CN103933562A - Use of a liquid allergy vaccine formulation for oromucosal administration - Google Patents

Abstract

The present invention relates to the use of an allergen for the manufacture of a liquid vaccine formulation for preventing or treating allergy in a subject by oromucosal administration in a dosing regimen comprising no progressive dosage.

Description

Be used for the purposes of the liquid allergy vaccine formulation of mouth mucosa drug administration

The application be that November 3, application number in 2006 are 200680045312.8 the applying date, divisional application that denomination of invention is the Chinese invention patent application of " for the purposes of the liquid allergy vaccine formulation of mouth mucosa drug administration ".

Technical field

The present invention relates to the allergy vaccine formulation for mouth mucosa drug administration.

Background of invention

The serious health problem of allergy in the country that is adaptation Western lifestyle.In addition, the prevalence rate of allergic disease day by day increases in these countries.Although conventionally do not think that allergy is life-threatening disease, asthma causes a large amount of death every year.In teenager, about 30% abnormal prevalence rate has caused the heavy losses of quality of life, working day and money, thereby becomes the class in the serious health problem in western countries.

Allergy is complicated disease.Many factors are facilitated sensitization event.One of them factor is the individual susceptibility of being determined by the interaction between the several genes that fully understand not yet so far.Another key factor is the allergenic exposure higher than some threshold value.Several envirment factors can be important in sensitization process, comprise pollution, childhood period infection, parasitic infection, enteral microorganism etc.Once individual by after sensitization and allergia immunoreation foundation, only a small amount of allergenic existence just can change into symptom effectively.

The natural history of allergic disease is accompanied by increasing the weight of in two levels conventionally.First, the progress of symptom and disease severity, and the progress of disease, for example, from pollinosis to asthma.The second, the propagation of aggressivity allergen (offending allergen) the most frequently occurs, thereby causes allergia multiple reactionness.Chronic inflammatory disease causes the generally weak of mucosal defense mechanisms, thereby causes nonspecific stimulation and the final mucosal tissue that destroys.Baby may be mainly milk allergy to food, thereby causes eczema or disorder of gastrointestinal tract; But, their these symptoms of undue growth spontaneously of the most common ground.These babies in their life afterwards in there is the danger of imbedibility allergy.

In airborne some the most general big or small granule of breathing at us, find most important allergen source.These sources are very general, comprise the faecal particles of careless pollen and house dust mite, and described material is responsible for forming all allergenic about 50% together.Animal hair scurf is that the hair scurf of cat and Canis familiaris L., pollen and for example alternaria of micromycete (Alternaria) of for example mugwort of other pollen also have global importance.But be basis taking area, other pollen can be preponderated, and for example, in Northern Europe and Central European birch pollen, at eastern united states and middle part hogweed, preponderate at Japanese Japanese cedar pollen.Insecticide, i.e. Apis and wasp venom, and food accounts for all allergenic about 2% separately.

Allergy, i.e. I type allergy, is caused by the incorrect immunoreation to external non-cause of disease material.The important clinical performance of allergy comprises asthma, pollinosis, eczema and gastrointestinal disorder.Atopic reaction is that moment breaks out and in 20 minutes, peaks after contact aggressivity allergen.In addition, atopic reaction specific individual be specific on to this meaning of the former allergy of specific degeneration, but individually not necessarily known other materials that cause allergic disease are shown to atopic reactions.Allergia phenotype be characterised in that target organ mucosa remarkable inflammation and be in circulation and on the surface of mastocyte and basophilic granulocyte, have the allergen specific antibody of IgE type.

In the time of the lip-deep high-affinity IgE specific receptor of antibodies mastocyte and basophilic granulocyte, external allergen causes allergia with reacting of allergen specific IgE antibody and attacks.Mastocyte and basophilic granulocyte comprise ready-made medium, i.e. histamine, trypsinlike enzyme and other materials, and described medium is released immediately after the IgE of two or more receptors bind is antibody linked.IgE antibody by being crosslinked in conjunction with an allergen molecule simultaneously.Therefore infer that the external allergen only with an antibodies epi-position does not cause atopic reaction.Being cross-linked of the IgE of the lip-deep receptors bind of mastocyte also causes being responsible for the release to the signal transducers of the position of atopic reaction by eosinophilic granulocyte, allergen specific T cell and other types cytotaxis.Meet with interactional this type of cell of allergen, IgE and effector lymphocyte the generation (delayed reaction) of again flashing that causes symptom after allergen for 12 to 24 hours.

The therapeutic scheme of allergic disease comprises diagnosis and treatment (comprising preventive therapy).The diagnosis of allergy relates to the confirmation of allergen specific IgE and the qualification in source, allergic effect source.Anamnesis can be enough for the diagnosis of allergy and the qualification of the allergenic source material of aggressivity in many cases.But, the most common ground, diagnosis is supported by objective measurement for example skin prick test, blood testing or provocative test.

Treatment option drops in 3 main category.The first probability is to hide allergen or reduce to expose.Although the in the situation that of food allergens for example, hiding allergen is obviously, for house dust mite allergen, it can be very difficult or expensive, for pollen allergen, is impossible.Second and the most widely used treatment option be to open the classical medicine for symptom as the prescription of antihistaminic and steroid.Safe and effective for the medicine of symptom; But they can not change the natural cause of disease, they can not control transmission of disease.The 3rd treatment option is that the specificity allergy that in most of the cases reduces or alleviate the allergic symptoms being caused by described allergen is inoculated.

Conventional specificity allergy inoculation is the causal treatment to allergic disease.It disturbs basic immunologic mechanism, thereby causes the lasting improvement of patient's immune state.Therefore, the protective effect of specificity allergy inoculation, contrary with symptomatic treatment pharmacotherapy, extend and exceed the treatment phase.Some patients that receive treatment are cured, in addition, and the alleviating of the disease severity that Most patients experience is experienced and symptom, or stopping of disease progression at least.Therefore, the inoculation of specificity allergy has the prevention of risk effect that minimizing pollinosis develops into the danger of asthma and reduces the new sensitivity of generation.

Successfully the details of allergy inoculation amynologic mechanism is behind unclear.Specific immune response, the generation of the antibody of for example anti-special pathogen, is known as adaptive immunity reaction.This reaction can be reacted and differentiate with innate immunity, and innate immunity reaction is the nonspecific reaction for pathogen.Allergy vaccine reacts for adaptive immunity, and it comprises cell and for example T cell of molecule and the productive B cell of antibody with antigenic specificity.B cell can not ripely be antibody generation sexual cell under the help that there is no corresponding specific T cell.The T cell that participates in the immunoreactive stimulation of allergen is mainly Th2 type.The foundation that has proposed the new balance between Th1 and Th2 cell is useful for vital for the immunologic mechanism of specificity allergy inoculation.This be produce due to the minimizing of Th2 cell, from the transformation of Th2 to Th1 cell or still have arguement due to what the rise of Th1 cell produced.Recently, having proposed regulatory T cells is very important for the mechanism of allergy inoculation.According to this model, regulatory T cells is Th3 or Tr1 cell, all lowers Th1 and Th2 cell corresponding to antigenic specificity.Although there is these indefinite property, it has been generally acknowledged that active vaccine must have the ability that stimulates the preferred TH1 cell of allergen specific T cell.

Although exist it to be worth, main because of two reasons, the inoculation of specificity allergy is not used widely.A reason is and is included in the inconvenience that in several months, the conventional vaccine program of for example (i.a.) injection of inoculation is relevant repeatedly.Another reason (prior) is the risk of allergia side reaction.Use single or minority several times the immunity inoculation of high dose can effectively carry out the common inoculation of infection agent.But this strategy can not be used for allergy inoculation, because pathology immunoreation is underway.

Thereby use the repeatedly subcutaneous inoculation inoculation using within the long-time time limit to carry out conventional specificity allergy inoculation.This process is divided into two periods, increases dosage phase and maintenance phase.Increasing, dosage is interim, conventionally within the period of 16 weeks, brings into use ever-increasing dosage from low dose.In the time reaching the maintenance dose of recommendation, this dosage, for maintenance phase, is injected 1 time conventionally for every 6 weeks.After each injection, due to the risk of anaphylaxis side reaction, patient must keep 30 minutes under medical treatment and nursing, although described anaphylaxis side reaction is quite rare in principle, and can life-threatening.In addition, should be equipped with clinical with support first aid process.Certainly, the vaccine based on different way of administration can be removed or reduce the risk of the intrinsic allergia side reaction of the current vaccine based on subcutaneous and contribute to it to use widely, even may make it possible to oneself's inoculation at home.

Over more than 30 year, carrying out improving the effort for the vaccine of specificity allergy inoculation always, and comprising several different methods.Several methods by change IgE reactivity and for allergen itself.Additive method is for route of administration.

Can arrive immune system by allergenic oral cavity and sublingual administration is known route of administration.Can be by bacterin preparation be placed in to Sublingual, then make it remain on this place and for example within about 2 minutes, carry out administration blink.

Use the conventional allergy vaccine of oral mucosa approach by the allergen solution composition that reaches daily dose.By comparing, given therapeutic (accumulation) maintenance dose is than high times of the maintenance dose of subcutaneous treatment.Known mouth mucosa drug administration does not cause or only causes little side effect, the side effect mainly existing with the form of scratching where it itches in mouth and sometimes scratch where it itches in E & E.

WO04/047794 discloses the rapid dispersion dosage form for the sublingual administration of allergy vaccine.

For be purchased the allergen that obtainable allergy vaccine comprises the liquid mixture that is dissolved in 50% glycerol and 50% water with drop form sublingual administration a kind of.

Use dosage regimen routine to use and be purchased the obtainable liquid allergy vaccine for sublingual administration, described dosage regimen comprises the dosage phase that increases, be generally administration every day of 10 to 20 days, wherein dosage is increased to maintenance dose level gradually, then be maintenance phase, wherein patient accepts maintenance dose.Recently, so-called impact by realizing in a few hours within a couple of days, in one day or has even been studied in much research to be increased dose therapies and increases the probability of dosage, wherein use ever-increasing dosage, between administration, only pass through for example 1 hour or the 2 hours very short time each time.But such impact increases dose therapies and has unfavorable aspect: can not get rid of the generation of serious side effect, thereby the same with subcutaneous administration, it needs allergy expert's monitoring.

The object of the invention is to provide by mouth mucosa drug administration the modification method of prevention or treatment experimenter's allergy.

Summary of the invention

Conventionally the present invention obtains this object, this object relates to the purposes of allergen for the preparation of liquid vaccine preparation, the allergy of described bacterin preparation for preventing or treat experimenter by the mouth mucosa drug administration of dosage regimen, described dosage regimen does not comprise increase dosage, can use maintenance dose by for example standard dosage regimen by maintenance phase and carry out initial treatment.

The present invention is based on clinical trial, described clinical trial shows the allergy inoculation that can use the mouth mucosa drug administration of liquid preparation in the situation that not using increase dosage, the side reaction that simultaneously keeps acceptable level surprisingly.This discovery is thinking during the increase dosage of some types that being in the necessary meaning of side effect of avoiding serious is astonishing so far always.

Avoid the probability that increases the dosage phase also to provide together and there is the dosage regimen of making favourable aspect simply too much in the oral mucosa therapy that uses liquid vaccine preparation.In addition, simple dosage regimen has increased patient's treatment compliance.

Detailed Description Of The Invention

allergen

The allergen of preparation of the present invention can be to be reported in it repeatedly individuality to be exposed to any naturally occurring protein that rear induction atopic reaction is the reaction of IgE mediation.Naturally occurring allergenic example comprises pollen allergen (pollen allergen of tree, medical herbs, weeds and grass), insecticide allergen (inhalant, saliva and venom allergen, such as mite allergen, Blatta seu periplaneta and midge allergen, hymenopteran (hymenopthera) venom allergen), animal hair and scurf allergen (locating such as Canis familiaris L., cat, horse, rat, mice etc.) and food allergens.From tree, the important allergen of the pollen of grass and medical herbs is to derive from Balanopsidales, sweet-scented osmanthus order, pine China fir order and Platanaceae (comprise for example birch (Betula), alder (Alder), hazel (Corylus), hornbeam (Carpinus) and Fructus Canarii albi (Olea), Cortex Cryptomeriae Fortunei Radicis (Cryptomeria and Juniperus Linn.), outstanding bell (plane)), Poales (comprises for example Lolium, ladder forage spp, annual bluegrass (Poa), Cynodon, orchardgrass, Holcus, phalaris arundinacea, the grass of rye (Secale cereale L.) and sorghum), chrysanthemum order and Urticales (comprise for example Ambrosia, the medical herbs of Herba Artemisiae annuae and Parietaria) taxonomy object pollen.Other important inhalant allergens are from Dermatophagoides and have a liking for mould demodicid mite genus, storeroom dirt demodicid mite is for example had a liking for slag demodicid mite and belongs to (Lepidoglyphys), the allergen of the house dust mite of Glyciphagus and Tyrophagus, from Blatta seu periplaneta, such as Blatella of midge and flea, Periplaneta, the allergen of Chironomous and Ct and from such as cat of mammal, the allergen of Canis familiaris L. and horse, venom allergen (comprises that for example classification comprises Apis (Apoidea) to the venom that derives from acupuncture or biting insects from Hymenoptera, wasp (Vespoidea), and the venom of Formica fusca (Formicoidea)).The important inhalant allergen from fungus and mycete is the inhalant allergen who for example derives from alternaria and Cladosporium.

In particular of the present invention, allergen is Bet v1, Aln g1, Cor a1 and Car b1, Que a1, Cry j1, Cry j2, Cup a1, Cup s1, Juna1, Jun a2, jun a3, Ole e1, Lig v1, Pla l1, Pla a2, Amb a1, Amb a2, Amb t5, Art v1, Art v2Par j1, Par j2, Par j3, Sal k1, Ave e1, Cyn d1, Cyn d7, Dac g1, Fesp1, Hol l1, Lol p1 and 5, Pha a1, Pas n1, Phl p1, Phl p5, Phl p6, Poa p1, Poa p5, Sec c1, Sec c5, Sor h1, Der f1, Der f2, Der p1, Der p2, , Der p7, Der m1, Eur m2, Gly d1, Lep d2, Blo t1, Tyr p2, Bla g1, Bla g2, Per a1, Fel d1, Can f1, Can f2, Bos d2, Equ c1, Equ c2, Equc3, Mus m1, Rat n1, Apis m1, Api m2, Ves v1, Ves v2, Ves v5, Dol m1, Dil m2, Dol m5, Pol a1, Pol a2, Pol a5, Sol i1, Sol i2, Sol i3and Sol i4, Alt a1, Cla h1, Asp f1, Bos d4, Mal d1, Gly m1, Gly m2, Gly m3, Ara h1, Ara h2, Ara h3, Ara h4, Ara h5 or from reorganization (shufflant) hybrid of any these allergenic molecular breedings.

In a preferred embodiment of the invention, allergen is selected from the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

In another embodiment of the invention, preparation comprises at least two kinds of different types of allergens that derive from identical allergen source or derive from different allergen sources, for example, respectively from different demodicid mites and grass product kind the 1st group grass allergen and the 5th group of grass allergen or the 1st group of mite allergen and the 2nd group of mite allergen, weeds antigen is as short and huge hogweed allergen, different fungus allergens are as alternaria and Cladosporium allergen, tree allergen is as birch, Semen coryli heterophyllae, hornbeam, Oak Tree and alder allergen, food allergens is as Semen arachidis hypogaeae, Semen sojae atricolor and milk allergen.

The allergen being integrated in preparation can exist with the form of the mutant of the allergen of the allergen of extract, purification, improvement, recombinant allergen or recombinant allergen.Allergenic extract can naturally comprise identical allergenic one or more of isotypes, but recombinant allergen only represents a kind of isotype of mutagen conventionally.Allergen exists with the form of extract in preferred embodiments.In a further preferred embodiment, allergen is recombinant allergen.In present invention further optimization embodiment, allergen is naturally occurring low IgE in conjunction with mutant or the low IgE that recombinates in conjunction with mutant.In addition, allergen can be for example 2 to 10 kinds of allergens of many allergens, 3 to 9 kinds of allergens especially, more particularly 4 to 8 kinds and 5 to 7 kinds of allergenic mixture the most especially.

The allergenic variable-scale that allergen can exist or exist with equimolar amounts, preferably equals 1:20.

In further embodiment of the present invention, low IgE is the allergen of WO99/47680, WO02/40676 or WO03/096869A2 in conjunction with allergen.

Wish that for the preferred usefulness of the single dose preparation of administration every day be 1 to 2000STU, more preferably 50 to 1000STU, and more preferably 100 to 500STU, and more preferably 130 to 350STU and most preferably 150 to 250STU.

Wish that for the preferred usefulness of the single dose preparation of administration every day be 100 to 500000SQ-u, more preferably 200 to 300000SQ-u, more preferably 500 to 200000SQ-u, and more preferably 1000 to 100000SQ-u, and more preferably 1500 to 80000SQ-u and most preferably 2000 to 50000SQ-u.

Depend on consumingly the variation of allergenic kind and change corresponding to the allergenic amount of given effect level.In further embodiment of the present invention, the main allergenic concentration of wishing the single dose that is used for administration every day is 0.05 to 50 μ g, more preferably 0.05 μ g to 30 μ g, more preferably 0.06 μ g to 25 μ g, more preferably 0.07 μ g to 20 μ g, more preferably 0.08 μ g to 15 μ g, more preferably 0.09 μ g to 10 μ g and more preferably 0.1 μ g to 7 μ g.

mouth mucosa drug administration method

Carrying out allergen administration by oral cavity and Sublingual, can to arrive immune system be known route of administration.Can carry out for example 30 to 300 seconds blink by bacterin preparation being placed in to Sublingual and allowing it be retained in this place, preferably 45 to 240 seconds, more preferably 60 to 180 seconds, more preferably 90 to 150 seconds and most preferably within 90 to 120 seconds, carry out administration.

Mouth mucosa drug administration method comprises any medication, and wherein preparation partially or completely contacts with patient's oral cavity and/or the mucosa of laryngopharynx portion.Mouth mucosa drug administration method comprises sublingual administration and buccal administration.

In one embodiment of the invention, experimenter's experience is comprised to the vaccination regimen of vaccine administration once a day.In another embodiment of the invention, vaccination regimen comprises every 2 days once, every 3 days once or every 4 days one time vaccine administration.For example, vaccination regimen comprises and exceedes 4 time-of-weeks, preferably exceedes 8 weeks, more preferably exceedes 12 weeks, more preferably exceedes 16 weeks, more preferably exceedes 20 weeks, more preferably exceedes 24 weeks, more preferably exceedes 30 weeks and most preferably exceedes the vaccine administration of 36 weeks.

The administration phase can be continuous period.Selectively, the administration phase is by discontinuous period disconnected during one or more non-administration.Preferably, (total) is non-gives (total) the administration phase that is shorter than.

In further embodiment of the present invention, once a day patient is used to vaccine.Selectively, twice patient is used to vaccine every day.Vaccine can be single dose vaccine.

liquid vaccine preparation

Liquid vaccine preparation of the present invention can further comprise any adjuvant and other excipient of being suitable for this type of preparation.This type of excipient is known to those skilled in the art, and it comprises such as solvent, emulsifying agent, wetting agent, plasticizer, coloring material, filler, antiseptic, viscous regulator, buffer agent, pH adjusting agent, isoosmotic adjusting agent, mucosa adhering substance etc.Preparing tactful example knows to those skilled in the art.

Adjuvant can be any conventional adjuvant, comprise oxygen metal salt, for example liposome of aluminium hydroxide, heat-labile toxin (LT), cholera toxin (CT), choleratoxin B subunit (CTB), polymerization, for example LTK63 of mutant toxin and LTR72, microcapsule, interleukin (for example IL-1 β, IL-2, IL-7, IL-12, INF γ), GM-CSF, MDF derivant, CpG ODN, LPS, MPL, phosphazo (phosphophazene), , glucosan, antigen preparation, liposome, DDE, DHEA, DMPC, DMPG, DOC/ Alumen complex, Fu Shi Freund's incomplete adjuvant, , LT Oral adjuvant, muramyldipeptide, monophosphoryl lipid A, muramyl-tripeptide and PHOSPHATIDYL ETHANOLAMINE.

The aqueous solution of oxygen metal salt has gel form conventionally.Preferably 0.035-1000mg/ml of the concentration of aluminium hydroxide in preparation, more preferably 0.10-100mg/ml, more preferably 0.25-10mg/ml and most preferably 0.5-5mg/ml.But preparation of the present invention also can have highly concentrated gel form or gel sample preparation.

In particular of the present invention, preparation of the present invention also comprises reinforcing agent.Reinforcing agent is the material that increases the bioavailability of pharmaceutically active substance, it passes through i) to increase active substance through biomembrane by opening paracellular pathway (closely connecting), increases absorption and/or the ii of active biomass) the bioadhesion effect of reinforcing agent by increasing soak time increases bioavailability.

The example of reinforcing agent is for example ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide, acetic acid dimethylamide preferably glycerine of alcohols.Reinforcing agent is preferably with 20% to 80% (v/v), and more preferably 30% (v/v) be to 70% (v/v), and most preferably 40% (v/v) exists to the amount of 60% (v/v).

Can, by adjuvant and other excipient (if necessary) are dissolved in solvent preferred water, add allergen, then allow allergen and adjuvant and other excipient reaction a period of time prepare preparation of the present invention.Response time can be 0.1 to 48 hour, preferably 12 to 24 hours.Preferably, at 4 to 45 DEG C, more preferably at the temperature of 4 to 20 DEG C, react.

oxygen metal salt

In a preferred embodiment of the invention, liquid vaccine preparation of the present invention comprises oxygen metal salt adjuvant.Preferably, the metal cation of oxygen metal salt is selected from Al, K, Ca, Mg, Zn, Ba, Na, Li, B, Be, Fe, Si, Co, Cu, Ni, Ag, Au and Cr.

The anion of oxygenatedchemicals can be any oxo-anions, comprises mixture organic or inorganic anion or organic or inorganic anion.The example of suitable oxygen metal salt be for example wherein anion be selected from sulfate radical, hydroxyl, phosphate radical, nitrate anion, iodate, bromate, carbonate, hydrate (hydrate), acetate, citrate, oxalate and tartrate anion with and the oxygen metal salt of mixed form.Oxygen metal salt also comprises co-ordination complex.The Handbook of Chemistry and Physics for example the 56th edition, Section B, has provided the definition of co-ordination complex in Chapter7 (197576).

In this description, express " mixed form " and wish to comprise the mixture of different aniones and the mixture with for example chloride and sulfide.

The example of oxygen metal salt of the present invention is aluminium hydroxide, aluminum phosphate, aluminum sulfate, aluminum acetate, aluminium potassium sulfate, calcium phosphate, Calcium d-tartrate, Maalox (mixture of aluminium hydroxide and magnesium hydroxide), beryllium hydroxide, zinc hydroxide, zinc carbonate, zinc sulfate and barium sulfate.

Most preferably aluminium hydroxide, aluminum phosphate, aluminum acetate, calcium phosphate, Calcium d-tartrate and zinc sulfate.

The pI of oxygen metal salt is conventionally in the scope of 2-11.The pI of allergen protein is conventionally in the scope of 4-9.Preferably, select like this allergen and oxygen metal salt so that allergenic pI lower than the pI of oxygen metal salt.

In the time using that for example aluminium hydroxide is as oxygen metal salt, preferably 0.035-1000mg/ml of the concentration of aluminium hydroxide in preparation, more preferably 0.10-100mg/ml, more preferably 0.25-10mg/ml and most preferably 0.5-5mg/ml.For other oxygen metal salt, preferably 0.035-1000mg/ml of the concentration of slaine, more preferably 0.35-100mg/ml, more preferably 0.7-50mg/ml and most preferably 1.0-20mg/ml.Preferably 0.01-100mg/ml of allergenic concentration in preparation, more preferably 0.1-10mg/ml.The allergenic ratio of oxygen metal salt pair preferably 0.1 to 100, more preferably 1 to 20.The degree that allergen is adsorbed to oxygen metal salt is generally 5 to 99% of addition, and more preferably 10 to 99%.Allergen to the absorption of oxygen metal salt depends on buffer system and residing reaction condition occurs in absorption, comprises temperature and response time.

Coordination, electronic configuration, quantivalence, bonding orbital and antibonding orbital, storage properties, adhesiveness, surface character, particle characteristic and the adjuvanticity of the ionic charge that can measure as absorption, solubility and dissolution character, with the form of isoelectric point, IP pI (for dissociable compound, the net charge of material is the pH of 0 o'clock) by many physical-chemical parameters, dissociation constant, complex characterize oxygen metal salt.

It is believed that biological active agents is adsorbed (or coupling) to oxygen metal salt, this absorption promotes effect of vaccine.Several factors are important for the absorption between active substance and oxygen metal salt or affect this absorption (referring to people such as such as P.M.Callahan, Pharmaceutical Research the 8th volume, No.7,851-858 (1991), and Vaccine Design.The Subunit and Adjuvant Approach).This type of factor comprises concentration, container, temperature, storage, buffer agent and the excipient of different component in time span that pH, adsorption reaction carry out, mixing condition, vaccine.The absorption of further finding active substance can be subject to the net charge/total electrical charge of slaine and the electric charge of active substance (both pH is dependent) impact.It is believed that important further feature is the solubility of oxygen metal salt.

Thereby thereby another feature of oxysalt is the protective effect to active substance by keep desirable pH to prevent acid degradation or material can be delivered produce by prolection material opposing enzymatic degradation for the active substance in microenvironment.

In addition, some oxygen metal salt have buffer capacity.This can cause producing prolection material and avoid microenvironment in the body in the bacterin preparation of degradable environment degradable.

The further feature of oxygen metal salt is its ability that is attached to mucosa.This ability it is believed that increases allergen by the absorption of mucosa.

For example, for several oxygen metal salt (Al (OH) 3, AlPO4, Ca3PO4), granular size scope is between 0.5 and 15 μ m.

Definition

Term " mouth mucosa drug administration " refers to such route of administration, in this route of administration, by dosage form be placed in Sublingual or oral cavity any other place so that active component contact with patient's oral cavity or the mucosa of laryngopharynx portion, thereby obtain part or the general effect of active component.The example of mouth mucosa drug administration approach is sublingual administration.

Term " sublingual administration " refers to that wherein part in order to obtain active component or general effect are placed in dosage form the route of administration in Sublingual.

Term " non-increase dosage " refers to that administration from the beginning is just used full dose and continues use full dose later, and wherein term " full dose " refers to the dosage for continual cure.

Term " liquid vaccine preparation " refers to any liquid or fluid preparation, comprises solution, suspension and has the gel of low and high viscosity.

Term " SQ-u " refers to standardized mass unit (Standardised Quality-Unit): according to ALK-Abell ó A/S s " SQ biopotency "-standardized method definition SQ-u, wherein 100,000SQ unit equals the subcutaneous maintenance dose of standard.Conventionally 1mg extract comprises 100,000 to 1,000, and 000SQ-unit depends on the allergen source of their origins and the preparation method using.Can determine that accurate allergen content is total main allergen and total allergenic activity by immunoassay.

Term " treatment " refers to partially or completely healing, mitigation symptoms or suppresses the cause of disease of symptom.

Term " prevention " refers to the preventive therapy of any type.

In the field of allergy extract, there is no internationally accepted standardized method.Having many different extract volume units is biopotency.The method using and the unit of use measure allergen content and biologic activity conventionally.About this, the example of any is SQ-unit (Standardization Quality unit), BAU (allergic effect source unit biology), BU (biological unit), UM (mass unit), IU (iu) and IR (reactivity indexes).Therefore,, if use the extract in non-source disclosed herein, need so them extract standardization disclosed herein to determine its usefulness with SQ unit or above mentioned any unit representation.Theme of the present invention is about " allergenic extract ", the people such as H.Ipsen, chapter20in Allergy, principle and practise (Ed.S.Manning) 1993, Mosby-Year Book, St.Louis and h. (1980) Arb Paul Ehrlich Inst75:122.

The biopotency (being allergenic activity in body) of given extract depends on many factors, the most important thing is main allergenic content in extract, and described content changes with the composition of biological origin material.

Change with the Change of types of described extract with the amount for the allergenic extract that obtains the biopotency of wanting gram representing, and for the extract of given type, the amount of allergenic extract aspect the actual biopotency of extract with batch difference change.

For given extract batch, can use following method be identified for obtaining the biopotency wanted with a gram amount for the allergenic extract representing:

A) determine the not commensurability biopotency with reference to extract by setting up with one or more of immunology in vivo tests with reference to the relation between biopotency and the amount of extract.The example of described immunology in vivo test is skin prick test (SPT), conjunctiva provocative test (CPT), use allergenic brinchial provocation test (Bronchial Challenge with Allergen) (BCA) and various clinical trials that wherein one or more of allergy symptoms are monitored, referring to people such as such as Haugaard, J Allergy Clin Immunol, the 91st volume, No.3, pp709-722, March1993.

B) biopotency based on setting up and with reference to the relation between extract, takes into account the effect, the ii that i) treat or alleviate the symptom of allergy) side effect and the iii that record in immunology in vivo test) i) and ii) individuality between the balance of factor of variability select the biopotency for the one or more of relevant dose of dosage form of the present invention.Carry out balance and do not experience unacceptable side effect level to obtain maximum enough treatment effects.Described in balance, the method for factor is known to those skilled in the art.

Can for example, represent the biopotency of one or more relevant dose of finding with any obtainable biopotency unit (SQ unit, BAU, IR unit, IU, with reference to above).

C) from prepare with reference to extract one or more of biopotency reference standard extracts and, if used, biopotency unit value based on being dispensed to one or more relevant dose calculates the biopotency unit value of reference standard extract, for example, the standard of such BAU can obtain from FDA as illustrational below.

D), for the reference standard extract of each extract type, select many for evaluating the parameter of biopotency of extract.The example of this type of evaluating is the bulk molecule composition of total allergy activity, definite main allergenic amount and extract.Can use external competition immunoassay for example ELISA and luminescence immunoassay (LIA), uses the standardized mixtures of antibodies (antibody for example producing in mice or rabbit) of the extract generation obtaining by standard method or allergia patients serum's mixture to measure total allergenic activity.Can for example pass through quantitatively main allergenic content of rocket immunoelectrophoresis (RIE), then by this content and reference standard comparison.Can use for example crossed immunoelectrophoresis (CIE) and sodium lauryl sulphate: polyacrylamide gel electrophoresis (SDS-PAGE) checks total molecular composition.

E) for the extract (tested extract) of biopotency the unknown of given batch, can be identified for as follows the amount (for the effective dose of solid dosage forms of the present invention) of the extract that obtains the biopotency level of wanting: for each evaluating of selecting, use above-mentioned relevant measurement method by tested extract and the comparison of reference standard extract, then calculate the amount of the extract with the biopotency of wanting based on measurement result.

SQ-unit: according to ALK-Abell ó A/S s " SQ biopotency "-standardized method determines SQ-unit, wherein 100,000 SQ units equal the subcutaneous maintenance dose of standard.Conventionally the extract of 1mg comprises 100,000 to 1,000,000SQ-unit, depend on they spread out from allergen source and the preparation method using, can determine accurate allergenic amount by immune survey method, i.e. total main allergen content and total allergenic activity.

STU represents specific treatment unit, and STU is the regnancy of the biologic activity of the allergenic extract separately based on for the inoculation of allergen specific allergy.1000STU is corresponding to the usefulness of the high maintenance dosage for liquid dosage form (for SLIT), and wherein maintenance dose is the dosage that obtains maximum security/effect ratio in allergia patient's average colony of recommending in the inoculation of specificity allergy.

BAU (allergen unit's biology) is for " Quantitative determination of relative potency of allergenic extracts " (" Methods of the allergen products testing Laboratory " " ELISAcompetition assay " .Page15 according to FDA, #49N-0012, FDA, October1993) in the definite biological efficiency unit of requirement of allergen product described.The content of the 2600-4700BAU that the dosage of the careless extract that comprises 100,000 SQ-units equals to obtain according to the method described above.Equally, can assess according to the method described above other extracts.

Detailed description of the invention

embodiment 1:without increase dosage Sublingual immunotherapy (SLIT) ( the therapeutic scheme of)-Xin

Introduction

In several years in the past, carry out several research, used Sublingual immunotherapy (SLIT) to produce the evidence (1) in conjunction with effect of favourable security feature.

For make patient obtain high-caliber automedication therapy as effect, compliance must very high (2).The basis of supposing compliance is convenience, will improve relatively this character of product.The good toleration of SLIT has caused considering to eliminate the probability that increases the dosage phase.This will improve patient's convenience, thereby can increase compliance and increase potentially therapeutic efficiency.This research design for assessment of in the situation that not increasing dosage, have the toleration in the patient of demodicid mite or grass sensitivity.

Materials and methods

medicament

(ALK-Abell ó) is the single dose liquid preparation of the solution that comprises the allergen dosage that 0.2ml contains 200STU, and wherein solution is 50% (v/v) glycerol and 50% (v/v) water.

patient

Altogether comprise 135 patients (66 grass and 69 demodicid mite allergia patients), the age 7 and 55 years old between, due to demodicid mite or careless sensitivity, it is all diagnosed with medium serious rhinitis or the nose binding film inflammation/do not have with symptoms of asthma.By positive skin prick test (prick test, ALK-Abell ó, S.A., 100BU/ml) and/or positive IgE, (2 grades of product of CAP >=pharmacy (pharmacy class2) are diagnosed.Recommend (3) according to WHO, test do not comprise wherein patient that taboo uses immunotherapy and treat, patient to the allergen sensitivity except the allergen of assessing in this test and before accepted the patient of immunotherapy.

research design

Research is that random, multicenter, double blinding, placebo compare, parallel group of research.Total duration is 80 days.

Patient is divided into 2 groups.Group 1 (N=69) accepts active treatment in whole research process.This research comprise 10 days increase dosage (T1), 20 days maintain treatment (T2) and maintaining the successive stages (T3 and T4) of two 30 day persistent period in treatment.Group 2 (N=66) accept placebo during T1 increases dosage, maintains, and in the time that T3 starts, start to carry out active treatment and proceed active treatment until research finishes (T4) at the placebo of T2.During in the time of baseline with at T1 to T4, collect data.Each patient receives the card that has wherein recorded any clinical events relevant to each therapeutic dose.Researcher has been pointed out adverse events in case report form.

Research is double blinding, and blind property can be interrupted at no time, until after having studied.All patients start to participate in having signed informed consent before test at them.Research has obtained and has participated in the Ethics Committee at center and the approval of health authority.

treatment

Will (ALK-Abell ó) carries out sublingual administration, and its extract by the mixture of demodicid mite extract (dermatophagoides pteronyssinus or dermatophagoides pteronyssinus (Dermatophagoides pteronyssinus)+dermatophagoides farinae) or grass (orchardgrass, grassy marshland fescue grass, rye grass, timothy grass, English grass, rye (Secale cereale L.)) forms.Treatment increased dosage (start from 1, be increased to 10) by 10 days that use multidose vial and uses the maintenance phase composition of single dose container.Carry out single administration every day.The main allergenic dosage of using in each single dose container is the main antiallergic agent 5 (for grass) of 2 μ g and the Der1/Der2 (for demodicid mite) of 0.8/0.4 μ g.

Outward appearance, the aroma and flavor of comfort therapeutic agent are similar to active therapeutic agent.

statistics

Use descriptive statistics.Description comprises patient's number (N), the patient's of the AE of experience percent (%) and people's order (E) of AE of report adverse events (AE).

Result

In 135 patients that add, 123 have completed research.Patient's feature is shown in table 1.Patient's age, the mean age of two treatment groups was 22 years old from 7 to 55 years old.

With in group 2 33 accept careless extract and accept demodicid mite extract and compare with 33, in group 1,36 patients accept careless extract, accept demodicid mite extract for 33.229 routine AE are altogether reported; 157 routine AE (group 1 and group have respectively 68 and 89 in 2) by researcher be evaluated as to treat relevant, thereby be included in analysis.The most often report to the relevant AE (patient of >5% in any group) for the treatment of be mouthful itch, ophthalmic pruritus, rhinitis and Sublingual edema (table 2); These events have occupied 57.3% of all relevant AE altogether.It is the AE relevant to treatment the most often reporting that mouth is itched; Reported that with 21 patients (31.8%) in group 2 39 example mouths itch compared with events, in group 1,16 patients (23.2%) have reported the 28 example mouths events of itching.It is the unique AE that exceedes 10% patient report in arbitrary group that mouth is itched, and it occupies 42.7% of all events altogether.

The total degree of the SLIT dosage of using in group 1 and group 2 is respectively 6258 and 6081 times.By time (T1-T4) every application dosage the mouth ratio of itching be shown in table 3.

About the patient of≤14 years old (child) and >14 year (teenager and adult) patient's the AE display list 4 relevant to treatment of the most often report in.

5 patients are because adverse events exits altogether.In group 1,3 experimenters are respectively owing to having a headache in the T1 stage, exiting in T1 stage asthma, rhinitis and pruritus with in T4 stage Sublingual edema.In group 2,2 experimenters are respectively due to dyspnea and cough in the T2 stage with at T4 stage tongue with saliva is swollen exits.

Discuss

The object of parallel group of research of this randomized double-blind placebo-controlled contrast is the toleration of the investigation SLIT that use every day without the initial increase dosage phase in the situation that.Result provided herein shows (grass and demodicid mite) tolerated well, and toleration is not increased the elliptical of dosage phase and affects.Accept the active dosage that increases with group 1() compared with, group 2(accepts placebo increases dosage) in patient's number of report AE some more a little, be also like this to the number situation of event.But it should be pointed out that (T1 and T2), has reported a large amount of events during placebo treatment in group 2.The most often the AE of report is that mouth is itched.To itch be expection and the side effect that know of Sublingual immunotherapy to mouth, and the mouth of report higher that degree and the identical of other authors (4-7) report or the frequency of mouthful itching report other authors of itching.

The use that increases dosage in SLIT is experimental and based on convention, and may come according to increasing transformation for the necessary progressively dosage of subcutaneous inoculation therapy.From clinical trial (4 before; 6) and the data of pharmacovigilance Journal of Sex Research (7) show the good toleration of SLIT, but will increase recently the dosage phase, the impact of toleration is proposed to discuss.In SLIT, increasing may affecting of dosage infers.The effect of supposing to increase in SLIT dosage is that this hypothesis of digital proof so provided herein is wrong for increasing the patient of safely use maintenance dose after dosage.Patient's number that report mouth is itched in T3 stage (in the time starting active treatment with maintenance dose) group 2 is more the people in T1 stage than group 1, but patient's number that in organizing 1 in the T2 stage, report mouth is itched is similar, on this T2 phases-time, the effect that increases the supposition of the toleration of dosage phase to patient should ensure that number report mouthful still less itches.The mouth of every application dosage is itched frequency that ratio also shows these event reports in the group 1 in T2 stage and is identical in the group 2 in T3 stage.In addition,, when in two groups relatively first 30 days of active treatment (for group 1, T1+T2 with for group 2, T3), the mouth of the every application dosage cumulative percentage of itching is respectively 0.83% and 0.74% for group 1 and group 2.This research do not allow the report that boil on the nape opposite the mouth is itched whether pass in time and reduce and make any definite conclusion compared with the short persistent period.But relatively few the exiting of observing shows intensity and the persistent period troublesome that patient does not think that mouth is itched.

Many in the frequency ratio group 1 of Sublingual edema report in group 2.In the time implementing active treatment, (T3 and T4) reported the event of the type in group 2, and is resolved in 3 days at 1 hour.Patient after the active treatment of minimum 30 days in the T4 stage because this AE exits research.In group 1, also report Sublingual edema in the T4 stage.

In the time that the mouth in child and teenager and adult is itched to comparison, according to data, seem mouth is itched in child report than more frequent in teenager and adult.Its reason is unclear, but it is the problem of further studying.But the number exiting in child and teenager and adult's the number that exits does not have difference.In addition, exiting in child (N=2) itched irrelevant with mouth.

In a word, these results of study show (demodicid mite and grass) has good toleration, and can carry out initial treatment safely and without increase the dosage phase.

List of references

(1)Wilson?DR,Torres?LM,Durham?SR.Sublingual?immunotherapy?for?allergic?rhinitis:systematic?review?and?meta-analysis.Allergy2005;60(1):4-12.

(2)Osterberg?L,Blaschke?T.Adherence?to?medication.N?Engl?J?Med2005;353(5):487-497.

(3)Bousquet?J,Lockey?RF,Malling?HJ.WHO?Position?Paper.Allergen?immunotherapy:Therapeutic?vaccines?for?allergic?diseases.Allergy1998;53(44):1-42.

(4)Pajno?GB,Morabito?L,Barberio?G,Parmiani?S.Clinical?and?immunologic?effects?of?long-term?sublingual?immunotherapy?in?asthmatic?children?sensitized?to?mites:a?double-blind,placebo-controlled?study.Allergy2000;55(9):842-849.

(5)Canonica?GW,Passalacqua?G.Noninjection?routes?for?immunotherapy.J?Allergy?Clin?Immunol2003;111(3):437-448.

(6)Quirino?T,Iemoli?E,Siciliani?E,Parmiani?S,Milazzo?F.Sublingual?versus?injective?immunotherapy?in?grass?pollen?allergic?patients:a?double?blind(double?dummy)study.Clin?Exp?Allergy1996;26(11):1253-1261.

(7)Di?Rienzo?V,Pagani?A,Parmiani?S,Passalacqua?G,Canonica?GW.Post-marketing?surveillance?study?on?the?safety?of?sublingual?immunotherapy?in?pediatric?patients.Allergy1999;54(10):1110-1113.

Table 1: patient characteristic

Table 2: the most often relevant AE (>5% in any group) for the treatment of of report

The most often percent (%), the number (E) of event and the time of reporting of the patient's of the adverse events of report number (according to the patient of >5% in any group), cohort body of report in two treatment groups.Group 1 is accepted active treatment from T1-T4, and group 2 is accepted placebo during T1 and T2.Just repeatedly report that the patient of the adverse events of same type revises patient's sum.

Table 3. is by the mouth ratio (%) of itching of every application dosage of report time

E: the itch number of event of mouth

According to report time, the mouth of the every application dosage in the adverse events (mouthful itch) of the most often report ratio (%) of itching.

Table 4., according to the age, has the most often patient's of the adverse events relevant to treatment of report number

According to the age, there is the most often patient's of the adverse events relevant to treatment of report number.

Specific embodiment of the invention scheme comprises:

1. allergen is for the preparation of the purposes of liquid vaccine preparation, described bacterin preparation does not comprise adjuvant, for the allergy that prevents or treat patient by mouth mucosa drug administration, wherein said liquid vaccine preparation comprises and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide.

2. the purposes of embodiment 1, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

3. the purposes of embodiment 1 or 2, wherein said mouth mucosa drug administration is sublingual administration.

4. the purposes of embodiment 3, wherein said reinforcing agent is selected from: ethanol, propylene glycol and glycerol.

5. the purposes of embodiment 4, wherein said reinforcing agent is glycerol.

6. the purposes of any one in foregoing embodiments, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

7. the purposes of embodiment 6, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

8. the purposes of embodiment 7, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

9. the purposes of embodiment 8, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.07 μ g to 20 μ g.

10. the purposes of embodiment 9, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The purposes of 11. embodiments 10, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The purposes of 12. embodiments 11, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

The purposes of any one in 13. foregoing embodiments, wherein said liquid vaccine preparation is non-increase dosage dosage form, and wherein said mouth mucosa drug administration is the form that does not comprise the dosage regimen that increases dosage.

14. allergens are for the preparation of the purposes of liquid vaccine preparation, described bacterin preparation is non-increase dosage dosage form and does not comprise adjuvant, for not comprising that increasing the dosage regimen of dosage prevents or treat the allergy in patient by mouth mucosa drug administration, wherein said liquid vaccine preparation comprises and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide.

The purposes of 15. embodiments 14, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

The purposes of 16. embodiments 14 or 15, wherein said mouth mucosa drug administration is sublingual administration.

The purposes of 17. embodiments 16, wherein said reinforcing agent is selected from: ethanol, propylene glycol and glycerol.

The purposes of 18. embodiments 17, wherein said reinforcing agent is glycerol.

The purposes of any one in 14-18 in 19. embodiments, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

The purposes of 20. embodiments 19, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

The purposes of 21. embodiments 20, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

The purposes of 22. embodiments 21, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.07 μ g to 20 μ g.

The purposes of 23. embodiments 22, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The purposes of 24. embodiments 23, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The purposes of 25. embodiments 24, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

26. liquid vaccine preparations for mouth mucosa drug administration, described liquid vaccine preparation contains allergen and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide, described liquid vaccine preparation does not comprise adjuvant.

The liquid vaccine preparation of 27. embodiments 26, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

The liquid vaccine preparation of 28. embodiments 26 or 27, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

The liquid vaccine preparation of any one in 29. embodiment 26-28, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

The liquid vaccine preparation of any one in 30. embodiment 26-29, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

The liquid vaccine preparation of any one in 31. embodiment 26-30, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The liquid vaccine preparation of any one in 32. embodiment 26-31, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The liquid vaccine preparation of any one in 33. embodiment 26-32, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

The liquid vaccine preparation of any one in 34. embodiment 26-33, wherein said mouth mucosa drug administration is the form that does not comprise the dosage regimen that increases dosage.

Claims (34)

1. allergen is for the preparation of the purposes of liquid vaccine preparation, described bacterin preparation does not comprise adjuvant, for the allergy that prevents or treat patient by mouth mucosa drug administration, wherein said liquid vaccine preparation comprises and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide.

2. the purposes of claim 1, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

3. the purposes of claim 1 or 2, wherein said mouth mucosa drug administration is sublingual administration.

4. the purposes of claim 3, wherein said reinforcing agent is selected from: ethanol, propylene glycol and glycerol.

5. the purposes of claim 4, wherein said reinforcing agent is glycerol.

6. the purposes of any one in aforementioned claim, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

7. the purposes of claim 6, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

8. the purposes of claim 7, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

9. the purposes of claim 8, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.07 μ g to 20 μ g.

10. the purposes of claim 9, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The purposes of 11. claim 10, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The purposes of 12. claim 11, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

The purposes of any one in 13. aforementioned claim, wherein said liquid vaccine preparation is non-increase dosage dosage form, and wherein said mouth mucosa drug administration is the form that does not comprise the dosage regimen that increases dosage.

14. allergens are for the preparation of the purposes of liquid vaccine preparation, described bacterin preparation is non-increase dosage dosage form and does not comprise adjuvant, for not comprising that increasing the dosage regimen of dosage prevents or treat the allergy in patient by mouth mucosa drug administration, wherein said liquid vaccine preparation comprises and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide.

The purposes of 15. claim 14, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

The purposes of 16. claims 14 or 15, wherein said mouth mucosa drug administration is sublingual administration.

The purposes of 17. claim 16, wherein said reinforcing agent is selected from: ethanol, propylene glycol and glycerol.

The purposes of 18. claim 17, wherein said reinforcing agent is glycerol.

The purposes of any one in 14-18 in 19. claim, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

The purposes of 20. claim 19, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

The purposes of 21. claim 20, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

The purposes of 22. claim 21, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.07 μ g to 20 μ g.

The purposes of 23. claim 22, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The purposes of 24. claim 23, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The purposes of 25. claim 24, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

26. liquid vaccine preparations for mouth mucosa drug administration, described liquid vaccine preparation contains allergen and is selected from following reinforcing agent: ethanol, chitosan, chitin, propylene glycol, glycerol, dimethyl sulfoxide, dimethyl formamide and dimethyl acetylamide, described liquid vaccine preparation does not comprise adjuvant.

The liquid vaccine preparation of 27. claim 26, wherein said allergen is selected from: the pollen allergen of tree, pollen allergen, house dust mite allergen, storeroom dust mite allergen, weeds allergen, mycete allergen, cat allergen and the Canis familiaris L. allergen of grass.

The liquid vaccine preparation of 28. claim 26 or 27, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 50 μ g.

The liquid vaccine preparation of any one in 29. claim 26-28, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.05 μ g to 30 μ g.

The liquid vaccine preparation of any one in 30. claim 26-29, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.06 μ g to 25 μ g.

The liquid vaccine preparation of any one in 31. claim 26-30, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.08 μ g to 15 μ g.

The liquid vaccine preparation of any one in 32. claim 26-31, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.09 μ g to 10 μ g.

The liquid vaccine preparation of any one in 33. claim 26-32, wherein wishes that the main allergenic concentration of the single dose that is used for administration every day is 0.1 μ g to 7 μ g.

The liquid vaccine preparation of any one in 34. claim 26-33, wherein said mouth mucosa drug administration is the form that does not comprise the dosage regimen that increases dosage.