Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro for their properties as bioreversible topically administered dermal prodrugs of naproxen. These ionizable prodrugs exhibited various aqueous solubilities and lipophilicities, depending on the pH of medium. As indicated by octanol-buffer partition coefficients (logP(app)) at pH 7.4, all of the prodrugs were significantly more lipophilic (logP(app)=0.7-3.9) than naproxen (logP(app)=0.3). Furthermore, the most aqueous of the soluble prodrugs (4b-d) were only 2-3-fold less soluble in an aqueous buffer of pH 7.4 ( approximately 30-50 mM) than was naproxen ( approximately 100 mM). At a pH of 5.0, prodrugs showed a generally higher aqueous solubility and similar logP(app) values, compared to naproxen. The chemical and enzymatic hydrolysis of prodrugs at 37 degrees C was investigated in aqueous buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs showed moderate chemical stability (t(1/2)=15-150 days at pH 5.0), and they were hydrolyzed enzymatically to naproxen, with half-lives ranging from 0.4 to 77 min. In permeation studies using post-mortem human skin in vitro, the flux of naproxen was 6.5 and 1.6 nmol/cm(2). h in a saturated aqueous buffer vehicle of pH 7.4 and 5.0, respectively. Among the prodrugs, two piperazinyl derivatives (4c and 4d) resulted in a 9- and 4-fold enhancement of permeation, respectively, when compared to naproxen itself at pH 7.4. 4c also resulted in a significantly (4-fold) better permeation than naproxen at pH 5.0. In conclusion, piperazinyl esters improved skin permeation of naproxen and are promising prodrugs of naproxen for topical drug delivery.