厚朴酚固体分散体的制备及生物利用度研究

Preparation and bioavailability of magnolol solid dispersions

目的采用热熔挤出技术制备厚朴酚固体分散体,提高厚朴酚体外溶出度及大鼠体内生物利用度。方法通过溶解度参数筛选与厚朴酚相容性较好的4种载体共聚维酮S-630(PS-630)、羟丙基纤维素(HPC)、丙烯酸树脂Eudragit EPO(EPO)和聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)用于制备不同载药量的固体分散体。以体外溶出度为指标,应用差示扫描量热分析(DSC)、X-射线衍射分析(XRPD)和红外光谱(IR)表征所制备的固体分散体;采用UPLC-MS/MS评价大鼠口服厚朴酚固体分散体后体内药动学行为。结果体外溶出度实验表明厚朴酚与PS-630、HPC和EPO这3种载体(质量比1∶6)分别制备的固体分散体均能显著提高厚朴酚的溶出度,且药物都是以无定形分散在载体中。体内生物利用度实验显示,PS-630和HPC制得的固体分散体中厚朴酚的血药峰浓度(Cmax)分别约为单体的5倍和2.3倍,药时曲线下面积(AUC0~t)分别提高了37.22%和70.88%,而EPO体系则未见生物利用度的提升。结论热熔挤出技术可应用于提高难溶性药物厚朴酚的体外溶出度和体内生物利用度。

Objective Hot-melt extrusion technique was applied to prepare magnolol solid dispersions, which can improve the in vitro solubility of magnolol and the in vivo bioavailability in rats. Methods Four kinds of excipients, such as PS-630, HPC, EPO, and Soluplus, which were compatible with magnolol were used to prepare solid dispersions of different drug loadings by solubility parameter calculation. The prepared solid dispersion was characterized by differential scanning calorimetry (DSC), X-ray diffraction analysis (XRPD) and infrared spectroscopy (IR) using in vitro dissolution as an indicator;UPLC-MS/MS was used to evaluate the pharmacokinetic behavior of rats after oral administration of magnolol solid dispersion. Results The in vitro dissolution test showed that the solid dispersion prepared by the 1∶6 drug loading of PS-630, HPC, and EPO can significantly improve the dissolution of magnolol, and the drug was dispersed in the carrier in an amorphous state. The in vivo bioavailability test showed that the Cmax of magnolol in the solid dispersion prepared by PS-630 and HPC was about five times and 2.3 times that of the monomer, respectively, and the AUC0-t was increased about 37.22% and 70.88%, respectively. There was no increase in the EPO system. Conclusion Hot melt extrusion technology can be successfully applied to improve the in vitro dissolution and in vivo bioavailability of the poorly soluble drug magnolol.