依托泊苷固体分散体的溶出与大鼠在体肠吸收研究

Dissolution in vitro and rat intestinal absorption in situ of etoposide solid dispersions

目的:制备依托泊苷(VP-16)固体分散体,对其在大鼠小肠各部位的吸收进行研究,以期提高口服生物利用度。方法:采用溶剂-熔融法制备VP-16-硬脂酸聚氧烃酯(S-40)或泊洛沙姆188(F68)固体分散体,按中华人民共和国药典2005年版溶出度第二法测定VP-16固体分散体的溶出,以差示扫描量热法(DSC)法和X-射线衍射法鉴定VP-16在体系中的状态,运用大鼠在体肠循环模型,采用HPLC法测定药物浓度,考察药物的吸收。结果:固体分散体中VP-16的溶出比原料药和物理混合物均有显著提高,随着载体质量比增加而增大。DSC图谱显示VP-16的特征峰消失,X-射线衍射图谱显示VP-16的结晶衍射峰消失,药物以无定形或分子状态分散在固体分散体中。VP-16在小肠上半段吸收较好,当载体对药物质量比≥3时,固体分散体在空肠段吸收有显著增加,且VP-16/S-40固体分散体的吸收比VP-16/F68固体分散体的吸收好。结论:S-40和F68两种表面活性剂均能显著提高VP-16的溶出度,并对VP-16在大鼠小肠的吸收有明显促进作用,S-40的吸收促进作用显著大于F68。

Objective：To prepare etoposide （VP-16） solid dispersions, and to investigate the absorption of solid dispersions in rat intestine with the intention of improving the oral bioavailability of the drug. Methods ： Solid dispersions of VP-16 containing polyoxyethylene stearate （S-40） or poloxamer188 （F68） were prepared by solventmelt method. The dissolution of drug was conducted by the Method II in Pharmacopoeia of the People＇s Republic of China （2005）. Differential scanning calorimetry method and powder X-ray diffraetometry （PXRD） were used to identify the state of VP-16 in the system. In situ recirculation model was used to evaluate the intestine absorption, and the concentrations of VP-16 were determined by HPLC. Results： The dissolution rate of VP-16 was dramatically increased after the formation of solid dispersion as compared with the pure drug powder and physical mixture. VP-16 existed in the solid dispersion as amorphous forms or solvates based on the profiles Of DSC and PXRD. The absorption of VP-16 was better in upper intestine, and the absorption of VP-16 solid dispersions in jejunum was improved remarkably. The absorption of VP-16/S-40 solid dispersion was much better than that of VP-16/F68 solid dispersion. Conclusion： S-40 and F68 can enhance the dissolution of VP-16 and improve its absorption in rat in- testine. The absorption of VP-16/S-40 in solid dispersions is higher than that of VP-16/F68.