摘要
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。
Gefitinib （1） is a novel medicament for a targeted tumor therapy. It is used in the treatment for late- stage non-small cell lung cancer. The marketed formulation of 1 is tablets with low absorption and oral bioavailability. However, the adverse reactions of 1 are exacerbated with the increasing of dosage. To improve the poor oral bioavailability of 1, its inclusion complexes had been environmental-friendly synthesized by mechanochemical technology with GMS 10-8 roll mill in this study. Arabinogalactan （AG） and hydroxypropyl-β-cyclodextrin （HP-β-CD） were separately used as inclusion carriers for 1. The synthesized complexes were characterized by nuclear magnetic resonance （NMR） relaxation technique （Y：）, scanning electron microscopy （SEM）, differential scanning calorimetry （DSC）, powder X-ray diffraction （P-XRD）. Results of in vitro tests showed that the solubility of 1 was increased from 0.77 g/L to 2.16 g/L, and the dissolution at 120 min was increased from 60 % to 92 % of its mechanochemical treated complexes with HP-β- CD. Similarily, the solubility of 1 in its complex with AG was increased to 1.32 g/L, and the dissolution at 120 min was increased to 75 %. Pharmacokinetic behaviors of these inclusion complexes were investigated with male SD rats as the animal models. The rats were divided into 4 groups： injection group with 1 （10 mg/kg）, intragastric administration groups with 1, 1/AG inclusion complexes or 1/HP-β-CD inclusion complexes （50 mg/kg）. Results showed that the absolute bioavailability of 1 in rats with intragastric administration were 56.94%, 81.63% and 78.48% for 1, 1/AG inclusion complexes and 1/HP-β-CD inclusion complexes, respectively. In conclusion, the two synthesized complexes of 1 were in formation of the inclusion, with increased solubility, dissolution in vitro and absorption in vivo. It indicated that the mechanochemical technology was a promising approach to develop 1 solid oral dosage forms with decreased dosage and improved oral bioava
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2017年第5期682-691,共10页
Chinese Journal of Pharmaceuticals
关键词
机械化学技术
包合物
表征
分子问作用力
溶解度
溶出度
口服生物利用度
mechanochemical technology
inclusion complex
characterization
intermolecular interaction
solubility
dissolution
oral bioavailability
