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为提高吉非替尼(1)口服吸收生物利用度,通过机械化学技术,即采用GMS 10-8型滚动式球磨机分别制备了以羟丙基-β-环糊精(HP-β-CD)与阿拉伯半乳聚糖(AG)为载体的1包合物,并采用核磁共振弛豫时间(T2)、扫描电镜(SEM)、差示热量扫描(DSC)、粉末X-射线衍射(P-XRD)对包合物进行物理表征。体外试验显示:1/HP-β-CD包合物将1溶解度由0.77 g/L增至2.16 g/L,药物在120 min时的溶出率由60%增至92%;1/AG包合物将1溶解度增至1.32 g/L,药物在120 min时的溶出率增至75%。大鼠体内试验显示:1原料药、1/AG包合物及1/HP-β-CD包合物的绝对生物利用度分别为56.94%、81.63%和78.48%。本试验制备的1与AG、HP-β-CD的球磨产物均为包合物,它们成功地改善了原料药的溶解度、体外溶出及体内吸收行为,可为后续开发低药物剂量、高口服吸收生物利用度的1剂型提供帮助。
To improve the bioavailability of gefitinib (1) orally, hydroxypropyl-β-cyclodextrin (HP-β-CD) was prepared by a mechanochemical technique using a GMS 10-8 rolling ball mill, And 1-inclusion complex with arabinogalactan (AG) as carrier were determined by means of nuclear magnetic resonance (T2), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction XRD) physical characterization of the inclusion complex. In vitro experiments showed that the dissolution rate of 1 / HP-β-CD inclusion increased the solubility of 1 from 0.77 g / L to 2.16 g / L, and the dissolution rate increased from 60% to 92% at 120 min. The solubility of 1 increased to 1.32 g / L, and the dissolution rate of the drug increased to 75% at 120 min. In vivo experiments in rats showed that: 1 The absolute bioavailability of 1 API, 1 / AG inclusion complex and 1 / HP-β-CD inclusion complex were 56.94%, 81.63% and 78.48%, respectively. The ball mill products of 1, AG and HP-β-CD prepared in this experiment are all inclusion compounds. They successfully improve the solubility, in vitro dissolution and in vivo absorption of the drug substance, which can be used for the subsequent development of low drug dosage and high oral absorption Bioavailability of 1 dosage form to help.