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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication Date: 2015-03-18 PubMed ID: 25890740DOI: 10.1016/j.biomaterials.2015.02.109Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research study investigates the use of injectable gels composed of specific polymers, loaded with a medicine called celecoxib, for sustained release of the drug within horse joints. The study findings show that these systems are well-tolerated, and can provide local and sustained release of celecoxib for up to four weeks, with only short and low levels of systemic exposure to the drug.
Methodology and Objectives
- The study aimed at examining intra-articular tolerability and suitability for local and sustained release of a specially formulated gel. The gel comprised 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, a non-steroidal anti-inflammatory drug commonly used in arthritis treatment.
- The systems were loaded with two doses of celecoxib – 50 mg/g (referred to as ‘low CLB gel’) and 260 mg/g (‘high CLB gel’).
- The gels were then injected into the joints of five healthy horses, and the outcomes were monitored.
Findings
- Initial response of the horses included a transient (temporary) inflammatory reaction that lasted for three days post-injection, irrespective of the dosage. This reaction can be compared to the response after application of Hyonate®, a commercial formula made of hyaluronic acid used for treating synovitis (inflammation of the joint lining) in horses.
- Horses showed signs of discomfort only following the injection of the ‘high CLB gel’ which manifested as lameness (scoring 1.6 ± 1.3 on a 5-point scale) but disappeared within three days post-injection. Notably, there were no signs of damage to cartilage.
- Celecoxib reached its maximum concentration in the joints at 8 h and 24 h after administration of the ‘low CLB gel’ and ‘high CLB gel’, respectively. Concentrations of the drug were still detected in the joints four weeks after administration.
- In the plasma, the drug was detected at a concentration of 150 ng/ml at day 3 post-administration, beyond which its levels fell below the detection limit.
Conclusion
- The results of this study suggest that the injectable gels show promise as vehicles for intra-articular drug delivery. This is attributed to their good tolerance, ability for localized and sustained release of celecoxib for up to four weeks, and minimal systemic exposure to the drug.
Cite This Article
APA
Petit A, Redout EM, van de Lest CH, de Grauw JC, Müller B, Meyboom R, van Midwoud P, Vermonden T, Hennink WE, René van Weeren P.
(2015).
Sustained intra-articular release of celecoxib from in situ forming gels made of acetyl-capped PCLA-PEG-PCLA triblock copolymers in horses.
Biomaterials, 53, 426-436.
https://doi.org/10.1016/j.biomaterials.2015.02.109 Publication
Researcher Affiliations
- InGell Labs BV, Groningen, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- InGell Labs BV, Groningen, The Netherlands.
- InGell Labs BV, Groningen, The Netherlands.
- InGell Labs BV, Groningen, The Netherlands.
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: r.vanweeren@uu.nl.
MeSH Terms
- Acetylation
- Animals
- Celecoxib / administration & dosage
- Celecoxib / pharmacokinetics
- Cyclooxygenase 2 Inhibitors / administration & dosage
- Cyclooxygenase 2 Inhibitors / pharmacokinetics
- Drug Carriers
- Gels
- Horses
- Joints / metabolism
- Polyesters / chemistry
- Polyethylene Glycols / chemistry
- Proton Magnetic Resonance Spectroscopy
- Synovial Fluid / metabolism
- X-Ray Diffraction
Citations
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