title: Sustained intra-articular release of celecoxib from in situ forming gels made of acetyl-capped PCLA-PEG-PCLA triblock copolymers in horses.
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.
authors.affiliation: InGell Labs BV, Groningen, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Audrey
authors.initials: A
authors.lastname: Petit
authors.affiliation: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Everaldo M
authors.initials: EM
authors.lastname: Redout
authors.affiliation: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Chris H
authors.initials: CH
authors.lastname: van de Lest
authors.affiliation: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Janny C
authors.initials: JC
authors.lastname: de Grauw
authors.affiliation: InGell Labs BV, Groningen, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Müller
authors.affiliation: InGell Labs BV, Groningen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Meyboom
authors.affiliation: InGell Labs BV, Groningen, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van Midwoud
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Vermonden
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: r.vanweeren@uu.nl.
authors.forename: P
authors.initials: P
authors.lastname: René van Weeren
mesh_terms: D000107:Acetylation; D000818:Animals; D000068579:Celecoxib / Q000008:administration & dosage* / Q000493:pharmacokinetics; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D005782:Gels; D006736:Horses; D007596:Joints / Q000378:metabolism*; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D013582:Synovial Fluid / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004337:Drug Carriers; D005782:Gels; D011091:Polyesters; C512884:poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol); D011092:Polyethylene Glycols; D000068579:Celecoxib
keywords: Celecoxib; Histology; Hyaluronic acid; Hydrogel; Intra-articular delivery; Local delivery