Complex formation with modified cyclodextrins for improving biopharmaceutical properties of baricitinib, a novel immunomodulatory drug

Abstract

Baricitinib is an orally active drug that has recently been approved by FDA and EMA for the treatment of rheumatoid arthritis, alopecia areata, COVID-19 and other inflammatory diseases. The application of baricitinib is limited by its poor aqueous solubility. In this context, this work aims to improve the pharmacologically important properties of baricitinib through inclusion complex formation with modified cyclodextrins. For the first time, the complexation of baricitinib with the modified cyclodextrins in aqueous solutions was studied using 1H NMR, capillary electrophoresis, and isothermal saturation method. Thermodynamic parameters of the complexation of the modified cyclodextrins with different ionized forms of baricitinib were obtained and analyzed. The impact of the nature of cyclodextrin substituents and the degree of ionization of baricitinib on the inclusion complex formation and solubilization is considered. The increase in baricitinib solubility in the presence of the modified cyclodextrins is accompanied by a decrease in the membrane permeability of the drug. It was shown that concentration dependences of the permeability coefficient can be used to predict the binding constants of baricitinib with cyclodextrins and the solubility-permeability interplay.