Evaluation Of The Formula Of Compound Cefaclor Dispersible Tablets By Pharmacokinetics

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.