【作者】 夏笔军；

【导师】 万新祥；

【作者基本信息】 第一军医大学 ， 药剂学， 2004， 硕士

【摘要】 食物与药物的相互作用能降低或增加药物的效应，可能引起治疗失败和药物毒性增加。研究食物对口服药物生物利用度(Bioavailability BA)的影响是指导临床合理用药、优化药物剂型设计所探索的课题，新药研制中也必须考虑食物可能会影响口服药物BA的因素。 药物的体内评价步骤繁琐，工作量大，为简化评价经常进行体外释放与体内吸收相关性研究，与体内吸收密切相关的体外释放条件可以直接用来评价药物的体内行为。 近年国外已模拟药物在胃肠道的溶出环境，建立了体外溶出模型，希望用体内外相关性好的体外溶出实验来代替人体实验。但此类研究才刚起步，仍不是很成熟，有不少局限性，有待进一步完善。 同时，东西方饮食习惯差异较大，按西方饮食习惯模拟的体外溶出模型在我国不一定适用。国内也未见专门研究食物对药物BA影响溶出模型的报道。本研究旨在探索建立符合我国饮食习惯的溶出模型，用体内外相关性来进一步研究食物对药物BA的影响，以指导临床合理用药、优化药物的剂型设计和减少人体实验负担。 本课题分体内实验和体外实验两部分，选用了临床运用非常广泛的喹诺酮类药物：氟罗沙星(Fleroxacin FXC)、加替沙星(GatifloxacinGFLX)和托氟沙星(Tosufloxacin TFLX)进行体内实验，获取空腹和进食条件下服药后的血药和尿药数据。体外实验是通过调节溶出仪的转速模拟胃肠蠕动、通过调整溶出介质模拟胃肠内环境等建立多种体外溶出模型，并在这些模型中对药物进行溶出测定，获取溶出参数。 采用体内外相关性研究方法对体内体外数据进行统计学处理。以食物对口服药物生物利用度影响体外溶出模型的研究中文摘要t时间体内吸收分数f为因变量，以对应时间体外累计溶出百分率x为变量，用最小二乘法线性回归得体内外相关性方程，来判断其相关性的优劣，从中筛选出体内外相关性好的溶出模型。 实验结果表明:1、人体实验表明:进食对FXC、GFLX、TFLX片的A UC影响不显著，不影响药物BA的程度，但进食条件会延迟药物的吸收。2、体外实验筛选出了GFLX和TFLX的空腹溶出模型:溶出仪的转速50 rpm，溶出介质为3mmol/L牛磺胆酸钠(NaTC)、0.75 mmol/L卵磷脂(Pe)、3.9 9 zL KHZPo4、7.79/L KCI、饱和NaOH调pH至6.5(温度为37士0.5℃)。此时GFLX和TFLX体外累积溶出率x与空腹服药的体内吸收分数f的相关性最好。GFLX的相关方程:f=0.83x一20.94:=0.9895TFLX的相关方程:f=0.79x一18.21r=0.98123、体外实验筛选出了GFLX和TFLX的进食溶出模型:溶出仪的转速40印m，溶出介质为12 mmol/L NaTe，3.75 mmol/L pe，8.659/L醋酸，15.29/LKCI，1009/L可溶性淀粉，饱和NaoH调pH至5.0(温度为37士0.5℃)。此时GFLx和TFLX体外累积溶出率x与进食后服药的体内吸收分数f的相关性最好，优于国内外现有溶出模型。GFLX的相关方程:f=o.7lx一8.53;= 0.9975TFLX的相关方程:f=0.68x一3.94;二0.99894、空腹和进食后GFLX和TFLX的体内同一时间吸收分率差举与对应时间它们在空腹与进食两溶出模型中累积溶出率差Jx亦有一定相关性。模拟空腹和进食两溶出模型中溶出率的差异在一定程度上能反映出两药物在空腹和进食后服药的体内吸收差异。5、在空腹和进食溶出模型中，GFLX和TFLX体内外相关性最好时的模拟条件一致，此结果显示用体外溶出数据一定程度上能较好的预测食物对口服药物生物利用度影响体外溶出模型的研究中文摘要药物在体内的吸收，为当前有限的体内外相关性研究提供了实例。 本实验从新的角度较全面地模拟胃肠道消化液和食糜对药物溶出的影响，通过改变溶出仪转速模拟胃肠蠕动对药物溶出的影响，确定了模拟空腹和进食后胃肠蠕动的最佳条件，弥补了现有溶出模型的不足，建立了新的体外溶出模型。 结果表明，多方面考虑溶出模型的pH、离子强度、消化液、食糜及胃肠的蠕动等因素对药物溶出的影响，一定条件下能获得与食物对药物 BA的影响有良好体内外相关性的溶出模型。溶出介质和实验条件越接近于体内胃肠道生理状态，越能得出体内相关性好的溶出/吸收曲线。 本研究对指导临床合理用药、新药开发剂型设计中药物配方的筛选、加速药物研制速度、控制药物制剂的内在质量、确保药品的安全有效和减少人体实验等都有非常重要的意义。更多还原

【Abstract】 Interactions between food and drug may alter the drug therapeutic effects, and result in treatment failures and increased toxicities. Investigation the effects of food to orally administered drugs bioavailability will be of great significance to clinical medication and optimizing pharmaceutical dosage forms, which should also be considered during the development of a new drug.In order to simplify the complicated in vivo assessment, the correlation between in vivo absorption and in vitro dissolution of a drug was studied. The in vitro release condition which is relative to the in vivo absorption can be used to assess the in vivo performance of a drug.In order to use in vitro data in place of in vivo data, gastrointestinal dissolution environment had been simulated, and in vitro dissolution module had also been established recently. However, this kind of study still need develop.In addition, eating habit of eastern and western nations is different; the in vitro dissolution module according to western eating habit may be not suitable in our country where there is still no any dissolution module study about the effect of meal to drugs bioavailability. The aim of this study is to establish dissolution module suitable to our country, and explore the impact of food on the pharmacokinetics of a drug using in vitro-in vivo correlations (IVIVC), these should be of great significance to clinical medication, formulation development and minimizing the number of human studies5required during product development.This study includes the experiments both in vivo and in vitro. In in vivo experiment, Fleroxacin(FXC), gatifloxacin(GTFX) and tosufloxacin(TLFX) were used to get the blood drug level and urine drug level data under fasting and fed conditions. The aim of the experiment in vitro is to establish dissolution modules in vitro, and then the dissolution parameters of the three drugs were obtained after dissolution tests under these modules. All analyses were done statistically on computer. Least square method was used in the statistical disposal to get the IVIVC equations, and then dissolution modules that provide significant relationships between in vitro and in vivo data were selected. Result:1. The experiment in vivo shows that food is unlikely to have a clinically significant effect on the AUC of FXC, GFLX and TFLX tablets, and the extent of bioavailability doesn’t alter either, but the absorption of these drugs may be delayed.2. The dissolution module under fasting condition was obtained through the experiment in vitro: tablets were dissolved in 900ml dissolution mediums(3mmol/L NaTC, 0.75 mmol/L PC, 3.9 g /L KH2PO4, 7.7 g /L KC1, pH 6.5 ) at 37 ?0.5 ; Rotation speed of dissolution test system is 50 pm. IVIVC equations of GFLX: /=0.83x - 20.94 r = 0.9895IVIVC equations of TFLX: /=0.79x - 18.21 r = 0.98123. The dissolution module under fed condition was obtained through the experiment in vitro: tablets were dissolved in 900ml dissolution mediums(12mmol/L NaTC, 3.75 mmol/L PC, 8.65 g /L HAc, 15.2 g /L KC1, l00g/L soluble starch, pH 5.0 ) at 37 ?0.5 癈; Rotation speed of dissolution test system is 40 rpm.IVIVC equations of GFLX: /=0.71x - 8.83 r = 0.9975 IVIVC equations of TFLX: /=0.68;c - 3.94 r = 0.99894. There was significant correlation between J/and zlx under fasting and fed conditions. The differences of dissolution rates under the two dissolution modules can reflect in vivo absorption differences of the two drugs under fasting and fed conditions.5. In this study, in vitro modeling of in vivo conditions might help provide a base for predicting in vivo drug behavior, which will be helpful to develop the study of IVIVC.The effects of gastrointestinal digestive and chyme to drug dissolution were simulated in new approaches. Through adjusting rotation speed of dissolution apparatus to simulate gastrointestinal motility, optimal rotation speed was confirmed and new in vitro dissolution modules were established.After comprehensively cons更多还原