Oral fulvestrant nanoparticles deliver high, sustained exposure: An alternative to IM injection

Background: Fulvestrant, a selective estrogen receptor degrader (SERD) for ER⁺ breast cancer, is available only as a monthly intramuscular (IM) injection in a viscous formulation that can be painful, and no oral product is available. Oral fulvestrant could improve convenience and adherence; however, extreme hydrophobicity and extensive first-pass metabolism have limited prior oral approaches. We developed an oral fulvestrant formulation based on nanoparticles composed of pharmaceutically acceptable natural lipids. Methods: Fulvestrant was incorporated into nanoscale natural-lipid particles using solvent-assisted mixing and sonication, followed by drying to yield a free-flowing powder suitable for oral capsule or tablet formulation. Female Sprague-Dawley rats received 10 mg/kg fulvestrant orally as the natural-lipid nanoparticle formulation. Serial blood samples were collected up to 216 h. Fulvestrant concentrations in plasma and whole blood were quantified by validated LC-MS/MS, and noncompartmental pharmacokinetic analysis was performed. Results: The oral natural-lipid formulation produced stable nanoscale particles (100-200 nm) with a narrow size distribution and favorable surface charge (−34.1 mV) in aqueous media. After oral administration of 10 mg/kg fulvestrant, plasma concentrations peaked at ~505 ng/mL at 72 h, with AUC₀-₇₂ h ≈ 1.4 × 10⁴ ng·h/mL. Exposure was persistent, with fulvestrant remaining quantifiable at 216 h (C₂₁₆ h 110 ng/mL in plasma; 140 ng/mL in whole blood). Peak concentrations of 510 ng/mL (72 h, plasma) and 470 ng/mL (120 h, whole blood) were observed. A second composition with increased natural-lipid content also achieved high systemic exposure (plasma AUC₀-₇₂ h 9.28 × 10³ ng·h/mL), supporting robustness to formulation optimization. Conclusions: A natural-lipid nanoparticle formulation achieved high and sustained systemic exposure of fulvestrant after a single oral dose in rats. Absolute bioavailability was not determined because intravenous fulvestrant dosing is not feasible due to poor aqueous solubility, and relative bioavailability could not be assessed because no oral reference formulation yields quantifiable systemic exposure; therefore, pharmacokinetic evaluation focused on systemic exposure following oral administration. The formulation uses pharmaceutically acceptable natural lipids and standard unit operations (mixing, drying, milling) and yields a free-flowing powder suitable for solid oral dosage forms. These findings support further evaluation and optimization of oral delivery for fulvestrant and other highly insoluble compounds. A U.S. provisional patent application covering the formulation and manufacturing process has been filed. Funding: Supported by NIH/NIMHD grant 2U54MD007595.