Testosterone 17β-N,N-dimethylglycinate hydrochloride: A prodrug with a potential for nasal delivery of testosterone

Abstract

The purpose of this study was to examine the potential of the nasal route for the systemic delivery of the poorly water-soluble drug testosterone (TS) using a water-soluble prodrug, TS 17β-N,N-dimethylglycinate hydrochloride. The physicochemical properties of the prodrug, in vitro hydrolysis in human liver homogenate, and in vivo nasal and intravenous experiments were performed in rats. The aqueous solubility of the prodrug was more than 100 mg/mL, compared with 0.01 mg/mL for TS, and its log partition coefficient between 0.05 M, phosphate buffer (pH 6) and octanol was 2.4. The prodrug was found to generate TS in 33% human liver homogenate and was absorbed from the nasal cavity rapidly and quantitatively. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous doses. These studies in rats suggest that this water-soluble prodrug of TS may have therapeutic utility for the management of TS deficiency. © 2002 Wiley-Liss, Inc.