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)-approved or endogenous excipients. The powders were characterized in terms of their geometrical size, mass density, and aerosolization properties. Small nonporous particles were also prepared using the same excipients and were physically characterized to insure that they possessed a similar mean aerodynamic 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 particle formulations were found to produce elevated systemic estradiol concentrations upon inhalation for approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%. Systemic estradiol concentrations following inhalation 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 inhalation of porous and nonporous estradiol powders. Small changes in neutrophil and macrophage populations were observed following inhalation of both the porous and nonporous powders.