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Received August II, 1999; accepted September 7, 1999
Purpose. The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application.
Methods. The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin.
Results. Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor.
Conclusions. The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.
KEY WORDS: transdermal; iontophoresis; prodrug; DHEA; skin.
INTRODUCTION
Dehydroepiandrosterone (DHEA), a naturally occurring adrenal steroid hormone, has received attention after the discovery that its endogenous level declines with aging (1). The restoration of serum levels by exogenous administration has been associated with physical and psychological well-being (2). DHEA administration has also been suggested for post-menopausal diseases (3), AIDS progression in HIV-1 infections (4), cardiovascular diseases (5) and depression (6). The hormonal therapy of age-related diseases using DHEA requires constant or pulsatile long-term administration. DHEA dosage forms suitable for long term therapy still have to be developed, since the only available route of administration is the oral, which suffers for an important first pass effect and low and variable bioavailability (7). The daily oral dose (25-50 mg/day) suggests that transdermal delivery could be an appropriate route for DHEA, in order to maintain plasma levels in the order of 3-5 µg/ml (7), with increased patient acceptability. In addition, transdermal iontophoresis, i.e. the application of electric current to enhance drug...