Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system

[Display omitted] •Up to now p38 MAPK inhibitors were not formulated for in intra-articular delivery.•The in vitro bioactivity of VX-745 was shown on synoviocytes reducing the IL-6 levels.•Bioactivity following intra-articular delivery in AIA mouse model was demonstrated.•VX-745 loaded microparticles with extended release over 3 months were obtained. 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.