Design, synthesis and characterization of a novel multicomponent salt of bexarotene with metformin and application in ameliorating psoriasis with T2DM.

ABSTRACT

Psoriasis is a common systemic inflammatory skin disorder affecting over 60 million people globally. Some patients with psoriasis are associated with a higher risk of type 2 diabetes mellitus (T2DM). Psoriasis and T2DM occur concurrently in some patients; however, there is no effective drug for the treatment of psoriasis with T2DM. Bexarotene (BEX) is a specific RXR agonist and an antineoplastic agent indicated by the FDA for cutaneous T-cell lymphoma (CTLA). Metformin (MET) is the first-line treatment for T2DM. To develop novel effective drugs for the treatment of psoriasis with T2DM, multicomponent salts containing MET and BEX were designed and synthesized based on the drug-drug combination strategy. MET-BEX (11) and MET-BEX-H2O (111) were obtained and structurally characterized. The in vitro evaluation results showed that the hygroscopicity of MET was significantly optimized by the salt formation strategy, while the solubility of BEX was improved, which laid the foundation for improving the bioavailability of BEX in vivo. In a mouse model of imiquimod-induced psoriasis with T2DM, MET-BEX ameliorated imiquimod-induced psoriasis morphological features and systematic inflammation and improved glucolipid metabolism. These results showed that the multicomponent drug combination strategy in this study optimized the physicochemical properties of MET and BEX simultaneously, providing a promising candidate therapy for psoriasis with T2DM.