兽用药物生物药剂学分类系统(BCS)的研究进展
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摘要
生物药剂学分类系统(Biopharmaceutics classification system,BCS)是根据药物的溶解性与渗透性进行分类的一种科学框架,已被欧洲药品管理局(EMEA)、美国食品药品管理局(FDA)、世界卫生组织(WHO)等认可并用作仿制药物生物等效性豁免的判断依据。随着人药BCS的发展,一些研究人员尝试将BCS引入到兽药领域,以指导兽用仿制药的开发和管理。针对BCS分类标准和概念、BCS在人药研发和管理中的应用、兽药BCS发展现状及其面临的挑战进行了总结,以期为兽药BCS分类系统的发展提供有益的借鉴和指导,为新兽药的开发和老药的改造提供参考。
Biopharmaceutics classification system( BCS) based on the solubility and permeability of drug is a scientific frame. It has been applied to judge the bioequivalence exemption of generic drug by European Medicines Agency( EMEA),Food and Drug Administration( FDA) and the World Health Organization( WHO),With the development of BCS,some researchers attempt to introduce it into the field of veterinary drug to guide the development and management of generics. This review mainly summarizes the standard and concept of BCS classification,the application of BCS in the research and administration of human drug,the BCS development status and challenges of veterinary drug BCS,and then providing some useful references and strategies for the development of veterinary drug BCS.
Biopharmaceutics classification system( BCS) based on the solubility and permeability of drug is a scientific frame. It has been applied to judge the bioequivalence exemption of generic drug by European Medicines Agency( EMEA),Food and Drug Administration( FDA) and the World Health Organization( WHO),With the development of BCS,some researchers attempt to introduce it into the field of veterinary drug to guide the development and management of generics. This review mainly summarizes the standard and concept of BCS classification,the application of BCS in the research and administration of human drug,the BCS development status and challenges of veterinary drug BCS,and then providing some useful references and strategies for the development of veterinary drug BCS.
引文
[1]Amidon G L,Lennemas H,Shah V P,et al.A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro drug product dissolution and in vivo bioavailability[J].Pharmaceutical Research,1995,12(3):413-420.
[2]张宁,平其能.生物药剂分类系统(BCS)及应用进展介绍[J].中国新药杂志,2008,17(19):1655-1658.Zhang N,Ping Q N.Introduction of Biopharmaceutics Classif ication System(BCS)and its applica tion progress[J].Chinese Journal of New Drugs,2008,17(19):1655-1658.
[3]许鸣镝,王琳,王铁松,等.生物药剂学分类系统差异比较及应用探讨[J].中国药学杂志,2016,51(10):777-779.Xu M D,Wang L,Wang T S,et al.Comparison of different Biopharmaceutics Classification Systems(BCS)and discussion of its application[J].Chinese Pharmaceutical Journal,2016,51(10):777-779.
[4]Lipinski C A,Lombardo F,Dominy B W,et al.Experimental and computational approaches to estimate solubility and permeability in durg discovery and development settings[J].Adv Drug Del Rev,1997,23(1/3):3.
[5]斯陆勤,黄建耿,李高.生物药剂学分类系统及其应用(下)[J].中国药师,2008,11(2):163-166.Si L Q,Huang J G,Li G.Biopharmacology classification system and its application(Part 2)[J].China Pharmacist,2008,11(2):163-166.
[6]叶雯,王永禄,李学明.生物药剂学分类系统在难溶性药物处方设计中的应用[J].中国医院药学杂志,2013,33(7):568-570.Ye W,Wang Y L,Li X M.Application of Biopharmacology classification system in the design of refractory drug prescriptions[J].Chinese Journal of Hospital Pharmacy,2013,33(7):568-570.
[7]张宁,平其能.口服仿制药生物等效豁免体系构建探讨[J].中国临床药理学杂志,2009,25(6):543-546.Zhang N,Ping Q N.Discussion about the construction of biowaiver system for oral generics[J].The Chinese Journal of Clinical Pharmacology,2009,25(6):543-546.
[8]王玲,陈泽.浅谈世界卫生组织的药品生物等效性豁免[J].药学与临床研究,2012,20(6):560-562.Wang L,Chen Z.Brief discussion on medicine biowaiver of World Health Organization[J].Pharmaceutical and Clinical Research,2012,20(6):560-562.
[9]Kasim N A,Whitehouse M,Ramachandran C,et al.Molecular properties of WHO essential drugs and provisional biopharmaceutical classification[J].Molecular Pharmaceutics,2004,1(1):85-96.
[10]Lindenberg M,Kopp S,Dressman J L.Classification of orally administered drugs on the wor Id Health Organization Model list of Essential Medidnes according to the biopharmaceutics classifieation system[J].Eur J Pharm Biopharm,2004,58(2):265-278.
[11]WHO.Technical Report Series No.937;Annex 7:Multisource(generic)pharmaceutical products:guidelineson registration requirements to establish interchange ability;Annex 8:Proposal towaive invivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release,solid oral dosage forms[S].
[12]FDA.Waiver of In Vivo Bioavailability and Bioequivalence Studies for ImmediateRelease Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System[S].
[13]Benet L Z,Wu C,Custodio J M.Predicting drug absorption and the effects of food on oral bioavailability[J].Bulletin Technique Gattefosse,2006,(99):9-16.
[14]刘曼,张文萍,张丽娜,等.基于生物药剂学分类系统的口服固体速释制剂生物豁免[J].中国新药杂志,2016,25(5):532-542.Liu M,Zhang W P,Zhang L N,et al.Biowaiver for immediaterelease solid oral dosage formsbased on biopharmaceutics classification system[J].Chinese Journal of New Drugs,2016,25(5):532-542.
[15]屠锡德.药剂学[M].第3版.北京:人民卫生出版社,2002:1111-1112.Tu X D.Pharmaceutics[M].Third Edition.Beijing:People's Medical Publishing House,2002:1111-1112.
[16]EMEA.Note for Guidance On Investigation Of Bioavailability And Bioequivalence CPMP/EWP/QWP/1401/98 Rev1,AppendixⅢ[S].
[17]刘维,杨丽,闫婷婷,等.基于药物体内处置的生物药剂学分类系统在预测药物体内过程中的应用[J].中国新药杂志,2014,23(16):1924-1930.Liu W,Yang L,Yan T T,et al.Appication of biopharmaceutics drug dispositionclassificationsystem in predicting disposition of drugs in vivo[J].Chinese Journal of New Drugs,2014,23(16):1924-1930.
[18]Dressman J B,Amidon G L,Reppas C,et al.Dissolution Testing as a Prognostic Tool for Oral Drug Absorption:Immediate Release Dosage Forms[J].Pharm.Res,1998,15:11-22.
[19]Chiou W L,Jeong H Y,Sang M C,et al.Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of43 drugs in humans[J].Pharmaceutical Research,2000,17(2):135-140.
[20]Martinez M,Amidon G,Clarke L,et al.Applying the biopharmaceutics classification system toveterinary pharmaceutical products[J].Part II.Physiological considerations.Adv Drug Deliv Rev,2002,54(6):825-850.
[21]Martinez M N,Papich M G.Factors influencing the gastric residence of dosage forms in dogs[J].J Pharm Sci,2009,98(3):844-860.
[22]Martinez M,Fahmy R.Establishing solubility criteria for veterinary species[J].J Vet Pharmacol Ther,2012,35(S1):81-86.
[23]Papich M G,Martinez M N.Applying Biopharmaceutical Classification System(BCS)Criteria to Predict Oral Absorption of Drugs in Dogs:Challenges and Pitfalls[J].The AAPS Journal,2015,17(4):948-964.
[24]Martinez M N,Papich M G,Riviere J E.Veterinary application of in vitro dissolution data and the Biopharmaceutics Classification System[J].Pharmacopeial Forum,2004,30(6):2295-2302.
[25]Gardner N,Haresign W,Spiller R,et al.Development and validation of a pig model for colon-specific drug delivery[J].J.Pharm.Pharmacol,1996,48(7):689-693.
[26]Davis S S,Illum L,Hinchcliffe M.Gastrointestinal transit of dosage forms in the pig[J].Journal of Pharmacy&Pharmacology,2001,53(1):33-39.
[27]Martinez M,Papich M.Drug solubility classification in the dog[J].J Vet Pharmacol Ther,2012,35(S1):87-91.
[28]Estell R E,Galyean M L.Relationship of rumen fluid dilution rate to rumen fermentation and dietary characteristics of beefsteers[J].J Anim Sci,1985,60(4):1061-1071.
[29]Tolle-Sander,Polli J E.Method considerations for Caco-2 permeability assessment in the biopharmaceutics classification system[J].Pharmacopoeial Forum,2002,28(1):164-168.
[30]Leon Shargel,Susanna Wu-Pong Andrew B.C.Yu.Applied Biopharmaceutics&Pharmacokinetics[M].李安良,吴艳芬.译.北京:化学工业出版社,2006:272.Leon Shargel,Susanna Wu-Pong Andrew B.C.Yu.Applied Biopharmaceutics﹠Pharmacokinetics[M].Li A L,Wu Y F.main interpreter.Bei Jing:Chemical Industry Pres,2006:272.
[31]张生芳,李娟.药物渗透与吸收评价方法的研究进展[J].亚太传统医药,2010,6(5):129-131.Zhang S F,Li J.Progress in evaluation of drug penetration and absorption[J].Asia-Pacific Traditional Medicine,2010,6(5):129-131.
[32]何承华,张振海,王舒,等.芹菜素在体肠吸收动力学的研究[J].中国中药杂志,2013,38(9):1416-1420.He C H,Zhang Z H,Wang S,et al.Study on intestinal absorption kinetics of apigenin in rats[J].China Journal of Chinese Materia Medica,2013,38(9):1416-1420.
[33]Smart J D,Kellaway I W.Pharmaceutical factors influencing the rate of gastrointestinal transit in an animal model[J].International Journal of Pharmaceutics,1989,53(1):79-83.
[34]王显著.时滞与p H敏感结合型结肠靶向制剂-盐酸左氧氟沙星结肠靶向小丸的研制[D].重庆:重庆医科大学,2004.Wang X Z.Time-lag combined p H-snsitive drug conlon-specific delivery system-The study on preparing hydrochloric levofloxacin oral colon-specific delivery pellets[D].Chong Qing:Chong Qing Medical University,2004.
[35]Dressman J B.Comparison of canine and human gastrointestinal physiology[J].Pharmaceutical Research,1986,3(3):123.
[36]Kabanda L,Lefebvre R A,Van Bree H J,et al.In Vitro and in Vivo Evaluation in Dogs and Pigs of a Hydrophilic Matrix Containing Propylthiouracil[J].Pharmaceutical Research,1994,11(11):1663-1668.
[37]Murata S,Ueda S,Shimojo F,et al.In vivo performance of timecontrolled explosion system(TES)in GI physiology regulated dogs[J].International Journal of Pharmaceutics,1998,161(2):161-168.
[38]Jantratid E,De MV,Ronda E,et al.Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form[J].European Journal of Pharmaceutical Sciences,2009,37(3/4):434-441.
[39]Uchida T,Kawata M,Goto S.In vivo evaluation of ethylcellulose microcapsules containing ampicillin using rabbits,beagle dogs and humans[J].Pharmacobiodyn,1986,(8):631-637.
[40]Aoyagi N,Ogata H,Kaniwa N,et al.Bioavailability of indomethacin capsules in humans.I:Bioavailability and effects of gastric acidity[J].International Journal of Clinical Pharmacology,Theraoy and Toxicology,1985,23(9):469-474.
[41]Oberle R L,Amidon G L.The influence of variable gastricemptying and intestinal transit rates on the plasma level curve of cimetidine;An explanation for the double peakphenomenon[J].J Pharmacokinet Biopharm,1987,15:529.
[42]Willmann S,Thelen K C,Dressman J B,et al.Mechanism-based prediction of particlesize-dependent dissolution and absorption:cilostazol pharmacokinetics in dogs[J].European European journal of pharmaceutics and biopharmaceutics,2010,76(1):83-94.
[43]Vertzoni M,Dressman J,Butler J,et al.Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds[J].European Journal of Pharmaceutics and Biopharmaceutics,2005,60(3):413-417.
[44]Baggot J D,Brown S A.Basis for selection of the dosage form.Development and Formulation of Veterinary Dosage Forms and Edition,Marcel Dekker,New York,1998:7-143.
[45]徐蕾,杨中林.大鼠在体单向灌流法研究橙皮苷肠道吸收性质[J].中国药学杂志,2009,44(8):594-597.Xu L,Yang Z L.Intestinal absorption properties of hesperidin by single pass perfusion model on rats[J].Chinese Pharmaceutical Journal,2009,44(8):594-597.
[46]臧洪梅.改良在体单向灌流实验探讨头孢氨苄大鼠小肠吸收机制[J].药学与临床研究,2008,6(16):450-453.Zang H M.In situ rats single pass perfusion intestinal absorption of cefalexin by mass balance analysis[J].Pharmaceutical and Clinical Research,2008,6(16):450-453.
[47]高杨,耿立冬.FDA,WHO和EMA关于基于生物药剂学分类系统的生物等效性豁免指导原则的比较[J].中国新药杂志,2012,21(24):2861-2869.Gao Y,Geng L D.Comparison and discussion of FDA,WHO and EMA guidelineson BCS-based biowaiver[J].Chinese Journal of New Drugs,2012,21(24):2861-2869.
[2]张宁,平其能.生物药剂分类系统(BCS)及应用进展介绍[J].中国新药杂志,2008,17(19):1655-1658.Zhang N,Ping Q N.Introduction of Biopharmaceutics Classif ication System(BCS)and its applica tion progress[J].Chinese Journal of New Drugs,2008,17(19):1655-1658.
[3]许鸣镝,王琳,王铁松,等.生物药剂学分类系统差异比较及应用探讨[J].中国药学杂志,2016,51(10):777-779.Xu M D,Wang L,Wang T S,et al.Comparison of different Biopharmaceutics Classification Systems(BCS)and discussion of its application[J].Chinese Pharmaceutical Journal,2016,51(10):777-779.
[4]Lipinski C A,Lombardo F,Dominy B W,et al.Experimental and computational approaches to estimate solubility and permeability in durg discovery and development settings[J].Adv Drug Del Rev,1997,23(1/3):3.
[5]斯陆勤,黄建耿,李高.生物药剂学分类系统及其应用(下)[J].中国药师,2008,11(2):163-166.Si L Q,Huang J G,Li G.Biopharmacology classification system and its application(Part 2)[J].China Pharmacist,2008,11(2):163-166.
[6]叶雯,王永禄,李学明.生物药剂学分类系统在难溶性药物处方设计中的应用[J].中国医院药学杂志,2013,33(7):568-570.Ye W,Wang Y L,Li X M.Application of Biopharmacology classification system in the design of refractory drug prescriptions[J].Chinese Journal of Hospital Pharmacy,2013,33(7):568-570.
[7]张宁,平其能.口服仿制药生物等效豁免体系构建探讨[J].中国临床药理学杂志,2009,25(6):543-546.Zhang N,Ping Q N.Discussion about the construction of biowaiver system for oral generics[J].The Chinese Journal of Clinical Pharmacology,2009,25(6):543-546.
[8]王玲,陈泽.浅谈世界卫生组织的药品生物等效性豁免[J].药学与临床研究,2012,20(6):560-562.Wang L,Chen Z.Brief discussion on medicine biowaiver of World Health Organization[J].Pharmaceutical and Clinical Research,2012,20(6):560-562.
[9]Kasim N A,Whitehouse M,Ramachandran C,et al.Molecular properties of WHO essential drugs and provisional biopharmaceutical classification[J].Molecular Pharmaceutics,2004,1(1):85-96.
[10]Lindenberg M,Kopp S,Dressman J L.Classification of orally administered drugs on the wor Id Health Organization Model list of Essential Medidnes according to the biopharmaceutics classifieation system[J].Eur J Pharm Biopharm,2004,58(2):265-278.
[11]WHO.Technical Report Series No.937;Annex 7:Multisource(generic)pharmaceutical products:guidelineson registration requirements to establish interchange ability;Annex 8:Proposal towaive invivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release,solid oral dosage forms[S].
[12]FDA.Waiver of In Vivo Bioavailability and Bioequivalence Studies for ImmediateRelease Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System[S].
[13]Benet L Z,Wu C,Custodio J M.Predicting drug absorption and the effects of food on oral bioavailability[J].Bulletin Technique Gattefosse,2006,(99):9-16.
[14]刘曼,张文萍,张丽娜,等.基于生物药剂学分类系统的口服固体速释制剂生物豁免[J].中国新药杂志,2016,25(5):532-542.Liu M,Zhang W P,Zhang L N,et al.Biowaiver for immediaterelease solid oral dosage formsbased on biopharmaceutics classification system[J].Chinese Journal of New Drugs,2016,25(5):532-542.
[15]屠锡德.药剂学[M].第3版.北京:人民卫生出版社,2002:1111-1112.Tu X D.Pharmaceutics[M].Third Edition.Beijing:People's Medical Publishing House,2002:1111-1112.
[16]EMEA.Note for Guidance On Investigation Of Bioavailability And Bioequivalence CPMP/EWP/QWP/1401/98 Rev1,AppendixⅢ[S].
[17]刘维,杨丽,闫婷婷,等.基于药物体内处置的生物药剂学分类系统在预测药物体内过程中的应用[J].中国新药杂志,2014,23(16):1924-1930.Liu W,Yang L,Yan T T,et al.Appication of biopharmaceutics drug dispositionclassificationsystem in predicting disposition of drugs in vivo[J].Chinese Journal of New Drugs,2014,23(16):1924-1930.
[18]Dressman J B,Amidon G L,Reppas C,et al.Dissolution Testing as a Prognostic Tool for Oral Drug Absorption:Immediate Release Dosage Forms[J].Pharm.Res,1998,15:11-22.
[19]Chiou W L,Jeong H Y,Sang M C,et al.Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of43 drugs in humans[J].Pharmaceutical Research,2000,17(2):135-140.
[20]Martinez M,Amidon G,Clarke L,et al.Applying the biopharmaceutics classification system toveterinary pharmaceutical products[J].Part II.Physiological considerations.Adv Drug Deliv Rev,2002,54(6):825-850.
[21]Martinez M N,Papich M G.Factors influencing the gastric residence of dosage forms in dogs[J].J Pharm Sci,2009,98(3):844-860.
[22]Martinez M,Fahmy R.Establishing solubility criteria for veterinary species[J].J Vet Pharmacol Ther,2012,35(S1):81-86.
[23]Papich M G,Martinez M N.Applying Biopharmaceutical Classification System(BCS)Criteria to Predict Oral Absorption of Drugs in Dogs:Challenges and Pitfalls[J].The AAPS Journal,2015,17(4):948-964.
[24]Martinez M N,Papich M G,Riviere J E.Veterinary application of in vitro dissolution data and the Biopharmaceutics Classification System[J].Pharmacopeial Forum,2004,30(6):2295-2302.
[25]Gardner N,Haresign W,Spiller R,et al.Development and validation of a pig model for colon-specific drug delivery[J].J.Pharm.Pharmacol,1996,48(7):689-693.
[26]Davis S S,Illum L,Hinchcliffe M.Gastrointestinal transit of dosage forms in the pig[J].Journal of Pharmacy&Pharmacology,2001,53(1):33-39.
[27]Martinez M,Papich M.Drug solubility classification in the dog[J].J Vet Pharmacol Ther,2012,35(S1):87-91.
[28]Estell R E,Galyean M L.Relationship of rumen fluid dilution rate to rumen fermentation and dietary characteristics of beefsteers[J].J Anim Sci,1985,60(4):1061-1071.
[29]Tolle-Sander,Polli J E.Method considerations for Caco-2 permeability assessment in the biopharmaceutics classification system[J].Pharmacopoeial Forum,2002,28(1):164-168.
[30]Leon Shargel,Susanna Wu-Pong Andrew B.C.Yu.Applied Biopharmaceutics&Pharmacokinetics[M].李安良,吴艳芬.译.北京:化学工业出版社,2006:272.Leon Shargel,Susanna Wu-Pong Andrew B.C.Yu.Applied Biopharmaceutics﹠Pharmacokinetics[M].Li A L,Wu Y F.main interpreter.Bei Jing:Chemical Industry Pres,2006:272.
[31]张生芳,李娟.药物渗透与吸收评价方法的研究进展[J].亚太传统医药,2010,6(5):129-131.Zhang S F,Li J.Progress in evaluation of drug penetration and absorption[J].Asia-Pacific Traditional Medicine,2010,6(5):129-131.
[32]何承华,张振海,王舒,等.芹菜素在体肠吸收动力学的研究[J].中国中药杂志,2013,38(9):1416-1420.He C H,Zhang Z H,Wang S,et al.Study on intestinal absorption kinetics of apigenin in rats[J].China Journal of Chinese Materia Medica,2013,38(9):1416-1420.
[33]Smart J D,Kellaway I W.Pharmaceutical factors influencing the rate of gastrointestinal transit in an animal model[J].International Journal of Pharmaceutics,1989,53(1):79-83.
[34]王显著.时滞与p H敏感结合型结肠靶向制剂-盐酸左氧氟沙星结肠靶向小丸的研制[D].重庆:重庆医科大学,2004.Wang X Z.Time-lag combined p H-snsitive drug conlon-specific delivery system-The study on preparing hydrochloric levofloxacin oral colon-specific delivery pellets[D].Chong Qing:Chong Qing Medical University,2004.
[35]Dressman J B.Comparison of canine and human gastrointestinal physiology[J].Pharmaceutical Research,1986,3(3):123.
[36]Kabanda L,Lefebvre R A,Van Bree H J,et al.In Vitro and in Vivo Evaluation in Dogs and Pigs of a Hydrophilic Matrix Containing Propylthiouracil[J].Pharmaceutical Research,1994,11(11):1663-1668.
[37]Murata S,Ueda S,Shimojo F,et al.In vivo performance of timecontrolled explosion system(TES)in GI physiology regulated dogs[J].International Journal of Pharmaceutics,1998,161(2):161-168.
[38]Jantratid E,De MV,Ronda E,et al.Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form[J].European Journal of Pharmaceutical Sciences,2009,37(3/4):434-441.
[39]Uchida T,Kawata M,Goto S.In vivo evaluation of ethylcellulose microcapsules containing ampicillin using rabbits,beagle dogs and humans[J].Pharmacobiodyn,1986,(8):631-637.
[40]Aoyagi N,Ogata H,Kaniwa N,et al.Bioavailability of indomethacin capsules in humans.I:Bioavailability and effects of gastric acidity[J].International Journal of Clinical Pharmacology,Theraoy and Toxicology,1985,23(9):469-474.
[41]Oberle R L,Amidon G L.The influence of variable gastricemptying and intestinal transit rates on the plasma level curve of cimetidine;An explanation for the double peakphenomenon[J].J Pharmacokinet Biopharm,1987,15:529.
[42]Willmann S,Thelen K C,Dressman J B,et al.Mechanism-based prediction of particlesize-dependent dissolution and absorption:cilostazol pharmacokinetics in dogs[J].European European journal of pharmaceutics and biopharmaceutics,2010,76(1):83-94.
[43]Vertzoni M,Dressman J,Butler J,et al.Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds[J].European Journal of Pharmaceutics and Biopharmaceutics,2005,60(3):413-417.
[44]Baggot J D,Brown S A.Basis for selection of the dosage form.Development and Formulation of Veterinary Dosage Forms and Edition,Marcel Dekker,New York,1998:7-143.
[45]徐蕾,杨中林.大鼠在体单向灌流法研究橙皮苷肠道吸收性质[J].中国药学杂志,2009,44(8):594-597.Xu L,Yang Z L.Intestinal absorption properties of hesperidin by single pass perfusion model on rats[J].Chinese Pharmaceutical Journal,2009,44(8):594-597.
[46]臧洪梅.改良在体单向灌流实验探讨头孢氨苄大鼠小肠吸收机制[J].药学与临床研究,2008,6(16):450-453.Zang H M.In situ rats single pass perfusion intestinal absorption of cefalexin by mass balance analysis[J].Pharmaceutical and Clinical Research,2008,6(16):450-453.
[47]高杨,耿立冬.FDA,WHO和EMA关于基于生物药剂学分类系统的生物等效性豁免指导原则的比较[J].中国新药杂志,2012,21(24):2861-2869.Gao Y,Geng L D.Comparison and discussion of FDA,WHO and EMA guidelineson BCS-based biowaiver[J].Chinese Journal of New Drugs,2012,21(24):2861-2869.