Development of an Oral Formulation for Oestrone 3-O-Sulphamate, a Potent Sulphatase Inhibitor

Abstract

Oestrone sulphatase is a key enzyme involved in oestrogen synthesis in breast tumours in postmenopausal women. As breast tumours can be endocrine-dependent, it is therefore feasible that blockage of this enzyme may be of value in the treatment of such tumours. Oestrone 3-O-sulphamate (EMATE) is the most potent inhibitor of oestrone sulphatase activity described to date. Here, we describe a preliminary examination of its physicochemical properties and the development of a self-emulsifying formulation for potential administration of EMATE by the oral route. A preliminary assessment of the absorption of the drug from the gut was undertaken, and pharmacological activity, determined as oestrone sulphatase inhibition, was studied following intravenous and oral administration. A high-performance liquid chromatography (HPLC) assay was developed to measure degradation of EMATE in the formulation and also its concentration in rat plasma. The drug was susceptible to degradation, but its stability in the formulation was satisfactory when stored at either 4°C or room-temperature over the timespan required for a clinical trial. Plasma EMATE concentrations after 2 h were a function of the dose of drug administered orally to rats over the 10–40 mg kg−1 range. After oral administration in the self-emulsifying system, EMATE appeared to be rapidly absorbed, with the peak plasma concentration being detected at 30 min, after which plasma concentrations rapidly decreased. After intravenous administration, a similar plasma EMATE concentration was detected at 1 h to that observed after oral administration. Rat liver sulphatase activity was almost completely inhibited (> 99%) within 30 min of oral or intravenous administration of EMATE.