Aerosol inhalation therapies have been traditionally used in the treatment of asthma and chronic pulmonary disorders. More recently there has been a significant thrust in expanding the role of aerosols as vehicles for the systemic delivery of biomolecules that can be used in the treatment of various diseases that include diabetes, cancer, osteoporosis, and multiple sclerosis and as vaccine delivery systems. Such interest stems largely from the fact that the bioavailability of biomolecules in the lungs can be retained to a larger extent compared to that seen in alternative delivery routes. Another important factor that makes aerosol therapy so attractive is its non-invasive nature, which not only helps increase patient compliance, but may also decrease risks for transmitting blood-born pathogens. Pressurized metered dose inhalers (pMDIs) are the least expensive inhalation therapy devices available, accounting for approximately 80 % of the total prescribed aerosols. pMDI-based formulations are, therefore, potential candidates for the delivery of pharmaceutically relevant biomolecules including peptides, DNA and proteins. Polar compounds, including biomolecules, have limited solubility in the low dielectric hydrofluoroalkane (HFA) propellants, and thus need to be formulated as dispersions. However, the lack of fundamental understanding on the solvation in the semi-fluorinated propellants is preventing us from designing moieties with high affinity to HFAs that could be used to modify the surface properties of the otherwise unstable colloidal particles. In this work we discuss a general methodology for preparing core-shell particles where the outer most layer of the shell (that is in contact with the HFA propellant) contains an HFA-philic moiety that interacts well with the propellant HFA, and is thus capable of providing excellent physical stability to the formulation. The core of the particle can be any polar drug, including biomolecules and combinations of small polar drugs and biomolecules. The aerosol performance, enzymatic activity and in vitro cytotoxicity of the core-shell formulation were investigated. Anderson Cascade Impaction results indicate significant improvement in the performance of the aerosol of the core-shell formulation in HFA227 when compared to traditional dispersion formulations (micronized drugs). A model protein encapsulated within the core of the particle shows a significant retention in its activity after successful dispersion in the propellant HFA. Cytotoxicity studies performed on lung epithelial cells show no toxic effects of the core-shell particles.

Keywords: pulmonary drug delivery; pressurized metered dose inhalers; cytotoxicity; biomolecules; HFA227