摘要
The combination of cardiotonic milrinone (MLN) and diuretics furosemide (FSM) is used to treat refractory heart failure clinically. However, the compatibility and stability issues of both limit the curative effect. For highlighting the superiority of cocrystallization technology in regulating drug performances, further getting new understanding for developing dual-drug cocrystals to realize their combination at the molecular level, a cocrystallization-driven drug-drug bidirectional optimization tactic is presented. By cocrystallizing MLN and FSM into the same lattice, for one thing, the in vitro/vivo properties of MLN can be optimized, and the photostability of FSM is raised simultaneously, thereby enhancing the bioavailability, and creating a prerequisite for the bidirectional optimization and the combination of these two drugs at the molecular level. Based on this, the dual-drug cocrystal MLN-FSM is successfully assembled and thoroughly characterized by multiple techniques. The evaluations of in vitro/vivo properties involving theory and experiment methods exhibit that the garnered cocrystal has achieved the simultaneous improvements in solubility and permeability versus pure MLN; meanwhile, the cocrystal formation also prominently enhances the stability of FSM relative to FSM itself. Interestingly, these bidirectional optimized in vitro properties change into in vivo pharmacokinetic strengths effectively, showcasing the raised bioavailability and extended half-life, thus laying a solid foundation for exerting the combined effect of the two drugs at the molecular level. Therefore, this research provides the first dual-drug cocrystal solid form with clinical combination drugs to treat cardiac failures, also offers innovative insights into leveraging the advantages of the cocrystallization-driven strategy for fulfilling the co-treatment of clinical combination drugs from the molecular levels.
危险品化学品经营许可证（带存储）