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数字胃肠道模型的建立及在硝苯地平缓释片人体吸收预测中的应用

Development of digital gastrointestinal model and its application in absorption prediction of nifedipine sustained-release tablets

  • 摘要: 以Excel 2003为平台,利用VBA程序建立数字胃肠道模型(DIM)。通过Ussing chamber大鼠肠吸收试验,研究不同肠段、不同pH、有无辅料存在条件下硝苯地平的吸收特性,获得DIM模型的输入层参数。再利用DIM模型预测硝苯地平缓释制剂人体的血药浓度-时间曲线并进行参数敏感性分析,找寻影响硝苯地平缓释制剂吸收的关键参数,为硝苯地平缓释制剂的处方设计提供参考和依据。实验结果表明,硝苯地平在大鼠十二指肠、空肠、回肠、结肠的表观通透系数(Papp)均大于1.0×10-6cm/s。辅料能显著增高硝苯地平的Papp,而在大鼠同一肠段不同pH对硝苯地平的Papp差异无统计学意义。硝苯地平在大鼠各肠段吸收良好,未见明显吸收窗现象。DIM模型参数敏感性分析表明,吸收速率的变化对硝苯地平的血药浓度-时间曲线影响不大,吸收速率不是硝苯地平吸收的限速步骤,溶出速率和小肠迁移时间才是影响硝苯地平吸收的关键因素。DIM模型可以为硝苯地平缓释制剂的处方设计提供依据。

     

    Abstract: The purpose of this reaearch was to predict plasma concentration-time profiles of nifedipine (NFP) sustained-release formulation,and identify the critical parameters of absorption via sensitivity analysis.Firstly,digital gastrointestinal model (DIM) was established using VBA program and input parameters was obtained through the investigation of intestinal absorption characteristics of NFP from different intestinal regions,different pH and with or without excipients,providing guidance for the design of NFP sustained-release formulation.Results showed that the apparent permeability coefficients (Papp) of NFP was larger than 1.0 ×10-6cm/s at intestinal and colon.Co-incubation with excipients could significantly influence the permeability of NFP.The pH of drug solution had little effect on the Papp of NFP.NFP is well absorbed at the whole intestine of rats.However,parameter sensitivity analysis showed that variation of the absorption rate had no distinct effect on the concentration-time profile of NFP.The dissolution rate and intestinal transit time were the critical parameters of NFP sustained-release formulation.In conclusion,DIM can provide guidance for the design of NFP sustained-release formulation.

     

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