格列美脲结晶抑制剂对其固体分散体的影响

The impact of glimepiride precipitation inhibitors on their solid dispersions

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 screen glimepiride precipitation inhibitors rapidly, and compare the imparct of different precipitation inhibitors on gilmepiride solid dispersions. Method Methods Glimepiride supersaturated solution was prepared by solvent-shift method to screen glimepiride supersaturation ratio with an obvious precipitation tendency. Further evaluation of polymers, like Soluplus, VA64, HPMC-E5, PVP K30,F68, PEG6000 and PEG4000, inhibiting precipitation of glimepiride superation solution were carded out, and polymers which can inhibit the precipitation of glimepiride supersaturation solution were selected to prepare solid dispersions. The evaluation of the ability of solid dispersions with a good dissolution behavior maintaining glimepiride supersatuation solution under non-sink condition of pH4.5 PBS was carried out, and the presence state of the drug in the carriers was measured by PLM, DSC, XRPD and IR. Results Glimepiride supersaturation solution has an obvious precipitation tendency when its supersaturation ratio was 68.20. The impact of polymers nhibiting precipitation of glimepiride superation solution ： Soluplus 〉 HPMC-E5 〉 PVPK30 I〉 VA64 〉 F68 〉 PEG4000 I〉 PEG6000. Carders of Soluplus, VA64, HPMC-E5 and PVP K30 were selected to prepare solid dispersions and all reached the maximum cumulative amount of dissolution when the ration of the drug to the polymer was 1： 4 or 1 ： 7 in pH7.8 PBS and without precipitation in 4 h. The rank order of solid dispersions maintaining glimepiride supersaturation solution under non-sink condition of pH4.5 PBS was the same as the results of precipitation inhibitors screening, and only solid dispersions prepared by VA64 showed a positive correlation between precipitation inhibiting ability and the carrier amount. The results of PLM, DSC, XRPD and IR indicated that the drug was in amorphous or molecular state. Conclusions Glimepiride pprecipitation inhibitors can maintain a relatively stable supersaturated state of solid dispersions solution in 4 h, and the drug is in amorphous or molecular state in carders with an ability of inhibiting crystallization.