Sandker Maria J, Duque Luisa F, Redout Everaldo M, Klijnstra Evelien C, Steendam Rob, Kops Nicole, Waarsing Jan H, van Weeren Rene, Hennink Wim E, Weinans Harrie
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.
ACS Biomater Sci Eng. 2018 Jul 9;4(7):2390-2403. doi: 10.1021/acsbiomaterials.8b00116. Epub 2018 May 23.
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)--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.
本研究的目的是开发一种能使抗炎药物他克莫司在关节内持续释放的制剂。基于聚（d - l - 丙交酯 - 聚乙二醇）- 聚（l - 丙交酯）多嵌段共聚物制备的负载他克莫司的单分散可生物降解微球的药物释放动力学可通过改变聚合物组成来调节，特别是疏水 - 亲水嵌段比。微球直径为30μm，根据制剂不同，药物在7至>42天内释放。选择表现出1个月持续释放的制剂进行进一步的体内评估。给大鼠膝关节注射三种不同剂量（10 wt%）的负载他克莫司的微球（2.5、5.0和10 mg），对侧对照膝关节注射生理盐水。显微CT和组织学检查显示软骨无负面变化，表明生物相容性良好。可见剂量依赖性的轻微骨赘形成，提示局部药物释放及其治疗作用。为了研究体内药物释放情况，将他克莫司微球注入马关节，之后采集多个血液和滑液样本。在整个四周的随访期间均观察到关节内持续释放，全身药物浓度可忽略不计（<1 ng/mL），证实了局部关节内给药且不引发全身效应的可行性。注射未负载微球导致短暂的炎症反应，通过滑膜白细胞总数测量（72小时）。在注射负载他克莫司微球的关节中，这种反应明显较低，这不仅表明他克莫司成功实现了局部递送，还显示出局部抗炎作用。这种无全身副作用的局部抗炎潜力在炎性关节疾病（包括骨关节炎）治疗中可能有益。
