CN1524578A - Dry heat processing stabilizer for prothrombin complex or factor v a IX preparation - Google Patents
Dry heat processing stabilizer for prothrombin complex or factor v a IX preparation Download PDFInfo
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- CN1524578A CN1524578A CNA031510582A CN03151058A CN1524578A CN 1524578 A CN1524578 A CN 1524578A CN A031510582 A CNA031510582 A CN A031510582A CN 03151058 A CN03151058 A CN 03151058A CN 1524578 A CN1524578 A CN 1524578A
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- dry heat
- heat treatment
- plasma thromboplastin
- prothrombin complex
- stabilizing agent
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Abstract
The invention relates to a stabilizing agent for preventing blood clotting factor reactive loss for prothrombin composite or blood clotting factor IX preparation during virus animatum eradication by dry heat, wherein the stabilizing agent is sucrose or / and arginine or its salt, it also can contain one or more of the conventional glycine, NaCl, citric acid trisodium and hamocura.
Description
Technical field
The present invention relates to medical technical field, is a kind of stabilizing agent of coagulation factor activity loss when preventing the xeothermic inactivation of viruses of prothrombin complex or plasma thromboplastin component.Particularly, be to add sucrose in prothrombin complex or the plasma thromboplastin component or/and arginine or its esters can be protected thrombin when xeothermic deactivation (80 ℃ or 100 ℃) virus, improve the response rate of thrombin.
Background technology
Prothrombin complex (Prothrombin Complex Concentrate, PCC), that is plasma thromboplastin component complex, comprise prothrombin, VII, IX, X and PROTEIN C, Protein S of vitamin k-dependent etc., can be used for the hemophilia B treatment because of containing plasma thromboplastin component, and owing to contain multiple thrombin, also can be used for vitamin K deficiency and the treatment of II, VII, IX, the X factor of secondary dysfunction of blood coagulation hemorrhage and that cause because of liver disease due to low.The plasma thromboplastin component preparation is the purified goods that contain the high-purity plasma thromboplastin component, is mainly used in the treatment hemophilia B, and its composition is simple, can avoid because the thrombosis class side reaction that other thrombin activation are brought out.
At present no matter bibliographical information prepares the plasma thromboplastin component or the method for prothrombin complex, it all is raw material with the human plasma, therefore can not get rid of the probability that infects hepatitis B virus (HBV), hepatitis C virus (HCV), HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) (HIV) or other Causative virus, preparation technology must comprise inactivation of virus or removal method for this reason.For example, in the production process of plasma thromboplastin component and prothrombin complex, mention among the U.S. Pat P4379085 with Pasteur's ablation method treatment articles; C.M.Heldebrant etc. [Transfusion1985 25 (6): 510-515] have compared Pasteur's deactivation (60 ℃, 20 hours) and the inactivating efficacy of xeothermic deactivation (98 ℃, 30 minutes) and the qualitative change such as half-life before and after the goods deactivation.Yu Rong etc. [" the Chinese biological goods are learned magazine " 1997 (10) 3:148-152] adopt organic solvent/detergent SD method to carry out the inactivation of virus of prothrombin complex.Use the virus among the nano-film filtration method removal PCC in the European patent EP 0860444, the particularly relative less non-lipid-coated virus of granule.
In above various inactivation of virus/removal method, the reaction condition of SD method is relatively gentleer, and is also fewer to the restriction of goods, only acts on the deactivation of lipid-coated virus but its action principle has limited it, to the not effect of non-fat peplos viroid.The molecular size of nano-film filtration method and goods, configuration, character are closely related, bigger as the fruit product molecular weight, select for use the less nanometer film in aperture then virus can't be separated with goods, the bigger film in aperture can't be realized the particulate removal of small virus again, and its scope of application has certain limitation.Therefore at present simultaneously the reliable method of deactivation fat peplos and non-lipid-coated virus be heating.Wet heating, as Pasteur's deactivation method is the virus inactivating method that uses the earliest, good reliability, but many activated proteins and enzyme can't stand following 60 ℃/10 hours rigor condition of wet heat condition, often need to add a large amount of stabilizing agents, and the stabilizing agent of high concentration can reduce the active loss of product biological, but the effect of inactivation of viruses also can be affected, simultaneously also increase many extra production stages, improved production cost, prolonged the production cycle.And dry heating method (60-100 ℃/10 minutes-72 hours, particularly 80 ℃/72 hours or 100 ℃/30 minutes) all effective to fat peplos and non-lipid-coated virus, and the final step that dry heat treatment is produced often, its cost is low, operability and controllability are stronger, and therefore increasing manufacturer selects for use dry heating method that goods are carried out inactivation of virus.In the various goods of xeothermic deactivation, also need to add certain amount of stabilizer protected, for example aminoacid, oligosaccharide, sugar alcohol and human albumin and various inorganic salt, organic salt etc.The used stabilizing agent of different goods is different; dry heat treatment method about prothrombin complex or plasma thromboplastin component preparation also has report at present; use inorganic salt or organic salt when proposing dry heat treatment among the Japan Patent JP62010019, as performance protective effects such as sodium chloride or sodium citrate.But protective effect is not ideal enough in actual the use, and the coagulation factor activity response rate before and after the actual dry heat treatment is difficult to meet or exceed 70%, is difficult to satisfy the big needs of producing.So far do not see relevant with sucrose or/and arginine is used for the report of prothrombin complex or plasma thromboplastin component preparation dry heat treatment stabilizing agent.
Summary of the invention
The invention provides the stabilizing agent of a kind of prothrombin complex or plasma thromboplastin component preparation dry heat treatment, make preparation in 80-100 ℃ of following dry heat treatment process, plasma thromboplastin component and II, VII, X are impaired few, and activity recovery reaches more than 70%.Stabilizing agent of the present invention is meant sucrose or/and arginine or its salt, also can contain in glycine commonly used, NaCl, trisodium citrate, the heparin one or more.The sucrose that adds 0.1-10% in plasma thromboplastin component or prothrombin complex is or/and 0.1%-5% arginine or its salt, just can 80-100 ℃ xeothermic time, can reach the inactivation of viruses effect, can reduce the loss of activity of thrombin in the goods again.
The specific embodiment
The protective effect to prothrombin complex preparation or plasma thromboplastin component preparation when the xeothermic inactivation of viruses elaborates to stabilizing agent of the present invention below in conjunction with embodiment.
Embodiment 1: stabilizing agent of the present invention is to the protective effect of prothrombin complex.
1. the preparation of prothrombin complex
According to a conventional method, the blood plasma supernatant of refrigerated plasma or removal cryoprecipitate adsorbs prothrombin complex with resin anion (R.A.) DEAE-Sepharose A50, with the eluent eluting that contains 2M NaCl, 0.02M trisodium citrate, the eluent of gained is with containing the 0.02M trisodium citrate, 0.6%NaCl, the ultrafiltration buffer of pH6.6-7.8 carries out desalination and concentration by ultrafiltration, obtains the prothrombin complex concentrated solution.
2. the adding stabilizing agent prepares prothrombin complex lyophilized formulations (until dry heat treatment)
According to a certain ratio sucrose and arginine are formed stabilizing agent (seeing Table 1), add the prothrombin complex of above-mentioned preparation respectively, degerming, packing, lyophilizing are after 80 ℃/72 hours, 100 ℃/30 minutes xeothermic inactivation of viruses are finished product.
3. observe the activity recovery of redissolution back sample clarity and plasma thromboplastin component
The goods of above-mentioned preparation are at room temperature redissolved with water for injection, not add stabilizing agent and only to add glycine also in contrast through same dry heat treatment as the prothrombin complex goods of stabilizing agent, observe the redissolution clarity, detect tiring of plasma thromboplastin component dry heat treatment front and back, calculate the activity recovery of the IX factor.The results are shown in Table 1.
The influence of the clarity and the plasma thromboplastin component response rate after table 1 different stabilizers is redissolved to the dry heat treatment preparation
| Group | Stabilizing agent | 80 ℃ of response rate (%) | 100 ℃ of response rate (%) | Clarity | ||
| Sucrose (%) | Arginine (%) | Before xeothermic | After xeothermic | |||
| Blank | ??????????- | ????54.2 | ????62.9 | Clarification | Opalescence | |
| Glycine | 2% glycine | ????69.9 | ????70.0 | Clarification | Little band opalescence | |
| ??1 | ????5 | ????5 | ????82.2 | ????82.0 | Clarification | Little band opalescence |
| ??2 | ????4 | ????4 | ????80.8 | ????86.8 | Clarification | Clarification |
| ??3 | ????2 | ????2 | ????83.1 | ????90.9 | Clarification | Clarification |
| ??4 | ????1 | ????1 | ????86.8 | ????89.7 | Clarification | Clarification |
| ??5 | ????0.5 | ????0.5 | ????91.9 | ????105.3 | Clarification | Clarification |
| ??6 | ????6 | ????3 | ????96.2 | ????97.7 | Clarification | Clarification |
| ??7 | ????4 | ????2 | ????94.3 | ????94.5 | Clarification | Clarification |
| ??8 | ????3 | ????1.5 | ????93.7 | ????97.3 | Clarification | Clarification |
| ??9 | ????2 | ????1 | ????96.2 | ????100.6 | Clarification | Clarification |
| ??10 | ????1 | ????0.5 | ????105.1 | ????102.7 | Clarification | Clarification |
As seen from Table 1, do not add stabilizing agent blank and with 2% glycine as the goods of stabilizing agent after 80 ℃ or 100 ℃ of dry heat treatment, the plasma thromboplastin component response rate all is no more than 70%, and be the preparation of stabilizing agent with the sucrose and the arginine of different proportionings, the IX factor response rate is all more than 80%.Though the outward appearance of each freeze-dried products does not have significant difference; but after the water for injection redissolution; add sucrose and arginic products appearance obviously than blank and only to add glycine more limpid as the goods of stabilizing agent, illustrate that stabilizing agent of the present invention can effectively protect prothrombin complex and plasma thromboplastin component thereof.
Embodiment 2: arginine is to the protection test of plasma thromboplastin component preparation
Routinely, the plasma thromboplastin component that obtains from heparin affinity chromatography Sepharose CL-6B post eluting is through the ultrafiltration desalination, and gained solution contains the 100IU/ml plasma thromboplastin component, adds 1% arginine.Respectively through 80 ℃/72 hours and 100 ℃/30 minutes dry heat treatment, that detects dry heat treatment front and back plasma thromboplastin component tires the calculated activity response rate after the lyophilizing.Compare with blank, do not add the arginic blank plasma thromboplastin component response rate and be respectively 50.9% (80 ℃/72 hours) and 57.8% (100 ℃/30 minutes), be respectively 90.8% (80 ℃/72 hours) and 92.0% (100 ℃/30 minutes) and add the 1% arginic response rate.The result shows with arginine can effectively protect plasma thromboplastin component as the goods of stabilizing agent in 80 ℃ and 100 ℃ of dry heat treatment.
Embodiment 3: sucrose is to the protection test of plasma thromboplastin component
According to a conventional method, the plasma thromboplastin component that obtains from heparin affinity chromatography Sepharose CL-6B post eluting is through ultrafiltration and concentration, the gained concentrated solution contains the 80IU/ml plasma thromboplastin component, add 1% sucrose, after the degerming lyophilizing respectively through 80 ℃/72 hours and 100 ℃/30 minutes dry heat treatment, detect the activity of dry heat treatment front and back plasma thromboplastin component, calculate its activity recovery.The plasma thromboplastin component response rate of blank is respectively 59.4% (80 ℃/72 hours) and 63.9% (100 ℃/30 minutes), and the response rate that adds 1% sucrose then is 92.9% (80 ℃/72 hours) and 94.7% (100 ℃/30 minutes).The result shows with sucrose can effectively protect plasma thromboplastin component as the goods of stabilizing agent in dry heat treatment.
Embodiment 4: arginine or sucrose are to the protection of plasma thromboplastin component, II, VII, X dry heat treatment
The prothrombin complex dried frozen aquatic products wherein contains plasma thromboplastin component 15IU/ml, factor II 20IU/ml, and factor VII 7IU/ml, factor X 20IU/ml also contains the 0.01M trisodium citrate, 0.05M NaCl, stabilizing agent sucrose or arginic content see Table 2.Through 80 ℃ of 72 hours dry heat treatment, and establish the contrast of blank and glycine, observe dry heat treatment, the results are shown in Table 2 prothrombin, VII, IX, the X response rate of tiring.
Table 2 arginine or sucrose are to the tire influence (%) of the response rate of different thrombin dry heat treatment
| Blank | 2% glycine | 0.5% arginine | 1% sucrose | |
| Plasma thromboplastin component | ????58.8 | ????70.3 | ????96.5 | ????94.1 |
| Prothrombin | ????62.4 | ????80.7 | ????90.3 | ????91.2 |
| Proconvertin | ????57.2 | ????77.5 | ????94.4 | ????93.8 |
| Stuart factor | ????50.3 | ????43.3 | ????95.9 | ????90.8 |
By table 2 as seen; compare with blank; 2% glycine can be protected II in the prothrombin complex, VII, the activity of the IX factor under 80 ℃ of 72 hours conditions to a certain extent; but the activity recovery of the X factor is lower, and sucrose, arginine can more effectively protect four kinds of thrombins to avoid long-time pyritous damage.
Embodiment 5: glycine and glycine+sucrose or/and arginine to the influence of dry heat treatment plasma thromboplastin component response rate test
Prothrombin complex solution after ultrafiltration contains factors IX 20IU/ml, the 0.01M trisodium citrate, and 0.5%NaCl, pH6.4-7.8 adds and adds sucrose by table 3 respectively again behind 2% glycine and arginine is prepared.Through 80 ℃/72 hours, 100 ℃/30 minutes dry heat treatment, detect the activity of dry heat treatment front and back plasma thromboplastin component respectively, calculate the activity recovery of the IX factor.With the comparison that compares that only adds glycine.
Table 3 different stabilizers prescription is to the tire influence of the response rate of the plasma thromboplastin component of dry heat treatment
| Numbering | Stabilizer formula | 80 ℃ of response rate (%) | 100 ℃ of response rate (%) |
| ????1 | 2% glycine | ????71.4 | ????79.9 |
| ????2 | 2% glycine+1% sucrose | ????88.1 | ????104.0 |
| ????3 | 2% glycine+0.5% sucrose | ????95.4 | ????89.3 |
| ????4 | 2% glycine+1% arginine | ????90.6 | ????91.5 |
| ????5 | 2% glycine+0.5% arginine | ????102.5 | ????97.3 |
| ????6 | 2% glycine+1% sucrose+1% arginine | ????82.2 | ????86.0 |
| ????7 | 2% glycine+0.5% sucrose+0.5% arginine | ????98.1 | ????97.3 |
As can be seen from Table 3, though glycine can improve the lyophilizing quality of prothrombin complex goods, under the situation that adds 2% glycine, further add sucrose or/and can more effectively protect IX factor active under the dry heat treatment behind the arginine.
In sum, the present invention provides effective stabilizer for the dry heat treatment of prothrombin complex or plasma thromboplastin component preparation.
Claims (8)
1. the dry heat treatment stabilizing agent of prothrombin complex or plasma thromboplastin component preparation, comprise aminoacid or/and saccharide is characterized in that said sugar is sucrose, said aminoacid is arginine or its esters, cane sugar content 0.1-10%, arginine or its esters content 0.1-5%.
2. the dry heat treatment stabilizing agent of prothrombin complex according to claim 1 or plasma thromboplastin component preparation is characterized in that said arginine salt is an arginine monohydrochloride.
3. the dry heat treatment stabilizing agent of prothrombin complex according to claim 1 and 2 or plasma thromboplastin component preparation is characterized in that also containing the 0.1-10% glycine.
4. the dry heat treatment stabilizing agent of prothrombin complex according to claim 1 and 2 or plasma thromboplastin component preparation is characterized in that also containing in sodium chloride, trisodium citrate, the heparin one or more.
5. the dry heat treatment stabilizing agent of prothrombin complex according to claim 3 or plasma thromboplastin component preparation is characterized in that also containing in sodium chloride, trisodium citrate, the heparin one or more.
6. claim 1,2, the application of 5 described dry heat treatment stabilizing agents in preparation prothrombin complex or plasma thromboplastin component preparation.
7. the application of the described dry heat treatment stabilizing agent of claim 3 in preparation prothrombin complex or plasma thromboplastin component preparation.
8. the application of the described dry heat treatment stabilizing agent of claim 4 in preparation prothrombin complex or plasma thromboplastin component preparation.
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| CN102416171A (en) * | 2011-12-06 | 2012-04-18 | 中国医学科学院输血研究所 | Protective agent in process for performing dry heat virus inactivation on high-purity prothrombin complex concentrate products |
| CN102441172A (en) * | 2011-12-06 | 2012-05-09 | 中国医学科学院输血研究所 | High-purity prothrombin complex product freeze-drying stabilizer |
| CN102604920A (en) * | 2012-04-06 | 2012-07-25 | 湖南紫光古汉南岳制药有限公司 | Preparation method of human prothrombin complex |
| CN102614219A (en) * | 2012-04-06 | 2012-08-01 | 湖南紫光古汉南岳制药有限公司 | Method for preparing human prothrombin complex with high yield |
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| CN105330736A (en) * | 2015-11-06 | 2016-02-17 | 上海洲跃生物科技有限公司 | Method for preparing human blood coagulation factors IX and VII subcutaneously from cold-glue-removed blood plasma |
| CN105879038A (en) * | 2016-05-27 | 2016-08-24 | 成都蓉生药业有限责任公司 | Dry-heat treatment stabilizer for preparing human prothrombin complex and application of dry-heat treatment stabilizer |
| CN114306578A (en) * | 2020-10-12 | 2022-04-12 | 华兰生物工程股份有限公司 | A pharmaceutical composition containing human blood coagulation factor IX and its preparation method |
| CN115814099A (en) * | 2022-12-19 | 2023-03-21 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human blood coagulation factor IX, preparation and preparation method thereof |
| CN115814099B (en) * | 2022-12-19 | 2024-04-26 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human coagulation factor IX, preparation and preparation method thereof |
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- 2003-09-18 CN CNB031510582A patent/CN100482272C/en not_active Expired - Lifetime
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| CN101759766B (en) * | 2008-11-19 | 2013-02-20 | 上海松力生物技术有限公司 | Method for preparing animal-based coagulable protein |
| CN102441172A (en) * | 2011-12-06 | 2012-05-09 | 中国医学科学院输血研究所 | High-purity prothrombin complex product freeze-drying stabilizer |
| CN102416171B (en) * | 2011-12-06 | 2013-12-25 | 中国医学科学院输血研究所 | Protective agent in process for performing dry heat virus inactivation on high-purity prothrombin complex concentrate products |
| CN102441172B (en) * | 2011-12-06 | 2014-05-07 | 中国医学科学院输血研究所 | High-purity prothrombin complex product freeze-drying stabilizer |
| CN102416171A (en) * | 2011-12-06 | 2012-04-18 | 中国医学科学院输血研究所 | Protective agent in process for performing dry heat virus inactivation on high-purity prothrombin complex concentrate products |
| CN102604920A (en) * | 2012-04-06 | 2012-07-25 | 湖南紫光古汉南岳制药有限公司 | Preparation method of human prothrombin complex |
| CN102614219A (en) * | 2012-04-06 | 2012-08-01 | 湖南紫光古汉南岳制药有限公司 | Method for preparing human prothrombin complex with high yield |
| CN104623701B (en) * | 2014-12-26 | 2017-12-29 | 四川远大蜀阳药业股份有限公司 | Parvovirus method and the preparation of acquisition in a kind of effectively inactivation PCC |
| CN104623701A (en) * | 2014-12-26 | 2015-05-20 | 四川远大蜀阳药业股份有限公司 | Method for effectively inactivating parvovirus in prothrombin complex and preparation obtained by method |
| CN105175486A (en) * | 2015-10-20 | 2015-12-23 | 上海洲跃生物科技有限公司 | Preparation method of high-purity human coagulation factor IX |
| CN105330736A (en) * | 2015-11-06 | 2016-02-17 | 上海洲跃生物科技有限公司 | Method for preparing human blood coagulation factors IX and VII subcutaneously from cold-glue-removed blood plasma |
| CN105879038A (en) * | 2016-05-27 | 2016-08-24 | 成都蓉生药业有限责任公司 | Dry-heat treatment stabilizer for preparing human prothrombin complex and application of dry-heat treatment stabilizer |
| CN105879038B (en) * | 2016-05-27 | 2020-03-27 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for preparing human prothrombin complex and application thereof |
| CN114306578A (en) * | 2020-10-12 | 2022-04-12 | 华兰生物工程股份有限公司 | A pharmaceutical composition containing human blood coagulation factor IX and its preparation method |
| CN115814099A (en) * | 2022-12-19 | 2023-03-21 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human blood coagulation factor IX, preparation and preparation method thereof |
| CN115814099B (en) * | 2022-12-19 | 2024-04-26 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human coagulation factor IX, preparation and preparation method thereof |
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