Aceclofenac-galactose conjugate: design, synthesis, characterization and pharmacological and toxicological evaluations

Aceclofenac is a popular analgesic, antipyretic and nonsteroidal anti-inflammatory drug (NSAID) used for prolonged treatment (at least three months) in musculoskeletal disorders. It is characterized by several limitations, such as poor water solubility and low oral bioavailability. The main side-effect of aceclofenac, as well as all NSAIDs, is the gastrotoxicity; among other adverse effects, there is the risk of bleeding since aceclofenac reversibly inhibits platelet aggregation. With the aim to reduce these drawbacks, we have designed, synthesized and characterized both in vitro and in vivo, an orally administrable pro-drug of aceclofenac (ACEgal). ACEgal was obtained by conjugating carboxyl group with the 6-OH group of D-galactose; its structure was confirmed by X-ray powder diffractometry. The pro-drug was shown to be stable at 37°C in simulated gastric fluid (SGF-without pepsin, pH=1.2), and moderately stable in phosphate buffered saline (PBS, pH=7.4). However, it hydrolyzed in human serum with a half-life (t1/2) of 36 minutes, producing aceclofenac. Furthermore, if compared to its parent drug, ACEgal was four times more soluble in SGF. In order to predict human intestinal absorption, cell permeability in a Caco-2 model of aceclofenac and ACEgal was determined. Anti-inflammatory, analgesic, and ulcerogenic activities have been investigated in vivo. In addition, oxidative stress parameters (thiobarbituric acid reactive substances, TBARS and glutathione, GSH) and platelet anti-aggregatory activity both of parent drug and pro-drug were evaluated. Results clearly showed that the conjugation of aceclofenac to a galactose molecule improves physico-chemical, toxicological (at gastric and blood level) and pharmacological profile of aceclofenac itself, without changing intestinal permeability and anti-platelet activity (in spite the new sugar moiety).