【作者】 龚倩；

【导师】 程泽能； 王霆；

【作者基本信息】 中南大学 ， 药剂学， 2007， 硕士

【摘要】 一、目的研究复方头孢克洛分散片处方在健康成人中使用的合理性,为该药Ⅱ期临床研究提供依据。研究内容分为两部分。其一,考察复方制剂中组方及工艺是否影响两主药的药动学参数;其二,考察两主药是否存在药动学环节相互作用。二、方法1给药方法1.1组方对药物药动学影响研究采用双周期、自身交叉对照试验设计,12名健康受试者,随机分为2组,每组男女各3人。各组受试者分别单剂量口服受试制剂复方头孢克洛分散片1片（含头孢克洛250 mg和溴己新8 mg）,或参比制剂头孢克洛片（250 mg）及盐酸溴己新片（8 mg）各1片,洗脱期（Wash-out）7天。1.2两主药药动学环节相互作用研究采用3×3拉丁方试验设计,12名健康受试者,随机分为6组,每组男女各1人,每组受试者在不同周期内分别多剂量口服头孢克洛片（250 mg/片）、盐酸溴己新片（8 mg/片）或头孢克洛片加盐酸溴己新片（250 mg/片+8 mg/片）,每天三次,连续服用5天,周期间洗脱时间（Wash-out）为14天。2.样品采集方法2.1血样采集2.1.1组方对药物药动学影响研究于给药当天,给药前（0 min）和给药后10 min、20 min、30 min、45 min、60min、1.5 h、2.0 h、2.5 h、3 h、4 h、6 h、8 h、10 h、14 h、24 h抽取肘静脉血5mL。将血样标本置于肝素化试管中,2700 r·min^-1离心5min,一部分分离出的血浆与冰醋酸按10∶1（v/v）的比例酸化,混匀后置于-70℃冷冻保存,用于测定头孢克洛;另一部分分离后血浆直接置于-70℃冷冻保存,用于测定溴己新。第二周期采血方法相同。2.1.2两主药药动学环节相互作用研究于第3、4天清晨给药前抽取肘静脉血5 mL。第5天给药前和给药后10 min、20min、30 min、45 min、60 min、1.5 h、2.0 h、2.5 h、3 h、4 h、6 h、8 h、10 h、12h、18 h、24 h抽血5 mL。每周期采血方法相同。将血样置于肝素化试管中,2700r·min^-1离心5 min,一部分分离出的血浆与冰醋酸按10∶1（v/v）的比例酸化,混匀后置于-70℃冷冻保存,用于测定头孢克洛;另一部分分离后血浆直接置于-70℃冷冻保存,用于测定溴己新。2.2尿样采集两主药药动学环节相互作用研究中,于给药第5天清晨给药后分别收集0—1 h,1—2 h,2—4 h,4—8 h,8—12 h,12—24 h时间段尿样。每周期收集方法相同。各时间段尿样测量体积后,取10mL于试管中与冰醋酸按10∶1（v/v）的比例酸化,混匀后置于-70℃贮存待测。3.血样、尿样测定方法血及尿样中头孢克洛浓度采用HPLC—UV法测定,溴己新浓度采用HPLC—MS法测定。三、结果1.组方对药动学的影响研究1.1组方对头孢克洛药动学的影响头孢克洛的主要药动学参数C_max、AUC_0-6（梯形面积）经对数转化后进行方差分析,结果表明复方制剂中头孢克洛与头孢克洛片相比,AUC_0-6无显著性差异,C_max无显著性差异,双单侧t检验表明,复方头孢克洛中头孢克洛与头孢克洛片生物等效。t_max经Mann-Whitney检验,结果表明无显著性差异。其它药动学参数(如:V_d/F、t_1/2、MRT)进行方差分析,结果表明无显著性差异。1.2组方对头溴己新药动学的影响溴己新的主要药动学参数C_max、AUC_0-24（梯形面积）经对数转化后进行方差分析,结果表明复方制剂中溴己新与盐酸溴己新片相比,C_max和AUC_0-24无显著性差异,双单侧t检验表明,复方制剂中溴己新与与盐酸溴己新片生物等效。t_max经Mann-Whitney检验,结果表明无显著性差异。其他药动学参数(如:V_d/F、t_1/2、MRT)进行方差分析,结果表明均无显著性差异。2.两主药药动学环节相互作用研究2.1合并使用溴己新对头孢克洛药动学参数的影响将合并给予头孢克洛及溴己新组与单独给予头孢克洛组,头孢克洛的主要药动学参数进行比较。头孢克洛的C_max、AUC_0-6（梯形面积）经对数转化后进行方差分析,结果表明二者均无显著性差异,双单侧t检验表明,两参数均落在各自相应的90%可信区间内,合用与单独使用相比,头孢克洛生物等效。t_max经Mann-Whitney检验,结果表明两组间无显著性差异。其他药动学参数(如:V_d/F、t_1/2、Cl_r及MRT等)进行方差分析,结果显示:V_d/F有显著性差异,其他参数无显著性差异。2.2合并使用头孢克洛对溴己新药动学参数的影响将合并给予头孢克洛和溴己新组与单独给予溴己新组,溴己新的主要药动学参数进行比较。溴己新的主要药动学参数C_max、AUC_0-24（梯形面积）经对数转化后进行方差分析,结果表明二者无显著性差异,双单侧t检验表明,两参数均落在各自相应的90%可信区间内,合用与单独使用相比,溴己新生物等效。t_max经Mann-Whitney检验,结果表明无显著性差异。其他药动学参数(如:V_d/F、t_1/2、Cl_r及MRT)进行方差分析,结果表明:参数均无显著性差异。四、结论1.与市售头孢克洛片及盐酸溴己新片相比,复方头孢克洛分散片的组方对二者的药动学参数均无差异,复方头孢克洛分散片处方组成合理。2.溴己新主要经肝脏代谢,少有以原型经尿液排泄,而头孢克洛主要经由肾脏以原型排泄。溴己新不影响头孢克洛在肾小球滤过或远曲小管的分泌及重吸收。联合服用盐酸溴己新片,头孢克洛的表观分布容积高于单用头孢克洛,可能合用通过提高低粘度蛋白的分泌而增加头孢克洛与支气管和肺泡的结合力等作用机制提高了其支气管和肺泡的穿透力。更多还原

【Abstract】 OBJECTIVESThe purpose of the study is to investigate the preparation rationality of Compound Cefaclor Dispersible Tablets in healthy volunteers.There are two studies. One is to investigate the effect of the preparation technology on the pharmacokinetic parameters of the two principal agents.The other is to investigate the pharmacokinetic interaction between the two principal agents.METHODS1.Drug administration1.1 The effect of the preparation technology on the pharmacokinetic parameters of the two principal agents.A two-phase cross over test with a wash out period of 7 days was applied in this test.12 subjects（6 female）were divided into two groups randomly.And these groups received Compound Cefaclor Dispersible Tablet or the same dose of 250mg of Cefaclor tablet,and 8mg of Bromhexine hydrochloride tablet in different phases,respectively. 1.2 To investigate the pharmacokinetic interaction between the two principal agents.12 subjects（6 female）were divided into 6 groups in a 3×3 Latin square design. In the multiple dose study,these groups（1 male and 1 female）received 250mg of Cefaclor tablet and 8mg of Brornhexine hydrochloride tablet,250mg of Cefaclor tablet, and 8mg of Bromhexine hydrochloride tablet three times daily for 5 days in the three different phases,respectively.The washout time is 14 days.2.Sample collection2.1 Blood samples collectionBlood samples were collected before and 0.17,0.33,0.5,0.75,1.0,1.5,2.0,2.5, 3.0,4.0,6.0,8.0,10.0,14.0 and 24.0 h after the drug administration in each phase to investigate the effect of the preparation technology on the pharmacokinetic parameters of the two principal agents.To investigate the pharmacokinetic interaction between the two principal agents, blood samples were collected just before the first drug administration in the third to fifth drug administration days.And blood samples were collected 0.17,0.33,0.5,0.75,1.0, 1.5,2.0,2.5,3.0,4.0,6.0,8.0,10.0,12.0,18.0 and 24.0 hours after the first dose in the fifth day.After centrifugalization,the plasma samples for cefaclor determination were acidified by glacial acetic acid with a ratio of 10:1（v/v）,and then stored at -70℃until analysis.Other blood samples for bromhexine were stored directly at -70℃until analysis.2.2 Urine samples collectionUrine samples were collected for the investigation of the pharmacokinetic interaction of the two principal agents.Urine samples were collected 0～1h,1～2h,2～4h,4～8h,8～12h,12～24h after the first drug administration in the fifth drug administration day.A aliquot of 10 mL of each sample was acidified by glacial acetic acid with a ratio of 10:1（v/v）after measuring urine volume,and then stored at -70℃until analysis.3.Samples analysisCefaclor and bromhexine concentration in all samples were determined by HPLC-UV and HPLC-MS,respectively.RESULTS1.Effect of the preparation technology on the pharmacokinetic parameters of the two principal agents.There were no significant differences of AUC_0-tand C_maxof CEF in logarithm between the two groups of administrations of Compound Cefaclor Dispersible Tablets or co-administration of CEF with BHX.Two one t-test showed that the CEF was bioequivalence between the two groups.There were no significant differences of t_max, MRT,t_1/2,V_d/F between the two groups.There were no significant differences of AUC_0-tand C_maxof BHX in logarithm between the two group of administrations of Compound Cefaclor Dispersible Tablets or co-administration of BHX with CEF.Two one t-test showed that the BHX was bioequivalence between the two groups.There were no significant differences of t_max, MRT,t_1/2,V_d/F between the two groups.2.Pharmacokinetie interaction of the two principal agents.There were no significant differences of AUC_0-tand C_maxof CEF in logarithm between the group of multiple administrations of CEF and the group of co-administration of CEF with BHX.Two one t-test showed that CEF was bioequivalence in the two groups.There were no significant differences of t_max,MRT, t_1/2and Cl_r between the two groups.V_d/F is significantly lower in the single CEF group than in the co-administration CEF and BHX group.There were no significant differences of AUC_0-tand C_maxof BHX in logarithm between the group of single administration of BHX and the group of co-administration of BHX with CEF.Two one t-test showed that BHX was bioequivalence in the two groups.There were no significant differences of t_max,MRT,t_1/2and Cl_r,V_d/F between the two groups.CONCLUSION1.Comparing with co-administration of cefaclor tablets and bromhexine hydrochloride tablets,Compound Cefaclor Dispersible Tablets prepared by this technology has the equivalent cefaclor and bromhexine pharmacokinetic parameters.The formula composition and preparation technology were rational.2.BHX was mainly transformed from the drug to metabolites by the hepatic pathway, which was mainly discharged by urine.CEF was mainly excreted by the nephric pathway in its original type.The increase of the apparent volume of the distribution of CEF in co-administration of the two drugs was attributed to the increasing of bronchi and pulmonary alveoli drug permeability and affinity or other unknown reasons.The increasing of low viscosity of the mucoprotein secretion,binding with CEF in bronchi and pulmonary alveoli,was thought to be the most possible mechanism of the high tissue drug affinity.更多还原