HPLC-MS/MS法测定人体色甘酸钠血浆浓度及其药动学研究
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摘要
目的:
建立人血浆中色甘酸钠含量的HPLC-MS/MS测定方法。采用HPLC-MS/MS法测定色甘酸钠经时血浓度,进行试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液的单剂鼻腔给药双交叉两周期人体生物等效性试验,为新药报批及其临床应用提供试验依据。
方法:
1.采用高效液相分离系统。流动相为乙酸铵:甲醇(含50%乙腈)(15:85,V/V),在线脱气;流速0.4mL·min-1;柱温30℃。固定相为AGT Venusil XBP C18(250mm×4.6mm,5μm)色谱柱。采用质谱检测系统,ESI离子源,正离子模式,雾化压力40 psi,干燥气(N2)流速10 L·min-1,干燥气温度为350℃,毛细管电压4000V,多级反应监测(MRM)方式,469→263.1(色甘酸钠),447.2→327.1(普伐他汀钠)。色甘酸钠碰撞能量为20V,碎片电压为150V,EMV=600;普伐他汀钠碰撞能量为20V,碎片电压为100V,EMV=600。以普伐他汀钠为内标,测定色甘酸钠血浆浓度,
2.试验采用两周期交叉设计。健康志愿者20名,男性,按体重配对后随机分为两组,分别专人给予试验制剂色甘酸钠鼻用喷雾剂或参比制剂色甘酸钠滴鼻液,于药前和药后0.17,0.33,0.5,0.67,0.83,1.0,1.25,1.5,2.0,3.0,4.0,5.0 h取肘静脉血4ml,立即移入肝素抗凝管中,静置,5000rpm离心5min,取血浆分双份于-20℃贮存备测。一周后重复上述试验。采用HPLC/MS/MS法测定色甘酸钠经时血浓度。色甘酸钠血浓度-时间数据经《DAS 2.0》实用药代动力学计算程序处理,得试验制剂和参比制剂色甘酸钠药代动力学参数,并根据试验制剂和参比制剂色甘酸钠AUC_(0-5)计算试验制剂的相对生物利用度。同时对主要药代动力学参数进行方差分析、双单侧t检验和(1-2α)置信区间分析,评价试验制剂和参比制剂的生物等效性。
结果:
1.采用HPLC-MS/MS法测定色甘酸钠血浆药物浓度,在0.3～20 ng·mL-1范围内色甘酸钠血药浓度呈线性关系,最低定量限为0.3ng·mL-1,回收率在94.1%以上,日内日间的RSD均小于14.3%。
2.试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液主要药代动力学参数t_(1/2)分别为(1.815±0.535)h和(1.592±0.518)h,T_(max)分别为(0.467±0.116)h和(0.442±0.147)h,C_(max)分别为(9.789±4.662)ng·ml~(-1)和(10.877±4.047)ng·ml~(-1),AUC_(0.5)分别为(11.519±3.461)ng·ml~(-1)·h和(12.629±4.228)ng·ml~(-1)·h,AUC_(0～∞)分别为(13.218±3.894)ng·ml~(-1)·h和(13.849±4.397)ng·ml~(-1)·h。试验制剂色甘酸钠鼻用喷雾剂相对生物利用度F为93.6%±13.8%。
结论:
1.本研究确立了以HPLC-MS/MS测定色甘酸钠生物样本中含量测定方法,该方法操作简单、灵敏度高、专属性强、重现性好,可用于人体药动学研究。
2.将单剂给药色甘酸钠后的血药浓度.时间数据用DAS2.0软件处理进行拟合,结果表明其在人体内代谢过程基本符合二室模型。多因素方差分析显示,色甘酸钠鼻用喷雾剂试验制剂和参比制剂单剂鼻腔给药双交叉试验主要药代动力学参数药物间和周期间无显著性差异。进一步双单侧t检验和(1-2α)置信区间分析个体间、周期间和剂型间符合生物等效的假设,即试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液具有生物等效性,为生物等效制剂。
Objective:
To develop a high performance liquid chromatography(HPLC) coupled with tandem mass spectrometry quantitative detection method for determining the concentrations of Sodium Cromoglycate in human plasma.And to evaluate the pharmacokinetics of naristillae and intranasal spraying agent of Sodium Cromoglycate.
Methods:
1.A C_(18) column was used to separate Sodium Cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol(involves 50%acetonitrile)(15:85) at a flow rate of 0.4mL·min~(-1).Electronic spray ionization(ESI) and multiple-reaction monitoring(MRM) was used for the determinition of Sodium Cromoglycate in human plasma.
2.20 Chinese healthy volunteers were screened according to two period cross-over design test and 4mL blood was collected before and 0.17,0.33,0.5,0.67,0.83,1.0,1.25,1.5,2.0, 3.0,4.0,5.0 h after a single oral dose Naristillae and intranasal spraying agent of Sodium Cromoglycate.The Sodium Cromoglycate in plasma was determined by HPLC-MS/MS methods and its main pharmacokinetic parameters were calculated and evaluated by DAS 2.0 software.To Evaluate bioequivalence of test preparation and reference preparation.
Results:
1.The linear range of the standard curve of Sodium Cromoglycate was 0.3～20 ng·mL~(-1), and the minimum concentration of detection was 0.3ng·mL~(-1).The extraction recovery was more than 94.1%,intra-day and inter-day RSD were less than 14.3%.
2.After a single dose of Sodium Cromoglycate,the main pharmacokinetics parameter of naristillae,intranasal spraying agent were as follows,t_(1/2)(1.815±0.535)h,(1.592±0.518) h;T_(max)(0.467±0.116)h,(0.442±0.147)h;C_(max)(9.789±4.662)ng·ml~(-1),(10.877±4.047)ng·ml~(-1);AUC_((0-1)),(11.519±3.461)ng·ml~(-1)·h,(12.629±4.228)ng·ml~(-1)·h,F 93.6%±13.8%.
Conclusions:
1.To establish a HPLC-MS/MS method for determining the concentrations of Sodium Cromoglycate in human plasma.The method is sensitive,fast and accurate.It is suitable for therapeutic drug monitoring and human pharmacokinetic studies of Sodium Cromoglycate..
2.It can be concluded that the disposition of Sodium Cromoglycate in human were fitted with three-compartment model.The test preparation and reference preparation have bioequivalence.
建立人血浆中色甘酸钠含量的HPLC-MS/MS测定方法。采用HPLC-MS/MS法测定色甘酸钠经时血浓度,进行试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液的单剂鼻腔给药双交叉两周期人体生物等效性试验,为新药报批及其临床应用提供试验依据。
方法:
1.采用高效液相分离系统。流动相为乙酸铵:甲醇(含50%乙腈)(15:85,V/V),在线脱气;流速0.4mL·min-1;柱温30℃。固定相为AGT Venusil XBP C18(250mm×4.6mm,5μm)色谱柱。采用质谱检测系统,ESI离子源,正离子模式,雾化压力40 psi,干燥气(N2)流速10 L·min-1,干燥气温度为350℃,毛细管电压4000V,多级反应监测(MRM)方式,469→263.1(色甘酸钠),447.2→327.1(普伐他汀钠)。色甘酸钠碰撞能量为20V,碎片电压为150V,EMV=600;普伐他汀钠碰撞能量为20V,碎片电压为100V,EMV=600。以普伐他汀钠为内标,测定色甘酸钠血浆浓度,
2.试验采用两周期交叉设计。健康志愿者20名,男性,按体重配对后随机分为两组,分别专人给予试验制剂色甘酸钠鼻用喷雾剂或参比制剂色甘酸钠滴鼻液,于药前和药后0.17,0.33,0.5,0.67,0.83,1.0,1.25,1.5,2.0,3.0,4.0,5.0 h取肘静脉血4ml,立即移入肝素抗凝管中,静置,5000rpm离心5min,取血浆分双份于-20℃贮存备测。一周后重复上述试验。采用HPLC/MS/MS法测定色甘酸钠经时血浓度。色甘酸钠血浓度-时间数据经《DAS 2.0》实用药代动力学计算程序处理,得试验制剂和参比制剂色甘酸钠药代动力学参数,并根据试验制剂和参比制剂色甘酸钠AUC_(0-5)计算试验制剂的相对生物利用度。同时对主要药代动力学参数进行方差分析、双单侧t检验和(1-2α)置信区间分析,评价试验制剂和参比制剂的生物等效性。
结果:
1.采用HPLC-MS/MS法测定色甘酸钠血浆药物浓度,在0.3～20 ng·mL-1范围内色甘酸钠血药浓度呈线性关系,最低定量限为0.3ng·mL-1,回收率在94.1%以上,日内日间的RSD均小于14.3%。
2.试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液主要药代动力学参数t_(1/2)分别为(1.815±0.535)h和(1.592±0.518)h,T_(max)分别为(0.467±0.116)h和(0.442±0.147)h,C_(max)分别为(9.789±4.662)ng·ml~(-1)和(10.877±4.047)ng·ml~(-1),AUC_(0.5)分别为(11.519±3.461)ng·ml~(-1)·h和(12.629±4.228)ng·ml~(-1)·h,AUC_(0～∞)分别为(13.218±3.894)ng·ml~(-1)·h和(13.849±4.397)ng·ml~(-1)·h。试验制剂色甘酸钠鼻用喷雾剂相对生物利用度F为93.6%±13.8%。
结论:
1.本研究确立了以HPLC-MS/MS测定色甘酸钠生物样本中含量测定方法,该方法操作简单、灵敏度高、专属性强、重现性好,可用于人体药动学研究。
2.将单剂给药色甘酸钠后的血药浓度.时间数据用DAS2.0软件处理进行拟合,结果表明其在人体内代谢过程基本符合二室模型。多因素方差分析显示,色甘酸钠鼻用喷雾剂试验制剂和参比制剂单剂鼻腔给药双交叉试验主要药代动力学参数药物间和周期间无显著性差异。进一步双单侧t检验和(1-2α)置信区间分析个体间、周期间和剂型间符合生物等效的假设,即试验制剂色甘酸钠鼻用喷雾剂与参比制剂色甘酸钠滴鼻液具有生物等效性,为生物等效制剂。
Objective:
To develop a high performance liquid chromatography(HPLC) coupled with tandem mass spectrometry quantitative detection method for determining the concentrations of Sodium Cromoglycate in human plasma.And to evaluate the pharmacokinetics of naristillae and intranasal spraying agent of Sodium Cromoglycate.
Methods:
1.A C_(18) column was used to separate Sodium Cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol(involves 50%acetonitrile)(15:85) at a flow rate of 0.4mL·min~(-1).Electronic spray ionization(ESI) and multiple-reaction monitoring(MRM) was used for the determinition of Sodium Cromoglycate in human plasma.
2.20 Chinese healthy volunteers were screened according to two period cross-over design test and 4mL blood was collected before and 0.17,0.33,0.5,0.67,0.83,1.0,1.25,1.5,2.0, 3.0,4.0,5.0 h after a single oral dose Naristillae and intranasal spraying agent of Sodium Cromoglycate.The Sodium Cromoglycate in plasma was determined by HPLC-MS/MS methods and its main pharmacokinetic parameters were calculated and evaluated by DAS 2.0 software.To Evaluate bioequivalence of test preparation and reference preparation.
Results:
1.The linear range of the standard curve of Sodium Cromoglycate was 0.3～20 ng·mL~(-1), and the minimum concentration of detection was 0.3ng·mL~(-1).The extraction recovery was more than 94.1%,intra-day and inter-day RSD were less than 14.3%.
2.After a single dose of Sodium Cromoglycate,the main pharmacokinetics parameter of naristillae,intranasal spraying agent were as follows,t_(1/2)(1.815±0.535)h,(1.592±0.518) h;T_(max)(0.467±0.116)h,(0.442±0.147)h;C_(max)(9.789±4.662)ng·ml~(-1),(10.877±4.047)ng·ml~(-1);AUC_((0-1)),(11.519±3.461)ng·ml~(-1)·h,(12.629±4.228)ng·ml~(-1)·h,F 93.6%±13.8%.
Conclusions:
1.To establish a HPLC-MS/MS method for determining the concentrations of Sodium Cromoglycate in human plasma.The method is sensitive,fast and accurate.It is suitable for therapeutic drug monitoring and human pharmacokinetic studies of Sodium Cromoglycate..
2.It can be concluded that the disposition of Sodium Cromoglycate in human were fitted with three-compartment model.The test preparation and reference preparation have bioequivalence.
引文
1.邓树海,刘兆平主编。药物动力学-理论与实践[M]。第一版,北京:人民卫生出版社,1998:1-9
2.药品临床试验管理规范[M]。北京:中国医药科技出版社,2000:1-112
3.中华医学会编。临床技术操作规范(护理分册)[M]。北京:人民军医出版社,2007:122-123
4.陈著声,介绍手压喷雾式鼻药瓶[J]。临床耳鼻咽喉科杂志,2000 14(3):111
5.Guo Yanrong,Meng Daping,Lu Me(?).Quality Control of Sodium Cromoglicate Nasal Drops.China Pharmaceutical.2004,13(3):56-57
6.HUANG Tao-min,YANG Hong,LIU Zheng.Determination of the Content of Dexamethasone Sodium Phosphate and Sod ium Cromoglycate by HPLC.Fudan Univ J Med Sci.2005,32(4):484-485
7.Osama A.Aswania,Sarah A.Corlett,Henry Chrystyn.Development and validation of an ion-pair liquid chromatographic method for the quantitation of sodium cromoglycate in urine following inhalation.J Chromatography B.1997,690:373-378
8.Guo Yanmng,Lu Me.Determination of Sodium Cromoglicate Nasal Drops by RP-HPLC.China Pharmacist:2004,7(5):360-361
9.Osama A.Aswania and Corlett,Henry Chrystyn.Validation of a high performance liquid chromatography assay for urinary nedocromil sodium following oral and inhaled administration.J Chromatography B.1998,718:290-295
10.ML Ozoux,J Girault,JM MalgouyatO Pasquier.Determination of sodium cromoglycate in human plasma by liquid chromatography-mass spectrometry in the turbo ion spray mode.J Chromatography B.2001,765:179-185
11.黄滔敏,杨鸿,刘振,沙云菲,段更利。高效液相色谱法测定色甘酸钠地塞米松滴鼻液含量[J]。复旦学报(医学版),2005,32(4):484-485
12.Aswania OA,Corlett SA,Chrystyn H,etal.Development and validation of an ion-pair liquid chromatographic method for the quantitation of sodium cromoglycate in urine following inhalation.Journal of Chromatography B:Biomedical Application,1997,690(1):373
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[14]Aberg N,Aberg B,Alestig K.The effect of inhaled and intranasal sidium cromoglycate on symptoms of upper respiratory tract infection.Clin Exp Allergy,1996,26(9):1045
[15] Businco L, Meglio P, Amato G, etal. Evaluation of the efficacy of oral cromolyon sodium or an oligoantigenic diet in children with atopic dermatitis:a multicenter study of 1085 patients. J Investig Allergol Clin Immunol, 1996, 6(2):103
2.药品临床试验管理规范[M]。北京:中国医药科技出版社,2000:1-112
3.中华医学会编。临床技术操作规范(护理分册)[M]。北京:人民军医出版社,2007:122-123
4.陈著声,介绍手压喷雾式鼻药瓶[J]。临床耳鼻咽喉科杂志,2000 14(3):111
5.Guo Yanrong,Meng Daping,Lu Me(?).Quality Control of Sodium Cromoglicate Nasal Drops.China Pharmaceutical.2004,13(3):56-57
6.HUANG Tao-min,YANG Hong,LIU Zheng.Determination of the Content of Dexamethasone Sodium Phosphate and Sod ium Cromoglycate by HPLC.Fudan Univ J Med Sci.2005,32(4):484-485
7.Osama A.Aswania,Sarah A.Corlett,Henry Chrystyn.Development and validation of an ion-pair liquid chromatographic method for the quantitation of sodium cromoglycate in urine following inhalation.J Chromatography B.1997,690:373-378
8.Guo Yanmng,Lu Me.Determination of Sodium Cromoglicate Nasal Drops by RP-HPLC.China Pharmacist:2004,7(5):360-361
9.Osama A.Aswania and Corlett,Henry Chrystyn.Validation of a high performance liquid chromatography assay for urinary nedocromil sodium following oral and inhaled administration.J Chromatography B.1998,718:290-295
10.ML Ozoux,J Girault,JM MalgouyatO Pasquier.Determination of sodium cromoglycate in human plasma by liquid chromatography-mass spectrometry in the turbo ion spray mode.J Chromatography B.2001,765:179-185
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