Inhalation chemotherapy has been suggested as an attractive alternative for the local delivery of chemotherapeutics to the lungs due to high therapeutic efficacy of antineoplastic agents and low systemic toxicity. Aqueous reverse aggregates in hydrofluoroalkanes (HFAs) can be used for the systemic delivery of anti cancer drugs to and through the lungs using pressurized metered dose inhalers (pMDIs). There are several potential advantages in using reverse aggregates compared to dispersion-based dispersions. For high potency drugs, where the total surface area of the drug may be comparable to that of the container walls, reverse aggregates may serve to improve dose reliability and control dose concentration. However, the methyl-based FDA approved surfactants for pMDIs have extremely low solubility in HFAs, and cannot stabilize water-in-HFA (W/HFA) microemulsions. Hence understanding the relationship between the chemistry of candidate surfactant tail moieties to their HFA-philicity, and surfactant balance at the HFA-water (HFA|W) interface is of great relevance for the development of such formulations.

In this work we investigate the activity of a series of non-ionic amphiphiles at the HFA134a-water interface using in situ high-pressure tensiometry. An optimal candidate surfactant molecule was identified, and its ability in forming aqueous reverse aggregates in HFA134a was studied by in situ UV-Vis spectroscopy (molecular probe). Small angle neutron scattering was used to investigate the structure of the reverse aggregates in the presence of the anti-cancer drug irinotecan hydrochloride (IrHCl). The aerosol characteristics of the formulations in the presence of IrHCl, and the effect of non-volatiles on the aerosol properties were investigated with an Anderson Cascade impactor. Cytotoxicity of the selected amphiphile was studied on the A549 cells, an alveolar type II epithelial cell line. This work is relevant in that it demonstrates the applicability of reverse-aqueous aggregates in HFAs as potential pMDI formulations for the non-invasive regional delivery of anti-cancer therapeutics to the lungs.