右兰索拉唑缓释胶囊在Beagle犬体内的生物等效性研究
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摘要
目的:建立测定Beagle犬血浆中右兰索拉唑浓度的方法,评价两种右兰索拉唑缓释胶囊的生物等效性。方法:6只Beagle犬随机分为参比制剂组和受试制剂组,每组3只,采用双周期交叉随机试验(清洗期为1周)设计,分别空腹单次口服右兰索拉唑缓释胶囊参比制剂和受试制剂各60 mg,并于给药前及给药后0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、6、7、8、10、12 h自前肢头静脉取血2mL,采用液相色谱-串联质谱法(LC-MS/MS)测定Beagle犬血浆中右兰索拉唑的浓度。以奥美拉唑为内标,色谱柱为Inertsil ODS,流动相为甲醇-0.1%甲酸溶液(90∶10,V/V);采用电喷雾离子源,以多反应监测模式进行正离子扫描,用于定量分析的离子对分别为m/z 369.9→251.7(右兰索拉唑)、m/z 345.7→197.9(内标)。采用DAS 3.1.6软件计算药动学参数,以双侧t检验及(1-2α)%置信区间(CI)法、Wilcoxon检验考察两种制剂的生物等效性。结果:右兰索拉唑血药浓度的线性范围为10~4 000 ng/mL,定量下限为10 ng/mL;批内、批间RSD<10%,准确度为94.40%~105.20%。空腹单次口服参比制剂或受试制剂的AUC_(0-t)分别为(8 892.48±1 399.67)、(8 683.71±1 167.88)ng·h/mL,AUC_(0-∞)分别为(8 925.73±1 399.64)、(9 053.08±1 553.46)ng·h/mL,t_(max)分别为(3.50±0.71)、(3.75±1.21)h,c_(max)分别为(2 980.00±487.40)、(2 863.33±331.34)ng/mL。受试制剂AUC_(0-t)、AUC_(0-∞)、c_(max)的90%CI均在参比制剂相应参数的80%~125%范围内,两制剂t_(max)间的差异无统计学意义(P>0.05)。结论:本研究建立的LC-MS/MS法适用于Beagle犬血浆中右兰索拉唑浓度的测定,且两种制剂在Beagle犬体内具有生物等效性。
OBJECTIVE:To establish a method for the determination of dexlansoprazole concentration in plasma of Beagle dogs,and to evaluate bioequivalence of 2 kinds of Dexlansoprazole sustained-release capsules. METHODS:A total of 6 Beagle dogs were randomly divided into reference preparation group and test preparation group,with 3 dogs in each group. In double cycle cross randomized trial(cleaning period lasting for one week)design,they were given reference preparation and test preparation of Dexlansoprazole sustained-release capsules 60 mg once. The blood sample 2 mL of forelimb vein were collected before medication,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,7,8,10,12 h after medication,respectively. The concentration of dexlansoprazole in plasma of Beagle dogs was determined by LC-MS/MS. Using omeprazole as internal standard,the determination was performed on Inertsil ODS with mobile phase consisted of methanol-0.1% formic acid solution(90 ∶ 10,V/V). ESI was used for positive ion scanning by multiple reaction monitoring mode. The ion pair for quantitative analysis were m/z 369.9→251.7(dexlansoprazole)and m/z 345.7→197.9(internal standard),respectively. The pharmacokinetic parameters were calculated by using DAS 3.1.6 software.The bioequivalence of two preparations were investigated by bilateral t test,(1-2α)confidence interval(CI)method and Wilcoxon test. RESULTS:The linear range of dexlansoprazole concentration was 10-4 000 ng/mL. The lower limit of quantitation was 10 ng/mL;RSDs of inter-batch and intra-batch were lower than 10%. The accuracy ranged 94.40%-105.20%. The pharmacokinetic parameters of reference preparation or test preparation of single fasting dose were as follows:AUC_(0-t)were(8 892.48±1 399.67),(8 683.71±1 167.88)ng·h/mL,AUC_(0-∞)were(8 925.73±1 399.64),(9 053.08±1 553.46)ng·h/mL,t_(max)were(3.50±0.71),(3.75±1.21)h,c_(max) were(2 980.00±487.40),(2 863.33±331.34)ng/mL,respectively. 90%CI of AUC_(0-t),AUC_(0-∞)and c_(max)for test preparation were80%-125% of corresponding parameters of reference preparation;there was no statistical significance in t_(max)between 2 preparations(P>0.05). CONCLUSIONS:LC-MS/MS is suitable for the determination of dexlansoprazole concentration in Beagle dogs plasma.Moreover,the two preparations are bioequivalent in Beagle dogs.
OBJECTIVE:To establish a method for the determination of dexlansoprazole concentration in plasma of Beagle dogs,and to evaluate bioequivalence of 2 kinds of Dexlansoprazole sustained-release capsules. METHODS:A total of 6 Beagle dogs were randomly divided into reference preparation group and test preparation group,with 3 dogs in each group. In double cycle cross randomized trial(cleaning period lasting for one week)design,they were given reference preparation and test preparation of Dexlansoprazole sustained-release capsules 60 mg once. The blood sample 2 mL of forelimb vein were collected before medication,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,7,8,10,12 h after medication,respectively. The concentration of dexlansoprazole in plasma of Beagle dogs was determined by LC-MS/MS. Using omeprazole as internal standard,the determination was performed on Inertsil ODS with mobile phase consisted of methanol-0.1% formic acid solution(90 ∶ 10,V/V). ESI was used for positive ion scanning by multiple reaction monitoring mode. The ion pair for quantitative analysis were m/z 369.9→251.7(dexlansoprazole)and m/z 345.7→197.9(internal standard),respectively. The pharmacokinetic parameters were calculated by using DAS 3.1.6 software.The bioequivalence of two preparations were investigated by bilateral t test,(1-2α)confidence interval(CI)method and Wilcoxon test. RESULTS:The linear range of dexlansoprazole concentration was 10-4 000 ng/mL. The lower limit of quantitation was 10 ng/mL;RSDs of inter-batch and intra-batch were lower than 10%. The accuracy ranged 94.40%-105.20%. The pharmacokinetic parameters of reference preparation or test preparation of single fasting dose were as follows:AUC_(0-t)were(8 892.48±1 399.67),(8 683.71±1 167.88)ng·h/mL,AUC_(0-∞)were(8 925.73±1 399.64),(9 053.08±1 553.46)ng·h/mL,t_(max)were(3.50±0.71),(3.75±1.21)h,c_(max) were(2 980.00±487.40),(2 863.33±331.34)ng/mL,respectively. 90%CI of AUC_(0-t),AUC_(0-∞)and c_(max)for test preparation were80%-125% of corresponding parameters of reference preparation;there was no statistical significance in t_(max)between 2 preparations(P>0.05). CONCLUSIONS:LC-MS/MS is suitable for the determination of dexlansoprazole concentration in Beagle dogs plasma.Moreover,the two preparations are bioequivalent in Beagle dogs.
引文
[1]韩英.右旋兰索拉唑的药理学特点及在胃食管反流病治疗中的应用[J].中国新药杂志,2012,21(6):581-583、595.
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[8]陈娟,张坤,杨志强,等.右兰索拉唑缓释胶囊溶出度测定方法的研究[J].中国新药杂志,2016,25(23):2659-2663.
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[10]国家药典委员会.中华人民共和国药典:四部[S].2015年版.北京:中国医药科技出版社,2015:363-368.
[11]孟庆彬,唐静雅,周立华,等.右旋兰索拉唑缓释胶囊在Beagle犬体内的药动学及生物等效性[J].沈阳药科大学学报,2015,32(5):370-375、399.
[12]HOTHA KK,VIJAYA BHARATHI D,JAGADEESH B,et al.Development and validation of a highly sensitive LC-MS/MS method for quantitation of dexlansoprazole in human plasma:application to a human pharmacokinetic study[J].Biomed Chromatogr,2012,26(2):192-198.
[13]房超,李周,丁存刚,等.右旋兰索拉唑双相释放胶囊在Beagle犬体内的药动学研究[J].中国医药工业杂志,2011,42(11):827-830.
[14]袁淋文,杨劲.Beagle犬药动学研究在缓释制剂评价体系中的作用比较[J].中国新药杂志,2015,24(10):1134-1140.
[15]KARARLI TT.Comparison of the gastrointestinal anatomy,physiology,and biochemistry of humans and commonly used laboratory animals[J].Biopharm Drug Dispos,1995,16(5):351-380.
[16]GRABOWSKI B,LEE RD.Absorption,distribution,metabolism and excretion of[14C]dexlansoprazole in healthy male subjects[J].Clin Drug Investig,2012,32(5):319-332.
[2]VAKILY M,ZHANG W,WU J,et al.Pharmacokinetics and pharmacodynamics of a known active PPIs with a novel dual delayed release technology,dexlansoprazole MR:a combined analysis of randomized controlled clinical trials[J].Curr Med Res Opin,2009,25(3):627-638.
[3]魏玉娜,杜秋,曾明.标准剂量和双倍剂量质子泵抑制剂对中到重度反流性食管炎内镜治愈率的网状Meta分析[J].实用药物与临床,2017,20(9):1022-1029.
[4]NOUBARANI M,KEYHANFAR F,MOTEVALIAN M,et al.Improved HPLC method for determination of four PPIs,omeprazole,pantoprazole,lansoprazole and rabeprazole in human plasma[J].J Pharm Pharm Sci,2010,13(1):1-10.
[5]FASS R,JOHNSON D,ORR W,et al.The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD[J].Am J Gastroenterol,2011,106(3):421-431.
[6]LEE RD,VAKILY M,MULFORD D,et al.Clinical trial:the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR,a novel dual delayed release formulation of a proton pump inhibitor:evidence for dosing flexibility[J].Aliment Pharmacol Ther,2009,29(8):824-833.
[7]宋素异,刘奎利,房伟.HPLC法测定右旋兰索拉唑缓释胶囊的光学纯度[J].中国药房,2014,25(29):2754-2756.
[8]陈娟,张坤,杨志强,等.右兰索拉唑缓释胶囊溶出度测定方法的研究[J].中国新药杂志,2016,25(23):2659-2663.
[9]国家食品药品监督管理局.化学药物非临床药代动力学研究技术指导原则[S].2005-03.
[10]国家药典委员会.中华人民共和国药典:四部[S].2015年版.北京:中国医药科技出版社,2015:363-368.
[11]孟庆彬,唐静雅,周立华,等.右旋兰索拉唑缓释胶囊在Beagle犬体内的药动学及生物等效性[J].沈阳药科大学学报,2015,32(5):370-375、399.
[12]HOTHA KK,VIJAYA BHARATHI D,JAGADEESH B,et al.Development and validation of a highly sensitive LC-MS/MS method for quantitation of dexlansoprazole in human plasma:application to a human pharmacokinetic study[J].Biomed Chromatogr,2012,26(2):192-198.
[13]房超,李周,丁存刚,等.右旋兰索拉唑双相释放胶囊在Beagle犬体内的药动学研究[J].中国医药工业杂志,2011,42(11):827-830.
[14]袁淋文,杨劲.Beagle犬药动学研究在缓释制剂评价体系中的作用比较[J].中国新药杂志,2015,24(10):1134-1140.
[15]KARARLI TT.Comparison of the gastrointestinal anatomy,physiology,and biochemistry of humans and commonly used laboratory animals[J].Biopharm Drug Dispos,1995,16(5):351-380.
[16]GRABOWSKI B,LEE RD.Absorption,distribution,metabolism and excretion of[14C]dexlansoprazole in healthy male subjects[J].Clin Drug Investig,2012,32(5):319-332.