Prolonged Anti-inflammatory Action of DL-lactide/glycolide Copolymer Nanospheres Containing Betamethasone Sodium Phosphate for an Intra-articular Delivery System in Antigen-induced Arthritic Rabbit

Purpose: The objective of the present study was to develop prolonged anti-inflammatory action of DL-lactide/glycolide copolymer (PLGA) nanosphere incorporating a water-soluble corticosteroid (betamethasone sodium phosphate; BSP). Another aim was to demonstrate the biocompatibility and biologic efficacy of these BSP-loaded nanospheres directly administered into ovalbumin-induced chronic synovitis in the rabbit.

Methods: BSP-loaded nanospheres were prepared by an emulsion solvent diffusion method in oil (caprylate and caprate triglyceride). The drug releasing properties of the nanospheres were measured in vitro in phosphate buffer saline (PBS: pH7.4), and in vivo in rat air-pouch (pseudo synovial fluid). The BSP-loaded nanosphere suspensions were administered into the joint cavity in a model of antigen-induced arthritic rabbit and evaluated by measuring the joint swelling, and the biocompatibility was appraised by histologic microscopy.

Results: The BSP-nanospheres were a unimodally-dispersed particulate system with a mean diameter ranging from 300 to 490 nm, and BSP was efficiently entrapped in the lipophilic copolymer (PLGA), although its hydrophilic properties. The drug release-rate from the nanospheres in PBS was controlled by the molecular weight and the lactic/glycolic acid (LA/GA) ratio of the polymers. The in vitro releasing study demonstrated that sustained drug release occurred for over three weeks. In the antigen-induced arthritic rabbit, the joint swelling decreased significantly by administering BSP-loaded nanospheres during a 21-day period after intra-articular challenge. With regards to the prolonged anti-inflammatory efficacy, serum antibody to ovalbumin showed a sustained reduction during the period, and the steroidal effect appeared by the degradation of the polymer in the synovium. The BSP-nanosphere administered was phagocytosed by the synovial activated-cells and the cartilage degradation was almost prevented.

Conclusions: Direct intra-articular injection of a PLGA nanosphere system with a water-soluble steroid provided a prolonged pharmacological efficacy in the joints of arthritic rabbits. The local anesthetic in the knee-joints was evaluated to be safe and without biologic damage.