| Autor: |
Sandker MJ; Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.; Department of Orthopaedics, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands., Duque LF; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands., Redout EM; Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands., Klijnstra EC; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands., Steendam R; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands., Kops N; Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands., Waarsing JH; Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands., van Weeren R; Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands., Hennink WE; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3512 JE Utrecht, The Netherlands., Weinans H; Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.; Department of Biomechanical Engineering, TUDelft, Mekelweg 2, 2628 CD Delft, The Netherlands. |
| Abstrakt: |
The aim of this study was to develop a formulation with a sustained intra-articular release of the anti-inflammatory drug tacrolimus. Drug release kinetics from the prepared tacrolimus loaded monodisperse biodegradable microspheres based on poly(d-l-lactide-PEG)- b -poly(l-lactide) multiblock copolymers were tunable by changing polymer composition, particularly hydrophobic-hydrophilic block ratio. The monospheres were 30 μm and released the drug, depending on the formulation, in 7 to >42 days. The formulation exhibiting sustained release for 1 month was selected for further in vivo evaluation. Rat knees were injected with three different doses of tacrolimus (10 wt %) loaded monospheres (2.5, 5.0, and 10 mg), contralateral control knees with saline. Micro-CT and histology showed no negative changes on cartilage, indicating good biocompatibility. Minor osteophyte formation was seen in a dose dependent fashion, suggesting local drug release and therapeutic action thereof. To investigate in vivo drug release, tacrolimus monospheres were injected into horse joints, after which multiple blood and synovial fluid samples were taken. Sustained intra-articular release was seen during the entire four-week follow-up, with negligible systemic drug concentrations (<1 ng/mL), confirming the feasibility of local intra-articular drug delivery without provoking systemic effects. Intra-articular injection of unloaded monospheres led to a transient inflammatory reaction, measured by total synovial leucocyte count (72 h). This reaction was significantly lower in joints injected with tacrolimus loaded monospheres, showing not only the successful local tacrolimus delivery but also local anti-inflammatory action. This local anti-inflammatory potential without systemic side-effects can be beneficial in the treatment of inflammatory joint diseases, among which is osteoarthritis. |
