Nebulized Glucocorticoids in Liposomes: Aerosol Characteristics and Human Dose Estimates

ABSTRACT

We have developed glucocorticoid (GC)-phosphatidylcholine (PC) liposome formulations for pulmonary administration in small-particle aerosol generated by continuous jet nebulizers from aqueous suspensions. Four PC derivatives, i.e., dilauroyl phosphatidylcholine (DLPC), dioleoyl phosphatidylcholine (DOPC), palmitoleoyl phosphatidylcholine (POPC), and egg-yolk phosphatidylcholine (EYPC) were suitable for efficient delivery of GC-liposome aerosol with different topically active GC, i.e., beclomethasone (Bec), budesonide (Bud), flunisolide (Flu), triamcinolone acetonide (Taa), and dexamethasone (Dex). Aqueous aerosol droplets containing GC-liposomes demonstrated a mass median aerodynamic diameter (MMAD) range of 1.2 - 1.9 μm and geometric standard deviation (GSD) range of 2.0 -2.6. A phase transition temperature (Tc) of PC below nebulizer temperature was critical for efficient GC-liposome nebulization. DLPC was selected for development because of its performance, increased stability, and low Tc. Sites of deposition in the human respiratory tract were calculated from a computer model based on the GC-liposome aerosol MMAD, GSD, and GC content. The predicted regional deposition of Bec-DLPC liposome aerosol in the oropharynx was 2.5%, 4.9% in Weibel airway generations 0-16, and 17.5% in generations 17-23, while 75.1% of aerosol will be exhaled. From these data, human dosages equivalent to those recommended by MDI could be delivered within 15-30 minutes of inhalation (depending on GC potency) to treat inflammatory diseases of the respiratory tract.