Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Pharmaceutical Sciences |
Vol/bind | 109 |
Udgave nummer | 4 |
Sider (fra-til) | P1529-1536 |
ISSN | 0022-3549 |
DOI | |
Status | Udgivet - 2020 |
Bibliografisk note
Copyright © 2020. Published by Elsevier Inc.
ID: 234642775