基于平行人工膜渗透分析法对药物溶出/吸收仿生系统优化及其药物渗透性评价研究

Optimization of DDASS based on PAMPA and drug permeability evaluation investigation

目的基于平行人工膜渗透分析法(Parallel artificial membrane permeability analysis, PAMPA)对药物溶出/吸收仿生系统(Drug dissolution and absorption simulating system,DDASS)的生物膜系统进行改进,以单硝酸异山梨酯、奥美拉唑和氢氯噻嗪为工具药进行渗透性考察,建立一种快速、简便的药物渗透性考察方法,以期进一步提高DDASS系统对药物渗透性评价的效率和准确性,并对药物体内吸收百分率进行预测。方法以疏水性半透膜为载体,将1%大豆卵磷脂和0.1%胆固醇的正十二烷溶液涂于疏水性聚偏氟乙烯中空纤维膜上制备人工渗透膜,以人工渗透膜取代DDASS中的大鼠肠管,以BCS I类药单硝酸异山梨酯,BCS II类药奥美拉唑和BCS III类药氢氯噻嗪为工具药考察其在DDASS系统中经人工渗透膜的表观渗透系数(Papp),采用大鼠在体单向肠灌流法对上述3种药物的有效渗透系数(Peff)的测定,验证人工渗透膜对药物BCS归类的准确性。结果单硝酸异山梨酯、奥美拉唑和氢氯噻嗪基于PAMPA优化DDASS法测得Papp分别为(3.644±0.291)×10^-6、(2.391±0.020)×10^-6、(0.129±0.032)×10^-6cm/s;上述药物基于大鼠在体单向肠灌流法测得Peff分别为(37.69±2.67)×10^-5、(33.72±5.02)×10^-5、(14.37±1.66)×10^-5cm/s。三者的体内吸收百分率预测值分别为95.36%、65.76%、5.61%,与Papp呈正相关。结论基于DDASS优化PAMPA法对3种不同BCS分类药物渗透性的考察结果与大鼠在体单向肠灌流结果一致,均证明单硝酸异山梨酯与奥美拉唑为高渗透性药物,氢氯噻嗪为低渗透性药物,符合FDA对三者的BCS分类。表明基于DDASS优化PAMPA法考察药物渗透性,结果准确,简单方便,节约资源,体内吸收百分率预测值具有参考价值,为仿制药申请生物等效性豁免及为创新药物口服生物利用度研究提供了可靠的体外预测平台。

Objective Drug dissolution and absorption simulating system(DDASS) is a device that combines the drug in vitro dissolution model and the transmembrane permeation model to continuously and dynamically simulate the process of dissolution and transmembrane permeation of drugs in vivo. Improvement of the biological membrane system of the Drug dissolution and absorption simulating system based on Parallel artificial membrane permeability analysis(PAMPA). Permeability studies were carried out by using isosorbide mononitrate, omeprazole and hydrochlorothiazide as tools, in order to establish a rapid and simple drug permeability test method and predict the percentage of absorption, in order to further improve the efficiency and accuracy of DDASS system for drug permeability evaluation. And predict the percentage of drug absorption in the body. Methods Using hydrophobic semi-permeable membrane as the carrier, the artificial permeable membrane was prepared by coating 1% soybean lecithin and 0.1%cholesterol n-dodecane solution on the hydrophobic polyvinylidene fluoride hollow fiber membrane. Replace the rat intestine in DDASS with an artificial permeability membrane. The Pappof the BCS I drug isosorbate, the BCS II drug omeprazole and the BCS III drug hydrochlorothiazide was investigated in the DDASS system through the artificial permeability membrane. the Peffof above three drugs were tested in the rat single-pass intestinal perfusion assay. Results Pappof isosorbide mononitrate, omeprazole and hydrochlorothiazide based on PAMPA optimized DDASS method were(3.644±0.291)×10^-6 cm/s,(2.391±0.020)×10^-6 cm/s,(0.129±0.032)×10^-6 cm/s;the Peffof above drugs were(37.69±2.67)×10^-5 cm/s,(33.72±5.02)×10^-5 cm/s,(14.37±1.66)×10^-5 cm/s based on the rat single-pass intestinal perfusion assay. The predicted percentages of absorption in the three drugs were 89.36%, 65.76% and 5.61%,respectively, which were positively correlated with Papp. Conclusion The results of the PAMPA optimized DDASS method for the permeability of three different BCS classification drugs were consistent with the results of the rat single-pass intestinal perfusion assay. It is proved that isosorbide mononitrate and omeprazole are high-permeability drugs, and hydrochlorothiazide is a lowpermeability drug, which conform to the BCS classification of the three drugs by FDA It shows that the PAMPA optimized DDASS method applying to investigate the drug permeability is convenient and simple, it can save resources, and the results are accurate, the predicted percentage of absorption have a reference. It can provide a reliable in vitro prediction platform for applying a bioequivalence exemption for generic drugs and oral bioavailability studies of innovative drugs.