Flurbiprofen (FLUR) is a potent non-steroidal anti-inflammatory drug used for the management of arthritis. Unfortunately, its therapeutic effect is limited by its rapid clearance from the joints following intra-articular injection. To improve its therapeutic efficacy, hyaluronic acid-coated bovine serum albumin nanoparticles (HA-BSA NPs) were formulated and loaded with FLUR to achieve active drug targeting. NPs were prepared by a modified nano-emulsification technique and their HA coating was proven via turbidimetric assay. Physicochemical characterization of the selected HA-BSA NPs revealed entrapment efficiency of 90.12 ± 1.06%, particle size of 257.12 ± 2.54 nm, PDI of 0.25 ± 0.01, and zeta potential of −48 ± 3 mv. The selected formulation showed in-vitro extended-release profile up to 6 days. In-vivo studies on adjuvant-induced arthritis rat model exhibited a significant reduction in joint swelling after intra-articular administration of FLUR-loaded HA-BSA NPs. Additionally, there was a significant reduction in CRP level in blood as well as TNF-α, and IL-6 levels in serum and joint tissues. Immunohistochemical study indicated a significant decrease in iNOS level in joint tissues. Histopathological analysis confirmed the safety of FLUR-loaded HA-BSA NPs. Thus, our results reveal that FLUR loaded HA-BSA NPs have a promising therapeutic effect in the management of arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with an intriguing pathophysiological mechanism that primarily affects the joints and leads to extra-articular manifestations. Leflunomide is one of the most effective disease-modifying anti-rheumatic drugs (DMARDs), utilized in RA treatment, but its use comes with frequent gastrointestinal adverse effects, which might necessitate therapy discontinuation. The current work aimed to explore the antirheumatic and gastroprotective effects of ectoine, a compatible solute found in nature, on adjuvant-induced arthritis (AIA) in rats, and to compare its efficacy with that of leflunomide. In this study, animals were divided into five groups: Normal control rats, Untreated adjuvant arthritis (AA) rats, Leflunomide group treated with 10 mg/kg/day, Ectoine group treated with 100 mg/kg/ day, and AA rats treated orally with the combination of ectoine and leflunomide daily with the same dosses. Ectoine administration significantly abolished both articular and extraarticular inflammatory responses in AA rats. Serum levels of nitric oxide (NOx), Interleukin-1β (IL-1β), and anti-cyclic citrullinated peptide (anti-CCP) were significantly reduced, with a significant increase in IL-10. It dramatically suppressed tibiotarsal tissue expression of tumor necrosis factor-α (TNF-α), nuclear factor-kappa B-p65 (NF-κB-p65), receptor activator of NF-κB ligand (RANKL), and matrix metalloproteinase-9 (MMP-9). Colonic examination also showed lower expression levels of TNF-α, NF-κB-p65, intracellular adhesion molecule-1 (ICAM-1), and MMP-9, in addition to a significant antioxidant effect by enhancing reduced glutathione synthesis (GSH) and reduction of myeloperoxidase (MPO) and malondialdehyde (MDA) levels. Our results demonstrate that ectoine has a strong potential for being an efficient anti-inflammatory and anti-rheumatic agent.