Yue-Ming Yu,Fan-Zhi Bu,Su-Su Meng,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
In order to highlight the advantages of cocrystallization technique in perfecting in vitro / vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both “pyrimidine-pyrimidine” and “pyrimidine-sugar” cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC 50 . Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.
Yue-Ming Yu,Lu Liu,Fan-Zhi Bu,Zhi-Long Zhao,Zhi-Yong Wu,Yan-Tuan Li
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.
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