SUD-35/羟丙基-β-环糊精包合物的制备及其小鼠体内药效学初步研究

Preparation of Inclusion Compound of SUD-35/HP-β-cyclodextrin and Its Pharmacodynamics Study on Mice in Vivo

目的:制备苯甲酰脲类微管微丝抑制剂SUD-35/羟丙基-β-环糊精包合物(SUD-35/HP-β-CD),以提高SUD-35的水溶性和稳定性,并对其小鼠体内药效学进行初步考察。方法:采用饱和水溶液法,以SUD-35/HP-β-CD投药比(A)、包合温度(B)、包合时间(C)、搅拌速度(D)为考察因素,以包合率为考察指标,设计正交试验筛选最佳制备工艺并进行验证试验和溶解度测定;以差示扫描量热(DSC)法及X射线衍射(XRD)法验证包合物;对肝癌H22细胞实体瘤模型小鼠腹腔注射包合物低、中、高剂量(以SUD-35计)每日1次,共7d,计算末次给药后24h的抑瘤率,并与环磷酰胺比较。结果:最佳制备工艺为A:1∶5,B:50℃,C:60min,D:100r·min-1;以此工艺所制3批包合物的平均包合率约为75.8%;SUD-35原料及其包合物在水中的溶解度分别为0.00032、0.65g·L-1;DSC和XRD法证实包合物形成;低、中、高剂量抑瘤率分别为(38.25±0.57)%、(63.45±1.20)%、(69.26±1.15)%,环磷酰胺组为(71.52±1.16)%。结论:SUD-35/HP-β-CD包合物的制备工艺简便、易行,可极大地提高SUD-35的水溶性,其高剂量对肝癌H22细胞在小鼠体内的生长具有与环磷酰胺相似的抑制作用。

OBJECTIVE：To prepare the inclusion compound of benzoylurea antitubulin SUD-35/HP-β-CD in order to increase the solubility and stability of SUD-35,and to investigate its pharmacodynamics in vivo.METHODS：The inclusion compound was prepared by saturated solution method.The preparation technology of inclusion compound was optimized by orthogonal experiments using ratio of SUD-35/HP-β-CD（A） ,inclusion temperature（B） ,inclusion time（C） and stirring rate（D） as factors and with inclusion rate as index.The validation test and solubility determination were conducted.DSC and X-ray diffraction（XRD） were used to verify the complex.Hepatic cancer H22 cell solid tumor model mice were given intraperitoneal injection of inclusion compounds at low-dose,medium-dose and high-dose（SUD-35） once a day for 7 days.The tumor inhibition rate was calculated 24 h after the last administration and compared with cyclophosphamide.RESULTS：The optimal preparation technology was as follows：A：1 ∶ 5,B：50 ℃,C：60 min,D：100 r·min-1.The average inclusion rate of 3 batches was 75.8%.The solubilities of SUD-35 raw material and inclusion compound in water were 0.000 32 g·L-1 and 0.65 g·L-1.The formation of inclusion compound was verified by DSC and XRD method.The tumor inhibition rates at low-dose,medium-dose and high-dose were（38.25±0.57） %,（63.45±1.20） %,（69.26±1.15） %,the cyclophosphamide group was（71.52±1.16） %.CONCLUSION：The preparation technology of inclusion compound of SUD-35/HP-β-CD is simple and feasible.It strengthens the water-solubility of SUD-35,and the high dose of it has similar inhibition on the growth of hepatic cancer H22 cells in mice with cyclophosphamide.