Novel sustained releasing triamcinolone acetonide polyesteramide microparticle platfform to reduce pain in the knee of a synoviatis rat model

Abstract

Purpose: Inflammation in an osteoarthritic joint predominantly causes pain and stimulates cartilage matrix breakdown. Triamcinolone acetonide (TAA) is intra-articularly injected to alleviate pain and temporarily reduce inflammation. Since multiple injections entail risks, local sustained TAA release can overcome such disadvantages. PLGA formulations of TAA has been shown to effectively prolong pain inhibition in OA, but limited to 4 weeks. A novel polyesteramide (PEA) microsphere platform based on natural α-amino acids previously showed release in the joint for over 3 months. To evaluate its capacity for sustained TAA release in inhibiting pain and inflammation, PEA microspheres loaded with TAA were locally delivered in a rat model of acute inflammatory arthritis. Methods: Localized synovitis was induced in the left knee of 18 adult Sprague-Dawley rats by intra-articular injection of streptococcal-cellwall- peptidoglycan-polysaccharide (PGPS with 5 mg rhamnose/mL) (priming, day -14). Synovitis flare-ups were evoked every 2 weeks by administration of intravenous PGPS. 2.5 hours prior first reactivation (day 0), 25 ml unloaded and loaded microspheres with 2.5 μg/ml TAA, using PEA and PLGA polymer as carrier or bolus TAA (2.5 μg/ml) were intra-articularly delivered in the affected knee. Joint thickness, dynamic weight-bearing, paw withdrawal latency and lameness was scored to compare the effect of prolonged sustained TAA release of two different polymer systems with bolus TAA injection. Results: Joint thickness was significantly increased due to synovitis flare-ups and bolus TAA injection could not reduce this swelling over the entire study period, whereas a single injection of controlled released TAA was able to reduce this, for both systems. Furthermore, sustained release of TAA restored paw withdrawal latencies, improved weight symmetry, paw surface placement and lameness of affected limb. Post-termination microCT images and corresponding histopathology are currently being analyzed. Conclusions: Sustained suppression of synovitis by controlled TAA release from the PEA platform provides prolonged reduction of joint inflammation, functional improvement and pain relief over an extended period after single injection. In addition, an improvement of PEA platform over PLGA MPs was observed with respect to joint thickness. Both Microparticle platforms showed advantage over single bolus injection of TAA. (Figure Presented).