CN1110323C - Rotavirus resisting immune globulin composite and its preparation and use - Google Patents
Rotavirus resisting immune globulin composite and its preparation and use Download PDFInfo
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- CN1110323C CN1110323C CN99100738A CN99100738A CN1110323C CN 1110323 C CN1110323 C CN 1110323C CN 99100738 A CN99100738 A CN 99100738A CN 99100738 A CN99100738 A CN 99100738A CN 1110323 C CN1110323 C CN 1110323C
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Abstract
The present invention relates to an anti-rotavirus immune globulin composition, a preparation method thereof and application thereof for treating rotavirus diarrhea. The composition is an enteric-coated solvent which contains an effective amount of anti-rotavirus specific immune globulin and pharmaceutically acceptable carriers, wherein the immune globulin is prepared from chickens without specific pathogens by means of reinforced immunization. The composition can be used for preventing or treating rotavirus diarrhea and have the advantages of good effect, safety, convenient administration for children, etc.
Description
The present invention relates to a kind of immune globulin composite and preparation method thereof and the purposes that is used to prevent, treat rotavirus diarrhea.
Infantile rotavirus enteritis is an all generable disease in a kind of world wide.According to the United Nations's health organization statistics, the annual rotavirus diarrhea of child below 5 years old number of the infected is 100,012,500 in developing country's (not comprising China), and wherein serious case is that 1,008 million peoples are inferior, and death reaches 870,000.Annual infantile rotavirus enteritis number of the infected is 3,000,000 in the U.S., and inpatient reaches 82,000 person-times.Annual infantile diarrhea case is about 3.5 hundred million person-times in China, and wherein about 40～50% case is caused by rotavirus.Even more noteworthy, except that supporting treatment, at present the treatment of rotavirus infection still there is not the specific treatment medicine.
In recent years, people discover that oral immune globulin can effectively prevent, treat infantile rotavirus enteritis.The scene protection result of the test of states such as the U.S., Australia and Bangladesh shows that oral specific immune globulin prevention infantile rotavirus enteritis can obtain to protect completely effect.Europe mountain many scholars drugmaker (SANDOZ) shows in gondola II clinical trial phase report, in the randomized controlled test, A organizes 98 disposable oral immune globulin 300mg/Kg of rotavirus diarrhea child, the infant diarrhoea time shortened to 76 hours by average 131 hours, the intestinal toxin expelling time shortened to 114 hours by average 180 hours, clinical efficacy is remarkable, and do not find any toxic and side effects (Guarino A, Canani RB, Russo S, et al.Oral immunoglobulins for treatment ofacute rotaviral gastroenteritis.Pediatrics, 1994,93 (1), 12-6.).Clinical research result in Bangladesh shows, adopt randomized, double-blind method controlled trial that 35 rotavirus diarrhea children are carried out oral Antybody therapy, no matter found that and to shorten aspect the course of disease or the alleviating diarrhoea, all there is significant difference (Mitra AK between treatment group and placebo group, Mahalanabis D, Ashraf H, et al.Hyperimmune cow colostrum reduces diarrhoea due to rotavirus:a doubie-blind, controlled clinical trail.Acta Poediatr 1995,84:996-1001.).Britain carries out the oral immune globulin treatment to the patient of the serious rotavirus diarrhea of bone marrow transplantation future trouble, as a result all infants all in 72 hours the recovery from illness (Kanfer EJ, Abrahamson G, Taylor J.et al.Severe rotavirus-associated diarrhoea fol lowingmarrow transplantation:treatment with oral immunoglobul in.BoneMarrow Transplant, 1994,14:(4) 651-2.).The research report of Sweden shows, oral immune globulin can shorten rotavirus patient's toxin expelling phase (Bogstedt AK, Johansen K, Hatta H significantly, et al.Passive immunity against diarrhoea.1996,85:(2) 125-8.).In addition, oral immune globulin can shorten clinical disease course (the Jjellstr B of serious Crohn ' s enteritis significantly, Stenhammar L, Magnusson KE.et al.Oral immunoglobulintreatment in Crohn ' s disease.Pcediatr, 1997,86:(2) 221-3.).The clinical trial of the U.S. is also found, to the concurrent serious Cryptosporidium diarrheal patient of AIDS patient in late period, oral immune globulin is alleviating diarrhoea degree and improve clinical symptoms (Greenberg PD significantly, Cello JP.Treatment of severe diarrhea caused by Cryptosporidium parvum withoral bovine immunoglobulin concentrate in patients with AIDS.J AcquirImmune Defic Syndr Hum Retrovirol, 1996,13:4 348-54.).But there is following problem in the oral immune globulin that uses in these researchs: the 1. preparation cost height of goods such as serum immune globulin and monoclonal antibody thereof, yield poorly, and can't satisfy heavy dose of requirement of oral administration.2. use the immunoglobulin without reinforced immunological, the antibody consumption is big and therapeutic effect is not good enough.3. degrade through gastric acid, digestive enzyme at gastrointestinal tract after the non-protection dosage form immunoglobulin oral administration, cause the immunoglobulin consumption big, antibody half life is short.These shortcomings increase the production of immunoglobulin and treatment cost, have limited their application clinically.
The purpose of this invention is to provide a kind of preparation cost low, be not subjected to gastric acid and the destructive rotavirus resisting immune globulin composite of gastric enzyme.
Another object of the present invention provides the method for the alleged rotavirus resisting immune globulin composite of a kind of the present invention of preparation.
A further object of the present invention provides the purposes of the alleged immune globulin composite of the present invention aspect prevention, treatment rotavirus diarrhea.
For achieving the above object, the present inventor gropes through experiment, obtains following technical proposals:
Immune globulin composite of the present invention comprises the anti-rotavirus specific immune globulin and the pharmaceutically acceptable dressing of effective dose.
In order to make oral immune globulin avoid the destruction of gastric acid and gastric enzyme, be convenient to children taking simultaneously, the present composition is the enteric solubility compositions, comprises enteric coated granule, enteric coated micropill and enteric microcapsule.
Dressing comprises enteric coating material, plasticizer, antiplastering aid, protein stabiliser, binding agent in above-mentioned enteric coated micropill or the enteric coated granule.Wherein the content of anti-rotavirus specific immune globulin is the 5-50% of composition weight; Be preferably 10-30%; Be preferably 20%.
The enteric coating material comprises hydroxypropylmethyl cellulose phthalate, carboxymethylethylcellulose, acrylic resin II number, acrylic resin III number, cellulose acetate phthalate, Lac, polyvinyl acetate phthalic acid ester, succinic acid hydroxypropylmethylcellulose acetate methylcellulose etc., preferred acrylic resins II number or acrylic resin III number.
Suitable plasticizer comprises triethyl citrate, triacetyl glycerine, acetylation triethyl citrate, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate, phthalic acid dibutyl ester, propylene glycol etc., preferred phthalic acid dibutyl ester or triethyl citrate.Antiplastering aid comprises magnesium stearate, Pulvis Talci, silicon dioxide, titanium dioxide etc., preferred magnesium stearate.
Protein stabiliser comprises mannitol, lactose, albumin, sorbitol, xylitol, arabitol etc., preferably uses mannitol or albumin used as stabilizers.
Binding agent comprises gelatin, sodium alginate, hydroxypropyl emthylcellulose, arabic gum etc., and preferred sodium alginate is made binding agent.
Filler comprises starch, lactose, sucrose, pregelatinized starch etc.
Above-mentioned enteric microcapsule dressing comprises the capsule material.Wherein the content of anti-rotavirus specific immune globulin is the 10-30% of composition weight.
Compositions of the present invention can be used for prevention and treatment rotavirus diarrhea.Indication is an infantile rotavirus enteritis.
Present composition route of administration is oral.Dosage is 30 ~ 300 milligrams of immunoglobulin/kg body weight.
The specific immune globulin compositions of anti-rotavirus of the present invention can prepare by the following method.Adopt II level cleaning level cultivating condition, no-special pathogen (SPF) chicken is carried out the rotavirus reinforced immunological; Adopt defat, saltout, desalination, concentrate and chromatographic technique extracts the specific immune globulin (IgY) of anti-rotavirus from the egg of reinforced immunological; Adopt corresponding enteric material and technology that specific immune globulin is prepared into the enteric solubility compositions.
Its advantage is: extractive technique 1. of the present invention can make immunoglobulin purity reach 90%; 2. adopt the SPF chicken as immune medium, can significantly reduce the background antibody in the egg, significantly reduce the irrelevant antibody in the immunoglobulin.Help to obtain the specific immune globulin at rotavirus of a large amount of homogeneous.3. owing to adopt the SPF cultural technique, can reduce the pathogen contamination risk of immune chicken and egg effectively.Thereby the immunoglobulin biological safety of preparation is improved greatly.
Immunoglobulin is owing to the virus neutralization that has significantly improved immunoglobulin through reinforced immunological is tired in the present composition; Simultaneously owing to adopt the SPF technology to lower irrelevant antibody background greatly and eliminated potential pathogenic microorganism in the antibody preparations; Enteric chemoproection dosage form improves the dosage form stability of specific immune globulin greatly, has avoided the degraded to immunoglobulin of gastric acid and gastric enzyme, and immunoglobulin was prolonged in the half-life of intestinal, lowers the irrelevant degraded at intestinal.These measures have significantly reduced the actual using dosage of immunoglobulin, thereby reduce the immunoglobulin production cost, improve productivity effect.
Below in conjunction with embodiment the present invention is done further detailed elaboration, but these embodiment do not limit the present invention.
The preparation of immunoglobulin
Embodiment one.
1. immunogen preparing:
1.1 adopting the human-like Wa strain rotavirus of ATCC standard, monkey type SA11 strain, cattle type WC3 strain is the virus production strain, cultivating host cell is MA-104 cell line.
1.2 the continuous passage of MA-104 cell is cultured to 2500ml rotating and culturing bottle (DMEM culture medium, contain 10% newborn calf serum, 1% antibiotic and 1.5% sodium bicarbonate), 37 ℃ of rotating and culturing 24 hours with the trypsin treatment cell of 20 μ g/ml 30 minutes, then add viral liquid 5ml absorption 1h, then inhale the venom of preventing or cure a disease, continue to cultivate 48-72 hour to keep liquid (serum-free medium contains 2 μ g/ml trypsin), it is viral to reach 75% o'clock results to cytopathy.
1.3 virus-culturing fluid multigelation three times is interrupted ultrasonication 2min, the centrifugal 15min of 6000rpm, add 8%PEG6000 in the supernatant, 4 ℃ are spent the night, 8500rpm4 ℃ of centrifugal 20min, and precipitation is resuspended with 0.05MPBS, last sample is to the capable gel filtration of Sepharose CL-4B, ultrafiltration and concentration (PELLICONCASSETTE, 100,000NMWL behind the collection main peak, MILLIPORE), concentrated solution carries out immunology, protein concentration and CPE mensuration.
2. animal immune:
2.1 adopt no-special pathogen in age in June (SPF) bird inlay (standard I I level cleaning level Animal House, three grades of air filtrations), every chicken is in breast, abdomen and femoribus internus multiple spot intramuscular injection deactivation bivalent virus liquid+incomplete freund adjuvant 1.5-2.0ml (Wa+SA11 or Wa+WC3, CPE2 * 10
-5Each 0.5ml is with equivalent freund 's incomplete adjuvant mixing and emulsifying).The injection of 2-4 week booster immunization once at interval.Regularly detecting serum and Yolk immunoglobulin tires.
3. immunoglobulin preparation
3.1 hyperimmune egg surface sterile is handled, remove Ovum Gallus domesticus album after homogenize handle, by the acidify sterile deionized water that adds pH4.0-5.0 at 1: 6,4 ℃ of standing over night after the homogenize, supernatant adds the saturated ammonium sulfate gradient precipitation of 20-50%, and 4 ℃ leave standstill 6h, the centrifugal 20min of 8000rpm, precipitation is resuspended with the PBS of 0.0SM, through Sapharose S-300 column chromatography gel filtration purification, collect the immune globulin white peak through desalination and concentration by ultrafiltration (PELLICON CASSETTE, 100,000NMWL, MILLIPORE).
3.2 the purification immunoglobulin adds protective agent after vacuum lyophilization is stand-by.
The system of enteric agents immune globulin composite respectively
Embodiment two: the preparation of enteric coated particles
Prescription and consumption:
Rotavirus antibody lyophilized powder 275 grams
Lactose 3000 grams
Gummi arabicum pulveratum 500 grams
Microcrystalline Cellulose 500 grams
2.5% hydroxypropyl emthylcellulose, 600 grams
Diethyl phthalate 10 grams
5% polyacrylic resin II number 800 grams
Magnesium stearate 100 grams
Preparation process:
1, the particulate preparation of rotavirus antibody
Take by weighing each dressing by the prescription consumption, cross 100 mesh sieves, abundant then mixing is made into soft material with suitable amount of adhesive solution, crosses 14 mesh sieves, and 50 ℃ were toasted 4 hours, with 14 mesh sieve granulate, crossed 30 mesh sieves, and sieve goes fine powder to get final product.
2, the preparation of rotavirus antibody enteric coated particles
Enteric coatings material polyacrylic resin is dissolved in the alcoholic solution for П number, adds diethyl phthalate and magnesium stearate, adopt the air suspension coating coating then.Promptly get the rotavirus antibody enteric coated particles.
The preparation of embodiment three, enteric coated particles
Prescription and consumption:
Rotavirus antibody lyophilized powder 800 grams
Lactose 800 grams
Pregelatinized starch 1000 grams
Mannitol 400 grams
Starch 500 grams
1% sodium alginate, 440 grams
Phthalic acid dibutyl ester 7 grams
5% polyacrylic resin III number 630 grams
Pulvis Talci 63 grams
Preparation process: with embodiment two
Embodiment four: the preparation of enteric coated particles
Prescription and consumption;
Rotavirus antibody lyophilized powder 350 grams
Starch 120 grams
Xylitol 200 grams
Lactose 400 grams
10% gelatin, 560 grams
Hydroxypropylmethyl cellulose phthalate 27 grams
Triethyl citrate 6 grams
Titanium dioxide 20 grams
Preparation process is with embodiment two.
Embodiment five: the preparation of enteric coated particles
Prescription and consumption:
Rotavirus antibody lyophilized powder 90 grams
Sorbitol 20 grams
Pregelatinized starch 40 grams
Microcrystalline Cellulose 10 grams
Lactose 20 grams
10% gelatin, 32 grams
Cellulose acetate phthalic acid fat 3 grams
Phthalic acid dibutylester 0.8 gram
Magnesium stearate 4.3 grams
Preparation process is with embodiment two.
Embodiment six: the preparation of rotavirus antibody enteric coated micropill
Prescription and consumption: with embodiment two to five;
Preparation method:
1, the preparation of rotavirus antibody micropill
By the particulate prescription consumption of preparation with rotavirus antibody and dressing (crossing 100 mesh sieves) mixing after, with suitable amount of adhesive formulations prepared from solutions soft material, cross 14 mesh sieves and make wet granular, place the coating pelletizing machine then, the conglobate micropill of rolling.
2, the system of rotavirus antibody enteric coated micropill respectively
The rotavirus antibody micropill places the coating pelletizing machine, adopts coating material or compound coating material and plasticizer and antiplastering aid coating solution coating promptly to get the rotavirus antibody enteric coated micropill.
Embodiment seven: the preparation of rotavirus antibody enteric-coated microcapsule
Prescription and consumption:
Rotavirus antibody lyophilized powder 0.3 gram
Hydroxypropylmethyl cellulose phthalate 2 grams
Magnesium stearate 0.12 gram
20 milliliters in acetone
160 milliliters of ammonium sulfates
Method step: the enteric material hydroxypropylmethyl cellulose phthalate is dissolved in is made into capsule material solution in the organic solvent-acetone, the rotavirus antibody lyophilized powder is suspended wherein, add ammonium sulfate, abundant stirring and emulsifying, heating under agitation then, organic solvent evaporation is removed, got the circular microcapsule that contains rotavirus antibody.
Embodiment eight: the preparation of rotavirus antibody enteric-coated microcapsule
Prescription and consumption:
Rotavirus antibody lyophilized powder 1.2 grams
Cellulose acetate phthalate 4 grams
Magnesium stearate 0.3 gram
40 milliliters in acetone
Liquid paraffin 180 grams
Method step: enteric material is dissolved in an amount of organic solvent cellulose acetate phthalate, the rotavirus antibody lyophilized powder is suspended wherein.Take by weighing liquid paraffin, adding magnesium stearate stirring and evenly mixing is standby.Under agitation slowly drip acetone solution in liquid paraffin, stir under the room temperature fully, filter the acetone volatilization, with petroleum ether give a baby a bath on the third day after its birth time microcapsule.
Embodiment nine: the preparation of rotavirus antibody enteric-coated microcapsule
Prescription and consumption:
Rotavirus antibody lyophilized powder 0.7 gram
Cellulose acetate phthalate 4 grams
Magnesium stearate 0.25 gram
40 milliliters in acetone
320 milliliters of ammonium sulfates
Method step: with embodiment seven
Listed several embodiment above, wherein data are only for clearly demonstrating the present invention.In fact, anti-rotavirus specific immune globulin and other carrier in the compositions can be adjusted arbitrarily in the scope that pharmacy allows, and might exceed the upper and lower ratio of embodiment of the invention proportioning and reach purpose of the present invention equally.Thereby those skilled in the art according to the present invention, can change and many embodiments.
The immunoglobulin analysis result of the embodiment of the invention one preparation
The purified immunoglobulin of the present invention carries out the mensuration of immunology, electrophoresis and protein concentration, result such as following table:
The two antibody purity protein concentration purification preceding 6 * 10 that expand of ELISA immunity
31.2-1.5 * 10 behind 1: the 32 60% 10.5mg/ml purification
41: 128 90% 120mg/ml
The protection effect of enteric agents immune globulin composite of the present invention
1. the dissolution experiment of enteric agents immune globulin composite
Get different pH value normal saline, mix 37 ℃ of incubation 30min respectively with the enteric agents immunoglobulin of above-mentioned preparation.The result is as follows:
Immunoglobulin enteric coated micropill solubility experiment
PH 3.0 4.0 5.0 6.0 7.0 8.0
Insoluble (+) (++) of dissolubility
The result shows that the enteric immunoglobulin of preparation is insoluble to the following solution of pH7.0.Can protect immunoglobulin to resist the degraded of acid solution effectively.
2. the stability experiment of enteric agents immune globulin composite
With the preparation the enteric agents immunoglobulin respectively in room temperature (18-22 ℃) and 4 ℃ of preservations, measure its ELISA immunizing potency respectively, the result is as follows:
Immunoglobulin enteric coated micropill stability experiment
Original 60 days 120 days 180 days 240 days
Room temperature 1: 12,000 1: 10,240 1: 10,240 1: 10,240 1: 9600
4℃ 1∶12000 1∶10240 1∶10240 1∶10240 1∶10240
3. enteric solubility immune globulin composite metabolism experiment in intestinal
Get the 18-20g Kunming mouse, oral administration gives enteric solubility immune globulin composite (containing the 5mg immunoglobulin), is contrast not add protectant common immunoglobulin.Get the whole small intestinals of mice in different time,, carry out the ELISA immunoassay through tissue homogenate, the centrifugal recovery supernatant of physiological buffer rinsing.
The enteric solubility immune globulin composite is the metabolism experiment in intestinal
ELISA detects 1: 1,200 1: 3,200 1: 2,400 1: 1,200 1: 1,200 1: the 800 normal control level of (branch) 60 90 120 150 180 240 enteric dosage form groups 1: 3,200 1: 2,400 1: 1,200 1: 800 1: 200 1: 100 of tiring the time
The specific immune globulin safety testing
Acute toxicity test in mice: get II level 18-20 gram BALB/C mice, divide the various dose group at random, give the various dose immunoglobulin, observed for 2 weeks through irritating stomach.The result shows, every mice gives 6mg immunoglobulin/g body weight (be equivalent to effective dose 40 times), is tried mice and all survives, and does not see the overt toxicity reaction.
The pharmacodynamic experiment of specific immune globulin compositions
1. the external virus neutralization of specific immune globulin is tired
1.1 the MA-104 cytopathy suppresses experiment
The MA-104 cell routine is spread 96 porocyte culture plates, and to wait that infecting rotavirus mixes with the immunoglobulin of doubling dilution, 37 ℃ act on 1 hour, the every hole of culture plate adds 100 μ l viruses, 37 ℃ of absorption 1 hour, add contain 2% calf serum keep liquid 100 μ l, pancreas enzyme concentration 2 μ g/ml.Mirror is observed testing result down after 72 hours.The result shows that it is 6.5 * 10 that prepared specific immune globulin is tired to the neutralization of Wa strain
4(TCID
50), to SA
11It is 8.5 * 10 that the neutralization of strain is tired
4(TCID
50)
2. the specificity rotavirus resisting immune globulin is to the protective effect of neonatal rat rotavirus diarrhea model
2.1 neonatal rat rotavirus diarrhea modelling
Get 30 of 5 age in days II levels cleaning level Bab/c neonatal rats, random packet, respectively with the different virus amount through irritating the stomach counteracting toxic substances, determine the minimum diarrhea virus dosage (DD that absolutely causes
100).
2.2 the specificity rotavirus resisting immune globulin is to the protective effect of neonatal rat infection model
2.2.1 with the rotavirus resisting immune globulin doubling dilution, mix with treating infective virus respectively, 37 ℃ of effects 1 hour, then through irritating stomach to 5 age in days neonatal rat intestinal counteracting toxic substances, in 96 hours with the persistent period of whether suffering from diarrhoea, suffer from diarrhoea, weight increase index analysis result.The result shows that newborn neonatal rat gives 0.15mg/g body weight, can make protection group neonatal rat 100% avoid diarrhoea.And there is marked difference between the matched group.
2.2.2 newborn 5 age in days neonatal rats give the rotavirus resisting immune globulin of doubling dilution through irritating stomach, irritate stomach after 1 hour and infect rotavirus, judge the protection effect in 96 hours.The result shows, the every gram body weight of neonatal rat administration 0.2mg immunoglobulin can protect infection neonatal rat 100% to avoid diarrhoea.There is marked difference with matched group.
2.2.3 newborn neonatal rat infects rotavirus through irritating stomach, 12 hours after the immunoglobulin of gastric infusion doubling dilution is judged the protection effect after 96 hours.The result shows, the every gram body weight of neonatal rat administration 0.2mg can significantly reduce diarrhoea time and the diarrhoea amount of treatment group neonatal rat, aspect the diarrhoea exponential sum weight increase and matched group have marked difference.
Claims (15)
1, a kind of rotavirus resisting immune globulin composite, it comprises the anti-rotavirus specific immune globulin and the pharmaceutically acceptable dressing of effective dose, described dressing comprises enteric coating material, plasticizer, antiplastering aid, protein stabiliser, binding agent, and the effective dose of described anti-rotavirus specific immune globulin is the 5-50% of composition weight.
According to the described compositions of claim 1, it is characterized in that 2, said composition is the enteric dosage form.
According to the described compositions of claim 2, it is characterized in that 3, this enteric dosage form is an enteric coated micropill.
According to the described compositions of claim 2, it is characterized in that 4, this enteric dosage form is an enteric coated granule.
According to the described compositions of claim 1, it is characterized in that 5, the proteic content of described anti-rotavirus specific immunity is the 10-30% of composition weight.
According to the described compositions of claim 5, it is characterized in that 6, the proteic content of described anti-rotavirus specific immunity is 20% of composition weight.
According to the described compositions of claim 1, it is characterized in that 7, described enteric coating material is acrylic resin II number or acrylic resin III number.
According to the described compositions of claim 1, it is characterized in that 8, described plasticizer is phthalic acid dibutyl ester or citron triethylenetetraminehexaacetic acid fat.
According to the described compositions of claim 1, it is characterized in that 9, described antiplastering aid is a magnesium stearate.
According to the described compositions of claim 1, it is characterized in that 10, described protein stabiliser is mannitol or albumin.
According to the described compositions of claim 1, it is characterized in that 11, described binding agent is a sodium alginate.
According to the described compositions of claim 2, it is characterized in that 12, described enteric dosage form is an enteric microcapsule.
According to the described compositions of claim 12, it is characterized in that 13, described enteric microcapsule comprises dressing capsule material.
According to the described compositions of claim 12, it is characterized in that 14, the content of described anti-rotavirus specific immune globulin is the 10-30% of composition weight.
15, the described anti-rotavirus specific immune globulin of a kind of preparation claim 1 method for compositions may further comprise the steps:
1) carries out the rotavirus reinforced immunological with the no-special pathogen chicken;
2) adopt defat, saltout, desalination, concentrate and chromatographic technique extracts the specific immune globulin of anti-rotavirus from the egg of reinforced immunological;
3) adopt corresponding enteric material and technology with 2) described in specific immune globulin be prepared into the enteric solubility compositions.
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|---|---|---|---|
| CN99100738A CN1110323C (en) | 1999-02-12 | 1999-02-12 | Rotavirus resisting immune globulin composite and its preparation and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201693A (en) * | 1998-04-01 | 1998-12-16 | 中德联合研究所 | Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity |
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| CN1201693A (en) * | 1998-04-01 | 1998-12-16 | 中德联合研究所 | Chick lecithal immune globulin products against rolavirus and its use and its testing method of activity |
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