(527b) Pressurized Metered-Dose Inhaler Formulations for the Systemic Delivery of Biomolecule

Water?in-hydrofluoroalkane (W/HFA) reverse microemulsions have the potential to solubilize biomolecular species that can be delivered to and through the lungs. Pressurized metered-dose inhalers (pMDIs) are the least expensive aerosol delivery formulations available in the market. However, the replacement of CFCs with the more environmentally friendly hydrofluoroalkane (HFA) propellants has led to an extensive reformulation of pMDIs. Perhaps the biggest hurdle in reformulating HFA-based pMDIs comes from the fact that CFCs and HFAs have significantly different solvent properties. For example the FDA-approved surfactants have negligible solubility in HFAs. Moreover, the lack of fundamental knowledge about the interfacial properties of the bare and surfactant modified HFA-Water (HFA|W) interface is also preventing us from extending the applicability of pMDIs to the delivery of polar drugs that can be used to treat medically important diseases including cancer, cystic fibrosis and diabetes.

We combined ab initio calculations with experimental techniques, including chemical force microscopy (CFM), and in situ high-pressure small angle neutron scattering (SANS), UV-Vis Spectroscopy, and tensiometry to design surfactants that are interfacially active at the HFA|W interface, and capable of curving about water. Interfacial activity and balance for two classes of amphiphiles, with methyl- (CH2) and ether-base (PO) tails has been determined using high-pressure tensiometry. The methyl-based surfactants, including the FDA-approved amphiphiles for use in pressurized metered-dose inhalers, did not present high activity at the HFA|W interface. On the other hand, ether-based surfactants are shown to be very interfacially active, with tension lowering as large as 27 mN.m-1 . These results are in direct agreement with the non-bonded pair interaction biding energy calculations of HFA-tail fragment pairs, where very favorable energies are seen for the HFA-PO pair. The results also corroborate the CFM measurements where lower adhesion forces are observed for PO-based moieties (compared to CH2) in 2H, 3H perfluoropentane (HPFP), a model solvent for HFAs. The critical microemulsion concentration (cìc) and the area per molecule (A) for the most promising PO surfactant system were determined. The presence of reverse aggregates was detected with UV-vis spectroscopy, and confirmed by SANS. Upon the addition of a co-solvent, W/HFA reverse microemulsions with a typical core-shell signature was detected by SANS. Such aggregates are shown to be capable of encapsulating biomolecules, as evidenced by an increase in the scattering intensity and the radius of the microemulsion.