Formulation design and pharmaceutical evaluation of an HFA 227-based furosemide metered dose inhaler

Abstract

A new hydrofluoroalkane (HFA 227) propellant was evaluated for the replacement of traditional chlorofluorocarbons (CFCs) in metered dose inhaler (MDI) formulations containing furosemide as a model drug for the treatment of asthma. The effect of ethanol as a cosolvent on the solubility of solvents and surfactants in HFA 227 was examined first. All solvents and surfactants used were miscible at 1% with HFA 227 containing 1% ethanol. The effects of ethanol and surfactants on the properties of the furosemide suspension in HFA 227 were examined. In the ethanol-HFA 227 system, the sedimentation time of primary drug particles in HFA 227 was increased by the addition of 10% ethanol, while the particle size of furosemide was larger than the size limit (5 μm) at ethanol concentrations over 10%. The content of ethanol in an HFA 227-based MDI should be lower than 10%. In the ethanol-surfactant-HFA 227 system containing 5% ethanol, the longest sedimentation time was 53 s/cm for 0.1% oleic acid, but the sedimentation time was 25 s/cm for 1.0% oleic acid. HFA 227-based furosemide MDIs were prepared using metered valves and aluminium canisters. The dose variation of HFA 227-based MDI with oleic acid using ethanol as a cosolvent remained within 10% over the expected actuation counts without any tail-off phenomenon. The in vitro deposition analysis using a glass twin impinger apparatus suggested that the HFA 227-based furosemide MDI with oleic acid and ethanol was equivalent to the corresponding CFC-based MDI, in regard to the delivery of furosemide to the lungs.