CN102416171B - Protective agent in process for performing dry heat virus inactivation on high-purity prothrombin complex concentrate products - Google Patents

Protective agent in process for performing dry heat virus inactivation on high-purity prothrombin complex concentrate products Download PDF

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CN102416171B
CN102416171B CN 201110400499 CN201110400499A CN102416171B CN 102416171 B CN102416171 B CN 102416171B CN 201110400499 CN201110400499 CN 201110400499 CN 201110400499 A CN201110400499 A CN 201110400499A CN 102416171 B CN102416171 B CN 102416171B
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dry heat
histidine
trehalose
high purity
viral inactivation
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CN102416171A (en )
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李长清
曹海军
黄亮
邱家山
赵红卫
何琦
喻洪跃
狄姗姗
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中国医学科学院输血研究所
四川大学
成都英德生物工程有限公司
中蓝晨光化工研究设计院有限公司
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Abstract

本发明涉及医药生物技术领域,是高纯度凝血酶原复合物制品(四种凝血因子II、VII、IX、X比活均≥3.5IU/mg蛋白)在100℃,30min干热病毒灭活过程,可有效防止制品中主要作用凝血因子IX及其他凝血因子II、VII、X失活的保护剂。 The present invention relates to the field of biotechnology medicine, high purity products, prothrombin complex (four kinds of coagulation factors II, VII, IX, X specific activity was ≥3.5IU / mg protein) at 100 ℃, 30min dry heat viral inactivation process , can effectively prevent the article major role of factor IX and other coagulation factors II, VII, X inactivation protective agent. 本发明的保护剂是指海藻糖或/和组氨酸,还含有常用的甘氨酸。 Protectant of the present invention refers to trehalose or / and histidine, but also contain conventional glycine. 试验表明,高纯度凝血酶原复合物只要含有0.1%-8%海藻糖或/和0.1%-8%组氨酸,就可以在100℃,30min干热病毒灭活过程中有效地保护凝血因子IX及凝血因子II、VII、X的活性。 Tests showed that a high purity as long as the prothrombin complex containing 0.1% -8% trehalose or / and 0.1 to 8% histidine, can be at 100 ℃, 30min during dry heat viral inactivation of coagulation factors effective protection coagulation factor IX and II, VII, X, active. 因此本发明可用作高纯度凝血酶原复合物干热病毒灭活过程中的保护剂。 Thus, the present invention is useful as a protective agent a high purity of thrombin during dry heat viral inactivation of the original complex.

Description

高纯度凝血酶原复合物制品干热病毒灭活过程中的保护剂 High purity thrombin protectant article during dry heat viral inactivation of the original composite

技术领域 FIELD

[0001] 本发明涉及医药生物技术领域,是几种和几组高纯度凝血酶原复合物制品(四种凝血因子I1、VI1、IX、X比活均≥3.5IU/mg)在100°C、30min干热病毒灭活过程,可有效防止制品中主要作用凝血因子IX及凝血因子I1、VI1、X失活的保护剂。 [0001] The present invention relates to the field of biotechnology medicine, and several sets of several high purity composite article prothrombin (coagulation factor four kinds I1, VI1, IX, X specific activity was ≥3.5IU / mg) at 100 ° C , 30min dry heat viral inactivation process, the article can be effectively prevented from clotting factors IX and main coagulation factor I1, VI1, X inactivation protective agent. 具体而言,高纯度凝血酶原复合物中加入0.1% -8%海藻糖或/和0.1% -8%组氨酸,干热病毒灭活过程中可有效保护凝血因子IX及凝血因子I1、VI1、X的活性。 Specifically, high purity prothrombin complex was added 0.1% to 8% trehalose or / and 0.1 to 8% histidine, dry heat viral inactivation process can be effectively protected and Factor IX clotting factor I1, VI1, active X's.

背景技术 Background technique

[0002]人凝血酶原复合物(Prothrombin Complex Concentrate, PCC),又称凝血因子IX复合物,是由健康人混合血浆制备成的冻干血浆蛋白制品,除含有凝血因子IX外,还含有其他依赖维生素K合成的凝血因子I1、VI1、X。 [0002] The human prothrombin complex (Prothrombin Complex Concentrate, PCC), also known as factor IX complex, plasma protein is a lyophilized product prepared from healthy human plasma as mixing, in addition to containing coagulation factor IX, also contain other synthesis of vitamin K dependent coagulation factor I1, VI1, X. 20世纪50年代PCC开始制备并用于临床,目前该制品除用于乙型血友病、有抗凝血因子VII的甲型血友病外,还广泛用于由肝脏疾病、维生素K缺乏所引起的凝血因子水平低下而导致的出血症及替代新鲜冰冻血浆逆转香豆素类抗凝剂过量而导致的各种出血性疾病,随着PCC临床适应症的扩大,其使用量也在逐年增加。 Outside the PCC began to prepare for clinical and 1950s, now the products except for hemophilia, hemophilia A have anti-clotting Factor VII, is also widely used by the liver disease, vitamin K deficiency caused low levels of coagulation factors caused by various bleeding disorders and hyperlipidemia fresh frozen plasma substitute coumarin anticoagulants reversal caused by excessive, with the expansion of clinical indications of the PCC, the amount used has also increased.

[0003]自PCC用于临床治疗以来,不断有临床输注后导致血栓形成并发症的报道,主要包括弥散性血管内凝血、静脉血栓、肺水肿及致死性心肌梗塞等。 [0003] Since PCC used in clinical treatment since, there have been post-infusion leading to thrombosis reported clinical complications, including disseminated intravascular coagulation, venous thrombosis, pulmonary edema and fatal myocardial infarction. 虽然PCC导致血栓形成的确切原因目前还未完全阐明,但动物模型实验揭示,制品中含有激活激肽释放酶原、高分子量激肽原、磷脂以及接触因子等都可能促使血栓形成,因此,高纯度PCC制品,其他杂质蛋白含有较少,可有效降低血栓形成的风险。 Although the exact cause of PCC cause thrombosis are not fully understood, but animal models revealed that products containing activating prekallikrein, high molecular weight kininogen, a phospholipid and a contact factor and so may promote thrombosis, therefore, high purity PCC products, proteins and other impurities contained less effective in reducing the risk of thrombosis. 当前国内成型PCC制品,凝血因子I1、VI1、IX、X的比活性大多在0.3-1.Οΐυ/mg之间,杂蛋白所含比例相对较大,在一定程度上增加了血栓副反应发生的机率。 The current domestic PCC molded article, clotting factor I1, VI1, IX, X specific activity mostly in the 0.3-1.Οΐυ / mg, the proportion of contaminating proteins contained relatively large thrombus increases side reactions occur to a certain extent probability.

`[0004] PCC由健康人血浆制备而成,但不能排除乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、艾滋病毒(HIV)、人嗜T细胞病毒(HTLV)等传染的可能,因此在制备过程中必须有病毒灭活或去除的方法。 `[0004] PCC prepared from human plasma from healthy, but not exclude hepatitis B virus (HBV), hepatitis C virus (of HCV), HIV (HIV), human T-cell tropic virus may (of HTLV) infection and the like , so there must be a method of viral inactivation or removal during preparation. 2002年5月,国家药品监督管理局《血液制品去除/灭活病毒技术方法及验证指导原则》中明确规定:凝血因子类制品生产过程中应有特定的能去除/灭活脂包膜和非脂包膜病毒的方法,可采用一种或多种方法联合去除/灭活病毒。 In May 2002, the State Drug Administration "blood product removal / inactivation of viruses technical methods and validation guidelines" clearly states: coagulation factor products like the production process should be specific to remove / inactivation of lipid-enveloped and non the method of lipid-enveloped viruses, the method can be combined with one or more removal / inactivation of viruses. 100°C、30min干热病毒灭活法对脂包膜和非脂包膜病毒均有灭活效果,该病毒灭活方法通常在制品冻干后进行,操作简便,可控性强,被很多生产厂家采用,但制品在100°C高温条件处理,有效活性蛋白易失活变性,因此在干热病毒灭活过程中,制品需加一定量的保护剂对活性蛋白进行保护。 100 ° C, 30min dry heat viral inactivation of lipid-enveloped method and are non-lipid-enveloped virus inactivation, the viral inactivation method is generally carried out in the article after lyophilization, easy to operate, control, and many are manufacturers use, but the article at 100 ° C high temperature processing conditions, the effective active protein denaturation easily deactivated, thus the dry heat viral inactivation process, the article need to add a certain amount of protective agent to protect the active protein.

[0005] 高纯度PCC,凝血因子纯度较高,蛋白含量相对较少,对保护剂的要求则更为苛刻,至今未见对高纯度PCC干热病毒灭活过程保护剂的研究,此外,也未见海藻糖或/和组氨酸用于PCC干热病毒灭活过程保护剂的报道。 [0005] PCC high purity, high purity coagulation factors, protein content is relatively small, the requirements of the protecting agent is more severe, so far no studies of high purity PCC during dry heat viral inactivation protective agent and, in addition, also no trehalose and / or histidine for PCC reported during dry heat viral inactivation of the protective agent.

发明内容[0006] 要解决的技术问题 SUMMARY [0006] To solve the technical problem

[0007] 为了减少高纯度PCC在干热病毒灭活过程中凝血因子的活性损失,提高制品活性回收率,本发明提供几种和几组高纯度PCC干热病毒灭活过程的保护剂,100°C、30min干热病毒灭活处理对凝血因子I1、VI1、IX、X有较好的保护效果,其中凝血因子IX活性收率均> 74%。 [0007] In order to reduce the loss of activity at high purity PCC during dry heat viral inactivation of coagulation factors, improve product recovery of activity, the present invention provides a protective agent, and several sets of high purity PCC dry heat viral inactivation process, 100 ° C, 30min dry heat viral inactivation treatment of blood coagulation factor I1, VI1, IX, X better protective effect, wherein the factor IX activity recovery rate> 74%.

[0008] 技术方案 [0008] Technical Solution

[0009] 本发明以高纯度PCC为实验材料,通过冷冻干燥、干热病毒灭活(100°C、30min)、活性测定、对比试验,获得2种和8组高纯度PCC干热病毒灭活处理的保护剂,具体步骤如下: [0009] In the present invention, as materials of high purity PCC, by freeze-drying, dry heat virus inactivation (100 ° C, 30min), activity measurement, comparison test, and 8 to obtain two kinds of groups of high purity PCC dry heat viral inactivation protectant treatment, the specific steps are as follows:

[0010] a)高纯度PCC制备 [0010] a) Preparation of high purity PCC

[0011] 健康人混合血浆2-4°C离心去除冷沉淀,以血浆上清为原料,利用扩张床技术制备高纯度PCC。 [0011] Healthy human pooled plasma by centrifugation 2-4 ° C remove cryoprecipitate, plasma supernatant as a raw material to prepare expanded bed technology using high purity PCC. 将收集的洗脱液用所含0.0lM柠檬酸钠、0.5% NaCl, pH7.0超滤缓冲液在超滤浓缩系统中超滤、脱盐、浓缩并活性测定,获得高纯PCC实验材料。 The collected eluent contained 0.0lM sodium citrate, 0.5% NaCl, pH7.0 buffer ultrafiltration system UF ultrafiltration, desalted, concentrated, and activity assays, experiments to obtain high purity PCC material.

[0012] 上述制备的高纯度PCC组成特征为: [0012] High-purity PCC composition prepared above wherein:

[0013] [0013]

Figure CN102416171BD00041

[0014] b)添加保护剂 [0014] b) adding the protecting agent

[0015] 适当调整浓缩液中凝血因子IX单位活性,按一定比例加入海藻糖或/和组氨酸保护剂,调整pH至7.0,除菌过滤、分装。 [0015] appropriately adjusted Factor IX activity units concentrate, certain proportion of trehalose and / or histidine protecting agent, adjusting the pH to 7.0, sterile filtered, aliquoted.

[0016] c)冷冻干燥 [0016] c) freeze-drying

[0017] 上述分装制品-40°C预冻8hr后,冻干机真空冷冻干燥。 [0017] After the above article dispensing pre-freezing -40 ° C 8hr, vacuum freeze drying lyophilizer.

[0018] d)干热病毒灭活 [0018] d) dry heat viral inactivation

[0019] 冻干后制品置于水浴中,升温至100°C计时,30min后取出。 [0019] After the freeze-dried product was placed in a water bath heated to 100 ° C timing, taken after 30min.

[0020] e)活性测定 [0020] e) Determination of activity

[0021] 注射用水溶解干热病毒灭活前后制品,一期法测定凝血因子活性,对比分析。 Determination of coagulation factor activity [0021] dissolved in water for injection before and after dry heat viral inactivation article, a method of comparative analysis.

[0022] 有益效果 [0022] beneficial effects

[0023] 本发明的有益效果是,提供了2种和8组高纯度PCC干热病毒灭活处理的保护剂,凝血因子IX的活性收率均高于74%,最优保护剂组合干热病毒灭活处理后I1、VI1、IX、X四种凝血因子活性回收率均可达98%以上。 [0023] Advantageous effects of the present invention, provides two sets of high purity PCC 8 and a dry heat virus inactivation treatment agent protection, the Factor IX activity recovery was higher than 74%, and most dry heat protectant composition after the virus inactivation treatment I1, VI1, IX, X four kinds of active coagulation factor recovery can reach 98%.

具体实施方式 detailed description

[0024] 结合实施例对本发明保护剂在干热病毒灭活过程对高纯度PCC的保护作用作详细说明,但本发明的实施方式不限于此。 [0024] Examples of embodiments in conjunction with the protection of the present invention in detail protective effect during dry heat viral inactivation of the PCC in high purity, but the embodiment of the present invention is not limited thereto.

[0025] 实施例1:海藻糖及组氨酸对高纯度凝血酶原复合物主要作用凝血因子IX的保护试验 [0025] Example 1: protection of trehalose and histidine Experimental thrombin clotting main raw composite high-purity factor IX

[0026] 未加保护剂的空白对照制品经100°C、30min干热病毒灭活处理后,凝血因子IX回收率低于58%,而添加不同浓度(1.5%、2.5%)海藻糖作保护剂的制品,凝血因子IX活性回收率在75%以上;添加不同浓度(1.5%、2.5%)组氨酸作保护剂的制品,凝血因子IX活性回收率在74%以上(见表1),说明本发明保剂在单因素条件下能对高纯PCC主要作用凝血因子IX进行有效保护。 [0026] The unprotected blank control agent by article 100 ° C, 30min after dry heat viral inactivation treatment, recovery of factor IX is less than 58%, while the addition of different concentrations (1.5%, 2.5%) as a protective trehalose article agent, factor IX clotting activity recovery of 75% or more; different concentrations (1.5%, 2.5%) as the article histidine protecting agent, coagulation factor IX activity recovery above 74% (see Table 1), agents of the invention can be described with reference to effectively protect the high purity PCC primary role of factor IX in the single factor.

[0027] 表1海藻糖及组氨酸对干热病毒灭活处理的高纯PCC凝血因子IX活性回收率的 [0027] Table 1 trehalose and histidine high purity PCC Factor IX activity recovery of dry heat viral inactivation process

影响 influences

[0028] [0028]

Figure CN102416171BD00051

[0029] 实施例2:海藻糖及组氨酸对高纯度凝血酶原复合物四种凝血因子的保护效果 [0029] Example 2: Histidine and Trehalose thrombin complex four kinds of the protective effect of the original high-purity coagulation factors

[0030] 未加保护剂的空白对照制品经干热病毒灭活处理后,四种凝血因子回收率不超过59%,而添加2.0%海藻糖作保护剂的制品,四种凝血因子活性回收率均在81%以上;添加2.0%组氨酸作保护剂的制品,四种凝血因子活性回收率均在76%以上(见表2),说明本发明保剂在单因素条件下即能有效保护高纯度PCC中的四种凝血因子。 After [0030] The unprotected blank article agent by dry heat viral inactivation treatment, is not more than four kinds of coagulation factor recovery of 59%, 2.0% added trehalose article a protective agent, four kinds of recovery of coagulation factor activity were more than 81%; 2.0% histidine article group as protecting agent, four kinds of clotting factor activity recovery was 76% (see Table 2), - retaining agent of the present invention is able to effectively protect the single factor PCC in highly pure coagulation factor four.

[0031] 表2海藻糖及组氨酸对干热病毒灭活处理的高纯PCC四种凝血因子活性回收率的影响 [0031] Table 2 trehalose and histidine high purity PCC dry heat viral inactivation treatment of four clotting activity recovery factor

[0032] [0032]

Figure CN102416171BD00052

[0033] 实施例3:海藻糖或/和组氨酸+甘氨酸对高纯度凝血酶原复合物主要作用凝血因子IX的保护试验 [0033] Example 3: trehalose and / or glycine + histidine protection assay thrombin clotting main raw composite high-purity factor IX

[0034] 在2.0%甘氨酸基础上,添加不同浓度(0.5%U.5% )海藻糖作保护剂,凝血因子IX活性收率在97%以上(见表3);在2.0%甘氨酸基础上,添加不同浓度(0.5%、1.5%)组氨酸作保护剂,凝血因子IX活性收率在76%以上(见表3),均高于2.0%甘氨酸对照组67.4%的收率。 [0034] 2.0% glycine based on different concentrations (0.5% U.5%) trehalose as a protective agent, coagulation factor IX activity yield of 97% or more (see Table 3); 2.0% glycine based on, different concentrations (0.5%, 1.5%) as a protective agent histidine, factor IX clotting activity yield of 76% (see Table 3), 2.0% glycine were higher than the control group 67.4% yield. 在2.0 %甘氨酸基础上,分别添加0.5%组氨酸+0.5%海藻糖、1.0%组氨酸+0.5%海藻糖、0.5%组氨酸+1.0 %海藻糖、1.0 %组氨酸+1.0 %海藻糖作保护剂,凝血因子IX最低活性收率为92.8% (见表4),均高于2.0%甘氨酸对照组,可明显看出,本发明保护剂海藻糖或/和组氨酸在干热灭活过程中对高纯度PCC主要作用凝血因子IX活性有很好的保护作用。 Based on the 2.0% glycine, respectively, 0.5% histidine + 0.5% trehalose, 1.0% histidine + 0.5% trehalose, 0.5% histidine + 1.0% trehalose, 1.0% histidine + 1.0% trehalose as protecting agent, the lowest active factor IX in a yield of 92.8% (see Table 4), 2.0% glycine were higher than the control group, is apparent, the present invention is the protective agent trehalose or / and dry histidine during heat inactivated factor IX activity have a good protective effect on the main role of high purity PCC.

[0035] 表3海藻糖+甘氨酸及组氨酸+甘氨酸对干热病毒灭活处理的高纯PCC凝血因子IX活性回收率的影响 [0035] Table 3 Effects of trehalose and glycine + histidine + glycine of high purity PCC coagulation factor dry heat virus inactivation treatment IX activity recovery

Figure CN102416171BD00061

[0037] 表4组氨酸+海藻糖+甘氨酸对干热病毒灭活处理的高纯PCC凝血因子IX活性回收率的影响 [0037] Table 4 Effect of Trehalose + histidine + glycine of high purity PCC coagulation factor dry heat virus inactivation treatment IX activity recovery

Figure CN102416171BD00062

[0039] 实施例4:海藻糖+组氨酸+甘氨酸对高纯凝血酶原复合物四种凝血因子保护效果 [0039] Example 4: Trehalose + glycine + histidine high purity prothrombin complex clotting factor four kinds of protective effect

[0040] 在2.0%甘氨酸基础上,添加0.5%组氨酸+1.0%海藻糖作保护剂,四种凝血因子活性收率最低为98.4% (见表5);在2.0%甘氨酸基础上,添加1.0%组氨酸+0.5%海藻糖作保护剂,四种凝血因子活性收率最低为95.3% (见表6),而2.0%甘氨酸对照组,四种凝血因子活性收率最高为70.1% (见表5和表6),由此可见,本发明保护剂海藻糖和组氨酸在干热灭活过程中对高纯度PCC四种凝血因子均有较好的活性保护作用。 [0040] Based on the 2.0% glycine, 0.5% histidine + 1.0% trehalose as protecting agent, the lowest four kinds of coagulation factor activity yield of 98.4% (see Table 5); 2.0% glycine based on the added 1.0% histidine + 0.5% trehalose as protecting agent, the lowest four kinds of coagulation factor activity yield of 95.3% (see Table 6), 2.0% glycine and the control group, four, clotting factor activity yield up to 70.1% ( tables 5 and 6), shows that the present trehalose-protecting agent and better protection of histidine in a dry heat inactivation process for high purity PCC are four kinds of coagulation factor activity.

[0041] 表5海藻糖+组氨酸+甘氨酸对干热病毒灭活处理的高纯PCC四种凝血因子活性 [0041] Table 5 Trehalose + histidine + glycine of high purity PCC dry heat viral inactivation process four clotting factor activity

回收率的影响 Impact of recovery

Figure CN102416171BD00063

凝血因子类型 2.0%甘氨酸对照 2.0%甘氨酸+0.5%组氨酸+1.0%海藻糖 Clotting factor type control 2.0% Glycine 2.0% Glycine + 0.5% histidine + 1.0% trehalose

Figure CN102416171BD00071

[0043] 表6海藻糖+组氨酸+甘氨酸对干热病毒灭活处理的高纯PCC四种凝血因子活性 [0043] Table 6 histidine + Trehalose + glycine of high purity PCC dry heat viral inactivation process four clotting factor activity

回收率的影响 Impact of recovery

Figure CN102416171BD00072

Claims (3)

  1. 1.海藻糖或/和组氨酸用作高纯度凝血酶原复合物干热病毒灭活保护剂的用途,海藻糖含量为0.1^-8%,组氨酸含量为0.1^-8¾^ 1. trehalose and / or histidine as the use of high purity of prothrombin complex concentrate dry heat viral inactivation protecting agent, trehalose content of from 0.1 to 8% ^, histidine content is 0.1 ^ -8¾ ^
  2. 2.根据权利要求1所述海藻糖或/和组氨酸用作高纯度凝血酶原复合物干热病毒灭活保护剂的用途,其特征在于:凝血酶原复合物四种凝血因子I1、VI1、IX、X比活均^ 3.5IU / mg ο 2. The trehalose according to claim 1 and / or histidine as the use of high-purity thrombin dry heat viral inactivation of the original composite protecting agent, characterized in that: four kinds of prothrombin complex clotting factor I1, VI1, IX, X specific activity were ^ 3.5IU / mg ο
  3. 3.根据权利要求1所述海藻糖或/和组氨酸用作高纯度凝血酶原复合物干热病毒灭活保护剂的用途,其特征在于:保护剂中还含有0-10%甘氨酸。 1 according to the trehalose and / or histidine as the use of high purity dry heat viral inactivation of thrombin protecting agent of the original composite, as claimed in claim wherein: the protective agent further comprises 0-10% glycine.
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