Synthesis and characterization of N-fumaroylated diketopiperazine for pulmonary drug delivery

Abstract

In this study, we developed (2E,2′E)-4,4′-((((2S,5S)-3,6-dioxopiperazine-2,5-diyl)bis(butane-4,1-diyl))bis(azanediyl))bis(4-oxobut-2-enoic acid) (FDKP), which is a new pulmonary inhalation excipient approved by the FDA in recent years. FDKP is an excellent drug carrier excipient, it shows different adsorption and release characteristics to various positively charged peptides, proteins and other drugs in different acidic environments, and finally the FDKP can distribute to other tissues and excreted from the body through the kidney in its prototype. In previous studies, the yield of FDKP was very low, the raw materials were difficult to obtain and the cost was too high. In this study, we optimized the reaction conditions and synthetic route, by changing inconvenient and expensive starting materials to easily available cheap materials, through five steps including dehydration cyclization, hydrogenation, condensation, saponification, and recrystallization, we finally obtained FDKP with 70% yield in total. And then we evaluated the cytotoxicity of FDKP in vitro through the MTT assay. It showed that FDKP synthesized by this method was safe. The viability of cells remains at high level (>80%) at the maximum concentration of 5 mg/ml for 24 h and also above 80% at 2.5 mg/ml for 48 h.