CN101352571B - Medicament for treating encephalitis b and preparation method thereof - Google Patents
Medicament for treating encephalitis b and preparation method thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a drug used for treating Japanese encephalitis and a preparation method thereof, belonging to the field of blood products. The invention provides a drug which can effectively treat Japanese encephalitis, thus solving the technical problem. The drug for treating Japanese encephalitis of the invention is a preparation prepared by taking Japanese encephalitis human immunoglobulin as an active ingredient and adding medicinally acceptable accessories. The drug can effectively cure Japanese encephalitis and provides a novel drug choice for Japanese encephalitis patients. In addition, the Japanese encephalitis human immunoglobulin intravenous injection prepared by the method of the invention has the advantages of better quality, high yield and purification, high virus safety and great application prospect.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of encephalitis B and preparation method thereof, belong to the blood products field.
Background technology
Epidemic encephalitis type B (Epidemic encephalitis B) is called for short encephalitis b, is to die of illness and acute arthropod borne infection that disability rate is all higher, and this disease number of dying of illness is to be only second to tuberculosis to sort and occupy deputy Category B notifiable disease.Its media control effect is not good enough, and this disease is a feature with hyperpyrexia, disturbance of consciousness, tic and meningeal irritation sign clinically.The patient with severe symptoms accompanies the maincenter respiratory failure, and case fatality rate can be lost neural spirit such as disturbance of consciousness, dementia, aphasia, paralysis, epilepsy, disabled in the back after being ill up to 20-50%, and incidence rate is 45%.Encephalitis b attenuated live vaccine preventive effect is better but whole people's inoculation has certain difficulty, and therefore, encephalitis b morbidity back effectively medicine becomes the emphasis that this area is studied.
At present, the relevant report of the medicine of still incompetent effectively treatment encephalitis b does not see that more useful encephalitis B human normal immunoglobulin treats the relevant report of encephalitis b.
Summary of the invention
First technical problem to be solved by this invention provides a kind of medicine that can effectively treat encephalitis B.
The medicine that the present invention treats encephalitis B is to be active component with the encephalitis B human normal immunoglobulin, adds the preparation that acceptable accessories is prepared from.
Further, the dosage form of above-mentioned preparation is intravenous injection or lyophilized injectable powder.
Further, the specification of above-mentioned encephalitis B human normal immunoglobulin intravenous injection is 50IU/ml, 40ml.
Further, above-mentioned encephalitis B human normal immunoglobulin adopts following method preparation and gets:
A, blood plasma melting: with the raw blood plasma of encephalitis B antibody titer 〉=8U/ml in 0～4 ℃ of thawing;
B, component separate: be that 0.9% sodium chloride solution diluting plasma to protein content is 45～55g/L with the quality percentage composition, regulate pH value to 7.0 ± 0.4, adding 95% ethanol to reactant liquor concentration of alcohol is 8%, the course of reaction temperature is controlled at-2.5 ± 0.5 ℃, the centrifugalize supernatant promptly gets the FI reactant liquor;
C, filtration: the FI reactant liquor is regulated pH value to 6.80 ± 0.10, adding 95% ethanol to ethanol final concentration is 20%, and reacting liquid temperature is controlled at 5.0 ± 0.5 ℃, adds diatomite adsorption impurity, stir, leave standstill, filter, the gained precipitation is the FII+III precipitation;
D, resolution of precipitate: with of the sodium chloride solution dissolving of FII+III precipitation with 0.01mol/L, regulator solution pH value to 5.10 ± 0.05, the regulator solution ionic strength is 0.01, adding 95% ethanol concentration of alcohol to the solution is 17%, the control solution temperature is-4.5 ± 0.5 ℃, stir, leave standstill, filter, gained filtrate is FII filtrate;
E, filtrate precipitation: add sodium chloride solution in the FII filtrate, the regulator solution ionic strength is 0.05, regulator solution pH value to 6.90 ± 0.05, adding 95% ethanol concentration of alcohol to the solution is 25%, every liter of ethanol is added 1mol/L sodium chloride solution 0.05L, control end reaction liquid temp is-7.5 ± 0.5 ℃, stirs, leaves standstill, filters, and promptly gets the FII precipitation;
F, chromatography: FII precipitation is dissolved after-filtration with water for injection, and filtrate is used the anion exchange gel chromatography then with the water for injection dealcoholysis of dialysing, and obtains IgG solution;
G, ultrafiltration: with the ultrafiltration of IgG solution, 4 times of gained ultrafiltrates concentrate, and regulate with water for injection then that protein concentration is 15 ± 5g/L in the ultrafiltrate, are no more than 350uS/cm with hydrochloric acid adjusting ultrafiltrate pH value to 4.8 ± 0.1, the electrical conductivity of 0.5mol/L;
H, Pasteur's inactivation of viruses: g step gained solution was heated 10 hours in 60 ± 0.5 ℃ of water-baths continuously;
I, low pH are incubated and are put inactivation of viruses:, concentrate (or concentrating back lyophilizing) with the filtration of the protein solution behind the h step inactivation of viruses, clarification, ultrafiltration once more, promptly get the encephalitis B human normal immunoglobulin.
Second technical problem to be solved by this invention provides a kind of preparation method of above-mentioned encephalitis B human normal immunoglobulin intravenous injection, and this method comprises the steps:
A, blood plasma melting: with the raw blood plasma of encephalitis B antibody titer 〉=8U/ml in 0～4 ℃ of thawing;
B, component separate: be that 0.9% sodium chloride solution diluting plasma to protein content is 45～55g/L with the quality percentage composition, regulate pH value to 7.0 ± 0.4, adding 95% ethanol to reactant liquor concentration of alcohol is 8%, the course of reaction temperature is controlled at-2.5 ± 0.5 ℃, the centrifugalize supernatant promptly gets the FI reactant liquor;
C, filtration: the FI reactant liquor is regulated pH value to 6.80 ± 0.10, adding 95% ethanol to ethanol final concentration is 20%, and reacting liquid temperature is controlled at 5.0 ± 0.5 ℃, adds diatomite adsorption impurity, stir, leave standstill, filter, the gained precipitation is the FII+III precipitation;
D, resolution of precipitate: with of the sodium chloride solution dissolving of FII+III precipitation with 0.01mol/L, regulator solution pH value to 5.10 ± 0.05, the regulator solution ionic strength is 0.01, adding 95% ethanol concentration of alcohol to the solution is 17%, the control solution temperature is-4.5 ± 0.5 ℃, stir, leave standstill, filter, gained filtrate is FII filtrate;
E, filtrate precipitation: add sodium chloride solution in the FII filtrate, the regulator solution ionic strength is 0.05, regulator solution pH value to 6.90 ± 0.05, adding 95% ethanol concentration of alcohol to the solution is 25%, every liter of ethanol is added 1mol/L sodium chloride solution 0.05L, control end reaction liquid temp is-7.5 ± 0.5 ℃, stirs, leaves standstill, filters, and promptly gets the FII precipitation;
F, chromatography: FII precipitation is dissolved after-filtration with water for injection, and filtrate is used the anion exchange gel chromatography then with the water for injection dealcoholysis of dialysing, and obtains IgG solution;
G, ultrafiltration: with the ultrafiltration of IgG solution, 4 times of gained ultrafiltrates concentrate, and regulate with water for injection then that protein concentration is 15 ± 5g/L in the ultrafiltrate, are no more than 350uS/cm with hydrochloric acid adjusting ultrafiltrate pH value to 4.8 ± 0.1, the electrical conductivity of 0.5mol/L;
H, Pasteur's inactivation of viruses: g step gained solution was heated 10 hours in 60 ± 0.5 ℃ of water-baths continuously;
I, low pH are incubated and are put inactivation of viruses: with the filtration of the protein solution behind the h step inactivation of viruses, clarification, ultrafiltration once more, adjust with the hydrochloric acid of 0.5mol/L then that the protein solution pH value is 3.8～4.4, encephalitis B antibody titer 〉=50U/ml, adding maltose to maltose mass concentration is 10%, filtration sterilization was placed 21 days in 23～25 ℃ then;
J, finished product packing: by required specification packing, promptly.
Wherein, the source of the raw blood plasma of above-mentioned encephalitis B antibody titer 〉=8U/ml is as follows:
1, immunity: use specification as the lyophilizing Japanese Encephalitis Vaccine,Live that 0.5ml/ props up, the blood donor is carried out inoculation.Once more the blood donor is carried out the booster immunization injection after 3 months.
2, encephalitis b antibody test
Collect the blood plasma of blood donor's booster immunization injection after 3 months, and measure encephalitis B antibody titer in the blood plasma, the blood plasma of encephalitis B antibody titer 〉=8U/ml is qualified blood plasma.
Encephalitis B antibody titer detection method is as follows:
Using the quantitative enzyme linked immunological kit of encephalitis b IgG to detect tired by test product encephalitis b immunoglobulin.
2.1 test sample:
That gathers behind the Vaccinum Encephalitidis Epidemicae booster immunization blood supplier contains the tire blood plasma of encephalitis b antibody of height.
2.2 reference substance:
Random collecting 〉=the common blood supplier's of 200 person-portions pooled serum.
2.3 test procedure
By the test sample of 100 multiples preparation dilution → be provided with blank, add test sample 100ul to ELISA Plate hole → 37 a ℃ wet box hatch 30 minutes → 3 times (cleaning mixture uses 20 times of dilutions of distilled water in advance in washing, thorough mixing) → add the wet box of enzyme conjugates solution (Enzymeconjugate) 100ul → 37 ℃ to hatch 30 minutes → washing 5 times → add tetramethyl benzidine colour developing liquid, the wet box of each 50ul of hydrogen peroxide chromophoric solution → 37 ℃ hatch 10 minutes → add stop bath (Sulphuric Acide) 50ul → wavelength 450nm to read extinction value (the prior preheating 20min of enzyme mark checkout equipment deducts the substrate blank)
2.3 interpretation of result
Set up index 2.3.1 establish reference substance OD value≤0.15 for experiment.
2.3.2 test sample encephalitis B antibody titer 〉=8U/ml is made as the immune blood plasma criterion of acceptability.
Used raw blood plasma also should adopt the diagnostic reagent of state approval to carry out the infectious pathogenic microorganisms mark in the above-mentioned a step: hbs antigen (HBsAg), HCV antibody, HIV (1+2) antibody, syphilis, ALT etc. check inspection, and the result should be negative.Reject undesirable blood plasma, strictness prevents undesirable plasma bags and normal plasma cross-contamination in melting the slurry operating process.Should sterilize in the plasma bags surface of dress blood plasma, then broken bag, blood plasma melting.
Wherein, the b step is that 0.9% the proteic purpose of sodium chloride solution diluting plasma is the content that increases IgG in the c step precipitation with the quality percentage composition.
Wherein, regulate the used pH value regulator of pH value in b, c, the d step and can be the intravenous fluid pH value regulator of routine, be preferably acetic acid-sodium acetate buffer of pH4.0.
Wherein, preferably and not waste kieselguhr to save cost for diatomaceous adsorption effect in the c step, the kieselguhr addition is preferably every liter of solution 18g.
Wherein, the d step is fully dissolved in order to make the component I gG in the precipitation, and resolution of precipitate is selected the 0.01mol/L sodium chloride solution dissolving with 6-12 times of W/V for use.
Wherein, the e step adds the 1mol/L sodium chloride solution, and adjusts pH value to 6.90 ± 0.05, and adding 95% ethanol to final concentration is 25%, its objective is the yield that improves high-purity IgG.Regulating the used pH value regulator of pH value in the e step is the NaHCO of 1mol/L
3Solution
Wherein, the molecular cut off of the used bag filter of f step dialysis dealcoholysis is 30KD, during f step chromatography, adopts PS370 type anion exchange gel column, it with pH value 6.7 ± 0.3 phosphate buffer balance chromatographic column, the adjustment protein concentration is that 15～45g/L, pH value are 6.7 ± 0.3, last sample, and flow speed control is 40～120cm/h, collect IgG, behind the end of the sample, the remaining IgG with on the phosphate buffer washing chromatographic column merges with the IgG liquid of collecting.Gel chromatography has been removed the foreign protein and the IgA of the overwhelming majority in the solution, makes purity 〉=99%, IgG monomer and dimeric content 〉=97% of effluent IgG.
Wherein, do not add the stabilizing agent of protecting IgG during the product of h step process centre, purpose is to strengthen the inactivation of viruses effect; But Pasteur's heating means deactivation fat peplos and non-lipid-coated virus, the pH value of conventional Pasteur's heating means deactivation product is 7.0, the pH value of solution is 4.8 ± 0.1 when adopting Pasteur's heating means fire extinguishing virus among the present invention, can improve deactivation speed, its inactivation of viruses kind spectrum significantly more simple low pH is incubated the method for putting extensively (effective to non-lipid-coated virus).H step inactivation of viruses result: deactivation HIV, VSV, Sindbis and Polio-1 viral load all 〉=4Log.
Wherein, the used ultrafilter membrane molecular cut off of the ultrafiltration once more described in the i step is 10KD.Complete in order to ensure inactivation of virus, the i step is hanged down pH and is incubated and put inactivation of viruses, low pH incubates that to put inactivation of viruses good to HAV (hepatitis A virus, Hepatitis AVirus) and human parvovirus B19's non-lipid-coated virus inactivating efficacies such as (human parvovirus B19).
The 3rd technical problem to be solved by this invention provides the purposes of encephalitis B human normal immunoglobulin in the medicine of preparation treatment encephalitis B.
Medicine of the present invention can effectively be treated encephalitis B, for the encephalitis B patient provides a kind of new medicament selection.The encephalitis B human normal immunoglobulin intravenous injection of the inventive method preparation, its better quality, yield and purity height (purity of IgG 〉=99%, IgG monomer and dimeric content 〉=98%), virus safe height have broad application prospects.
The specific embodiment
Below in conjunction with embodiment the specific embodiment of the present invention is further described.
The preparation of embodiment 1 encephalitis B human normal immunoglobulin intravenous injection
1, produce before every bag of blood plasma adopt the diagnostic reagent of state approval to carry out infectious pathogenic microorganisms mark such as hbs antigen (HBsAg), HCV antibody, HIV (1+2) antibody, syphilis, ALT etc. to check inspection, the result should be negative.Reject undesirable blood plasma, strictness prevents undesirable plasma bags and normal plasma cross-contamination in melting the slurry operating process.
2, plasma bags surface sterilization, broken bag, blood plasma melting temperature to 0～4 ℃, carry out component by cold ethanol Protein Separation method and separate:
With 9g/L sodium chloride solution diluting plasma protein content to 45～55g/L, regulate pH value 7.0 ± 0.4, adding 95% ethanol to reactant liquor concentration of alcohol is 8%.Reacting liquid temperature is controlled at-2.5 ± 0.5 ℃.
3, the FI reactant liquor is regulated pH value 6.80 ± 0.10, adding 95% ethanol to reactant liquor concentration of alcohol is 20%.Reacting liquid temperature is controlled at 5.0 ± 0.5 ℃, adds kieselguhr, stir after-filtration, the precipitation of collection is immediately in depositing below-30 ℃.
4, after the dissolving of FI+II+III precipitate, regulate pH value 5.10 ± 0.05, adding 95% ethanol to reactant liquor concentration of alcohol is 17%, and the control reacting liquid temperature is at-4.5 ± 0.5 ℃.Stir, leave standstill after-filtration.
5, every liter of filtered solution adds 1mol/L sodium chloride solution 0.04L, conditioned reaction liquid pH value 6.90 ± 0.05, adding 95% ethanol to reactant liquor concentration of alcohol is 25%, every liter of ethanol is added 1mol/L sodium chloride solution 0.05L end reaction liquid temp and is controlled at-7.5 ± 0.5 ℃, after-filtration is left standstill in stirring, collecting precipitation.
6, the FII precipitate dissolves after-filtration with water for injection, and filtered solution is with the water for injection dealcoholysis of dialysing.Adopt PS370 type anion exchange gel column,, adjust protein concentration 15～45g/L, pH6.7 ± 0.3 with pH6.7 ± 0.3 phosphate buffer balance chromatographic column, last sample, flow velocity 40～120cm/h makes the FII flow of solution pass chromatographic column, collects IgG.Behind the end of the sample,, wear the liquid merging with stream and change down operation over to the remaining IgG on the phosphate buffer washing chromatographic column.Be adsorbed on foreign protein on the chromatographic column with 1～2mol/L sodium chloride solution eluting, regenerate with 0.2～1mol/L sodium hydroxide solution.Inserts full load, regeneration use and are no more than 400 circulations.
7, ultrafiltration behind the chromatography, adjustment protein concentration 15 ± 5g/L, pH4.8 ± 0.1, electrical conductivity are imported Pasteur's deactivation jar after being no more than 350uS/cm.
8, goods were heated 10 hours in 60 ± 0.5 ℃ of water-baths continuously, with the residual Virus Pollution of deactivation possibility.
9, ultrafiltration once more after the deactivation is adjusted pH 3.8～4.4, the encephalitis b antibody titer is not less than 50U/ml, and aseptic filtration in 23～25 ℃, is placed goods 21 days, hangs down pH and incubates and put inactivation of viruses.Deactivation finishes to change goods over to 2～8 ℃ of freezers and deposits.
Stock solution is purified, be immunoglobulin stock solution after the ultrafiltration, aseptic filtration.
10, press finished product specification preparation, make that IgG content is not less than 50g/L in the finished product, the encephalitis b antibody titer is not less than 50U/ml, and add into maltose to 10%.
11, carry out packing at the 100 grades of clean rooms in ten thousand grades of parts, and every bottle of packing 2000IU (50U/ml, 40ml)/bottle, contain human blood source encephalitis b antibody 2000U, tiring is not less than 50U/ml, loading amount 40ml.
The quality testing and the result of test example 1 encephalitis B human normal immunoglobulin intravenous injection
Quiet notes encephalitis b human normal immunoglobulin, and specification: 2000U (50U/ml, 40ml)/bottle, testing result sees Table 1.
The quality testing and the result of table 1 encephalitis B human normal immunoglobulin intravenous injection
The 2 encephalitis B human normal immunoglobulin intravenous injection evaluations of pesticide effectiveness of test example
1, encephalitis B human normal immunoglobulin (test), human normal immunoglobulin's (contrast) respectively with dilution encephalitis b virus liquid (about 200PFU/0.4ml) mixed in equal amounts, put 37 ℃ of water-baths 90 minutes, inoculate 6 orifice plate BHK21 cells, every hole 0.4ml, put 37 ℃ and cultivated 90 minutes, add the culture medium covering that contains methylcellulose, cultivated 5 days in 37 ℃, 5% carbon dioxide incubator, dyeing, plaque counting.
The result: among the encephalitis B human normal immunoglobulin and the cell plaques counting after the virus obviously is less than among the human normal immunoglobulin and virus after the plaque counting of cell, there is significant significant difference in the two.
2, encephalitis B human normal immunoglobulin intravenous injection (test group), human normal immunoglobulin's (matched group) respectively with dilution encephalitis b virus liquid (virulence 〉=7.0logLD in the brain
50/ 0.02ml) mixed in equal amounts is put 37 ℃ of water-baths 90 minutes, adopts each 10 of 3-5 age in days neonatal rats, every intracerebral injection 0.02ml.Observe 14 days survival rate (dead person disregards in inoculating 3 days, but death toll must not be greater than 20% in 3 days).
The result: the test group mouse survives entirely, the dead mouse of matched group 〉=70%.
From above-mentioned test as can be seen, encephalitis B human normal immunoglobulin of the present invention to treat the encephalitis B effect remarkable.
Claims (5)
1. the preparation method of encephalitis B human normal immunoglobulin intravenous injection is characterized in that: comprise the steps:
A, blood plasma melting: with the raw blood plasma of encephalitis B antibody titer 〉=8U/ml in 0～4 ℃ of thawing;
B, component separate: be that 0.9% sodium chloride solution diluting plasma to protein content is 45～55g/L with the quality percentage composition, regulate pH value to 7.0 ± 0.4, adding 95% ethanol to reactant liquor concentration of alcohol is 8%, the course of reaction temperature is controlled at-2.5 ± 0.5 ℃, the centrifugalize supernatant promptly gets the FI reactant liquor;
C, filtration: the FI reactant liquor is regulated pH value to 6.80 ± 0.10, adding 95% ethanol to ethanol final concentration is 20%, and reacting liquid temperature is controlled at 5.0 ± 0.5 ℃, adds diatomite adsorption impurity, stir, leave standstill, filter, the gained precipitation is the FII+III precipitation;
D, resolution of precipitate: with of the sodium chloride solution dissolving of FII+III precipitation with 0.01mol/L, regulator solution pH value to 5.10 ± 0.05, the regulator solution ionic strength is 0.01, adding 95% ethanol concentration of alcohol to the solution is 17%, the control solution temperature is-4.5 ± 0.5 ℃, stir, leave standstill, filter, gained filtrate is FII filtrate;
E, filtrate precipitation: add sodium chloride solution in the FII filtrate, the regulator solution ionic strength is 0.05, regulator solution pH value to 6.90 ± 0.05, adding 95% ethanol concentration of alcohol to the solution is 25%, every liter of ethanol is added 1mol/L sodium chloride solution 0.05L, control end reaction liquid temp is-7.5 ± 0.5 ℃, stirs, leaves standstill, filters, and promptly gets the FII precipitation;
F, chromatography: FII precipitation is dissolved after-filtration with water for injection, and filtrate is used the anion exchange gel chromatography then with the water for injection dealcoholysis of dialysing, and obtains IgG solution;
G, ultrafiltration: with the ultrafiltration of IgG solution, 4 times of gained ultrafiltrates concentrate, and regulate with water for injection then that protein concentration is 15 ± 5g/L in the ultrafiltrate, are no more than 350uS/cm with hydrochloric acid adjusting ultrafiltrate pH value to 4.8 ± 0.1, the electrical conductivity of 0.5mol/L;
H, Pasteur's inactivation of viruses: g step gained solution was heated 10 hours in 60 ± 0.5 ℃ of water-baths continuously;
I, low pH are incubated and are put inactivation of viruses: with the filtration of the protein solution behind the h step inactivation of viruses, clarification, ultrafiltration once more, adjust with the hydrochloric acid of 0.5mol/L then that the protein solution pH value is 3.8～4.4, encephalitis B antibody titer 〉=50U/ml, adding maltose to maltose mass concentration is 10%, filtration sterilization was placed 21 days in 23～25 ℃ then;
J, finished product packing: by required specification packing, promptly.
2. the preparation method of encephalitis B human normal immunoglobulin intravenous injection according to claim 1 is characterized in that: regulating the used pH value regulator of pH value in b, c, the d step is acetic acid-sodium acetate buffer of pH4.0.
3. the preparation method of encephalitis B human normal immunoglobulin intravenous injection according to claim 1 is characterized in that: diatomaceous addition is every liter of solution 18g in the c step.
4. the preparation method of encephalitis B human normal immunoglobulin intravenous injection according to claim 1 is characterized in that: regulating the used pH value regulator of pH value in the e step is the NaHCO of 1mol/L
3Solution.
5. the preparation method of encephalitis B human normal immunoglobulin intravenous injection according to claim 1 is characterized in that: the molecular cut off of the used bag filter of f step dialysis dealcoholysis is 30KD; The used ultrafilter membrane molecular cut off of ultrafiltration once more described in the i step is 10KD.
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| CN102443059A (en) * | 2011-11-07 | 2012-05-09 | 武汉中原瑞德生物制品有限责任公司 | Method for preparing intravenous injection human immunoglobulin |
| CN111760022A (en) * | 2020-08-07 | 2020-10-13 | 山东泰邦生物制品有限公司 | Human immunoglobulin liposome pharmaceutical composition and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2141342C1 (en) * | 1996-05-05 | 1999-11-20 | Кировский НИИ гематологии и переливания крови | Method of preparing human immunoglobulin for intravenous administration against tick-borne encephalitis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2141342C1 (en) * | 1996-05-05 | 1999-11-20 | Кировский НИИ гематологии и переливания крови | Method of preparing human immunoglobulin for intravenous administration against tick-borne encephalitis |
Non-Patent Citations (2)
| Title |
|---|
| 李亚利等.中和抗体阳性血浆治疗乙型脑炎的效果评价.《中国临床医学》.2005,第12卷(第5期),862-863. * |
| 王岱明等.流行性乙型脑炎特异性免疫球蛋白的临床观察.《中华儿科杂志》.1994,(第1期),34-35. * |
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Address after: 610214 Sister Erwei, Zhonghe Town, Chengdu High-tech Zone, Sichuan Province Co-patentee after: Wei Xianyi Patentee after: Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd. Address before: 610214 Jieeryan, Huayang Town, Shuangliu County, Chengdu City, Sichuan Province Co-patentee before: Wei Xianyi Patentee before: Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd. |
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