Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China.
Institute of Solid State Chemistry and Mechanochemistry, Novosibirsk, Russia.
Int J Pharm. 2017 Dec 20;534(1-2):108-118. doi: 10.1016/j.ijpharm.2017.10.011. Epub 2017 Oct 6.
In the present work, complexes of simvastatin (SIM) with polysaccharide arabinogalactan (AG) or disodium salt of glycyrrhizin acid (NaGA) have been prepared using mechanochemical technique to improve the solubility of SIM and enhance its oral bioavailability. The interactions of SIM with AG or NaGA were investigated by FTIR, DSC, XRD and SEM. Self-association of SIM in various solvents was investigated by UV/Vis and NMR techniques. The molecular masses of supramolecular systems-inclusion complexes and micelles, which are the "hosts" for SIM molecules were measured. The parallel artificial membrane permeability assay (PAMPA) revealed a strong increasing of SIM permeability in the presence of NaGA in comparison with pure SIM used as a control. On the other hand, the rapid storage assay (+40°C for 3 months) showed that the chemical stability of SIM/AG complexes was similar to pure SIM, but SIM/NaGA complexes had an enhanced stability. Pharmacokinetic tests in vivo on laboratory animals showed a significant increase in SIM's bioavailability after its introduction as a complex with NaGA or AG. Moreover, SIM/AG inclusion complex performed better than SIM in reducing total cholesterol level. Therefore, the mechanochemically synthesized complexes of SIM with AG or NaGA might have a promising future as novel formulations for hyper-cholesterolemia treatment.
在本工作中，采用机械化学技术制备了辛伐他汀（SIM）与多糖阿拉伯半乳聚糖（AG）或甘草酸二钠（NaGA）的配合物，以提高 SIM 的溶解度并增强其口服生物利用度。通过傅里叶变换红外光谱（FTIR）、差示扫描量热法（DSC）、X 射线衍射（XRD）和扫描电子显微镜（SEM）研究了 SIM 与 AG 或 NaGA 的相互作用。通过紫外/可见分光光度法（UV/Vis）和核磁共振（NMR）技术研究了 SIM 在各种溶剂中的自缔合行为。测量了超分子体系-包合物和胶束的分子量，这些体系是 SIM 分子的“主体”。平行人工膜渗透测定法（PAMPA）显示，与用作对照的纯 SIM 相比，在存在 NaGA 的情况下，SIM 的渗透能力有了显著提高。另一方面，快速储存试验（+40°C 储存 3 个月）表明，SIM/AG 配合物的化学稳定性与纯 SIM 相似，但 SIM/NaGA 配合物的稳定性增强。在实验室动物体内的药代动力学试验表明，将 SIM 与 NaGA 或 AG 制成配合物后，其生物利用度显著提高。此外，SIM/AG 包合物在降低总胆固醇水平方面的效果优于 SIM。因此，SIM 与 AG 或 NaGA 的机械化学合成配合物可能作为治疗高胆固醇血症的新型制剂具有广阔的前景。
