title: Release behavior and intra-articular biocompatibility of celecoxib-loaded acetyl-capped PCLA-PEG-PCLA thermogels.
abstract: In this study, we investigated the in vitro and in vivo properties and performance of a celecoxib-loaded hydrogel based on a fully acetyl-capped PCLA-PEG-PCLA triblock copolymer. Blends of different compositions of celocoxib, a drug used for pain management in osteoarthritis, and the acetyl-capped PCLA-PEG-PCLA triblock copolymer were mixed with buffer to yield temperature-responsive gelling systems. These systems containing up to 50 mg celecoxib/g gel, were sols at room temperature and converted into immobile gels at 37 °C. In vitro, release of celecoxib started after a ∼10-day lag phase followed by a sustained release of ∼90 days. The release was proven to be mediated by polymer dissolution from the gels. In vivo (subcutaneous injection in rats) experiments showed an initial celecoxib release of ∼30% during the first 3 days followed by a sustained release of celecoxib for 4-8 weeks. The absence of a lag phase and the faster release seen in vivo were likely due to the enhanced celecoxib solubility in biological fluids and active degradation of the gel by macrophages. Finally, intra-articular biocompatibility of the 50 mg/g celecoxib-loaded gel was demonstrated using μCT-scanning and histology, where no cartilage or bone changes were observed following injection into the knee joints of healthy rats. In conclusion, this study shows that celecoxib-loaded acetyl-capped PCLA-PEG-PCLA hydrogels form a safe drug delivery platform for sustained intra-articular release.
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Audrey
authors: A
authors: Petit
authors: Department of Orthopaedics, Erasmus Medical Center, 3015 GJ Rotterdam, The Netherlands.
authors: Marjan
authors: M
authors: Sandker
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands.
authors: Benno
authors: B
authors: Müller
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands.
authors: Ronald
authors: R
authors: Meyboom
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands.
authors: Paul
authors: P
authors: van Midwoud
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands.
authors: Peter
authors: P
authors: Bruin
authors: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors: Everaldo M
authors: EM
authors: Redout
authors: Department of Inorganic Chemistry and Catalysis, Debye Institute for Nanomaterials Science, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Marjan
authors: M
authors: Versluijs-Helder
authors: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors: Chris H A
authors: CH
authors: van der Lest
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Sytze J
authors: SJ
authors: Buwalda
authors: InGell Labs BV, 9747 AT Groningen, The Netherlands.
authors: Leo G J
authors: LG
authors: de Leede
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Tina
authors: T
authors: Vermonden
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Robbert Jan
authors: RJ
authors: Kok
authors: Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, 3584 CX Utrecht, The Netherlands; Department of Biomechanical Engineering, TU Delft, 2628 CN Delft, The Netherlands.
authors: Harrie
authors: H
authors: Weinans
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands. Electronic address: W.E.Hennink@uu.nl.
authors: Wim E
authors: WE
authors: Hennink
mesh_terms: D000107:Acetylation; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D000068579:Celecoxib; D002850:Chromatography, Gel; D065546:Drug Liberation; D005782:Gels / Q000737:chemistry*; D007719:Knee Joint / Q000187:drug effects* / Q000502:physiology; D008297:Male; D044367:Phase Transition; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D012212:Rheology; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013696:Temperature
chemical_list: D001672:Biocompatible Materials; D005782:Gels; D011091:Polyesters; D011720:Pyrazoles; D013449:Sulfonamides; C512884:poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol); D011092:Polyethylene Glycols; D000068579:Celecoxib
keywords: Biocompatibility; Celecoxib; In vitro release; PCLA-PEG-PCLA; Pharmacokinetics; Temperature-responsive gelling hydrogel