| Aerosol inhalation therapies have been traditionally used in the treatment of asthma and chronic pulmonary disorders. However, there is 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 including diabetes, cancer, osteoporosis, and multiple sclerosis, and as vaccine delivery systems. Pressurized metered-dose inhalers (pMDIs) are the most widely used oral inhalation devices for the regional delivery of drugs (small molecular weight) to the lungs due to their low cost and high patience compliance. However, the mandatory replacement of CFCs with more environmentally friendly hydrofluoroalkane (HFA) propellants has caused a significant reformulation challenge, due mostly to the lack of fundamental knowledge on the solvation in HFAs. This has also hindered the development of novel pMDI formulations for the local and systemic delivery of therapeutic biomolecules.;In this work we address this very basic issue of solvation in HFAs at the molecular level. An HFA-philicity scale is developed, where promising candidate chemistries for the design of stabilizers in low dielectric HFAs are quantitatively identified. Based on this fundamental knowledge, various pMDI formulations for pulmonary delivery of both small molecules and therapeutic biomacromolecules including proteins and peptides were developed. The studies in this dissertation are not only expected to provide an opportunity for expanding the use of pMDIs within the oral inhalation market, but also, and perhaps most importantly, to increase the overall market share of oral inhalation formulations by tapping into areas currently exclusive to i.v. or the oral routes of delivery. |
