基于溶解性和渗透性分析的尼可地尔生物药剂学分类研究及在仿制药一致性评价中的应用
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摘要
目的:研究尼可地尔的生物药剂学分类(BCS),并对原研和仿制的原料药溶解性及渗透性进行评价。方法:采用μDiss~(TM)型和μFlux~(TM)型光纤药物溶解性、渗透性测试系统,测定尼可地尔原料药的溶解度、固有溶出速率、有效渗透性和LogD_(7.4)值,分析药物的BCS分类,并考察原研企业与仿制企业原料药的差异。结果:尼可地尔为高溶解性药物,在酸性介质中溶解度较高。在pH 6. 8磷酸盐缓冲液中测得的有效渗透率,以及由LogD_(7.4)计算出的LogP值均低于美托洛尔,为低渗透性药物。原研企业和仿制企业原料药的溶解度、固有溶出速率、有效渗透性和LogD_(7.4)基本一致。结论:尼可地尔为BCS第三类药物。通过比较原研企业与仿制企业原料药的关键参数,可为药物的体外溶出行为评价和体内外相关性研究提供数据支撑。
Objective: To study the biopharmaceutics classification system( BCS) classification of nicorandil,and evaluate the solubility and permeability of the original and generic drug substances. Methods: The μDiss~(TM) and μFlux~(TM)fiber-based drug solubility and permeability test systems were used to determine the solubility,intrinsic dissolution rate,effective permeability and LogD_(7.4) value of nicorandil in different media. The BCS classification of the drug was analyzed and the differences between the original and generic drug substances were examined.Results: Nicorandil was a highly soluble drug with high solubility in acidic media. The effective permeability measured in pH 6.8 phosphate buffer and the LogP value calculated by LogD_(7.4) were lower than metoprolol,which is a low permeability drug. There was no significant difference in solubility,intrinsic dissolution rate,effective permeability and LogD_(7.4) between the original and generic drug substances. Conclusion: Nicorandil is classified into class III in the biopharmaceutics classification system. By comparing the key parameters of the original and generic drug substances,data support can be provided for the in vitro dissolution behavior evaluation and in vitro and in vivo correlation research of the drug.
Objective: To study the biopharmaceutics classification system( BCS) classification of nicorandil,and evaluate the solubility and permeability of the original and generic drug substances. Methods: The μDiss~(TM) and μFlux~(TM)fiber-based drug solubility and permeability test systems were used to determine the solubility,intrinsic dissolution rate,effective permeability and LogD_(7.4) value of nicorandil in different media. The BCS classification of the drug was analyzed and the differences between the original and generic drug substances were examined.Results: Nicorandil was a highly soluble drug with high solubility in acidic media. The effective permeability measured in pH 6.8 phosphate buffer and the LogP value calculated by LogD_(7.4) were lower than metoprolol,which is a low permeability drug. There was no significant difference in solubility,intrinsic dissolution rate,effective permeability and LogD_(7.4) between the original and generic drug substances. Conclusion: Nicorandil is classified into class III in the biopharmaceutics classification system. By comparing the key parameters of the original and generic drug substances,data support can be provided for the in vitro dissolution behavior evaluation and in vitro and in vivo correlation research of the drug.
引文
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[15]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.
[16]许鸣镝,南楠,马玲云,等.对仿制药质量和疗效的一致性评价的多维思考和实践分析[J].中国新药杂志,2018,27(20):2393-2396.
[17] LENNERNAS H. Intestinal permeability and its relevance forabsorption and elimination[J]. Xenobiotica,2007,37(10-11):1015-1051.
[18] ALEX A,STEFANIE B,LI DI,et al. PAMPA-critical factors for better predictions of absorption[J]. J Pharm Sci,2007,96(11):2893-2909.
[19] AVDEEF A,ARTURSSON P,NEUHOFF S,et al. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKa(flux)method[J]. Eur J Pharm,2005,24(4):333-349.
[2]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.
[3] FDA. Guidance for industry:“Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system guidance for industry”[EB/OL].[2017-12-01]. http://www. fda.gov/Drugs/Guidance Compliance Regulatory Information/Guidances/default. htm.
[4] WHO. Technical report series No. 937; annex 7:multisource(generic)pharmaceutical products:guidelineson registration requirements to establish interchangeability; annex 8:proposal to waive in vivo bioequivalence requirements for WHO model list of essential medicines immediate-release,solid oral dosage forms[S]. 2006.
[5] EMA. Note for guidance on the investigation of bioavailability and bioequivalence CPMP/EWP/QWP/1401/98 Rev1,AppendixⅢ[S]. 2010.
[6] CHEN M,YU L. The use of drug metabolism for prediction of intestinal permeability[J]. Mol Pharm,2009,6(1):74-81.
[7] RODRIGO C,CHANG C,JENNIFER BD,et al. Comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system:a cross-sectional survey with 500 bioequivalence studies[J]. J Pharm Sci,2013,102(9):3136-3144.
[8]王琳,张喆,胡琴,等.两种生物药剂学分类系统比较及应用探讨[J].中国药学杂志,2018,53(20):38-42.
[9]徐敏,姜丽丽.尼可地尔在心脏病治疗中的作用[J].中国新药杂志,1999,8(9):590-592.
[10] NICHD,FDA. Intra-Agency Agreement Between the Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD)and FDA Oral Formulations Platform-Report 1[EB/OL]. http://www. Accessdata. Fda. Gov/scripts/cder/drugsatfda/index.
[11] WHO. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release,solid oral dosage forms[S]. 2006.
[12] DDF. BCS database search:provisional BCS classification[DB/OL]. http://tsrlinc. com/resources/services/.
[13]冯敏,杜娟,林宁.尼可地尔在大鼠小肠吸收研究[J].医药导报,2015,34(11):1448-1450.
[14] CFDA. 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].[2015-02-05]. http://samr. cfda. gov. cn/WS01/CL1036/114286. html.
[15]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.
[16]许鸣镝,南楠,马玲云,等.对仿制药质量和疗效的一致性评价的多维思考和实践分析[J].中国新药杂志,2018,27(20):2393-2396.
[17] LENNERNAS H. Intestinal permeability and its relevance forabsorption and elimination[J]. Xenobiotica,2007,37(10-11):1015-1051.
[18] ALEX A,STEFANIE B,LI DI,et al. PAMPA-critical factors for better predictions of absorption[J]. J Pharm Sci,2007,96(11):2893-2909.
[19] AVDEEF A,ARTURSSON P,NEUHOFF S,et al. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKa(flux)method[J]. Eur J Pharm,2005,24(4):333-349.