Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation

• Published in: Journal of pharmaceutical sciences 2020-04, Vol.109 (4), p.1529-1536
• Main Authors: Storgaard, Ida Hagen, Kristensen, Jesper, Larsen, Claus, Mertz, Nina, Østergaard, Jesper, Larsen, Susan Weng
• Format: Article
• Language: English
• Subjects: chemical stability; hydrolysis; injectables; kinetics; long-acting; physicochemical properties; prodrug
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2020.01.003

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 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 and 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.