Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation
| Autor: | Nina Mertz, Susan Weng Larsen, Jesper Østergaard, Jesper L. Kristensen, Claus Larsen, Ida Hagen Storgaard |
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| Rok vydání: | 2020 |
| Předmět: |
Diclofenac
Bioconversion Depot Kinetics Pharmaceutical Science 02 engineering and technology Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences Hydrolysis Dogs 0302 clinical medicine medicine Animals Synovial fluid Prodrugs Horses Chemistry Anti-Inflammatory Agents Non-Steroidal Esters Prodrug 021001 nanoscience & nanotechnology In vitro Rats 0210 nano-technology medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 109:1529-1536 |
| ISSN: | 0022-3549 |
| DOI: | 10.1016/j.xphs.2020.01.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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