Reverse aqueous microemulsions in hydrofluoroalkane propellants and their aerosol characteristics

In this work we describe the structure and environment of reverse aqueous microemulsions formed in 1,1,1,2-tetrafluoroethane (HFA134a) propellant in the presence of a non-ionic ethoxylated copolymer, and the aerosol characteristics of the corresponding pressurized metered dose inhaler (pMDI) formulations. The activity of selected polypropylene oxide–polyethylene oxide–polypropylene oxide (POmEOnPOm) amphiphiles at the HFA134a–water interface was studied using in situ high-pressure tensiometry, and those results were used as a guide in the selection of the most appropriate candidate surfactant for the formation of microemulsions in the compressed HFA134a. The environment and structure of the aggregates formed with the selected surfactant candidate, PO22EO14PO22, was probed via UV–vis spectroscopy (molecular probe), and small angle neutron scattering (SANS), respectively. High water loading capacity in the core of the nanoaggregates was achieved in the presence of ethanol. At a water-to-surfactant molar ratio of 21 and 10% ethanol, cylindrical aggregates with a radius of 18 Å, and length of 254 Å were confirmed with SANS. Anderson Cascade Impactor (ACI) results reveal that the concentration of the excipients (Cexp, including surfactant, water and ethanol) has a strong effect on the aerosol characteristics of the formulations, including the respirable fraction, and the mass mean aerodynamic diameter (MMAD), and that the trend in MMAD can be predicted as a function of the Cexp following similar correlations to those proposed to common non-volatile excipients, indicating that the nanodroplets of water dispersed in the propellant behave similarly to molecularly solubilized compounds. Cytotoxicity studies of PO22EO14PO22 were performed in A549 cells, an alveolar type II epithelial cell line, and indicate that, within the concentration range of interest, the surfactant in question decreases cell viability only lightly. The relevance of this work stems from the fact that aqueous-based HFA-pMDIs are expected to be versatile formulations, with the ability to carry a range of medically relevant hydrophilic compounds within the nanocontainers, including high potency drugs, drug combinations and biomacromolecules.

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