ORAL DELIVERY OF A SUSTAINED ESTRADIOL DELIVERY SYSTEM

STUDIES ARE PROPOSED TO EVALUATE THE FEASIBILITY OF ORAL 17BETA-ESTRADIOL (E2) ADMINISTRATION USING A NOVEL REDOX SYSTEM. THIS CHEMICAL DELIVERY SYSTEM (CDS) IS BASED ON AN INTERCONVERSION OF A LIPOPHILIC DIHYDROPYRIDINE TO A HYDROPHILIC PYRIDINIUM SALT, ANALOGOUS TO THE NADH NAD+ COENZYME SYSTEM. IT PERMITS ENHANCED ANDSUSTAINED DELIVERY OF E2 TO THE CENTRAL NERVOUS SYSTEM BY HYDROLYSIS OF A "LOCKED-IN," CHARGED PRECURSOR. SUSTAINED LEUTINIZING HORMONE (LH) INHIBITION AND INCREASED BRAIN DRUGCONCENTRATIONS WERE SHOWN IN RATS AFTER INTRAVENOUS (I.V.) E2-CDS TREATMENT. NO SERUM E2 CHANGE WAS DETECTED, INDICATING THAT E2 WAS RELEASED CENTRALLY FROM CHARGED E2-CDS AND DECREASED LH VIA CENTRAL ACTION AND/OR VIA PORTALVESSEL TRANSIT OF E2 TO THE PITUITARY. DEVELOPMENT OF AN ORAL FORMULATION FOR E2-CDS OFFERS SEVERALADVANTAGES OVER CURRENTLY AVAILABLE ESTROGEN THERAPIES INCLUDING: (1) DELIVERY OF A NATURALLY OCCURRING GONADAL STEROID, (2) DECREASED PERIPHERAL ESTROGEN ACTIVITY, AND (3) INCREASED DOSING INTERVALS. THE FIRST STUDY WILL ESTABLISH BIOAVAILABILITY OF THE DRUG. THE SECOND STUDY WILL COMPARE LH-INHIBITING ACTIVITY OF ORAL AND I.V. E2-CDS ADMINISTRATION. THE THIRD STUDY WILL EXAMINE THE TISSUE DISTRIBUTION OF DRUG AND SELECTED METABOLITES OVER TIME AFTER ORAL E2-CDS TREATMENT.