Oral Delivery of a Sustained Estradiol Delivery System

Period of Performance: 09/30/1988 - 08/31/1989


Phase 2 SBIR

Recipient Firm

Pharmos Corporation
Alachua, FL 32615
Principal Investigator


Based on the demonstrated feasibility shown in Phase I studies for oral administration of 17 beta-Estradiol (E2) using a novel redox system, Phase II studies are proposed which are designed to develop and test prototype formulations for bioavailability. The redox- based 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 and sustained E2 delivery to the central nervous system by hydrolysis of a "locked-in" charged precursor to E2 and the non- toxic carrier. Studies in rats showed sustained LH inhibition, decreased body weight gain and increased brain drug levels after i.v. treatment which were not associated with elevated serum E2 values. The E2-CDS was incorporated into a modified cyclodextrin inclusion complex which stabilized the labile drug and greatly improved water solubility. Significantly bioavailability was shown after oral dosing in rats which appears to be the result of oral mucosa or buccal absorption. The objectives of proposed studies i) screen CDS-E2 analog for improved oral bioavailability, ii) pharmaceutically evaluate formulations toward a prototype oral/buccal tablet, and iii) establish pharmacokinetics and bioavailability of the prototype formulation in a non-rodent model. Development of an oral or oral mucosa formulation for E2-CDS offers several advantages over currently available therapies including: i) delivery of a naturally occurring steroid, ii) decreased peripheral estrogen activity and iii) increased dosing interval.