CN1290580C - Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity - Google Patents
Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity Download PDFInfo
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- CN1290580C CN1290580C CNB981072542A CN98107254A CN1290580C CN 1290580 C CN1290580 C CN 1290580C CN B981072542 A CNB981072542 A CN B981072542A CN 98107254 A CN98107254 A CN 98107254A CN 1290580 C CN1290580 C CN 1290580C
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Abstract
The present invention relates to a product, a health product and a medicine which comprises A group rotavirus resisting chicken egg yolk immunoglobulin and has the activity of an antibody thereof. Effective components of the present invention have high purity and activity after being refined, the present invention is an ideal article for preparing the health product and the medicine, and the product, the health product and the medicine used for preventing and curing infantile diarrhea diseases caused by A group rotavirus infection have the advantages of strong specificity, high cure rate and superior effects to conventional medicines; meanwhile, the present invention also provides a high-efficiency activity detection method.
Description
The present invention relates to the immune globulin products of biological field, especially a kind of have higher anti-rotavirus activity about egg yolk immunoglobulin (IgY) product, this product.And the present invention relates to contain this product or health product and the medicine formed by them and use their controls and infect the infantile diarrhea that causes because of the A group rotavirus.
The rotavirus extend over the entire globe is the important cause of disease of infantile diarrhea disease, and annual nearly 900,000 people in the world die from this disease.Show through investigation: the annual sufferer of infantile diarrhea below five years old of China reaches 2.5 hundred million person-times, and wherein sizable ratio causes because of the A group rotavirus infects.Except that adopting oral or intravenous injection fluid infusion correct dehydration, also there is not specific therapy for many years for this disease.Aspect prevention, the use of Rotavirus Vaccine also is in the experimental stage, and because the infant immune system is grown also not exclusively, special rotavirus resisting immune is reflected at digestive system and plays a role and also have obstacle.
Current, existing minority scholar utilizes immunoglobulin preparation (IgG) treatment and prevention rotavirus infection to obtain significant curative effect.Behind the hen that lays eggs with antigen immune, chicken can produce corresponding antibody and shift and accumulate in yolk, and this antibody is Yolk immunoglobulin (IgY).With A group wheel virus antigen immunity chicken, collect institute after 10 days and lay eggs, and can obtain corresponding anti-A group rotavirus chicken yolk immunoglobulin (anti--ARV IgY) by certain step.Compare with IgG, IgY output is big, homogeneity is good, IgY can not activate mammiferous complement system, chicken belongs to birds, and planting system between mammal, that distance takes place is big, can not intersect seroreaction between IgY and the mammalian immune globulin, thus IgY to be used for the immune detection test more more economical than prepare antibody with animal, conveniently.The purity of IgY is having higher requirement aspect diagnosis, the disease preventing and treating.
The separation of anti--ARV IgY is purified, and main difficulty is how effectively to remove the lipid of contained high concentration in the yolk, and settled the present discloses many separation, the method for the anti--ARV IgY that purifies.Its main process is to remove lipid.Separation and purification.Concentrate end-product.Saltout as removing the phospholipoprotein complex with chloroform, glycerol, acetone and other organic solvent, relending, method such as ultracentrifugation extracts anti--ARV IgY.These methods can cause adverse effect because of residual organic solvent in the extract and some other chemical substances to people, animal and environment, and complicated operating process, and productive rate and purity are low, so limited its application.
The anti-rotavirus chicken yolk immunoglobulin is used for animals such as cattle, Mus, experiment shows prevention and good result is all arranged treatment animal diarrhoea but bovine rota and Human reoviruslike agent have certain difference, and has only zoopery, do not have human body clinical experiment result, yet there are no with anti--ARV IgY product makes health product and medicine is used for human body.
The objective of the invention is to overcome above-mentioned shortcoming, a kind of anti-A group rotavirus chicken yolk immunoglobulin (anti--ARV IgY) that contains is provided, and product, health product and medicine with its antibody activity, and use their controls because of the A group rotavirus infects the infantile diarrhea that causes, the ELIAS blocking-up method of inspection of anti--ARV IgY also is provided simultaneously.
Technical scheme of the present invention is achieved in that
Collects its Huang of being laid eggs after 10 days with A group wheel virus antigen subcutaneous injection immunity bird inlay, by known extraction resist-method of ARV IgY crude product obtains crude product, again through following step purification:
A. will slightly carry anti--ARV IgY and cross diethylamino ethyl glucosan A50 gel chromatographic columns, add buffer solution elution, desalination, lyophilization is dissolved again;
B. cross glucosan G200 gel chromatographic columns, add buffer solution elution, desalination, lyophilization is resisted-the pure product of ARV IgY.
In a, b two steps, take following measure to help purifying: after will slightly carrying anti--ARV IgY and crossing diethylamino ethyl glucosan A50 gel chromatographic columns, it with the PH that includes 0.01M-0.14M LINEAR N aCl concentration of 0.01M 6.8 PB phosphate buffer eluting, flow velocity is 20 milliliters/hour, collection has the protein peak of antibody activity, collect the liquid desalination of in distilled water, dialysing, after the lyophilization with the dissolving of PB buffer.
Crude product is crossed behind the glucosan G200 gel chromatographic columns with 0.01M, the PBS buffer solution elution of PH7.0, and flow velocity is 11～13 milliliters/hour, collects the desalination of dialysing in distilled water of the protein peak with antibody activity, promptly gets pure product after the lyophilization.
Anti--ARV IgY is the active ingredient of the diarrhoeal diseases that causes of control A group rotavirus, and its purity is high more favourable more to control.And effective content is all having certain effect more than 10%, and commonly used has 30%～50%, and 85%～98% to be used to make up a prescription be best.
Anti--ARV IgY the product that only has antibody activity just produces effect, it is active relevant with the antigen type and the quantity of immune usefulness, set up check anti--the active method of ARV IgY is significant to its applications, the ELIAS blocking test method of the present invention's employing, highly sensitive, energy fast measuring activity, and energy semiquantitative determination content, amount of samples is few, and various active detection sensitivity in the past is poor, poor accuracy, sample consumption is big.Therefore effective application of anti--ARV IgY is hindered.
The health product and the medicine that are used for human body must be through strict toxicological experiment and clinical experiments, and the zoopery that disease preventing and treating is only arranged is not enough.Anti--ARV IgY active ingredient is equipped with adjuvant commonly used, for example edible monosaccharide or polysaccharide, and other flavoring agent can make health product, the ability of enhancing infant prevention A group rotavirus infringement; Also can be equipped with edible monosaccharide or polysaccharide and other pharmaceutic adjuvants commonly used, the medicine of the diarrhoeal diseases that causes as control A group rotavirus.
Provided by the present invention resisting-ARV IgY product is through ion-exchange chromatography and gel permeation chromatography, purity is greater than 99.9%, it is the desirable raw material of preparation health product and medicine, because of anti--ARV IgY high specificity, anti--ARV IgY that purity is high can be used in the multiple test, as double immunodiffusion test, single immunodiffusion test, immunoelectrophoresis, rocket electrophoresis, the radiosiotope immunity test.Because of its fixing mammal complement not, not fixedly staphylococcal protein A, fixing mammal Fc receptor not, also not with rheumatoid factor generation specific reaction, highly purified anti--ARV IgY effect when the diagnosis infantile rotavirus enteritis is sick outclass other immunoglobulins.These bright health product that contain anti--ARV IgY that provide, medicine show that through a large amount of clinical experiments rotavirus infection in infants is had the passive immunity protective effect, and therapeutic effect obviously is better than other routine administrations.Show safety non-toxic through safety testing.The present invention provides foundation for anti--industrialization that ARV IgY moves towards health product, medicine from the laboratory research stage having made extensive work aspect purify preparation clinical experiment and the safety testing.
Describe the present invention in detail below in conjunction with embodiment:
Embodiment 1: select health to lay eggs after one week of breeding hen isolated rearing, it is fully emulsified that ARVIgY antigen suspension is added emulsifying agent, multi-point injection under the Corium Gallus domesticus, and inoculation is once again after two weeks.Produce immunne response after 10 days, contain effectively anti--ARV IgY composition in the yolk of being laid eggs.Collect institute's Huang of laying eggs, by known extraction anti--method of ARV IgY crude product obtains crude product, crude product purity is 15%～55%, again through following step purification:
A. will slightly carry anti--ARV IgY and cross diethylamino ethyl sephadex chromatography post, add buffer solution elution, desalination, lyophilization is dissolved again;
B. cross glucosan G200 gel chromatographic columns, add buffer solution elution, desalination, lyophilization is resisted-the pure product of ARV IgY, and purity is 99.2%.
Embodiment 2: the pure product of pressing the method preparation of embodiment 1, in a step, after will slightly carrying anti--ARV IgY and crossing diethylamino ethyl glucosan A50 gel chromatographic columns, it with the PH that includes 0.01M-0.14M LINEAR N aCl concentration of 0.01M 6.8 PB phosphate buffer eluting, flow velocity is 20 milliliters/hour, collection has the protein peak of antibody activity, collects the liquid desalination of dialysing in distilled water, after the lyophilization with the dissolving of PB buffer.
Embodiment 3: the pure product of pressing the method preparation of embodiment 1, in the b step, intermediate product is crossed behind the glucosan G200 gel chromatographic columns with 0.01M, the PBS buffer solution elution of PH7.0, flow velocity is 11～13 milliliters/hour, the protein peak that collection has the antibody activity desalination of dialysing in distilled water promptly gets pure product after the lyophilization.
Embodiment 4: the goods that will contain anti--ARV IgY active ingredient add other adjuvants and are mixed with anti--ARV IgY content and are no less than 10% product.
Embodiment 5: the goods that will contain anti--ARV IgY active ingredient add other adjuvants and are mixed with anti--ARV IgY content and are no less than 30% product.
Embodiment 6: the goods that will contain anti--ARV IgY active ingredient add other adjuvants and are mixed with anti--ARV IgY content at 30%～50% and 85%～98% product.
Embodiment 7: any one described product among the embodiment 1-6 is made health product and medicine, and be used to prevent and treat the infantile diarrhea that the A group rotavirus causes.
Embodiment 8: in embodiment 4-7 in any one described product add adjuvant and contain edible monosaccharide or polysaccharide single or that be mixed.
Embodiment 9: the goods that will contain anti--ARV IgY active ingredient add following adjuvant single or that be mixed and are made into health product or medicine: dextrin, lentinan, sucrose, astragalus polysaccharides, maltose, glucose, monkey mushroom polysaccharide, high fructose syrup, starch, Fructus Hordei Germinatus powder.
Embodiment 10: get 3 parts of maltodextrins, lentinan is sterilized for 3 parts, in sterilizing room is anti--4 parts of mix homogeneously of ARV IgY crude product of 20% with itself and purity, sends into automatic filling machine and records capsule, and the gained capsule polishes, and is aluminum-plastic packaged.Make the specification of product: every edition 12 capsules, every contains 200 milligrams of contents, as medicine for treatment, oral 3 times of instructions of taking every day, one time 1～3.
Embodiment 11: get 2 parts of sucrose, 4 parts of astragalus polysaccharidess, purity is anti--ARV IgY goods of 50%, makes every capsule that contains 100 milligrams of contents by embodiment 10 methods, instructions of taking every day 2～3 times, one time 1.
Embodiment 12: adopt 5 parts of maltodextrins, and 2 parts of maltose, 1～2 part of monkey mushroom polysaccharide, slightly carrying of purity 40% be anti--and medicine part is made in ARV IgY1～8.
Embodiment 13: gather anti--70 on ARV IgY immunity egg, separate obtaining 1000 milliliters of egg yolk, thin up to 8000 milliliter, centrifugal 7000 milliliters of the clear liquids that obtain, the employing Hollow Fiber Ultrafiltration extracts, be concentrated at last 700 milliliters stand-by, wherein contain and slightly carry anti--ARV IgY18 gram.With maltodextrin 50 grams, maltose 20 grams, sucrose 12 grams add 100 milliliters of dissolvings of water, sterilize 30 minutes cooling for 100 ℃.With adjuvant and 70 milliliters of ultrafiltrate mix homogeneously of handling, lyophilization, aseptic pulverizing is packaged into bag, and every pouch includes 0.5 gram.As treating the infantile diarrhea that the A group rotavirus causes.
Embodiment 14: anti--2 parts of pure product of ARV IgY of getting that any one provides among the embodiment 1-3, and 4 parts of maltose, 2 parts of methods by embodiment 10 of starch are made the capsule of 100 milligrams of contents.
Embodiment 15: get purity and be anti--1 part of ARV IgY crude product of 30%, and 3 parts of glucoses, 1 part of ganoderan, 25 parts of distilled water are made into health care liquid.
Embodiment 16: get 100 on the immune egg of anti--ARV IgY, obtain 1400 milliliters of egg yolk liquids, add 3 times of water dilutions and add 3.5% PEG6000 mixing, centrifugal 3500 milliliters of the supernatant that obtain add PEG6000 again and left standstill 4 hours centrifugal collecting precipitation to final concentration 12%.With 400 milliliters of dissolvings of distilled water, 60 gram glucoses, 20 kairine sesame polysaccharide, with 100 ml distilled waters dissolving IgY precipitation.Mix above-mentioned two kinds of solution, by the biofilter degerming, in embedding to the 10 milliliter Packaging Bottle, obtain/100 milliliters of total protein 0.4 grams, anti--ARV IgY0.12 restrains/10 milliliters health care liquid.Be used to the infantile diarrhea that prevents anti-A group rotavirus to cause.Instructions of taking every day 2-3 time, each one bottle.
Embodiment 17: get 20 of healthy mices, and establish matched group, fasting is 16 hours before the administration, anti--ARV IgY solution with 0.15 grams per milliliter restrains body weight volume gastric infusions by 0.8 milliliter/20, and respectively at 6 hours, give the anti--ARV IgY solution of same dosage after 24 hours again, observed reaction of animals 7 days.Mice through irritate stomach anti--ARV IgY6.0 gram/kilogram (be equivalent to people's clinical application 1800 times), its diet, activity, fur, defecation etc. all do not have unusually, none Mus death.Compare with matched group, through irritate the stomach high dose anti--mice of ARV IgY, its diet, weight ratio only have increase slightly slightly, difference is not remarkable.Above result shows anti--ARV IgY goods safety non-toxic.
Embodiment 18: the health product or the medicine that will contain anti--ARV IgY active ingredient are used for 200 routine children's's rotavirus enteritis patient passive immunity protection improvement.The rotaviral enteritis epidemic period infant of being in hospital, age is below 2 years old, the course of disease is within seven days, and clinical diagnosis is rotavirus enteritis and detects through stool ELISA and to be wheel virus antigen positive person (negative patient rejecting), is divided into anti--ARV IgY treatment group and routine medication group at random.
Therapeutic Method and dosage: anti--ARV IgY treatment group is only taken each one of anti--ARV IgY, three times on the one.The routine medication group is a matched group.Unified regulation is not done in medication, and the doctor selects to use 1 to multiple medications by medication custom separately by seeing and treating patients.As dried element, dioctahedral smectite, beautiful pearl intestinal pleasure, Birid Triple Viable, Pulvis Biofermini Co No, virazole, butylamine card geomycin, the cefoperazone etc. of scratching.Two groups are all carried out fluid-supplement therapy, and correct dehydration, electrolyte disturbance are adjusted acid-base balance.Nutritious bad person gives supporting treatment.
The infant that observational technique A lists observation in collects all that fresh stool makes routine tests and rotavirus ELISA detects and confirms, detects blood electrolyte, blood gas analysis in case of necessity.Inquiring about disease history and physical examination are in detail filled in clinical observation table.
The curative effect judgment criteria: A times of defecation≤2 time/Japan and China return to normal number of times, and the stool character recovers normal, and the clinical symptoms complete obiteration is for curing.(be divided in view of the above～1 day ,～2 days ,～3 days ,～cured in 4 days).Calculated curative day to the 4 days.Invalid: after four days (96 hours) treatment, though the diarrhoea number of times have minimizing still＞2 time/day or character do not have and be clearly better, even the state of an illness increases the weight of and changes the medicine person is all invalid.
Two groups of clinical datas distribute: the complete person of data collection is anti--and IRV IgY treatment group totally 162 examples, male's 115 examples (70.99%) in routine medication group 160 examples, the treatment group, women's 47 examples (29.01%), matched group male 125 examples (78.13%), women's 35 examples (21.87%).1 years old age organized 123 examples (75.92%) with interior person's treatment, reckling 37 days; Matched group 129 examples (80.63%), reckling 40 days.Two groups of time morbidity natural law of being in hospital see Table 1, and clinical manifestation sees Table 2.The stool microscopy has the leukocyte, and 45 examples (27.78%) are organized in person's treatment, matched group 48 examples (30%).(it is 62.96% that this treatment group has 102 examples, and it is 48.13% that matched group has 77 examples except that " vomiting " item in two groups of clinical manifestations.The treatment group obviously overweights matched group, P＜0.01, difference has statistical significance), other performance and sex, age, the course of disease, all conditions of stool microscopy roughly similar (learn by statistics and handle the P value all＞0.05, the difference not statistically significant) have comparability.
The result:
Anti--ARV IgY treatment group total cure rate 143 examples (88.27%) in this research, matched group 96 examples (60.0%).Learn by statistics and handle X
2=33.08, P＜0.01 (seeing Table 3).Average antidiarrheal natural law treatment group 2.86 ± 1.34 (X ± S) day, matched group 4.31 ± 1.62 (X ± S) day.Learn by statistics and handle μ=8.77, P＜0.01.Two groups of differences have the highly significant meaning.
Embodiment 19:ELIAS blocking test: all testing sample protein contents are decided to be 3mg/ml; Get viral 100 μ l, the quick A group wheel virus antigen enzyme labeled diagnosis reagent box central reaction hole that provides by the biological Advanced Technology Center of the Guangdong Zhujiang River is provided, be coated with anti--ARV IgY in this central reaction hole, 37 ℃ of temperature were bathed 30 minutes, after the distilled water flushing reacting hole is more than 10 times, pH7.2 is filled it up with in every hole, 0.01MPBS contain the washing liquid of 0.5% tween, room temperature is placed hypsokinesis in 3 minutes and gone to pat dry, every hole adds the enzyme connection and resists-ARV IgY100 μ l, left standstill 30 minutes in 37 ℃, more than 10 times, wash 2 times with washing liquid: every hole successively adds benzidine again with distilled water flushing, each 50 μ l of hydrogen peroxide, left standstill 3-5 minute in room temperature, develop the color for adding 8NH after the blueness immediately
2SO
430-50 μ l/ hole, cessation reaction, displaing yellow is used DG
3022The type enzyme-linked immunosorbent assay instrument is surveyed light absorption value OD
450Nm.This result of the test male measurement result of blocking the control wells of Kong Yuxian feminine gender apparent with sample or little apparent blueness is calculated the blocking-up rate, is 50% positive result.Computing formula is as follows:
Embodiment 20: any one described product among the embodiment 1-6 is added in milk product, coffee, Mel and various other beverage.
Morbidity natural law (routine number) relatively when table 1 a liang group was admitted to hospital
| Group | ～1 day | ～2 days | ～3 days | ～4 days | ～5 days | ～6 days | ～7 days | Add up to |
| Anti--IRV IgY treatment group routine medication group | 21 31 | 35 41 | 48 42 | 25 24 | 27 13 | 4 2 | 2 7 | 162 160 |
X
2＝10.33 P＞0.05
Clinical symptoms when table 2 a liang group is admitted to hospital (routine number) relatively
| Group | Times of defecation | Body temperature | Vomiting | Dehydration | |||||
| ＜10 times/day | 〉=10 times/day | Normally | Heating | Have | Do not have | Do not have | Gently--in | Heavy | |
| Anti--IRV IgY treatment group conventional medicine matched group | 83 93 | 79 67 | 46 33 | 116 127 | 102 77 | 60 83 | 2 8 | 158 150 | 2 2 |
| Two groups are compared X 2Value | X 2＝1.54 P＞0.05 | X 2＝2.62 P＞0.05 | X 1＝7.18 P＜0.01 | X 2＝3.80 P＞0.05 | |||||
Table 3 liang group effect relatively
| Group | ～1 day | ～2 days | ～3 days | ～4 days | Invalid | Total cure rate | ||||||
| The example number | ％ | The example number | ％ | The example number | ％ | The example number | ％ | The example number | ％ | The example number | ％ | |
| Anti--IRV IgY treatment group conventional medicine matched group | 24 1 | 14.81 0.63 | 45 13 | 28.40 8.13 | 49 49 | 30.25 30.63 | 24 33 | 14.81 20.63 | 19 64 | 11.73 40.0 | 143 96 | 88.27 60.0 |
X
2＝33.08 P＜0.01
Claims (1)
1, the anti-A group rotavirus chicken yolk immunoglobulin that contains specificity anti-rotavirus antibody activity, the product of promptly anti--ARV IgY, its preparation method adopts the antigen that contains the A group rotavirus with subcutaneous injection mode immunity bird inlay, collecting them after 10 days lays eggs, separate yolk, extract anti-ly-ARV IgY crude product by the polyethylene glycol 6000 sedimentation method or water dilution process, again through following step purification:
A, will slightly carry anti--ARV IgY and cross diethylamino ethyl-polydextran gel A50 ion-exchange type gel chromatography column, phosphate buffer eluting with the pH6.8 that contains 0.01M-0.14M LINEAR N aCl concentration of 0.01M, flow velocity is 20 milliliters/hour, collection has the protein peak of antibody activity, collect the liquid desalination of in distilled water, dialysing, with the phosphate buffer dissolving, get product A after the lyophilization;
B, product A is crossed sephadex G 200 gel chromatography columns, with 0.01M, the phosphate buffer of pH7.0 is washed and is dashed, flow velocity be the 11-13 milliliter/hour, the protein peak that collection has the antibody activity desalination of dialysing in distilled water, lyophilization is resisted-the pure product of ARV IgY.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB981072542A CN1290580C (en) | 1998-04-01 | 1998-04-01 | Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB981072542A CN1290580C (en) | 1998-04-01 | 1998-04-01 | Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity |
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| CN1201693A CN1201693A (en) | 1998-12-16 |
| CN1290580C true CN1290580C (en) | 2006-12-20 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1110323C (en) * | 1999-02-12 | 2003-06-04 | 中国人民解放军军事医学科学院微生物流行病研究所 | Rotavirus resisting immune globulin composite and its preparation and use |
| CN100360566C (en) * | 1999-09-08 | 2008-01-09 | 中德联合研究院 | Pyloric bacillary spirillum resisting yolk immunoglobulin product and its application |
| CN1318449C (en) * | 2003-05-13 | 2007-05-30 | 雅臣药业集团（远东）有限公司 | Anti SARS specificity IgY and combination preparation thereof |
| BR112013012594A2 (en) * | 2010-11-23 | 2018-10-16 | Pantheryx Inc | compositions and methods for treatment in broad spectrum undifferentiated or mixed clinical applications |
| CN114853885A (en) * | 2022-06-01 | 2022-08-05 | 广西博生生物科技有限公司 | Preparation method of specific biological extraction protein-gamma protein |
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1998
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