苦参碱葡萄糖注射液细菌内毒素检查方法研究
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摘要
苦参碱葡萄糖注射液现行质量标准为国家食品药品监督管理局批准的试行标准,根据该试行标准规定,该产品的热原检查用家兔法。苦参碱葡萄糖注射液为苦参碱与葡萄糖的灭菌水溶液,适用于慢性肝炎的氨基转移酶及胆红素异常。
由于苦参碱葡萄糖注射液有一定的刺激性,在进行热原实验时常引起家兔的躁动,容易对实验结果产生影响。故本研究的目的就是参照药品细菌内毒素检查的实验设计对以细菌内毒素检查法取代热原检查法的可行性进行实验研究,并建立苦参碱葡萄糖注射液细菌内毒素检查方法,为该产品的质量标准转正提供数据支持。
细菌内毒素检查法是利用鲎试剂来检测或量化由革兰阴性菌产生的细菌内毒素,以判断供试品中细菌内毒素的限量是否符合规定的一种方法。细菌内毒素检查包括两种方法,即凝胶法和光度测定法。后者包括浊度法和显色基质法。自20世纪60年代鲎血凝集机制的发现和鲎实验方法的建立,引起了各国药政管理部门的极大兴趣,并使细菌内毒素检查法在药品的热原限量控制中得到了广泛的应用和发展。特别是《中国药典》2005年版细菌内毒素检查法正式收载,使细菌内毒素定量检查法在我国得到肯定、应用和推广,它还将有力地推动细菌内毒素检查法在我国的新进展。本研究从细菌内毒素基础知识着手,介绍了细菌内毒素的概念、化学结构及化学组份、生物活性、耐热性、致病机理及作用机理等基础理论。参照《中国药典》2005年版二部附录XI E细菌毒素检查法的要求,通过试验摸索,该产品采用凝胶法在稀释2倍后不干扰细菌内毒素试验;采用动态比浊法,对该产品稀释液进行定量检测,在8倍稀释时无干扰作用,从而确立了苦参碱葡萄糖注射液细菌内毒素检查方法。同时对细菌内毒素检查法的常见可能影响因素进行了分析,并对采取的相应对策进行了摸索、探讨。
最后研究结果建立的细菌内毒素检查法快速、简便、重复性好、灵敏度高,苦参碱葡萄糖注射液采用细菌内毒素检查法代替热原检查法,方法可行,并能进行定量检测。
The current quality control standard of Matrine and Glucose Injection is the one standard approved by State Food and Drug Administration. According to the standard, the pyrogen is determined in rabbit pyrogen test. Matrine and Glucose Injection composed of matrine and glucose sterile aqueous solution is applied to improve the abnormality of aminopherase and bilirubin caused by chronic hepatitis.
There is some irritation of Matrine and Glucose Injection. When carrying out the experiment in rabbit pyrogen test, the rabbit will be restlessness, so the result tends to be affected. Thus, the objective of the research is to study the feasibility that replace the bacterial endotoxin test with the pyrogen test. In addition, we will establish a method to test the bacterial endotoxin in Matrine and Glucose Injection. Therefore , we can get the reasonable data to regularize the quality control standard.
Bacterial endotoxin test is a method that is used to detect or quantitatively determine the bacterial endotoxin produced by Gram-negative bacteria with tachypleus amebocyte lysate, so that we can judge if the quantitative limitation of bacterial endotoxin in the simple products accords with the standard. Bacterial endotoxin test includes two methods: microcolumn gel assay and spectrophotometry. The latter also includes turbidimetric method and chromogenic substrate method. Bacterial endotoxin test has aroused the interest of drug administration in many countries, and has been extensively applied and developed in quantitative limitation of pyrogen. Especially, since the bacterial endotoxin test was recorded in Pharmacopoeia of the People's Republic of China (2005 Edition), the test has been assured, applied and extended as well as its future development in China.
The research is based on the knowledge of the bacterial endotoxin, introducing the concept, chemical constitution and ingredient, bioactivity, pathopoiesis mechanism. By referring to the bacterial endotoxin test in the appendix XI E of the second section of Pharmacopoeia of the People's Republic of China (2005 Edition), the experimental condition was formulated, namely, there was no interference from bacterial endotoxin test using the microcolumn gel assay when the product was diluted two times. Also, there was no interference using the turbidimetric method when the product was diluted eight times. For the reasons, the method used to detect the bacterial endotoxin in Matrine and Glucose Injection was established. Meanwhile, we exploited the possible influential factors on the test, and took the correlated means to analyze and resolve them.
The bacterial endotoxin test that we established according to the experimental results is fast, simple, practical with good repeatability and high sensitivity. Replacing the bacterial endotoxin test with the pyrogen test is practical and it can be applied to quantitative determination of the bacterial endotoxin.
由于苦参碱葡萄糖注射液有一定的刺激性,在进行热原实验时常引起家兔的躁动,容易对实验结果产生影响。故本研究的目的就是参照药品细菌内毒素检查的实验设计对以细菌内毒素检查法取代热原检查法的可行性进行实验研究,并建立苦参碱葡萄糖注射液细菌内毒素检查方法,为该产品的质量标准转正提供数据支持。
细菌内毒素检查法是利用鲎试剂来检测或量化由革兰阴性菌产生的细菌内毒素,以判断供试品中细菌内毒素的限量是否符合规定的一种方法。细菌内毒素检查包括两种方法,即凝胶法和光度测定法。后者包括浊度法和显色基质法。自20世纪60年代鲎血凝集机制的发现和鲎实验方法的建立,引起了各国药政管理部门的极大兴趣,并使细菌内毒素检查法在药品的热原限量控制中得到了广泛的应用和发展。特别是《中国药典》2005年版细菌内毒素检查法正式收载,使细菌内毒素定量检查法在我国得到肯定、应用和推广,它还将有力地推动细菌内毒素检查法在我国的新进展。本研究从细菌内毒素基础知识着手,介绍了细菌内毒素的概念、化学结构及化学组份、生物活性、耐热性、致病机理及作用机理等基础理论。参照《中国药典》2005年版二部附录XI E细菌毒素检查法的要求,通过试验摸索,该产品采用凝胶法在稀释2倍后不干扰细菌内毒素试验;采用动态比浊法,对该产品稀释液进行定量检测,在8倍稀释时无干扰作用,从而确立了苦参碱葡萄糖注射液细菌内毒素检查方法。同时对细菌内毒素检查法的常见可能影响因素进行了分析,并对采取的相应对策进行了摸索、探讨。
最后研究结果建立的细菌内毒素检查法快速、简便、重复性好、灵敏度高,苦参碱葡萄糖注射液采用细菌内毒素检查法代替热原检查法,方法可行,并能进行定量检测。
The current quality control standard of Matrine and Glucose Injection is the one standard approved by State Food and Drug Administration. According to the standard, the pyrogen is determined in rabbit pyrogen test. Matrine and Glucose Injection composed of matrine and glucose sterile aqueous solution is applied to improve the abnormality of aminopherase and bilirubin caused by chronic hepatitis.
There is some irritation of Matrine and Glucose Injection. When carrying out the experiment in rabbit pyrogen test, the rabbit will be restlessness, so the result tends to be affected. Thus, the objective of the research is to study the feasibility that replace the bacterial endotoxin test with the pyrogen test. In addition, we will establish a method to test the bacterial endotoxin in Matrine and Glucose Injection. Therefore , we can get the reasonable data to regularize the quality control standard.
Bacterial endotoxin test is a method that is used to detect or quantitatively determine the bacterial endotoxin produced by Gram-negative bacteria with tachypleus amebocyte lysate, so that we can judge if the quantitative limitation of bacterial endotoxin in the simple products accords with the standard. Bacterial endotoxin test includes two methods: microcolumn gel assay and spectrophotometry. The latter also includes turbidimetric method and chromogenic substrate method. Bacterial endotoxin test has aroused the interest of drug administration in many countries, and has been extensively applied and developed in quantitative limitation of pyrogen. Especially, since the bacterial endotoxin test was recorded in Pharmacopoeia of the People's Republic of China (2005 Edition), the test has been assured, applied and extended as well as its future development in China.
The research is based on the knowledge of the bacterial endotoxin, introducing the concept, chemical constitution and ingredient, bioactivity, pathopoiesis mechanism. By referring to the bacterial endotoxin test in the appendix XI E of the second section of Pharmacopoeia of the People's Republic of China (2005 Edition), the experimental condition was formulated, namely, there was no interference from bacterial endotoxin test using the microcolumn gel assay when the product was diluted two times. Also, there was no interference using the turbidimetric method when the product was diluted eight times. For the reasons, the method used to detect the bacterial endotoxin in Matrine and Glucose Injection was established. Meanwhile, we exploited the possible influential factors on the test, and took the correlated means to analyze and resolve them.
The bacterial endotoxin test that we established according to the experimental results is fast, simple, practical with good repeatability and high sensitivity. Replacing the bacterial endotoxin test with the pyrogen test is practical and it can be applied to quantitative determination of the bacterial endotoxin.
引文
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[2]许剑平,何晓凡,熊石龙,等.血小板对单核细胞促凝活性的影响[J].中华血液学杂志,2001,22(9):478-479.
[3] HardawayRM. A review of septic shock[J ].Am Surg ,2000,66(1):22-29.
[4]贺石林.弥漫性血管内凝血[A].李家增,贺石林.血栓形成与临床医学[M].长沙:湖南科学出版社,1991.382-383.
[5] Zhang MH,TraceyKJ. Endotoxin and cancer [A].Brade H,OpalSM,Vogel SN , et al . Endotoxin in health and disease[M]. NewYork :Mar2cel Dekker,1999.915-926.
[6] Carswell EA,OldLJ , Kassel RL , et al . An endotoxin2indused serumfactor that cause necrosis of tumors[J ] . Proc Natl Acad Sci USA ,1975,72(9) :3666-3670.
[7] Engelhardt R,OttoF,Mackensen A , et al .Endotoxin(Salmonella abor2tus equi) in cancer patients. Clinical and immunological findings [J].Prog Clin Biol Res ,1995,392(2):253-261.
[8] Levin J. The history of the development of the limulus amebocyte lysate test .Prog Clin Biol Res. 1985,189-191.
[9] Levin J, Bang FB. Clotlable protein in limulus: its localization andkinetics of its coagulation by endotoxin. Thrombos Diathes Haemorrh.1968,19:186-197.
[10] Kakinuma A,AsanoT, ToriiH,et al.Gelation of limulus amoebo2cyte lysate by an antitumor (1→3)2β2D2glucan.Bioch and Bioph ResComm.1981,101:434–439.
[11]黄清泉.特异性鲎试剂和普通鲎试剂测定自来水、蒸馏水和灭菌注射用水中细菌内毒素的对比.中国海洋药物,1999,18-25.
[12]国家药典委员会编.中华人民共和国药典,2005年版二部:附录85-88.
[13]国家药典委员会编.中华人民共和国药典,2005年版二部:附录85-86.
[14]国家药典委员会编.中华人民共和国药典,2005年版二部:附录85-87.
[15]李波,蔡彤,张国来.细菌内毒素检查法的国内外发展概况和存在的问题.中国药学杂志,2002,12(12):956-957.
[16]国家药典委员会编.中华人民共和国药典,2005年版二部:附录86-87.
[17]苑庆华,唐元泰、孙淑莲.动态浊度法定量检测丹参注射液中细菌内毒素(J).药物分析杂志,1999增刊,19(增刊):51-54.
[18]劳海燕,罗宇芬,林秋晓.注射用头孢他啶细菌内毒素定量法的研究.中国药理学通报,2002;18(3):305-306.
[19]邓鸣,张索芬,潘静.氯霉素葡萄糖注射液的内毒素定量检测.中国药业,2002;11(3):51-52.
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