Synthesis and in vitro evaluation of novel morpholinyl- and methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy-2-naphthyl)propionic acid (naproxen) for topical drug delivery

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evalu ated in vitro for topical drug delivery as potential prodrugs of naproxen ( 1). Compounds 3a-f were prepared by coupling the corresponding naproxen hyd roxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyri dine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen i n human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (l og P-app), at pH 5.0 when compared to naproxen. At pH 7.4 they were signifi cantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1 .5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperaziny l group yields prodrugs that are partially un-ionized under neutral and sli ghtly acidic conditions, and thus, a desirable combination is achieved in t erms of aqueous solubility and lipophilicity. Moreover, the resulting combi nation of biphasic solubility and fast enzymatic hydrolysis of the methylpi perazinylacyloxyalkyl derivatives gave improved topical delivery of naproxe n.