Intra-Articular Hyaluronic Acid and Chondroitin Sulfate: Pharmacokinetic Investigation in Osteoarthritic Rat Models

BACKGROUND: Viscosupplementation of synovial fluid with intra-articular (IA) injections of hyaluronic acid (HA) is widely used for symptomatic treatment of osteoarthritis (OA). Herein we present HCS, a new combination of chemicals, associating HA and chondroitin sulfate (CS), both members of the glycosaminoglycan (GAGs) family, which are major components of the joint. HA provides viscosity to the synovial fluid and CS provides elasticity to the cartilage. Reduced levels of HA and CS are observed in OA joints and are associated with progressive cartilage damage and loss. OBJECTIVE: The objective of the study was to evaluate the pharmacokinetic (PK) properties of both HA and CS after IA administration in a validated OA animal model. METHODS: Motion impairment measurements and histological examinations were used to validate the ability of an IA injection of mono-iodoacetate (MIA) in the knee of rats to induce OA symptoms. Then, the PK properties of HA and CS after IA administration were characterized and each active ingredient was independently profiled: HA was labeled with tritium (3H-HA) and CS was labeled with carbon 14. (14C-CS) The final radio-labeled solution reproduced the cold HCS formulation. RESULTS: Four male Sprague-Dawley rats received a 1 mg MIA injection on day 1, then motor impairment was monitored from day 4 to day 18. Chondrocyte necrosis, loss of GAGs and other cartilage damage were observed. Twelve other rats received a MIA IA injection on day 1 then a radio-labeled HCS IA injection (50 µL) on day 8. Plasma and knee cartilage were collected postadministration and the terminal half-life was similar in both matrices (about 5 days), for both 3H-HA and 14C-CS. CONCLUSIONS: Despite differences in their molecular size, HA and CS showed PK behavior similarly characterized by prolonged residence inside the joint and slow release in plasma, favoring long-term beneficial effects. (Curr Ther Res Clin Exp. 2020; 92:XXX–XXX)