CN105254754A - Preparation method for intravenous injection human immune globulin (PH4) - Google Patents
Preparation method for intravenous injection human immune globulin (PH4) Download PDFInfo
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Abstract
The invention discloses a method for preparing intravenous injection human immune globulin (PH4) from plasma fractions II+III. The method comprises the following steps of 1 fraction II+II precipitate suspending; 2 octanoic acid solution extracting; 3 filter pressing; 4 anion exchange column chromatography performing; 5 ultra-filtering, concentrating and regulating; 6 sterilizing and filtering; 7 low-PH incubating; 8 virus removing with nano films and filtering; 9 sterilizing, filtering and subpackaging. According to the method, a low-PH suspended buffer solution is selected and used to enable fraction II+II precipitates to be fully suspended, an octanoic acid extracting solution is mixed with the suspension liquid to enable IgG to be selectively dissolved out, a crude IgG solution is obtained, and purification on IVIG is completed through a step of anionic column chromatography; the method is short in technological process, few in procedure and low in energy consumption, the product is high in yield and stable in quality, the key technical indexes such as IgA, ACA, PKA and polymers are all superior to those of a traditional technology, and the yield can reach up to about 2200 bottles per ton of plasma.
Description
Technical field
The invention belongs to field of biological pharmacy, relate to a kind of preparation technology of blood product, be specifically related to a kind of method preparing quiet note human normal immunoglobulin (PH4) from component I I+III.
Background technology
Human normal immunoglobulin (immunoglobulin) is a kind of protein with antibody activity, is mainly present in blood plasma, also sees in other body fluid, tissue and some juices.Immunoglobulin (Ig) can be divided into IgG, IgA, IgM, IgD, IgE five class, and the main component of human serum immunoglobulin (Ig) is IgG, accounts for the 70-75% of total immunoglobulin (Ig).
Human serum immunoglobulin IgG is the most lasting in primary immune response, most important antibody, only exists with monomeric form.Most of germ resistance, toxin immunity and antiviral antibody belong to IgG, leading role is played in anti-infective, the phagolysis of mononuclear macrophage can be promoted, neutralize bacteriotoxic toxicity and be combined the ability making virus lose host cells infected with virus antigen.IgG is uniquely by the immunoglobulin (Ig) of placenta, plays an important role in natural passive immunity.In addition, IgG also has opsonophagocytosis and in conjunction with effects such as SPA.
Human normal immunoglobulin divides intramuscular injection human normal immunoglobulin and quiet note human normal immunoglobulin.Widely use more intramuscular injection human normal immunoglobulin clinically and have anti-hepatitis b human normal immunoglobulin, rabies human normal immunoglobulin, Human Antitetanus Immunoglobulin etc., use if merge with microbiotic, the curative effect to some serious bacterial and virus infection can be improved.
Quiet note human normal immunoglobulin (IVIG) is extracted after a large amount of healthy donates blood slurry mixing, containing various antiviral, bacterial antigens specific antibody, there is adjustment neutralizing effect, can improve rapidly after intravenous injection and make IgG level in receptor's blood, therefore IVIG is rapid-action, good effect, few side effects, becomes that human normal immunoglobulin is clinically the most used, usage quantity is maximum kind.IVIG is used for treating multiple primary immunoglobulin deficiency disease and various Secondary cases immuno-compromised at first as immune-mediated thrombopenia, mucocutaneous lymphnode syndrome etc.At present, the clinical application of IVIG is extended to 50 various diseases as aplastic anemia anaemia, hemolytic disease of newborn, post-transfusion purpura, idiopathic thrombocytopenic purpura, epilepsy, myasthenia gravis, multiple sclerosis, multiple myeloma, polymyositis, polyneuropathy, internal organs enlargement, acquired immune deficiency syndrome (AIDS) etc., play a part more and more important in the rescue of critical illness.
Because IVIG application is clinically increasingly extensive, its clinical demand also significantly increases, whole world IVIG consumption is increased to 51.6 tons of 2003 from 1992 19.4 tons, within 2006,78.2 tons are reached, according to annual growth, estimate that the IVIG consumed for 2016 will reach 129.4 tons (China's blood transfusion magazine 2008,21 (11): 903-905).
Domestic sampled plasma amount wretched insufficiency for a long time, the output of domestic IVIG can not meet clinical demand far away, but simultaneously, domestic blood product company adopts traditional processing technology yield general lower, is generally not more than 2000 bottles of/ton of blood plasma (2.5 grams/bottle).
Traditional production technique mostly adopts multistep chilled alcohol precipitation method; as patent CN104479011A; after I+II+III is dissolved; first through two step cold ethanols (15%; V/V) precipitate; press filtration removes most of foreign protein; then supernatant liquor (component I I) is added ethanol (20% in neutral conditions; V/V) be precipitated out, precipitation is redissolved, through ultrafiltration, dialysis, concentrate; add ethanol (2% again; V/V) precipitation is once, and supernatant liquor is collected in press filtration, again ultrafiltration dialysis, concentrated add protective material after aseptic subpackaged.Minority is had to adopt chilled alcohol precipitation column chromatography, as patent CN103554253A, with component I I+III for starting raw material, after dissolving, add ethanol (18%, V/V) precipitate, supernatant liquor is collected in press filtration, and then dialyse dealcoholysis, desalination, through two step column chromatographies, collect stream and wear liquid, ultrafiltration again, dialysis, concentrated, hatch after Sterile Filtration, rear except virus filtration aseptic subpackaged finished product again.
Because cold ethanol method mostly needs repeatedly alcohol settling, inevitably cause the sex change of Partial Protein impaired, also easily cause protein co-precipitate phenomenon, so the purity of product is not very high, often contain more foreign protein as IgA, IgM and polymer etc.; Although the also column chromatography purification had, have employed two step column chromatographies, make flow process complicated, yield declines.
This invention exploits one with component I I+III for starting raw material, the purifying to IgG is completed with sad low-temperature extraction combine with technique one step Anionic column chromatography, there is flow process succinct, with short production cycle, the advantage that purity is high, IgA, PKA, ACA contained by product and polymer all decline to a great extent than traditional technology; Simultaneously owing to avoiding the use of ethanol, reduce the probability that protein denaturation is impaired, make product more stable; About present invention process product yield can reach 2200 bottles of/ton of blood plasma, far above Conventional cryogenic ethanol.
Summary of the invention
It is advanced that technical problem to be solved by this invention is to provide a kind of technique, and simple to operate, purity is high, yield is high, can the preparation method of quiet note human normal immunoglobulin (PH4) of suitability for industrialized production.
A kind of method preparing quiet note human normal immunoglobulin (PH4) from component I I+III, comprises the steps:
(1) suspension of component I I+III precipitation
Precipitated by freezing component I I+III and take out from freezer, be cut into fragment, then by certain feed ratio, drop in the buffer suspension liquid prepared in advance, uniform stirring 1-3 hour, makes the abundant suspended dispersed of precipitation;
(2) sad solution extraction
The suspension that step (1) is obtained and mixing containing sad extraction liquid of preparing in advance, stir 2-5 hour, make the abundant stripping of target protein, obtain uniform suspension;
(3) press filtration
Suspension press filtration at 2 ~ 10 DEG C that step (2) is obtained, the Supradur50P filter plate that filter plate adopts PALL company to produce; Collect filtrate, be slightly pure IgG solution; Glycine 1-3%(w/w is added in time in filtrate), fully stir and make it dissolve;
(4) anion exchange chromatography
Anion-exchange column on the IgG solution that step (3) obtains, control the linear flow speed of sample solution not higher than 100cm/h, pillar uses equilibration buffer in advance; In upper prop process, collect stream and wear liquid, after upper prop terminates, use Equilibration buffer wash pillar, washing fluid is become a mandarin and wears in liquid;
(5) ultrafiltration and concentration and adjustment
Liquid is worn with the stream that the ultra-filtration membrane enrichment step (4) of molecular weight cut-off 10K-30K obtains, then with dialyzate constant volume dialysis 4-6 times, then protein concentration 6-7% (w/v) left and right is concentrated into, wash film bag after migrating out ultra-filtration membrane Bao Bingyong dialyzate, then adjust protein concentration to 5.30-5.50% (w/v) with dialyzate;
(6) low PH hatching
With the protein solution described in the degerming filter element filtering step (5) of 0.22 micron, be placed on incubation at room temperature 21 days;
(7) nanometer film is except virus filtration
The protein solution terminated with filter element filtering step (6) hatching of 20 nanometers is to remove virus;
(8) Sterile Filtration packing.
Feed ratio described in step (1) is 1:8-12, and namely the component I I+III precipitation of a weight is put in the dissolving damping fluid of 8-12 part weight; Described buffer suspension liquid is the Acetic acid-sodium acetate damping fluid of 10-30mmol/L; The pH value of buffer suspension liquid is 4.00-4.80; The temperature of buffer suspension liquid is 0-5 DEG C.
Extraction liquid described in step (2) consists of 10-30mM sodium-acetate, and 20-60mM is sad; The pH value of extraction liquid is 5.20-6.00; The temperature of extraction liquid is 5 ~ 10 DEG C; Described extraction liquid weight is 0.8-1.2 times of step (1) gained suspension gross weight.
Anion-exchange column filler used described in step (4) is any one in CaptoQ, CaptoDEAE, QSepharoseFF and DEAESepharoseFF; Described level pad is the Acetic acid-sodium acetate solution of 10-20mmol/L, and the PH of level pad is 5.20-6.00.
Dialyzate described in step (5) is 1-3% (w/w) glycine solution; The pH value of dialyzate is 3.95-4.05; The temperature of dialyzate is 2-8 DEG C.
beneficial effect of the present invention is:(1), preparation technology avoids the use of ethanol, and reduce the probability that protein denaturation is impaired, product is more stable, and polymer, IgA, PKA and ACA of goods all decline to a great extent than traditional technology; (2), employing makes the target protein selectivity stripping in component I I+III containing sad extraction liquid, other foreign protein is then in coagulated state, and namely a step extraction reaches very high IgG purity; (3), adopt sad abstraction technique, eliminate the step of ethanol repeated precipitation in traditional technology, substantially reduce the production cycle, alleviate the labour intensity of operator; (4), in ultrafiltration dialysis operation, all add protein protective agent in protein solution and dialyzate, decrease the shear property model of ultrafiltration to albumen; (5), adopt sad extraction to complete the purifying to IgG in conjunction with anion exchange chromatography technology, flow process is short, and operation is few, and energy consumption is low, and purity is high, and yield can reach about 2200 bottles, high traditional technology far away.
Accompanying drawing explanation
Accompanying drawing for preparing the FB(flow block) of quiet note human normal immunoglobulin (PH4) from component I I+III.
Embodiment
Below in conjunction with accompanying drawing and embodiment, the present invention is further illustrated; embodiment is just in order to make those skilled in the art understand the present invention better; unintelligible is restriction to right protection scope of the present invention; on the contrary; for the common scientific research personnel of this area; the change of any unsubstantiality that all the present invention of utilization carry out or adjustment, all should fall within protection scope of the present invention.
embodiment one,
The suspension of 1, component I I+III precipitation: take component I I+III and precipitate 1kg, drop into 8kg and dissolve in damping fluid (the Acetic acid-sodium acetate damping fluid of 20mmol/L, PH4.10-4.20,0 ~ 1 DEG C), uniform stirring 3 hours, makes precipitation fully suspend;
2, sad extraction: above suspension and 9kg extraction liquid (20mmol/L sodium-acetate, 40mmol/L is sad, PH5.90-6.00,5 ~ 6 DEG C) are mixed, stir 5 hours, makes target protein fully extract from precipitation, obtains unit for uniform suspension;
3, press filtration: the above suspension of press filtration at 2 ~ 3 DEG C, and after wash precipitation, collect filtrate 18.6kg altogether, add glycine 0.19kg, fully stir and make it dissolve;
4, anion exchange chromatography: with CaptoQ post in the upper prop linear velocity of 90-100cm/h, pillar uses level pad (the Acetic acid-sodium acetate solution of 20mmol/L, PH5.20-5.30) to balance in advance, collects stream and wears liquid; After upper prop terminates, use Equilibration buffer wash pillar, washing fluid is become a mandarin and wears liquid;
5, dialyse, concentrate and regulate: with 30k ultra-filtration membrane (0.5M
2) concentrated wear liquid to about 1.5kg with upper reaches, then use 6kg dialyzate (1% (w/w) glycine solution, PH3.95-4.05) to dialyse, after again concentrate, transfer and after wash ultra-filtration membrane, collect 1.91kg; Adjust protein concentration to 5.35% (w/v) with dialyzate, weigh 2.42kg;
6, low PH hatching: with the above solution of degerming filter element filtering of 0.22 micron, collects filtrate in sterile chamber, is placed in incubation at room temperature 21 days;
7, nanometer film is except virus filtration: after hatching terminates, with 20nm filter core except virus filtration;
8, packing after Sterile Filtration.
embodiment two,
1,component I I+III precipitates suspension: take 1kg component I I+III and precipitate, and drop into 10kg and dissolve in damping fluid (the Acetic acid-sodium acetate damping fluid of 10mmol/L, PH4.40-4.50,4 ~ 5 DEG C), uniform stirring 2 hours, makes precipitation fully suspend;
2, sad extraction: mixed by the extraction liquid (the Acetic acid-sodium acetate damping fluid of 30mmol/L, 50mmol/L is sad, PH5.50-5.60,9 ~ 10 DEG C) of above suspension and 12kg, stir 3 hours, makes target protein fully extract from precipitation, obtains unit for uniform suspension;
3, press filtration: the above suspension of press filtration at 5-7 DEG C, and after wash precipitation, collect filtrate 24.7kg altogether, add glycine 0.50kg, fully stir and make it dissolve;
4, anion exchange chromatography: with DEAESepharoseFF post in the upper prop linear flow speed of 60-70cm/h, use level pad (the Acetic acid-sodium acetate solution of 10mmol/L, PH5.50-5.60) to balance in advance, collects stream and wears liquid; After upper prop terminates, use Equilibration buffer wash pillar, washing fluid is become a mandarin and wears liquid;
5, dialyse, concentrate and regulate: with 10k ultra-filtration membrane (0.5M
2) concentrate and wear liquid to about 1.5kg with upper reaches, then use the dialyzate of 9kg (containing the aqueous solution of 2% glycine, PH3.95-4.05) to dialyse, after again concentrate, wash ultra-filtration membrane after transfer also, collect 1.98kg, adjust protein concentration to 5.35% (w/v) with dialyzate; Weigh 2.53kg;
6 ~ 8,with embodiment one.
embodiment three,
1, component I I+III precipitates suspension: take component I I+III and precipitate 1kg, and drop into 12kg and dissolve in damping fluid (the Acetic acid-sodium acetate damping fluid of 30mmol/L, PH4.70-4.80,2 ~ 3 DEG C), uniform stirring 1 hour, makes precipitation fully suspend;
2, sad extraction: above suspension and 10.4kg extraction liquid liquid (the Acetic acid-sodium acetate damping fluid of 10mmol/L, 60mmol/L is sad, PH5.20-5.30,5 ~ 6 DEG C) are mixed, stir 4 hours, makes target protein fully extract from precipitation, obtains unit for uniform suspension;
3, press filtration: the above suspension of press filtration at 3 ~ 4 DEG C, and after wash precipitation, collect filtrate 24.1kg altogether, add glycine 0.73kg, fully stir and make it dissolve;
4, anion exchange chromatography: with QSepharoseFF post in the upper prop linear velocity of 50-60cm/h, pillar uses equilibration buffer in advance, balance liquid is the Acetic acid-sodium acetate solution of 15mmol/L, PH5.90-6.00, collects stream and wears liquid; After upper prop terminates, use Equilibration buffer wash pillar, washing fluid is become a mandarin and wears liquid;
5, dialyse, concentrate and regulate: wear liquid to about 1.5kg with 10k ultra-filtration membrane is concentrated with upper reaches, then dialyzate (the aqueous solution of 3% glycine is used, PH3.95-4.05) 7.5kg dialyses, after again concentrate, wash ultra-filtration membrane after transfer also, collect 1.69kg, with dialyzate rare tune protein concentration to 5.35% (w/v); Weigh 2.39kg;
6~ 8, with embodiment one.
table IV IG preproduction key technical index table look-up
Note: traditional technology IVIG yield is generally 1600-2000 bottle/ton blood plasma, IgA is 50-100mg/L.
Claims (9)
1. from component I I+III, prepare a method for quiet note human normal immunoglobulin (PH4), it is characterized in that: comprise the steps:
(1) suspension of component I I+III precipitation
Precipitated by freezing component I I+III and take out from freezer, be cut into fragment, then by certain feed ratio, drop in the buffer suspension liquid prepared in advance, uniform stirring 1-3 hour, makes the abundant suspended dispersed of precipitation;
(2) sad solution extraction
The suspension that step (1) is obtained and mixing containing sad extraction liquid of preparing in advance, stir 2-5 hour, make the abundant stripping of target protein, obtain uniform suspension;
(3) press filtration
Suspension press filtration at 2 ~ 10 DEG C that step (2) is obtained, the Supradur50P filter plate that filter plate adopts PALL company to produce; Collect filtrate, be slightly pure IgG solution; Glycine 1-3%(w/w is added in time in filtrate), fully stir and make it dissolve;
(4) anion exchange chromatography
Anion-exchange column on the IgG solution that step (3) obtains, control the linear flow speed of sample solution not higher than 100cm/h, pillar uses equilibration buffer in advance; In upper prop process, collect stream and wear liquid, after upper prop terminates, use Equilibration buffer wash pillar, washing fluid is become a mandarin and wears in liquid;
(5) ultrafiltration and concentration and adjustment
Liquid is worn with the stream that the ultra-filtration membrane enrichment step (4) of molecular weight cut-off 10K-30K obtains, then with dialyzate constant volume dialysis 4-6 times, then protein concentration 6-7% (w/v) left and right is concentrated into, wash film bag after migrating out ultra-filtration membrane Bao Bingyong dialyzate, then adjust protein concentration to 5.30-5.50% (w/v) with dialyzate;
(6) low PH hatching
With the protein solution described in the degerming filter element filtering step (5) of 0.22 micron, be placed on incubation at room temperature 21 days;
(7) nanometer film is except virus filtration
The protein solution terminated with filter element filtering step (6) hatching of 20 nanometers is to remove virus;
(8) Sterile Filtration packing.
2. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the feed ratio described in step (1) is 1:8-12, namely the component I I+III precipitation of a weight is put in the dissolving damping fluid of 8-12 part weight.
3. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the dissolving damping fluid described in step (1) is the Acetic acid-sodium acetate damping fluid of 10-30mmol/L; The pH value dissolving damping fluid is 4.00-4.80; The temperature of dissolving damping fluid is 0-5 DEG C.
4. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the extraction liquid described in step (2) consists of 10-30mM sodium-acetate, and 20-60mM is sad; The pH value of extraction liquid is 5.20-6.00; The temperature of extraction liquid is 5 ~ 10 DEG C.
5. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the extraction liquid described in step (2), and its weight is 0.8-1.2 times of step (1) gained suspension gross weight.
6. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the sad concentration described in step (3) and the zone of reasonableness of pH value refer to, content sad in suspension is 10-35mmol/ liter; The pH value of suspension is 4.50-5.50.
7. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the anion-exchange column filler used described in step (4) is any one in CaptoQ, CaptoDEAE, QSepharoseFF and DEAESepharoseFF.
8. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the level pad described in step (4) is the Acetic acid-sodium acetate solution of 10-20mmol/L, the PH of level pad is 5.20-6.00.
9. one according to claim 1 prepares the method for quiet note human normal immunoglobulin (PH4) from component I I+III, it is characterized in that: the dialyzate described in step (5) is 1-3% (w/w) glycine solution; The pH value of dialyzate is 3.95-4.05; The temperature of dialyzate is 2-8 DEG C.
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| CN111166877A (en) * | 2019-12-30 | 2020-05-19 | 西安回天血液制品有限责任公司 | Preparation method of rabies human immunoglobulin |
| CN112574296A (en) * | 2020-12-30 | 2021-03-30 | 中国医学科学院输血研究所 | Separation and purification method of IVIg-simulated multi-human-part mixed human plasma IgG sample |
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| CN115389291A (en) * | 2022-10-26 | 2022-11-25 | 北京肿瘤医院(北京大学肿瘤医院) | Enrichment, purification and protection method of urine trace protein |
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