Residual Property of SI-613, a Novel Drug for Osteoarthritis, in Knee Joint

Abstract

Osteoarthritis is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have reported that the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), exerted a potent and long-lasting analgesic eŠect in experimental arthritis models. In this study, we evaluated the properties of residual SI-613 in the knee joint after an intra-articular (IA) administration. After IA administration of ‰uorescent labeled SI-613 (FA-SI-613) or ‰uorescent labeled hyaluronic acid (FA-HA) to rabbits, ‰uorescence intensities in the synovial membrane and cartilage were higher in the FA-SI-613 group until 7 d after administration than in the FA-HA group. After IA administration of radiolabeled SI-613 ( 14 C-SI-613) to rabbits, the radioactivity remained in the joint cavity and the joint tissues such as synovial membrane and cartilage until 84 d after administration. This residual radioactivity was identiˆed mainly as HA linked with DF, since 14 C-SI-613 was labeled at the benzene ring of DF and since more DF-linked HA oligomer was detected on metabolite analysis than free DF in the synovial membrane and synovial lavage ‰uid up to 28 d after administration. These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological eŠects of both HA and DF by remaining in the joint as HA linked with DF.

Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model

“…In a previous study, radiolabeling showed that DF-HA remained in the joints for up to 4 weeks post-administration and released DF continuously [ 30 ]. In addition, a study [ 12 ] in which DF-HA was administered after inducing arthritis with silver nitrate in the knees of rabbits suggested that the DF concentration in the synovium remained > 10 ng/g and significantly reduced swelling from the day after its administration until 4 weeks later.…”

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“…Serum Hyaluronan: Hyaluronan (HYA) is a linear extracellular polysaccharide in all tissues and bodily fluids, with the largest amounts in loose connective tissue 37 . It's found in synovial fluid, responsible for the fluid's distinctive rheological qualities, and cartilage, responsible for the backbone of proteoglycan aggregates and synovial tissue and joint capsule.…”

“…Hyaluronan is a connective tissue polysaccharide that has also been found in blood serum in concentrations < 100 micrograms/L (average 30-40 micrograms/L in middle-aged persons 37 .…”