CN102048712B - Stable film agent medicinal composition containing allergen and preparation method thereof - Google Patents

Abstract

The invention discloses a stable film agent medicinal composition containing an allergen, which comprises a theoretically effective amount of allergen, a film-forming material and a pharmaceutically acceptable carrier. In a preferable embodiment, the film-forming material accounts for 30 to 99 percent of the mass of the entire film agent medicinal composition. In addition, the invention also relates to a preparation method of the film agent medicinal composition. The application of the allergen film agent makes the standard medicament administration in allergen specific immunotherapy convenient.

Description

A kind of stable allergenic membrane pharmaceutical composition and preparation method thereof that contains

Technical field

The invention belongs to bio-pharmaceutical technical field, be specifically related to a kind of stable allergenic membrane pharmaceutical composition and preparation method thereof that contains.

Background technology

Anaphylactic disease (also claiming allergic disease) is that a class sickness rate is high, harm is serious, the large disease of social influence.2005 the world allergy tissue (WAO) announced the anaphylactic disease Epidemiological study that 30 countries are carried out, result is in 1,200,000,000 total populations of these countries, 22% crowd suffers from the anaphylactic disease of IgE mediation.In developed country, anaphylactic disease leaps to the sixth-largest chronic disease with its high incidence, about 15～20% crowd suffers from various anaphylactic disease, wherein mainly comprises allergic asthma, allergic rhinitis, atopic dermatitis, anaphylaxis conjunctivitis etc.

Allergy is abnormal, harmful, pathologic immunoreation.Cause that allergic antigenic substance is called allergen (allergen).Allergen can be complete antigen (as microorganism, parasite, pollen, heterogenous animal serum etc.), can be also hapten (as medicine and some chemicals).There is the self component of time variation as autoantigen, also can cause that allergy occurs.Allergic generation can be divided into two stages: the sensitization stage, when body contacts after allergen for the first time, need to there is an incubation period (1～2 week), immunologically competent cell could produce corresponding antibodies or primed lymphocyte, body is without any abnormal response during this period, but possessed the allergic potential ability of generation.Allergy stage of development, when sensitization body again with same allergen contact, allergen is combined with corresponding antibodies or primed lymphocyte, cause body physiological function disorder or tissue injury, namely abnormal immune reaction occurs, this process occurs very fast, several seconds to tens seconds at least, and 2～3 days at most.The reason one that allergy occurs is individual immune function state; The 2nd, enter allergenic character, purity and the approach etc. of body.In these two factors, principal element is for the former, the difference that individual immunity is replied.The feature that allergy occurs is: must have allergenic stimulation; Have strict specific aim, i.e. the allergen of twice contact must be identical; There is certain incubation period, must experience occur from sensitization to allergy two stages; Person exists must to have allergic constitution.The reason that allergy occurs and performance are very complicated, and its classification was once had to different viewpoints.But mostly according to the mechanism that causes immunopathogenesis, allergy is divided into four classes: I type (anaphylactic type), II type (cell toxicant type), III type (immune complex type), IV type (delayed) at present.

Specific active immunotherapy (special immunotherapy, SIT) claim again desensitization treatment, is to treat for the cause of disease of allergic disease.SIT is started to try out by German Dunbar etc. for 1903.Noon and Freeman etc. were developed SIT and were promoted widely afterwards, just had a large amount of clinical research reports by 1911.The therapeutic modality of SIT is regularly to increase progressively administration with allergenic activity composition, the anaphylactic disease causing as treated pollen or dirt demodicid mite etc.A large amount of clinical research results show, all effective to treatment allergic rhinitis, allergic asthma, atopic dermatitis and anaphylaxis conjunctivitis aspect clinically, and can reduce the generation of inflammation.Result also shows, immunization therapy short term efficacy is not as antihistaminic or steroid Drug therapy, but long-term efficacy is better than Drug therapy.Clinical practice confirm through regular desensitization treatment person is many can lifelong benefit, this is that general Drug therapy is unapproachable.The immunization therapy of standardization allergen specific can change the basic pathology physiological mechanism of allergic disease, is the etiological treatment of World Health Organization (WHO) and global each allergy, the unique common recommendation of asthma and immunology association.

The administering mode that has two kinds of standardization specific active immunotherapies of comparatively generally acknowledging at present, i.e. subcutaneous injection administering mode and sublingual administration administering mode.And, the advantage representing in curative effect and safety due to sublingual administration desensitization treatment, during the ARIA that World Health Organization (WHO) delivered in calendar year 2001 reports, formal recommendation sublingual administration is the specific active immunotherapy method of alternative traditional subcutaneous injection mode, and suggestion is used in adult and the irritated patient of child.The dosage form of drug desensitization sublingual administration administration is at present mainly sublingual administration drop, but sublingual administration drop belongs to liquid preparation, and allergen is a kind of activated protein, activated protein generally all needs cryopreservation could keep active in to ensure curative effect, and this just gives to transport, store, carry and use and makes troubles; And dosage is ascending to be increased progressively gradually, during particularly to best maintained dosage because of liquid dosage volume make greatly patient especially child and gerontal patient's accurate quantitative analysis administration make troubles, be unfavorable for the enforcement of standardization administration.

Summary of the invention

The object of this invention is to provide a kind of stable allergenic membrane pharmaceutical composition and preparation method thereof that contains.

For achieving the above object, first aspect present invention provides a kind of stable allergenic membrane pharmaceutical composition that contains, and it comprises allergen, film forming matter and the pharmaceutically acceptable carrier for the treatment of effective dose.In a preferred embodiment, described membrane pharmaceutical composition is made up of allergen, film forming matter and the pharmaceutically acceptable carrier for the treatment of effective dose.

In another preferred embodiment, described film forming matter is selected from glucose, sucrose, starch, pulullan polysaccharide, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxy methocel, methylcellulose, hyaluronic acid, chitosan, chitin, Sorbitol, xylitol, sodium alginate, collagen protein, xanthan gum, arabic gum, gelatin, pectin, Konjac glucomannan, poly(ethylene oxide), polyvinylpyrrolidone, polyvinyl alcohol, Polyethylene Glycol, polyacrylic acid, methyl methacrylic acid copolymer, C974P BufferGel or its combination.

In a preferred embodiment, the mass percent that described film forming matter accounts for whole membrane pharmaceutical composition is 30%～99%.

Also want in preferred embodiment at one, described film forming matter is the compositions of sodium alginate and pulullan polysaccharide, and wherein, the mass ratio of sodium alginate and pulullan polysaccharide is 1: 1～10: 1.In a most preferred embodiment, the mass percent that described sodium alginate accounts for whole membrane pharmaceutical composition is 20%～85% (better 40%～75%), and the mass percent that described pulullan polysaccharide accounts for whole membrane pharmaceutical composition is 5%～25% (better 8%～20%).

Also want in preferred embodiment at another, described film forming matter is the compositions of sodium alginate and sucrose, and wherein, the mass ratio of sodium alginate and sucrose is 1: 1～10: 1.In another the most preferred embodiment, the mass percent that described sodium alginate accounts for whole membrane pharmaceutical composition is 20%～85% (better 40%～75%), and the mass percent that described sucrose accounts for whole membrane pharmaceutical composition is 5%～25% (better 8%～20%).

At one, preferably in embodiment, described allergen is selected from dust mite allergen, pollen allergen, insecticide allergen, animal skin allergen, food allergen, microorganism allergen or its combination.At another, preferably in embodiment, described allergen is natural allergen or the recombinant allergen etc. of natural allergen extracting solution, purification.

Also having one preferably in embodiment, described membrane pharmaceutical composition is airtight vacuum packaging.

In a preferred embodiment, in the quality of whole membrane pharmaceutical composition, described membrane pharmaceutical composition is the allergen by treatment effective dose, the sodium alginate of mass percent 20%～85%, the pulullan polysaccharide of mass percent 5%～25% or sucrose, the filler of mass percent 0%～65%, the plasticizer of mass percent 0%～20%, the surfactant of mass percent 0%～5%, the defoamer of mass percent 0%～5%, the antiseptic of mass percent 0%～3%, the salt of mass percent 0.01%～5%, and the water of mass percent 0.01%～20% composition.The above all components mass percent sum is 100%.

In a preferred embodiment, the mass percent that the allergen of described treatment effective dose accounts for whole membrane pharmaceutical composition is 0.0001%～10%.

Second aspect present invention provides a kind of method of preparing above-mentioned membrane pharmaceutical composition, comprises the steps:

A) film forming matter and pharmaceutically acceptable carrier are dissolved in solvent, leave standstill, obtain film forming liquid;

B) film forming liquid allergen and step a) being obtained mixes, degassed;

C) mixed liquor coating drying and forming-film step b) being obtained.

At one preferably in embodiment, described step c) in, the method for described coating is selected from contrary print roll coating, intaglio plate coating, dip coated, extrusion coated, roll-type scraper for coating, airblade coating or dropping curtain coating.At another preferably in embodiment, described step c) in, the dry temperature of described coating is 20 DEG C～50 DEG C.

Also having one preferably in embodiment, described preparation method also comprises that the film that described step c) is made divides the step that cuts off film, sterilizing, airtight vacuum packaging.Preferably, the method for described sterilizing adopts the method for ultraviolet sterilization.

Provided by the inventionly contain allergenic membrane pharmaceutical composition can dissolve rapidly (rapid dispersion) in oral cavity, absorbed very soon by hypoglossis mucous membrane, onset is very fast.Because membrane at room temperature can keep the stable of biological activity (allergenic activity) for a long time, so steady quality; In addition content is accurate, and volume is little, lightweight, is convenient to transport, store, carry and use.In addition membrane use the use that has facilitated child and gerontal patient, for the standardization administration of allergen specific immunization therapy is provided convenience.

Specific embodiments

Particularly, the invention provides one and contain allergenic membrane pharmaceutical composition, it comprises allergen, film forming matter and the pharmaceutically acceptable carrier for the treatment of effective dose.Term " comprising ... " herein refers in this pharmaceutical composition and can also contain any other component, these components can exist with any content, as long as this component existing with this content is that human body is acceptable, and there is no substantial impact for the biological activity (comprising stability) of active component in pharmaceutical composition of the present invention and the physicochemical property of membrane pharmaceutical composition.In a preferred embodiment, described membrane pharmaceutical composition is made up of allergen, film forming matter and the pharmaceutically acceptable carrier for the treatment of effective dose.

Film forming matter of the present invention generally should have following characteristic: can be dissolved in water (or being at least that part can be dissolved in water), and inflatable disintegrate after water suction.Preferably, described film forming matter at least can increase by 20% weight after water suction.In addition, being applicable to film forming matter of the present invention should be the material that can be used in oral administration.

At one, preferably in embodiment, described film forming matter is selected from glucose, sucrose, starch, pulullan polysaccharide, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxy methocel, methylcellulose, hyaluronic acid, chitosan, chitin, Sorbitol, xylitol, sodium alginate, collagen protein, xanthan gum, arabic gum, gelatin, pectin, Konjac glucomannan, poly(ethylene oxide), polyvinylpyrrolidone, polyvinyl alcohol, Polyethylene Glycol, polyacrylic acid, methyl methacrylic acid copolymer, C974P BufferGel or its combination.

Preferably, the mass percent that described film forming matter accounts for whole membrane pharmaceutical composition is 30%～99%, also wants good 60%～95%.In a better embodiment, described film forming matter is the compositions of sodium alginate and pulullan polysaccharide, and wherein, the mass ratio of sodium alginate and pulullan polysaccharide is 1: 1～10: 1, also wants good 2: 1～5: 1.At another, preferably in embodiment, described film forming matter is the compositions of sodium alginate and sucrose, and wherein, the mass ratio of sodium alginate and sucrose is 1: 1～10: 1, also wants good 2: 1～5: 1.Wherein, the viscosity of preferred sodium alginate (1%, 20 DEG C) is 50mPas～200mPas, and the molecular weight of preferred pulullan polysaccharide is 1 × 10 ⁵～5 × 10 ⁵.

Select different film forming matters to have a significant impact for the viscosity of film forming liquid, general preferred viscosity is 100cps～100000cps, and more preferably 500cps～80000cps also wants preferred 1000cps～40000cps.Can adopt distinct methods to adjust the viscosity of film forming liquid, for example, add the polymer of high molecular or cross-linking agent (as calcium salt, sodium salt, potassium salt) can increase the viscosity of film forming liquid; Temperature also can affect the viscosity of film forming liquid.

At another, preferably in embodiment, described allergen is selected from dust mite allergen, pollen allergen, insecticide allergen, animal skin allergen, food allergen, microorganism allergen or its combination.Wherein said dust mite allergen is taking dirt demodicid mite as the allergen that source obtains, and includes but not limited to following dust mite allergen: dust mite (Dermatophagoides farinae), dermatophagoides pteronyssinus (Dermatophagoides pteronyssinus), micro-angle dirt demodicid mite (Dermatophagoides microceras), bury interior Europe dirt demodicid mite (Euroglyphus maynei) allergen etc.Pollen allergen is the allergen obtaining as source taking pollen, include but not limited to following pollen allergen: artemisia (Artemisia) pollen, Ambrosia (Ambrosia) pollen, Ricinus (Ricinus) pollen, Humulus (Hummlus) pollen, Chenopodium (Chenlpldum) pollen, Amaranthus (Amaranthus) pollen, Casuarina (Casuarina) pollen, Betula (Betula) pollen, Pinus (Pinus) pollen, Picea (Picea) pollen, Cryptomeria (Cryptomeria) pollen, plane (Platanus) pollen allergen etc.Wherein, artemisia (Artemisia) pollen allergen mainly comprises: north Chinese mugwort (Artemisia vulgaris Linn.) pollen, Herba Artemisiae annuae (Artemisia annuaLinn.) pollen, Artemisia sieversiana Willd. (Artemisia sieversiana Ehrhart ex Willd.) pollen, Chinese mugwort (Artemisia argyiL é vl.et Van.) pollen allergen etc.Insecticide allergen is taking insecticide as the allergen that source obtains, and includes but not limited to following insecticide allergen: periplaneta americana (Periplaneta americana), Peroplaneta fluligginosa (Periplanetafuliginosa), Groton bug (Blattella germanica), housefly (Musca domestica) allergen etc.Animal skin allergen comprises cat epithelium, Canis familiaris L. epidermal allergen etc.Microorganism allergen of the present invention includes but not limited to, various antibacterials, fungus, yeast, virus, actinomycetes, mycoplasma, chlamydia, rickettsia, protozoacide allergen etc.Food allergen comprises and derives from any type of food allergen, includes but not limited to: processing, undressed, ripe, raw food allergen (for example, raw Penaeus seu panulirus/Eriocheir sinensis, ripe Penaeus seu panulirus/crab allergen) etc.

Be to be understood that, allergen of the present invention can be allergen (the Derf I allergen of for example dust mite of single component, or the Art v1 allergen of north Chinese mugwort pollen etc.), also can be allergen mixture (for example dust mite allergen extracting solution in source identical (single source), or ragweed pollen allergen extracting solution etc.), do not affecting under the active prerequisite with tiring of allergen self, also can be multiple allergen source, allergen compositions (for example allergenic compositions of dust mite allergen and dermatophagoides pteronyssinus of mixing by any way, or dust mite allergen and the allergenic compositions of ragweed pollen etc.).

In addition, allergen of the present invention can be to buy from commercial channels, also can use the method that does not make the mode of allergen degraded or inactivation extract from natural materials or animals and plants in any prior art to obtain, can also obtain by genetic engineering means the recombinant allergen with biological activity (allergenic activity) (comprising the mutant of the recombinant allergen consistent with natural allergen sequence, modification allergen or recombinant allergen etc.) of any kind.

Generally from natural materials or animals and plants, extracting allergenic step is: 1) raw material (as dirt demodicid mite, pollen etc.) is carried out to ungrease treatment; 2) use buffer (as normal saline, phosphate buffer, coca ' s liquid etc.) lixiviate; 3) through centrifugal or filtration, then aseptic process, allergen extracting solution obtained; 4) lyophilization, removes moisture.Wherein, described step 4) be optional step.Adopt the total protein concentration of measuring allergen extracting solution (thing) such as BCA method, Lowry method, adopt the content of measuring main allergen protein such as ELISA method.Wherein, main allergen protein content generally accounts for 1%～25% (mass percent) of allergen extracting solution total protein concentration, and more common is 5%～15% (mass percent).Common main allergen protein includes but not limited to, dust mite allergen protein I, II (Derf I, Derf II), dermatophagoides pteronyssinus allergen protein I, II (Derp I, Derp II), north Chinese mugwort pollen allergen albumen 1 (Art v1), ragweed pollen allergen protein 1 (Amb a1), Betula platyphylla Suk. pollen allergen albumen 1 (Betv1), cat (epithelium) allergen protein 1 (Fel d1), Canis familiaris L. (epithelium) allergen protein 1 (Can f1), Blattella Germanica allergen albumen 1,2 (Bla g1, Bla g2) etc.

It should be noted that, for the not too many restriction of allergenic dose concentration in membrane pharmaceutical composition of the present invention, as long as it can play effective treatment (treating the allergen of effective dose).According to the requirement of specific active immunotherapy (desensitization treatment), membrane pharmaceutical composition of the present invention can be prepared into the preparation of multiple dose concentrations, and first from the administration of low dosage concentration, dosage is ascending again to be increased progressively gradually, to best maintained dose concentration.In recent years, also there is the desensitization treatment scheme that continues medication with single dose.Therefore, term " allergen for the treatment of effective dose " refers to single dose or ascending-dose and takes once or repeatedly take the dosage that can cause for example adaptive immune response and therefore make patient desensitize.Certainly,, for the patient of different degree of allergic reactions, its best therapeutic dose may be different from therapeutic scheme.

Generally, the total protein that contains allergenic extract in membrane of the present invention is about 0.01 μ g～10mg/ sheet, is preferably about 0.1 μ g～5mg/ sheet, and the preferred 1 μ g～2.5mg/ sheet that is about, also will preferably be about 10 μ g～1mg/ sheets; Or the main allergen protein containing in membrane of the present invention is about 0.001 μ g～1mg/ sheet, be preferably about 0.01 μ g～0.5mg/ sheet, the preferred 0.1 μ g～0.25mg/ sheet that is about, also will preferably be about 1 μ g～0.1mg/ sheet.Generally, in membrane pharmaceutical composition of the present invention, the mass percent that allergen accounts for whole membrane pharmaceutical composition is 0.0001%～10%, preferably 0.001%～5%, more preferably 0.01%～2.5%, also preferred 0.1%～1% (in the total protein of allergenic extract).

Of the present inventionly contain allergenic membrane pharmaceutical composition and can be used for the treatment of the anaphylactic disease (I metallergy disease) being caused by described allergen, described anaphylactic disease includes but not limited to, allergic asthma, allergic rhinitis, urticaria, atopic dermatitis, anaphylaxis conjunctivitis or its complication.For example, contain the allergenic membrane pharmaceutical composition of dust mite, the allergic asthma that can be caused by dust mite according to the Regimen Chemotherapy of clinical desensitization treatment, allergic rhinitis, atopic dermatitis, anaphylaxis conjunctivitis or its complication.

Membrane pharmaceutical composition of the present invention is preferably by oral mucosa administration (more preferably sublingual administration), therefore, this membrane pharmaceutical composition can adhere to oral mucosa (more preferably hypoglossis mucous membrane) surface of containing saliva easily, and disintegrate rapidly, discharges active substance (allergen), and disintegration is preferably for being less than 120 seconds, better for being less than 90 seconds, also want good for being less than 60 seconds, the best for being less than 30 seconds, even for being less than 10 seconds.The thickness of described membrane pharmaceutical composition is preferably 3 μ m～250 μ m, more preferably 50 μ m～200 μ m, also preferred 75 μ m～150 μ m.General 1mg～the 100mg/ of the quality sheet of described membrane pharmaceutical composition, preferably 2mg～50mg/ sheet, more preferably 5mg～30mg/ sheet, also wants preferred 10mg～20mg/ sheet.And there is no too many restriction for the shape of membrane, as long as being easy to patient takes, generally can select triangle, rectangle, parallelogram, circle, square etc.The size of general every membrane is 0.1cm ²～10cm ², preferably 0.5cm ²～2cm ².The packaging material of described membrane pharmaceutical composition answer avirulence, be easy to prevent pollute, easy to use, can't with allergen or film forming matter generation physical and chemical effect (reaction).Described membrane pharmaceutical composition should airtight vacuum packaging, prevent from making moist, mouldy, rotten.

Term " pharmaceutically acceptable carrier " includes but not limited to: saccharide, as lactose, trehalose; Lubricant, as stearic acid, magnesium stearate, calcium sulfate; Vegetable oil, as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, Semen Maydis oil, cupu oil; Aminocaproic acid, alginic acid, fatty acid; Defoamer, as Simethicone; Surfactant, as lecithin, dodecyl sodium sulfate, Tweens (polysorbate esters); Wetting agent, as sodium lauryl sulfate; Plasticizer, as glycerol, propylene glycol, glyceryl acetate, diacetate, triacetate, glycerol triacetate, hexadecanol, triethyl citrate, tributyl citrate and analog thereof; Coloring agent, as pigment, titanium dioxide (titanium white); Correctives, as dihydrochalcone, Fructus Momordicae extract, glycyrrhizin, stevioside, thaumati, saccharin sodium, cyclohexyl-n-sulfonate, LaspartylLphenylalanine methylester, acesulfame potassium, sucralose, palatinose, aspartame, cyclamate; Filler, as calcium carbonate, silicon dioxide, dextrin; Antioxidant; Antiseptic, as phenol, thimerosal, benzoic acid, sorbic acid, potassium sorbate, parabens (parabens), benzyl alcohol, phenethanol; Salt, as sodium chloride, phosphate; Water etc., or its combination.

It should be noted that herein, in the time of film forming, may there is partial solvent (as hydrone) to remain in the film preparation finally obtaining, the mass percent that general water accounts for whole membrane pharmaceutical composition is 0.01%～20%, more preferably 0.1%～10%, also to be preferably 1%～5%.

In addition, in the time preparing allergen extracting solution, in required Extraction buffer, generally have salt component (preferably sodium chloride, phosphate or its combination), therefore, also can residual a small amount of salt in final film preparation, the mass percent that general salt accounts for whole membrane pharmaceutical composition is 0.01%～5%, more preferably 0.1%～3%.

In one embodiment of the invention, in the quality of whole membrane pharmaceutical composition, described membrane pharmaceutical composition is the allergen by treatment effective dose, the sodium alginate of mass percent 20%～85% (preferably 40%～75%), pulullan polysaccharide or the sucrose of mass percent 5%～25% (preferably 8%～20%), mass percent 0%～65% (preferably 1%～65%, more preferably 10%～60%) filler, mass percent 0%～20% (preferably 0.01%～10%, more preferably 0.1%～5%) plasticizer, mass percent 0%～5% (preferably 0.01%～5%, more preferably 0.1%～3%) surfactant, mass percent 0%～5% (preferably 0.01%～5%, more preferably 0.05%～3%, also will be preferably 0.1%～2%) defoamer, the antiseptic of mass percent 0%～3% (preferably 0.01%～3%), the salt of mass percent 0.01%～5% (preferably 0.1%～3%), and mass percent 0.01%～20% (preferably 0.1%～10%, more preferably 1%～5%) water composition.The above all components mass percent sum is 100%.

In technique scheme, the allergenic mass percent of described treatment effective dose is 0.0001%～10%, preferably 0.001%～5%, more preferably 0.01%～2.5%, and also will be preferably 0.1%～1%.

Described filler is selected from calcium carbonate, silicon dioxide, dextrin or its combination; The silicon dioxide of preferred mass percentage ratio 0%～65%, more preferably 1%～65% silicon dioxide, also preferably 10%～60% silicon dioxide, most preferably 30%～60% silicon dioxide.

Described plasticizer is selected from glycerol, propylene glycol, glyceryl acetate, diacetate, triacetate, glycerol triacetate, hexadecanol, triethyl citrate, tributyl citrate and analog thereof or its combination; The glycerol of preferred mass percentage ratio 0%～20%, more preferably 0.01%～10% glycerol, also preferably 0.1%～5% glycerol, most preferably 1%～5% glycerol.

Described surfactant is selected from phospholipid, dodecyl sodium sulfate, Tweens (polysorbate esters) or its combination; The Tween 80 of preferred mass percentage ratio 0%～5%, more preferably 0.01%～3% Tween 80, also preferably 0.1%～3% Tween 80, most preferably 1%～3% Tween 80.

The Simethicone of described defoamer preferred mass percentage ratio 0.01%～5%, more preferably 0.05%～3% Simethicone, also preferably 0.1%～2% Simethicone, most preferably 1%～2% Simethicone.

Described antiseptic is selected from phenol, thimerosal, benzoic acid, sorbic acid, potassium sorbate, parabens (parabens), benzyl alcohol, phenethanol or its combination; The potassium sorbate of preferred mass percentage ratio 0.05%～0.5%, more preferably 0.1%～0.3% potassium sorbate.

Generally, the investigation index of whether " stablizing " in order to evaluated for film agent medicine compositions is total allergenic activity and main allergen protein content.In the present invention, the assay method of total allergenic activity is that the suppression ratio that detects sIgE reflects total allergenic activity; The assay method of main allergen protein content is to use commercially available ELISA test kit to carry out.Concrete grammar can be referring to embodiment.Certainly, those skilled in the art also can measure above-mentioned two by other method and investigate index.

Membrane pharmaceutical composition of the present invention is stable preserve 6 months (better preservation 12 months, better preservation 24 months also take good preservation 36 months) under the condition of 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10% after.

Wherein, term " is stablized " and to be represented: in described pharmaceutical composition, the loss of total allergenic activity is less than 50%, is goodly less than 30%, is goodly less than 20%, also wants good and be less than 10%, and the best is less than 5%; Or/and the loss of at least one main allergen protein content is less than 50%, be goodly less than 30%, be goodly less than 20%, also want good and be less than 10%, the best is less than 5%.

In a preferred embodiment, describedly contain allergenic membrane pharmaceutical composition and preserve after 36 months under the condition of 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10%, the loss of the total allergenic activity in described pharmaceutical composition is less than 10%, and the loss of at least one main allergen protein content is less than 25%.

The present invention also provides a kind of method of preparing above-mentioned membrane pharmaceutical composition in addition, comprises the steps:

A) film forming matter of film forming effective dose and pharmaceutically acceptable carrier are dissolved in solvent, leave standstill, obtain film forming liquid;

B) film forming liquid allergen and step a) being obtained mixes, degassed;

C) mixed liquor coating drying and forming-film step b) being obtained;

D) divide and cut off film, sterilizing, airtight vacuum packaging.

Wherein, in technique scheme, described steps d) be optional step.

In a preferred embodiment, the method for described coating is selected from contrary print roll coating, intaglio plate coating, dip coated, extrusion coated, roll-type scraper for coating, airblade coating or dropping curtain coating.In one embodiment of the invention, selected the method for contrary print roll coating.The applicator roll gyratory directions of contrary print roll coating is contrary with base material traffic direction, conventionally contains three or four rollers.Can be divided into two kinds of bottom feed formula and roll gap feeding types by its feed feature, the mode range of application of roll gap feeding type three roller coat cloth is the widest, is characterized in that coating is the most accurate, can carry out the coating of flawless point.Be coated with dry temperature and be generally-20 DEG C～50 DEG C, be preferably 20 DEG C～50 DEG C, better 25 DEG C～40 DEG C.Wherein, under cryogenic conditions, be lyophilizing film forming.Be coated with the dry time generally also relevant with temperature, temperature higher drying time can be shorter, and be preferably 1 minute～12 hours drying time, and more preferably 30 minutes～6 hours, also will be preferably 1 hour～3 hours.

Bubble in described film forming liquid can have a strong impact on the homogeneity of membrane.Therefore, generally in the time of preparation film forming liquid, can add defoamer, as Simethicone (formed by 90.5～99% polydimethylsiloxane and 4～7% silicon dioxide mixture), the ratio of preferably adding is 0.01%～5% (mass ratio), more preferably 0.05%～3% (mass ratio), also preferred 0.1%～2% (mass ratio).Or after film forming liquid has been prepared, also can adopt degassed method to eliminate bubble, preferred degassed method is centrifugal degassing method, vacuum outgas method, ultrasonic degas method etc.Also can both in film forming liquid, add defoamer, and adopt again degassed method to eliminate bubble.In one embodiment of the invention, first in preparation film forming liquid, add defoamer Simethicone, then adopted again centrifugal degassing method: 3500 revs/min, 20 minutes degassed.

Therefore,, in a better embodiment, the method for preparing membrane pharmaceutical composition of the present invention comprises the steps:

A) film forming matter and pharmaceutically acceptable carrier are dissolved in solvent (preferred water, more preferably purified water) by mass volume ratio 1: 5～1: 35 (better 1: 10～1: 25); 30 DEG C～50 DEG C temperature are bathed, fully stirring and evenly mixing; Leave standstill 1 hour～16 hours, eliminate the bubble producing in blending process, obtain film forming liquid;

B) allergen is slowly joined in the film forming liquid that step a) obtains, add while stirring and evenly mixing, degassed;

C) mixed liquor coating drying and forming-film step b) being obtained, is coated with dry temperature and is generally-20 DEG C～50 DEG C, is preferably 20 DEG C～50 DEG C, better 25 DEG C～40 DEG C;

D) divide and cut off film, ultraviolet sterilization, airtight vacuum packaging.

Wherein, in technique scheme, described steps d) be optional step.

The membrane that in the embodiment of the present invention, each formula makes is tested according to " Pharmacopoeia of People's Republic of China 2005 version two " annex XA " inspection technique disintegration ", and result shows that the disintegration of all membrane is between 30 seconds～60 seconds.The membrane that in the embodiment of the present invention, each formula makes is tested according to " Pharmacopoeia of People's Republic of China 2005 version two " annex X E " Content uniformity test ", and result shows and meets the requirements.

Below in conjunction with embodiment, the present invention is described in further detail.But should be appreciated that enumerating these embodiment is in order to play an illustration, and be not for limiting the scope of the invention.

The preparation of embodiment 1 allergen extracting solution

(1) preparation of dust mite (Dermatophagoides farinae) allergen extracting solution

(1) cleaning, grinding, defat, dry

In flour culture medium, cultivate dust mite, 25 DEG C of temperature, humidity 70%～80%, makes its density reach 300～500/gram.Suspend and separate with saturated NaCl solution, collect dust mite demodicid mite body.The dust mite demodicid mite body obtaining is suspended and cleaned with normal saline, after drying, be placed in-20 DEG C and save backup.Take polypide, polypide carried out to liquid nitrogen grinding, use continuously acetone soak degreasing 3 times, each 4 hours, to the acetone after defat be colourless after, by the solids natural drying after defat to without weighing after acetone taste.

(2) lixiviate

By dust mite polypide and normal saline, the two soaked and extracts (be dust mite polypide 25 ml physiological saline solution extract) after every 1 gram of defat with 1: 25 (W/V), 4 DEG C intermittently magnetic agitation within 72 hours, (each mixing time is 8 hours, magnetic agitation 8 hours again after hold over night, so repeatedly).

(3) filter

Above-mentioned lixiviating solution is first used to common filter paper filtering, obtain coarse filtration liquid.The coarse filtration liquid obtaining is carried out to filtration sterilization with the aseptic microporous filter membrane of aperture 0.22 μ m, and the filtrate obtaining is dust mite allergen extracting solution, in 4 DEG C of cryopreservation.

(4) mensuration of total protein concentration

With the BCA protein determination kit mensuration total protein concentration of Pierce company.The total protein concentration of dust mite allergen extracting solution is 1.2mg/ml.

(2) preparation of north Chinese mugwort (Artemisia vulgaris) pollen allergen extracting solution

(1) pollen defat is with dry

Take dry north Chinese mugwort pollen, add acetone at 1: 5 by mass volume ratio, continuous stirring defat 2 hours, then leave standstill 30 minutes, and remove upper strata acetone, repeat above-mentioned skimming processes 5 times; Solid after defat is paved, dry in ventilating kitchen, to being powdered, and there is no acetone abnormal smells from the patient.

(2) lixiviate

Take above-mentioned defat pollen, add sodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution of pH8.0 by mass volume ratio at 1: 30, under 4 DEG C of conditions, continuous stirring lixiviate 60 hours.

(3) filter

Above-mentioned lixiviating solution is first used to common filter paper filtering, remove large particulate matter; Slowly adding sodium dihydrogen phosphate to reconcile pH is 6.0; Re-use 0.45 μ m, the aseptic microporous filter membrane of 0.22 μ m filters successively, obtains north Chinese mugwort pollen allergen extracting solution, in 4 DEG C of cryopreservation.

(4) mensuration of total protein concentration

With the BCA protein determination kit mensuration total protein concentration of Pierce company.The total protein concentration of north Chinese mugwort pollen allergen extracting solution is 1.0mg/ml.

(3) preparation of artemisiifolia (Ambrosia artemisiifolia) pollen allergen extracting solution

(1) pollen defat is with dry

Take dry ragweed pollen, add acetone at 1: 5 by mass volume ratio, continuous stirring defat 2 hours, then leave standstill 30 minutes, and remove upper strata acetone, repeat above-mentioned skimming processes 5 times; Solid after defat is paved, dry in ventilating kitchen, to being powdered, and there is no acetone abnormal smells from the patient.

(2) lixiviate

Take above-mentioned defat pollen, add sodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution of pH8.0 by mass volume ratio at 1: 30, under 4 DEG C of conditions, continuous stirring lixiviate 60 hours.

(3) filter

Above-mentioned lixiviating solution is first used to common filter paper filtering, remove large particulate matter; Slowly adding sodium dihydrogen phosphate to reconcile pH is 6.0; Re-use 0.45 μ m, the aseptic microporous filter membrane of 0.22 μ m filters successively, obtains ragweed pollen allergen extracting solution, in 4 DEG C of cryopreservation.

(4) mensuration of total protein concentration

With the BCA protein determination kit mensuration total protein concentration of Pierce company.The total protein concentration of ragweed pollen allergen extracting solution is 0.8mg/ml.

The preparation of embodiment 2 membrane

(1) preparation of film forming liquid

Table 1 is filled a prescription to 1～formula 6 in each component be dissolved in respectively in 120ml purified water, 40 DEG C of temperature are bathed, fully swelling, leave standstill 2～8 hours, until eliminate the bubble producing in blending process.

Table 1

Formula 1

Formula 2

Formula 3

Formula 4

Formula 5

Formula 6

Sodium alginate

4.2g

3.3g

5.7g

2.9g

9.7g

2.2g

Pulullan polysaccharide

1.1g

0.6g

1.4g

Sucrose

0.9g

2.2g

1.0g

Glycerol

0.15g

0.25g

0.44g

Tween 80

0.18g

0.25g

Silicon dioxide

2.2g

6.6g

Simethicone

0.1g

0.1g

0.1g

0.1g

0.1g

0.1g

Potassium sorbate

0.01g

0.01g

0.01g

0.01g

0.01g

0.01g

Note: the viscosity of sodium alginate (1%, 20 DEG C) is 80mPas, and the molecular weight of pulullan polysaccharide is 2 × 10 ⁵.

(2) sneak into allergen

The dust mite allergen extracting solution 10ml that the protein concentration that embodiment 1 () is made is 1.2mg/ml slowly joins in the film forming liquid of formula 1, formula 2, add while stirring and evenly mixing, 3500 revs/min, centrifuge, 20 minutes degassed, obtains mixed liquor 1, mixed liquor 2.

The north Chinese mugwort pollen allergen extracting solution 10ml that the protein concentration that embodiment 1 (two) is made is 1.0mg/ml slowly joins in the film forming liquid of formula 3, formula 4, add while stirring and evenly mixing, 3500 revs/min, centrifuge, 20 minutes degassed, obtains mixed liquor 3, mixed liquor 4.

The ragweed pollen allergen extracting solution 10ml that the protein concentration that embodiment 1 (three) is made is 0.8mg/ml slowly joins in the film forming liquid of formula 5, formula 6, add while stirring and evenly mixing, 3500 revs/min, centrifuge, 20 minutes degassed, obtains mixed liquor 5, mixed liquor 6.

(3) coating drying and forming-film

Respectively get above-mentioned mixed liquor 1～mixed liquor 6 coating film formings of 0.2g, it be 25 DEG C, mixed liquor 2 is that 37 DEG C, mixed liquor 5 are 40 DEG C with mixed liquor 6 with mixed liquor 4 that coating baking temperature is respectively mixed liquor 1 and mixed liquor 3, makes membrane 1～membrane 6.

All the other mixed liquors adopt contrary roll coater coating drying and forming-film, and coating baking temperature is same as above, after film forming, divide and cut off film, and ultraviolet sterilization, packs in airtight package and evacuation.Called after membrane one～membrane six respectively.

The assay method of embodiment 3 allergenic activities

(1) mensuration of total allergenic activity

Method: by the allergen to be measured standard serum mixture equal-volume mix homogeneously corresponding with it respectively, use corresponding standard serum mixture and purified water equal-volume mixed liquor in contrast simultaneously, 37 DEG C of incubations 1 hour, then take out and be statically placed in 4 DEG C of refrigerator overnight (9～12 hours).Sample after 4 DEG C are spent the night is transferred in sterilized teat glass, (according to the Immun CAP diagnostic system of Pharmacia Corp of Sweden, the automatic vitro detection anaphylactogen of Uni CAP system specification operates to carry out sIgE assay with Unicap100 instrument (Pharmacia Corp of Sweden).) the sIgE relative amount that records of dust mite standard serum mixture (mixing with purified water equal-volume) is 85.36KUA/L, the sIgE relative amount that north Chinese mugwort pollen standard serum mixture (mixing with purified water equal-volume) records is 71.94KUA/L.The sIgE relative amount that ragweed pollen standard serum mixture (mixing with purified water equal-volume) records is 77.61KUA/L.

Principle: standard serum mixture contains for certain allergenic specific IgE (sIgE).Total allergenic activity in product to be tested becomes the sIgE of branch in serum to be combined to generate complex, sIgE concentration free in serum is reduced, then with the content of sIgE in UniCAP system detection serum.In product to be tested, total allergenic activity is higher, and after standard serum mixture and product to be tested effect, it is lower that its sIgE concentration will be fallen.Now detect and can find that sIgE free in standard serum mixture can corresponding minimizing by UniCAP system, before and after adding by product to be tested relatively, the variation of standard serum mixture sIgE concentration just can obtain in product to be tested always allergenic activity.In serum, sIgE is not by product to be tested the complete combination of allergen in the situation that, and in this process, the reduction degree of total allergenic activity and serum sIgE concentration is positively related.Can obtain total allergenic activity in product to be tested according to the suppression ratio of sIgE, the suppression ratio of sIgE is higher, and in product to be tested, total allergenic activity is higher.

Calculate: sIgE suppression ratio (%)=(1-mixes the sIgE value ÷ of hatching rear standard serum mixture and mixes the sIgE value of standard serum mixture afterwards with purified water equal-volume with allergen) × 100%.

(2) mensuration of main allergen protein content

The main allergen protein Derf of dust mite I, Derf II use the ELISA immue quantitative detection reagent box that Indoor Biotechnologies company of Britain produces to detect, according to the appended description operation of test kit.

During using, the main allergen protein Art of north Chinese mugwort pollen v1 provides the ELISA immue quantitative detection reagent box detection that Chinese arteries and veins (Beijing) Bioisystech Co., Ltd produces, according to the appended description operation of test kit.

The main allergen protein Amb of ragweed pollen a1 uses the ELISA immue quantitative detection reagent box that Indoor Biotechnologies company of Britain produces to detect, according to the appended description operation of test kit.

The comparison of allergenic activity before and after embodiment 4 film forming

(membrane 1, membrane 2 are for containing the allergenic membrane pharmaceutical composition of dust mite to get the membrane that embodiment 2 makes, membrane 3, membrane 4 are for containing the membrane pharmaceutical composition of north Chinese mugwort pollen allergen, membrane 5, membrane 6 are for containing the allergenic membrane pharmaceutical composition of ragweed pollen) be dissolved in 2ml purified water, method according to embodiment 3 () is measured total allergenic activity, measures main allergen protein content according to the method for embodiment 3 (two).With corresponding mixed liquor (respectively getting 0.2g) add purified water to 2ml in contrast, also measure its total allergenic activity and main allergen content.Testing result is in table 2～table 4.

Table 2

	Unicap value (d2-sIgE) (KUA/L)	D2-sIgE suppression ratio (%)	DerfI(ng/ml)	DerfII(ng/ml)
					Membrane 1	25.52	70.10	59.3	12.0
Mixed liquor 1	24.81	70.93	60.1	12.9
					Membrane 2	25.24	70.43	59.5	12.8
Mixed liquor 2	24.02	71.86	61.0	14.2

Note: d2-sIgE represents dust mite allergen specific IgE, and Derf I, Derf II are the main allergen protein of dust mite.

Table 3

	Unicap (w6-sIgE) is worth (KUA/L)	W6-sIgE suppression ratio (%)	Art v1(ng/ml)
				Membrane 3	10.71	85.11	82.8
Mixed liquor 3	10.12	85.93	88.3
				Membrane 4	11.54	83.96	80.1
Mixed liquor 4	10.27	85.72	87.8

Note: w6-sIgE represents north Chinese mugwort pollen allergen specific IgE, and Art v1 is the main allergen protein of north Chinese mugwort pollen.

Table 4

	Unicap (w1-sIgE) is worth (KUA/L)	W1-sIgE suppression ratio (%)	Amb a1(ng/ml)
				Membrane 5	16.22	79.10	33.6
Mixed liquor 5	14.54	81.27	38.5
				Membrane 6	16.12	79.23	34.9
Mixed liquor 6	14.23	81.66	40.3

Note: w1-sIgE represents ragweed pollen allergen specific IgE, and Amb a1 is the main allergen protein of ragweed pollen.

From the result of table 2～table 4, after all mixed liquor film forming, the loss of its main allergen protein content is less than 15%, less (being less than 3%) of loss of total allergenic activity.Result of the test explanation, the allergen film preparation preparing according to the inventive method, before and after film forming, the loss of allergenic activity is very little.

Embodiment 5 long-term stable experiments

The membrane one～six that embodiment 2 is made, 25 DEG C ± 2 DEG C of temperature, carries out long-term stable experiment under the condition of relative humidity 60% ± 10% (SPX-250C type constant temperature and humidity incubator, Shanghai Medical Equipment Plant of Bo Xun armarium company limited).Concrete scheme is: got film sample in 0,3,6,9,12,18,24,36 month and be dissolved in the purified water of equivalent, method according to embodiment 3 () is measured total allergenic activity, measures main allergen protein content according to the method for embodiment 3 (two).Testing result is in table 5～table 10.

The long-term stable experiment of table 5 membrane one

Time (moon)	Unicap value (d2-sIgE) (KUA/L)	D2-sIgE suppression ratio (%)	Derf I(ng/ml)	Derf II(ng/ml)
					0	25.32	70.34	58.8	12.3
3	25.74	69.85	55.9	11.8
					6	26.21	69.29	54.2	11.3
9	26.92	68.46	52.9	11.0
					12	28.14	67.03	51.7	10.8
18	29.22	65.77	50.1	10.4
					24	30.50	64.27	47.5	9.8
36	31.13	63.53	44.1	9.3

Note: d2-sIgE represents dust mite allergen specific IgE, and Derf I, Derf II are the main allergen protein of dust mite.

The long-term stable experiment of table 6 membrane two

Time (moon)	Unicap value (d2-sIgE) (KUA/L)	D2-sIgE suppression ratio (%)	Derf I(ng/ml)	Derf II(ng/ml)
					0	24.91	70.82	59.3	12.0
3	25.22	70.45	58.2	11.8
					6	25.55	70.07	59.6	12.1
9	24.88	70.85	57.8	11.7
					12	26.62	68.81	55.5	11.2
18	27.12	68.23	52.9	10.8
					24	27.67	67.58	50.5	10.3
36	28.30	66.85	47.7	9.7

Note: d2-sIgE represents dust mite allergen specific IgE, and Derf I, Derf II are the main allergen protein of dust mite.

The long-term stable experiment of table 7 membrane three

Time (moon)	Unicap (w6-sIgE) is worth (KUA/L)	W6-sIgE suppression ratio (%)	Art v1(ng/ml)
				0	10.94	84.79	82.9
3	11.32	84.26	81.2
				6	12.54	82.57	78.7
9	13.25	81.58	74.6
				12	13.91	80.66	72.9
18	14.82	79.40	70.4
				24	15.84	77.98	58.8
36	16.02	77.73	62.3

Note: w6-sIgE represents north Chinese mugwort pollen allergen specific IgE, and Art v1 is the main allergen protein of north Chinese mugwort pollen.

The long-term stable experiment of table 8 membrane four

Time (moon)	Unicap (w6-sIgE) is worth (KUA/L)	W6-sIgE suppression ratio (%)	Art v1(ng/ml)
				0	11.57	83.92	80.6
3	11.85	83.53	77.2
				6	11.62	83.85	80.7
9	11.94	83.40	77.1
				12	12.36	82.82	74.5
18	12.83	82.17	72.9
				24	13.48	81.26	68.3
36	14.69	79.58	64.6

Note: w6-sIgE represents north Chinese mugwort pollen allergen specific IgE, and Art v1 is the main allergen protein of north Chinese mugwort pollen.

The long-term stable experiment of table 9 membrane five

Time (moon)	Unicap (w1-sIgE) is worth (KUA/L)	W1-sIgE suppression ratio (%)	Amb a1(ng/ml)
				0	16.14	79.20	32.9
3	16.32	78.97	32.2
				6	17.54	77.40	31.3
9	18.25	76.48	29.6
				12	18.91	75.63	28.9
18	19.82	74.46	27.8
				24	20.84	73.15	26.3
36	22.27	71.31	24.7

Note: w1-sIgE represents ragweed pollen allergen specific IgE, and Amb a1 is the main allergen protein of ragweed pollen.

The long-term stable experiment of table 10 membrane six

Time (moon)	Unicap (w1-sIgE) is worth (KUA/L)	W1-sIgE suppression ratio (%)	Amb a1(ng/ml)
				0	15.94	79.46	34.6
3	15.85	79.58	34.2
				6	16.62	78.59	33.7
9	16.94	78.17	32.1
				12	17.36	77.63	31.5
18	17.83	77.03	30.6
				24	18.48	76.19	28.3
36	19.19	75.27	27.7

Note: w1-sIgE represents ragweed pollen allergen specific IgE, and Amb a1 is the main allergen protein of ragweed pollen.

From the result of table 5～table 10, membrane one～membrane six is 25 DEG C ± 2 DEG C of temperature, under the condition of relative humidity 60% ± 10%, be all less than 25% through the loss of 36 months its main allergen protein content, the loss of membrane two, membrane four, membrane six is even less than 20%; Less (being less than 10%) of loss of total allergenic activity.Result of the test absolutely proves, allergen film preparation of the present invention is 25 DEG C ± 2 DEG C of temperature, and the allergenic activity under the condition of relative humidity 60% ± 10% is stable.

Although the invention describes concrete example, having is a bit significantly to those skilled in the art, can the present invention be made various changes and be changed under the premise without departing from the spirit and scope of the present invention.Therefore, claims have covered all these variations within the scope of the present invention.Unless otherwise indicated, each technical characterictic in the application in all embodiments can combination in any form new technical scheme, and all these technical schemes are all believed to comprise within the scope of the literal record of present specification.

Claims (37)

1. one kind stable contains allergenic membrane pharmaceutical composition, it is characterized in that, in the quality of whole membrane pharmaceutical composition, this membrane pharmaceutical composition is the allergen by treatment effective dose, the sodium alginate of mass percent 20%～85%, the pulullan polysaccharide of mass percent 5%～25% or sucrose, the filler of mass percent 0%～65%, the plasticizer of mass percent 0%～20%, the surfactant of mass percent 0%～5%, the defoamer of mass percent 0%～5%, the antiseptic of mass percent 0%～3%, the salt of mass percent 0.01%～5%, and the water of mass percent 0.01%～20% composition, described salt is selected from sodium chloride, phosphate or its combination,

The above all components mass percent sum is 100%.

2. membrane pharmaceutical composition according to claim 1, is characterized in that, described allergen is selected from dust mite allergen, pollen allergen, insecticide allergen, animal skin allergen, food allergen, microorganism allergen or its combination.

3. membrane pharmaceutical composition according to claim 2, described allergen is selected from dust mite allergen, dermatophagoides pteronyssinus allergen, Artemisia pollen allergen, Ambrosia pollen allergen, Humulus pollen allergen, Cryptomeria pollen allergen, platanus pollen allergen or its combination.

4. membrane pharmaceutical composition according to claim 1, described allergen is selected from natural allergen or the recombinant allergen of natural allergen extracting solution, purification.

5. membrane pharmaceutical composition according to claim 1, is characterized in that, the thickness of described membrane pharmaceutical composition is 3 μ m～250 μ m.

6. membrane pharmaceutical composition according to claim 5, is characterized in that, the thickness of described membrane pharmaceutical composition is 50 μ m～200 μ m.

7. membrane pharmaceutical composition according to claim 6, is characterized in that, the thickness of described membrane pharmaceutical composition is 75 μ m～150 μ m.

8. membrane pharmaceutical composition according to claim 1, is characterized in that, the area of described membrane pharmaceutical composition is 0.1cm ²～10cm ².

9. membrane pharmaceutical composition according to claim 8, is characterized in that, the area of described membrane pharmaceutical composition is 0.5cm ²～2cm ².

10. membrane pharmaceutical composition according to claim 1, is characterized in that, described filler is selected from calcium carbonate, silicon dioxide, dextrin or its combination.

11. membrane pharmaceutical compositions according to claim 10, is characterized in that the silicon dioxide that described filler is 1%～65%.

12. membrane pharmaceutical compositions according to claim 11, is characterized in that the silicon dioxide that described filler is 10%～60%.

13. membrane pharmaceutical compositions according to claim 12, is characterized in that the silicon dioxide that described filler is 30%～60%.

14. membrane pharmaceutical compositions according to claim 1, it is characterized in that, described plasticizer is selected from glycerol, propylene glycol, glyceryl acetate, diacetate, triacetate, glycerol triacetate, hexadecanol, triethyl citrate, tributyl citrate or its combination.

15. membrane pharmaceutical compositions according to claim 14, is characterized in that the glycerol that described plasticizer is 0.01%～10%.

16. membrane pharmaceutical compositions according to claim 15, is characterized in that the glycerol that described plasticizer is 0.1%～5%.

17. membrane pharmaceutical compositions according to claim 16, is characterized in that the glycerol that described plasticizer is 1%～5%.

18. membrane pharmaceutical compositions according to claim 1, is characterized in that, described surfactant is selected from phospholipid, dodecyl sodium sulfate, Tweens or its combination.

19. membrane pharmaceutical compositions according to claim 18, is characterized in that the Tween 80 that described surfactant is 0.01%～3%.

20. membrane pharmaceutical compositions according to claim 19, is characterized in that the Tween 80 that described surfactant is 0.1%～3%.

21. membrane pharmaceutical compositions according to claim 20, is characterized in that the Tween 80 that described surfactant is 1%～3%.

22. membrane pharmaceutical compositions according to claim 1, is characterized in that the Simethicone that described defoamer is 0.01%～5%.

23. membrane pharmaceutical compositions according to claim 22, is characterized in that the Simethicone that described defoamer is 0.05%～3%.

24. membrane pharmaceutical compositions according to claim 23, is characterized in that the Simethicone that described defoamer is 0.1%～2%.

25. membrane pharmaceutical compositions according to claim 24, is characterized in that the Simethicone that described defoamer is 1%～2%.

26. membrane pharmaceutical compositions according to claim 1, is characterized in that, described antiseptic is selected from phenol, thimerosal, benzoic acid, sorbic acid, potassium sorbate, parabens, benzyl alcohol, phenethanol or its combination.

27. membrane pharmaceutical compositions according to claim 26, is characterized in that the potassium sorbate that described antiseptic is 0.05%～0.5%.

28. membrane pharmaceutical compositions according to claim 27, is characterized in that the potassium sorbate that described antiseptic is 0.1%～0.3%.

29. membrane pharmaceutical compositions according to claim 1, is characterized in that, the mass percent of described sodium alginate is 40%～75%.

30. membrane pharmaceutical compositions according to claim 1, is characterized in that, the mass percent of described pulullan polysaccharide or sucrose is 8%～20%.

31. membrane pharmaceutical compositions according to claim 1, is characterized in that, the mass percent of described salt is 0.1%～3%.

32. membrane pharmaceutical compositions according to claim 1, is characterized in that, the mass percent of described water is 0.1%～10%.

33. membrane pharmaceutical compositions according to claim 32, is characterized in that, the mass percent of described water is 1%～5%.

34. membrane pharmaceutical compositions according to claim 1, is characterized in that, the allergenic mass percent of described treatment effective dose is 0.0001%～10%.

35. membrane pharmaceutical compositions according to claim 1, is characterized in that, described membrane pharmaceutical composition is airtight vacuum packaging.

Prepare the method for membrane pharmaceutical composition described in claim 1-35 any one for 36. 1 kinds, it is characterized in that, described method comprises the steps:

A) film forming matter and pharmaceutically acceptable carrier are dissolved in solvent, leave standstill, obtain film forming liquid;

B) film forming liquid allergen and step a) being obtained mixes, degassed;

C) mixed liquor coating drying and forming-film step b) being obtained.

37. methods according to claim 36, is characterized in that, described method comprises the steps:

A) film forming matter and pharmaceutically acceptable carrier are dissolved in solvent, leave standstill, obtain film forming liquid;

B) film forming liquid allergen and step a) being obtained mixes, degassed;

C) mixed liquor coating drying and forming-film step b) being obtained;

D) divide and cut off film, sterilizing, airtight vacuum packaging.