pH对达比加群酯的溶解和油水分配系数的影响  

Influence of pH on dissolution and oil-water partition coefficient of dabigatran etexilate

作　　者：王希冉 刘鹏[2] 王松会[2] 徐为人[1,2] 孙敏[2] 汤立达[2,3] 

机构地区：[1]天津医科大学,天津300070 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300193 [3]天津药物研究院天津释药技术与药动学国家重点实验室,天津300193

出　　处：《中国新药杂志》2013年第24期2933-2937,共5页Chinese Journal of New Drugs

基　　金：国家"重大新药创制"科技重大专项(2011ZX09401-009)

摘　　要：目的:探讨pH对达比加群酯的溶解以及油水分配系数的影响,为阐明其生物利用度低的问题及设计新的制剂提供依据。方法:采用HPLC法测定达比加群酯在不同溶剂及不同pH值水溶液中的表观溶解度,采用摇瓶法测定达比加群酯在不同pH值下的表观油水分配系数和解离常数,考察5种常用表面活性剂在不同pH值的缓冲溶液中对达比加群酯的增溶效果。结果:达比加群酯在有机溶剂中的溶解性较好,在水中的溶解度仅为0.83μg·mL-1,其表观溶解度随溶液pH值的增大而减小。达比加群酯的lgD值具有显著的pH值依赖性,其lgP值为4.17,pKa值为6.99。5种增溶剂在模拟胃肠环境的不同pH值水溶液中的增溶效果差异较大,聚山梨酯80和HP-β-CD在pH 3.0以上的缓冲液中表现了较好的增溶作用。结论:随pH值的升高达比加群酯溶解度减小而油水分配系数增加,推测pH变化导致的溶解性和透膜性向相反方向变化是其生物利用度较低的关键原因,提示聚山梨酯80以及HP-β-CD等增溶剂具备一定的增加其生物利用度的可行性。Abstract：Objective： To investigate the influence of pH on dissolution and oil-water partition coefficient of dabigatran etexilate for providing a basis for clarifying its low bioavailability and designing of new preparations. Methods： A high performance liquid chromatography （HPLC） method was established and used to detect the concentration of dabigatran etexilate in water, some organic solvents and buffered salt solution. The partition coefficients for the n-octanol-water/buffer solution systems and dissociation constants were determined by a shake flask method. Also the solubility of dabigatran etexilate in certain surfactants under different pH was determined. Results： Dabigatran etexilate had great solubility in organic solvents. The apparent solubility of dabigatran etexilate in water was 0.83 μg·mL-1, that would decrease with the increasing pH of the solution. The lgD of dabigatran etexilate had a significant dependence on the pH value, and its lgP=4.17 and pKa=6.99. The 5 surfactants showed quite different effects at different pHs in buffer solutions that simulated gastrointestinal environment. Tween-80 and HP-β-CD showed good results in the buffer with pH〉3. Conclusion： As the increasing of pH, dabigatran etexilate shows an increasing oil-water partition coefficient accompanied by a decreasing solubility. It is suggested that the opposite effect of solubility and permeability induced by pH change is the key reason for its low bioavailability. Some surfactant such as Tween-80 and HP-β-CD may have a feasibility to increase its bioavailability.

关 键 词：达比加群酯 生物利用度 溶解性 油水分配系数 

分 类 号：R972.7[医药卫生—药品]