用非模型依赖法和威布尔模型法研究富马酸替诺福韦酯口服固体制剂的溶出行为

Study on the dissolution behavior of the oral solid preparations of tenofovir disoproxil fumarate by non-model dependent method and Weibull model method

目的:建立HPLC法测定富马酸替诺福韦酯(tenofovir disoproxil fumarate,TDF)口服固体制剂的溶出度,并用两种评价方法对国内4个厂家生产的TDF口服固体制剂仿制药与其原研药的溶出度进行一致性评价。方法:建立并验证测定TDF口服固体制剂在4种溶出介质中浓度的HPLC法。在桨转速优化和耐用性评价的基础上,建立TDF口服固体制剂溶出度评价方法,并采用非模型依赖法和威布尔模型法评价TDF口服固体制剂仿制药与原研药溶出行为的一致性。结果:所建立的HPLC法专属性良好,TDF在103.01~1030.10μg/ml范围内线性关系良好(r>0.999),精密度RSD均<2%,平均回收率在99%~102%,TDF对照品溶液于37℃放置3 h及室温放置12 h均稳定。溶出介质温度、桨转速的微小变动及溶出介质是否脱气均对TDF口服固体制剂的溶出行为无显著影响(P>0.05)。用非模型依赖法评价时,在4种溶出介质中,除胶囊剂外,其余3种TDF仿制药片与原研药均在15 min内溶出>85%。用威布尔模型法评价时,3种仿制药片与原研药的溶出参数存在差异,国内不同厂家生产的TDF片的溶出参数也存在较大差异,其中C厂生产的TDF片在4种溶出介质中药物溶出50%的时间参数(T 50)、药物溶出63.2%的时间参数(T d)和药物溶出85%的时间参数(T 85)分别是A厂产品的35.31、18.08及5.21倍。结论:本研究建立的HPLC法适用于TDF口服固体制剂溶出度的一致性评价。仅用非模型依赖法评价TDF口服固体制剂的溶出行为存在局限,用威布尔模型法可以更准确地描述不同厂家仿制药的溶出行为。不仅TDF口服固体制剂仿制药与原研药的溶出行为存在差异,而且国内不同厂家生产的TDF仿制药片剂的溶出行为也存在显著差异。

Objective:To establish a HPLC method for dissolution determination of tenofovir disoproxil fumarate(TDF),and also to evaluate dissolution consistency between the original tablets and generic oral solid preparations of TDF produced by four domestic manufacturers through two different methods.Methods:The HPLC method for the content determination of TDF in the four dissolution media was established and validated.Based on the optimization of the paddle rotation speed and evaluation of durability,the dissolution evaluation method of the oral solid preparations of TDF was established.Both the non-model dependent method and Weibull model method were used to evaluate dissolution behavior consistency between the generic and original oral solid preparations of TDF.Results:The established HPLC method showed good specificity,and the calibration curve was linear within the range of 103.01-1030.10μg/ml(r>0.999)for TDF.Precision RSD was less than 2%,and the average recovery rates were 99%-102%.The TDF sample solution was stable when stored at 37℃for 3 hours and stored at room temperature for 12 hours.Neither slight changes in the dissolution medium temperature and the paddle rotation speed nor degassing of the dissolution medium had any significant effects on the dissolution behavior of the oral solid preparations of TDF(P>0.05).When evaluated by non-model dependent method,the generic and the original tablets of TDF all dissolved for over 85%in the four dissolution media within 15 minutes,with the exception of the capsule.When evaluated by the Weibull model method,the dissolution parameters of the three generic tablets were different from those of the original tablets.And the dissolution parameters of TDF tablets produced by different domestic manufacturers were also different.The time parameters for release of 50%(T 50),the time parameters for release of 63.2%(T d)and the time parameters for release of 85%(T 85)in the four dissolution media of TDF generic tablets produced by manufacturer C were 35.31,18.08 and 5.21 times of the product by manufacturer A.Conclusion:The established HPLC method could be used in consistency evaluation of the dissolution of the oral solid preparations of TDF.However,there were limitations in dissolution evaluation,when the non-model dependent method was used alone.Weibull model method could more accurately describe the dissolution behavior of generic TDF tablets produced by different domestic manufacturers.Not only there existed differences in dissolution behavior of generic and original oral solid preparations of TDF,but significant differences in the dissolution behavior of TDF generic tablets produced by different domestic manufacturers were obviously noticeable.