Aqueous dispersions in hydrofluoroalkane propellants for the pulmonary delivery of polar drugs including biomolecules.

摘要

One of the biggest challenges the medical spray industry is facing in transitioning from CFCs and HCFCs to the more environmentally friendly HFA propellants is the lack of fundamental understanding of the physicochemical and solvation properties of this new class of semi-fluorinated solvents. Such limitations have negatively impacted the reformulation of CFC-based pMDIs with HFAs, and have also limited the development of novel pMDI formulations. While reverse aqueous microemulsions in HFAs are considered promising carriers for the delivery of therapeutic biomolecules and vaccines to and through the lungs for treating medically relevant diseases such as diabetes and cancer, and constitute one such novel oral inhalation formulation, limited success has been achieved so far, in part due to the difficulties in probing the interface in situ (under pressure). Within this context, we present in this work a rational approach for the design of amphiphiles for the HFA-water interface where we utilized high-pressure tensiometry to characterize the bare and surfactant-modified interface. Amphiphiles capable of forming reverse aqueous aggregates in water-HFA systems were identified. The ability of these aggregates to uptake model polar solutes, including biomacromoleucles, and the aerosol characteristics of the corresponding formulations were investigated. The microstructure of the reverse aggregates and characteristics of the polar environment were also addressed via in situ spectroscopy and SANS. In vitro cytotoxicity studies of a selected formulation and preliminary transport investigations across an in vitro model of the lung epithelial is also discussed. Surfactant systems that are capable of self-emulsify water and HFA have been identified. These results suggest the use of reverse aqueous aggregates of water in HFA as potential candidates for the regional and systemic delivery of therapeutics to and through the lungs utilizing the simple and inexpensive pMDIs as delivery devices, thus opening up new market opportunities for oral inhalation formulations.