Pharmacological effects of N-[2-[[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]ethyl]hyaluronamide (diclofenac Etalhyaluronate, SI-613), a novel sodium hyaluronate derivative chemically linked with diclofenac.

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have investigated the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), which is a potentially safer and more effective treatment for OA knee pain. In this study, we evaluated the pharmacological effects of SI-613 in experimental arthritis models.

METHODS: We compared the analgesic and anti-inflammatory effects of intra-articularly administered SI-613, hyaluronic acid (HA), and of orally administered diclofenac sodium (DF-Na) in rat silver nitrate-induced arthritis model and rabbit antigen-induced arthritis model.

RESULTS: A single intra-articular (IA) administration of SI-613 significantly suppressed pain responses in rats in a dose-dependent manner. The analgesic effects were greater than those of HA, a mixture of DF-Na and HA, or an oral once-daily administration of DF-Na. In the rabbit arthritis model, SI-613 significantly reduced knee joint swelling compared with that in the control group on day 1 after a single IA injection. This significant anti-inflammatory effect was observed until day 28. In the pharmacokinetic study, the DF concentration in the synovium after SI-613 administration reached its maximum concentration of 311.6 ng/g on day 1, and gradually declined to 10 ng/g by day 28. It fell below the lower limit of quantification on day 35. Thus, a clear correlation was found between pharmacokinetics and pharmacodynamics. These results demonstrate that SI-613 exerts its long-lasting and potent anti-inflammatory effect by sustainable release of DF in the knee joint tissues.

CONCLUSION: A single IA injection of SI-613 was shown to exert analgesic and anti-inflammatory effects for 28 days in non-clinical pharmacological studies, suggesting that SI-613 will be a promising candidate in the treatment of osteoarthritis pain.