Sustained intra-articular release of celecoxib from in situ forming gels made of acetyl-capped PCLA-PEG-PCLA triblock copolymers in horses

• Published in: Biomaterials 2015-06, Vol.53, p.426-436
• Main Authors: Petit, Audrey, Redout, Everaldo M, van de Lest, Chris H, de Grauw, Janny C, Müller, Benno, Meyboom, Ronald, van Midwoud, Paul, Vermonden, Tina, Hennink, Wim E, René van Weeren, P
• Format: Article
• Language: English
• Subjects: Acetylation; Advanced Basic Science; Animals; Celecoxib; Celecoxib - administration & dosage; Celecoxib - pharmacokinetics; Cyclooxygenase 2 Inhibitors - administration & dosage; Cyclooxygenase 2 Inhibitors - pharmacokinetics; Dentistry; Discomfort; Drug Carriers; Drug delivery systems; Forming; Gels; Histology; Horses; Hyaluronic acid; Hydrogel; Indication; Inflammatory response; Intra-articular delivery; Joints - metabolism; Local delivery; Polyesters - chemistry; Polyethylene Glycols - chemistry; Proton Magnetic Resonance Spectroscopy; Surgical implants; Sustained release; Synovial Fluid - metabolism; X-Ray Diffraction
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.02.109

Abstract In this study, the intra-articular tolerability and suitability for local and sustained release of an in situ forming gel composed of an acetyl-capped poly(ε-caprolactone- co -lactide)- b -poly(ethylene glycol)- b -poly(ε-caprolactone- co -lactide) (PCLA-PEG-PCLA) copolymer loaded with celecoxib was investigated in horse joints. The systems were loaded with two dosages of celecoxib, 50 mg/g (‘low CLB gel’) and 260 mg/g (‘high CLB gel’). Subsequently, they were injected into the joints of five healthy horses. For 72 h after intra-articular injection, they induced a transient inflammatory response, which was also observed after application of Hyonate® , a commercial formulation containing hyaluronic acid for the intra-articular treatment of synovitis in horses. However, only after administration of the ‘high CLB gel’ the horses showed signs of discomfort (lameness score: 1.6 ± 1.3 on a 5-point scale) 1 day after injection, which completely disappeared 3 days after injection. Importantly, there was no indication of cartilage damage. Celecoxib Cmax in the joints was reached at 8 h and 24 h after administration of the ‘low CLB gel’ and ‘high CLB gel’, respectively. In the joints, concentrations of celecoxib were detected 4 weeks post administration. Celecoxib was also detected in plasma at concentrations of 150 ng/ml at day 3 post administration and thereafter its concentration dropped below the detection limit. These results show that the systems were well tolerated after intra-articular administration and showed local and sustained release of celecoxib for 4 weeks with low and short systemic exposure to the drug, demonstrating that these injectable in situ forming hydrogels are promising vehicles for intra-articular drug delivery.