CHMFL-KIT-110固体分散体制备、理化性质及大鼠体内药动学研究
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1.中国药科大学药学院;2.合肥合源药业有限公司,创新药物成药性评价安徽省重点实验室

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国家“重大新药创制”科技重大专项


Preparation, physicochemical properties and pharmacokinetics in rats of CHMFL-KIT-110 solid dispersions
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    摘要:

    分别以聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、泊洛沙姆407(Poloxamer 407)、聚乙二醇6000(PEG 6000)、共聚维酮(Kollidon VA64)为载体,十二烷基硫酸钠(SDS)、吐温80(Tween 80)、聚氧乙烯氢化蓖麻油(Cremophor RH40)为增溶剂,采用溶剂法制备难溶性药物CHMFL-KIT-110的固体分散体,以动力学溶解度和溶液过饱和现象为指标优化固体分散体的处方。通过傅里叶变换红外光谱法、差热分析法、X射线粉末衍射法对成品进行物相表征,并考察其初步稳定性及大鼠体内药动学行为。结果表明,当CHMFL-KIT-110、Soluplus和SDS质量比为1: 4: 0.5时,CHMFL-KIT-110动力学溶解度显著提高且无药物晶体析出。CHMFL-KIT-110以无定形状态分散于载体中,在加速条件下(40℃、75%相对湿度)敞口放置30天未发生结晶现象。大鼠体内药动学表明,CHMFL-KIT-110固体分散体的Cmax和AUC0→t较原料药分别提高373.1倍和358.7倍。本研究为CHMFL-KIT-110的制剂开发和临床研究提供了基础。

    Abstract:

    Solid dispersions of the insoluble compound CHMFL-KIT-110 were prepared by solvent method with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), Poloxamer 407, PEG 6000, Copovidone (Kollidon VA64) as carriers and SDS, Tween 80, Cremophor RH40 as solubilizers. The optimal formulation was screened and obtained with dynamic solubilities and supersaturation performances as indexes. The final product was characterized by Fourier transform infrared (FT-IR), differential thermal analysis (DTA) and X-ray powder diffraction (XRPD). The stability and pharmacokinetic behavior in rats were also investigated. Results suggested that the weight ratio of CHMFL-KIT-110/Soluplus/SDS was 1: 4: 0.5, dynamic solubility of the solid dispersion was significantly improved with no recrystallization. In the accelerated condition (40℃, 75% RH) for 30 days, CHMFL-KIT-110 in the solid dispersion was still amorphous with no crystal observed. The results of pharmacokinetics in rats showed that the Cmax and AUC0→t of CHMFL-KIT-110 solid dispersion were 373.1 times and 358.7 times higher than those of free drugs, respectively. The results from this research help to understand the formulation development and clinical practice of CHMFL-KIT-110.

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  • 收稿日期:2020-05-12
  • 最后修改日期:2020-06-16
  • 录用日期:2020-07-30
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