O-羧甲基壳聚糖提高生物药剂学分类系统Ⅱ类药物溶解度能力的研究

Study on potential of O-carboxymethyl chitosan to improve the solubility of BCSⅡ drugs

目的探究羧甲基壳聚糖作为过饱和药物递送系统载体提高生物药剂学分类系统Ⅱ类药物溶解度的潜力,为难溶性药物的辅料选择提供新的参考。方法选择O-CMCS、N-CMCS两种羧甲基壳聚糖聚合物作为研究对象,瑞格列奈作为模型药物。首先将聚合物与药物进行分子对接,通过打分函数预测聚合物与药物的相互作用;其次,使用溶剂转移法,验证分子对接结果,考察聚合物的沉淀抑制能力。制备瑞格列奈与羧甲基壳聚糖的固体分散体,进行差式扫描量热、红外光谱表征,以及非漏槽条件溶出试验研究。结果分子对接结果显示:N-CMCS和O-CMCS与瑞格列奈的结合能分别为-4.95、-7.60 kcal·mol^(-1),O-CMCS与瑞格列奈结合效果较好,具有3个强氢键的结合。溶剂转移法实验也证明:O-CMCS的沉淀抑制能力优于N-CMCS。制剂表征结果显示:固体分散体中的瑞格列奈呈无定形状态,通过强氢键与O-CMCS进行结合。非漏槽条件下的溶出结果显示:50%载药量的固体分散体溶出率为原料药的7倍,且维持过饱和浓度长达24 h。结论O-CMCS通过氢键与模型药物瑞格列奈相互结合,可促进药物溶出,抑制沉淀析出,维持较长时间的过饱和浓度。提示O-CMCS具有作为过饱和药物递送系统载体的潜力,为难溶性药物辅料的选择提供了新的参考。

OBJECTIVE Using molecular docking technology to predict the potential of carboxymethyl chitosan as carrier of supersaturated drug delivery system,and with experimental means to verify and further to provide a new reference for expanding the carrier matrix of supersaturated drug delivery system.METHODS Two carboxymethyl chitosan polymers,O-CMCS and N-CMCS,were selected as the research objects,and repaglinide was used as the model drug.Firstly,the molecular docking of polymer and drug was carried out,and the interaction between polymer and drug was predicted by the scoring function.Secondly,the solvent transfer method was used to investigate the precipitation inhibition of the polymer.The solid dispersion prepared by O-CMCS and repaglinide was characterized by differential scanning calorimetry and infrared spectrum.To elucidate the stabilization mechanism of solid dispersion,the molecular docking results were verified.Finally,the experimental study on the condition of non-sink condition was carried out.RESULTS The three-dimensional structure of the polymer was successfully constructed.The results of molecular docking showed that O-CMCS combined with repaglinide had the best effect.It processed three strong hydrogen bonds with binding energy of-7.60 kcal·mol^(-1),binding energy for N-CMCS and repaglinide of-4.95 kcal·mol^(-1).The solvent shift method was also proved that the precipitation inhibition of O-CMCS was better than N-CMCS.The results of preparation characterization showed that repaglinide in the solid dispersion was amorphous and was bound to O-CMCS by strong hydrogen bond.The dissolution results under non-sink condition showed that the dissolution rate of solid dispersion with 50%drug loading was 7 times higher than that of the API,and the supersaturated concentration was maintained for up to 24 hours.CONCLUSION Combination of O-CMCS with the model drug repaglinide through strong hydrogen bonds can not only promote the dissolution of the drug,but also maintain the supersaturated concentration and inhibit the precipitation.It is suggested that O-CMCS has the potential as the carrier of supersaturated drug delivery system.