US20040102416A1 - Antiallergic composition - Google Patents

Antiallergic composition Download PDF

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Publication number
US20040102416A1
US20040102416A1 US10/702,607 US70260703A US2004102416A1 US 20040102416 A1 US20040102416 A1 US 20040102416A1 US 70260703 A US70260703 A US 70260703A US 2004102416 A1 US2004102416 A1 US 2004102416A1
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stachyose
atopic dermatitis
dermatitis
group
antiallergic
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US10/702,607
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Toshiro Sato
Shuichi Kamo
Yutaka Ohtani
Yasushi Ueno
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Honen Corp
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Honen Corp
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Assigned to KABUSHIKI KAISHA HONEN CORPORATION reassignment KABUSHIKI KAISHA HONEN CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAMO, SHUICHI, OHTANI, YUTAKA, SATO, TOSHIRO, UENO, YASUSHI
Publication of US20040102416A1 publication Critical patent/US20040102416A1/en
Priority to US11/187,913 priority Critical patent/US7166582B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to an antiallergic composition, particularly to an antiallergic composition usable for daily intake for preventing onset of atopic dermatitis, and medicines, beverages and foods using the composition.
  • Atopic dermatitis occurs as dry lichen like eczema, and is an intractable disease accompanying severe itch. While little is known about the mechanism of the onset of eczema of the atopic dermatitis, it has been made clear that the disease is related to allergic reactions type I and type IV.
  • a type I allergy is an immediate allergy mainly related to IgE antibodies, wherein chemical transmitters such as histamine and leukotriene, and enzymes are released upon reaction of allergenic substances (allergens) with IgE on mast cells and basophils to cause inflammatory reactions on the skin.
  • type I allergies are considered not to be directly related to lesions of eczema caused by the atopic dermatitis.
  • a type IV allergy is called as a delayed allergy or cell mediated allergy that causes an inflammatory reaction related to lymphocytes, and the onset of the disease takes 24 to 72 hours after sensitization.
  • stachyose has an antiallergic action, particularly an action for suppressing atopic dermatitis, and have completed the present invention.
  • the present invention provides an antiallergic composition comprising stachyose as an effective ingredient.
  • Stachyose is a tetrasaccharide contained, for example, in soy beans. Stachyose is a hardly digestible oligosaccharide, and has been known as a factor for activating Lactobacillus bifidus known to have an intestinal function controlling drug among intestinal bacteria, and for accelerating absorption of calcium through the digestive intestine.
  • the action for suppressing atopic dermatitis as disclosed in the present invention has not been known in the art.
  • a standard of the desirable amount of intake is 1 to 15 g per day.
  • a content of less than 1 g is not so effective, while a content of more than 20 g may induce temporary diarrhea, although it depends on physical conditions.
  • FIG. 1 is a graph showing the scores of dermatitis in the stachyose administration group and control group
  • FIG. 2 is a graph showing the scores of dermatitis in the saccharose administration group and control group
  • FIG. 3 is photographs of appearances of test mice
  • FIG. 4 is a graph showing the IgE levels in the stachyose administration group, and saccharose administration group and control group.
  • FIG. 5 is a graph showing scores of dermatitis in the stachyose administration group and conrol group in the conventional NC/Nga mice.
  • NC/Nga Tnd Crj male mice at six weeks of age were habituated for two weeks.
  • the animals decided as healthy were used for the experiments after an observation of general conditions and body weight measurement.
  • the mice were divided into three groups so that the body weight was averaged
  • One group was composed of nine mice.
  • a purified livesock feed (AIN93G produced by Oriental Yeast Co.) was used as a basic feed.
  • mice in Group 1 (a control group) was fed with the purified feed, while the mice in Groups 2 and 3 were fed with a feed prepared by adding the test samples as shown in Table 1 in the basic feed.
  • Table 1 TABLE 1 Group 1 AIN93G feed Group 2 AIN93G feed + stachyose 0.5%
  • Stachyose used in this test was purified to a purity of 98% by ion exchange chromatography after extracting from soybeans with 70% ethanol. Saccharose used in this test was purchased from Wako Junyaku Kabushiki Kaisha.
  • mice at eight weeks of age were used for sensitization as follows.
  • the abdomen of the mouse anesthetized with ether was clipped with a pair of hair clippers and a solution of 2,4,6-trinitrochlorobenzene (named as picryl chloride (PiCl) hereinafter) for sensitization was applied on the abdomen after clipping and on the footpad in a proportion of 150 ⁇ L/one animal.
  • Induction was started four days after sensitization, and repeated once a week for five weeks.
  • the back of the mouse anesthetized with ether was clipped with a pair of hair clippers, and the PiCl solution (150 ⁇ L/one animal) was applied on the clipped back and right and left ears (at the outer and inner sides of each ear).
  • the hair was clipped after the second induction depending on the growth of the hair.
  • the symptoms of the atopic dermatitis were observed as follows. The skin condition was observed twice a week starting from a day before the first induction, and the following items were evaluated based on the criteria of clinical syndromes of the human atopic dermatitis. Each mouse was photographed on the day of autopsy.
  • the serum total IgE concentration was measured as follows.
  • the blood was extracted on day four before administration, and on 43rd day after administration (the day for starting administration is counted as the first day).
  • the blood (200 ⁇ L) is sampled from the orbital plexus venosus using a heparinated capillary.
  • the blood sampled was placed in a tube, centrifuged (at about 4° C. and 1660 g for 15 minutes), and IgE in the supernatant was used for the serum total IgE measurement by an enzyme-linked immunosorbent assay (EIA).
  • EIA enzyme-linked immunosorbent assay
  • FIGS. 1 and 2 The data of the score of dermatitis are shown in FIGS. 1 and 2. As shown in FIG. 1, progress of the atopic dermatitis was evidently bred in the stachyose administration group (Group 2). No effects were observed in the saccharose administration group (Group 3) as shown in FIG. 2. The photograph of the appearance of a representative mouse in each group is shown in FIG. 3. An evident difference of the appearance of the skin was observed in the mouse in the stachyose administration group as compared with the mouse in the control group (Group 1).
  • stachyose While the expression mechanism of the anti-atopic dermatitis action of stachyose has not been made clear yet, it may be conjectured that stachyose probably acts on intestinal microorganisms to improve immunity of the digestive intestine. Otherwise, stachyose may directly act on the cells related to immunity of the digestive intestine. While the atopic dermatitis is considered to be related to the immediate allergy and delayed allergy (type IV), it was made clear from the results of the present invention that stachyose has a function against the delayed allergy since stachyose does not influence the level of IgE.
  • raffinose as a minute component of the soy bean oligosaccharide has an ant-atopic dermatitis action (Japanese Patent Application Laid-open No. Hei 11-255656), raffinose has an action for suppressing production of IgE (Japanese Patent Application Laid-open No. 2001-288093). Accordingly, the action of stachyose shown in the present invention is evidently different from the action of raffinose.
  • mice at four weeks of age were habituated for one week The mice were divided into two groups so that the body weight was averaged. One group was composed of six mice. All the mice were freely fed on the purified livestock feed (AIN93G) before grouping, and the stachyose administration group was fed on a feed supplemented with 1% stacyose after grouping. The sldn conditions were observed and evaluated once per two weeks from the day of start of grouping. The evaluation method was the same as in performance evaluation method 1.
  • stachyose used in the present invention are not particularly rested, and any one of natural stachyose, chemically synthesized stachyose and enzymatically synthesized stachyose may be used.
  • stachyose originating from soy beans is economically advantageous. Since stachyose is a principal ingredient of the soybean oligosaccharide, the oligosaccharide may be direly used as the stachyose source, or it may be used after purification by ion exchange chromatography.
  • Beverage supplemented with soy bean oligosaccharide and stachyose was produced with sterilization after mixing.
  • composition blended with stachyose of the present invention exhibits an atopic dermatitis suppressing effect.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Food Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Nutrition Science (AREA)
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  • Polymers & Plastics (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Non-Alcoholic Beverages (AREA)
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Abstract

The present invention provides a safe and excellent antiallergic composition, and more particularly a preventive and therapeutic composition for atopic dermatitis, including an antiallergic composition blended with stachyose as an effective ingredient, and a medicine, food and beverage containing the composition.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The present invention relates to an antiallergic composition, particularly to an antiallergic composition usable for daily intake for preventing onset of atopic dermatitis, and medicines, beverages and foods using the composition. [0002]
  • 2. Description of the Related Art [0003]
  • Allergic diseases such as atopic dermatitis have caused severe problems in recent years. Atopic dermatitis occurs as dry lichen like eczema, and is an intractable disease accompanying severe itch. While little is known about the mechanism of the onset of eczema of the atopic dermatitis, it has been made clear that the disease is related to allergic reactions type I and type IV. A type I allergy is an immediate allergy mainly related to IgE antibodies, wherein chemical transmitters such as histamine and leukotriene, and enzymes are released upon reaction of allergenic substances (allergens) with IgE on mast cells and basophils to cause inflammatory reactions on the skin. However, type I allergies are considered not to be directly related to lesions of eczema caused by the atopic dermatitis. A type IV allergy is called as a delayed allergy or cell mediated allergy that causes an inflammatory reaction related to lymphocytes, and the onset of the disease takes 24 to 72 hours after sensitization. [0004]
  • Many protective and therapeutic actions have been attempted for preventing atopic dermatitis. Representative examples thereof include (1) an external medication using external medicines such as adrenocortical hormones, and (2) administration of medicines that suppress immediate reactions such as antihistamine agents. However, the effect of medication is not always sufficient depending on the physical conditions of patents, and the medication has a risk of rebound. [0005]
  • In addition, people with allergic physical conditions have been increasing every year. In extreme examples, the allergic symptom is so sever that daily life of the patient is hindered, which leads to social problems. Under these situations, there is an urgency to develop safe and excellent antiallergic medicines to solve the above mentioned problems, particularly prophylactics and medicaments of the atopic dermatitis. [0006]
    • SUMMARY OF THE INVENTION
  • It is an object of the present invention to provide a safe and excellent antiallergic composition, particularly preventive and therapeutic compositions of the atopic dermatitis by solving the problems above on allergic diseases. [0007]
  • The inventors have found, through intensive studies for attaining the objects above, that stachyose has an antiallergic action, particularly an action for suppressing atopic dermatitis, and have completed the present invention. [0008]
  • The present invention provides an antiallergic composition comprising stachyose as an effective ingredient. [0009]
  • Stachyose is a tetrasaccharide contained, for example, in soy beans. Stachyose is a hardly digestible oligosaccharide, and has been known as a factor for activating [0010] Lactobacillus bifidus known to have an intestinal function controlling drug among intestinal bacteria, and for accelerating absorption of calcium through the digestive intestine. However, the action for suppressing atopic dermatitis as disclosed in the present invention has not been known in the art.
  • While the content of stachyose in the antiallergic composition is not particularly restricted, a standard of the desirable amount of intake is 1 to 15 g per day. A content of less than 1 g is not so effective, while a content of more than 20 g may induce temporary diarrhea, although it depends on physical conditions.[0011]
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a graph showing the scores of dermatitis in the stachyose administration group and control group; [0012]
  • FIG. 2 is a graph showing the scores of dermatitis in the saccharose administration group and control group; [0013]
  • FIG. 3 is photographs of appearances of test mice; [0014]
  • FIG. 4 is a graph showing the IgE levels in the stachyose administration group, and saccharose administration group and control group; and [0015]
  • FIG. 5 is a graph showing scores of dermatitis in the stachyose administration group and conrol group in the conventional NC/Nga mice.[0016]
    • DESCRIPTION OF THE PREFERRED EMBODIMENTS Performance Evaluation Test 1
  • The performance of stachyose mixed in livestock feeds was evaluated against the dermatitis induced by repeated application of hapten on an NC/Nga mouse frequently used as an atopic dermatitis model animal (M. Okada et al., Oyo Yakuri/Pharmcometrics, vol. 59, 135-139 (2000)). [0017]
    • Test Method
  • NC/Nga Tnd Crj male mice at six weeks of age (purchased from Nihon Charles River) were habituated for two weeks. The animals decided as healthy were used for the experiments after an observation of general conditions and body weight measurement. The mice were divided into three groups so that the body weight was averaged One group was composed of nine mice. A purified livesock feed (AIN93G produced by Oriental Yeast Co.) was used as a basic feed. [0018]
  • The mice in Group 1 (a control group) was fed with the purified feed, while the mice in [0019] Groups 2 and 3 were fed with a feed prepared by adding the test samples as shown in Table 1 in the basic feed.
    TABLE 1
    Group 1 AIN93G feed
    Group
    2 AIN93G feed + stachyose 0.5%
    Group 3 AIN93G feed + saccharose 0.5%
  • Stachyose used in this test was purified to a purity of 98% by ion exchange chromatography after extracting from soybeans with 70% ethanol. Saccharose used in this test was purchased from Wako Junyaku Kabushiki Kaisha. [0020]
  • The mice at eight weeks of age were used for sensitization as follows. The abdomen of the mouse anesthetized with ether was clipped with a pair of hair clippers and a solution of 2,4,6-trinitrochlorobenzene (named as picryl chloride (PiCl) hereinafter) for sensitization was applied on the abdomen after clipping and on the footpad in a proportion of 150 μL/one animal. Induction was started four days after sensitization, and repeated once a week for five weeks. In the induction period, the back of the mouse anesthetized with ether was clipped with a pair of hair clippers, and the PiCl solution (150 μL/one animal) was applied on the clipped back and right and left ears (at the outer and inner sides of each ear). The hair was clipped after the second induction depending on the growth of the hair. [0021]
  • The symptoms of the atopic dermatitis were observed as follows. The skin condition was observed twice a week starting from a day before the first induction, and the following items were evaluated based on the criteria of clinical syndromes of the human atopic dermatitis. Each mouse was photographed on the day of autopsy. [0022]
  • (1) Observed items [0023]
  • a. pruritus/itching [0024]
  • b. erythema/hemorrhage [0025]
  • c. edema [0026]
  • e. excoriation/erosion [0027]
  • f. scaring/dryness [0028]
  • (2) Evaluation point [0029]
  • 0 no syndrome [0030]
  • 1 mild syndrome [0031]
  • 2 intermediate syndrome [0032]
  • 4 severe syndrome [0033]
  • The serum total IgE concentration was measured as follows. The blood was extracted on day four before administration, and on 43rd day after administration (the day for starting administration is counted as the first day). The blood (200 μL) is sampled from the orbital plexus venosus using a heparinated capillary. The blood sampled was placed in a tube, centrifuged (at about 4° C. and 1660 g for 15 minutes), and IgE in the supernatant was used for the serum total IgE measurement by an enzyme-linked immunosorbent assay (EIA). [0034]
  • The score of dermatitis, serum total IgE concentration, and the average body weight and standard deviation thereof were calculated. The significant difference was evaluated by the student's test. A significance level of 5% was evaluated as significant, and the results of the Students t-test were expressed by dividing into a level of less than 5% (P<0.05) and less than 1% (P<0.01). [0035]
    • Results and Discussion
  • The data of the score of dermatitis are shown in FIGS. 1 and 2. As shown in FIG. 1, progress of the atopic dermatitis was evidently bred in the stachyose administration group (Group 2). No effects were observed in the saccharose administration group (Group 3) as shown in FIG. 2. The photograph of the appearance of a representative mouse in each group is shown in FIG. 3. An evident difference of the appearance of the skin was observed in the mouse in the stachyose administration group as compared with the mouse in the control group (Group 1). [0036]
  • The levels of the serum total IgE as an immediate type (type I) allergy inducing substance are shown in FIG. 4. These levels were not different from the level in the control group. [0037]
  • While the expression mechanism of the anti-atopic dermatitis action of stachyose has not been made clear yet, it may be conjectured that stachyose probably acts on intestinal microorganisms to improve immunity of the digestive intestine. Otherwise, stachyose may directly act on the cells related to immunity of the digestive intestine. While the atopic dermatitis is considered to be related to the immediate allergy and delayed allergy (type IV), it was made clear from the results of the present invention that stachyose has a function against the delayed allergy since stachyose does not influence the level of IgE. While it is known in the art that raffinose as a minute component of the soy bean oligosaccharide has an ant-atopic dermatitis action (Japanese Patent Application Laid-open No. Hei 11-255656), raffinose has an action for suppressing production of IgE (Japanese Patent Application Laid-open No. 2001-288093). Accordingly, the action of stachyose shown in the present invention is evidently different from the action of raffinose. [0038]
    • Performance Evaluation Test 2
  • The effect of stachyose on the dermatitis was investigated using conventional grade NC/Nga mice that spontaneously start the atopic dermatitis without applying any haptens (H. Matsuda et al., International Immunology, vol. 9. 461-466 (1997)). [0039]
    • Test Method
  • Conventional grade female NC/Nga mice at four weeks of age (purchased from Nihon SLC) were habituated for one week The mice were divided into two groups so that the body weight was averaged. One group was composed of six mice. All the mice were freely fed on the purified livestock feed (AIN93G) before grouping, and the stachyose administration group was fed on a feed supplemented with 1% stacyose after grouping. The sldn conditions were observed and evaluated once per two weeks from the day of start of grouping. The evaluation method was the same as in [0040] performance evaluation method 1.
    • Results
  • While the dermatitis was observed on the face of five of six mice in the control group on the week four after grouping, no onset of the dermatitis was observed in the stachyose administration group. While evident dermatitis was observed not only on the face but also on the ears in the [0041] control group 6 to 8 weeks after grouping, no onset of dermatitis was observed at all in the stachyose administration group. The scores of dermatitis are shown in FIG. 5. The scores of dermatitis show that the effect of stachyose is evident
  • The origin and production method of stachyose used in the present invention are not particularly rested, and any one of natural stachyose, chemically synthesized stachyose and enzymatically synthesized stachyose may be used. However, stachyose originating from soy beans is economically advantageous. Since stachyose is a principal ingredient of the soybean oligosaccharide, the oligosaccharide may be direly used as the stachyose source, or it may be used after purification by ion exchange chromatography. [0042]
    • EXAMPLES
  • While the present invention is described with reference to examples, the present invention is by no means restricted by the examples as set forth below. [0043]
    • Example 1
  • [0044]
    [Ingredient of Capsule]
    Starting Material Blend (mg) per 1 Capsule
    (1) Stachyose 50
    (2) DHA Oil 50
    (3) Beefsteak Plant Oil 50
    (4) Bee Wax 50
  • These materials were capsulated using gelatin after mixing. [0045]
    • Example 2
  • [0046]
    [Tablet]
    Starting Material Blend (mg) per 1 Capsule
    (1) Stachyose 100
    (2) Lactose 100
    (3) Cellulose Powder 50
    (4) Reduced Maltose 30
    (5) Processed Starch 10
    (6) Calcium Carbonate 1
  • These materials were formulated into tablets after mixing. [0047]
    • Example 3
  • [0048]
    [Beverage]
    Starting Material Blend (g) per 1 Bottle
    (1) Soy Bean Oligosaccharide (Stachyose 50%) 2
    (2) Sucrose 10
    (3) Coffee Powder 5
    (4) Cow Milk 183
  • Beverage supplemented with soy bean oligosaccharide and stachyose was produced with sterilization after mixing. [0049]
  • It is evident that the composition blended with stachyose of the present invention exhibits an atopic dermatitis suppressing effect. [0050]

Claims (5)

What is claimed is:
1. An antiallergic composition comprising stachyose as an effective ingredient.
2. The antiallergic composition according to claim 1, wherein the stachyose is originated from soybeans.
3. The antiallergic composition according to any one of claims 1 and 2. wherein an antiallergic function is an action for suppressing atopic dermatitis.
4. The antiallergic composition according to any one of claims 1 to 3, wherein the antiallergic function is an action for suppressing a delayed allergy.
5. A medicine, and beverage and food comprising the antiallergic composition according to any one of claims 1 to 4.
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EP1529532A1 (en) * 2003-11-07 2005-05-11 Kabushiki Kaisha Honen Corporation Antiallergic composition comprising stachyose
JP7274720B2 (en) * 2018-09-26 2023-05-17 株式会社クラブコスメチックス Estrogen receptor expression promoter and cell proliferation promoter

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US5994326A (en) * 1998-03-10 1999-11-30 Nippon Tensaiseito Kabushiki Kaisha Anti-atopic dermatitis composition
US20030157200A1 (en) * 2000-07-07 2003-08-21 Frederic Bonte Use of oligosaccharides to stimulate beta-endorphin production

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KR20010015628A (en) 1998-07-27 2001-02-26 존 이. 앤더슨 Topical compositions containing sialyl sugars and their derivatives
FR2802414B1 (en) 1999-12-20 2003-06-27 G Pharm Lab COMPOSITION, ESPECIALLY COSMETIC OR DERMATOLOGICAL, CONTAINING OLIGOSACCHARIDES, METHOD FOR THE PREPARATION THEREOF AND METHOD FOR THE COSMETIC TREATMENT
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US5994326A (en) * 1998-03-10 1999-11-30 Nippon Tensaiseito Kabushiki Kaisha Anti-atopic dermatitis composition
US20030157200A1 (en) * 2000-07-07 2003-08-21 Frederic Bonte Use of oligosaccharides to stimulate beta-endorphin production

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