Pradal Julie, Zuluaga Maria-Fernanda, Maudens Pierre, Waldburger Jean-Marc, Seemayer Christian Alexander, Doelker Eric, Gabay Cem, Jordan Olivier, Allémann Eric
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Division of Rheumatology, Department of Internal Medicine, University Hospital and Department of Pathology and Immunology, University of Geneva, School of Medicine, Switzerland.
Eur J Pharm Biopharm. 2015 Jun;93:110-7. doi: 10.1016/j.ejpb.2015.03.017. Epub 2015 Mar 30.
In the treatment of arthritic diseases, oral or systemic administration of anti-inflammatory substances, such as p38 MAPK inhibitors, is hampered by numerous side effects. To overcome them, formulations of rapid and extended drug delivery systems were studied in intra-articular administration. For the first time, VX-745, a highly selective p38 MAPK inhibitor, demonstrated in vivo bioactivity, similar to dexamethasone activity, following intra-articular administration in an antigen-induced arthritic (AIA) mouse model. The in vitro bioactivity of VX-745 was also shown on synoviocytes, reducing the IL-6 concentration. Process and formulation parameters (i.e., polymer concentration, aqueous/organic phase ratio, emulsification speed and process, and evaporation pressure) and particle characterisation (i.e., drug loading, size of particle, and surface aspect) were extensively examined to produce optimised formulations. Indeed, a burst release provides a rapid saturation of intracellular p38 MAPK to relieve patients from pain and inflammation. Then, drug diffusion would be sufficient to maintain an effective dose over 2-3 months. This study confirms the effectiveness of encapsulated p38 MAPK inhibitors in extended drug delivery systems and seems to be a promising strategy for intra-articular treatment.
在关节炎疾病的治疗中,口服或全身给药抗炎物质(如p38丝裂原活化蛋白激酶抑制剂)会受到诸多副作用的阻碍。为克服这些副作用,人们研究了关节内给药的快速和长效药物递送系统制剂。首次在抗原诱导性关节炎(AIA)小鼠模型中进行关节内给药后,高选择性p38丝裂原活化蛋白激酶抑制剂VX-745表现出与地塞米松活性相似的体内生物活性。VX-745对滑膜细胞也显示出体外生物活性,可降低白细胞介素-6浓度。为制备优化制剂,人们广泛研究了工艺和制剂参数(即聚合物浓度、水相/有机相比、乳化速度和工艺以及蒸发压力)以及颗粒特性(即载药量、颗粒大小和表面形貌)。事实上,突释可使细胞内p38丝裂原活化蛋白激酶迅速饱和,从而缓解患者的疼痛和炎症。然后,药物扩散足以在2至3个月内维持有效剂量。这项研究证实了包封的p38丝裂原活化蛋白激酶抑制剂在长效药物递送系统中的有效性,似乎是一种有前景的关节内治疗策略。