared to CFCs. This has caused significant challenges in reformulating traditional dispersion and solution HFA-based pMDIs. For example, the FDA-approved surfactants, which are generally required excipients in pMDIs, have poor solubility in HFAs. In spite of significant progress and research in the area, very little is understood about the nature and strength of interaction between the semi-fluorinated propellants and HFA-philes. This has prevented us from extending the use of pMDIs to areas including vaccine delivery, and the treatment of medically relevant diseases including cancer and diabetes.

In this work, we show how we use a combined computational and experimental approach to understand HFA-philicity at the molecular level, and to develop novel formulations for the systemic delivery of drugs to and through the lungs. The employed computational tools include ab-initio calculations and molecular dynamics computer simulations, while experimental methods include chemical force microscopy (CFM), colloidal probe microscopy (CPM), and in-situ high pressure tensiometry and small angle neutron scattering (SANS). We have applied ab initio calculations to quantitatively relate the chemistry of candidate surfactant tail groups to their HFA-philicity, by calculating the non-bonded interaction energy of HFA-surfactant tail fragment pairs. These results are corroborated by adhesion force measurements from CFM, where AFM tip and substrate are modified with the same functionalities studied quantum mechanically. Amphiphiles are then synthesized with the most promising tail candidates. Their ability in stabilizing dispersions in HFAs is tested. Novel formulations including reverse aqueous aggregates, and solid dispersions such as core-shell nanoparticles are developed. We use high-pressure tensiometry to optimize surfactant balance at the fluid-fluid (HFA|Water) interface. The ability of the amphiphiles to stabilize reverse aqueous aggregates containing biomolecules in HFAs is further analyzed using in situ high-pressure UV-vis spectroscopy and SANS. CPM is used to investigate the effect of surface modification on particle-particle (small solutes and biomolecules) interaction in hydrofluoroalkanes. Such a comprehensive approach allows us to understand this new class of solvents from a molecular perspective, creating opportunities to develop new pMDI-based formulations.