Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation

Abstract Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are promising for management of joint pain. As candidates for this delivery approach, five diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse and human of 3.44 – 141 min, 2.51 – 14 min, 0.58 – 1.31 min, and 0.23 – 1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6 to 28-fold larger than in plasma. The results highlight the significance of species as well as tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.