黄体酮阴道环中药物释放速率与溶解度及扩散速率间相互关系的研究

Relationship between the release rate and the solubility and diffusion coefficient of drug in progesterone intravaginal ring

目的:研究阴道环中药物在硅橡胶中的溶解度(CSIL)及扩散系数(DSIL)与药物释放速率的具体关系。方法:采用差示扫描量热分析法测定黄体酮、孕二烯酮、米非司酮在硅橡胶中的溶解度;采用注塑成型法制备载药基质型阴道环,加热硫化法包裹控释膜,将其制成储库型阴道环;采用释放度测定法考察各类型阴道环7d的体外释放情况。结果:黄体酮、孕二烯酮、米非司酮在MED-6382中的溶解度分别为13.06,18.71,7.5mg/g,而载药量为300mg的3种阴道环7d的体外累积释放量由大到小依次为黄体酮(149.8mg)、孕二烯酮(29.2mg)、米非司酮(15.6mg),表明药物的释放速率与药物在硅橡胶中的溶解度不完全成线性关系。硅藻土、壳聚糖、乳糖、异丙醇等添加物通过影响药物的扩散系数而影响药物的释放速率和释放量。加入硅藻土、乳糖及壳聚糖可以阻碍药物分子的扩散,降低药物的释放速率;加入挥发性物质异丙醇则可以促进药物向阴道环表面扩散,增加基质型阴道环的突释。结论:药物的释放速率是由溶解度和扩散系数二者共同决定的,调节药物释放速率,需综合考虑药物的溶解度、各类添加物对药物扩散系数的影响等多方面因素。

Objective：To investigate the relationships between the release rate of drug and the solubility（CSIL）or the diffusion coefficient（DSIL）in silicone elastomer in intravaginal ring（IVR）.Methods：The solubilities of progesterone（PGT）,gestodene（GEST）,and mifepristone（RU486）in silicone elastomer were investigated by the methods of differential scanning calorimetry（DSC）.The matrix-type IVR was prepared by injection molding method,and the core of reservoir-type IVR was was the matrix-type IVR,and the controlling sheath was prepared by heating vulcanization method.The release rate of the IVRs in 7 days were tested by in vitro releasing measurement.Results：The solubilities of progesterone,gestodene,mifepristone in MED-6382 were 13.06 mg/g,18.71 mg/g,and 7.5 mg/g,respectively.The cumulative releases of the IVRs carried 300 mg drugs in 7 days were progesterone（149.8 mg）,gestodene（29.2 mg）,mifepristone（15.6 mg）,which had showed that the release rates and solubilities of drugs in silicone elastomer had no completely linear relationships.The diffusion coefficient of drug was changed by adding diatomite,chitosan,lactose and isopropyl alcohol,which caused the changes of the release rate and daily release.The diffusions of the drugs were prevented by adding diatomite,lactose and chitosan,which reduced the release rates,but the isopropyl alcohol could promote the drugs to the surface of IVRs,which increased day 1 burst of matrix type vaginal rings.Conclusion：The release rate of drug is determined by both the solubility and the diffusion coefficient of drug in silicone elastomer.In order to regulating the release rates of drugs,the solubilities of drugs in silicone elastomer and the diffusion coefficients influenced by various additives must be considered.