Previous studies highlighted an increase of the randomly-methylated-ß-cyclodextrin (RAMEB) solubilizing power towards oxaprozin when used in combination with L-arginine (ARG) or sepiolite nanoclay (SV). Therefore, the aim of this work was to investigate the possibility of maximising the RAMEB solubilizing efficacy by a joined approach based on the entrapment in SV of the drug-RAMEB-ARG complex. The quaternary nanocomposite was prepared by different techniques and characterized for solid state and dissolution properties, compared to ternary drug combinations with RAMEB-ARG, RAMEB-SV or ARG-SV. The dissolution rank order was drug-RAMEB-ARG-SV>>drug-RAMEB-ARG≈drug-RAMEB-SV>>drug-ARG-SV. The new hybrid nanocomposite enabled an increase from 60 up to 90% of oxaprozin dissolution parameters compared to the ternary systems with RAMEB-ARG and RAMEB-SV. Moreover, the lowest solubilizing efficacy of ternary systems with ARG-SV evidenced the specific synergic effect of both ARG and SV with RAMEB in enhancing oxaprozin dissolution properties. The superior performance of the quaternary nanocomposite was maintained after incorporation in a tablet formulation. In vivo studies on rats proved that the developed fast-dissolving tablet formulation, containing oxaprozin as cofused system with RAMEB, ARG and SV was more effective than the marketed tablet in terms of faster and more intense pain relieving effect in the treatment of adjuvant-induced arthritis.