CN101974070A - Preparation process of human prothrombin compound - Google Patents
Preparation process of human prothrombin compound Download PDFInfo
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- CN101974070A CN101974070A CN 201010534827 CN201010534827A CN101974070A CN 101974070 A CN101974070 A CN 101974070A CN 201010534827 CN201010534827 CN 201010534827 CN 201010534827 A CN201010534827 A CN 201010534827A CN 101974070 A CN101974070 A CN 101974070A
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Abstract
The invention relates to a preparation process of a human prothrombin compound, belonging to the field of biological pharmacy. The preparation process comprises the following steps of: absorbing blood plasma, washing, eluting and clarifying by filtration; inactivating viruses by using the S/D (Solvent/Detergent) method; purifying by absorption; subpackaging; freeze-drying; and inactivating viruses by the dry heat method. The human prothrombin compound is directly absorbed from blood plasma by using gel, only the gel chromatography technology is used in the entire extraction process, so that the production steps are simplified, the pollution of various factors on the production process of the product is reduced, meanwhile, the yield of the product is increased by 25-30%. In addition, the S/D method is used for removing lipid-enveloped viruses and the dry heat method is used for removing non lipid-enveloped viruses in the production process, and the safety of clinic medication is obviously increased through the two virus inactivation steps.
Description
Technical field
The present invention relates to a kind of Human Factor's preparation technology, belong to field of biological pharmacy.
Background technology
The Human Factor is contained vitamin K and is relied on it in four kinds of thrombogens of liver synthetic, VII, IX, X.Vitamin K deficiency and serious liver disease all can cause the shortage of these four factors.And the shortage of above-mentioned any one factor all can cause blood coagulation disorders.The infusion Human Factor can improve the concentration of thrombogen in the blood, VII, IX, X.Therefore, be mainly used in the congenital and acquired thrombogen of treatment, VII, IX, X deficiency disease.The method for making of standard is; Get fresh separated liquid blood plasma, the refrigerated plasma of healthy blood donor, use DIRECT GEL absorption method or cold ethanol and polyoxyethylene glycol method protein isolate in blood plasma also to purify with the method for authorized by state.Be mixed with the solution of normality behind inactivation of viruses, add an amount of stablizer, degerming filters, sterile filling, and lyophilize is in time made.In the prior art as publication number CN 1475569A, denomination of invention " lyophilized prothrombin complex contrates's production method ", it includes following operation: be precipitated as raw material through the separation of dissolving → low-temperature centrifugation, the absorption → washing of filtration → gel, wash-out gel → ultrafiltration and concentration → S/D inactivation of viruses → two-step gelation absorption → washing and wash-out gel → ultrafiltration dialysis → microporous membrane Sterile Filtration packing → lyophilize with FIII, place 98-100 ℃ boiling water bath to carry out xeothermic deactivation 30 minutes the lyophilized prothrombin complex contrates.This lyophilized prothrombin complex contrates has the IX factor content greater than 2010/ml, and IX factor specific activity is more thorough greater than proteic European Pharmacopoeia standard of 0.610/ag and inactivation of virus, uses safer advantage.
Summary of the invention
The purpose of this invention is to provide a kind of gel of taking directly from blood plasma absorption Human Factor, only adopt the gel chromatography technology in the whole process of extraction, simplified production stage, reduced various factors to the pollution in the process of producing product, the yield of product improves simultaneously, has significantly improved the Human Factor's of clinical application safety preparation technology through the secondary inactivation of virus.
The object of the present invention is achieved like this, and its preparation technology is as follows:
(1), absorption
The blood plasma that will meet the removal cryoprecipitate of pharmacopeia requirement is warming up to 8-10 ℃, and the 0.8-1.5% that presses this plasma volume adds the A-50 gel of using the balance liquid pre-equilibration, more than whip attachment 45-60 minute, collects gel, and supernatant liquor is incorporated in the blood plasma jar;
(2), washing
Be no less than at every turn step (1) the washings of 1 times of volume of gel content wash this gel 2-3 time, put driedly after stirring at every turn, the collection washings is incorporated in the blood plasma jar;
(3), wash-out
Be no less than at every turn step (2) washing after this gel of elutriant wash-out 3 times of 1 times of volume of gel content, stir at every turn and put driedly in 10 minutes, collect albumen elutriant behind the wash-out in clean container; Filter the albumen filtered liquid after the filtration of collecting with the clarification filter of 0.45-1.0 filter core;
(4), ultrafiltration
Carry out ultrafiltration dialysis more than 3 times, use the albumen filtered liquid equal-volume dialyzate that gets with step (3) to carry out ultrafiltration dialysis at every turn, concentrate and collect concentrated solution, make dialysis fluid electric conductivity value be lower than 15ms, tire at 20-50IU/ml, the concentrated liquid measure of weighing, PH is at 6.5-7.5;
(5), with S/D method inactivation of virus
10% of the concentrated solution total amount of (4) adding 11%S/D solution stirring is even set by step, gets mixed liquid of protein, and mixed liquid of protein is transferred to the deactivation jar; Stirring is warming up to 24-26 ℃ and is incubated 6 hours continuously, and write down the mixed liquid of protein temperature once per half an hour;
(6), adsorption and purification again
1. gel column and A-50 Gel Treatment: use 0.5mol/LNaOH to smear gel column, the A-50 gel uses 0.5mol/LNaOH to soak 2 hours;
2. ultrafilter is extremely neutral with the water for injection flushing;
3. absorption: with the mixed liquid of protein after the S/D deactivation, stir, the 1.0-1.5% that presses plasma volume adds with the good A-50 gel of balance liquid pre-equilibration, and absorption was collected gel more than 45 minutes, and effluent liquid is abandoned;
4. washing: be no less than at every turn step 3. the S/D washings of 1 times of volume of gel content wash this gel 10 times, put driedly after stirring at every turn, the scrub stream fluid is abandoned;
5. wash-out: be no less than at every turn step 4. washing after this gel of elutriant wash-out 3 times of 1 times of volume of gel content, stir at every turn and put driedly in 20 minutes, collect albumen elutriant behind the wash-out in clean container;
6. with the clarification filter filtration step of 0.45-1.0 filter core 5. the albumen elutriant, the albumen filtered liquid after the filtration of collection;
7. ultrafiltration: carry out ultrafiltration dialysis more than 3 times, use the albumen filtered liquid equal-volume dialyzate that 6. gets with step to carry out ultrafiltration dialysis at every turn, make dialysis fluid electric conductivity value be lower than 10 ms, begin to concentrate, concentrated solution is tired more than 30IU/ml, concentrates the back concentrated solution is changed over to preparing tank, the concentrated liquid measure of weighing, adjustment PH is 6.5-7.5, gets 20ml after stirring, and 3 bottles of samples are done the stoste calibrating; According to the verification result dosing, extraordinarily go into heparin sodium with 0.2 of total titer, finally press product weight and add glycine, making glycine content is 2%;
(7), packing;
Tire according to rare dosing, determine to divide loading amount, with 0.2 filter core (PVDF) degerming packing;
(8), freeze-drying;
1. goods normal temperature advances cabinet,
2. dividing plate 10 minutes is reduced to 0 ℃ from normal temperature, keeps 30 minutes;
3. dividing plate 30 minutes drops to-40 ℃ from 0 ℃, keeps 1.5 hours at-40 ℃;
4. driving vacuum pump, to reach 0.3mbar to vacuum stable;
5. 1 hour dividing plate is warmed up to-33 ℃, keeps 1 hour;
6. 5 hours dividing plates are warmed up to 0 ℃, keep 30 hours;
7. 2 hours dividing plates are warmed up to 10 ℃, keep 6 hours;
8. 2 hours dividing plates are warmed up to 35 ℃, keep 6 hours;
9. made vacuum arrive 0.05mbar in 1 hour, kept 1 hour;
(9), xeothermic deactivation;
With 99.5 ± 0.5 ℃ of xeothermic deactivations of water-bath 30 minutes;
Wherein
Balance liquid contains 0.08mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
Washings contains 0.14 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
The S/D washings contains 0.05 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
Elutriant contains 2mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water;
Dialyzate contains the 0.01mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
11%S/D solution adds water to the method preparation of 1L by 110ml tween-80 and 33ml TNBP;
Above per-cent removes and specifies that all the other all are weight percentage.
The present invention uses advanced chromatographic technique, take gel directly from blood plasma absorption Human Factor, extracting the gel chromatography technology that whole process just adopts the advanced person, simplified production stage, reduced various factors to the pollution in the process of producing product, the yield of product improves 25-30% simultaneously.Adopt S/D method removal lipid-coated virus and 99.5 ± 0.5 ℃ of dry heating methods to remove non-lipid-coated virus in addition in the production process, significantly improved clinical application safety through these 2 inactivation of virus steps.
Embodiment
Embodiment:
One, basic demand:
1, the collection of raw blood plasma and quality should meet the regulation of blood products production with human plasma;
2, blood plasma should not have grumeleuse, and no scleroproein is separated out, no haemolysis etc.;
3, plasma removing cryoprecipitate, thrombin eight etc.;
4, production unit pipeline utensil is answered cleaning-sterilizing etc.
Two, main agents preparation:
The preparation balance liquid contains 0.08mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
The preparation washings contains 0.14 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
Preparation S/D washings contains 0.05 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
The preparation elutriant contains 2mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water;
The preparation dialyzate contains the 0.01mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
The 11%S/D prescription: 110ml tween-80+TNBP33ml adds water to 1L;
2mol/L glacial acetic acid proportioning: the 1200ml glacial acetic acid is to 10000ml water for injection;
0.5mol/LNaOH proportioning: 200gNaOH to 10000ml water for injection;
0.1mol/LNaOH proportioning: 40gNaOH to 10000ml water for injection;
Three, the specific embodiment of the invention is embodied in summary of the invention, and summary of the invention can be directly used in embodiment.
Described in preparation technology such as the summary of the invention to blood plasma adsorb, washing, wash-out and clarification filtration; Inactivation of virus (S/D method); Adsorption and purification again; Packing; Freeze-drying; Xeothermic deactivation.
In dosing, add heparin sodium, be by 0.2 method of calculation that add the amount of heparin sodium of tiring:
Amount=protein concentrated solution the total amount that adds heparin sodium
(L) * tire
IU/ml * 0.2 * 1000=
IU
Claims (1)
1. a Human Factor preparation technology is characterized in that preparation technology is as follows:
(1), absorption
The blood plasma that will meet the removal cryoprecipitate of pharmacopeia requirement is warming up to 8-10 ℃, and the 0.8-1.5% that presses this plasma volume adds the A-50 gel of using the balance liquid pre-equilibration, more than whip attachment 45-60 minute, collects gel, and supernatant liquor is incorporated in the blood plasma jar;
(2), washing
Be no less than at every turn step (1) the washings of 1 times of volume of gel content wash this gel 2-3 time, put driedly after stirring at every turn, the collection washings is incorporated in the blood plasma jar;
(3), wash-out
Be no less than at every turn step (2) washing after this gel of elutriant wash-out 3 times of 1 times of volume of gel content, stir at every turn and put driedly in 10 minutes, collect albumen elutriant behind the wash-out in clean container; Filter the albumen filtered liquid after the filtration of collecting with the clarification filter of 0.45-1.0 filter core;
(4), ultrafiltration
Carry out ultrafiltration dialysis more than 3 times, use the albumen filtered liquid equal-volume dialyzate that gets with step (3) to carry out ultrafiltration dialysis at every turn, concentrate and collect concentrated solution, make dialysis fluid electric conductivity value be lower than 15ms, tire at 20-50IU/ml, the concentrated liquid measure of weighing, PH is at 6.5-7.5;
(5), with S/D method inactivation of virus
10% of the concentrated solution total amount of (4) adding 11%S/D solution stirring is even set by step, gets mixed liquid of protein, and mixed liquid of protein is transferred to the deactivation jar; Stirring is warming up to 24-26 ℃ and is incubated 6 hours continuously, and write down the mixed liquid of protein temperature once per half an hour;
(6), adsorption and purification again
1. gel column and A-50 Gel Treatment: use 0.5mol/LNaOH to smear gel column, the A-50 gel uses 0.5mol/LNaOH to soak 2 hours;
2. ultrafilter is extremely neutral with the water for injection flushing;
3. absorption: with the mixed liquid of protein after the S/D deactivation, stir, the 1.0-1.5% that presses plasma volume adds with the good A-50 gel of balance liquid pre-equilibration, and absorption was collected gel more than 45 minutes, and effluent liquid is abandoned;
4. washing: be no less than at every turn step 3. the S/D washings of 1 times of volume of gel content wash this gel 10 times, put driedly after stirring at every turn, the scrub stream fluid is abandoned;
5. wash-out: be no less than at every turn step 4. washing after this gel of elutriant wash-out 3 times of 1 times of volume of gel content, stir at every turn and put driedly in 20 minutes, collect albumen elutriant behind the wash-out in clean container;
6. with the clarification filter filtration step of 0.45-1.0 filter core 5. the albumen elutriant, the albumen filtered liquid after the filtration of collection;
7. ultrafiltration: carry out ultrafiltration dialysis more than 3 times, use the albumen filtered liquid equal-volume dialyzate that 6. gets with step to carry out ultrafiltration dialysis at every turn, make dialysis fluid electric conductivity value be lower than 10 ms, begin to concentrate, concentrated solution is tired more than 30IU/ml, concentrates the back concentrated solution is changed over to preparing tank, the concentrated liquid measure of weighing, adjustment PH is 6.5-7.5, gets 20ml after stirring, and 3 bottles of samples are done the stoste calibrating; According to the verification result dosing, extraordinarily go into heparin sodium with 0.2 of total titer, finally press product weight and add glycine, making glycine content is 2%;
(7), packing;
(8), freeze-drying;
1. goods normal temperature advances cabinet,
2. dividing plate 10 minutes is reduced to 0 ℃ from normal temperature, keeps 30 minutes;
3. dividing plate 30 minutes drops to-40 ℃ from 0 ℃, keeps 1.5 hours at-40 ℃;
4. driving vacuum pump, to reach 0.3mbar to vacuum stable;
5. 1 hour dividing plate is warmed up to-33 ℃, keeps 1 hour;
6. 5 hours dividing plates are warmed up to 0 ℃, keep 30 hours;
7. 2 hours dividing plates are warmed up to 10 ℃, keep 6 hours;
8. 2 hours dividing plates are warmed up to 35 ℃, keep 6 hours;
9. made vacuum arrive 0.05mbar in 1 hour, kept 1 hour;
(9), xeothermic deactivation;
Wherein
Balance liquid contains 0.08mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
Washings contains 0.14 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
The S/D washings contains 0.05 mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
Elutriant contains 2mol/L NaCl and 0.02mol/L citrate three sodium, and surplus is a water;
Dialyzate contains the 0.01mol/L citrate three sodium, and surplus is a water, and PH is at 6.8-7.2;
11%S/D solution adds water to the method preparation of 1L by 110ml tween-80 and 33ml TNBP;
Above per-cent removes and specifies that all the other all are weight percentage.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105039295A (en) * | 2015-09-15 | 2015-11-11 | 上海洲跃生物科技有限公司 | Method for preparing human thrombin from cold-removing glue plasma |
| CN105326859A (en) * | 2015-11-09 | 2016-02-17 | 上海洲跃生物科技有限公司 | Method for preparing human prothrombin complex from Cohn blood plasma component III |
| CN105821024A (en) * | 2016-05-30 | 2016-08-03 | 成都蓉生药业有限责任公司 | Method for preparing human prothrombin complex |
| CN106676089A (en) * | 2017-03-01 | 2017-05-17 | 广东双林生物制药有限公司 | Method for preparing human prothrombin complex from plasma |
| CN108660126A (en) * | 2018-06-08 | 2018-10-16 | 博雅生物制药集团股份有限公司 | A kind of preparation process of freeze dried human zymoplasm |
| CN112574979A (en) * | 2020-12-14 | 2021-03-30 | 北京华创精科生物技术有限公司 | Gel treatment equipment and method for plasma |
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| CN1475569A (en) * | 2002-08-15 | 2004-02-18 | 华兰生物工程股份有限公司 | Production method of freeze dried human prothrombin compound |
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| CN1475569A (en) * | 2002-08-15 | 2004-02-18 | 华兰生物工程股份有限公司 | Production method of freeze dried human prothrombin compound |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| CN105039295A (en) * | 2015-09-15 | 2015-11-11 | 上海洲跃生物科技有限公司 | Method for preparing human thrombin from cold-removing glue plasma |
| CN105326859A (en) * | 2015-11-09 | 2016-02-17 | 上海洲跃生物科技有限公司 | Method for preparing human prothrombin complex from Cohn blood plasma component III |
| CN105821024A (en) * | 2016-05-30 | 2016-08-03 | 成都蓉生药业有限责任公司 | Method for preparing human prothrombin complex |
| CN106676089A (en) * | 2017-03-01 | 2017-05-17 | 广东双林生物制药有限公司 | Method for preparing human prothrombin complex from plasma |
| CN106676089B (en) * | 2017-03-01 | 2020-01-10 | 广东双林生物制药有限公司 | Method for preparing human prothrombin complex from blood plasma |
| CN108660126A (en) * | 2018-06-08 | 2018-10-16 | 博雅生物制药集团股份有限公司 | A kind of preparation process of freeze dried human zymoplasm |
| CN112574979A (en) * | 2020-12-14 | 2021-03-30 | 北京华创精科生物技术有限公司 | Gel treatment equipment and method for plasma |
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Address after: 344000 Jiangxi city of Fuzhou province high tech Industrial Park Hui Road No. 333 Patentee after: Boya biopharmaceutical group Limited by Share Ltd Address before: 344000 No. 161 Gan Dong Avenue, Fuzhou, Jiangxi Patentee before: Jiangxi Boya Bio-Pharmaceutical Co., Ltd. |
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