形成多药晶体提高药物溶解度和细胞毒性。

Improving Dissolution and Cytotoxicity by Forming Multidrug Crystals.

机构信息

Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.

College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400016, China.

出版信息

Molecules. 2020 Mar 16;25(6):1343. doi: 10.3390/molecules25061343.

Both rosiglitazone and metformin have effects on blood glucose regulation and the proliferation of liver cancer cells. Combination therapy with these two drugs is common and effective for the treatment of diabetes in the clinic, however, the application of these two drugs is influenced by the poor dissolution of rosiglitazone and the gastrointestinal side-effect of metformin resulting from a high solubility. The formation of a multidrug crystal form (Rsg-Met) by a solvent evaporation method can solve the solubility issue. Crystal structure data and intramolecular hydrogen bonds were detected by X-ray diffraction and infrared spectroscopy. Surprisingly, Rsg-Met shortens the time spent in solubility equilibrium and multiplies the dissolution rate of Rsg. Finally, we found that a low concentration of Rsg-Met enhanced the proliferation inhibition effect on liver cancer cells (HepG2, SK-hep1) compared with rosiglitazone, without affecting the human normal cell line LO2.

罗格列酮和二甲双胍均对血糖调节和肝癌细胞增殖有作用。这两种药物联合治疗在临床上常用于治疗糖尿病，效果显著，然而，这两种药物的应用受到罗格列酮溶解差和二甲双胍高溶解度引起的胃肠道副作用的影响。溶剂蒸发法形成多药晶体形式（Rsg-Met）可以解决溶解度问题。通过 X 射线衍射和红外光谱检测晶体结构数据和分子内氢键。令人惊讶的是，Rsg-Met 缩短了在溶解度平衡中花费的时间，并使 Rsg 的溶解速率增加。最后，我们发现与罗格列酮相比，低浓度的 Rsg-Met 增强了对肝癌细胞（HepG2、SK-hep1）的增殖抑制作用，而对正常细胞系 LO2 没有影响。