CN104109202B - Method for adsorbing human prothrombin complex from plasma - Google Patents

Method for adsorbing human prothrombin complex from plasma Download PDF

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CN104109202B
CN104109202B CN201410340403.0A CN201410340403A CN104109202B CN 104109202 B CN104109202 B CN 104109202B CN 201410340403 A CN201410340403 A CN 201410340403A CN 104109202 B CN104109202 B CN 104109202B
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pcc
fixed bed
plasma
blood plasma
column
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CN104109202A (en
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马山
张翠萍
朱孟沼
周安
马杰
董雪
吴菲菲
陈振
陈晨
席智赢
菅长永
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Shandong Taibang Biological Product Co Ltd
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    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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)
    • C12N9/6432—Coagulation factor Xa (3.4.21.6)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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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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    • C12N9/00—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)
    • C12N9/6437—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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    • 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)
    • C12Y304/21005—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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    • 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)
    • C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
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    • 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

A kind of method adsorbing Human Factor Ⅸ Complex from blood plasma
Technical field
The present invention relates to biological product and blood products production technical field, relate generally to people's blood coagulation during blood products produce The fixed bed column chromatography purification process of proenzyme complex.
Background technology
Human Factor Ⅸ Complex (prothrombin complex, pcc) is to extract via human normal plasma, mainly Plasma protein products containing human blood coagulation ii, vii, ix, x.Chinese Pharmacopoeia requires human blood coagulation ix potency in this product It is not less than 10iu/ml, it is not less than 0.5iu/ml than living.This product be mainly used in treat and prevent due to ii, vii, ix, x because Son lacks the bleeding causing, such as hemophilia B, hepatopathy etc..
Pcc typically selects deaesephadex a50 gel to produce, because this gel swelling factor is under different salinity Change greatly, production technology is all adsorbed using batch in actual production in domestic and international blood products enterprise, will gel directly with Blood plasma in retort mixes, and directly filters out gel and washed and eluting again after the completion of absorption.Batch adsorption method is to open Put formula operation, complex operation, and have the risk of gel leakage and cross-contamination.Although the document report also having correlation is using expansion Bed technique produces pcc, but the case really applied aborning has no report it is seen that expanding the large-scale application of bed technique also Immature.It is special that General Electric Co. Limited (ge) once specially developed the gel kind with quartzy core for the streamline series For expanding bed technique, but find that practicality is very poor through popularization in a few years, be substantially eliminated.
Have no relevant report using the production technology that fixed bed chromatographic technique directly adsorbs pcc from blood plasma, it is mainly former Because having at following 2 points:
Firstth, filter the restriction to blood plasma separation purifying technique for the clarification technique.Because plasma fraction is complicated, except containing blood Outside slurry albumen, also contain a small amount of hemocyte or fragment, the insoluble matter such as fat or chylomicrons, insoluble matter size is not One, fatty or chyle also results in blood plasma and has larger viscosity.These characteristics make large-scale plasmapheresis clarification process be difficult to Realize.Simultaneously as containing substantial amounts of thrombin in blood plasma, negatively charged filter medium may provide to thrombin Activated surface, causes Coagulation test, causes irremediable loss, and the production to blood products causes tremendous influence.
Secondth, the deaesephadex a50 gel commonly using in traditional handicraft, because swelling coefficient changes greatly Be not suitable for fixed bed chromatography technique.
Content of the invention
Present invention aims to adsorbing pcc with fixed bed column chromatographic technique from blood plasma, and through washing and eluting Preparation pcc.Particularly ensureing on the premise of plasma coagulation factorses are not activated it is achieved that the fairly large in-depth filtration of blood plasma And fine filtering, and filter out the gel being suitable for absorption and isolating and purifying pcc, it is directly used in fixed bed chromatographic column, with chromatographing skill Art is directly adsorbed from blood plasma and purification obtains pcc, thoroughly solves traditional batch absorbing process and easily causes pollution, intersection is dirty Dye, gel leakage and the problems such as trivial operations.
The technical solution adopted in the present invention specifically includes that (1) removes CPP；(2) plasmapheresis, makes blood plasma reach Filtering accuracy required by column chromatography and clarity, and after guaranteeing in filter process and filtering the thrombin in blood plasma not by Activation or inactivation；(3) fixed bed column chromatographic technique purification pcc, with anion-exchange gel directly from blood plasma capture pcc so as to He directly flows through from chromatographic column plasma protein, chromatographic column is washed and eluting, thus obtaining the pcc of purification.Specific skill Art scheme is as follows:
Above-mentioned concretely comprise the following steps
(1) remove cryoprecipitate:
By Fresh Frozen human plasma melt mix after, through continuous flow centrifuge remove blood plasma in cryoprecipitate, obtain from Plasma supernatant after the heart；
(2) plasmapheresis
Using edta solution, filtering material is carried out, then with liquor sodii citratises, filtering material is carried out, and Wash away the edta of residual, after the completion of flushing, drain the solution in equipment, for plasmapheresis, the filtering material being adopted is medicinal Rank cellulose filter plate；
(3) fixed bed column chromatographic isolation and purification pcc
Gel is seated in fixed bed chromatographic column, the ratio of the plasma volume of bed volume and loading is 1:10 ~ 1:50, dress The chromatographic column filled in uses buffer a to balance 2 ~ 5 column volumes, and the blood plasma after in-depth filtration is entered using 0.2 μm of filter element Chromatographic column is pumped into, loading flow velocity is 60 ~ 120cm/h, washs chromatographic column with buffer b, uses buffer c after the online membrane filtration of row Elution chromatography post, obtains pcc product, and according to the activity calculating of thrombin ix, the yield of pcc can reach 75% ~ 90%, than work Property can reach more than 5.5iu/mg.
The concentration of above-mentioned edta solution is 0.1%-10%, and consumption is 100 ~ 300l/m2.
The concentration of above-mentioned liquor sodii citratises is 0.2% ~ 10%, and consumption is 100 ~ 300l/m2.
In above-mentioned steps (2) plasmapheresis, the number of plies of described cellulose filter plate is monolayer or bilayer.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification pcc, described buffer a by 25mmol/l sodium citrate and 20mmol/l arginine hydrochloride forms, and the ph of described buffer is 7.0.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification pcc, described buffer b by 25mmol/l sodium citrate/ The nacl composition of 20mmol/l arginine hydrochloride and 0.1 ~ 0.4mol/l.
In above-mentioned steps (3) fixed bed column chromatographic isolation and purification pcc, described buffer c by 25mmol/l sodium citrate/ The nacl composition of 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 anion-exchange gel capto deae.
The invention has the beneficial effects as follows: blood plasma, through the membrane filtration of in-depth filtration and 0.2 μm, can reach fixed bed chromatography Clarity needed for technique, can effectively improve the linear velocity during loading；And can guarantee that in blood plasma after filtration thrombin and Enzyme is not activated or inactivates, and still retains its activity.Blood plasma after filtration adopts fixed bed chromatographic technique, is coagulated using capto deae Pcc in glue Direct Acquisition blood plasma, while the yield that improve pcc and specific activity, it is to avoid existing batch adsorbs work The shortcoming of skill it is achieved that the short time of blood plasma, high flow rate, sealed pipe type process；Avoid pollution, cross-contamination, gel are let out The risk of leakage；Simplify production technology, mitigate intensity of workers.
Specific embodiment:
For a better understanding of the present invention, describe technical scheme in detail with instantiation below, but this Invention is not limited thereto.
Embodiment 1: blood plasma in-depth filtration
Different filter plates and corresponding fixture is selected to be assembled.It is carried out according to the cleaning way in following table, filter 2 ~ 8 DEG C of placement 24h of blood plasma afterwards, observe clotting of plasma situation.
Embodiment 2: human blood coagulation activity recovery checking in blood plasma after filtration
90sp(14cm using 3m company2) according to 10%edta 300l/m2, 10% sodium citrate 300l/m2Method enter After row cleaning, filtered plasma 200ml, detects to thrombin ii, vii, ix, the x in feed liquid before and after filtering.
The above results show, using the filter plate after the filter plate balance liquid containing sodium citrate composition is processed, carry out blood plasma After filtration, do not cause the activation of main component thrombin ii, vii, ix, x activity or inactivation in Human Factor Ⅸ Complex. Therefore, filter the blood plasma after clarification and can be completely used for fixed bed column chromatography purification Human Factor Ⅸ Complex.
Embodiment 3: fixed bed column chromatographic isolation and purification pcc
1lcapto deae gel is packed into fixed bed chromatographic column, using buffer a(25mmol/l sodium citrate, 20mmol/l arginine hydrochloride buffer, ph7.0) 2 ~ 5 column volumes of balance.30l blood plasma after in-depth filtration passes through again Chromatographic column is pumped into, loading flow velocity is 60 ~ 120cm/h after 0.2 μm of membrane-filter system.Again with the nacl's containing 160mmol/l Buffer a washs chromatographic column, collects and flows through the isolating and purifying for other albumen with cleaning mixture.Finally with containing 500mmol/l Nacl buffer a elution chromatography post, obtain pcc product.
Wherein the ix factor can reach more than 5.5iu/mg than work, is to be inhaled using traditional deaesephadex a50 gel batch In the pcc of attached technique productions, the ix factor is than more than 10 times living.

Claims (5)

1. a kind of method adsorbing Human Factor Ⅸ Complex from blood plasma, including removal cryoprecipitate, plasmapheresis and fixed bed Column chromatographic isolation and purification pcc；
Concretely comprise the following steps:
(1) remove cryoprecipitate:
By Fresh Frozen human plasma after melting mixing, remove the cryoprecipitate in blood plasma through continuous flow centrifuge, after being centrifuged Plasma supernatant；
(2) plasmapheresis
Using edta solution, filtering material is carried out, then with liquor sodii citratises, filtering material is carried out, and wash away The edta of residual, drains the solution in equipment after the completion of flushing, for plasmapheresis, the filtering material being adopted is medicinal rank Cellulose filter plate；
(3) fixed bed column chromatographic isolation and purification pcc
Gel is seated in fixed bed chromatographic column, the ratio of the plasma volume of bed volume and loading is 1:10 ~ 1:50, fills Chromatographic column use buffer a balance 2 ~ 5 column volumes, through filtration after blood plasma carried out using 0.2 μm of filter element online Chromatographic column is pumped into, loading flow velocity is 60 ~ 120cm/h, washs chromatographic column with buffer b, with buffer c elution chromatography after membrane filtration Post, obtains pcc product；
In described step (3) fixed bed column chromatographic isolation and purification pcc, described buffer a by 25mmol/l sodium citrate and 20mmol/l arginine hydrochloride forms, and the ph of described buffer a is 7.0；
In described step (3) fixed bed column chromatographic isolation and purification pcc, described buffer b by 25mmol/l sodium citrate, The nacl composition of 20mmol/l arginine hydrochloride and 0.1 ~ 0.4mol/l；
In described step (3) fixed bed column chromatographic isolation and purification pcc, described buffer c by 25mmol/l sodium citrate, The nacl composition of 20mmol/l arginine hydrochloride and 0.5 ~ 1.0mol/l.
2. according to claim 1 a kind of from blood plasma adsorb Human Factor Ⅸ Complex method it is characterised in that: institute The concentration stating edta solution is 0.1% ~ 10%, and consumption is 100 ~ 300l/m2.
3. according to claim 1 a kind of from blood plasma adsorb Human Factor Ⅸ Complex method it is characterised in that: institute The concentration stating liquor sodii citratises is 0.2% ~ 10%, and consumption is 100 ~ 300l/m2.
4. according to claim 1 a kind of from blood plasma adsorb Human Factor Ⅸ Complex method it is characterised in that: institute State in step (2) plasmapheresis, the number of plies of described cellulose filter plate is monolayer or bilayer.
5. according to claim 1 a kind of from blood plasma adsorb Human Factor Ⅸ Complex method it is characterised in that: institute State in step (3) fixed bed column chromatographic isolation and purification pcc, described gel is anion-exchange gel captodeae.
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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
EP3262409B1 (en) 2015-02-25 2020-03-25 Omrix Biopharmaceuticals Ltd. Method for purifying and quantifying thrombin and its degradation polypeptides
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
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
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
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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