Piperazinylalkyl prodrugs of naproxen improve in vitro skin permeation

Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro for their properties as bioreversible topically admi nistered dermal prodrugs of naproxen. These ionizable prodrugs exhibited va rious aqueous solubilities and lipophilicities, depending on the pH of medi um. As indicated by octanol-buffer partition coefficients (log P-app) at pH 7.4, all of the prodrugs were significantly more lipophilic (log P-app=0.7 -3.9) than naproxen (log P-app=0.3). Furthermore, the most aqueous of the s oluble prodrugs (4b-d) were only 2-3-fold less soluble in an aqueous buffer of pH 7.4 (similar to 30-50 mM) than was naproxen (similar to 100 mM). At a pH of 5.0, prodrugs showed a generally higher aqueous solubility and simi lar log P-app values, compared to naproxen. The chemical and enzymatic hydr olysis of prodrugs at 37 degrees C was investigated in aqueous buffer solut ions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The pr odrugs showed moderate chemical stability (t(1/2)=15-150 days at pH 5.0), a nd 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 v itro, the flux of naproxen was 6.5 and 1.6 nmol/cm(2).h in a saturated aque ous 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 enhancemen t of permeation, respectively, when compared to naproxen itself at pH 7.4. 4c also resulted in a significantly (4-fold) better permeation than naproxe n at pH 5.0. In conclusion, piperazinyl esters improved skin permeation of naproxen and are promising prodrugs of naproxen for topical drug delivery. (C) 2000 Elsevier Science B.V. All rights reserved.