Inhalation of estradiol for sustained systemic delivery

Large porous estradiol particles were formulated by spray drying estradiol in combination with various U.S. Food and Drug Administration (FDA)-approve d or endogenous excipients. The powders were characterized in terms of thei r geometrical size, mass density, and aerosolization properties. Small nonp orous particles were also prepared using the same excipients and were physi cally characterized to insure that they possessed a similar mean aerodynami c size as the large porous particles. The two powders were aerosolized into the lungs of rats via an endotracheal tube or subcutaneously injected as a control to assess relative bioavailability. Two different large porous par ticle formulations were found to produce elevated systemic estradiol concen trations upon inhalation for approximately 5 days, with relative bioavailab ilities of 59.7% and 86.0%. Systemic estradiol concentrations following inh alation of two different small nonporous particle powders remained elevated for only approximately 1 day, with relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was performed up to 96 hours after inhalatio n of porous and nonporous estradiol powders. Small changes in neutrophil an d macrophage populations were observed following inhalation of both the por ous and nonporous powders.