CN103554252B - A kind of Giant cell human immunoglobulin and preparation method thereof - Google Patents
A kind of Giant cell human immunoglobulin and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of Giant cell human immunoglobulin, its cytomegalovirus NAT is more than or equal to 1:400, immunoglobulin purity is more than or equal to 96% of total protein, the invention also discloses the preparation method of described Giant cell human immunoglobulin, comprise the steps: the blood plasma raw material that (1) filters out cytomegalovirus NAT titre and is more than or equal to 1:50; (2) pooled plasma trial-product is prepared; (3) described pooled plasma trial-product is pressed cold ethanol or chromatography protein separating method, separation and Extraction immunoglobulin components, after filtration, chromatography, ultrafiltration, inactivation of virus, after configuration packing obtain product.Giant cell human immunoglobulin of the present invention can be treated cytomegalovirus targetedly, is the active drug for the treatment of Cytomegalovirus Infection, has larger Social benefit and economic benefit.
Description
Technical field
The present invention relates to field of biological pharmacy, particularly relate to a kind of Giant cell human immunoglobulin and preparation method thereof.
Background technology
Cytomegalovirus CMV(Cytomegalovirus) be the DNA virus that herpetoviridae β belongs to, the pregnant woman caused by cytomegalovirus, newborn infant, Organ Transplantation Patients, immunosuppression person's infectious age can reach 50 ~ 80%.Cytomegalovirus human normal immunoglobulin CMV-IgG because of can special in and cytomegalovirus, mainly clinically treat with it cytomegalovirus severe infection that pregnant woman, newborn infant, immunosuppressed patient and organ transfer operation print and distribute.Cytomegalovirus Natural infection rate in general population can reach more than 80%, screen from healthy population and gather the blood plasma containing high-titer cytomegalovirus IgG antibody, adopt Low-temperature Ethanol Processes separation purification method to prepare Giant cell human immunoglobulin medicine, the severe infection caused because of cytomegalovirus for treatment has irreplaceable clinical value.
Summary of the invention
The technical problem to be solved in the present invention is to provide human normal immunoglobulin providing a kind of effective treatment cytomegalovirus severe infection and preparation method thereof.
A kind of Giant cell human immunoglobulin, its cytomegalovirus NAT is more than or equal to 1:400, and immunoglobulin purity is more than or equal to 96% of total protein.
Giant cell human immunoglobulin of the present invention, wherein said immunoglobulin (Ig) is compared with normal human serum, and major precipitation line is IgG.
Giant cell human immunoglobulin of the present invention, IgG monomer and the dimer content sum of wherein said immunoglobulin (Ig) are more than or equal to 96%.
Giant cell human immunoglobulin of the present invention, the formulation of wherein said immunoglobulin (Ig) is liquid preparation or freeze-dried formulation.
A preparation method for Giant cell human immunoglobulin, comprises the steps:
(1) filter out by neutralization test method the blood plasma raw material that cytomegalovirus NAT titre is more than or equal to 1:50;
(2) pooled plasma trial-product is prepared with the described blood plasma raw material after screening, described pooled plasma raw material is mixed by the described blood plasma raw material being no less than 500 Plasma donors, and the cytomegalovirus NAT titre of described pooled plasma trial-product is more than or equal to 1:80;
(3) by described pooled plasma trial-product by cold ethanol press filtration in conjunction with chromatography protein separating method, separation and Extraction immunoglobulin components, after filtration, chromatography, ultrafiltration, inactivation of virus, after configuration packing obtain product.
The preparation method of Giant cell human immunoglobulin of the present invention, wherein, the described neutralization test method of step (1) specifically comprises the steps:
(A) diluted sample:
Plasma sample cell maintenance medium carries out 1:10 in advance and dilutes rear 56 DEG C of deactivations 30 minutes;
Open 96 porocyte plates of q.s, indicate viral residual titration plate and specimen test plate, and on each sample test board, indicate the numbering of this plate test sample;
In the various kinds sample wells of specimen test plate, add 40ul cell maintenance medium, viral residual titration hole and negative control hole add 50 μ l cell maintenance mediums;
The sample liquid of deactivation is in advance joined respectively the corresponding position of corresponding 96 porocyte plates, every hole adds sample 10 μ l, and every sample parallel does holes;
The DMEM liquid of described cell maintenance medium to be volume ratio the be foetal calf serum of 5%;
(B) challenge virus
Prepare challenge virus liquid: the number of samples maintenance medium according to test prepares enough challenge virus liquid, and application virus will be diluted to 100CCID
50/ 0.05ml; Except viral residual titration hole and negative control hole, all the other each Kong Zhongjun add 50 μ l containing 100CCID
50challenge virus liquid;
Residual titration 100CCID
50challenge virus liquid: challenge virus liquid is done 10 with cell maintenance medium
-1, 10
-2, 10
-3dilution, by challenge virus liquid and its 10
-1, 10
-2, 10
-3the virus liquid of concentration joins corresponding viral residual titration with in 96 porocyte plate holes, and each extent of dilution adds 10 holes, 50 μ l/ holes;
Negative control: add 50 μ l cell maintenance mediums to each Kong Zhongzai of negative control;
All 96 porocyte plates are put into 37 DEG C, containing CO
2percent by volume is the incubator neutral incubation 2 hours of 5%;
(C) preparation of cell suspension and interpolation
The preparation of cell suspension: the MRC-5 cell getting q.s, counting after digestion, test concentration of cell suspension should be 1 × 10
5individual/ml, the enchylema prepared uses immediately or puts 4 DEG C and saves backup;
Cell is outstanding to be added: after neutral incubation, every hole adds cell suspension 100 μ l, and about 1 × 10
4individual/hole;
(D) cultivate and observe statistics
The 96 porocyte plates completing above operation are placed 37 DEG C, containing CO
2percent by volume is cultivate 11 days in the incubator of 5%, the 7th day basis of microscopic observation cell growth status after virus inoculation, the 9th day observation of cell pathology situation, the 11st day final result of determination, and record statistics.
The preparation method of Giant cell human immunoglobulin of the present invention, wherein, step (3) specifically comprises the steps:
A) by described pooled plasma trial-product centrifugal segregation cryoprecipitate at 2 DEG C;
B) the blood plasma normal saline dilution after removing cryoprecipitate becomes reaction solution, described reacting liquid pH value to 6.5 is regulated with the acetate buffer solution that pH value is 4.0, add in volume percent 95% ethanol to described reaction solution, final ethanol contend per-cent is made to be 20%, use refrigerant to control reacting liquid temperature to-4.5 DEG C, filter press is separated to obtain precipitation;
C) by step b) precipitation that obtains stirs by the NaCl solution of 0 DEG C, 10 times 0.01mol/L and dissolves;
D) to step c) add volume percent 50% ethanol forming reactions liquid in the lysate of gained, final ethanol contend per-cent is made to be 17%, the pH value to 5.1 of reaction solution is regulated with acetate buffer solution, refrigerant is used to control reacting liquid temperature to-4.5 DEG C, filter press is separated removing precipitation, collects supernatant liquor;
E) by steps d) upper DEAE-Sepharose-FastFlow weak anionic displacement chromatography after the supernatant liquor ultrafiltration dialysis collected four times, temperature of reaction is 10 DEG C, collects effluent liquid;
F) by step e) effluent liquid carry out ultrafiltration again, with acetate buffer solution adjust ph to 4.0, temperature to 10 DEG C;
G) dialyse concentrated after 8 times;
H) the Glacial acetic acid tune pH to 3.85 of concentrated solution 2mol/L will obtained after concentrated, add mass percent be 30% maltose make ultimate density 10% as protective material, add physiological saline and make protein mass percentage composition be 5.8%, obtain stoste;
I) described stoste is incubated at 24 ~ 25 DEG C the Geminivirus inactivation treatment of putting and using nano-film filtration for 21 days afterwards;
J) product is obtained after aseptic subpackaged.
Giant cell human immunoglobulin difference from prior art of the present invention is:
Giant cell human immunoglobulin provided by the invention, giant cells NAT is more than or equal to 1:256, can treat cytomegalovirus targetedly, is the active drug for the treatment of Cytomegalovirus Infection, has larger Social benefit and economic benefit.
The advantage of preparation method of the present invention:
(1) adopt the cytomegalovirus strain of the existing standard of country as detection carrier, the specificity raw blood plasma with higher titre is filtered out from healthy population, its standard meets " biological products production blood plasma " regulation in the Pharmacopoeia of the People's Republic of China 2010 editions, prepare the Giant cell human immunoglobulin of high titre through cold ethanol filter-pressing process column chromatography purification, specificity is high.
(2) adopt neutralization test method raw material and product to be carried out to the detection of antibody titer, the method has strong operability, the advantage highly sensitive, specificity is good.
(3) the specificity raw blood plasma of collecting, adopt the immunoglobulin preparation that cold ethanol filter-pressing process column chromatography purification is prepared, purity is high, steady quality.
Embodiment
Embodiment 1
1, the plasma screening collection of Plasma donors:
Select blood plasma, selected blood plasma should meet the following conditions: detect the giant cells neutralizing antibody in blood plasma with neutralization test method, Neutralizing titer titre is more than or equal to 1:50; Protein content (biuret method detection) is more than or equal to 55g/L; Alanine aminotransferase (reitman-frankel method monitoring) is not higher than 35 units; Hepatitis B surface antigen(HBsAg) is negative, and syphilis is negative, HIV-1/HIV-2 negative antibody, the Giant cell human immunoglobulin raw blood plasma that HCV negative antibody etc. are all qualified, and cryogenic freezing stores, and preservation period is no more than 2 years.
The measuring method of neutralization test method comprises the steps:
A) using human embryonic lung diploid fibroblast MRC-5 as indicator cells, nutrient solution is containing 10%(V/V) DMEM of foetal calf serum, preparation cell concn is 1 × 10
4~ 1 × 10
6the MRC-5 cell suspension of individual/ml;
B) after plasma sample trial-product cell maintenance medium (be the DMEM liquid of the foetal calf serum of volume percent 5%, lower with) being carried out 1:10 dilution, 56 DEG C of deactivations 30 minutes.
Get the cell plate of q.s, in sample panel, add 40ul/ porocyte maintenance medium, then add each sample liquid 10ul/ hole of corresponding 1:10 pre-dilution deactivation, every sample parallel 2 hole.
C) get cytomegalovirus CMV to be diluted to test concentration (i.e. 100 × CCID50/0.05ml) equivalent with cell maintenance medium and to add in trial-product plate hole, and Positive control wells, negative control hole and viral residual titration hole are set simultaneously.
Virus (positive) control wells: first add cell maintenance medium 50ul/ hole in plate hole, then adds application virus liquid 50ul/ hole, mixing;
Cell (feminine gender) control wells: directly add cell maintenance medium 100ul/ hole;
Virus residual titration hole: first add cell maintenance medium 50ul/ hole in plate hole, after then application virus liquid being carried out 10 doubling dilutions, get 10 respectively
0~ 10
-3the virus liquid of concentration adds in corresponding viral residual titration hole, 50ul/ hole;
D) neutralization reaction: by liquid in each plate hole on vortex mixer in the rearmounted CO2gas incubator of careful mixing 37 DEG C, 5%CO2 is hatched and carried out neutralization reaction 2 hours.
E) cell:
The preparation of cell suspension: the MRC-5 cell getting q.s, counting after digestion, regulates test concentration of cell suspension to should be 1 × 10 with cell maintenance medium
5individual/ml, the enchylema prepared uses immediately or puts 4 DEG C and saves backup.
Cell is outstanding to be added: after the neutralization reaction time is full, every hole adds cell suspension 100 μ l, and about 1 × 10
4individual/hole.
F) cultivate: the cell plate completing above operation are placed 37 DEG C, 5%CO
2cultivate 11 days in incubator, in the 7th day basis of microscopic observation cell growth status, the 9th day observation of cell pathology situation, the 11st day final result of determination, and record statistics.
Each test must have virus control and cell controls, and virus control must occur pathology, and cell controls must be normal.Result judges: do not occur that can protect 50% cell the trial-product extent of dilution of pathology is as Neutralizing titer.In the present invention, all neutralization test methods mentioned are all that above-mentioned identical mode is carried out, hereinafter referred to as neutralization test method.
Specific plasma containing higher titre carries out hybrid detection before operation, and antibody titers is not less than 1:80, and continuous three batches of pooled plasma detected results are in table 1.
The continuous three batches of pooled plasma detected results of table 1.
First
| Test item | A(normal plasma) | B(is containing the specific plasma of higher titre) |
| Protein content | 56g/L | 57g/L |
| HCMV NAT | 1:23 | 1:128 |
Second batch
| Test item | A(normal plasma) | B(is containing the specific plasma of higher titre) |
| Protein content | 56g/L | 56g/L |
| HCMV NAT | 1:20 | 1:128 |
3rd batch
| Test item | A(normal plasma) | B(is containing the specific plasma of higher titre) |
| Protein content | 57g/L | 55g/L |
| HCMV NAT | 1:20 | 1:137 |
Note:
1.A: for screening rear antibody titers common pooled plasma against regulation
2.B: the mixed slurry of specific plasma that the antibody titers through above-mentioned neutralization method screening acquisition is higher
3. the same batch of blood plasma source of three batches of blood plasma more than is identical, and the anti-HCMV blood plasma of the high-titer filtered out by neutralization test method is B, and remaining part is A.
2, the preparation of Giant cell human immunoglobulin:
(1) mixed by the blood plasma thawing of more than 500 Plasma donors, after mixing, volume is 300L, and detecting mixed prize Neutralizing titer by neutralization test method is 1:128;
(2) mixed blood plasma, centrifugal segregation cryoprecipitate 24Kg at 2 DEG C;
(3) blood plasma (275L) after removing cryoprecipitate uses 28L normal saline dilution, reacting liquid pH value to 6.5 is regulated with pH4.0 acetate buffer solution 720ml, add 95% ethanol 75L in reaction solution, final alcohol concn is made to be 20%, reaction solution final volume is 345L, use refrigerant to control reacting liquid temperature to-4.5 DEG C, filter press is separated to obtain precipitation 25kg;
(4) by the precipitation of step (3) 0 DEG C of 0.01mol/LNaCl solution 225L stirring and dissolving, final solution volume is 250L;
(5) in supernatant liquor, 50% ethanol 128L is added in reaction solution, final alcohol concn is made to be 17%, reacting liquid pH value to 5.1 is regulated with acetate buffer solution 1580ml, reaction solution final volume is 380L, refrigerant is used to control reacting liquid temperature to-4.5 DEG C, filter press is separated removing precipitation, and collection supernatant liquor is 330L;
(6) upper DEAE-Sepharose-FastFlow weak anionic displacement chromatography after supernatant liquor being carried out ultrafiltration dialysis four times, temperature of reaction is 10 DEG C, collects effluent liquid 310L.
(7) effluent liquid of step (6) is carried out ultrafiltration again, with acetate buffer solution 3100ml adjust ph to 4.0, temperature to 10 DEG C.Dialyse after 8 times and be concentrated into 22L(protein content: 7.2%, pH value: 3.5).
(8) the Glacial acetic acid 120ml of the concentrated solution 2mol/L of step (7) is adjusted pH to 3.85; add 30% maltose 11L and make ultimate density at the protective material of 10%(as inactivation of virus albumen); adding 3L physiological saline makes protein content be 5.6%, and configuration final volume is 36L.
(9) above-mentioned steps (8) gained stoste is incubated at 24 ~ 25 DEG C the Geminivirus inactivation treatment of putting and using nano-film filtration for 21 days afterwards;
(10) step (9) gained Giant cell human immunoglobulin is distributed into 1800 bottle products, gets 25 bottles of samples and send quality arbitration portion to examine and determine.
With neutralization test method, detect its giant cells NAT and equal 1:549.
3, prepare through extensive trial production the sample obtained, carry out the Giant cell human immunoglobulin of examining and determine above-mentioned steps gained according to this product manufacture of enterprise's revision and the relevant regulations of vertification regulation and the Pharmacopoeia of the People's Republic of China 2010 editions three.The results are shown in Table 2.
Table 2. Giant cell human immunoglobulin survey report
Conclusion: this product manufactures vertification regulation inspection by quiet note Giant cell human immunoglobulin, and result conforms with the regulations.
Above-described embodiment is only be described the preferred embodiment of the present invention; not scope of the present invention is limited; under not departing from the present invention and designing the prerequisite of spirit; the various distortion that those of ordinary skill in the art make technical scheme of the present invention and improvement, all should fall in protection domain that claims of the present invention determines.
Claims (1)
1. a preparation method for Giant cell human immunoglobulin, is characterized in that: comprise the steps:
(1) filter out by neutralization test method the blood plasma raw material that cytomegalovirus NAT titre is more than or equal to 1:50;
(2) prepare pooled plasma trial-product with the described blood plasma raw material after screening, the cytomegalovirus NAT titre of described pooled plasma trial-product is more than or equal to 1:80;
(3) described pooled plasma trial-product is carried out albumen sepn by cold ethanol albumen sepn filter press technique in conjunction with chromatography, separation and Extraction immunoglobulin components, after filtration, chromatography, ultrafiltration, inactivation of virus, after configuration packing obtain product;
The described neutralization test method of step (1) specifically comprises the steps:
(A) diluted sample:
Plasma sample cell maintenance medium carries out 1:10 in advance and dilutes rear 56 DEG C of deactivations 30 minutes;
Open 96 porocyte plates of q.s, indicate viral residual titration plate and specimen test plate, and on each sample test board, indicate the numbering of this plate test sample;
In the various kinds sample wells of specimen test plate, add 40ul cell maintenance medium, viral residual titration hole and negative control hole add 50 μ l cell maintenance mediums;
The sample liquid of deactivation is in advance joined respectively the corresponding position of corresponding 96 porocyte plates, every hole adds sample 10 μ l, and every sample parallel does holes;
The DMEM liquid of described cell maintenance medium to be volume ratio the be foetal calf serum of 5%;
(B) challenge virus
Prepare challenge virus liquid: the number of samples maintenance medium according to test prepares enough challenge virus liquid, will apply viral dilution to 100CCID
50/ 0.05ml; Except viral residual titration hole and negative control hole, all the other each Kong Zhongjun add 50 μ l containing 100CCID
50challenge virus liquid;
Residual titration 100CCID
50challenge virus liquid: challenge virus liquid is done 10 with cell maintenance medium
-1, 10
-2, 10
-3dilution, by challenge virus liquid and its 10
-1, 10
-2, 10
-3the virus liquid of concentration joins corresponding viral residual titration with in 96 porocyte plate holes, and each extent of dilution adds 10 holes, 50 μ l/ holes;
Negative control: add 50 μ l cell maintenance mediums to each Kong Zhongzai of negative control;
All 96 porocyte plates are put into 37 DEG C, containing CO
2percent by volume is the incubator neutral incubation 2 hours of 5%;
(C) preparation of cell suspension and interpolation
The preparation of cell suspension: the MRC-5 cell getting q.s, counting after digestion, test concentration of cell suspension should be 1 × 10
5individual/ml, the enchylema prepared uses immediately or puts 4 DEG C and saves backup;
Cell is outstanding to be added: after neutral incubation, every hole adds cell suspension 100 μ l, and 1 × 10
4individual/hole;
(D) cultivate and observe statistics
The 96 porocyte plates completing above operation are placed 37 DEG C, containing CO
2percent by volume is cultivate 11 days in the incubator of 5%, the 7th day basis of microscopic observation cell growth status after virus inoculation, the 9th day observation of cell pathology situation, the 11st day final result of determination, and record statistics;
Step (3) specifically comprises the steps:
A) by described pooled plasma trial-product centrifugal segregation cryoprecipitate at 2 DEG C;
B) the blood plasma normal saline dilution after removing cryoprecipitate becomes reaction solution, described reacting liquid pH value to 6.5 is regulated with the acetate buffer solution that pH value is 4.0, add in volume percent 95% ethanol to described reaction solution, final ethanol contend per-cent is made to be 20%, use refrigerant to control reacting liquid temperature to-4.5 DEG C, filter press is separated to obtain precipitation;
C) by step b) precipitation that obtains stirs by the NaCl solution of 0 DEG C, 10 times 0.01mol/L and dissolves;
D) to step c) add volume percent 50% ethanol forming reactions liquid in the lysate of gained, final ethanol contend per-cent is made to be 17%, the pH value to 5.1 of reaction solution is regulated with acetate buffer solution, refrigerant is used to control reacting liquid temperature to-4.5 DEG C, filter press is separated removing precipitation, collects supernatant liquor;
E) by steps d) upper DEAE-Sepharose-FastFlow weak anionic displacement chromatography after the supernatant liquor ultrafiltration dialysis collected four times, temperature of reaction is 10 DEG C, collects effluent liquid;
F) by step e) effluent liquid carry out ultrafiltration again, with acetate buffer solution adjust ph to 4.0, temperature to 10 DEG C;
G) dialyse concentrated after 8 times;
H) the Glacial acetic acid tune pH to 3.85 of concentrated solution 2mol/L will obtained after concentrated, add mass percent be 30% maltose make ultimate density 10% as protective material, add physiological saline and make protein mass percentage composition be 5.8%, obtain stoste;
I) described stoste is incubated at 24 ~ 25 DEG C the Geminivirus inactivation treatment of putting and using nano-film filtration for 21 days afterwards;
J) product is obtained after aseptic subpackaged.
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| CN105669860B (en) * | 2016-01-28 | 2019-11-22 | 哈尔滨派斯菲科生物制药股份有限公司 | A kind of hand-foot-and-mouth disease resistant human immunoglobulin and preparation method thereof |
| CN105601735B (en) * | 2016-01-28 | 2019-04-19 | 哈尔滨派斯菲科生物制药股份有限公司 | A kind of intravenous Giant cell human immunoglobulin and preparation method thereof |
| CN105601736B (en) * | 2016-01-28 | 2019-04-23 | 哈尔滨派斯菲科生物制药股份有限公司 | A kind of anti respiratory syncytial virus human immunoglobulin(HIg) and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1553189A (en) * | 2003-06-05 | 2004-12-08 | 旭 马 | Four causative agent differential immunoglobulin G antibody and affinity index testing reagent box |
| CN101361973A (en) * | 2008-09-24 | 2009-02-11 | 四川远大蜀阳药业股份有限公司 | Medicine for treating chicken pox and preparation method thereof |
| CN102286099A (en) * | 2011-08-05 | 2011-12-21 | 深圳市卫武光明生物制品有限公司 | Human cytomegalovirus immunoglobulin for intravenous injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1553189A (en) * | 2003-06-05 | 2004-12-08 | 旭 马 | Four causative agent differential immunoglobulin G antibody and affinity index testing reagent box |
| CN101361973A (en) * | 2008-09-24 | 2009-02-11 | 四川远大蜀阳药业股份有限公司 | Medicine for treating chicken pox and preparation method thereof |
| CN102286099A (en) * | 2011-08-05 | 2011-12-21 | 深圳市卫武光明生物制品有限公司 | Human cytomegalovirus immunoglobulin for intravenous injection and preparation method thereof |
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