Soluplus®-Stabilized Cucurbitacin B Nanosuspension Enhances Biopharmaceutical Performance and Attenuates FCA-Induced Rheumatoid Arthritis in Rats

Cucurbitacin B (CucB) has anti-inflammatory potential, but poor aqueous solubility and permeability limit its oral development. This study developed and evaluated a Soluplus®-stabilized CucB nanosuspension (CucB-NS). The formulation was prepared by antisolvent precipitation, optimized using a Box–Behnken design, and evaluated for physicochemical properties, dissolution, ex vivo permeation, pharmacokinetics, anti-arthritic efficacy, safety, and stability. The optimized formulation had a particle size of 201.12 ± 2.21 nm, polydispersity index of 0.115 ± 0.023, zeta potential of −19.89 ± 1.89 mV, and desirability of 0.981. Compared with pure CucB, it increased saturation solubility from 5.6 ± 1.3 to 18.5 ± 1.5 µg/mL, 24 h dissolution from 29.89 ± 4.32% to 61.93 ± 2.45%, and 16 h permeation from 26.5 ± 3.4% to 48.9 ± 5.8%. Oral administration increased Cmax from 35.55 ± 2.66 to 116.59 ± 5.25 ng/mL and AUC0–∞ from 184.46 ± 10.49 to 1266.79 ± 54.24 ng·h/mL, yielding 686.75 ± 8.01% relative bioavailability without altering Tmax. In FCA-induced arthritis, CucB-NS reduced clinical and synovial inflammatory outcomes and improved joint histology. No overt toxicity was observed, and physical stability was maintained for 3 months at 4 ± 2 °C. CucB-NS improved oral exposure and anti-arthritic activity, supporting further preclinical development.