In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

A series of acyloxyalkyl esters of ketoproien and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl pro drugs. All of the prodrugs were more lipophilic than their parent molecules , as evaluated by drug partitioning between l-octanol and phosphate buffer at pH 7.4 (log P-app). However, their solubilities in aqueous solutions dec reased markedly compared with the parent molecules. The prodrugs were stabl e toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrol yzed to the parent drug both in 80% human serum and in human skin homogenat e, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respec tively. The abilities of the selected naproxen acyloxyalkyl prodrugs to del iver naproxen through excised human skin were evaluated. Generally, the pro drugs showed similar dermal delivery as the parent drug through cadaver ski n. In the present series of lipophilic prodrugs of naproxen, the prodrug wi th the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.