目的 制备酮康唑-泊洛沙姆188-结晶固体分散体(TKZ-P188-CSD),并对泊洛沙姆188(P188)调控酮康唑(ketoconazole,TKZ)粒径的机制进行初步研究,探讨结晶固体分散体(crystalline solid dispersions,CSD)的载药量与其结晶动力学之间的内在关系,以达到通过减小TKZ粒径提高溶出速率的目的。方法 旋转蒸发法制备TKZ-P188-CSD,采用扫描电子显微镜、偏光显微镜和粉末X射线衍射法对CSD进行制剂学表征并对其结晶动力学进行研究,为科学推测CSD的增溶机制打下基础,最后评价酮康唑的体外溶出行为。结果 PXRD结果显示,在CSD中TKZ未发生转晶现象,结晶动力学提示P188先结晶,TKZ后结晶,呈现两步结晶机制;CSD的载药量越小,药物晶粒尺寸越小,这可能是由于P188的空间位阻作用,阻碍了药物结晶,使药物晶体尺寸较原料药减小,加之P188的润湿性,导致CSD中药物的溶出行为显著增加。结论 TKZ-P188-CSD中药物的溶出速率显著增加,其增溶机制可能是由于药物晶体尺寸与泊洛沙姆润湿性协同起效,达到了预期的效果。
Abstract
OBJECTIVE To improve the dissolution rate of ketoconazole(TKZ) by reducing the TKZ particle size in vitro, prepare ketoconazole poloxamer188 crystalline solid dispersion (TKZ-P188-CSD), and explore the intrinsic relationship between the drug load of CSD and crystallization kinetics. METHODS The scanning electron microscope (SEM), polarizing microscope (POM) and powder X-ray diffraction (PXRD)was used to study its crystallization kinetics and solubilization mechanism, the dissolution behavior of ketoconazole was evaluated by HPLC in vitro. RESULTS TKZ did not transform in CSD by PXRD, crystallization kinetics suggested that P188 crystallized first and TKZ crystallized later, showing a two-step crystallization mechanism. The crystallite size decreased with the decrease of the drug-loading. This may be due to the steric hindrance of P188, which hinders drug crystallization and makes the crystallite size of the drug smaller in CSD, and the wettability of P188 lead to a significant increase in drug dissolution behavior in CSD. CONCLUSION The size of the drug crystals and the wettability of P188 can effectively improve drug dissolution behavior in TKZ-P188-CSD.
关键词
酮康唑 /
结晶动力学 /
结晶固体分散体 /
溶出速率
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Key words
ketoconazole /
crystallization kinetics /
crystalline solid dispersion /
dissolution rate
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中图分类号：
R944
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参考文献
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脚注
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基金
国家自然科学基金项目资助(82060644);2022年中科院“西部之光”人才培养计划
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