Preparation of Tofacitinib-Loaded Poly(lactic-co-glycolic acid) Sustained Release Nanoparticles by High-Gravity Nanoprecipitation Technique and Its Performance in Rheumatoid Arthritis

Rheumatoid arthritis (RA), an autoimmune disease, is related to environmental factors, sex hormones, genetics, and other factors, affecting 0.5–1% of the global population. The JAK-STAT pathway plays an important role in the signal transduction of inflammatory cytokines and chemokines in the pathogenesis of RA. Tofacitinib (TF), the first approved JAK inhibitor for treating RA, can reduce inflammatory reactions, improve RA conditions, prevent irreversible joint injury, and improve the quality of life of patients. However, the traditional oral administration of TF causes poor compliance and severe side effects owing to the long-term and high-frequency treatment. Therefore, highly efficient pharmaceutical formulations for TF are necessitated. Here, a novel TF-loaded poly(lactic-co-glycolic acid) (PLGA) sustained release nanoparticle (NanoTF-PLGA) was prepared using a high-gravity nanoprecipitation technique (HGNPT), and its therapeutic effect on RA was verified in vitro and in vivo. The influence of the different operation parameters of HGNPT on the particle size of PLGA, including the rotating speed of the rotating bed, the volume ratio of solvent to antisolvent, and the concentration of the surfactant, was investigated using an orthogonal design. The optimum reaction conditions for preparing PLGA nanoparticles were selected by optimizing the formula, and TF was then added to the reaction mixture to prepare NanoTF-PLGA. The results demonstrated that NanoTF-PLGA had a smaller size (603.8 nm), a more uniform shape, a higher drug loading efficiency, and long-term sustained release properties (over 14 days). Furthermore, in vitro experiments proved that NanoTF-PLGA could enter RAW264.7 cells by cell uptake, demonstrated good biocompatibility, inhibited the migration of RAW264.7 cells, and simultaneously inhibited the expression of IL-6, IL-1β, and TNF-α in a dose-dependent manner. In vivo experiments showed that subcutaneous administration of NanoTF-PLGA significantly alleviated articular cartilage injury and reduced the level of inflammatory cell infiltration into the joint cavity. This study presents a promising technique for preparing sustained drug formulations that can be extended to numerous therapeutic drugs.