WO2023169351A1 - 血清基质的胃功能三项复合质控品及其制备方法 - Google Patents

血清基质的胃功能三项复合质控品及其制备方法 Download PDF

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WO2023169351A1
WO2023169351A1 PCT/CN2023/079793 CN2023079793W WO2023169351A1 WO 2023169351 A1 WO2023169351 A1 WO 2023169351A1 CN 2023079793 W CN2023079793 W CN 2023079793W WO 2023169351 A1 WO2023169351 A1 WO 2023169351A1
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quality control
matrix
serum
gastric function
control product
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French (fr)
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刘功成
渠文涛
万鹏
李晓燕
史小芹
李晓霞
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郑州安图生物工程股份有限公司
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/595—Gastrins; Cholecystokinins [CCK]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96472—Aspartic endopeptidases (3.4.23)
    • G01N2333/96475—Aspartic endopeptidases (3.4.23) with definite EC number
    • G01N2333/96477—Pepsin (3.4.23.1; 3.4.23.2; 3.4.23.3)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of medical testing, and in particular to a three-item composite quality control product for gastric function in a serum matrix and a preparation method thereof.
  • the three items of gastric function include pepsinogen I (PGI), pepsinogen II (PGII), and gastrin 17 (G-17), which are the three commonly used serological test indicators in clinical evaluation of gastric function.
  • PKI pepsinogen I
  • PGII pepsinogen II
  • G-17 gastrin 17
  • Expert consensus on early gastric cancer screening process in China 2017, Shanghai
  • proposed a new gastric cancer screening scoring system which provides a comprehensive score based on age, gender, HP infection, PGI, PGII, and G-17. The score determines whether the screener belongs to a high-risk group for gastric cancer and whether further gastroscopy is needed. Only a tube of blood is needed to assess gastric function. Compared with gastroscopy, it has the advantages of low cost, non-invasiveness, and high acceptability, and is gradually being widely accepted.
  • G-17 is very unstable in serum (Liu Zhimin, Zhou Haiqing, Li Jing. Effects of different separation times and storage methods on the determination of gastrin 17 [J]. Experimental and Laboratory Medicine, 2017, 035(005): 717-718 .), therefore, the existing G-17 quality control products are not serum matrix, and generally adopt the form of adding G-17 antigen in a buffer containing protective proteins such as BSA and casein. Because this type of quality control product does not use a serum matrix, there is often a certain matrix effect problem between it and real clinical samples.
  • Patent CN111024964A reports a composite quality control product and detection kit for gastric function testing. It provides a composite quality control product of pepsinogen I, pepsinogen II and gastrin 17, but the quality control product is not serum matrix. Composite quality control products. Therefore, there is no report on the three-item composite quality control product of gastric function in serum matrix.
  • quality control products should have a similar or identical matrix to the patient samples to be tested. Quality control products should be uniform and stable. If conditions permit, they can be stored for one year or more. Bottle-to-bottle variability should be less than the variability of the analytical system. Therefore, the development of a serum-based three-item composite quality control product for gastric function is an urgent need for clinical laboratories.
  • the present invention provides a serum-based three-item gastric function composite quality control product and a preparation method thereof; used for quality control of a three-item gastric function detection kit.
  • a unique technical solution was adopted to overcome the technical problem of G-17 being unstable in serum samples, thereby realizing the possibility of preparing three composite quality control products for gastric function in serum matrix.
  • the present invention provides the use of a blood coagulant in improving the stability of G-17 in a serum matrix.
  • blood coagulants can inhibit the degradation of G-17 by proteases in serum.
  • the present invention also provides the use of a blood coagulant in the preparation of a three-item gastric function composite quality control product and/or a three-item gastric function detection kit.
  • the added amount of the blood accelerator is 1% to 5% (v/v).
  • the present invention also provides a method for preparing the matrix fluid of a three-item composite quality control product for gastric function in a serum matrix. After inactivating the serum, it is mixed with a blood coagulant and a preservative, and filtered through a membrane to obtain the obtained product. Describe the matrix fluid of three composite quality control products for gastric function in serum matrix.
  • the blood The added amount of the coagulant is 1% to 5% (v/v); the added amount of the preservative is 0.2% (v/v).
  • the present invention also provides the matrix liquid of the three gastric function composite quality control products of the serum matrix prepared by the preparation method.
  • the present invention also provides a three-item composite quality control product for gastric function in a serum matrix, including a matrix fluid of the three-item complex quality control product for gastric function in a serum matrix, pepsinogen I antigen, and pepsinogen II antigen. and gastrin 17 antigen, as well as acceptable excipients or auxiliaries.
  • the present invention also provides a method for preparing the three-term composite quality control product for gastric function in serum matrix.
  • the preparation method the matrix liquid of the three-term composite quality control product for gastric function in serum matrix is prepared. , mixed with pepsinogen I antigen, pepsinogen II antigen and gastrin 17 antigen, divided into packages, and freeze-dried to prepare three composite quality control products for gastric function of the serum matrix.
  • the present invention also provides the matrix liquid of the three-term composite quality control product of gastric function in the serum matrix, the three-term composite quality control product of the gastric function in the serum matrix, or the serum matrix prepared by the preparation method.
  • the present invention also provides a kit for detecting three items of gastric function in serum matrix, including a matrix liquid of the three-item composite quality control product of gastric function in serum-matrix, and the three-item composite quality control product of gastric function in serum matrix is product, or the three-item composite quality control product of gastric function of the serum matrix prepared by the preparation method, as well as acceptable excipients, auxiliaries or carriers.
  • the present invention also provides a method for detecting three items of gastric function in serum matrix.
  • the sample to be tested is passed through the matrix liquid of the three-item composite quality control product of gastric function in serum matrix.
  • the gastric function in serum matrix is Three-item composite quality control product, the three-item complex quality control product for gastric function of the serum matrix prepared by the described preparation method or the three-item gastric function detection kit for detection.
  • the present invention provides three composite quality control products for gastric function in serum matrix.
  • the mixed serum is inactivated at 56°C, and then 1%-5% (v/v) blood coagulant is added and filtered.
  • the quality control product matrix solution was obtained, and the technical problem of G-17 being unstable in conventional serum matrix was overcome, thereby realizing the feasibility of using PGI, PGII, and G-17 as a composite quality control product in serum matrix.
  • the matrix of this quality control is close to the matrix of clinical samples, thus effectively avoiding the occurrence of matrix effect problems.
  • the use of three-in-one composite quality control products provides great convenience for use in clinical laboratories and improves work efficiency.
  • the present invention discloses a serum-based three-item composite quality control product for gastric function and a preparation method thereof. Persons skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments. Relevant persons can obviously make modifications or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of this invention.
  • the object of the present invention is to provide a serum-based three-item composite quality control product for gastric function and a preparation method thereof.
  • the present invention can adopt the following technical solutions.
  • the present invention describes a serum matrix gastric function three-item composite quality control product, including the following specific preparation steps:
  • the normal human mixed serum can be replaced with hormone-free serum or serum obtained by processing plasma through a certain process, and there will be no changes in subsequent steps.
  • the mixed serum is inactivated at 56°C, and then 1%-5% (v/v) blood coagulant is added and filtered to obtain quality control.
  • the product matrix solution has overcome the technical problem of G-17 being unstable in conventional serum matrix, thereby realizing the feasibility of using PGI, PGII, and G-17 as a composite quality control product in serum matrix.
  • the quality control The matrix is close to the matrix of clinical samples, thus effectively avoiding the occurrence of matrix effect problems.
  • the use of three-in-one composite quality control products provides great convenience for use in clinical laboratories and improves work efficiency.
  • the key point of the present invention is to discover a formula and preparation process of a quality control matrix solution, inactivate the serum, and add an appropriate amount of blood coagulant, thereby solving the technical problem of G-17 being unstable in serum, and thereby achieving A serum matrix gastric function three-item composite quality control product was prepared; it filled the technical gap in the absence of a serum matrix gastric function three-item composite quality control product.
  • the stability is poor; if the serum is inactivated in advance and then the G-17 antigen is added, the stability will be improved to a certain extent; the author is studying G-17 samples in different vacuum blood collection tubes
  • manufacturer A's coagulation-promoting tube or separation gel coagulation-promoting tube the G-17 sample has better stability; other manufacturers' coagulation-promoting tubes or separation gel coagulation-promoting tubes do not. The main reason is that they are made by different manufacturers.
  • the coagulant formula used in the coagulation accelerator tube or the separation gel coagulation accelerator tube is different. Except for procoagulant tubes or separation gel procoagulant tubes, the stability of G-17 is not good when using other types of blood collection tubes.
  • the coagulant used in manufacturer A's coagulant tube or separation gel coagulant tube was added to the serum, and the G-17 sample had better stability.
  • the coagulant used in manufacturer A's coagulant tube or separation gel coagulant tube was added to the serum, and the G-17 sample had better stability.
  • a key point of the present invention is: a serum matrix gastric function three-item composite quality control product and its preparation method; (Because G-17 is unstable in serum, it is a technical problem in the industry, and this quality has not been seen yet. Control products and their reports; patent CN111024964A reports a composite quality control product of buffer matrix, non-serum matrix).
  • PGI and PGII are stable in serum, and there are currently two serum matrix quality control products.
  • Another key point of the present invention lies in: the preparation process of the matrix liquid of the serum matrix quality control product.
  • the key point of the process is to first inactivate the serum, and then add a blood coagulant, thereby achieving the stabilization of the G-17 antigen.
  • Blood accelerators are generally suitable for use as coagulants in vacuum blood collection tubes.
  • the present invention uses blood accelerators as stabilizers for G-17 and achieves unexpected effects.
  • the serum matrix gastric function three-item composite quality control products provided by the present invention can also be made into a liquid state, except for those in a freeze-dried state in the present invention.
  • the liquid form cannot be stored at 2-8°C and needs to be stored at 2-8°C.
  • To be stored at -20°C and below will increase the cost of transportation and storage.
  • the validity period may be shorter than that of freeze-dried quality control materials.
  • a blood coagulant (liquid) is added to the matrix solution of the quality control product of the present invention, and blood coagulant powder (solid) can also be used instead of the blood coagulant.
  • the present invention breaks through the industry technical problem of G-17 being unstable in serum, and discloses for the first time a serum-based three-item composite quality control product for gastric function.
  • the matrix is a serum matrix, which is close to the clinical sample matrix, which can effectively reduce the occurrence of matrix effect problems.
  • the raw materials and reagents used can be purchased from the market.
  • the blood coagulant was purchased from Yangpu Medical.
  • G-17 has a significant advantage in storing samples at 2-8°C for up to 5 days.
  • the sample storage time of G-17 at 2-8°C is about 3 hours. It was confirmed that different vacuum blood collection tubes have an impact on the sample stability of G-17.
  • Yangpu's coagulation accelerator tube and the separation gel coagulation accelerator tube are both contain a coagulant. It is speculated that the coagulant is the main factor that stabilizes the G-17 sample. Therefore, we purchased Yangpu Medical’s blood coagulant to verify its effect.
  • Use ordinary tubes from three manufacturers: Sanli, Kangjian and Sekishui to collect samples in two tubes each. The first tube is used as a control, and the second tube is added with 5% blood coagulant and incubated at room temperature for 30 minutes. After centrifugation, place it at 2 Store at -8°C, and detect at 0h, 3h, 1 day, 2 days, 3 days, 5 days and 7 days. Each tube is compared with the results at 0h, and the results corresponding to a change of less than 10% The time is the sample storage time. The results are shown in Table 2:
  • Comparative Example 4 Preparation method of quality control matrix solution (serum inactivated, adding 0.5% blood accelerator)
  • Quality control product 1 Example 1, the serum has been inactivated, and 5% (v/v) blood coagulant (purchased from Yangpu Medical) was added;
  • Quality control product 2 Comparative example 1, the serum is not inactivated and no blood coagulant is added;
  • Quality control product 3 Comparative Example 2, the serum was not inactivated, and 5% (v/v) blood coagulant was added (purchased from Yangpu Medical);
  • Quality control product 4 Comparative example 3, the serum has been inactivated and no blood coagulant is added;
  • Quality control product 5 Comparative example 4, the serum has been inactivated and 0.5% (v/v) blood coagulant (purchased from Yangpu Medical) was added.
  • the amplitude is set to ⁇ 10% to meet the requirements. It can be seen from the experimental data in Table 1 that the quality control product 1 provided by the present invention can be stably stored for at least 7 days at 2-8°C; the quality control product 2 (comparative example 1) It can be stored stably for 8 hours at 2-8°C; quality control product 3 (comparative example 2) can be stored stably for up to 5 days at 2-8°C; quality control product 4 (comparative example 3) can be stored stably for up to 1 day at 2-8°C.
  • quality control product 5 (Comparative Example 4) can be stably stored for up to 1 day at 2-8°C; the stability of PGI and PGII in the Comparative Example all meet the requirements, mainly because the stability of G-17 changes by more than 10%. This is the biggest advantage of the quality control products and comparative examples of the present invention.
  • Test Example 3 Real-time stability assessment of quality control products of the present invention
  • the validity period of the quality control product of the present invention can be set as 24 months.
  • the quality control product of the present invention (prepared in Example 2) is tested for uniformity according to the following method, and the coefficient of variation within the bottle (CV within the bottle ) and the coefficient of variation between bottles (CV between bottles ) are calculated. The result should not be greater than 10%.
  • each concentration is randomly numbered 1 to 10, and measure three times in the following order.
  • n i the number of repeated measurements of sample i
  • n 0 The number of valid measurements

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Abstract

本发明涉及医学检测领域，特别涉及血清基质的胃功能三项复合质控品及其制备方法。本发明提供了血清基质的胃功能三项复合质控品，将混合血清经过56℃下进行灭活，再加入1％～5％(v/v)的血液促凝剂，过滤，得到质控品基质液，攻克了G-17在常规血清基质中不稳定的技术难题，从而实现了将PGI、PGII、G-17做成血清基质的复合质控品的可行性。该质控的基质与临床样本的基质接近，从而有效避免了基质效应问题的发生。此外，采用三合一的胃功能复合质控品，为临床实验室的使用提供了极大的方便，提高了工作效率。

Description

血清基质的胃功能三项复合质控品及其制备方法
本申请要求于2022年03月09日提交中国专利局、申请号为202210222407.3、发明名称为“血清基质的胃功能三项复合质控品及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医学检测领域，特别涉及血清基质的胃功能三项复合质控品及其制备方法。
背景技术
胃功能三项包括胃蛋白酶原I(PGI)、胃蛋白酶原II(PGII)、胃泌素17(G-17),是目前临床上评估胃功能常用的三个血清学检测指标。中国早期胃癌筛查流程专家共识意见(2017年，上海)提出了一种新型胃癌筛查评分系统，根据年龄、性别、HP感染、PGI、PGII、G-17几个指标给出综合评分，根据分值高低，确认筛查者是否属于胃癌高风险人群，是否需要进一步进行胃镜检查。只需要抽一管血，就可以实现对胃功能的评估，与做胃镜相比较，具有成本低、无侵入性、可接受度高等优势，逐渐被广泛接受。
为保证胃功能三项的检测结果准确性，实验室每天都要进行三个项目的质控品检测，确保质控在控才能进行临床样本的检测。然而，目前市面上常见的质控品并不理想。
G-17在血清中很不稳定(刘志敏,周海青,李静.不同分离时间和保存方法对胃泌素17测定的影响[J].实验与检验医学,2017,035(005):717-718.)，所以，现有的G-17质控品都不是血清基质，一般都是采用在含有BSA、酪蛋白等保护蛋白的缓冲液中添加G-17抗原的形式。该类质控品由于采用的不是血清基质、与真实临床样本之间往往会存在一定的基质效应问题。
虽然PGI和PGII在血清中稳定性相对较好，不存在上述G-17面临的问题，但是，如果想做成一种便于临床实验室使用的血清基质的胃功能 三项复合质控品，最大的难点是要解决G-17在血清基质中不稳定的技术难题。
有的厂家可以提供PGI和PGII的血清基质复合质控品，但G-17是单独一种质控基质的质控品。专利CN111024964A报道了胃功能检测用复合质控品及检测试剂盒，其提供了一种胃蛋白酶原I、胃蛋白酶原II和胃泌素17复合质控品，但该质控品不是血清基质的复合质控品。所以，尚未见报道有血清基质的胃功能三项复合质控品。
根据WS/T 641—2018《临床实验室定量测定室内质量控制指南》的要求，质控品应与患者待测样本具有相似或相同的基质。质控品应均一和稳定，如条件允许，可储存一年或以上的用量。瓶间变异性应小于分析系统的变异。因此，开发一种血清基质的胃功能三项复合质控品是临床实验室的迫切需求。
发明内容
有鉴于此，本发明提供了一种血清基质的胃功能三项复合质控品及其制备方法；用于胃功能三项检测试剂盒的质量控制。采用一种独特的技术方案、攻克了G-17在血清样本中不稳定的技术难题，从而实现了制备血清基质的胃功能三项复合质控品的可能性。
为了实现上述发明目的，本发明提供以下技术方案：
第一方面，本发明提供了血液促凝剂在提高血清基质中G-17稳定性中的应用。具体的，血液促凝剂能够抑制血清中蛋白酶对G-17的降解。
第二方面，本发明还提供了血液促凝剂在制备胃功能三项复合质控品和/或胃功能三项检测试剂盒中的应用。
在本发明的一些具体实施方案中，以所述血清基质为基准，所述血液促凝剂的添加量为1％～5％(v/v)。
第三方面，本发明还提供了血清基质的胃功能三项复合质控品的基质液的制备方法，取血清灭活后，与血液促凝剂、防腐剂混合，滤膜过滤，制得所述血清基质的胃功能三项复合质控品的基质液。
在本发明的一些具体实施方案中，以所述血清基质为基准，所述血液 促凝剂的添加量为1％～5％(v/v)；所述防腐剂的添加量为0.2％(v/v)。
第四方面，本发明还提供了所述制备方法制得的所述血清基质的胃功能三项复合质控品的基质液。
第五方面，本发明还提供了血清基质的胃功能三项复合质控品，包括所述血清基质的胃功能三项复合质控品的基质液，胃蛋白酶原I抗原、胃蛋白酶原II抗原和胃泌素17抗原，以及可接受的辅料或助剂。
第六方面，本发明还提供了所述的血清基质的胃功能三项复合质控品的制备方法，按照所述制备方法制得所述血清基质的胃功能三项复合质控品的基质液，与胃蛋白酶原I抗原、胃蛋白酶原II抗原和胃泌素17抗原混合，分装，冷冻干燥，制得所述血清基质的胃功能三项复合质控品。
第七方面，本发明还提供了所述血清基质的胃功能三项复合质控品的基质液，所述血清基质的胃功能三项复合质控品，或所述制备方法制得的血清基质的所述胃功能三项复合质控品在制备血清基质的胃功能三项检测试剂盒中的应用。
第八方面，本发明还提供了血清基质的胃功能三项检测试剂盒，包括所述血清基质的胃功能三项复合质控品的基质液，所述血清基质的胃功能三项复合质控品，或所述制备方法制得的所述血清基质的胃功能三项复合质控品，以及可接受的辅料、助剂或载体。
第九方面，本发明还提供了血清基质的胃功能三项检测方法，取待测样本经所述的血清基质的胃功能三项复合质控品的基质液，所述的血清基质的胃功能三项复合质控品，所述的制备方法制得的所述血清基质的胃功能三项复合质控品或所述的胃功能三项检测试剂盒检测。
综上，本发明提供了血清基质的胃功能三项复合质控品，将混合血清经过56℃下进行灭活，再加入1％-5％(v/v)的血液促凝剂，过滤，得到质控品基质液，攻克了G-17在常规血清基质中不稳定的技术难题，从而实现了将PGI、PGII、G-17做成血清基质的复合质控品的可行性。该质控的基质与临床样本的基质接近，从而有效避免了基质效应问题的发生。此外，采用三合一的复合质控品，为临床实验室的使用提供了极大的方便，提高了工作效率。
具体实施方式
本发明公开了血清基质的胃功能三项复合质控品及其制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明的目的在于提供一种血清基质的胃功能三项复合质控品及其制备方法。为临床实验室提供一种便于使用、稳定性好的血清基质的胃功能三项复合质控品，以满足临床实验室对胃功能三项质量控制的需求。
为实现上述目的，本发明可采用以下技术方案。
本发明所述的一种血清基质的胃功能三项复合质控品，包括以下具体制备步骤：
①取正常人混合血清1000mL，在56℃下进行灭活处理30-120min，冷却至室温备用；
②在①制备的灭活的正常混合人血清中，加入1％-5％(v/v)的血液促凝剂，再加入0.2％(v/v)的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液；
③分别将适量PGI、PGII和G-17的抗原投到②中制备的质控品基质液中，搅拌均匀，配制成需要浓度的液态质控品；
④将③中得到的液态质控品按照指定规格进行分装、采用真空冷冻干燥机进行冻干，即得到血清基质的胃功能三项复合质控品，置于2-8℃保存。
所述的正常人混合血清可以替换为去激素血清、或者血浆经过某种工艺处理得到的血清，后续步骤无变化。
本发明提供的血清基质的胃功能三项复合质控品，将混合血清经过56℃下进行灭活，再加入1％-5％(v/v)的血液促凝剂，过滤，得到质控品基质液，攻克了G-17在常规血清基质中不稳定的技术难题，从而实现了将PGI、PGII、G-17做成血清基质的复合质控品的可行性。该质控的 基质与临床样本的基质接近，从而有效避免了的基质效应问题的发生。此外，采用三合一的复合质控品，为临床实验室的使用提供了极大的方便，提高了工作效率。
本发明的关键点是发现了一种质控基质液的配方和制备工艺，将血清灭活处理，并加入适量血液促凝剂，从而解决G-17在血清中不稳定的技术难题，进而实现了一种血清基质的胃功能三项复合质控品的制备；填补了没有血清基质胃功能三项复合质控品的技术空白。
将G-17抗原直接投到血清中，稳定性较差；如果将血清提前灭活处理，再加入G-17抗原，稳定性有一定提升；作者在研究不同的真空采血管中G-17样本稳定性时意外发现，使用A厂家的促凝管或分离胶促凝管时，G-17样本稳定性较好；其他厂家的促凝管或分离胶促凝管则不行，主要原因是不同厂家的促凝管或分离胶促凝管中用的促凝剂配方不同。除了促凝管或分离胶促凝管，用其他类型的采血管G-17稳定性均不好。于是将A厂家的促凝管或分离胶促凝管中使用的促凝剂(本文中使用的血液促凝剂)加入到血清中，G-17样本稳定性较好。将血清灭活，并加入血液促凝剂，再加入G-17抗原，其稳定性有了显著的提升，2-8度保存时间可从8h延长到7天；
本发明的一个关键点在于：一种血清基质的胃功能三项复合质控品及其制备方法；(因为G-17在血清中不稳定是行业的技术难题、目前尚未见到过这种质控品及其报道；专利CN111024964A报道的是缓冲液基质的复合质控品，非血清基质)。
注：PGI、PGII在血清中是稳定的，目前有两项的血清基质质控品。
本发明的另一个关键点在于：血清基质质控品的基质液的制备工艺，工艺的关键点，首先是要将血清灭活处理，其次加入血液促凝剂，从而实现了G-17抗原稳定的目的。血液促凝剂，一般适用于真空采血管的促凝剂使用，本发明使用血液促凝剂作为G-17的稳定剂，获得了意想不到的效果。
本发明提供的血清基质的胃功能三项复合质控品除了本发明中做成冻干态的除外，还可以做成液态的，但是，液态的不能在2-8℃保存，需 要保存于-20℃以及下，会增加运输和保存的成本。而且有效期可能会短于冻干态的质控品。
本发明质控品的基质液中添加了血液促凝剂(液体)，也可以用血液促凝粉(固体)代替血液促凝剂。
与现有技术相比，本发明突破了G-17在血清中不稳定的行业技术难题，首次公开了一种血清基质的胃功能三项复合质控品。基质为血清基质，和临床样本基质较为接近，可以有效降低基质效应问题的发生。
本发明提供的血清基质的胃功能三项复合质控品及其制备方法中，所用原料及试剂均可由市场购得。其中，血液促凝剂购自阳普医疗。
下面结合实施例，进一步阐述本发明：
预实验例1不同厂家、不同类型真空采血管中胃泌素17稳定性考核
我们在使用阳普医疗的促凝管采集样本时，意外发现，G-17样本较之前更稳定，和既往经验不一致，怀疑不同真空采血管之间会有差异。于是我们验证了不同厂家、不同类型采血管对胃泌素17样本稳定性的影响。分别使用四个厂家(三力、阳普、康健和积水)各六种真空采血管(普通管、促凝管、分离胶促凝管、EDTA-K2管、柠檬酸钠管和肝素钠管)采集样本，离心后置于2-8℃保存，分别在0h、3h、1天、2天、3天、5天和7天的时间点进行检测，每一种管均和0h的结果进行比较，变幅＜10％对应的时间为样本保存时间。结果见表1：
表1不同厂家、不同类型真空采血管中胃泌素17稳定性考核

由表5可知，当使用阳普的促凝管和分离胶促凝管时，G-17在2-8℃的样本保存时间长达5天，具有显著优势。当使用阳普的其他类型采血管、或者其他厂家的采血管时，G-17在2-8℃的样本保存时间约为3h。证实了不同真空采血管对G-17的样本稳定性有影响。
预实验例2促凝剂对G-17的稳定效果考核
在预实验例1中，阳普的促凝管和分离胶促凝管的共性是均含有促凝剂，推测该促凝剂是使G-17样本稳定的主要因素。因此，我们采购了阳普医疗的血液促凝剂，验证其效果。使用三力、康健和积水三个厂家的普通管采集样本各两管，第一管作为对照，第二管添加5％的血液促凝剂、室温温育30min，离心处理后，置于2-8℃保存，分别在0h、3h、1天、2天、3天、5天和7天的时间点进行检测，每一种管均和0h的结果进行比较，变幅＜10％对应的时间为样本保存时间。结果见表2：
表2促凝剂对G-17稳定效果考核
由上表可知，三力、康健和积水三个厂家普通管中G-17的保存时间约为3h，但在三个厂家的普通管中添加阳普的血液促凝剂之后，G-17的样本保存时间可延长到5天，进一步证明了阳普的血液促凝剂对延长G-17的样本保存时间具有积极作用。这一发现为胃功能三项复合质控品的研制奠定了基础，于是就有了本发明的血清基质的胃功能三项复合质控品。
实施例1本发明质控基质液的制备方法
量取正常人混合血清1000mL，在56℃下进行灭活处理60min，冷却至室温备用；加入5％(v/v)的血液促凝剂(购自阳普医疗)，再加入0.2％(v/v)的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液；
实施例2血清基质的胃功能复合质控的制备
取实施例1中制备的质控品基质液，分别投入适量PGI、PGII和G-17的抗原，搅拌均匀，配制成需要浓度的液态质控品；按照指定规格进行分装、采用真空冷冻干燥机进行冻干，即得到血清基质的胃功能三项复合质控品，置于2-8℃保存。
对比例1质控品基质液的制备方法(血清未灭活，未加血液促凝剂)
量取正常人混合血清1000mL，再加入0.2％(v/v)的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液。
对比例2质控品基质液的制备方法(血清未灭活，加5％血液促凝剂)
量取正常人混合血清1000mL，加入5％(v/v)的血液促凝剂(购自阳普医疗)，再加入0.2％(v/v)的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液。
对比例3质控品基质液的制备方法(血清灭活，未加血液促凝剂)
量取正常人混合血清1000mL，在56℃下进行灭活处理60min，冷却至室温备用；加入0.2％(v/v)的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液。
对比例4质控品基质液的制备方法(血清灭活，加0.5％血液促凝剂)
量取正常人混合血清1000mL，在56℃下进行灭活处理60min冷却至室温备用；加入0.5％(v/v)的血液促凝剂(购自阳普医疗)，加入0.2％(v/v) 的防腐剂Proclin300，搅拌均匀，用0.22um无菌滤膜过滤，得到质控品基质液。
测试例1不同质控基质液制备的质控品的复溶稳定性效果考核
分别使用实施例1中本发明的质控品基质液、对比例1、对比例2、对比例3和对比例4中的质控品基质液，按照实施例2中描述的方法制备五种胃功能复合质控品，依次是：
质控品1：实施例1，血清已灭活、添加5％(v/v)血液促凝剂(购自阳普医疗)；
质控品2：对比例1，血清未灭活、未添加血液促凝剂；
质控品3：对比例2，血清未灭活、添加5％(v/v)血液促凝剂(购自阳普医疗)；
质控品4：对比例3，血清已灭活、未添加血液促凝剂；
质控品5：对比例4，血清已灭活、添加0.5％(v/v)血液促凝剂(购自阳普医疗)。
将五种冻干质控品复溶后在2-8℃保存，使用AutoLumo A2000 plus检测系统及其配套的试剂盒，对五种复合质控品中的PGI、PGII和G-17进行检测，考核时间点分别设置在0h、8h、1天、3天、5天、7天，每个质控点检测复孔求均值，比较五种质控品的稳定性有无差异。结果见表3：
表3 2-8℃条件下五种复合质控品复溶稳定性考核


设定变幅＜10％为满足要求，由表1的实验数据可以看出，本发明提供的质控品1在2-8℃可以稳定保存至少7天；质控品2(对比例1)在2-8℃可以稳定保存8h；质控品3(对比例2)在2-8℃最多可以稳定保存5天；质控品4(对比例3)在2-8℃最多可以稳定保存1天；质控品5(对比例4)在2-8℃最多可以稳定保存1天；对比例中PGI、PGII的稳定性均满足要求，主要是G-17稳定性变幅超过了10％。这一点正是本发明质控品与对比例最大的优势所在。
测试例2本发明质控品的热加速稳定性考核
考核本发明(实施例2制得)质控品的热加速破坏稳定性，采用倒序的形式将质控品置于37℃的温箱中分别放置14天、10天和7天，到时间后一块取出，恢复室温后，与2-8℃保存的对照一块进行考核，比较热加速破坏后质控品的稳定性变幅，结果见表4：
表4本发明质控品的热加速稳定性考核

由表4数据可知，本发明的质控品在37度放置7天、10天、14天后，与2-8℃保存的质控品相比，稳定性变幅＜10％，满足要求。
测试例3本发明质控品的实时稳定性考核
将配套考核试剂盒冻存于-20℃以下，每次使用时取出一套。考核本发明(实施例2制得)质控品在2-8℃实时保存0个月、3个月、6个月、12个月、18个月、24个月的稳定性，均与0个月的检测结果进行比较，观察质控品在2-8℃是实时保存稳定性的变幅，以确定质控品的有效期，结果见表5：
表5本发明质控品的实时稳定性考核

由表5可知，本发明的质控品在2-8℃实时保存24个月后，与0个月相比，PGI、PGII和G-17的变幅均小于10％，满足要求。所以，本发明质控品的有效期可定为24个月。
测试例4本发明质控品的均匀性考核
按照下列方法对本发明(实施例2制得)质控品进行均匀性检验，并计算瓶内变异系数(CV瓶内)和瓶间变异系数(CV瓶间)，结果应不大于10％。
随机抽取10套质控品，每个浓度随机编号1～10，按照下列顺序分别测量3次。
测量顺序：1、3、5、7、9、2、4、6、8、10、10、9、8、7、6、5、4、3、2、1、2、4、6、8、10、1、3、5、7、9。
记录测量结果，并按照式(2)～(11)进行计算F、sbb、sr、CV瓶内和CV瓶间：


式4    SS瓶内＝SS总和-SS瓶间






式中：
SS—方差；
v—自由度；
MS—均方；
F—F检验值；
ni—样品i重复测量次数；
n0—有效测量次数；
sbb—瓶间标准差；
sr—重复性标准差；
x—测量或计算结果；
—总平均值；
当统计结果F值小于等于10时，认为质控品瓶间均匀性较好，可以作为校准物，并计算所有测试结果的平均值，然后进行CV瓶内和CV瓶间的计算；当统计结果F值大于10时，认为质控品瓶间均匀性较差，不宜作为质控品，同时不再计算CV瓶内和CV瓶间。
当统计结果F≤1时，以瓶内标准差代替瓶间标准差即sbb＝sr。
结果见表6：
表6本发明质控品的均匀性考核结果
由表6可知，本发明质控品中PGI、PGII和G-17的瓶内、瓶间变异系数均小于10％，满足要求。
以上对本发明所提供的血清基质的胃功能三项复合质控品及其制备方法进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (11)

  1. 血液促凝剂在提高血清基质中G-17稳定性中的应用。
  2. 血液促凝剂在制备胃功能三项复合质控品和/或胃功能三项检测试剂盒中的应用。
  3. 如权利要求1或2所述的应用，其特征在于，以所述血清基质为基准，所述血液促凝剂的添加量为1％～5％(v/v)。
  4. 血清基质的胃功能三项复合质控品的基质液的制备方法，其特征在于，取血清灭活后，与血液促凝剂、防腐剂混合，滤膜过滤，制得所述血清基质的胃功能三项复合质控品的基质液。
  5. 如权利要求4所述的制备方法，其特征在于，以所述血清基质为基准，所述血液促凝剂的添加量为1％～5％(v/v)；所述防腐剂的添加量为0.2％(v/v)。
  6. 如权利要求4或5所述的制备方法制得的所述血清基质的胃功能三项复合质控品的基质液。
  7. 血清基质的胃功能三项复合质控品，其特征在于，包括如权利要求6所述的血清基质的胃功能三项复合质控品的基质液，胃蛋白酶原I抗原、胃蛋白酶原II抗原和胃泌素17抗原，以及可接受的辅料或助剂。
  8. 如权利要求7所述的血清基质的胃功能三项复合质控品的制备方法，其特征在于，按照权利要求4或5所述的制备方法制得所述血清基质的胃功能三项复合质控品的基质液，与胃蛋白酶原I抗原、胃蛋白酶原II抗原和胃泌素17抗原混合，分装，冷冻干燥，制得所述血清基质的胃功能三项复合质控品。
  9. 如权利要求6所述的血清基质的胃功能三项复合质控品的基质液，如权利要求7所述的血清基质的胃功能三项复合质控品，或如权利要求8所述的制备方法制得的血清基质的所述胃功能三项复合质控品在制备血清基质的胃功能三项检测试剂盒中的应用。
  10. 血清基质的胃功能三项检测试剂盒，其特征在于，包括如权利要求6所述的血清基质的胃功能三项复合质控品的基质液，如权利要求7 所述的血清基质的胃功能三项复合质控品，或如权利要求8所述的制备方法制得的所述血清基质的胃功能三项复合质控品，以及可接受的辅料、助剂或载体。
  11. 血清基质的胃功能三项检测方法，其特征在于，取待测样本经如权利要求6所述的血清基质的胃功能三项复合质控品的基质液，如权利要求7所述的血清基质的胃功能三项复合质控品，如权利要求8所述的制备方法制得的所述血清基质的胃功能三项复合质控品或如权利要求10所述的胃功能三项检测试剂盒检测。
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