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目的快速地筛选格列美脲的结晶抑制剂,比较不同结晶抑制剂对其制备的格列美脲固体分散体的影响。方法通过溶剂改变法制备格列美脲的过饱和溶液,筛选出药物具有明显沉降趋势的过饱和度。进一步考察Soluplus、VA64、HPMC-E5、PVP K30、F68、PEG6000和PEG4000等聚合物抑制格列美脲的过饱和溶液的沉降能力,选择有抑晶作用的聚合物制备格列美脲固体分散体。考察溶出较好的固体分散体在非漏槽条件,pH4.5的PBS溶液中维持药物过饱和溶液的能力,并用偏光显微镜法、差示扫描量热法、X-射线衍射法和红外光谱法考察药物在载体中的存在状态。结果格列美脲过饱和溶液在过饱和度约为68.20时,沉降趋势明显。聚合物对格列美脲的抑晶作用强弱为:Soluplus>HPMC-E5>PVP K30≥VA64>F68>PEG4000≥PEG6000,选取Soluplus、VA64、HPMC-E5和PVP K30为载体。采取溶剂法制备格列美脲固体分散体,不同载体制备的固体分散体都可在药物与聚合物的质量比为1∶4或1∶7时,在pH7.8PBS溶液中达到最大累计溶出量,且4h不沉降。固体分散体在非漏槽条件pH4.5的PBS溶液中维持药物过饱和溶液的能力同结晶抑制剂筛选的结果一致,而且只有VA64制备的固体分散体的抑晶作用和载体量成正相关。根据偏振光显微镜法、差示扫描量热、X-射线衍射和红外光谱考察结果,格列美脲在对其具有抑晶作用的载体制备的固体分散体中以无定型或分子形式存在。结论格列美脲结晶抑制剂能够在4h内维持其固体分散体溶液相对稳定的过饱和状态。药物在有抑晶作用的载体中以无定型或分子形式存在。
OBJECTIVE: To rapidly screen the crystal inhibitors of glimepiride and compare the effects of different crystal inhibitors on their prepared glimepiride solid dispersions. Methods The supersaturated solution of glimepiride was prepared by solvent modification method, and the supersaturation of the drug with obvious sedimentation tendency was screened out. We further investigated the ability of polymers such as Soluplus, VA64, HPMC-E5, PVP K30, F68, PEG6000 and PEG4000 to inhibit the sedimentation capacity of glymelamine in supersaturated solutions. The polymers with antidegradability were selected to prepare the solid dispersion of glimepiride . The ability of the well-dissolved solid dispersions to maintain a supersaturated solution of the drug in a PBS solution at pH 4.5 in a non-draining condition was investigated and characterized by polarized light microscopy, differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy Investigate the presence of drug in the carrier. Results When the supersaturated solution of glimepiride was supersaturated about 68.20, the sedimentation tendency was obvious. The inhibition effect of polymer on glimepiride was: Soluplus> HPMC-E5> PVP K30≥VA64> F68> PEG4000≥PEG6000. Soluplus, VA64, HPMC-E5 and PVP K30 were selected as carriers. Solvent preparation of glimepiride solid dispersion, solid dispersion prepared by different carriers can be in the drug and polymer mass ratio of 1: 4 or 1: 7, the maximum cumulative dissolution in pH7.8PBS solution , And 4h does not settle. The ability of the solid dispersion to maintain a supersaturated solution of the drug in PBS solution at pH 4.5 with no draining conditions was consistent with the results of the screening by crystallization inhibitors. Only the solid dispersion prepared by VA64 was positively correlated with the amount of carrier. According to the results of polarization microscopy, differential scanning calorimetry, X-ray diffraction and infrared spectroscopy, glimepiride exists as an amorphous or molecular form in a solid dispersion prepared from a support having a suppressive effect on the glimepiride. Conclusion The glimepiride crystal inhibitor can maintain the relatively stable supersaturation state of its solid dispersion solution within 4 hours. The drug exists in an amorphous or molecular form in a carrier that suppresses the crystal growth.