Enhancing the Solubility, Oral Bioavailability, and Antitumor Effects of Ribociclib through Multicomponent Salt Formation with NSAIDs

Ribociclib (RBC), an antitumor drug, is categorized as a BCS Class IV drug with low solubility and permeability. Despite achieving clinically relevant bioavailability in its marketed malate salt form, the limited aqueous solubility of RBC still poses significant challenges for formulation development. In this work, three novel RBC salts with nonsteroidal anti-inflammatory drugs (diclofenac, DIC; ibuprofen, IBU; loxoprofen, LOX) were successfully synthesized and comprehensively characterized. Among them, compared with pure RBC, the multicomponent RBC-LOX salt showed 2.97-fold higher solubility and 1.90-fold faster dissolution rate in pH 7.4 buffer, and 1.73-fold stronger in vitro cytotoxicity against MDA-MB-231 breast cancer cells. Moreover, in vivo pharmacokinetic evaluations revealed that the RBC-LOX salt significantly improved the oral bioavailability of RBC (1.49-fold), demonstrating enhanced bioavailability. Overall, these findings highlight the potential of RBC-NSAID salts as a strategy to enhance the solubility, anticancer activity, and bioavailability of ribociclib, offering a promising approach for optimizing its therapeutic efficacy.