CN1261161C - Compound interferon inducing agent lozenge - Google Patents
Compound interferon inducing agent lozenge Download PDFInfo
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- CN1261161C CN1261161C CN 200310110892 CN200310110892A CN1261161C CN 1261161 C CN1261161 C CN 1261161C CN 200310110892 CN200310110892 CN 200310110892 CN 200310110892 A CN200310110892 A CN 200310110892A CN 1261161 C CN1261161 C CN 1261161C
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Abstract
The present invention discloses an inducing agent buccal tablet of compound interferon, particularly an endogenous interferon inducing agent in cell bioengineering, which relates to the technical field of medical bioengineering. The present invention aims to provide a buccal tablet which has the advantages of good curative effects, small dosage, small side effect and broad application, and can induce human bodies to generate endogenous interferon. Each buccal tablet contains 10 to 120 hemagglutination units of newcastle disease virus attenuation live vaccine or newcastle disease virus inactivation vaccine, 1 to 2000 mg of milkvetch roots, 1 to 1000 mg of glycyrrhizic acid, supplementary materials and stabilizing agents, wherein the supplementary materials are at least three of 5 to 20 mg of lactose, 30 to 45 mg of starch, 10 to 20 mg of dextrin, 0.15 to 0.25 mg of magnesium stearate, and the stabilizing agents are at least two of 2 to 6 mg of human serum albumin, 3 to 6 mg of chicken egg white protein, 3 to 8 mg of mannitol and 3 to 6 mg of polyethylene glycol. The inducing agent buccal tablet of compound interferon is suitable for preventing the popularization of atypical pneumonia and preventing and treating viral infectious diseases of respiratory tracts, and has auxiliary therapeutic functions on various patients with tumors, hepatitis b and hepatitis c.
Description
Technical field
The present invention relates to the bioengineering technical field.Endogenous interferon inducer in the cell biological engineering particularly.
Background technology
Interferon system is a ubiquitous system in the organism, and it is a kind of opposing adventitious viruses invasion that body self produces, and keeps the defensive material of body or cell Selfstabilizing.Suppressing virus replication and breeding, is a characteristic the most general substantially of interferon, and it almost causes that to all human disease's sexually transmitted disease (STD) poison is all effective.In virus infection, producing interferon is a kind of universal phenomenon, and the interferon that a kind of viral infection produced can produce repellence to multiple virus.
The various biological effect such as reply because interferon has broad-spectrum antiviral and immunomodulating, now existing more than 40 state approval uses interferon formulation, treats more than 30 kind of disease, and it is the first that product sales occupies medicine.Existing interferon formulation all is an exogenous interferon, mainly contains the α 2a that produces with genetic engineering, α 2b, the LeIF of α 1b and natural disturbance element and lymphoblast interferon.Exogenous interferon, complex manufacturing, it is restricted to originate, the cost height, price is expensive, and side reaction is big, uses inconvenient.
Understand self and produce endogenous interferon after organism infection virus, it has all biological activity and the function of interferon.Endogenous interferon is compared with the like product exogenous interferon, and it is unrestricted to have a source, and hypotype is complete, glycosylation, and stable performance, antigenicity is stronger, good effect, advantage such as have no side effect.
Summary of the invention
Given this, the invention provides a kind of good effect, dosage is little, side effect is little, preparation is easy, cost is low, cheap, use the wide human body of inducing and produce the compound interferon inducer buccal tablet of endogenous interferon.
The present invention adopts Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine as main derivant, and Chinese medicine astragalus, glycyrrhizin are as the helper-inducer agent, and adjuvant, stabilizing agent are formed the compound interferon inducer and realized its purpose.
Compound interferon inducer buccal tablet of the present invention, every contains Avian pneumo-encephalitis virus attenuated live vaccine or 10～120 HAUs of Avian pneumo-encephalitis virus inactivated vaccine, the Radix Astragali 1～2000mg, glycyrrhizin 1～1000mg, adjuvant and stabilizing agent, above-mentioned adjuvant is at least three kinds among lactose 5～20mg, starch 30～45mg, dextrin 10～20mg and the magnesium stearate 0.15～0.25mg, and the aforementioned stable agent is at least two kinds among human serum albumin 2～6mg, egg white powder 3～6mg, mannitol 3～8mg and the Polyethylene Glycol 3～6mg.Wherein:
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 10～40 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～60 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 60～100 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 5～10mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 10～15mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 15～20mg, and glycyrrhizin is 1～4mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 4～6mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 6～8mg.
Can be that Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, the Radix Astragali be 1～4mg, and glycyrrhizin is 8～10mg.
1. the characteristic of each component among the present invention:
1.1. Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are in the present invention as main derivant.
1.1.1 it is the strongest to induce a interferon ability, this strain is a strain low virulent strain that filters out from newcastle disease virus strain, is universally acknowledged best interferon inducer, and China early this strain of approved is used for human leukocyte interferon large-scale production.
1.1.2 safety is good: this Tobamovirus is paid myxovirus, and natural reservoir (of bird flu viruses) is chicken and duck, to people's no pathogenicity, promptly is wild-type virus, and is pathogenic also very weak to the people, may cause conjunctivitis and pharyngolaryngitis once in a while.
1.1.3 China uses this attenuated strain already, production Avian pneumo-encephalitis virus live vaccine, and the Avian pneumo-encephalitis virus that is used for preventing chicken is popular the chicken group's, obtains good result.
1.1.4 prepare easy convenient sources, available chick embryo allantoic liquid or chick-embryo cell large-scale culture breeding preparation virus, and technical maturity.
1.1.5 Avian pneumo-encephalitis virus and coronavirus, natural reservoir (of bird flu viruses) all is spinal animals such as chicken, duck, the coronavirus infection chicken, can cause the respiratory virus infection symptom of chicken asthma, the newcastle disease virus infection chicken can cause fowl plague, and clinical symptoms is similar with diseased region, therefore infer that possible both antigenicities are similar.
At present, more existing ani mal coronavirus attenuated live vaccines can effectively prevent Porcine epidemic diarrhea virus and infectious bronchitis.Therefore the present invention prevents the popular of SARS disease with the Avian pneumo-encephalitis virus attenuated live vaccine, gets a good chance of.
1.2. the Radix Astragali, among the present invention as the helper-inducer agent.
1.2.1 the Radix Astragali be a kind of interferon short inducer and inducer, the Radix Astragali has the short virus ability of inducement interferon in vivo, can increase to induce that the output of interferon reaches 1～5 times in the process.
1.2.2 the Radix Astragali on cell culture, in animal and the human body, all has certain antivirus action, and interferon system is had tangible stimulation.
1.2.3. the Radix Astragali can be regulated humoral immunization, and SigA reduction person is recovered normally, can regulate cellular immunization and promote lymphocyte transfer reaction to recover, activating macrophage promotes the NK cytoactive.
1.2.4 the Radix Astragali can induce r interferon (immunomodulatory effect of r interferon is higher 10～100 times than interferon-alpha approximately) in people and mice body.
1.2.5 but Radix Astragali preventing cold can fall end sickness rate more than 50%, and can reduce sickness rate as the Radix Astragali and interferon use in conjunction preventing cold and reach more than 70%.
1.3. glycyrrhizin, among the present invention as the helper-inducer agent.
1.3.1 now confirm, but the glycyrrhizin coordinating the actions of various ingredients in a prescription has activating immune cell, strengthen lymphokine and produce, can significantly strengthen the NK cytoactive, suppress effects such as virus multiplication.
1.3.2 glycyrrhizin can induce the r interferon in vivo, interleukin-22, and have the function of similar hormone.
1.3.3 Germany scientist studies have shown that recently, glycyrrhizin, and the SARS virus in the pair cell has inhibitory action to have to help the human SARS virus of hitting.
The Japan scholar makes mixture with glycyrrhizin and glycine and cysteine, is the potenxin glycyrrhizin, is widely used in the treatment hepatitis B in Japan.
1.3.4 glycyrrhizin and interferon use in conjunction play coordinative role.
1.4. adjuvant: lactose, starch, dextrin and magnesium stearate.
Above-mentioned lactose is the ideal filler of tablet, and is very stable in air because of it, but used as stabilizers; Slightly sweet taste can be made the bright and clean aesthetic property that seasoning also can increase finished product.
Above-mentioned starch is made filler, adsorbent, disintegrating agent and binding agent.The normal mixing with dextrin, Icing Sugar made filler, to increase cohesive.
Above-mentioned dextrin is made filler, binding agent, often mixes use with starch, Icing Sugar.
Above-mentioned magnesium stearate is made lubricant, and greasy property is strong and have good tack, is easy to the granule mixing, smooth and beautiful appearance behind the tabletting.
1.5. stabilizing agent: human serum albumin, egg white powder, mannitol and Polyethylene Glycol.
Above-mentioned human serum albumin and egg white powder all are protein, are virus and interferon stabilizing agents (protective agent) commonly used, and that with the most use is the human serum albumin.
Above-mentioned mannitol belongs to sugar alcohols, is equivalent to about 70% of sucrose, because of dissolving in water is slowly pretended stabilizing agent, and slow releasing agent, normal and albumin is used with, makes the stabilizing agent of medicine.
Above-mentioned Polyethylene Glycol, but used as stabilizers, lubricant, slow releasing agent, and can promote that tablet dissolves fully.
From the above, the objective of the invention is to adopt Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine as main derivant, this derivant, inducibility is strong, to people's no pathogenicity, be a strain low virulent strain, it can be in human body, induce a large amount of endogenous interferons, the simultaneous excitation body improves immunologic function.Adopt Chinese medicine astragalus, glycyrrhizin is as the helper-inducer agent, they can promote Avian pneumo-encephalitis virus, the output of inducing interferon in vivo, and can induce the r interferon, cytokines and the humoral immunization and the cellular immune function of regulating body such as interleukin-22, the Chinese medicine and western medicine combination, use in conjunction plays mutual coordination, the a large amount of persistent generations in human body of common promotion endogenous interferon reach more effective prevention of atypical pneumonia and respiratory viral infection disease.
2. common blank pelletizing press sheet technology is adopted in the preparation of compound interferon inducer buccal tablet of the present invention, contains following operation successively:
2.1. will be by the Avian pneumo-encephalitis virus attenuated live vaccine or the Avian pneumo-encephalitis virus inactivated vaccine of proportioning dosage, the Radix Astragali, glycyrrhizin, stabilizing agent, in the sterilizing stainless steel dish, mix, become lyophilized powder with the freezer dryer lyophilization.
2.2. in hot air oven, under 100～105 ℃ of temperature, do roasting each adjuvant component.
2.3. weigh by each adjuvant component weight proportion, under toilet's aseptic condition, mix, cross 80～100 mesh sieves, obtain the powder mixes adjuvant soft material of mixing.
2.4. the adjuvant soft material is crossed 12～16 mesh sieves, put in the baking vessel, under 50～80 ℃ of temperature, getting moisture content through dried bake in 4～6 hours is 3～5% blank granule.
2.5. lyophilized powder and the blank granule of equivalent with making fully mix in sterilizing stainless steel dish or blender, mixture fully mixes with remaining blank granule again.
2.6. under Cool Room 4 or room temperature, use the tablet machine direct compression, make this compound interferon inducer buccal tablet.
The active titration method of Avian pneumo-encephalitis virus attenuated live vaccine among the present invention or Avian pneumo-encephalitis virus inactivated vaccine, can measure with the hemagglutination method, also can measure (as: cytopathy political reform, plaque method and Red blood corpuscle adsorption test method etc.) with the cell infection titration method.Its measurement result can be converted into corresponding hemagglutination and tires.
3. the preclinical test of compound interferon inducer buccal tablet of the present invention
3.1. pharmacology test
3.1.1. absorption approach test
Compound interferon inducer buccal tablet with mice oral cavity buccal various dose.By test, find out effective dose unit.By the oral cavity buccal, stomach is irritated, intramuscular injection, and different approaches administrations such as subcutaneous injection prove that sucking is the effective way of compound interferon inducer, proves that simultaneously the powder dosage form is better than liquid dosage form assimilation effect.
3.1.2. activate NK cells in mice (natural killer cell) activity test
Compound interferon inducer buccal tablet with mice oral cavity buccal various dose.Should prove by test, after mice is sucked the compound interferon inducer, compare, can significantly activate the NK cytoactive with matched group.
3.1.3. activate the mouse macrophage activity test
Behind the buccal compound interferon inducer of mice oral cavity, can activate macrophage activity in the mice body, its activation capability should be suitable with the macrophage activation agent, or there were significant differences with matched group.
3.1.4. mice oral cavity partial mucosa SigA (the white egg A of secreting type immunity ball) content test
By the test should confirm, suck the compound interferon inducer after, local mucosal immunity is had regulatory function, can directly act on oral mucosa, significantly improve the type SigA of merocrine secretion level.
3.1.5. antivirus test
Test as model with influenza virus and white mice.Use the compound interferon inducer, mice is sucked, every day 2 times.Continuous 10 days, observe the protective rate of medicine to animal.Requirement reaches the protective rate of flu-prevention virus to be compared with matched group with the protective rate of treatment influenza virus, and all there were significant differences.With the specified effective antiviral thing of country---virazole is compared, and preventive effect should be better than the virazole therapeutic effect should be suitable with virazole.
3.2. safety and toxicity test
3.2.1. mice oral administered compound interferon inducer acute toxicity toxicity test
With 100～200 times of administrations that are higher than human dose, to observe 14 days, animal should not manifest acute toxic reaction, and animal is strong deposits, and body weight should be positive growth, does not observe clinical disease, does not find that the internal organs physiological pathology changes, and organ weights is compared zero difference with matched group.
3.2.2. rat oral cavity buccal compound interferon inducer chronic toxicity test
With 100～200 times of administrations that are higher than human dose be higher than human body 3 times of times of the course of treatment, to observe animal and do not manifest the chronic toxicity reaction, animal all should be good for and be deposited, body weight should be positive growth, clinical condition do not occur and levy, internal organs do not have pathology and change, and organ weights is compared with matched group and answered zero difference.
3.3. endogenous interferon produces the curve test
This test is to do animal model with mice.Behind the buccal compound interferon inducer of mice oral cavity, respectively 4,12,24,48,72 hours and 1 all 2 weeks, get mice oral mucosa juice and serum detection interferon and tire, produce curve chart, estimate taking medicine back 4 hours to observe endogenous interferon, will produce endogenous interferon, 48～72 hours, in oral mucosa and serum, all can find high-caliber interferon, descend gradually later on, generally after 2 weeks, just can not check.
4. the clinical research of compound interferon inducer buccal tablet control upper respiratory tract infection disease of the present invention
Viral upper respiratory tract infection disease incidence height involves wide, and multiple complications is arranged, and particularly nearly all propagates by upper respiratory tract in the SARS virus of Chinese outbreak of epidemic in 2003.These diseases not only have a strong impact on human health, also influence production and construction and national stable.Yet, also there is not a kind of effectively preventing medicine so far to this class disease.
Compound interferon inducer buccal tablet, adopt Avian pneumo-encephalitis virus and Chinese herb astragalus, the glycyrrhizin etc. of attenuation to form compound preparation, pass through mouth mucosa drug administration, directly induce, human activin produces a large amount of endogenous interferons and antibody, the simultaneous excitation body improves immunologic function, enhancing body defend against computer virus invasive ability, suppress virus replication, thereby elimination virus is kept body homeostasis, reaches the purpose of control upper respiratory tract disease toxicity disease.The present invention makes buccal tablet with the compound interferon inducer.Carry out viral upper respiratory tract infection prevention and treatment of diseases effect test, the clinical use value of said preparation is made an appraisal.
Plant 4.1. research is sick: atypical pneumonia (SARS), influenza, flu, child's repetitive upper respiratory tract infection.Diagnostic criteria with reference to " the sars prevention and control technical scheme " and " lemology " of Ministry of Public Health issue is definite.
4.2. case is selected and grouping
4.2.1. atypical pneumonia (SARS)
Select before winter and the early spring SARS epidemic season, in the crowd of between twenty and fifty (15～40 years old), establish and suck group and α 2b interferon (matched group).
4.2.2. influenza, flu: select epidemic season,, among the crowd of living condition's basically identicals such as school, establish and suck group and α 2b interferon spray group (matched group) in factory.
4.2.3. child's repetitive upper respiratory tract infection is the separating tests group at random: select 1～14 years old age, the child of repetitive upper respiratory tract infection more than 3 times in half a year.Divide treatment group and matched group.The treatment group is divided 2 groups again according to the age: 2～4 years old group.If matched group.
4.2.4. each phase respectively organizes determining of case load and group technology is undertaken by " provisions for new drugs approval ".
4.3. medication
4.3.1. prevention of atypical pneumonia (SARS) administration by the following method: buccal tablet (contains virus-4 0 HAU, Radix Astragali 2mg, glycyrrhizin 2mg) sublingual administration, 1～2 of every day be sure not to chew or swallow, tablet should be contained in the Sublingual, dissolve gradually about 5～10 minutes after the administration, so that oral mucosa fully absorbs.In 30 minutes, do not take food or drinking-water before and after taking medicine, serveing on 10 days is a course of treatment.Period in a medicine must not add and use other antiviral drugs; Matched group adopts α 2b interferon spray, every day 1～2 nasal spray, 10 days is a course of treatment.
4.3.2. prevention and treatment influenza, flu, administration by the following method: buccal tablet (containing viral 20 HAUs, Radix Astragali 1mg, glycyrrhizin 1mg) sublingual administration, every day, early, the evening each a slice, be sure not to chew or swallow, tablet should be contained in the Sublingual, dissolve gradually about 5～10 minutes after the administration, so that oral mucosa fully absorbs.In 30 minutes, do not take food or drinking-water before and after taking medicine, the treatment group serve on 5 days, and (10) are a course of treatment, the prevention group, and serveing on 10 days is a course of treatment.Period in a medicine must not add and use other antiviral drugs; Matched group adopts takes Radix Isatidis granules, the treatment group, day clothes secondary, each bag serve on 5 days (10 bag), the prevention group serve on 10, every day secondary, each bag (20 bag) is a course of treatment.
4.3.3. prevention and treatment child repetitive upper respiratory tract infection, administration by the following method: test group: during the infant morbidity, treatment gives antiinflammatory, brings down a fever processing such as cough-relieving routinely.Simultaneously buccal inf oral tablet (containing viral 20 HAUs, Radix Astragali 1mg, glycyrrhizin 1mg) every day early, evening or each a slice of upper and lower noon, serve on 10.Matched group: conventional therapy, do not take buccal tablet.Venous blood samples before and after taking medicine detects the total cell (CD of T with immunofluorescence
3 +), t helper cell (CD
4 +), T suppresses cell (CD
8 +).
4.4. observation index
4.4.1. prevention of atypical pneumonia (SARS)
4.4.1.1. symptom and sign
Record heating (＞38 ℃) and cough are breathed and are quickened, tachypnea, or respiratory distress syndrome, pulmonary's sound of vomiting sound, or situation such as pulmonary consolidation sign.
4.4.1.2. the real chamber of grinding is checked
Numeration of leukocyte should not increase or reduce.
4.4.1.3. immune system changes
Lymphsystem, the T cell is at first under attack, T
4And T
8The cell number average significantly reduces.
4.4.1.4. pulmonary's imaging examination
There is lamellar in various degree in pulmonary, patch shape wellability shade or be netted change.
4.4.2. prevention and treatment influenza, flu
4.4.2.1. methods of clinical observation: each case is responsible for observation by full-time medical worker, fills in " influenza, the summary sheet day by day of catching a cold ", and the upper and lower noon is respectively surveyed body temperature once, each three minutes.Symptom, sign is made " having ", " nothing " qualitative record.
4.4.2.2. experimental check: select the typical case of symptom.Gather pharynx liquid, nasopharynx is wiped away specimen and paired sera, carries out influenza virus separation and the TPPA reliability with the checking clinical effectiveness according to a conventional method.
4.4.3. control child repetitive upper respiratory tract infection
4.4.3.1. number of times and degree that test group and matched group upper respiratory tract infection take place,
4.4.3.2. every day at the upper and lower noon is respectively surveyed body temperature once, observes body temperature and changes.
Venous blood samples before and after 4.4.3.3. take medicine detects the total cell (CD of T with immunofluorescence
3 +), t helper cell (CD
4 +), T suppresses cell (CD
8 +).The immune variation of human body after observation is taken medicine.
4.5. safety and curative effect determinate standard
Safety judges that by " new drug evaluation way " specified standard the reference scheme that curative effect is formulated with reference to " whole nation prevents and treats the chronic tracheitis working conference " divides produce effects, effective and invalid.Statistical procedures is judged prevention and therapeutic effect.
5. compound interferon inducer buccal tablet of the present invention is to the control of model case
Compound interferon inducer buccal tablet is prevented and treated repeated respiratory tract infections in children
Repeated respiratory tract infections in children is the disease that is caused by the viral infection respiratory tract, is usual diseases of childhood, and frequently-occurring disease is normal relevant with dysimmunity.With compound interferon inducer buccal tablet,, induce by mouth mucosa drug administration, produce a large amount of endogenous interferons in the human activin, suppress virus breeding, the simultaneous excitation body's immunity, thus the repeated respiratory tract infections in children disease is obtained good preventing and therapeutic effect.
5.1. materials and methods
5.1.1. treatment target
Recurrent respiratory tract infection infant in the Pediatric Clinic or the prescription on individual diagnosis of being in hospital divides treatment group and matched group, and two groups of cases all require more than 30 examples, and meet national recurrent respiratory tract infection diagnostic criteria in 1987.Require infant to fall ill repeatedly in half a year more than 3 times, fall ill had heating in 2 days, coughed watery nasal discharge, pharyngeal hyperemia, clinical symptoms such as the pulmonary respiration sound is thick.
5.1.2. observational technique
After two groups of infants are gone to a doctor, give general antibiotic infection, brought down a fever conventional therapies such as cough-relieving simultaneously.The treatment group adds with compound interferon inducer buccal tablet (every contains viral 20 HAUs, Radix Astragali 1mg, glycyrrhizin 1mg), each 1, every day 2 times, sublingual administration, medication front and back 30 minutes, fasting, prohibit water, serve on 10 days two groups respectively at before the treatment and after the treatment, venous blood samples.Specimen detected the total cell (CD of T with immunofluorescence in 4 hours
3 +), t helper cell (CD
4 +), T suppresses cell (CD
8 +).
5.1.3. observation item and content
5.1.3.1. short term effect: observe treatment group and matched group and bringing down a fever, the effect of cough-relieving has zero difference.
5.1.3.2. late result: observe more than half a year, two groups have zero difference in morbidity.
Curative effect judging standard is :≤2 times/half a year of recurrence, symptom significantly alleviates and is produce effects, and≤3 times/half a year of recurrence, sx be effective, otherwise invalid.
5.1.3.3. detect treatment group and matched group CD
3 +, CD
4 +, CD
8 +Variation and difference.
5.1.4. case choice criteria
5.1.4.1. the age of treatment group and matched group (3～12 years old), sex (man, woman) birthplace (city, rural area) should not have significant difference.
5.1.4.2. the medical history of treatment group and matched group infant (morbidity year number), the course of disease (course of disease natural law) should not have significant difference.
5.1.4.3. the nutriture of treatment group and matched group infant (normal, good, not good enough), clinical characters (watery nasal discharge is swallowed redly for heating, cough, and lungs sound is thick), surrounding hemogram (erythrocyte, leukocyte, neutrophilic granulocyte).Compare for two groups and should not have significant difference.
5.2. therapeutic outcome
5.2.1. feel youngster's treatment group again, temperature recovery situation after the treatment of control group
Feel youngster's treatment group again,, all use the axil temperature for two groups with the objective indicator of matched group fever time as curative effect, every day 2 times, along with body temperature descends, also corresponding improvement of other symptom and sign or disappearance.Two groups of temperature recovery normal times significant difference of comparing.The results are shown in Table 1.
Table 1 treatment back temperature recovery situation
| Group | Observation number (people) | The 1st day (%) in treatment back | The 1.5th day body temperature in treatment back recovers normal ratio (%) | Treat back 2 days (%) |
| The treatment group | 40 | 71.6 | 82.1 | 100 |
| Matched group | 35 | 39 | 56.7 | 63.5 |
5.2.2. feel youngster's treatment group again, the T cell subsets changes before and after the treatment of control group
Feel CD behind containing of the youngster's treatment group compound interferon inducer again
3, CD
4Obviously rise CD
8Decline is arranged slightly, CD
4/ CD
8Ratio obviously rises, and the change of matched group T cell subsets is not obvious.The results are shown in Table 2.
The T cell subsets changes before and after table 2 treatment
| Group | CD 3 | CD 4 | CD 8 | CD 4/CD 8 | |
| Just usually be lower than | Just usually be lower than | Just usually be lower than | Just usually be lower than | ||
| Treatment group (40 people) | Before the treatment | 29 11 | 9 31 | 0 10 | 35 0 |
| After the treatment | 15 25 | 2 38 | 8 0 | 2 17 | |
| Matched group (36 people) | Before the treatment | 31 5 | 13 23 | 0 8 | 36 0 |
| After the treatment | 31 5 | 7 19 | 0 0 | 36 0 | |
5.2.3. feel youngster's late result observation again: feel youngster's treatment group again, matched group is respectively observed half a year, and the curative effect of treatment group obviously is better than matched group, and two groups of comparing differences are remarkable.The results are shown in Table 3.
Table 3 is felt youngster's treatment group again, matched group late result (preventive effect)
| Group | The observation number | Produce effects | Effectively | Invalid |
| The treatment group | 35 | 31(88.5％) | 3(8.5％) | 1(2.8％) |
| Matched group | 30 | 5(16.6％) | 14(46.6％) | 11(36.6％) |
5.3. conclusion
5.3.1. short term effect: treatment group body temperature is faster than matched group body temperature decrease speed, and the time is short, and the 1st day body relaxing the bowels with purgatives of warm nature in treatment group treatment back reduced to normal person and accounted for 71.6%, the 1.5 day body temperature and recover normal person to account for body temperature full recovery in 82.15%, the 2 day normal.
5.3.2. late result: the treatment group, total effective rate accounts for 97.2%, and obvious effective rate accounts for 88.5%, and the matched group total effective rate accounts for 63.3%, and obvious effective rate accounts for 16.6%, two group of difference highly significant.
5.3.3. the T cell subsets is observed: CD
3CD
4, CD
4/ CD
8After treatment, all significantly raise and CD
8Level but reduces.Each is organized amynologic index and all is better than matched group.
The result proves absolutely compound interferon inducer buccal tablet, and the recurrent respiratory tract infection infant is had good antiviral therapy and preventive effect and can play the effect of regulating immunologic function disorder.
6. the side effect of interferon inducer and avoid measure
6.1 the side effect of interferon inducer
6.1.1 toxic reaction: a large amount of animal data point out that when using polyinosini (poly I:c) inducing interferon, the ability that produces endogenous interferon links to each other closely with its toxicity, and its dosage that presents toxic reaction is very near therapeutic dose.
6.1.2 induce low reaction: when repeatedly giving interferon inducer in the body, induce the low reaction state, this is the general character of interferon inducers, but degree has nothing in common with each other.
6.1.3 pyrogenicity reaction: a lot of interferon induceres, as virus, bacteriotoxin etc. are injected in rabbit or the human body, and the pyrogenicity reaction is arranged, and body temperature one property crossed rising is irrelevant with the purity of goods.
6.1.4 gastrointestinal reaction: during the dragon inducer of the terraced Lip river of n of high dose oral (more than the 6mg/kg), can cause nausea, vomit, gastrointestinal reaction such as diarrhoea.
6.1.5 blood change: when large bolus injection bacteria lipopolysaccharide or synthesizing pyran copolymer inducer, can cause that the property a crossed hemocyte and platelet suppress.
6.1.6 hypotension, shock reaction: the large bolus injection bacteria lipopolysaccharide as prodigiosin, can cause toxic reactions such as hypotension, cutaneous necrosis or shock.
6.1.7 refreshing smart symptom: n of high dose oral ladder Lip river dragon repeatedly can cause dizziness, insomnia or symptom such as drowsiness.
6.2. the present invention is the measure of avoiding side effect to take
The low good interferon inducers of toxicity is to avoid the side effect ground foundation 6.2.1 the selection inducibility is strong.The present invention adopts the Avian pneumo-encephalitis virus low virulent strain as main inducer, the strong and avirulence of this strain inducing interferon ability.Chinese medicine astragalus, glycyrrhizin element have the effect that induces and urge to induce endogenous interferon, and the present invention is as the helper-inducer agent, and two kinds of Chinese medicine is non-toxic reaction all.
6.2.2 selecting suitable route of administration and method is to reduce the important key of side effect.Mucosa, eye, nose, dermatologic are not reported tangible toxicity.The present invention adopts the buccal tablet dosage form, the oral transmucosal administration, and side effect is rare.
Use 6.2.3 low dose of different types of interferon inducer mixes: according to report, the toxic and side effects of interferon inducer is relevant with dosage, number of times and time, and side effect can be avoided or reduce to low dose of medication at interval.Different types of interferon inducer mixes or hands over justice to use, and can remedy mutually, reduces side effect.And can increase curative effect.The present invention adopts different types of three kinds of inducers to mix and uses, the Chinese medicine and western medicine combination, and all be to adopt low dose of drug combination, side effect seldom takes place.
6.2.4 interferon-induced low reaction: interferon inducers has the broad-spectrum disease resistance cytotoxic activity in animal body, and containing the interferon level in this protective effect and the serum has important relationship.Discover; behind the single administration; the serum interferon retention time is very short; after the continuous several times administration; then produce the low reaction state (the serum interferon level is not high) of interferon inducer, but still keep tangible antivirus action, and phagocytic function still keeps increasing; do not influence protection, and can strengthen resistance virus.Antivirus action and serum interferon level are inconsistent in vivo so think interferon inducer, and with its activating macrophage phagocytic function substantial connection are arranged.Owing to major-minor inducer, low dose of drug combination that the present invention adopts, suck measure such as dosage form, thus compound interferon inducer buccal tablet of the present invention not only safety, but also have no side effect.
The present invention has following obvious advantage and remarkable result compared with prior art.
One, the interferon among the present invention belongs to endogenous interferon, is different from exogenous interferon, and it is ubiquity in the humans and animals body, but level is very low, and this low-level interferon has constituted the natural cover of body to viral infection.Normal cell is under physiological status, its interferon system is resting state, unautogenous generation interferon, behind viral infection, can produce endogenous interferon in early days, and amount is quite big, and antivirus action persistent period while is longer than exogenous interferon, and plays an important role in convalescent period at viral infection.
The present invention contains attenuated live virus or inactivation of viruses in the compound interferon inducer, after infecting human body, can very fast generation endogenous interferon, can activate simultaneously body and produce specific immune response, comprise humoral immunization and cellullar immunologic response, the diffusion in vivo of control virus, thus in viral infection, play an important role.
Two, the compound interferon inducer of the present invention's employing, it is strong to induce ability, no toxicity.
The present invention adopts the Chinese medicine and western medicine combination, form the compound interferon inducer, directly induce, produce a large amount of endogenous interferons and antibody in the human activin, simultaneous excitation body raise immunity, enhancing body defend against computer virus invasive ability suppresses virus replication, thereby elimination virus reaches the purpose of preventing and treating viral disease.
Inducer with antivirus action has kind more than 1000 approximately, but is proved to be the good interferon inducer that can be used to prevent and treat, but for counting seldom.The poly born of the same parents (poly I:c) of bifilar RNA of discovery such as Fiell in 1967 and synthetic can induce the generation interferon, opened up new road for utilizing endogenous interferon, but these inducers, the ability that induces is all not strong and present toxic reaction, and the dosage of the toxic reaction that it presents is very near therapeutic dose.
Three. the present invention is the buccal tablet dosage form, adopts low dosage oral mucosa administration, thereby has reduced dosage and side effect.
Route of administration and drug formulation, tend to affect the treatment and medication after reaction.To local patholoic change is main viral disease, with local application for well, pharmaceutical dosage form with tablet for well.
Exogenous interferon, in clinical practice, the dispenser means are by intramuscular injection and subcutaneous injection dual mode, have following shortcoming: the one, inconvenient, increase patient's misery, patient often can not adhere to for a long time; The 2nd, side effect is bigger, and as fever, nervous system toxicity suppresses hemopoietic function and anaphylaxis etc. and side reaction strengthens even stops injection because of severe reaction along with the increasing of dosage; The 3rd, dosage is big, and price is expensive, and patient is difficult to bear its financial burden.
In view of the above-mentioned shortcoming of injecting drug use, the invention provides the buccal tablet dosage form of compound interferon inducer.Its mechanism of action is newcastle disease virus infection oral cavity partial and produce interferon, the interferon receptors on the interferon through port transmucosal and play antivirus action.The existence of interferon receptors is interferon is brought into play its biological function by cell a essential condition.Prove after deliberation, the intravital interferon receptors of people mainly is distributed in oral cavity, palate, throat and nasal membrane portion, experimental results show that, as long as a spot of interferon is with the receptors bind at above-mentioned position, the biological activity of interferon can be transmitted in the cell, then bring into play antiviral, the effect of antitumor and adjusting immunologic function.Experiment is proof also, and interferon can cause immune activation, and its active site may be also in the oral cavity---bottleneck throat.Oral administration also has the advantage that absorbs fast (1～3 minute), as tablet is contained in the Sublingual, then absorb faster, because hypoglossis mucous membrane rich blood vessel, medicine is easy to through the blood circulation and organizes osmotic absorption, and in the mucomembranous surface cohesion a large amount of interferon receptors, sublingual administration is arranged, can cause immune activation, thereby improve the curative effect of interferon.In addition, the dosage of local application often lacks than systemic administration dosage; Its dosage only is the one thousandth of systemic administration dosage.With the interferon inducer of low dose, through port, throat administration stimulate local cells, lymphoid tissue, thereby trigger internal's extensive reaction, and side effect is minimum.
In addition, buccal tablet dosage form of the present invention, it is accurate, easy to use also to have dosage, volume is little, carry, storage, convenient transportation, and aboundresources, preparation are simple, can automatic mass production, cost is low, system easy to control the quality, advantage such as activity stabilized.
The present invention's compound interferon inducer of the present invention buccal tablet can be used for preventing and prevents and treats multiple viral disease and the low disease of body's immunity.As:
1. prevention of atypical pneumonia is popular.
2. prevent and the treatment influenza, flu waits the upper respiratory tract infection disease.
3. various tumor patients of auxiliary treatment, B-mode and hepatitis C patients.
By mouth mucosa drug administration, induce, produce in the human activin a large amount of endogenous interferons, simultaneous excitation body's immunity.Reach the purpose of the popular of prevention of atypical pneumonia and Respirovirus sexually transmitted disease.And various tumors and B-mode, hepatitis C patients there is the auxiliary treatment effect.The present invention has aboundresources, prepare simple, cheap, the advantage of applying easily.
Below, reuse embodiment is further described the present invention.
The specific embodiment
Embodiment 1
A kind of compound interferon inducer buccal tablet of the present invention is pressed table 4～5 dosages.Carry out as follows:
1. get aseptic Avian pneumo-encephalitis virus attenuated live vaccine, the Radix Astragali, glycyrrhizin, stabilizing agent earlier, mix placing aseptic stainless steel disc, be frozen into the principal agent lyophilized powder with freezer dryer.
2. get each adjuvant, after in 100～105 ℃ of baking ovens, doing sterilization in roasting 1 hour earlier, get dextrin, lactose, magnesium stearate again, behind the mix homogeneously, again with the starch mix homogeneously, cross 80～100 mesh sieves and make the mixed accessories soft material, again the adjuvant soft material is crossed 12～16 mesh sieves and in 60 ℃ of baking ovens, done roasting 4～6 hours, make moisture content and be lower than 5% blank granule.
3. the principal agent lyophilized powder is fully mixed with the blank granule of equivalent, mixture fully mixes with remaining blank granule again, to guarantee that composition is even in the mixture.
4. mixture directly is pressed into 10000, is stored in 4 ℃,, make this lyophilizing compound interferon inducer buccal tablet through the amount calibrating.
Embodiment 2
A kind of compound interferon inducer buccal tablet of the present invention is pressed table 4～5 dosages.Carry out as follows:
1. earlier aseptic Avian pneumo-encephalitis virus deactivation is become dead virus, carry out ultrafiltration and concentration again.Get the Radix Astragali, glycyrrhizin, stabilizing agent again, place aseptic stainless steel disc, fully be mixed into the principal agent mixture.
2. get each adjuvant, after in 100～105 ℃ of baking ovens, doing sterilization in roasting 1 hour earlier, get dextrin, lactose, magnesium stearate again, behind the mix homogeneously, again with the starch mix homogeneously, cross 80～100 mesh sieves and make the mixed accessories soft material, again the adjuvant soft material is crossed 12～16 mesh sieves and in 60 ℃ of baking ovens, done roasting 4～6 hours, make moisture content and be lower than 5% blank granule.
3. the principal agent mixture is fully mixed with the blank granule of equivalent, mixture fully mixes with remaining blank granule again, to guarantee that composition is even in the mixture.
4. mixture directly is pressed into 10000, is stored in 4 ℃,, make this compound interferon inducer buccal tablet through quality arbitration.
Embodiment 3
A kind of compound interferon inducer buccal tablet of the present invention is pressed table 4～5 dosages.By usually extensive flaking method preparation, its step is as follows:
1. principal agent is handled: get the killed vaccine of aseptic Avian pneumo-encephalitis virus attenuation inactivated vaccine or deactivation earlier, carry out ultrafiltration and concentration and handle, and standby after sterility test is qualified.
2. adjuvant, stabilizing agent are handled: adjuvant, stabilizing agent elder generation under 100～105 ℃ of temperature, are done roasting 1 hour, and standby after sterility test is qualified.
3. prepare blank granule: adjuvant and stabilizing agent that the step 2. of learning from else's experience is handled, after in mixer, fully mixing, cross 100 mesh sieves 3 times, add 40% ethanol, stir into soft material, cross 14 mesh sieves, through 56 ℃ of bakings 4～5 hours, make blank granule.
4. preparation interferon inducer granule: with spray method principal agent is after treatment fully mixed the back in 37 ℃ of bakings 4～5 hours with blank granule, 18 mesh sieves make moisture content and be lower than 5% interferon inducer granule.
5. get the interferon inducer granule, under low temperature or room temperature, be pressed into tablet, be stored in 4 ℃,, make this compound interferon inducer buccal tablet through quality arbitration with tablet machine.
The each component dosage of every buccal tablet of table 4 various embodiments of the present invention
| Embodiment | Principal agent | Adjuvant (excipient) | Stabilizing agent (protective agent) | ||||||||
| Virus (HAU) | The Radix Astragali (mg) | Glycyrrhizin (mg) | Starch (mg) | Dextrin (mg) | Magnesium stearate (mg) | Lactose (mg) | Human serum albumin (mg) | Mannitol (mg) | Polyethylene Glycol (mg) | Egg white powder (mg) | |
| 1 | 10-40 | 1-4 | 1-4 | 35-40 | 10-16 | 0.15-0.25 | 15-20 | 2-5 | 4-8 | 3-6 | 3-6 |
| 2 | 10-60 | 1-4 | 1-4 | 35-40 | 10-16 | 0.15-0.25 | 15-20 | 2-5 | 4-8 | 3-6 | 3-6 |
| 3 | 10-100 | 1-4 | 1-4 | 35-40 | 10-16 | 0.15-0.25 | 15-20 | 2-5 | 4-8 | 3-6 | 3-6 |
| 4 | 40-80 | 5-10 | 1-4 | 35-45 | 10-16 | 0.15-0.25 | 15-20 | 2-5 | 4-8 | 3-6 | 3-6 |
| 5 | 40-80 | 10-15 | 1-4 | 35-45 | 10-16 | 0.15-0.25 | 15-20 | 4-6 | 6-8 | 3-6 | 3-6 |
| 6 | 40-80 | 10-20 | 1-4 | 35-45 | 15-20 | 0.15-0.25 | 15-20 | 4-6 | 6-8 | 3-6 | 3-6 |
| 7 | 40-80 | 1-4 | 4-6 | 35-45 | 15-20 | 0.15-0.25 | 15-20 | 4-6 | 6-10 | 4-6 | 4-6 |
| 8 | 40-80 | 1-4 | 4-6 | 30-35 | 15-20 | 0.15-0.25 | 15-20 | 4-6 | 6-10 | 4-6 | 4-6 |
| 9 | 40-80 | 1-4 | 6-8 | 30-35 | 15-20 | 0.15-0.25 | 15-20 | 4-6 | 6-10 | 4-6 | 4-6 |
| 10 | 40-80 | 1-4 | 8-10 | 30-35 | 15-20 | 0.15-0.25 | 15-20 | 4-6 | 6-10 | 4-6 | 4-6 |
The each component dosage of 10000 buccal tablets of table 5 various embodiments of the present invention
| Embodiment | Principal agent | Adjuvant (excipient) | Stabilizing agent (protective agent) | ||||||||
| Virus (ten thousand HAUs) | The Radix Astragali (g) | Glycyrrhizin (g) | Starch (g) | Dextrin (g) | Magnesium stearate (g) | Lactose (g) | Human serum albumin (g) | Mannitol (g) | Polyethylene Glycol (g) | Egg white powder (g) | |
| 11 | 40 | 40 | 20 | 400 | 160 | 2 | 200 | 20 | 80 | 60 | |
| 12 | 60 | 30 | 20 | 400 | 160 | 2 | 200 | 20 | 80 | 60 | |
| 13 | 100 | 30 | 20 | 400 | 160 | 2 | 200 | 20 | 80 | 60 | |
| 14 | 40 | 50 | 40 | 450 | 180 | 2 | 200 | 40 | 80 | 30 | 30 |
| 15 | 40 | 100 | 40 | 450 | 180 | 2 | 150 | 40 | 80 | 30 | 30 |
| 16 | 40 | 200 | 40 | 450 | 180 | 2 | 150 | 40 | 80 | 30 | 30 |
| 17 | 40 | 40 | 80 | 450 | 160 | 2 | 150 | 20 | 100 | 50 | 20 |
| 18 | 60 | 40 | 100 | 450 | 160 | 2 | 150 | 20 | 100 | 50 | 20 |
| 19 | 80 | 200 | 200 | 350 | 180 | 2 | 150 | 40 | 100 | 30 | 30 |
| 20 | 100 | 100 | 100 | 350 | 180 | 2 | 150 | 20 | 100 | 50 | 20 |
| 21 | 40 | 40 | 20 | 400 | 120 | 1.5 | 50 | 40 | |||
| 22 | 60 | 30 | 20 | 400 | 120 | 1.5 | 50 | 40 | |||
| 23 | 100 | 30 | 20 | 400 | 120 | 1.5 | 50 | 40 | |||
| 24 | 40 | 50 | 40 | 400 | 120 | 1.5 | 50 | 40 | |||
| 25 | 40 | 100 | 40 | 450 | 100 | 1.5 | 40 | 50 | |||
| 26 | 40 | 200 | 40 | 450 | 100 | 1.5 | 40 | 50 | |||
| 27 | 40 | 40 | 40 | 450 | 100 | 1.5 | 40 | 50 | |||
| 28 | 80 | 40 | 60 | 350 | 150 | 1.5 | 30 | 60 | |||
| 29 | 80 | 40 | 80 | 350 | 150 | 1.5 | 30 | 60 | |||
| 30 | 80 | 40 | 100 | 350 | 150 | 1.5 | 30 | 60 | |||
| 31 | 40 | 40 | 20 | 400 | 120 | 2 | 30 | 60 | 30 | ||
| 32 | 60 | 30 | 20 | 400 | 120 | 2 | 30 | 60 | 30 | ||
| 33 | 100 | 30 | 20 | 400 | 120 | 2 | 30 | 60 | 30 | ||
| 34 | 40 | 50 | 40 | 400 | 120 | 2 | 40 | 60 | 30 | ||
| 35 | 40 | 100 | 40 | 450 | 100 | 2 | 40 | 50 | 40 | ||
| 36 | 40 | 200 | 40 | 450 | 100 | 2 | 40 | 50 | 40 | ||
| 37 | 40 | 40 | 40 | 450 | 100 | 2 | 40 | 50 | 40 | ||
| 38 | 80 | 40 | 60 | 350 | 150 | 2 | 50 | 40 | 50 | ||
| 39 | 80 | 40 | 80 | 350 | 150 | 2 | 50 | 40 | 50 | ||
| 40 | 80 | 40 | 100 | 350 | 150 | 2 | 50 | 40 | 50 | ||
| 41 | 40 | 40 | 20 | 400 | 120 | 2.5 | 50 | 50 | |||
| 42 | 60 | 30 | 20 | 400 | 120 | 2.5 | 50 | 50 | |||
| 43 | 100 | 30 | 20 | 400 | 120 | 2.5 | 50 | 50 | |||
| 44 | 40 | 50 | 40 | 400 | 120 | 2.5 | 50 | 50 | |||
| 45 | 40 | 100 | 40 | 450 | 100 | 2.5 | 40 | 40 | |||
| 46 | 40 | 200 | 40 | 450 | 100 | 2.5 | 40 | 40 | |||
| 47 | 40 | 40 | 40 | 450 | 100 | 2.5 | 40 | 40 | |||
| 48 | 80 | 40 | 60 | 350 | 150 | 2.5 | 60 | 30 | |||
| 49 | 80 | 40 | 80 | 350 | 150 | 2.5 | 60 | 30 | |||
| 50 | 80 | 40 | 100 | 350 | 150 | 2.5 | 60 | 30 | |||
| 51 | 40 | 40 | 20 | 400 | 120 | 2 | 40 | 30 | |||
| 52 | 60 | 30 | 20 | 400 | 120 | 2 | 40 | 30 | |||
| 53 | 100 | 30 | 20 | 400 | 120 | 2 | 40 | 30 | |||
| 54 | 40 | 50 | 40 | 400 | 120 | 2 | 40 | 30 | |||
| 55 | 40 | 100 | 40 | 450 | 100 | 2 | 40 | 30 | |||
| 56 | 40 | 200 | 40 | 450 | 100 | 2 | 40 | 30 |
| 57 | 40 | 40 | 40 | 450 | 100 | 2 | 40 | 30 | |||
| 58 | 80 | 40 | 60 | 350 | 150 | 2 | 40 | 30 | |||
| 59 | 80 | 40 | 80 | 350 | 150 | 2 | 40 | 30 | |||
| 60 | 80 | 40 | 100 | 350 | 150 | 2 | 40 | 30 |
Claims (10)
1. compound interferon inducer buccal tablet, it is characterized in that every contains Avian pneumo-encephalitis virus attenuated live vaccine or 10～120 HAUs of Avian pneumo-encephalitis virus inactivated vaccine, the Radix Astragali 1～20mg, glycyrrhizin 1～10mg, adjuvant and stabilizing agent, above-mentioned adjuvant is at least three kinds among lactose 5～20mg, starch 30～45mg, dextrin 10～20mg and the magnesium stearate 0.15～0.25mg, and the aforementioned stable agent is at least two kinds among human serum albumin 2～6mg, egg white powder 3～6mg, mannitol 3～8mg and the Polyethylene Glycol 3～6mg.
2. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 10～40 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 1～4mg.
3. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～60 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 1～4mg.
4. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 60～100 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 1～4mg.
5. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 5～10mg, and glycyrrhizin is 1～4mg.
6. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 10～15mg, and glycyrrhizin is 1～4mg.
7. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 15～20mg, and glycyrrhizin is 1～4mg.
8. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 4～6mg.
9. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 6～8mg.
10. compound interferon inducer buccal tablet according to claim 1 is characterized in that wherein said Avian pneumo-encephalitis virus attenuated live vaccine or Avian pneumo-encephalitis virus inactivated vaccine are 40～80 HAUs, and the Radix Astragali is 1～4mg, and glycyrrhizin is 8～10mg.
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| WO2016057978A1 (en) * | 2014-10-10 | 2016-04-14 | Merial Inc. | Reduced foaming vaccine compositions |
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| WO2016057978A1 (en) * | 2014-10-10 | 2016-04-14 | Merial Inc. | Reduced foaming vaccine compositions |
| CN107106667A (en) * | 2014-10-10 | 2017-08-29 | 梅里亚股份有限公司 | The reduced vaccine combination of foaming |
| AU2015330716B2 (en) * | 2014-10-10 | 2018-12-06 | Abic Biological Laboratories Ltd | Reduced foaming vaccine compositions |
| US10213509B2 (en) | 2014-10-10 | 2019-02-26 | Merial Inc. | Reduced foaming vaccine compositions |
| US10610596B2 (en) | 2014-10-10 | 2020-04-07 | Abic Biological Laboratories Ltd. | Methods of making solid vaccine compositions having reduced foaming |
| CN107106667B (en) * | 2014-10-10 | 2022-03-15 | 勃林格殷格翰动物保健美国公司 | Vaccine compositions with reduced foaming |
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