Inhalation of estradiol for sustained systemic delivery

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Pulmonary Drug Delivery

Background:

• Estradiol is a crucial hormone with therapeutic applications.
• Optimizing estradiol delivery for sustained systemic concentrations remains a challenge.
• Particle engineering offers potential for controlled drug release.

Purpose of the Study:

• To formulate and characterize large porous estradiol particles for inhalation.
• To compare the in vivo bioavailability of porous versus nonporous estradiol particles.
• To evaluate the impact of particle morphology on estradiol pharmacokinetics.

Main Methods:

• Estradiol formulated into large porous and small nonporous particles via spray drying using FDA-approved excipients.
• Characterization of particle size, density, and aerosolization properties.
• In vivo assessment of relative bioavailability in rats via endotracheal intubation and subcutaneous injection.

Main Results:

• Large porous particles achieved sustained systemic estradiol levels for ~5 days with bioavailabilities of 59.7% and 86.0%.
• Small nonporous particles provided elevated estradiol levels for only ~1 day with bioavailabilities of 18.3% and 38.7%.
• Bronchoalveolar lavage showed minimal inflammatory cell changes (neutrophils, macrophages) after inhalation of either particle type.

Conclusions:

• Large porous estradiol particles significantly enhance systemic bioavailability and prolong drug release compared to nonporous particles.
• Spray-dried porous particle technology is a promising approach for sustained pulmonary delivery of estradiol.
• Particle engineering, specifically porosity, is critical for controlling estradiol release kinetics and bioavailability.