CN103554252A - Giant cell human immunoglobulin and preparation method thereof - Google Patents
Giant cell human immunoglobulin and preparation method thereof Download PDFInfo
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- CN103554252A CN103554252A CN201310573517.5A CN201310573517A CN103554252A CN 103554252 A CN103554252 A CN 103554252A CN 201310573517 A CN201310573517 A CN 201310573517A CN 103554252 A CN103554252 A CN 103554252A
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Abstract
The invention discloses a giant cell human immunoglobulin. The valence of a cytomegalovirus-neutralizing antibody is greater than or equal to 1:400, the purity of the immunoglobulin is greater than or equal to 96% of total protein. The invention further discloses a preparation method of the giant cell human immunoglobulin, which comprises the following steps: (1) screening out the plasma raw material the cytomegalovirus-neutralizing antibody valence titer of which is greater than or equal to 1:50; (2) preparing a mixed plasma test sample; (3) separating and extracting immunoglobulin components from the mixed plasma test sample by adopting a low-temperature alcohol or chromatographic protein separation method, and performing filtering, chromatography, ultrafiltration, virus inactivation and allocation and subpackaging to obtain the product. The giant cell human immunoglobulin can specifically treat cytomegalovirus, thus being an effective medicine of cytomegalovirus infection symptoms, and having greater social and economic benefits.
Description
Technical field
The present invention relates to field of biological pharmacy, particularly relate to a kind of giant cells human normal immunoglobulin and preparation method thereof.
Background technology
Cytomegalovirus CMV(Cytomegalovirus) be the DNA virus that herpetoviridae β belongs to, the pregnant woman who is caused by cytomegalovirus, newborn infant, Organ Transplantation Patients, immunosuppression person infect mortality ratio can reach 50～80%.Cytomegalovirus human normal immunoglobulin CMV-IgG, because of in can be special and cytomegalovirus, mainly treats with it cytomegalovirus severe infection that pregnant woman, newborn infant, immunosuppressed patient and organ transfer operation are printed and distributed clinically.Cytomegalovirus natural infection rate in general population can reach more than 80%, from healthy population, screen and gather the blood plasma containing high-titer cytomegalovirus IgG antibody, adopt Low-temperature Ethanol Processes separation purification method to prepare giant cells human normal immunoglobulin medicine, the severe infection causing 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 provides human normal immunoglobulin of a kind of effective treatment cytomegalovirus severe infection and preparation method thereof.
A human normal 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 cells human normal immunoglobulin of the present invention, wherein said immunoglobulin (Ig) is compared with normal human serum, and main precipitation line is IgG.
Giant cells human normal 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 cells human normal immunoglobulin of the present invention, the formulation of wherein said immunoglobulin (Ig) is liquid preparation or freeze-dried formulation.
A preparation method for giant cells human normal immunoglobulin, comprises the steps:
(1) by neutralization test method, filter out the blood plasma raw material that cytomegalovirus NAT titre is more than or equal to 1:50;
(2) with the described blood plasma raw material after screening, prepare pooled plasma trial-product, described pooled plasma raw material is mixed by the described blood plasma raw material that is 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) described pooled plasma trial-product is pressed to cold ethanol press filtration in conjunction with chromatography protein separating method, separation and Extraction immunoglobulin components, after filtration, packing obtains product after chromatography, ultrafiltration, inactivation of virus, configuration.
The preparation method of giant cells human normal immunoglobulin of the present invention, wherein, the described neutralization test method of step (1) specifically comprises the steps:
(A) diluted sample:
Plasma sample carries out in advance 1:10 with cell maintenance medium and dilutes rear 56 ℃ of deactivations 30 minutes;
Open 96 porocyte plates of q.s, indicate plate and specimen test plate for viral residual titration, and on each sample test board, indicate the numbering of this plate test sample;
In each sample well 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 ，Mei hole, corresponding position that the sample liquid of deactivation is in advance joined respectively to corresponding 96 porocyte plates adds sample 10 μ l, parallel two holes of doing of every sample;
Described cell maintenance medium is that volume ratio is the DMEM liquid of 5% foetal calf serum;
(B) challenge virus
Prepare challenge virus liquid: according to the number of samples of test, by maintenance medium, prepare enough challenge virus liquid, 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 to 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 ℃, contained CO
2percent by volume is 5% incubator neutral incubation 2 hours;
(C) preparation of cell suspension and interpolation
The preparation of cell suspension: get the MRC-5 cell of q.s, counting after digestion, test should be 1 * 10 with concentration of cell suspension
5individual/ml, the enchylema preparing is used immediately or puts 4 ℃ and saves backup;
Cell is outstanding to be added: after neutral incubation, every hole adds cell suspension 100 μ l, approximately 1 * 10
4individual/hole;
(D) cultivate and observe statistics
The 96 porocyte plates that complete above operation are placed to 37 ℃, contained CO
2percent by volume is to cultivate 11 days in 5% incubator, observation of cell growing state under the 7th day microscope after virus inoculation, the 9th day observation of cell pathology situation, the 11st day final decision result, and record statistics.
The preparation method of giant cells human normal immunoglobulin of the present invention, wherein, step (3) specifically comprises the steps:
A) by described pooled plasma trial-product centrifugal removal cryoprecipitate at 2 ℃;
B) blood plasma of removing after cryoprecipitate becomes reaction solution with normal saline dilution, with the acetate buffer solution that pH value is 4.0, regulate described reacting liquid pH value to 6.5, add volume percent 95% ethanol to described reaction solution, making final ethanol volume percent is 20%, use refrigerant to control reacting liquid temperature to-4.5 ℃, filter press separation must precipitate;
C) by step b) NaCl solution stirring the dissolving of 0 ℃, 10 times 0.01mol/L for the precipitation that obtains;
D) to step c) add volume percent 50% ethanol in the lysate of gained and form reaction solution, making final ethanol volume percent is 17%, with acetate buffer solution, regulate the pH value to 5.1 of reaction solution, use refrigerant to control reacting liquid temperature to-4.5 ℃, precipitation is removed in filter press separation, collects supernatant liquor;
E) by steps d) upper DEAE-Sepharose-Fast Flow weak anionic displacement chromatography after the supernatant liquor ultrafiltration dialysis collected four times, temperature of reaction is 10 ℃, collects effluent liquid;
F) by step e) effluent liquid carry out ultrafiltration again, with acetate buffer solution, regulate pH value to 4.0, temperature to 10 ℃;
G) dialyse concentrated after 8 times;
H) by the Glacial acetic acid tune pH to 3.85 of the concentrated solution use 2mol/L obtaining after concentrated, add mass percent be 30% maltose make ultimate density 10% as protective material, adding physiological saline, to make protein mass percentage composition be 5.8%, obtains stoste;
I) described stoste is incubated at 24～25 ℃ and put the Geminivirus inactivation treatment of using afterwards nano-film filtration for 21 days;
J) after aseptic subpackaged, obtain product.
Giant cells human normal immunoglobulin difference from prior art of the present invention is:
Giant cells human normal immunoglobulin provided by the invention, giant cells NAT is more than or equal to 1:256, can to cytomegalovirus, treat targetedly, is the active drug for the treatment of Cytomegalovirus Infection, has larger Social benefit and economic benefit.
Preparation method's of the present invention advantage:
(1) adopt the cytomegalovirus strain of the existing standard of country as detecting carrier, from healthy population, filter out the specificity raw blood plasma with higher titre, its standard meets " biological products production blood plasma " regulation in < < Pharmacopoeia of People's Republic of China > > 2010 editions, the giant cells human normal immunoglobulin of preparing 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, the immunoglobulin preparation that adopts cold ethanol filter-pressing process column chromatography purification to prepare, 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: with neutralization test method, detect the giant cells neutralizing antibody in blood plasma, neutralize the titre of tiring and be 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, and HCV negative antibodies etc. are qualified giant cells human normal immunoglobulin raw blood plasma all, 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 for 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) plasma sample cell maintenance medium for trial-product (be the DMEM liquid of the foetal calf serum of volume percent 5%, lower with) is carried out after 1:10 dilution to 56 ℃ of deactivations 30 minutes.
Get the cell plate of q.s, in sample panel, add 40ul/ porocyte maintenance medium, then add corresponding 1:10 to dilute in advance each sample liquid 10ul/ hole of deactivation, parallel 2 holes of every sample.
C) get cytomegalovirus CMV and with cell maintenance medium, be diluted to test and add in trial-product plate hole by concentration (i.e. 100 * CCID50/0.05ml) equivalent, and positive control hole, 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 add application virus liquid 50ul/ hole, mix;
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, then application virus liquid is carried out, after 10 doubling dilutions, getting respectively 10
0～10
-3the virus liquid of concentration adds in corresponding viral residual titration hole, 50ul/ hole;
D) neutralization reaction: liquid in each plate hole is carefully mixed in rearmounted CO2gas incubator to 37 ℃ on vortex mixer, and 5%CO2 is hatched and carried out neutralization reaction 2 hours.
E) cell:
The preparation of cell suspension: get the MRC-5 cell of q.s, after digestion, counting, should be 1 * 10 with cell maintenance medium adjusting test with concentration of cell suspension
5individual/ml, the enchylema preparing is used immediately or puts 4 ℃ and saves backup.
Cell is outstanding to be added: after the neutralization reaction time is full, every hole adds cell suspension 100 μ l, approximately 1 * 10
4individual/hole.
F) cultivate: the cell plate that complete above operation are placed to 37 ℃, 5%CO
2in incubator, cultivate observation of cell growing state under the 7th day microscope, the 9th day observation of cell pathology situation, the 11st day final decision result, and record statistics 11 days.
Each test must have virus control and cell contrast, and pathology must appear in virus control, and cell contrast must be normal.Result is judged: can protect the trial-product extent of dilution that pathology does not appear in 50% cell to tire as neutralization.In the present invention, all neutralization test methods of mentioning are all that above-mentioned identical mode is carried out, hereinafter to be referred as neutralization test method.
Specificity blood plasma containing higher titre mixes 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 | The common blood plasma of A() | B(is containing the specificity blood plasma of higher titre) |
| Protein content | 56g/L | 57g/L |
| HCMV NAT | 1:23 | 1:128 |
Second batch
| Test item | The common blood plasma of A() | B(is containing the specificity blood plasma of higher titre) |
| Protein content | 56g/L | 56g/L |
| HCMV NAT | 1:20 | 1:128 |
The 3rd batch
| Test item | The common blood plasma of A() | B(is containing the specificity blood plasma of higher titre) |
| Protein content | 57g/L | 55g/L |
| HCMV NAT | 1:20 | 1:137 |
Note:
1.A: for screening the against regulation common pooled plasma of rear antibody titers
2.B: the higher mixed slurry of specificity blood plasma of antibody titers obtaining through above-mentioned neutralization method screening
3. same batch of blood plasma source of above three batches of blood plasma is identical, and the anti-HCMV blood plasma of high-titer filtering out by neutralization test method is B, and remaining part is A.
2, the preparation of giant cells human normal immunoglobulin:
(1) blood plasma thawing of 500 above Plasma donors is mixed, after mixing, volume is 300L, detects mixed prize neutralization tire as 1:128 by neutralization test method;
(2) mixed blood plasma, centrifugal removal cryoprecipitate 24Kg at 2 ℃;
(3) blood plasma (275L) of removing after cryoprecipitate is used 28L normal saline dilution, with pH4.0 acetate buffer solution 720ml, regulate reacting liquid pH value to 6.5, add 95% ethanol 75L to reaction solution, making final alcohol concn is 20%, reaction solution final volume is 345L, use refrigerant to control reacting liquid temperature to-4.5 ℃, filter press separation must precipitate 25kg;
(4) by 0 ℃ of 0.01mol/LNaCl solution 225L stirring and dissolving for the precipitation of step (3), final solution volume is 250L;
(5) in supernatant liquor, add 50% ethanol 128L to reaction solution, making final alcohol concn is 17%, with acetate buffer solution 1580ml, regulate reacting liquid pH value to 5.1, reaction solution final volume is 380L, use refrigerant to control reacting liquid temperature to-4.5 ℃, precipitation is removed in filter press separation, and collection supernatant liquor is 330L;
(6) supernatant liquor is carried out to upper DEAE-Sepharose-Fast Flow weak anionic displacement chromatography after ultrafiltration dialysis four times, temperature of reaction is 10 ℃, collects effluent liquid 310L.
(7) effluent liquid of step (6) is carried out to ultrafiltration again, with acetate buffer solution 3100ml, regulate pH value to 4.0, temperature to 10 ℃.Dialyse and be concentrated into 22L(protein content after 8 times: 7.2%, pH value: 3.5).
(8) concentrated solution of step (7) is adjusted to pH to 3.85 with the Glacial acetic acid 120ml of 2mol/L; add 30% maltose 11L make ultimate density at 10%(the protective material as inactivation of virus albumen); adding 3L physiological saline, to make protein content be 5.6%, and configuration final volume is 36L.
(9) above-mentioned steps (8) gained stoste is incubated and put the Geminivirus inactivation treatment of using afterwards nano-film filtration for 21 days at 24～25 ℃;
(10) step (9) gained giant cells human normal immunoglobulin is distributed into 1800 bottle products, gets 25 bottles of samples and send the calibrating of quality arbitration portion.
With neutralization test method, detect its giant cells NAT and equal 1:549.
3, through the resulting sample of extensive trial production preparation, the relevant regulations that this product manufacture of revising according to enterprise and vertification regulation and < < Pharmacopoeia of People's Republic of China > > are 2010 editions three are examined and determine the giant cells human normal immunoglobulin of above-mentioned steps gained.The results are shown in Table 2.
Table 2. giant cells human normal immunoglobulin survey report
Conclusion: this product is manufactured vertification regulation check by quiet notes giant cells human normal immunoglobulin, and result is up to specification.
Above-described embodiment is described the preferred embodiment of the present invention; not scope of the present invention is limited; design under the prerequisite of spirit not departing from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention, all should fall in the definite protection domain of the claims in the present invention book.
Claims (7)
1. a giant cells human normal immunoglobulin, is characterized in that: its cytomegalovirus NAT is more than or equal to 1:400, and immunoglobulin purity is more than or equal to 96% of total protein.
2. giant cells human normal immunoglobulin according to claim 1, is characterized in that: described immunoglobulin (Ig) is compared with normal human serum, and main precipitation line is IgG.
3. giant cells human normal immunoglobulin according to claim 2, is characterized in that: IgG monomer and the dimer content sum of described immunoglobulin (Ig) are more than or equal to 96%.
4. giant cells human normal immunoglobulin according to claim 1, is characterized in that: the formulation of described immunoglobulin (Ig) is liquid preparation or freeze-dried formulation.
5. the preparation method of giant cells human normal immunoglobulin described in any one claim in claim 1～4, is characterized in that: comprise the steps:
(1) by neutralization test method, filter out the blood plasma raw material that cytomegalovirus NAT titre is more than or equal to 1:50;
(2) with the described blood plasma raw material after screening, prepare pooled plasma trial-product, 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 pressed to cold ethanol press filtration in conjunction with chromatography protein separating method, separation and Extraction immunoglobulin components, after filtration, packing obtains product after chromatography, ultrafiltration, inactivation of virus, configuration.
6. the preparation method of giant cells human normal immunoglobulin according to claim 5, is characterized in that: the described neutralization test method of step (1) specifically comprises the steps:
(A) diluted sample:
Plasma sample carries out in advance 1:10 with cell maintenance medium and dilutes rear 56 ℃ of deactivations 30 minutes;
Open 96 porocyte plates of q.s, indicate plate and specimen test plate for viral residual titration, and on each sample test board, indicate the numbering of this plate test sample;
In each sample well 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 ，Mei hole, corresponding position that the sample liquid of deactivation is in advance joined respectively to corresponding 96 porocyte plates adds sample 10 μ l, parallel two holes of doing of every sample;
Described cell maintenance medium is that volume ratio is the DMEM liquid of 5% foetal calf serum;
(B) challenge virus
Prepare challenge virus liquid: according to the number of samples of test, by maintenance medium, prepare enough challenge virus liquid, 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 to 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 ℃, contained CO
2percent by volume is 5% incubator neutral incubation 2 hours;
(C) preparation of cell suspension and interpolation
The preparation of cell suspension: get the MRC-5 cell of q.s, counting after digestion, test should be 1 * 10 with concentration of cell suspension
5individual/ml, the enchylema preparing is used immediately or puts 4 ℃ and saves backup;
Cell is outstanding to be added: after neutral incubation, every hole adds cell suspension 100 μ l, approximately 1 * 10
4individual/hole;
(D) cultivate and observe statistics
The 96 porocyte plates that complete above operation are placed to 37 ℃, contained CO
2percent by volume is to cultivate 11 days in 5% incubator, observation of cell growing state under the 7th day microscope after virus inoculation, the 9th day observation of cell pathology situation, the 11st day final decision result, and record statistics.
7. the preparation method of giant cells human normal immunoglobulin according to claim 5, is characterized in that: step (3) specifically comprises the steps:
A) by described pooled plasma trial-product centrifugal removal cryoprecipitate at 2 ℃;
B) blood plasma of removing after cryoprecipitate becomes reaction solution with normal saline dilution, with the acetate buffer solution that pH value is 4.0, regulate described reacting liquid pH value to 6.5, add volume percent 95% ethanol to described reaction solution, making final ethanol volume percent is 20%, use refrigerant to control reacting liquid temperature to-4.5 ℃, filter press separation must precipitate;
C) by step b) NaCl solution stirring the dissolving of 0 ℃, 10 times 0.01mol/L for the precipitation that obtains;
D) to step c) add volume percent 50% ethanol in the lysate of gained and form reaction solution, making final ethanol volume percent is 17%, with acetate buffer solution, regulate the pH value to 5.1 of reaction solution, use refrigerant to control reacting liquid temperature to-4.5 ℃, precipitation is removed in filter press separation, collects supernatant liquor;
E) by steps d) upper DEAE-Sepharose-Fast Flow weak anionic displacement chromatography after the supernatant liquor ultrafiltration dialysis collected four times, temperature of reaction is 10 ℃, collects effluent liquid;
F) by step e) effluent liquid carry out ultrafiltration again, with acetate buffer solution, regulate pH value to 4.0, temperature to 10 ℃;
G) dialyse concentrated after 8 times;
H) by the Glacial acetic acid tune pH to 3.85 of the concentrated solution use 2mol/L obtaining after concentrated, add mass percent be 30% maltose make ultimate density 10% as protective material, adding physiological saline, to make protein mass percentage composition be 5.8%, obtains stoste;
I) described stoste is incubated at 24～25 ℃ and put the Geminivirus inactivation treatment of using afterwards nano-film filtration for 21 days;
J) after aseptic subpackaged, obtain product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105601735A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Intravenously injected cytomegalovirus human immune globulin and preparation method thereof |
| CN105601736A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Respiratory syncytial virus resistance human immune globulin and preparation method thereof |
| CN105669860A (en) * | 2016-01-28 | 2016-06-15 | 哈尔滨派斯菲科生物制药股份有限公司 | Human immunoglobulin resisting hand-foot-and-mouth disease and preparation method of human immunoglobulin |
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| 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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| 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 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601735A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Intravenously injected cytomegalovirus human immune globulin and preparation method thereof |
| CN105601736A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Respiratory syncytial virus resistance human immune globulin and preparation method thereof |
| CN105669860A (en) * | 2016-01-28 | 2016-06-15 | 哈尔滨派斯菲科生物制药股份有限公司 | Human immunoglobulin resisting hand-foot-and-mouth disease and preparation method of human immunoglobulin |
| 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 |
| 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 |
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| Publication number | Publication date |
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| CN103554252B (en) | 2016-03-30 |
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