CN104109202A - Method for adsorbing human prothrombin complex from plasma - Google Patents
Method for adsorbing human prothrombin complex from plasma Download PDFInfo
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- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6429—Thrombin (3.4.21.5)
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- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6437—Coagulation factor VIIa (3.4.21.21)
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/644—Coagulation factor IXa (3.4.21.22)
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21005—Thrombin (3.4.21.5)
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21006—Coagulation factor Xa (3.4.21.6)
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21022—Coagulation factor IXa (3.4.21.22)
Abstract
The invention relates to a production method for adsorbing a human complex from plasma by a fixed bed column chromatography technique, which comprises the following steps: (1) cryoprecipitation plasma removal: filtering by using a cellulose deep filter plate which is cleaned by an EDTA (ethylene diamine tetraacetic acid) solution and a sodium citrate solution; (2) filtering the plasma subjected to deep filtration through a 0.2 mu m filter element membrane while fixed bed loading; (3) balancing 2-5 column volumes in a fixed bed chromatographic column filled with anion exchange gel Capto DEAE by using a buffer solution A at the plasma loading flow rate of 60-120 cm/hour, washing the chromatographic column with a buffer solution B, and eluting the chromatographic column with a buffer solution C to obtain a PCC (prothrombin complex concentrate) product. When the calculation is based on coagulation factor IX, the yield of the PCC can reach 75-90%, and the specific activity can reach 5.5 IU/mg above.
Description
Technical field
The present invention relates to biological products and blood products production technical field, relate generally to the fixed bed column chromatographic separation purification process of Human Factor Ⅸ Complex in blood products production.
Background technology
Human Factor Ⅸ Complex (Prothrombin Complex, PCC) extracts via human normal plasma, mainly contains the plasma protein products of human blood coagulation II, VII, IX, X.Chinese Pharmacopoeia requires in these goods human blood coagulation IX to tire and is not less than 10IU/ml, and its specific activity is not less than 0.5IU/ml.This product is mainly used in treatment and prevents because II, VII, IX, the X factor lack cause hemorrhage, as hemophilia B, hepatopathy etc.
PCC generally selects DEAESephadex A50 gel to produce, because this gel swelling factor changes larger under different salt concn, blood products enterprise all adopts batch formula absorption production technique in actual production both at home and abroad, be about to the blood plasma of gel directly and in retort and mix, adsorbed rear direct filtration and gone out gel and wash again and wash-out.Batch formula adsorption method is open-sky technique, complex operation, and have gel to leak and the risk of crossed contamination.Although also there is relevant bibliographical information to use expanding bed technology to produce PCC, the real case of application aborning has no report, and the large-scale application of visible expanding bed technology is also immature.General Electric Corporation (GE) had once developed specially Streamline series and had been specifically designed to expanding bed technology with the gel kind of quartzy core, but found that through popularization in a few years practicality is very poor, was now substantially eliminated.
Use the production technique that fixed bed chromatography technology is directly adsorbed PCC from blood plasma to have no relevant report, its major cause has following 2 points:
The first, filter the restriction of clarification technique to separating plasma purifying process.Because plasma component is complicated, except containing plasma proteins, also contain a small amount of hemocyte or fragment, the insolubless such as fat or chyle particle, insolubles size differs, and fat or chyle also cause blood plasma to have larger viscosity.These characteristics make large-scale plasmapheresis clarification process be difficult to realize.Because contain a large amount of thrombin in blood plasma, electronegative filtration medium may provide activated surface to thrombin simultaneously, causes blood coagulation reaction, causes irremediable loss, and the production of blood products is caused to tremendous influence.
The second, the DEAESephadex A50 gel generally using in traditional technology, because swelling coefficient changes compared with being not suitable for greatly fixed bed chromatography technique.
Summary of the invention
The object of the invention is to use fixed bed column chromatographic technique from blood plasma, to adsorb PCC, and prepare PCC through washing and wash-out.Particularly guaranteeing under the prerequisite that plasma coagulation factors is not activated, fairly large Depth Filtration and the fine filtering of blood plasma have been realized, and filter out the gel that is applicable to absorption and separation and purification PCC, be directly used in fixed bed chromatography post, with chromatographic technique, from blood plasma, directly adsorb also purifying and obtain PCC, thoroughly solve tradition batch formula absorbing process and easily cause pollution, crossed contamination, the problems such as gel leakage and trivial operations.
The technical solution adopted in the present invention mainly comprises: (1) removes CPP; (2) plasmapheresis, makes blood plasma reach the desired filtering accuracy of column chromatography and clarity, and guarantees that the thrombin in blood plasma is not activated or deactivation at filtration procedure with after filtering; (3) fixed bed column chromatographic technique purifying PCC, directly catches PCC from blood plasma with anionresin gel, and other plasma proteinss are worn from the direct stream of chromatography column, chromatography column is washed and wash-out, thus the PCC of acquisition purifying.Concrete technical scheme is as follows:
Above-mentioned concrete steps are
(1) remove cryoprecipitate:
Fresh Frozen human plasma, after thawing mixes, is removed to the cryoprecipitate in blood plasma through continuous flow centrifuge, obtain the blood plasma supernatant liquor after centrifugal;
(2) plasmapheresis
Use EDTA solution to clean filtering material, with liquor sodii citratis, filtering material is cleaned again, and wash away residual EDTA, after having rinsed, drain the solution in equipment, for plasmapheresis, the filtering material adopting is medicinal rank Mierocrystalline cellulose filter plate;
(3) fixed bed column chromatographic isolation and purification PCC
Gel is seated in fixed bed chromatography post, the ratio of the plasma volume of column volume and loading is 1:10 ~ 1:50, the chromatography column filling is used 2 ~ 5 column volumes of buffer A balance, blood plasma after Depth Filtration is used the filter core of 0.2 μ m to carry out pumping into chromatography column after online membrane filtration, loading flow velocity is 60 ~ 120cm/h, by buffer B, wash chromatography column, with damping fluid C elution chromatography post, obtain PCC goods, according to the activity of plasma thromboplastin component, calculate, the yield of PCC can reach 75% ~ 90%, more than specific activity can reach 5.5IU/mg.
The concentration of above-mentioned EDTA solution is 0.1%-10%, and consumption is 100 ~ 300L/m
2.
The concentration of above-mentioned liquor sodii citratis is 0.2% ~ 10%, and consumption is 100 ~ 300L/m
2.
In above-mentioned steps (2) plasmapheresis, the number of plies of described Mierocrystalline cellulose filter plate is individual layer or bilayer.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification PCC, described buffer A is comprised of 25mmol/L Sodium Citrate and 20mmol/L arginine hydrochloride, and the PH of described damping fluid is 7.0.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification PCC, described buffer B is comprised of the NaCl of 25mmol/L Sodium Citrate/20mmol/L arginine hydrochloride and 0.1 ~ 0.4mol/L.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification PCC, described damping fluid C is comprised of the NaCl of 25mmol/L Sodium Citrate/20mmol/L arginine hydrochloride and 0.5 ~ 1.0mol/L.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification PCC, described gel is anionresin gel C apto DEAE.
The invention has the beneficial effects as follows: blood plasma, through the membrane filtration of Depth Filtration and 0.2 μ m, can reach the required clarity of fixed bed chromatography technique, can effectively improve the linear velocity in loading process; And after guaranteeing to filter in blood plasma thrombin and enzyme be not activated or deactivation, still retain its activity.Blood plasma after filtration adopts fixed bed chromatography technology, use the PCC in Capto DEAE gel Direct Acquisition blood plasma, when having improved the yield and specific activity of PCC, avoided the shortcoming of existing batch of formula absorbing process, realized short period of time, high flow rate, the sealed pipe type of blood plasma and processed; The risk of having avoided pollution, crossed contamination, gel to leak; Simplify production technique, alleviated intensity of workers.
embodiment:
In order to understand better the present invention, with specific examples, describe technical scheme of the present invention in detail below, but the present invention is not limited thereto.
Embodiment 1: blood plasma Depth Filtration
Select different filter plates and corresponding fixture to assemble.According to the cleaning way in following table, clean, 2 ~ 8 ℃ of placement 24h of blood plasma after filtration, observe clotting of plasma situation.
Embodiment 2: human blood coagulation activity recovery checking in blood plasma after filtering
Use the 90SP(14cm of 3M company
2) according to 10%EDTA 300L/m
2, 10% Sodium Citrate 300L/m
2method clean after, filter blood plasma 200ml, prothrombin, VII, IX, X in feed liquid before and after filtering are detected.
The above results shows, uses the filter plate after the filter plate balance liquid containing Sodium Citrate composition is processed, and carries out after plasmapheresis, does not cause activation or the inactivation of main component prothrombin in Human Factor Ⅸ Complex, VII, IX, X activity.Therefore the blood plasma, filtering after clarification completely can be for fixed bed column chromatographic separation Purification of Human Prothrombin Complex Concent-.
Embodiment 3: fixed bed column chromatographic isolation and purification PCC
1LCapto DEAE gel is packed into fixed bed chromatography post, uses buffer A (25mmol/L Sodium Citrate, 20mmol/L arginine hydrochloride damping fluid, pH7.0) 2 ~ 5 column volumes of balance.30L blood plasma after Depth Filtration pumps into chromatography column again after the online membrane filtration of 0.2 μ m, and loading flow velocity is 60 ~ 120cm/h.With the buffer A washing chromatography column of the NaCl that contains 160mmol/L, collect stream and wear and the separation and purification of washings for other albumen again.Finally, with the buffer A elution chromatography post of the NaCl that contains 500mmol/L, obtain PCC goods.
More than wherein IX factor specific activity can reach 5.5IU/mg, be to use traditional DEAESephadex A50 gel to criticize the more than 10 times of IX factor specific activity in the PCC of formula absorbing process production.
Claims (9)
1. from blood plasma, adsorb Human Factor Ⅸ Complex's a method, comprise and remove cryoprecipitate, plasmapheresis and fixed bed column chromatographic isolation and purification PCC.
2. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 1, is characterized in that: described concrete steps are
(1) remove cryoprecipitate:
Fresh Frozen human plasma, after thawing mixes, is removed to the cryoprecipitate in blood plasma through continuous flow centrifuge, obtain the blood plasma supernatant liquor after centrifugal;
(2) plasmapheresis
Use EDTA solution to clean filtering material, with liquor sodii citratis, filtering material is cleaned again, and wash away residual EDTA, after having rinsed, drain the solution in equipment, for plasmapheresis, the filtering material adopting is medicinal rank Mierocrystalline cellulose filter plate;
(3) fixed bed column chromatographic isolation and purification PCC
Gel is seated in fixed bed chromatography post, the ratio of the plasma volume of column volume and loading is 1:10 ~ 1:50, the chromatography column filling is used 2 ~ 5 column volumes of buffer A balance, blood plasma after Depth Filtration is used the filter core of 0.2 μ m to carry out pumping into chromatography column after online membrane filtration, loading flow velocity is 60 ~ 120cm/h, by buffer B, wash chromatography column, with damping fluid C elution chromatography post, obtain PCC goods.
3. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, is characterized in that: the concentration of described EDTA solution is 0.1%-10%, and consumption is 100 ~ 300L/m
2.
4. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, is characterized in that: the concentration of described liquor sodii citratis is 0.2% ~ 10%, and consumption is 100 ~ 300L/m
2.
5. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, is characterized in that: in described step (2) plasmapheresis, the number of plies of described Mierocrystalline cellulose filter plate is individual layer or bilayer.
6. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, it is characterized in that: in described step (3) fixed bed column chromatographic isolation and purification PCC, described buffer A is comprised of 25mmol/L Sodium Citrate and 20mmol/L arginine hydrochloride, and the PH of described damping fluid is 7.0.
7. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, it is characterized in that: in described step (3) fixed bed column chromatographic isolation and purification PCC, described buffer B is comprised of the NaCl of 25mmol/L Sodium Citrate/20mmol/L arginine hydrochloride and 0.1 ~ 0.4mol/L.
8. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, it is characterized in that: in described step (3) fixed bed column chromatographic isolation and purification PCC, described damping fluid C is comprised of the NaCl of 25mmol/L Sodium Citrate/20mmol/L arginine hydrochloride and 0.5 ~ 1.0mol/L.
9. a kind of method of adsorbing Human Factor Ⅸ Complex from blood plasma according to claim 2, is characterized in that: in described step (3) fixed bed column chromatographic isolation and purification PCC, described gel is anionresin gel C apto DEAE.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104328036A (en) * | 2014-10-28 | 2015-02-04 | 成都英德生物医药装备技术有限公司 | Human prothrombin complex adsorption and separation device |
| 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 |
| 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 |
| 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 |
| CN106497903A (en) * | 2016-09-26 | 2017-03-15 | 河北大安制药有限公司 | A kind of technique for purifying blood coagulation proenzyme 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 |
| CN107406840A (en) * | 2015-02-25 | 2017-11-28 | 奥姆里克斯生物药品有限公司 | Method for purifying and quantifying fibrin ferment and its polypeptide of degrading |
| CN109705208A (en) * | 2018-12-29 | 2019-05-03 | 山东泰邦生物制品有限公司 | A kind of technique of single step chromatography preparation high-purity vWF ELISA |
| CN111965303A (en) * | 2020-07-25 | 2020-11-20 | 山东泰邦生物制品有限公司 | Device for batch type adsorption separation test and using method |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104328036B (en) * | 2014-10-28 | 2016-08-24 | 成都英德生物医药装备技术有限公司 | A kind of Human Factor Ⅸ Complex's adsorption separation device |
| CN104328036A (en) * | 2014-10-28 | 2015-02-04 | 成都英德生物医药装备技术有限公司 | Human prothrombin complex adsorption and separation device |
| US11008560B2 (en) | 2015-02-25 | 2021-05-18 | Omrix Biopharmaceuticals Ltd. | Method for purifying and quantifying thrombin and its degradation polypeptides |
| CN107406840A (en) * | 2015-02-25 | 2017-11-28 | 奥姆里克斯生物药品有限公司 | Method for purifying and quantifying fibrin ferment and its polypeptide of degrading |
| US11149263B2 (en) | 2015-02-25 | 2021-10-19 | Omrix Biopharmaceuticals Ltd. | Method for purifying and quantifying thrombin and its degradation polypeptides |
| CN107406840B (en) * | 2015-02-25 | 2021-05-28 | 奥姆里克斯生物药品有限公司 | Method for purifying and quantifying thrombin and polypeptides degraded thereby |
| 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 |
| 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 |
| CN106497903A (en) * | 2016-09-26 | 2017-03-15 | 河北大安制药有限公司 | A kind of technique for purifying blood coagulation proenzyme complex |
| CN106497903B (en) * | 2016-09-26 | 2018-07-20 | 河北大安制药有限公司 | A kind of technique for purifying blood coagulation proenzyme compound |
| 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 |
| CN109705208A (en) * | 2018-12-29 | 2019-05-03 | 山东泰邦生物制品有限公司 | A kind of technique of single step chromatography preparation high-purity vWF ELISA |
| CN109705208B (en) * | 2018-12-29 | 2022-04-26 | 山东泰邦生物制品有限公司 | Process for preparing high-purity von willebrand factor by single-step chromatography |
| CN111965303A (en) * | 2020-07-25 | 2020-11-20 | 山东泰邦生物制品有限公司 | Device for batch type adsorption separation test and using method |
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