ABSORPTION OF ORAL ETHINYLESTRADIOL IS DELAYED BY ITS EUTECTIC MIXTURE WITH CHOLESTEROL

A solid dispersion of ethinylestradiol-cholesterol (EE & CHOL; eutectic 1:4 W/W) was prepared by melting and rapid cooling. The fused material was then mixed with lactose as vehicle. Soft gelatin capsules were filled with 50 mg of the final mixture to give 0.050 mg of ethinylestradiol. Six female volunteers received, one capsule of the eutectic combination of EE: CHOL or one 50-mu-g tablet of ethinylestradiol (Dianor, Syntex), in a cross-over study and in fasting state. Venous blood samples were drawn at 0, 10, 20, 30, 40, 50, 60, 90, 120, 240, 360, 480, 720, 1440 minutes after dosing. Immunoreactive EE was measured by radioimmunoassay to assess the serum concentration-time course. All subjects exhibited a significant increase in EE levels after oral administration. Mean peak EE levels, 1350 pg/ml vs 91 pg/ml (p < 0.001), were achieved 360 minutes and 90 minutes (p < 0.01), after administration of the eutectic and reference formulation, respectively. Eutectic mixture showed a greater area under the serum concentration-time curve, longer mean residence time of the drug in the body, and four times the value of the elimination half-life of the reference formulation. It is concluded that the combination of ethinylestradiol with cholesterol forming an eutectic mixture, when administered orally to normal women, modulates the absorption and the bioavailability of the EE. This approach may be suitable for long-acting oral treatment with sex steroids.