琥珀布考固体分散体的制备及其Beagle犬体内药物动力学研究

Preparation of Succinobucol Solid Dispersion and Its Pharmacokinetics in Beagle Dogs

以共聚维酮S630为载体,采用喷雾干燥技术制备难溶性药物琥珀布考的固体分散体,用于提高其口服生物利用度的研究。通过扫描电镜(scanning electron microscopy,SEM)、差示扫描量热(differential scanning calorimetry,DSC)、X射线粉末衍射(X-ray powder diffraction,XRPD)对制备的固体分散体进行表征,通过溶出试验考察其溶出特性。结果表明,琥珀布考以无定形状态分布在载体中,且固体分散体能显著提高药物的溶出程度以及溶出速率。固体分散体在体外30 min的溶出率可超过80%,而原料药与载体的物理混合物60 min时的溶出率仍低于40%。同时以Beagle犬为动物模型,对琥珀布考原料药以及其固体分散体进行体内药动学研究。结果表明,固体分散体的cmax和AUC0→t分别为原料药的2.85和2.78倍,证实以共聚维酮S630为载体制备的琥珀布考固体分散体可显著提高药物的口服生物利用度。

In order to improve the bioavailability of the insoluble drug, succinobucol, its solid dispersion(SSD) was prepared with crospovidone(Plasdone S630) by a spray drying method. The SSD was characterized by scanning electron microscopy(SEM), differential scanning calorimetry(DSC) and X-ray powder diffraction(XRPD). The dissolution behavior of SSD was also investigated. The experimental results showed that succinobucol existed in an amorphous state in solid dispersion. The dissolution rate of succinobucol from SSD was significantly increased to more than 80% within 30 min, while that of physical mixture of the free drug and the carrier was below 40% within 60 min. A LC-MS/MS method was established for determination of succinobucol in plasma of Beagle dogs. The pharmacokinetic profiles in Beagle dogs showed that the plasma peak concentration(cmax) and AUC0→t of succinobucol from SSD were respectively 2.85 times and 2.78 times higher than those of succinobucol, which proved that the solid dispersion prepared with crospovidone could significantly improve the oral bioavailability of water-insoluble succinobucol.