Aerosol generation by metered-dose inhalers containing dimethyl ether/propane inverse microemulsions.

Water soluble compounds were incorporated into metered-dose inhalers (MDIs) by using water-in-propellant lecithin microemulsions, in which dimethyl ether (DME) and propane acted as both continuous phase and propellant. Lecithin, water, and water soluble compounds were added to glass MDI containers, valves were crimped on, and propellants were added using a pressure burette. Aerosols were produced using commercially available actuators, and inertial impaction was used to determine the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction (FPF) of the resulting aerosols. The DME/propane/lecithin microemulsion MDIs generated aerosols with particle size distributions suitable for pulmonary delivery (eg, MMAD 3.1 microm, FPF 59% for DME with lecithin content 3%, water content 2.5% [wt/wt]). Increasing water concentration (up to 8% wt/wt) was correlated with a reduction in FPF. Freezing and rewarming had no adverse effect on MMAD, GSD, or FPF. Storage of microemulsion samples for up to 3 weeks did not adversely affect the MMAD, GSD, or FPF. This approach may enable the pulmonary delivery of water soluble therapeutic agents via MDIs.

Lecithin microemulsions in dimethyl ether and propane for the generation of pharmaceutical aerosols containing polar solutes.

Water soluble compounds have been incorporated into solution phase metered dose inhalers (MDIs) utilizing lecithin inverse microemulsions in dimethyl ether (DME) and propane. DME and propane acted as both solvent and propellant. Experiments utilizing model propellants (dimethylethyleneglycol (DMEG) and hexane) were used to investigate microemulsion physicochemical phenomena, and the results were used to design and interpret the technically more challenging MDI experiments. NMR and viscosity experiments with model propellants were consistent with a "sphere-to-string" micellar shape change as the solvent was varied from pure DMEG to pure hexane. Water soluble solutes, including selected peptides and fluorescently labeled poly-alpha, beta-[N-(2-hydroxyethyl) D,L-aspartamide] (fPHEAs), dissolved in DME/propane dependent on lecithin and water content. MDIs containing microemulsions generated aerosols with mass median aerodynamic values ranging from 2.7 to 3.1 microns, within the range of commercially available formulations. Fine particle fraction values (50-70%) exceeded those of commercial formulations. fPHEA up to 18 kDa did not adversely affect the aerosol characteristics. Deposition of the aerosol onto a water surface resulted in the formation of liposomes with partially entrapped solute.