CN106011007A - Combined drug-resistant bacterium immunoreactive protein, and preparation method and application thereof - Google Patents
Combined drug-resistant bacterium immunoreactive protein, and preparation method and application thereof Download PDFInfo
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- CN106011007A CN106011007A CN201610398980.4A CN201610398980A CN106011007A CN 106011007 A CN106011007 A CN 106011007A CN 201610398980 A CN201610398980 A CN 201610398980A CN 106011007 A CN106011007 A CN 106011007A
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0258—Escherichia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0266—Klebsiella
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/085—Staphylococcus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/104—Pseudomonadales, e.g. Pseudomonas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/70—Multivalent vaccine
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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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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a combined drug-resistant bacterium immunoreactive protein, and a preparation method and application thereof. The combined drug-resistant bacterium immunoreactive protein is characterized in that a plurality of drug-resistant pathogenic bacteria are used as raw materials and subjected to culture and amplification, sterilization and concentration, detoxification and wall breaking, extraction of the cell walls, cell membranes and capsules of the bacteria and synthesis of a combined drug-resistant bacterium immunoreactive protein biological product. The drug-resistant pathogenic bacteria comprise one or a mixture of two selected from a group consisting of Pseudomonas aeruginosa and Pseudomonas maltophila and a mixture of two or more selected from a group consisting of Klebsiella pneumonia, Haemophilus influenza, Acinetobacter baumannii, Staphylococcus aureus, Neisseria meningitidis, Mycobacterium tuberculosis, Escherichia coli and Staphylococcus albus. The combined drug-resistant bacterium immunoreactive protein provided by the invention is used for preparing preparations applicable to human mucosal absorption, mainly including nasal drops, oral liquid, tablets, electuary, injections and throat sprays. The combined drug-resistant bacterium immunoreactive protein can overcome the problems that drug-resistant bacteria continuously increase and threaten the health of mankind and animals.
Description
Technical field
The present invention relates to a kind of multi-joint fastbacteria immunoreactive protein and its production and use.Belong to medicine biological technique
Field.
Background technology
It is well known that there is great hazardness to human health in pathogenic bacteria.Antibiotic there is treatment effect so that
Human longevity doubles.However as the prolongation of antibiotic usage time, the drug resistance of pathogenic bacteria increases, and medicine causes a disease
Bacterium quickly grows, and makes the antibacterial efficacy of antibiotic go down.At present, the bacterial resistance extensively occurred all over the world is in constantly increasing
Long trend, threatens the health of human and animal.Drug-fast bacteria infection consequence is serious, prolongs including course of disease delay, hospital stays
Length, case fatality rate rising, hospitalization cost increase etc..Bacterial resistance not only poses a health risk, due also to disease causes the productivity
Decline the economic loss (including humans and animals) brought.Drug resistance controls to need long-term input, including to developing country
Provide with funds and technical support, develop new medicine, diagnostic method, vaccine and other intervening measures, and strengthen health
System administration, to guarantee to more efficiently use antibacterials.
Therefore, World Health Organization (WHO) seriously proposes current pathogenic bacterium resistance problems Universal Mobile plan for 2015, encourages
Study and invest and develop new biological product.
Bacterial resistance has become as the public health problem that the whole world is severe, and World Health Organization (WHO) (WHO) was in the world in 2011
The appealing of " containment drug resistance is held fire today, and tomorrow just can be used without medicine " is proposed health day, and in 2014
Disclose whole world drug resistance investigation report, world community and area drug resistance situation are analyzed, and have issued " control in December
Bacterial resistance Universal Mobile plan (draft) processed (Draft global action plan on antimicrobial
resistance)”。
Summary of the invention
An object of the present invention, is in order to solve bacterial resistance be continuous growth trend, threatens that human and animal's is strong
The problem of health, it is provided that a kind of multi-joint fastbacteria immunoreactive protein.
The two of the purpose of the present invention, are to provide for the preparation method of a kind of multi-joint fastbacteria immunoreactive protein.
The three of the purpose of the present invention, are to provide for the purposes of a kind of multi-joint fastbacteria immunoreactive protein.
An object of the present invention can be achieved through the following technical solutions:
Multi-joint fastbacteria immunoreactive protein, it is characterised in that: with several drug resistance pathogenic bacterium as raw material, expand through cultivating
Increase, sterilizing concentrates, poison breaking cellular wall, extracts the cell wall of antibacterial, cell membrane and film, synthesizes multi-joint fastbacteria immunity and lives
Property protein biology goods；Described drug resistance pathogenic bacterium include the one in Pseudomonas aeruginosa, Pseudomonas Maltophilia or two
Kind of combination, and klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, brain
Two kinds of combination of the above in film inflammation diplococcus, tubercule bacillus, large intestine Ai Xi Salmonella and Staphylococcus albus.
An object of the present invention can also be achieved through the following technical solutions:
A kind of preferred version is that described multi-joint fastbacteria immunoreactive protein, for having digested road mucosa covering epithelium
The protein of absorption characteristic.
A kind of preferred version is, motionless by Pseudomonas aeruginosa, klebsiella pneumoniae, hemophilus influenza, Boydii
Bacillus and staphylococcus aureus, totally five kinds of drug-resistant bacterias are raw material, break by cultivating amplification, sterilizing concentration and poison
Wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes 5-linked fastbacteria immunocompetence egg
White biological product；Or by Pseudomonas aeruginosa, klebsiella pneumoniae, hemophilus influenza and Acinetobacter baumannii,
Totally four kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract the cell of antibacterial respectively
The activated protein of wall, cell membrane and film, synthesizes tetrad fastbacteria immunoreactive protein biological product；Or by Aerugo
Pseudomonas, klebsiella pneumoniae and hemophilus influenza, totally three kinds of drug-resistant bacterias are raw material, expanded by cultivation,
Sterilizing concentrates and poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes three
Fastbacteria immunoreactive protein biological product.
A kind of preferred version is, by Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza, Boydii not
Lever bacterium and staphylococcus aureus, totally five kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison
Breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes 5-linked fastbacteria immunocompetence
Protein biology goods；Or it is motionless by Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza and Boydii
Bacillus, totally four kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract antibacterial respectively
The activated protein of cell wall, cell membrane and film, synthesize tetrad fastbacteria immunoreactive protein biological product；Or
By Pseudomonas Maltophilia, klebsiella pneumoniae and hemophilus influenza, totally three kinds of drug-resistant bacterias are raw material, pass through
Cultivate amplification, sterilizing concentrates and poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively,
Synthesize three fastbacteria immunoreactive protein biological product.
A kind of preferred version is, by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, influenza addicted to
Blood bacillus, Acinetobacter baumannii and staphylococcus aureus, totally six kinds of drug-resistant bacterias are raw material, by cultivating amplification, going out
Bacterium concentrates and poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes six drug resistances
Bacterial immunity activated protein biological product.
A kind of preferred version is, by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, influenza addicted to
Blood bacillus, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella
And Staphylococcus albus, totally ten kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, respectively
Extract the cell wall of antibacterial, cell membrane and the activated protein of film, synthesize ten fastbacteria immunoreactive protein biology systems
Product.
A kind of preferred version is, by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, influenza addicted to
Blood bacillus, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus and large intestine Ai Xi Salmonella,
Totally nine kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract the cell of antibacterial respectively
The activated protein of wall, cell membrane and film, synthesizes nine fastbacteria immunoreactive protein biological product.
A kind of preferred version is, by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, influenza addicted to
Blood bacillus, Acinetobacter baumannii, staphylococcus aureus, meningococcus and tubercule bacillus, totally eight kinds of drug resistances are thin
Bacterium is raw material, by cultivate amplification, sterilizing concentrate and poison breaking cellular wall, extract respectively the cell wall of antibacterial, cell membrane and
The activated protein of film, synthesizes eight fastbacteria immunoreactive protein biological product.
A kind of preferred version is, by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, influenza addicted to
Blood bacillus, Acinetobacter baumannii, staphylococcus aureus and meningococcus, totally seven kinds of drug-resistant bacterias are raw material, logical
Cross cultivation amplification, sterilizing concentrates and poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively,
Synthesize seven fastbacteria immunoreactive protein biological product.
The two of the purpose of the present invention, can reach by adopting the following technical scheme that:
The preparation method of multi-joint fastbacteria immunoreactive protein, it is characterised in that comprise the steps:
1) composition mixed bacteria liquid
Get Pseudomonas aeruginosa, Pseudomonas Maltophilia, and klebsiella pneumoniae, hemophilus influenza, Bao ready
Family name's acinetobacter calcoaceticus, staphylococcus aureus, meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella and white grapes
Coccus；With the one in described Pseudomonas aeruginosa, Pseudomonas Maltophilia or two kinds of combinations, with kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, big
In intestinal Ai Xi Salmonella and Staphylococcus albus two kinds or combination of the above, form mixed bacteria liquid；
2) drug resistance strain amplification
Take the mixed bacteria liquid 5ml containing 1 grade of strain, the mixed bacteria liquid 100ml containing 2 grades of strains, the mixed bacteria liquid containing 3 grades of strains
2000ml, the test tube of the mixed bacteria liquid containing 1 grade of strain expands, and the bottle of the mixed bacteria liquid containing 2 grades of strains expands, containing 3 grades of bacterium
The mixed bacteria liquid conical flask planted expands or directly plants and expands into fermentation tank；
3) use basal medium to drug resistance spawn culture
One or two or more kinds in peptone, beef extract, sodium chloride, yeast extract and glucose is used to be combined as
Basal medium, to Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, Acinetobacter baumannii,
Staphylococcus aureus and flu haemophilus are cultivated, and use aforementioned base culture medium to add lactose and constitute lactose cultivation
Staphylococcus aureus is cultivated by base, and the Ph value of described basal medium and lactose medium is 7.4-7.6；
Other bacteria culture medias are pressed nutritional need and are equipped with culture medium；
4) multi-joint fastbacteria immunoreactive protein is prepared
4-1) drug resistance strain is put in liquid basal medium or lactose medium, cultivate under the temperature conditions of 37 DEG C
After 24-48 hour, collect bacterium solution, after formaldehyde sterilizing, carry out centrifugation, precipitation；Then supernatant, taking precipitate are abandoned,
Being stored in hold-up tank by described precipitate, storage temperature is 4-8 DEG C；
In hold-up tank, 4-2) again put into basal medium, carry out ferment in second time cultivation, through high-temperature physics sterilizing → connect
After planting novel bacterial → Zengjing Granule → formaldehyde sterilizing program, speed continuous centrifugal takes precipitation, abandons supernatant, taking precipitate,
Precipitate separates through breaking cellular wall, extracts cell wall and cell membrane activated protein, forms multi-joint immunoreactive protein.
The two of the purpose of the present invention, it is also possible to reach by adopting the following technical scheme that:
Further, step 4-1) in, drug resistance strain is put in liquid basal medium or lactose medium, refers to
Thalline is liquefied.
Further, step 4-1) in, described centrifugation is that electric degree gradient centrifugation separates, separation and Extraction cell wall
With cell membrane activated protein.
Further, step 4-2) in, the concentration of formaldehyde used in formaldehyde sterilizing is 0.1%-0.5%.
Further, step 4-2) in, precipitate separates through breaking cellular wall, refers to that precipitate wall-breaking machine is by antibacterial therein
Breaking cellular wall, makes the composition of thalline separate.
Further, step 4-2) in, form multi-joint immunoreactive protein, from the collection of lane, effect duration is 2 years 6 certainly
Individual month.
The three of the purpose of the present invention, can reach by adopting the following technical scheme that:
The purposes of multi-joint fastbacteria immunoreactive protein, it is characterised in that: it is applicable to human body mucosa absorption for making
Preparation, mainly includes nasal drop, oral liquid, tablet, electuary, injection or spray larynx mist agent.
There is advantages that
1, the multi-joint fastbacteria immunoreactive protein that the present invention relates to, with several medicine pathogenic bacterium as raw material, expands through cultivating
Increase, sterilizing concentrates, poison breaking cellular wall, extracts the cell wall of antibacterial, cell membrane and film, synthesizes multi-joint fastbacteria immunity and lives
Property protein biology goods；Described drug resistance pathogenic bacterium include the one in Pseudomonas aeruginosa, Pseudomonas Maltophilia or two
Kind of combination, and klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, brain
Two kinds of combination of the above in film inflammation diplococcus, tubercule bacillus, large intestine Ai Xi Salmonella and Staphylococcus albus；Accordingly, it is capable to
Enough solving bacterial resistance is continuous growth trend, the healthy problem threatening human and animal, is to fastbacteria infection
Functional product, gastrointestinal mucosal immunity can be induced, with system rabbit epidemic disease can be put forward again, shoot the arrow at the target, reach to replace anti-
The therapeutic purposes of raw element overriding resistance pathogenic bacterium, have good immune effect.
The special case of the multi-joint fastbacteria immunoreactive protein that 2, the present invention relates to, uses Pseudomonas aeruginosa (to have 11
Individual type, can be only by a type, such as the 6th type), Pseudomonas Maltophilia, staphylococcus aureus, kerekou pneumonia
White Salmonella, flu haemophilus and Acinetobacter baumannii are raw material, cultivate amplification, inactivation poison, breaking cellular wall separation respectively
Extract cell wall, cell membrane and film activity albumen, synthesize six fastbacteria immunoreactive protein goods, cause for drug resistance
Courses of infection patient improves Active immunity, has good immune effect.
3, the multi-joint fastbacteria immunoreactive protein that the present invention relates to, can be used for making the system being applicable to human body mucosa absorption
Agent, mainly includes nasal drop, oral liquid, tablet, electuary, injection or spray larynx mist agent, for human body mucosa absorption,
To reach the purpose for the treatment of, there is good immunity and therapeutic effect.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further illustrated.
Specific embodiment 1:
The multi-joint fastbacteria immunoreactive protein that the present embodiment relates to, by Pseudomonas aeruginosa, Pseudomonas Maltophilia,
Klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii and staphylococcus aureus, totally six kinds of drug-resistant bacterias are
Raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extracts the cell wall of antibacterial, cell membrane and film respectively
Activated protein, synthesizes six fastbacteria immunoreactive protein biological product.
Described multi-joint fastbacteria immunoreactive protein, for having the protein of digested road mucosa covering epithelium absorption characteristic.
The preparation method of the multi-joint fastbacteria immunoreactive protein that the present embodiment relates to, it is characterised in that comprise the steps:
1) composition mixed bacteria liquid
Get Pseudomonas aeruginosa, Pseudomonas Maltophilia, and klebsiella pneumoniae, hemophilus influenza, Bao ready
Family name's acinetobacter calcoaceticus, staphylococcus aureus, meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella and white grapes
Coccus；With the one in described Pseudomonas aeruginosa, Pseudomonas Maltophilia or two kinds of combinations, with kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, big
In intestinal Ai Xi Salmonella and Staphylococcus albus two kinds or combination of the above, form mixed bacteria liquid；
2) drug resistance strain amplification
Take the mixed bacteria liquid 5ml containing 1 grade of strain, the mixed bacteria liquid 100ml containing 2 grades of strains, the mixed bacteria liquid containing 3 grades of strains
2000ml, the test tube of the mixed bacteria liquid containing 1 grade of strain expands, and the bottle of the mixed bacteria liquid containing 2 grades of strains expands, containing 3 grades of bacterium
The mixed bacteria liquid conical flask planted expands or directly plants and expands into fermentation tank；
3) use basal medium to drug resistance spawn culture
One or two or more kinds in peptone, beef extract, sodium chloride, yeast extract and glucose is used to be combined as
Basal medium, to Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, Acinetobacter baumannii,
Staphylococcus aureus and flu haemophilus are cultivated, and use aforementioned base culture medium to add lactose and constitute lactose cultivation
Staphylococcus aureus is cultivated by base, and the Ph value of described basal medium and lactose medium is 7.4-7.6；
Other bacteria culture medias are pressed nutritional need and are equipped with culture medium；
4) multi-joint fastbacteria immunoreactive protein is prepared
4-1) drug resistance strain is put in liquid basal medium or lactose medium, cultivate under the temperature conditions of 37 DEG C
After 24-48 hour, collect bacterium solution, after formaldehyde sterilizing, carry out centrifugation, precipitation；Then supernatant, taking precipitate are abandoned,
Being stored in hold-up tank by described precipitate, storage temperature is 4-8 DEG C；
In hold-up tank, 4-2) again put into basal medium, carry out ferment in second time cultivation, through high-temperature physics sterilizing → connect
After planting novel bacterial → Zengjing Granule → formaldehyde sterilizing program, speed continuous centrifugal takes precipitation, abandons supernatant, taking precipitate,
Precipitate separates through breaking cellular wall, extracts cell wall and cell membrane activated protein, forms multi-joint immunoreactive protein.
In the present embodiment:
Step 4-1) in, drug resistance strain is put in liquid basal medium or lactose medium, refers to liquefy thalline.
Described centrifugation is that electric degree gradient centrifugation separates, separation and Extraction cell wall and cell membrane activated protein.
Step 4-2) in, the concentration of formaldehyde used in formaldehyde sterilizing is 0.1%-0.5%.Precipitate separates through breaking cellular wall, is
Refer to that precipitate wall-breaking machine, by antibacterial breaking cellular wall therein, makes the composition of thalline separate.Form multi-joint immunoreactive protein, from
From doing to collect, effect duration is 2 years 6 months.
The present embodiment further relates to following technological process:
Stock solution merges: adding preservative agent 2,5-5,0g/L, by the stock solution of different strain, becomes multi-joint immunity by suitable concentration combination
Activated protein；
Dialysis: flowing water dialysis 24h, is diluted to proportioning solubility with PBS, finished product not adding preservative agent；
Subpackage: be diluted to 10ml/ bottle, quite containing bacteria concentration 6*1010,1*1010 capsule or sugar pill, (finished product).
Production equipment:
Superclean bench, microscope pressure boiler, incubator (room), 2, high-speed and continuous centrifuge, fermentation tank
(50/L) 2, GMP streamline:
Arbitrary 2/L drug resistance strain is entered (50/L fermentation tank) in 30/L culture fluid → 37 DEG C of cultivations by 1-production procedure respectively
After 24-48 hour → collection bacterium solution → formaldehyde sterilizing → be centrifuged → abandon supernatant → taking precipitate → storage 4-8 DEG C；
In 2-ferment in second time → tank, culture medium feeds intake → high-temperature physics sterilizing → inoculation novel bacterial → increase bacterium the most one by one again
Cultivation → formaldehyde sterilizing (0,1%-0,5%) → speed continuous centrifugal → take precipitation, from do collection say effect duration be 2 years 6
Individual month；
Control laboratory includes；
(1) examination and test of products room: product is the sterile milk micro-turbid liquid of white, (should not have and not dissipate precipitation and foreign body)；
(2) assay: measure concentration, and spectrophotometry with bacterial turbidity, under 660nm wavelength, A value should be；
(3) abnormal toxicity test: carry out by [biological product abnormal toxicity test code].With PBS, stock solution is diluted to
Every 1ml activated protein, suitable 6X109 (bacterial turbidity), take 0,5ml abdominal cavity and penetrate 18 20g mice 5.Before injected in mice
Weighing body weight, calculate the TBW of noted mice, observe 7 days, mice is strong deposits, and TBW should have increase.
(4) antiseptic content measures.
(5) environment-friendly laboratory: bacillus subtilis harmless treatment.
(6), before packaging, the examination and test of products should be the most qualified.
Industrial water:
Process water source water meets national drinking water standard；Purified water and water for injection should meet existing " Chinese Pharmacopoeia "
Standard.
Production utensil
It is directly used in metal or the glass wares of production, cleans and sterilization treatment through strict.
Produce and animal is used in calibrating
Mice, Cavia porcellus meet cleaning grade standard.
3, strain
Regulation calibrating about strain is carried out by " vaccine manufacture and vertification regulation " item.
4, prepared by stock solution
4-1 production strain
After working seed lots strain breakdown, it is inoculated on LIA inclined-plane or other appropriate medias, puts 37 DEG C
Cultivate-48 hours is first generation strain.First generation strain can preserve 15 at 2-8 DEG C.
By on first generation strain subcultivation liver agar or other appropriate medias, put 37 DEG C and cultivate-48 hours for second filial generation bacterium
Kind, after naked eyes pure bacterium passed examination, wash lower lawn with sterile physiological sodium chloride solution and make suspension.In this, as life
Product strain, is used for producing.
4-2 production culture medium
Other culture medium ratified with LIA or national drug administrative authority.
Six fastbacteria strain inoculation and cultivations (inoculum concentration and concentration are equal) respectively.
After inoculation of medium production strain, putting 37 DEG C and cultivate 24-48 hour, naked eyes, by bottle inspection, have miscellaneous bacteria then
Discarded.
4-3 gathers and merges (six bacterial concentrations are equal)
Wash lower lawn or scraping lawn with sterile physiological sodium chloride solution, make bacterium solution, be incorporated in sterilizing bottle, merge
After bacterium solution do pure bacterium test.
4-4 stock solution
After merging, stock solution by the concentration of bacterium solution, is adjusted to every 1ml quite 6*1011 Han bacterium by " China's bacterial turbidity standard "
It is subsequently added phenol final concentration 0,25 0,5/L sterilization.
4-5 antibacterial breaking cellular wall
Abandon bacterial endotoxin with wall-breaking machine by centrifugal for antibacterial breaking cellular wall continuous high speed, take precipitation PBS and wash three times,
Bacterium solution qualified for sterility test is diluted to quite containing bacterium by 4-6 semi-finished product preparation sterile physiological sodium chloride solution
10ml/6*1010
Do sterility test, should be without varied bacteria growing.
4-7 semi-finished product are examined and determine
Carry out by 3.2.
Carry out by " biological product code in batches " in batches.
4-8 subpackage
Carry out by this edition code general rule " biological product subpackage code ".Not adding preservative agent in goods.Ying Yu after dress ampoule
70-80 DEG C is heated l hour.
4-9 specification
Collunarium specification is every 10ml, quite the 6*1010 Han bacterium.
Food capsule (grain) quite (1*1010) Han bacterium
4-10 packs
Carry out by " biological product packaging code ".
5 calibratings
5-1 sterility test
Carry out by " biological product sterility test code " A item.
5-2 semi-finished product are examined and determine
Sterility test
In addition to carrying out by " biological product sterility test code " A item, another inoculation 2 pipe agar slants, put 37 DEG C and cultivate 7
My god, should be without miscellaneous bacteria and this bacteria growing.
The present embodiment is by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza, Bao
Family name's acinetobacter calcoaceticus, staphylococcus aureus, six kinds of drug-resistant bacterias are raw material, are expanded by cultivation, and sterilizing concentrates, and poison is broken
Wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively.Synthesize six fastbacteria immunoreactive proteins
Biological product.
Specific embodiment 2:
The feature of the specific embodiment of the invention 2 is: by Pseudomonas aeruginosa, Pseudomonas Maltophilia, kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, big
Intestinal Ai Xi Salmonella and Staphylococcus albus, totally ten kinds of drug-resistant bacterias are raw material, by cultivate amplification, sterilizing concentrate and
Poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes ten fastbacteria immunocompetences
Protein biology goods.Preparation Method And The Use is with specific embodiment 1.
Specific embodiment 3:
The feature of the specific embodiment of the invention 3 is: by Pseudomonas aeruginosa, Pseudomonas Maltophilia, kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus and big
Intestinal Ai Xi Salmonella, totally nine kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract respectively
The activated protein of the cell wall of antibacterial, cell membrane and film, synthesizes nine fastbacteria immunoreactive protein biological product.
Preparation Method And The Use is with specific embodiment 1.
Specific embodiment 4:
The feature of the specific embodiment of the invention 4 is: by Pseudomonas aeruginosa, Pseudomonas Maltophilia, kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus and tubercule bacillus, altogether
Eight kinds of drug-resistant bacterias are raw material, by cultivate amplification, sterilizing concentrate and poison breaking cellular wall, extract respectively antibacterial cell wall,
Cell membrane and the activated protein of film, synthesize eight fastbacteria immunoreactive protein biological product.Its preparation method and use
Way is with specific embodiment 1.
Specific embodiment 5:
The feature of the specific embodiment of the invention 5 is: by Pseudomonas aeruginosa, Pseudomonas Maltophilia, kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus and meningococcus, totally seven kinds of drug resistances are thin
Bacterium is raw material, by cultivate amplification, sterilizing concentrate and poison breaking cellular wall, extract respectively the cell wall of antibacterial, cell membrane and
The activated protein of film, synthesizes seven fastbacteria immunoreactive protein biological product.Preparation Method And The Use is with concrete real
Execute example 1.
Specific embodiment 6:
The feature of the specific embodiment of the invention 6 is: by Pseudomonas aeruginosa, Pseudomonas Maltophilia, kerekou pneumonia Bai Shi
Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, big
Intestinal Ai Xi Salmonella and Staphylococcus albus, totally ten kinds of drug-resistant bacterias are raw material, by cultivate amplification, sterilizing concentrate and
Poison breaking cellular wall, extracts the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesizes ten fastbacteria immunocompetences
Protein biology goods.Preparation Method And The Use is with specific embodiment 1.
Specific embodiment 7:
The feature of the specific embodiment of the invention 7 is: by Pseudomonas aeruginosa, klebsiella pneumoniae, hemophilus influenza,
Acinetobacter baumannii and staphylococcus aureus, totally five kinds of drug-resistant bacterias are raw material, and by cultivating amplification, sterilizing concentrates
With poison breaking cellular wall, extracting the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesis 5-linked fastbacteria is exempted from
Epidemic disease activated protein biological product；Or by Pseudomonas aeruginosa, klebsiella pneumoniae, hemophilus influenza and Boydii
Acinetobacter calcoaceticus, totally four kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract respectively
The activated protein of the cell wall of antibacterial, cell membrane and film, synthesizes tetrad fastbacteria immunoreactive protein biological product；
Or by Pseudomonas aeruginosa, klebsiella pneumoniae and hemophilus influenza, totally three kinds of drug-resistant bacterias are raw material, logical
Cross cultivation amplification, sterilizing concentrates and poison breaking cellular wall, extracts the active egg of the cell wall of antibacterial, cell membrane and film respectively
In vain, three fastbacteria immunoreactive protein biological product are synthesized.Preparation Method And The Use is with specific embodiment 1.
Specific embodiment 7:
The feature of the specific embodiment of the invention 7 is: by Pseudomonas Maltophilia, klebsiella pneumoniae, the bloodthirsty bar of influenza
Bacterium, Acinetobacter baumannii and staphylococcus aureus, totally five kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing
Concentrate and poison breaking cellular wall, extract the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesize 5-linked drug resistance
Bacterial immunity activated protein biological product；Or by Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza
And Acinetobacter baumannii, totally four kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, point
Taking the activated protein of the cell wall of antibacterial, cell membrane and film indescribably, synthesis tetrad fastbacteria immunoreactive protein is biological
Goods；Or by Pseudomonas Maltophilia, klebsiella pneumoniae and hemophilus influenza, totally three kinds of drug-resistant bacterias are
Raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extracts the cell wall of antibacterial, cell membrane and film respectively
Activated protein, synthesize three fastbacteria immunoreactive protein biological product.Preparation Method And The Use is with being embodied as
Example 1.
The present invention is a kind of protein extracted from drug resistance pathogenic bacterium.By drug resistance pathogenic bacterium through inactivation poison, the cell of extraction
Wall, cell membrane and film immunoreactive protein, be can the protein that absorbs of digested road mucosa covering epithelium.Research shows
Activated protein sucks from gastrointestinal mucosal, is the optimal path of drug resistance pathogenic activity albumen absorption, can be from viscous absorption
Reactive protein, provides important evidence for developing with exploitation immunoreactive protein.Research proves the cell wall of drug resistance pathogenic bacterium,
Cell membrane and protein clostridium matter, can improve stool body active immunity.By six drug resistance pathogenic activity protein products, to little
The induction immunoreation research of Mus gavage.With appropriate six activated proteins of resistance to bacterium to mouse stomach after, observe the blood of mice
Specificity IgA in cleer and peaceful small intestinal flushing liquor, IgG antibody significantly raises.Result proves six pathogenic activity protein products,
Can significantly induce system NALT, GALT immunoreation, show that the fastbacteria activated protein of the present invention can reach good immunity
Effect, is to fastbacteria anti-infective functional product.Gastrointestinal mucosal immunity can be induced, with carrying again system rabbit
Epidemic disease, shoots the arrow at the target, and reaches to replace the therapeutic purposes of antibiotic overriding resistance pathogenic bacterium.
Claims (10)
- The most multi-joint fastbacteria immunoreactive protein, it is characterised in that: with several drug resistance pathogenic bacterium as raw material, through cultivating Amplification, sterilizing concentrate, poison breaking cellular wall, extract the cell wall of antibacterial, cell membrane and film, synthesize the immunity of multi-joint fastbacteria Activated protein biological product；Described drug resistance pathogenic bacterium include the one in Pseudomonas aeruginosa, Pseudomonas Maltophilia or Two kinds of combinations, and klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, Two kinds of combination of the above in meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella and Staphylococcus albus.
- Multi-joint fastbacteria immunoreactive protein the most according to claim 1, it is characterised in that: described multi-joint drug resistance Bacterial immunity activated protein, for having the protein of digested road mucosa covering epithelium absorption characteristic.
- Multi-joint fastbacteria immunoreactive protein the most according to claim 1 and 2, it is characterised in that: by Aerugo vacation list Born of the same parents bacterium, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii and staphylococcus aureus, totally five kinds resistance to Medicine antibacterial is raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extracts the cell wall of antibacterial, cell respectively Film and the activated protein of film, synthesize 5-linked fastbacteria immunoreactive protein biological product；Or by Pseudomonas aeruginosa, Klebsiella pneumoniae, hemophilus influenza and Acinetobacter baumannii, totally four kinds of drug-resistant bacterias are raw material, by cultivating Amplification, sterilizing concentrate and poison breaking cellular wall, extract the activated protein of the cell wall of antibacterial, cell membrane and film respectively, close Become tetrad fastbacteria immunoreactive protein biological product；Or by Pseudomonas aeruginosa, klebsiella pneumoniae and influenza Haemophilus, totally three kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract respectively The activated protein of the cell wall of antibacterial, cell membrane and film, synthesizes three fastbacteria immunoreactive protein biological product.
- Multi-joint fastbacteria immunoreactive protein the most according to claim 1 and 2, it is characterised in that: by false addicted to Fructus Hordei Germinatus Zymomonas mobilis, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii and staphylococcus aureus, totally five kinds Drug-resistant bacteria is raw material, by cultivating amplification, sterilizing concentrate and poison breaking cellular wall, extract the cell wall of antibacterial, thin respectively After birth and the activated protein of film, synthesize 5-linked fastbacteria immunoreactive protein biological product；Or by addicted to Fructus Hordei Germinatus vacation list Born of the same parents bacterium, klebsiella pneumoniae, hemophilus influenza and Acinetobacter baumannii, totally four kinds of drug-resistant bacterias are raw material, logical Cross cultivation amplification, sterilizing concentrates and poison breaking cellular wall, extracts the active egg of the cell wall of antibacterial, cell membrane and film respectively In vain, synthesis tetrad fastbacteria immunoreactive protein biological product；Or by Pseudomonas Maltophilia, kerekou pneumonia Bai Shi Bacterium and hemophilus influenza, totally three kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, point Take the activated protein of the cell wall of antibacterial, cell membrane and film indescribably, synthesize three fastbacteria immunoreactive proteins biological Goods.
- Multi-joint fastbacteria immunoreactive protein the most according to claim 1 and 2, it is characterised in that: by Aerugo vacation list Born of the same parents bacterium, Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii and golden yellow Portugal Grape coccus, totally six kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract antibacterial respectively The activated protein of cell wall, cell membrane and film, synthesize six fastbacteria immunoreactive protein biological product.
- Multi-joint fastbacteria immunoreactive protein the most according to claim 1 and 2, it is characterised in that: by Aerugo vacation list Born of the same parents bacterium, Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, golden yellow Portugal Grape coccus, meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella and Staphylococcus albus, totally ten kinds of drug-resistant bacterias For raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extract the cell wall of antibacterial, cell membrane and film respectively Activated protein, synthesize ten fastbacteria immunoreactive protein biological product；Or by Pseudomonas aeruginosa, addicted to Fructus Hordei Germinatus Pseudomonas, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meninges Scorching diplococcus, tubercule bacillus and large intestine Ai Xi Salmonella, totally nine kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing Concentrate and poison breaking cellular wall, extract the activated protein of the cell wall of antibacterial, cell membrane and film respectively, synthesize nine fastbacteria Immunoreactive protein biological product；Or by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, Hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus and tubercule bacillus, totally eight kinds Drug-resistant bacteria is raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, extracts the cell wall of antibacterial, cell respectively Film and the activated protein of film, synthesize eight fastbacteria immunoreactive protein biological product；Or by Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus And meningococcus, totally seven kinds of drug-resistant bacterias are raw material, by cultivating amplification, sterilizing concentration and poison breaking cellular wall, respectively Extract the cell wall of antibacterial, cell membrane and the activated protein of film, synthesize seven fastbacteria immunoreactive protein biology systems Product.
- The preparation method of the most multi-joint fastbacteria immunoreactive protein, it is characterised in that comprise the steps:1) composition mixed bacteria liquidGet Pseudomonas aeruginosa, Pseudomonas Maltophilia, and klebsiella pneumoniae, hemophilus influenza, Bao ready Family name's acinetobacter calcoaceticus, staphylococcus aureus, meningococcus, tubercule bacillus, large intestine Ai Xi Salmonella and white grapes Coccus；With the one in described Pseudomonas aeruginosa, Pseudomonas Maltophilia or two kinds of combinations, with kerekou pneumonia Bai Shi Bacterium, hemophilus influenza, Acinetobacter baumannii, staphylococcus aureus, meningococcus, tubercule bacillus, big In intestinal Ai Xi Salmonella and Staphylococcus albus two kinds or combination of the above, form mixed bacteria liquid；2) drug resistance strain amplificationTake the mixed bacteria liquid 5ml containing 1 grade of strain, the mixed bacteria liquid 100ml containing 2 grades of strains, the mixed bacteria liquid containing 3 grades of strains 2000ml, the test tube of the mixed bacteria liquid containing 1 grade of strain expands, and the bottle of the mixed bacteria liquid containing 2 grades of strains expands, containing 3 grades of bacterium The mixed bacteria liquid conical flask planted expands or directly plants and expands into fermentation tank；3) use basal medium to drug resistance spawn cultureOne or two or more kinds in peptone, beef extract, sodium chloride, yeast extract and glucose is used to be combined as Basal medium, to Pseudomonas aeruginosa, Pseudomonas Maltophilia, klebsiella pneumoniae, Acinetobacter baumannii, Staphylococcus aureus and flu haemophilus are cultivated, and use aforementioned base culture medium to add lactose and constitute lactose cultivation Staphylococcus aureus is cultivated by base, and the Ph value of described basal medium and lactose medium is 7.4-7.6；4) multi-joint fastbacteria immunoreactive protein is prepared4-1) drug resistance strain is put in liquid basal medium or lactose medium, cultivate under the temperature conditions of 37 DEG C After 24-48 hour, collect bacterium solution, after formaldehyde sterilizing, carry out centrifugation, precipitation；Then supernatant, taking precipitate are abandoned, Being stored in hold-up tank by described precipitate, storage temperature is 4-8 DEG C；In hold-up tank, 4-2) again put into basal medium, carry out ferment in second time cultivation, through high-temperature physics sterilizing → connect After planting novel bacterial → Zengjing Granule → formaldehyde sterilizing program, speed continuous centrifugal takes precipitation, abandons supernatant, taking precipitate, Precipitate separates through breaking cellular wall, extracts cell wall and cell membrane activated protein, forms multi-joint immunoreactive protein.
- The preparation method of multi-joint fastbacteria immunoreactive protein the most according to claim 7, it is characterised in that: step Rapid 4-1) in, drug resistance strain is put in liquid basal medium or lactose medium, refers to liquefy thalline；Described Centrifugation be electric degree gradient centrifugation separate, separation and Extraction cell wall and cell membrane activated protein.
- The preparation method of multi-joint fastbacteria immunoreactive protein the most according to claim 7, it is characterised in that: step Rapid 4-2) in, the concentration of formaldehyde used in formaldehyde sterilizing is 0.1%-0.5%；Precipitate separates through breaking cellular wall, refers to precipitation Thing wall-breaking machine, by antibacterial breaking cellular wall therein, makes the composition of thalline separate；Form multi-joint immunoreactive protein, certainly do collection From effect duration be 2 years 6 months.
- The purposes of the most multi-joint fastbacteria immunoreactive protein, it is characterised in that: be used for making be applicable to human body mucosa inhale The preparation received, mainly includes nasal drop, oral liquid, tablet, electuary, injection or spray larynx mist agent.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101022826A (en) * | 2004-06-07 | 2007-08-22 | 哈罗尔·戴维·贡 | Bacterial compositions for the treatment of cancer |
| CN101636176A (en) * | 2006-10-27 | 2010-01-27 | 哈罗尔·戴维·贡 | Be used for the treatment of cancer immunne response organize the directionality antigenic activation |
| CN103140238A (en) * | 2010-07-26 | 2013-06-05 | Qu生物制药公司 | Immunogenic anti-inflammatory compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101022826A (en) * | 2004-06-07 | 2007-08-22 | 哈罗尔·戴维·贡 | Bacterial compositions for the treatment of cancer |
| CN101636176A (en) * | 2006-10-27 | 2010-01-27 | 哈罗尔·戴维·贡 | Be used for the treatment of cancer immunne response organize the directionality antigenic activation |
| CN103140238A (en) * | 2010-07-26 | 2013-06-05 | Qu生物制药公司 | Immunogenic anti-inflammatory compositions |
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