格列美脲片的体外溶出行为研究
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摘要
目的比较研究格列美脲片仿制药与参比制剂的溶出行为,利用计算机模拟技术对两种制剂进行虚拟生物等效性评价。方法通过测定格列美脲在不同pH介质中的溶解性与平行人工膜(PAMPA)渗透性,分析研究了药物的生物药剂学特征;绘制药物制剂在多种介质中的溶出曲线,比较研究格列美脲片仿制药与参比制剂的溶出行为一致性;基于制剂的溶出曲线数据,利用计算机技术模拟研究格列美脲片体外溶出与体内吸收的相关性,并对两种制剂进行虚拟生物等效性评价。结果格列美脲的溶解性随pH值的升高而增大;渗透性随pH值的升高而降低;格列美脲片在pH 1.2与pH 5.0的介质中溶出小于10%;在pH 6.0～7.4、Fa SSIF与Fe SSIF介质中主成分有不同程度的溶出(20%～90%);格列美脲片在FaSSIF中的体外溶出与体内吸收之间显示出较高的相关性。结论格列美脲的生物药剂学分类为BCSⅡ类,即低溶解度,高渗透性药物;格列美脲片的溶出量随着介质pH值的升高而增多,溶出速率随着介质pH值的升高而加快。制剂在pH 1.2、pH 6.0、pH 6.8与pH 7.4介质中的溶出曲线可作为格列美脲片的特征溶出曲线。仿制药与参比制剂体外溶出行为相似,虚拟生物等效性研究结果显示,两种制剂生物等效(n=24)。本实验可以为药物制剂的处方筛选、生物药剂学分类判定与生物等效性风险评价提供参考。
OBJECTIVE To study and compare the dissolution behaviors of glimepiride tablets from two manufacturers,and investigate the correlation between dissolution and absorption. METHODS The solubility and permeability of glimepiride in different pH media were determined,and the biopharmaceutical characteristics of glimepiride tablets were studied and analyzed. The dissolution curves of glimepiride tablets in different media were plotted by the second dissolution method. The dissolution behaviors of glimepiride tablets from two manufacturers were studied and compared. Based on the data of dissolution curves in vitro,the correlation between dissolution and absorption of glimepiride tablets was studied by computer simulation. The virtual bioequivalence study of the two preparations was evaluated in silico. RESULTS The solubility of glimepiride increased with the increase of pH value; the permeability decreased with the increase of pH value; the dissolution of glimepiride tablets was less than 10 % in the media of pH 1. 2 and pH 5. 0; the dissolution of principal components in the media of pH 6. 0-7. 4,FaSSIF and FeSSIF ranged from 20 % to 90 %; the dissolution and absorption of glimepiride tablets in FaSSIF showed high correlation. CONCLUSION Glimepiride is classified as a BCS Ⅱ class drug( low solubility and high permeability drugs). The dissolution amount and rate of glimepiride tablets increase with the increase of pH value of the medium. The dissolution curves of glimepiride tablets in media of pH 1. 2,pH 6. 0,pH 6. 8 and pH 7. 4 could be used as the characteristic dissolution curves of the preparation. The reference preparation A and generic preparation B of glimepiride tablets are similar in dissolution behavior and shows bioequivalence in the virtual bioequivalence study( n = 24). This study can provide reference for drug formulation screening,biopharmaceuticals classification determination and bioequivalence risk assessment.
OBJECTIVE To study and compare the dissolution behaviors of glimepiride tablets from two manufacturers,and investigate the correlation between dissolution and absorption. METHODS The solubility and permeability of glimepiride in different pH media were determined,and the biopharmaceutical characteristics of glimepiride tablets were studied and analyzed. The dissolution curves of glimepiride tablets in different media were plotted by the second dissolution method. The dissolution behaviors of glimepiride tablets from two manufacturers were studied and compared. Based on the data of dissolution curves in vitro,the correlation between dissolution and absorption of glimepiride tablets was studied by computer simulation. The virtual bioequivalence study of the two preparations was evaluated in silico. RESULTS The solubility of glimepiride increased with the increase of pH value; the permeability decreased with the increase of pH value; the dissolution of glimepiride tablets was less than 10 % in the media of pH 1. 2 and pH 5. 0; the dissolution of principal components in the media of pH 6. 0-7. 4,FaSSIF and FeSSIF ranged from 20 % to 90 %; the dissolution and absorption of glimepiride tablets in FaSSIF showed high correlation. CONCLUSION Glimepiride is classified as a BCS Ⅱ class drug( low solubility and high permeability drugs). The dissolution amount and rate of glimepiride tablets increase with the increase of pH value of the medium. The dissolution curves of glimepiride tablets in media of pH 1. 2,pH 6. 0,pH 6. 8 and pH 7. 4 could be used as the characteristic dissolution curves of the preparation. The reference preparation A and generic preparation B of glimepiride tablets are similar in dissolution behavior and shows bioequivalence in the virtual bioequivalence study( n = 24). This study can provide reference for drug formulation screening,biopharmaceuticals classification determination and bioequivalence risk assessment.
引文
[1] ROYAL H,VIVIAN G. Dissolution Technology[M]. Beijing:China Medical Science and Technology Press,2007.
[2] DRESSMAN J,AMIDON G. Dissolution testing as a prognostic tool for oral drug absorption:immediate release dosage forms[J].Pharm Res,1998(15):11-22.
[3] DRESSMAN J,AMIDON G,FLEISHER D. Absorption potential:Estimating the fraction absorbed for orally administered compounds[J]. J Pharm Sci,1985,74(5):588-589.
[4] AVDEEF A. The rise of PAMPA[J]. Expert Opin,2005,1(2):325-342.
[5] HIDALGO I J. Assessing the absorption of new pharmaceuticals[J]. Curr Top Med Chem,2001,1(5):385-401.
[6] ENIKOBORBAS. The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations[J]. Eur J Pharm,2018,114(3):310-317.
[7] AVDEEF A,TSINMAN O. PAMPA-a drug absorption in vitro model 13. Chemical selectivity due to membrane hydrogen bonding:in combo comparisons of HDM-,DOPC-,and DS-PAMPA models[J]. Eur J Pharm,2006,28(1-2):43-50.
[8] BRISCOE V J,GRIFFITH M L,DAVIS S N. The role of glimepiride in the treatment of type 2 diabetes mellitus[J]. Expert Opin Drug Metab Toxicol,2010,6(2):2 2 5-2 2 7.
[9] FRICK A,MLLER H,WIRBITZKI E. Biopharmaceutical characterization of oral immediate release drug products. In vitro/in vivo comparison of phenoxymethylpenicillin potassium,glimepiride and levofloxacin[J]. Eur J Pharm Biopharm,1998,46(3):305-311.
[10] BADIAN M,KORN A,LEHR K H,et al. Absolute bioavailability of glimepiride(Amaryl)after oral administration[J].Drug Metab Drug Interact,1994,11(4):331-340.
[11] The guideline for the dissolution test of ordinary oral solid preparations and the technical guideline for the stability of chemical drugs(materials and preparations)[EB/OL]. China Food and Drug Administration,2015,No. 3,Attachment 1[2015-02-05]. http://samr. cfda. gov. cn/WS01/CL1036/114286. html.
[12] Ch. P(2015)VolⅣ(中国药典2015年版.四部)[S]. 2015:121-124.
[13] YU L X,LIPKA E,CRISON J R,et al. Transport approaches to the biopharmaceutical design of oral drug delivery systems:prediction of intestinal absorption[J]. Adv Drug Deliv Rev,1996,19(3):359-376.
[14] BADIAN M,KORN A,LEHR K H,et al. Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride(Amaryl)after intravenous administration[J]. Drug Metab Drug Interact,1996,13(1):69-85.
[15] The information form of Glimepiride(AmarylR)[EB/OL]. Japan Pharmaceuticals and Medical Device Agency,2017,Edition22[2017-03] http://www. info. pmda. go. jp/go/interview/1/780069_3961008F4070_1_022_1F.
[16] AMIDON G L,LENNERNAS 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].Aaps J,2014,16(5):894-898.
[17] AMIDON G,SHAH V. A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro,drug product dissolution and in vivo,bioavailability[J]. Pharm Res,1995,12(3):413-420.
[18] LENNERNAS H. Intestinal permeability and its relevance for absorption and elimination[J]. Xenobiotica,2007,37(10-11):1015-1051.
[19] ANO R,KIMURA Y,SHIMA M,et al. Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes:application to prediction of Caco-2 cell permeability[J]. Bioorgani Med Chem,2004,12(1):257-264.
[20] KERNS E H,DI L,PETUSKY S,et al. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery[J]. J Pharm Sci,2010,93(6):1440-1453.
[21] WALTER E,JANICH S,ROESSLER B J,et al. HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium:in vitro-in vivo correlation with permeability data from rats and humans[J]. J Pharm Sci,1996,85(10):1070-1076.
[22] KRISHNA R,YU L. Biopharmaceutics Applications in Drug Development[M]. Beijing:Peking University Medical Press,2012.
[23] FU H,WANG L,ZHANG Z. Dissolution and permeability behavior of diclofenac sodium enteric-coated tablets in-vitro[J].Chin Pharm J(中国药学杂志),2018,53(20):1778-1784.
[24] FU H,SUN Y,YANG W L. In-vitro dissolution behaviors of diclofenac sodium enteric-coated tablets[J]. Chin Pharm J(中国药学杂志),2018,53(8):1419-1424.
[25] LOBENBERG R,KRAMER J,SHAH V P,et al. Dissolution testing as a prognostic tool for oral drug absorption:dissolution behavior of glibenclamide[J]. Pharm Res,2000,17(4):439-444.
[26] SHAH V P,KONECNY J J,EVERETT R L,et al. In vitro dissolution profile of water-insoluble drug dosage forms in the presence of surfactants[J]. Pharm Res,1989,6(7):612-618.
[27] SUAREZ-SHARP S,MIN L,DUAN J,et al. Regulatory experience with in vivo in vitro correlations(IVIVC)in new drug applications[J]. AAPS J,2016,18(6):1-12.
[28] TIAN L,HUANG Y L,HUA L. Pharmacokinetic studies of glimepiride and its hydroxy-metabolite in healthy volunteers[J]. Chin J Clin Pharmacol Ther(中国临床药理学与治疗学),2006,11(8):868-872.
[2] DRESSMAN J,AMIDON G. Dissolution testing as a prognostic tool for oral drug absorption:immediate release dosage forms[J].Pharm Res,1998(15):11-22.
[3] DRESSMAN J,AMIDON G,FLEISHER D. Absorption potential:Estimating the fraction absorbed for orally administered compounds[J]. J Pharm Sci,1985,74(5):588-589.
[4] AVDEEF A. The rise of PAMPA[J]. Expert Opin,2005,1(2):325-342.
[5] HIDALGO I J. Assessing the absorption of new pharmaceuticals[J]. Curr Top Med Chem,2001,1(5):385-401.
[6] ENIKOBORBAS. The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations[J]. Eur J Pharm,2018,114(3):310-317.
[7] AVDEEF A,TSINMAN O. PAMPA-a drug absorption in vitro model 13. Chemical selectivity due to membrane hydrogen bonding:in combo comparisons of HDM-,DOPC-,and DS-PAMPA models[J]. Eur J Pharm,2006,28(1-2):43-50.
[8] BRISCOE V J,GRIFFITH M L,DAVIS S N. The role of glimepiride in the treatment of type 2 diabetes mellitus[J]. Expert Opin Drug Metab Toxicol,2010,6(2):2 2 5-2 2 7.
[9] FRICK A,MLLER H,WIRBITZKI E. Biopharmaceutical characterization of oral immediate release drug products. In vitro/in vivo comparison of phenoxymethylpenicillin potassium,glimepiride and levofloxacin[J]. Eur J Pharm Biopharm,1998,46(3):305-311.
[10] BADIAN M,KORN A,LEHR K H,et al. Absolute bioavailability of glimepiride(Amaryl)after oral administration[J].Drug Metab Drug Interact,1994,11(4):331-340.
[11] The guideline for the dissolution test of ordinary oral solid preparations and the technical guideline for the stability of chemical drugs(materials and preparations)[EB/OL]. China Food and Drug Administration,2015,No. 3,Attachment 1[2015-02-05]. http://samr. cfda. gov. cn/WS01/CL1036/114286. html.
[12] Ch. P(2015)VolⅣ(中国药典2015年版.四部)[S]. 2015:121-124.
[13] YU L X,LIPKA E,CRISON J R,et al. Transport approaches to the biopharmaceutical design of oral drug delivery systems:prediction of intestinal absorption[J]. Adv Drug Deliv Rev,1996,19(3):359-376.
[14] BADIAN M,KORN A,LEHR K H,et al. Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride(Amaryl)after intravenous administration[J]. Drug Metab Drug Interact,1996,13(1):69-85.
[15] The information form of Glimepiride(AmarylR)[EB/OL]. Japan Pharmaceuticals and Medical Device Agency,2017,Edition22[2017-03] http://www. info. pmda. go. jp/go/interview/1/780069_3961008F4070_1_022_1F.
[16] AMIDON G L,LENNERNAS 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].Aaps J,2014,16(5):894-898.
[17] AMIDON G,SHAH V. A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro,drug product dissolution and in vivo,bioavailability[J]. Pharm Res,1995,12(3):413-420.
[18] LENNERNAS H. Intestinal permeability and its relevance for absorption and elimination[J]. Xenobiotica,2007,37(10-11):1015-1051.
[19] ANO R,KIMURA Y,SHIMA M,et al. Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes:application to prediction of Caco-2 cell permeability[J]. Bioorgani Med Chem,2004,12(1):257-264.
[20] KERNS E H,DI L,PETUSKY S,et al. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery[J]. J Pharm Sci,2010,93(6):1440-1453.
[21] WALTER E,JANICH S,ROESSLER B J,et al. HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium:in vitro-in vivo correlation with permeability data from rats and humans[J]. J Pharm Sci,1996,85(10):1070-1076.
[22] KRISHNA R,YU L. Biopharmaceutics Applications in Drug Development[M]. Beijing:Peking University Medical Press,2012.
[23] FU H,WANG L,ZHANG Z. Dissolution and permeability behavior of diclofenac sodium enteric-coated tablets in-vitro[J].Chin Pharm J(中国药学杂志),2018,53(20):1778-1784.
[24] FU H,SUN Y,YANG W L. In-vitro dissolution behaviors of diclofenac sodium enteric-coated tablets[J]. Chin Pharm J(中国药学杂志),2018,53(8):1419-1424.
[25] LOBENBERG R,KRAMER J,SHAH V P,et al. Dissolution testing as a prognostic tool for oral drug absorption:dissolution behavior of glibenclamide[J]. Pharm Res,2000,17(4):439-444.
[26] SHAH V P,KONECNY J J,EVERETT R L,et al. In vitro dissolution profile of water-insoluble drug dosage forms in the presence of surfactants[J]. Pharm Res,1989,6(7):612-618.
[27] SUAREZ-SHARP S,MIN L,DUAN J,et al. Regulatory experience with in vivo in vitro correlations(IVIVC)in new drug applications[J]. AAPS J,2016,18(6):1-12.
[28] TIAN L,HUANG Y L,HUA L. Pharmacokinetic studies of glimepiride and its hydroxy-metabolite in healthy volunteers[J]. Chin J Clin Pharmacol Ther(中国临床药理学与治疗学),2006,11(8):868-872.