伏立康唑/羟丙基倍他环糊精包合物的制备及性质考察

The preparation and property investigation of voriconazole and HP-β-CD inclusion complex

目的选用羟丙基倍他环糊精(HP-β-CD)对难溶性药物伏立康唑进行包合,以期提高其溶出速率,并对包合过程进行研究。方法采用研磨法、超声法、溶液搅拌法制备伏立康唑包合物。通过差示扫描量热法和X射线粉末衍射法,考察伏立康唑/HP-β-CD包合物形成特征。比较pH值为1.0、4.0、7.0条件下,HP-β-CD对伏立康唑的增溶能力并与磺丁基醚倍他环糊精(SBE-β-CD)进行比较。最后考察包合过程中pH值、温度及潜溶剂等因素对溶解度相图的影响。结果以溶液搅拌法制备伏立康唑包合物,当包合温度为25℃,pH值为6.0,不加潜溶剂,以及药物与HP-β-CD的投料质量比为1∶12时,伏立康唑/HP-β-CD包合物形成的ΔH、ΔG和ΔS分别为-36.85、-13.63和-77.90。结论研究制备的伏立康唑/HP-β-CD包合物,性质稳定,包合量可以达到临床用药剂量的要求,包合过程中得到的相关热力学参数,为包合条件的优化提供理论依据。

Objective To improve the solubility of a poorly water-soluble drug-voriconazole,HP-β-CD is used as inclusion materials to prepare voriconazole/HP-β-CD complexes and to study the process of inclusion.Methods Voriconazole/HP-β-CD complexes were prepared by milling method,ultrasound method and unsaturated agitating method respectively.Differential scanning calorimetry（DSC） and X-ray diffractometry（XRD） were applied to characterize the voriconazole /HP-β-CD complex.The solubility enhancement effect of HP-β-CD and SBE-β-CD on voriconazole was compared at pH 1.0,pH 4.0 and pH 7.0.At last,the apparent stability constant at different pH,temperature and addition of cosolvent were counted,respectively.Results The unsaturated agitating method was feasible for the preparing of voriconazole/HP-β-CD complex.When in the condition of 25 ℃,pH 6.0,without addition of cosolvent and the ratio of voriconazole and HP-β-CD was 1∶ 12,the ΔH,ΔG and ΔS of voriconazole/HP-β-CD inclusion complex were-36.85,-13.63and-77.90.Conclusions The voriconazole/HP-β-CD inclusion complex has a good stability and the inclusion content can reach the requirements of clinical dosage.The obtained thermodynamic parameters can provide theory basis for the optimization of inclusion.