CN103550780B - Protein protective agent for Pasteur inactivating human intravenous immunoglobulin and inactivation method of protein protective agent - Google Patents
Protein protective agent for Pasteur inactivating human intravenous immunoglobulin and inactivation method of protein protective agent Download PDFInfo
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- CN103550780B CN103550780B CN201310525253.6A CN201310525253A CN103550780B CN 103550780 B CN103550780 B CN 103550780B CN 201310525253 A CN201310525253 A CN 201310525253A CN 103550780 B CN103550780 B CN 103550780B
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Abstract
The invention provides a protein protective agent for Pasteur inactivating human intravenous immunoglobulin and an inactivation method of the protein protective agent. A Pasteur inactivation method of human intravenous immunoglobulin comprises the following steps of adding the protein protective agent to a human intravenous immunoglobulin solution before inactivating; adjusting the content of sampled protein to be 40 to 60g/L, and adjusting pH (Potential of Hydrogen) to be 4.7 to 5.3; agitating for 30 minutes; transferring into a water bath under 60+/- 1 DEG C; maintaining the solution at temperature of 60+/ -0.5 DEG C for 10 hours after the solution temperature reaches 60 DEG C, thus accomplishing the inactivation of human intravenous immunoglobulin, wherein the protein protective agent is saccharose, arginine, glycine and sorbitol which are respective 50 to 70g/L, 20 to 40g/L, 30 to 60g/L and 240 to 260g/L in final content. According to the protein protective agent, simple sorbitol is used as the protective agent, the content of a polymer is decreased from 4.12% to 1.96%, thus the protein can be protected well, and the product quality can be improved.
Description
Technical field
The invention provides protein protectant and ablation method thereof, the protein protectant of especially a kind of pasteurization quiet note human normal immunoglobulin and ablation method thereof.
Background technology
Human normal immunoglobulin is one group of protein with antibody activity, after infusion, can improve rapidly the IgG level in receptor's blood, the anti-infection ability of enhancing body and immunoloregulation function.Because the raw material of quiet note human normal immunoglobulin is human normal plasma, although adopt various detectable to screen blood plasma and within 2007, to come into effect system 90 day quanrantine to Plasma donors, make patient greatly away from the risk of virus attack, but still be subject to the potential threat of the susceptiveness of plasma screening reagent and the restriction of technology and unknown virus.Therefore blood products in process of production on the one hand, by strict screening Plasma donors to reduce or to get rid of the virus that may exist in raw blood plasma; On the other hand in preparation process, introduce effective virus inactivation technology, this also fundamentally eliminate blood products may cause viral infection effective guarantee.National Drug Administration issued in 2002 one " blood products removal/inactivation of viruses technical method and test positive guideline " for this reason, list conventional virus inactivating method and indicator virus in principle, wherein pasteurization method is exactly a kind of conventional effective method in blood products production process.It shows in the application clinical practice decades result of human albumin, and this method is safe to HIV and hepatitis virus.It is also the selection of numerous enterprises for quiet note human normal immunoglobulin, but goods are after heated, all can occur the situation that polymer increases, and screening one or more protective agents becomes the required homework of numerous blood products enterprise.
Summary of the invention
The invention provides protein protectant and the ablation method thereof of a kind of pasteurization quiet note human normal immunoglobulin, solving in the inactivation process of existing human albumin, after heated, there is the problem that polymer increases in goods.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A pasteurization quiet note human normal immunoglobulin's protein protectant, comprise sucrose, arginine, glycine and sorbitol, its final content is respectively: 50g/L ~ 70g/L, 20g/L ~ 40g/L, 30g/L ~ 60g/L and 240g/L ~ 260g/L.
Further, a preferred embodiment of the present invention: final 60g/L, 30g/L, 40g/L, 250g/L of described sucrose, arginine, glycine, sorbitol.
Protein protectant of the present invention can be widely used in the deactivation of blood products.
A quiet note human normal immunoglobulin's pasteurization method, comprises the following steps:
First the quiet note human normal immunoglobulin solution before deactivation is added protein protectant; then sample protein matter content 40g/L ~ 60g/L is adjusted; pH value 4.7 ~ 5.3; stir after 30 minutes; put into 60 DEG C ± 1 DEG C water-bath; treat that solution temperature is to 60 DEG C of timing; keep solution temperature 60 DEG C ± 0.5 DEG C 10 hours; namely the deactivation of quiet note human normal immunoglobulin is completed; described protein protectant comprises sucrose, arginine, glycine and sorbitol, and its final content is respectively: 50g/L ~ 70g/L, 20g/L ~ 40g/L, 30g/L ~ 60g/L and 240g/L ~ 260g/L.
Further, a preferred embodiment of the present invention: final 60g/L, 30g/L, 40g/L, 250g/L of described sucrose, arginine, glycine, sorbitol.
The protectant Selecting research of different proteins:
First the quiet note human normal immunoglobulin solution before deactivation is added protein protectant; then sample protein matter content 40g/L ~ 60g/L is adjusted; pH value 4.7 ~ 5.3; stir after 30 minutes; put into 60 DEG C ± 1 DEG C water-bath; treat that products temperature is to 60 DEG C of timing, keep products temperature 60 DEG C ± 0.5 DEG C 10 hours.Measure polymer change before and after heating after rear taking-up, compare.Assay method measures according to " Chinese Pharmacopoeia " version in 2010 three annex VI R " human normal immunoglobulin's based article IgG monomer adds dimer algoscopy ".
1, the combination based on sorbitol is compared, and the results are shown in following table 1.
The result of table 1 various combination
Note: polymer 1.86% before heating, lower same.
By testing above and can reaching a conclusion: using sorbitol, glycine, sucrose, arginine as protein protectant, better than combined effect wherein.
2, the screening of arginine concentrations
The concentration of sorbitol, glycine, sucrose is decided to be respectively 15% (g/ml), 5% (g/ml), 5% (g/ml), arginine concentrations is respectively by 1% (g/ml), 3% (g/ml), 5% (g/ml), 7% (g/ml), 10% (g/ml), and concrete outcome is in table 2.
The selection result of table 2 arginine concentrations
By this experiment, arginine is from 3%(g/ml) more than, the change of its polymer is little.We think that arginine concentrations locates 3%(g/ml) comparatively suitable.
3, the screening of glycine concentration
Sorbitol, sucrose, arginic concentration are decided to be 15%(g/ml respectively), 5%(g/ml), 3%(g/ml), glycine concentration is respectively by 2%(g/ml), 4%(g/ml), 6%(g/ml), 8%(g/ml), 10%(g/ml), concrete outcome is in table 3.
The result of the screening of table 3 glycine concentration
As can be seen from the above table, glycine concentration location 4%(g/ml) better.
4, the screening of sucrose concentration
The concentration of sorbitol, arginine, glycine is decided to be 15%(g/ml respectively), 3%(g/ml), 4%(g/ml), sucrose concentration is respectively by 2%(g/ml), 4%(g/ml), 6%(g/ml), 8%(g/ml), 10%(g/ml), concrete outcome is in table 4.
The result of the screening of table 4 sucrose concentration
As can be seen from the above table, sucrose concentration location 6%(g/ml) better.
5, the screening of sorbitol concentration
The concentration of sucrose, arginine, glycine is decided to be 6%(g/ml respectively), 3%(g/ml), 4%(g/ml), sorbitol concentration is respectively by 10%(g/ml), 15%(g/ml), 20%(g/ml), 25%(g/ml), 30%(g/ml), concrete outcome is in table 5.
The selection result of table 5 sorbitol concentration
As can be seen from the above table, sorbitol concentration location 25%(g/ml) better.
The index measuring other quiet note human normal immunoglobulin in addition in experiment, with consistent as the result of protein protectant according to sorbitol, shows to adopt protein protectant of the present invention other physical and chemical indexs on quiet note human normal immunoglobulin not affect.
Beneficial effect of the present invention:
Protein protectant of the present invention, can ensure goods effectively, polymerization little after heating; with simple sorbitol as protective agent; polymeric content is 4.12% dropped to 1.96%, well protects the protein in blood products, improves product quality.
Detailed description of the invention
Below in conjunction with this specific embodiment, be clearly and completely described technical scheme of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1
A quiet note human normal immunoglobulin's pasteurization method, comprises the following steps:
First the quiet note human normal immunoglobulin solution before deactivation is added protein protectant; then sample protein matter content 40g/L ~ 60g/L is adjusted; pH value 4.7 ~ 5.3; stir after 30 minutes; put into 60 DEG C ± 1 DEG C water-bath, treat that solution temperature is to 60 DEG C of timing, keep solution temperature 60 DEG C ± 0.5 DEG C 10 hours; namely complete the deactivation of quiet note human normal immunoglobulin, described protein protectant comprises sucrose 60g/L, arginine 30g/L, glycine 40g/L and sorbitol 250g/L.After deactivation, measure polymer change before and after heating after taking out, assay method measures according to " Chinese Pharmacopoeia " version in 2010 three annex VI R " human normal immunoglobulin's based article IgG monomer adds dimer algoscopy ".The polymer change content measured is 1.90%, and the polymer change content before deactivation is 1.88%.
Embodiment 2
A quiet note human normal immunoglobulin's pasteurization method, comprises the following steps:
First the quiet note human normal immunoglobulin solution before deactivation is added protein protectant; then sample protein matter content 40g/L ~ 60g/L is adjusted; pH value 4.7 ~ 5.3; stir after 30 minutes; put into 60 DEG C ± 1 DEG C water-bath, treat that solution temperature is to 60 DEG C of timing, keep solution temperature 60 DEG C ± 0.5 DEG C 10 hours; namely complete the deactivation of quiet note human normal immunoglobulin, described protein protectant comprises sucrose 70g/L, arginase 12 0g/L, glycine 30g/L and sorbitol 260g/L.After deactivation, measure polymer change before and after heating after taking out, assay method measures according to " Chinese Pharmacopoeia " version in 2010 three annex VI R " human normal immunoglobulin's based article IgG monomer adds dimer algoscopy "; The polymer change content measured is 1.97%, and the polymer change content before deactivation is 1.88%.
Embodiment 3
A quiet note human normal immunoglobulin's pasteurization method, comprises the following steps:
First the quiet note human normal immunoglobulin solution before deactivation is added protein protectant; then sample protein matter content 40g/L ~ 60g/L is adjusted; pH value 4.7 ~ 5.3; stir after 30 minutes; put into 60 DEG C ± 1 DEG C water-bath, treat that solution temperature is to 60 DEG C of timing, keep solution temperature 60 DEG C ± 0.5 DEG C 10 hours; namely complete the deactivation of quiet note human normal immunoglobulin, described protein protectant comprises sucrose 50g/L, arginine 40g/L, glycine 20g/L l and sorbitol 240g/L.After deactivation, measure polymer change before and after heating after taking out, assay method measures according to " Chinese Pharmacopoeia " version in 2010 three annex VI R " human normal immunoglobulin's based article IgG monomer adds dimer algoscopy "; The polymer change content measured is 1.98%, and the polymer change content before deactivation is 1.88%.
Passable by above embodiment, protein protectant of the present invention has good protective effect to quiet note human normal immunoglobulin, and the Content of polymer before and after deactivation there is no change, and does not affect quiet other physical and chemical index of note human normal immunoglobulin.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (4)
1. the protein protectant of a pasteurization quiet note human normal immunoglobulin; it is characterized in that: comprise sucrose, arginine, glycine and sorbitol, its final content is respectively: 50g/L ~ 7 0g/L, 20g/L ~ 4 0g/L, 30g/L ~ 6 0g/L and 240g/L ~ 260g/L.
2. the protein protectant of a kind of pasteurization according to claim 1 quiet note human normal immunoglobulin, is characterized in that: its final content of described sucrose, arginine, glycine, sorbitol is respectively: 50g/L ~ 7 0g/L, 20g/L ~ 4 0g/L, 30g/L ~ 6 0g/L and 240g/L ~ 260g/L.
3. the purposes of the protein protectant of pasteurization as claimed in claim 1 or 2 quiet note human normal immunoglobulin, is characterized in that, for the deactivation of blood products.
4. the pasteurization method of a quiet note human normal immunoglobulin, it is characterized in that, comprise the following steps: first the quiet note human normal immunoglobulin solution before deactivation is added protein protectant, then sample protein matter content 40g/L ~ 6 0g/L is adjusted, pH value 4.7 ~ 5.3, stir after 30 minutes, put into 60 DEG C ± 1 DEG C water-bath, treat that solution temperature is to 60 DEG C of timing, keep solution temperature 60 DEG C ± 0.5 DEG C 10 hours, namely the deactivation of quiet note human normal immunoglobulin is completed, described protein protectant comprises sucrose, arginine, glycine and sorbitol, its final content is respectively: 50g/L ~ 7 0g/L, 20g/L ~ 4 0g/L, 30g/L ~ 6 0g/L and 240g/L ~ 260g/L.
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| CN104829709B (en) * | 2015-05-05 | 2016-11-16 | 广东卫伦生物制药有限公司 | Virus inactivating method in human serum immunoglobulin |
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| CN104826117B (en) * | 2015-05-05 | 2017-11-14 | 广东卫伦生物制药有限公司 | Storage stabilizing agent for human serum immunoglobulin solution preparation |
| CN114099721B (en) * | 2021-11-30 | 2023-07-14 | 华兰生物工程重庆有限公司 | Globulin pasteurization process using combined protectant |
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| CN1147318C (en) * | 2000-01-25 | 2004-04-28 | 长春长生基因药业股份有限公司 | Recombined alpha-type interferon freeze-drying protective agent |
| CN101612404B (en) * | 2009-07-29 | 2010-11-10 | 哈药集团生物疫苗有限公司 | Heat-resisting lyophilized protectant for chicken newcastle disease and chicken infectious bronchitis dual living vaccine |
| CN102018956A (en) * | 2010-11-16 | 2011-04-20 | 中国医学科学院医学生物学研究所 | F-gene type attenuated live mumps vaccine and preparation method and application thereof |
| CN102626520B (en) * | 2012-04-23 | 2013-07-03 | 青岛农业大学 | Application of heat-resisting cryoprotectant of mink canine distemper live vaccine |
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| CN104829709B (en) * | 2015-05-05 | 2016-11-16 | 广东卫伦生物制药有限公司 | Virus inactivating method in human serum immunoglobulin |
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Owner name: ZHENGZHOU LAISHI BLOOD PRODUCTS CO., LTD. Free format text: FORMER NAME: ZHENGZHOU BANGHE BIO-PHARMACEUTICAL CORPORATION |
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Address after: Magnolia high tech Development Zone in Henan province 450000 Zhengzhou Street No. 22 Patentee after: ZHENGZHOU RAAS BLOOD PRODUCTS CO., LTD. Address before: Magnolia high tech Industrial Development Zone, Henan province Zhengzhou City 450000 Street No. 22 Patentee before: Zhengzhou Banghe Bio-Pharmaceutical Corporation |