Antiallergic agent

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an anti-allergic agent containing polysaccharide containing galactose, glucose and rhamnose as ingredients, wherein polysaccharide contains galactose, glucose and rhamnose in molar ratio 3-5:1-3:1, and polysaccharide has certain structure.

EFFECT: invention provides extending the range of antiallergic agents.

12 cl, 6 ex, 6 dwg, 1 tbl

 

Area of technology

The present invention relates to an antiallergic tool

The level of technology

In respect of a microorganism belonging to the genusBifidobacterium(hereinafter also referred to as "Bifidobacterium"), one of the predominant bacteria in the intestine, there have been a multitude of reports about the effects of such microorganism in intestinal regulation and immunoregulation.

Some bifidobacteria reported as producing extracellular polysaccharides. A lot of posts is related to the characteristics of the components and structures of polysaccharides. The polysaccharide produced by Bifidobacterium, reported in relation to their immunostimulatory functions (patent documents 1 and 2).

There are some messages about anti-allergic effects of polysaccharides produced non-bifidobacteria microorganisms. In patent document 3 described anti-inflammatory drug which contains as active ingredient a polysaccharide obtained from a culture broth of the bacteriumLactobacillusand inpatent document 4 describes that the immune modulator, which contains a polysaccharide produced byLactobacillus fermentumas the active ingredient, has anti-inflammatory effect, protivole�quarter effect and an inhibitory effect on proliferation of the tumor. In patent document 5 described the overwhelming allergic reaction composition, which contains the polysaccharide Levan produced by the optionnatto Bacillus subtilisas the active ingredient.

Optionnatto Bacillus subtilisis not a microorganism that lives in the intestines as local bacteria. In a healthy intestinal bifidobacteria in most cases are dominated by lactic acid bacteria. Yet no reports of anti-allergic effects of bifidobacteria that produce extracellular polysaccharide, among bifidobacteria, which are the predominant bacteria in the gut.

The prior art documents

Patent documents

Patent document 1: WO 07/007562

Patent document 2: Japanese laid patent publication No. 58-203913

Patent document 3: Japanese laid patent publication No. 7-70209

Patent document 4: Japanese laid patent publication No. 2008-245576

Patent document 5: Japanese laid patent publication No. 2006-1922

Summary of the invention

Issues that will be resolved with the help of inventions

The purpose of the present invention is to offer an antiallergic drug without the risk of any side effects.

�a means of solving problems

The present invention relates to anti-allergic agent comprising a polysaccharide comprising galactose, glucose and rhamnose as constituents.

In a variant implementation, the polysaccharide comprises galactose, glucose and rhamnose in a molar ratio of 3-5:1 to 3:1.

In a variant implementation, the polysaccharide comprises the following structure:

Formula 1

In a variant implementation, the polysaccharide is prepared from a microorganism belonging to the genusBifidobacterium.

In an additional embodiment of the microorganism belonging to the genusBifidobacteriumrepresents aBifidobacterium longum.

In yet another additional embodiment, the implementation ofBifidobacterium longumis a strain ofJBL05Bifidobacterium longum(NITE BP-82).

The present invention also relates to the anti-allergic agent comprising a microorganism, wherein the microorganism belongs to the genusBifidobacteriumand produces an extracellular polysaccharide, as described above.

In an embodiment, the implementation of a Bifidobacterium, which produces an extracellular polysaccharide, as described above, is a strain JBL05Bifidobacterium longum(NITE BP-82).

The present invention also relates to compositions for oral administration comprising protowall�ergicheskoe tool. This antiallergic drug is an antiallergic drug, including produced by Bifidobacterium polysaccharide specified above, or antiallergic agent, which includes producing the exopolysaccharide Bifidobacterium forth above.

The present invention also relates to compositions for topical application comprising an antiallergic agent. This antiallergic drug is an antiallergic drug, including produced by Bifidobacterium polysaccharide specified above.

In a variant implementation, the composition for oral administration or composition for external use is intended for suppression of atopic dermatitis or contact dermatitis.

Effects of the invention

The present invention relates to anti-allergic agent, exhibiting overwhelming medical allergic reaction exposure without the risk of any side effects.

Brief description of the drawings

Fig.1 shows graphs illustrating the production of interferon-γ (IFN-γ) (A), production of interleukin-4 (IL-4) (B) and the ratio between IFN-γ and IL-4 (C), produced in response to stimulation of splenocytes produced by Bifidobacterium polysaccharide in vitro.

Fig.2 showing� graph showing the change over time in average thickening of the ear in mice treated by oral administration produced by Bifidobacterium polysaccharide, after the beginning of sensitization.

Fig.3 shows photomicrographs of stained H&E sections of the ears exposed mice, including mice receiving the oral introduction produced by bifidobacteria polysaccharide on day 20 after the beginning of sensitization.

Fig.4 shows a graph showing the change over time in average thickening of the ear in mice receiving by oral administration of exopolysaccharide producing a Bifidobacterium, after the beginning of sensitization.

Fig.5 shows photomicrographs of stained H&E cut ears-exposed mice, including mice, receiving by oral administration of exopolysaccharide producing the Bifidobacterium on day 20 after the beginning of sensitization.

Fig.6 shows a graph showing the change over time in average thickening of the ear in mice receiving when applied topically produced by Bifidobacterium polysaccharide after the beginning of sensitization.

Method of carrying out the invention

Produced by Bifidobacterium polysaccharide and producing actpo�ishared a Bifidobacterium

In the present invention is used polysaccharide containing galactose, glucose and rhamnose as constituents. The polysaccharide may contain galactose:glucose:rhamnose in a molar ratio of 3-5:1 to 3:1. Polysaccharide, in which the molar ratio of galactose:glucose:rhamnose is, for example, 4:2:1, may contain a repeating structure represented by the following formula (I)

Formula 2

In the formula (I) Galp represents galactopyranose, Glcp is a glucopyranose and Rhap is rhamnopyranose, meaning that galactose, glucose and rhamnose have a pyranose structure. The above polysaccharide may further contain pyruvic acid and pyruvic acid can enter into the composition of the polysaccharide in an amount up to 10 wt%. Identification of the components of the polysaccharide, the determination of the amounts or fractions of the components in the polysaccharide and structural analysis of the polysaccharide will be described in detail below. Polysaccharide possessing a given structure, can be obtained by using a microorganism belonging to the genusBifidobacteriumor, in particular,Bifidobacterium longumfor example,strain JBL05(Bifidobacterium longumNITE BP-82), which is extracted from the human intestine. Therefore, this polysaccharide for UD�bscva herein also referred to as "produced by Bifidobacterium polysaccharide", but this phrase is not intended to limit the microorganisms that produce polysaccharide.

In the present invention are also using a microorganism belonging to the genusBifidobacteriumand producing extracellular polysaccharide, as described above. The phrase "producing extracellular polysaccharide" means that the microorganism produces a polysaccharide capsule around itself. This microorganism for convenience, herein also referred to as "exopolysaccharide producing a Bifidobacterium".

In the present invention the strain JBL05Bifidobacterium longum(NITE BP-82) cited as an example of the microorganism used for the production produced by Bifidobacterium of polysaccharide or exopolysaccharide producing a Bifidobacterium. Bacteriological properties of the strain JBL05Bifidobacterium longum(NITE BP-82) are shown in table 1 below.

Table 1
A. Morphological properties
(1) the Formfrom 0.6 to 0.8 × 1.0 to 4.0 µm, clavate, Y-shaped and spiral-shaped gram-positive Bacillus
(2) Mobility-
(3) Dispute -
V. Properties of culture*1
(1) the FormSpherical sphere, smooth surface, and circumferentially
(2) SizeDiameter from 0.5 to 2.5 mm
(3) BulgingBulges in the shape of a hemisphere
(4) ColorYellowish-brown or off-white
(5) CharacteristicsSlightly viscous
*1The properties of colonies obtained when applied on BL agar medium (NISSUI PHARMACEUTICAL CO., LTD.), followed by cultivation for 48 hours at 37°C under anaerobic conditions in a closed container containing an AnaeroPack (MITSUBISHI GAS CHEMICAL COMPANY, INC.)
C. Physiological properties
(1) nitrate reduction-
(2) Production of indole-
(3) Catalase-
(4) Optimum temperature for growth 37°C

(5) Optimum pH levelThe pH from 6.5 to 7.0
(6) the Degree of anaerobioticObligately anaerobic
(7) Flatulence-
(8) Assimilation of sugars
Arabinose+
Xylose+
Ribose+
Glucose+
Galactose+
Mannose+
Fructose+
Sucrose+
Maltose+
Cellobiose-
Lactose+
Trehalose-
Melibiose +
Raffinoses+
Melezitose+
Starch±
Glycerin-
Mannitol-
Sorbitol-
Inositol-
(+: positive, -: negative, ±: slightly positive)

On the basis of taxonomic characteristics of the phenotype of the strain JBL05 identified asBifidobacterium longumunder the guide Bergey's Manual of Systematic Bacteriology Vol. 2 (1984), and were deposited in Incorporated Administrative Agency, National Institute of Technology and Evaluation, Patent Microorganisms Depositary (NPMD) (address: 2-5-8 Kazusakamatari, Kisarazu-shi, Chiba-ken 292-0818, Japan) on March 3, 2005 (initial date of Deposit) and adopted as NITE BP-82.

In order to obtain a polysaccharide, a strain JBL05Bifidobacterium longum(NITE BP-82) can be cultivated in a suitable environment for cultivation. The cultivation procedure will be illustrated below, but is not limited to this.

An example environment for the cultivation of an environment for cultivating that contains a carbon source and a nitrogen source, to�which can be used by microorganisms belonging to the genus Bifidobacterium, and optionally contains cysteine hydrochloride, sodium ascorbate and a trace amount of inorganic salts. In particular, the medium for culturing containing skim milk or milk component, is preferable to obtain a large amount of polysaccharide, and can be preferable to use a culture medium that contains enzymatically digested skim milk, cultivator (fish extract, manufactured by Yaizu Suisankagaku Industry Co., Ltd.), lactose and sodium ascorbate, where enzymatic digested low-fat milk produced by cleavage of skim milk with an enzyme, such as protease.

When the strain JBL05Bifidobacterium longum(NITE BP-82) anaerobic cultured in the medium with stirring or alone when the cultivation temperature from 20 to 45°C for 12 to 60 hours, preferably from 15 to 50 hours, while the pH is adjusted to a value of 4 to 7, preferably 5 to 6, can be obtained viscous substance (polysaccharide) in the culture broth.

The polysaccharide can be collected from the obtained culture broth, using methods commonly used by professionals in the field to collect for the substance from the culture broth, including heating, processing of the enzyme, centrifuging, filtering, fashion designs�Itanium membrane and draining. For example, a culture broth which contains a viscous substance (polysaccharide) and the cells of the microorganism, centrifuged to remove cells. When the viscosity of the culture broth is high, the culture broth can be diluted with water, and then centrifuged to remove the cells, for example. Subsequently, the obtained supernatant is treated with an appropriate organic solvent to precipitate proteins, and the precipitate is removed by centrifugation or the like. Additionally, the supernatant is treated with an organic solvent to precipitate the polysaccharide, and the polysaccharide is collected by centrifugation or the like. In more detail, to the supernatant from which cells have been removed, add ethanol to a final concentration of 20% volume and then centrifuged to remove containing protein precipitate, and to the resulting supernatant add ethanol to a final concentration of 50% by volume, and then centrifuged, and the collected precipitate, thus obtaining the crude polysaccharide.

Alternatively, you can also apply the methods for collecting the polysaccharide in combination of organic solvent and cation(s). For example, you can apply the methods for collecting using a monovalent cation(s) and organic solvent, to collect IP�altanium divalent cation(s) and organic solvent (Japanese laid patent publication No. 58-5301) and for collection using trivalent cation(s) and organic solvent (Japanese laid patent publication No. 59-196099) and in a similar way. The cation(s) is preferably used to improve the degree of collection of the polysaccharide. Examples of the monovalent cation(s) include sodium ions, potassium ions and the like; examples of the divalent cation(s) include magnesium ions, calcium ions and the like; and examples of the trivalent cation(s) include aluminum ions, and the like ions. Such cations can be added to the viscous solution, which contains polysaccharide, together with an organic solvent, such as ethanol, to collect polysaccharide in large quantities. To improve the degree of collection of the polysaccharides, it is possible to use divalent or trivalent cation(s) than the monovalent cation(s).

The polysaccharide can be cleaned of crude polysaccharide, using methods widely used by professionals in the field, for example, fractionation using ion exchange resins or fractionation by gel filtration alone or in combination. There are no specific limitations to the method using the ion-exchange resin. For example, the polysaccharide adsorbs on the anion-exchange resin (for example, product name: DEAE Sephadex A-50 (Pharmacia Corporation) or the like), and then eluted in a gradient of sodium chloride. Examples of a method simply�PTO gel filtration include methods using a product called TOYOPEARLHW65S (Tosoh Corporation) and the like.

The structure of the polysaccharide can be determined in the manner specified below. The purified polysaccharide is subjected to acid hydrolysis using an acid, such as formic acid, diluted hydrochloric acid or trifluoroacetic acid, and the hydrolysate is then subjected to HPLC to determine the saccharides (monosaccharides), which is a polysaccharide. The product is then acid hydrolysis in the usual way acetylate and then subjected to gas chromatography (GC) to determine the composition of the constituting saccharides (ratio between the constituent saccharides). Moreover, the purified polysaccharide in the usual way will methylate and then subjected to acid hydrolysis and the hydrolysate restore and then acetylate, and the resulting product was subjected to GC-MS (gas chromatography/mass spectrometry) to determine the type of glycosidic bonds to the components of the polysaccharide. In addition, the polysaccharide analyze NMR in order to identify monosaccharides glycosidic bonds with each other. Pyruvic acid that is associated with the polysaccharide can be qualitatively and quantitatively determined by measuring the recovery of pyruvic acid to lactic acid with the use of lactate dehydrogenase in the presence of NADH.

Strain JBL05Bifidobacterium longum(NITE BP-82) can produce a polysaccharide having SL�blowing following characteristics:

(1) polysaccharide contains galactose, glucose and rhamnose as constituents;

(2) the polysaccharide has a molar ratio of galactose:glucose:rhamnose 3-5:1-3:1;

(3) the polysaccharide may contain pyruvic acid in an amount up to 10 wt%.;

(4) the polysaccharide has a molecular weight in the range from about 50000 to 10000000, preferably from about 200,000 to 2500000 (as determined by gel permeation chromatography/detection multiangle laser light scattering (GPS-MALLS)); and

(5) the polysaccharide may have a repeating structure represented by below formula (I), where the polysaccharide has a molar ratio of galactose:glucose:rhamnose, for example, 4:2:1.

Formula 3

Polysaccharide having the above characteristics can be obtained in the purified polysaccharide fraction obtained after the procedure described in example 1 below.

Molecular weight of the polysaccharide varies depending on the cultivation conditions and the conditions of collection/cleaning. Also, the molecular weight can be adjusted by choosing the suitable culturing conditions and the like.

Polysaccharide possessing a given structure, can are produced by the strain JBL05Bifidobacterium longum(NITE BP-82), isolated from human intestine, although it is possible to apply other microorgan�of SMI to obtain the polysaccharide. Such microorganisms can be determined, for example, releasing intestinal bacteria and analyzing polysaccharides originating from strains, which, as defined, produce capsule polysaccharides of bacteria around, and the collection and purification of the polysaccharide can be carried out as described above.

Strain JBL05Bifidobacterium longum(NITE BP-82) cited as an example of how producing the exopolysaccharide Bifidobacterium, although other bifidobacteria, producing extracellular derived from bifidobacteria polysaccharide, can also be used in the present invention.

Producing the exopolysaccharide of the Bifidobacterium for use in the present invention may constitute Bifidobacterium, which is contained in the bacterial cells obtained from the culture broth after the Bifidobacterium cultured to obtain the polysaccharide. As exopolysaccharide producing bifidobacteria can be applied directly to the culture broth bifidobacteria after cultivation or applying centrifugation method using membrane filtration and the like to obtain cells containing culture broth. Such kind of culture broth can also be used in concentrated, dried or powdered form, or the like. Together with bacterial cell�mi, the chopping means and the like may enter into the composition of exopolysaccharide producing bifidobacteria. The Bifidobacterium can be obtained in the form of viable bacteria according to a widely used technique. Culture broth containing bacterial cells or concentrated or dried form, or the like, can be subjected to sterilization such as sterilization by heating and irradiation, and then optionally followed by homogenization, for receiving the dead bacteria, which can also be used in the present invention. The techniques used to produce such bacterial cells, consistent with the methodology usually used by professionals in the field.

Antiallergic drug

Produced by Bifidobacterium polysaccharide and exopolysaccharide producing a Bifidobacterium exhibit antiallergic action. Anti-allergic action includes as non-limiting examples, the effect of improving the ratio of Th1/Th2 modulating effect in relation Th16, overwhelming inflammation effect that inhibits IgE production, an effect that inhibits the release of chemical mediator such as histamine) and activating lymphocytes impact. Therefore, the present invention produced bifidobacterial or exopolysaccharide producing the Bifidobacterium can be used as an antiallergic drug, and offers anti-Allergy remedy containing produced by Bifidobacterium polysaccharide or exopolysaccharide producing a Bifidobacterium.

Produced by Bifidobacterium polysaccharide or exopolysaccharide producing a Bifidobacterium may enter into the composition as an antiallergic drug of any composition. Action anti-allergic medicines include as non-limiting examples, the suppression of allergic reactions of type I allergic reactions type IV, atopic dermatitis, allergic conjunctivitis and bronchial asthma. Such compositions are applicable for preventing or treating allergic symptoms. Preferably they can suppress atopic dermatitis and contact dermatitis.

Such compositions can be used for food, pharmaceuticals and cosmetics. Compositions can be prepared and applied, in particular, but without limitation, in the form of, for example, powders, granules, tablets, capsules, pastes, creams, gels and liquids. The composition can be applied after mixing with inorganic or organic substances, such as fillers, binders, disintegrants, flavoring remedies, soljubilizatory, suspendresume substance and covering means if necessary. The compositing�tion can be obtained, using methods well known to specialists in this field, for the industrial production of foods, pharmaceutical products and cosmetics.

Compiled for the formulation amount produced by Bifidobacterium polysaccharide can appropriately be determined depending on the purpose, intended use, type, dosage form, symptom, body weight and the like, for oral administration or injection of the composition is preferably prepared so that it was possible to take 1 mg to 10 g, more preferably from 10 mg to 2 g produced by polysaccharide from Bifidobacterium per day. For administration by application to the skin or mucous compiled recipes for quantity produced by Bifidobacterium polysaccharide is preferably from 0.001 to 10 wt.%, more preferably from 0.01 to 1 wt%. of the total weight of the product.

Compiled for the formulation amount of exopolysaccharide producing bifidobacteria can also appropriately be determined depending on the purpose, intended use, type, dosage form, symptom, body weight and the like, and a Bifidobacterium contained in such quantity that can be taken preferably from 106up to 1012more preferably, from 108up to 1011cell transplantatio� a day.

Compositions containing produced by Bifidobacterium polysaccharide or exopolysaccharide producing the Bifidobacterium can be used as compositions for oral use. For example, compositions for oral use can be applied in food compositions or pharmaceutical compositions due to their anti-allergic effect by oral ingestion and can be added to pharmaceutical products for oral administration, liquid food, products, health food, baby food products, food products with the requirement profile of nutrients, foods with specific healing assignments and the like. Compositions containing produced by Bifidobacterium polysaccharide or exopolysaccharide producing a Bifidobacterium, can be prepared in conventional food & beverage products, for example, including as non-limiting examples of various beverages such as milk, soft drinks and jelly, various confectionery products such as candy, gummy sweets, chocolate, biscuits and crackers, and various foodstuffs, such as rice, bread, Udon noodles and sauces. Compositions containing viable cells of exopolysaccharide producing bifidobacteria, can be used for milk fermentation and so Galeev yogurt and fermented milk product which can be taken.

Compositions containing produced by Bifidobacterium polysaccharide, can be used as compositions for external use. For example, the composition for external use can be used as cosmetic compositions or pharmaceutical compositions due to their anti-allergic effect when applying or applied to the skin or mucosa. Cosmetics, in which it is possible to formulate compositions that include as non-limiting examples, for example, facial cleansers, skin lotions, serum, lotions-lotion, sprays, materials for masks, creams, ointments, supplements for baths and the like. Cosmetic compositions can also include compositions produced and sold as therapeutic cosmetics. Pharmaceutical products, in which it is possible to prepare compositions that include as non-limiting examples of compositions for application to mucosa of the nose (e.g., nasal drops and sprays), compositions for use on the mucous membrane of the eye (e.g., eye drops and eye lotions), compositions for application to mucosa of the throat (for example, medicinal mouthwash, oral rinses, sprays and pastilles), and the like. Such pharmaceutical products also include environments�TWA hygiene, such as plasters, bandages and Bandaids.

The present invention will be described in more detail below in the examples, but the present invention is not restricted by them.

EXAMPLES

Example 1: Cultivation of exopolysaccharide producing bifidobacteria and receipt produced by Bifidobacterium polysaccharide

Cultivation of the strain JBL05Bifidobacterium longum(NITE BP-82) and purification of the polysaccharide produced by microorganisms, was performed as described in patent document 1, which is described in detail below.

To a solution of 9 wt%. skim milk was added Pancreatin (Amano Enzyme Inc.) and silicone to a final concentration of 0.36% of the mass. and 0.01% of the mass. accordingly, using 10n NaOH brought the pH of the reaction product up to 8 and allowed to undergo reaction at 55°C for four hours, thereby obtaining enzyme-digested skimmed milk. To enzymatic splitting obezjirennam milk added cultivator (fish extract, manufactured by Yaizu Suisankagaku Industry Co., Ltd.), lactose and sodium ascorbate to a final concentration of 3.0 wt.%, 2,5% of the mass. and 0.2% of the mass. respectively, and then sterilized in autoclave at 121°C for 15 minutes. The reaction product was used as liquid medium for the cultivation.

Strain JBL05Bifidobacterium longum(NITE BP-82) were pre-cultured in a liquid medium, Paul�Chennai, as indicated above, and then inoculable in 5 liters of the same liquid medium to a concentration of 1% (vol./about.) and anaerobic cultured alone at 37°C for 40 hours to obtain a viscous material. The culture broth was centrifuged to remove bacterial cells. Subsequently, the supernatant ethanol was added to a final concentration of 20%, and the reaction product was defended at 4°C overnight and then centrifuged to remove containing protein precipitate. In addition to the supernatant was added ethanol to a final concentration of 50%, and the reaction product was defended at 4°C overnight and then centrifuged and the precipitate was collected, thereby obtaining the crude polysaccharide fraction. Fraction liofilizirovanny and stored.

The crude polysaccharide fraction was additionally fractionally using a column filled with DEAE Sephadex A-50, and suirable using from 0.07 M to 0.5 M NaCl. Fraction was obtained liofilizirovanny to obtain a purified fraction of the polysaccharide.

Example 2: Structural analysis produced by Bifidobacterium polysaccharide

Purified fraction of the polysaccharide obtained in example 1 was subjected to gel filtration on a column filled with TOYOPEARL HW65S, and then checked in terms of molecular weight by GPC-MALLS, and polysaccharide, as has been detected�eno, had a molecular weight of approximately 540000.

Next, the fraction after gel filtration (polysaccharide) hydrolyzable formic acid and the hydrolysate was dried under reduced pressure. Then, the resulting product hydrolyzable trifluoroacetic acid, to obtain a product of hydrolysis. The hydrolysis product was subjected to HPLC using a column of ION-300 (Tokyo Chemical Industry Co., Ltd). As a consequence, the polysaccharide was found to be consisted of galactose, glucose and rhamnose.

The product of hydrolysis in the usual manner restored with the aid of sodium borohydride and then azetilirovanie with acetic anhydride and pyridine. The reaction product was subjected to GC on column R-225 (J&W Scientific). As a consequence, the polysaccharide was found to be consisted of galactose, glucose and rhamnose in a molar ratio of 4:2:1.

When the hydrolysis product was treated by lactate dehydrogenase in the presence of NADH, to form lactic acid, thereby detecting the presence of polysaccharide fraction of pyruvic acid and pyruvic acid in the polysaccharide 5% of the mass.

In order to determine the type of glycosidic bonds of constituents of the polysaccharide, analyzed methylation of the polysaccharide. Fraction after gel filtration (polysaccharide) in the usual way-methylated and then hydrolizable when pomoskovie acid, and the hydrolysate recovered and then azetilirovanie. The obtained product was subjected to GC-MS (mass spectrometry). As a consequence, received methylated saccharides, as shown below: 1,5-di-O-acetyl-2,3,4,6-Tetra-O-methylglycerol,

1,5-di-O-acetyl-2,3,4,6-Tetra-O-methylglycerol,

1,3,4,5-Tetra-O-acetyl-2,6-di-O-Metalmania,

1,3,5-tri-O-acetyl-2,4,6-tri-O-methylglycerol,

1,4,5-tri-O-acetyl-2,3,6-tri-O-methylglycerol,

1,4,5-tri-O-acetyl-2,3,6-tri-O-methylglycerol and

1,4,5,6-Tetra-O-acetyl-2,3-di-O-methylglycerol.

In addition, the glycosidic linkages of the components was checked by NMR. It was found from these data that the polysaccharide had the following structure I (a repetitive pattern)

Formula 4

Example 3: Improving the ratio of Th1/Th2 effect produced by Bifidobacterium polysaccharide

Splenocytes obtained from mice C3H/HeJ (age 8 weeks, male, CLEA Japan, Inc.), were cultured at 37°C for 72 hours in an atmosphere of 5% CO2in RPMI-1640 medium containing fetal bovine serum and antibiotics (a mixture of antibiotics-antifungal agent, Nacalai Tesque, Inc.), supplemented with purified polysaccharide fraction obtained in example 1, was dissolved in water to final concentration of 20 μg/ml or 200 μg/ml. the Culture supernatant was recovered and measured variations�radio interferon-γ (IFN-γ), which is a Th1 cytokine, and interleukin-4 (IL-4), which is a Th2 cytokine, using ELISA (BIOSOURCE, Invitrogen). A control culture was prepared using the same procedure described above, except that the same amount of water was added instead of the purified polysaccharide fraction.

The results are shown in Fig.1 (A) to (C). Fig. 1(A) is a graph showing the number of IFN-γ produced in response to stimulation of splenocytes produced by Bifidobacterium polysaccharide in vitro. The vertical axis presents the number of produced IFN-γ (PG/ml), and the horizontal axis shows the experimental group. Fig.1(B) is a graph showing the amount of IL-4 produced in response to stimulation of splenocytes produced by Bifidobacterium polysaccharide in vitro. The vertical axis presents the number of produced IL-4 (PG/ml), and the horizontal axis shows the experimental group. Fig.1(C) is a graph showing the relationship between IFN-γ and IL-4 produced in response to stimulation of splenocytes produced by Bifidobacterium polysaccharide in vitro. The vertical axis presents the ratio of IFN-γ to IL-4 (IFN-γ/IL-4), and the horizontal axis shows the experimental group.

These results demonstrate that d�the addition of purified polysaccharide fraction (produced by Bifidobacterium polysaccharide) increases the amount of produced IFN-γ and reduces the amount of produced IL-4 concentration-dependent manner compared with the control culture with the same amount of water is added to the purified polysaccharide fraction.

Therefore, it has been shown that the addition produced by Bifidobacterium polysaccharide increases levels of the Th1 cytokine, and thus, Th1 becomes predominant in the ratio of Th1/Th2, namely, providing anti-allergic effect.

Example 4: Anti-allergic effect produced by Bifidobacterium polysaccharide

Purified fraction of the polysaccharide obtained in example 1 was dissolved in phosphate buffer (PBS) and was orally given separately five mice BALB/c (at the age of 8 weeks, males, Kiwa Laboratory Animals Co., Ltd.) with the help of nourishing probe every day (20 mg/kg body weight/day). For the control group was orally given PBS alone five mice each day. For the positive control group was orally given prednisolone (Sigma) of five mice each day (3 mg/kg body weight/day). On the 4th day after the start of administration of 10 μl of 0.3% 2,4,6-trinitro-1-chlorobenzene (TNCB) (Tokyo Chemical Industry Co., Ltd) dissolved in acetone (Nacalai Tesque, Inc.), inflicted (sensitization) on their right ears and the same amount of acetone alone was applied to their left ears, which was repeated every day from 4 days to 19 days after start of application of TNCB (sensitization). Oral administration, as described above, also continued� after the beginning of sensitization. The thickness of ears was measured by applying each applying TNCB from the first day of sensitization. Measurements carried out each day the same researcher in the same conditions, and expected mean values (five mice per group). 20 days after the beginning of sensitization of the ear examined histologically. For histological examination, the sections were prepared after dissection of the ears, fixed in 10% containing neutral buffer formalin (Wako Pure Chemical Industries, Ltd.), and then stained with hematoxylin-eosin (H&E) (ordered Applied Medical Research Laboratory) and examined under a microscope.

Fig.2 is a graph showing the change with time of the thickness of the ears in mice treated by oral administration produced by Bifidobacterium polysaccharide after the beginning of sensitization (five mice per group). The vertical axis presents the thickness of auricles (mm) and the horizontal axis is days after the beginning of sensitization (days). The shaded circle represents the control group (only PBS), the unfilled circle represents the positive control group (prednisolone), filled triangle represents the group treated by oral administration produced by Bifidobacterium polysaccharide.

Fig.3 shows photomicrographs of stained H&E �cuts ears-exposed mice including mice receiving the oral introduction produced by Bifidobacterium polysaccharide on day 20 after the beginning of sensitization. Photomicrographs represent, starting from the top image to the control group (only PBS), positive control group (prednisolone) and the treated group with the introduction produced by Bifidobacterium polysaccharide.

Oral administration of purified polysaccharide fraction (produced by Bifidobacterium polysaccharide) significantly inhibited the increase in the thickness of the auricles, as in the case of the positive control, treated by oral administration of prednisolone, compared with controls, treated by oral administration of PBS alone (Fig.2). The results of histological examination of the ears also showed that oral administration of purified polysaccharide fraction (produced by Bifidobacterium polysaccharide) inhibits inflammation induced in the auricles, and inhibits the increase in the thickness of the auricles, as in the case of the positive control, treated by oral administration of prednisolone (Fig.3). Thus, the purified polysaccharide fraction showed anti-allergic effect.

Example 5: Anti-allergic effect of exopolysaccharide producing bifidobacteria

The impact of strain JBL05Bifdobacterium longum (NITE BP-82) was tested using the same method as in example 4.

Cells JBL05Bifidobacterium longumproducing exopolysaccharide bifidobacteria, suspended in PBS and then oral was administered to five mice BALB/c (at the age of 8 weeks, males, Kiwa Laboratory Animals Co., Ltd.) with the help of nourishing probe every day (108viable bacterial cells/mouse/day). For the control group was orally given PBS alone five mice each day. For the positive control group was orally given prednisolone (Sigma) of five mice each day (3 mg/kg body weight/day). On the 4th day after the start of administration of 10 μl of 0.3% 2,4,6-trinitro-1-chlorobenzene (TNCB) (Tokyo Chemical Industry Co., Ltd) dissolved in acetone (Nacalai Tesque, Inc.), inflicted (sensitization) on their right ears and the same amount of acetone alone was applied to their left ears, which was repeated every day from 4 days to 19 days after start of application of TNCB (sensitization). Oral administration, as described above, also continued after the beginning of sensitization. The thickness of the auricle was measured by applying each application of TNCB, from the first day of sensitization. Measurements carried out each day the same researcher in the same conditions, and expected mean values (five mice per group). On day 20 after the beginning of sensitization of the ear examined histologically. For histo�oricheskogo research after dissection sections were prepared from the ears, fixed in 10% containing neutral buffer formalin (Wako Pure Chemical Industries, Ltd.), and then stained with hematoxylin-eosin (H&E) (ordered in Applied Medical Research Laboratory) and examined under a microscope.

Fig.4 is a graph showing the change with time of the thickness of the ear in mice treated by oral administration of exopolysaccharide producing the Bifidobacterium after the beginning of sensitization (five mice per group). The vertical axis presents the thickness of the auricle (mm), and the horizontal axis is days after the beginning of sensitization (days). The shaded circle represents the control group (only PBS), the unfilled circle represents the positive control group (prednisolone), filled triangle represents the group treated by oral administration of exopolysaccharide producing a Bifidobacterium.

Fig.5 shows photomicrographs of stained H&E sections of the ears exposed mice, including mice, receiving by oral administration of exopolysaccharide producing the Bifidobacterium on day 20 after the beginning of sensitization. Micrograph from the top, represent the image for the control group (only PBS), positive control group (prednisolone) and the treated group with the introduction producira�th the exopolysaccharide of the Bifidobacterium.

Oral administration of viable cells ofBifidobacterium longumstrain ofJBL05 (exopolysaccharide producing bifidobacteria) significantly inhibited the increase in the thickness of the ear compared with the control group treated by oral administration of PBS alone (Fig.4). The results of histological examination of the ears also showed that oral administration of viable cells ofstrain ofJBL05Bifidobacterium longum(exopolysaccharide producing bifidobacteria) inhibits inflammation induced in the ear, and inhibits the increase in the thickness of the auricle (Fig.5). Thus, viable cells ofstrain ofJBL05Bifidobacterium longumshowed antiallergic action.

Example 6: Anti-allergic properties when applied topically produced by Bifidobacterium polysaccharide

Nine mice NC/Nga (aged 7 weeks, male, Japan SLC, Inc.) applied 10 µl of 0.5% of 2,4,6-trinitro-1-chlorobenzene (TNCB) (Tokyo Chemical Industry Co., Ltd) dissolved in acetone (Nacalai Tesque, Inc.), on their right ears (sensitization) and the same amount of acetone alone was applied to their left ears, what was repeated twice every day, starting 4 days after the start of application of TNCB (sensitization). Mice were divided into three groups so that the thickness of the skin of the auricle was uniform (three mice per group). Ml purified polysaccharide fraction, obtained in example 1 dissolved in water (1 mg/ml), were applied to the front and rear surfaces of the ear of each of three mice each day, starting 9 days after the beginning of sensitization. Similarly inflicted water as control, the other three mice and prednisolone in water (25 mg/ml) as positive control were applied to other mice. TNCB was applied to mice for more than 30 minutes before topical application produced by Bifidobacterium polysaccharide, water, or prednisolone every other day. The thickness of the auricle was measured by applying, for each application of TNCB from the first day of sensitization. Measurements carried out each day the same researcher in the same conditions, and calculated average values (three mice per group).

Fig.6 is a graph showing the change with time of the thickness of the ears in mice treated with external application produced by Bifidobacterium polysaccharide after the beginning of sensitization (three mice per group). The vertical axis presents the thickness of auricles (mm), and the horizontal axis is days after the beginning of sensitization (days). Shaded circles represent the control group of application (only water), unfilled circles represent group applying positive control (prednisolone), filled triangles before�property group treated with external application produced by Bifidobacterium polysaccharide.

External application of purified polysaccharide fraction (produced by Bifidobacterium polysaccharide) inhibits the increase in the thickness of the auricles, as in the case of prednisolone (positive control) compared with the group treated when applying water only (control) (Fig.6). Thus, produced by Bifidobacterium polysaccharide also showed anti-allergic properties when applied topically.

Industrial applicability

The present invention has provided an opportunity to provide antiallergic action, using Bifidobacterium, which can be preferentially colonize the human intestine. Produced by Bifidobacterium polysaccharide or exopolysaccharide producing the Bifidobacterium can be prepared in the form of food, cosmetics, pharmaceutical products and the like to take advantage of their anti-allergic effect.

1. Antiallergic agent containing a polysaccharide containing galactose, glucose and rhamnose as constituents, where the polysaccharide contains galactose, glucose and rhamnose in a molar ratio of 3-5:1 to 3:1 and
the polysaccharide contains any of the following structures:
[formula 1]
br/> [formula 2]

2. Anti-allergic agent according to claim 1, wherein the polysaccharide is prepared from a microorganism belonging to the genus Bifidobacterium.

3. Anti-allergic agent according to claim 2, wherein the microorganism belonging to the genus Bifidobacterium is a Bifidobacterium longum.

4. Anti-allergic agent according to claim 3, in which Bifidobacterium longum is a strain JBL05 Bifidobacterium longum (NITE BP-82).

5. The use of a polysaccharide according to claim 1 as part of an antiallergic drug.

6. Antiallergic agent containing the microorganism,
wherein the microorganism belongs to the genus Bifidobacterium and produces extracellular polysaccharide containing galactose, glucose and rhamnose as constituents, where the polysaccharide contains galactose, glucose and rhamnose in a molar ratio of 3-5:1 to 3:1 and
the polysaccharide contains any of the following structures:
[formula 1]

[formula 2]

7. Anti-allergic agent according to claim 6, wherein the microorganism is a strain JBL05 Bifidobacterium longum (NITE BP-82).

8. Agent for oral use containing anti-allergic agent according to any one of claims. 1-4, 6 and 7.

9. Remedy for oral administration according to claim 8 for the suppression of atopic dermatitis and conta�Togo dermatitis.

10. Agent for external use containing the anti-allergic agent according to any one of claims. 1-4.

11. The agent for external use according to claim 10 for the inhibition of atopic dermatitis and contact dermatitis.

12. The use of the genus Bifidobacterium according to claim 6 as components of an antiallergic drug.



 

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