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.
PURPOSE: The aim of this work was to synthesize ionizeddehydroepiandrosterone (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 DHEAionized 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.
Authors: O M Wolkowitz; V I Reus; E Roberts; F Manfredi; T Chan; W J Raum; S Ormiston; R Johnson; J Canick; L Brizendine; H Weingartner Journal: Biol Psychiatry Date: 1997-02-01 Impact factor: 13.382
Authors: J E Buster; P R Casson; A B Straughn; D Dale; E S Umstot; N Chiamori; G E Abraham Journal: Am J Obstet Gynecol Date: 1992-04 Impact factor: 8.661