Allergic disease inhibiting composition

Abstract

To provide an anti-allergic composition.SOLUTION: An anti-allergic composition of this invention includes as active principle: one or more selected from a group consisting of vegetable estrogen having a benzyl butane skeleton, mammal lignan derived from the vegetable estrogen, and a dehydrated condensate of the vegetable estrogen, or salt thereof; or a prodrug of those substances.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for suppressing, for example, allergic diseases. [Background technology]

[0002] In recent years, the number of people suffering from allergic diseases such as food allergies, atopic dermatitis, and hay fever has been increasing, becoming a social problem. In particular, the number of people suffering from hay fever has increased significantly, and a survey conducted by the Tokyo Metropolitan Government in 2016 reported that approximately 48.8% of Tokyo residents suffer from cedar pollen allergy (Non-Patent Document 1). Hay fever causes various problems in daily life, such as allergic rhinitis such as sneezing, runny nose, and nasal congestion, and allergic conjunctivitis such as itchy eyes, leading to a decrease in the patient's QOL.

[0003] Allergic rhinitis and allergic conjunctivitis that develop in association with hay fever are classified as type I allergies based on their onset mechanism. Type I allergies develop from antigen-specific immunoglobulin E (IgE). IgE produced in the body in response to antigen sensitization forms a cross-linked structure with mast cells, basophils, etc., and binds to antigens that have entered the body from the outside, causing degranulation of mast cells, etc. At this time, histamine, as well as physiologically active substances such as leukotrienes and prostaglandins produced by the metabolism of fatty acids, are released, leading to the onset of allergies (Non-Patent Document 2).

[0004] Research into allergic diseases has revealed that food-derived components are involved in allergic diseases. Among these, not only are there those involved in the onset and progression of symptoms, but also those that contribute to the suppression and improvement of symptoms. The possibility that ingesting these food-derived components may be able to control the onset of allergies has attracted attention.

[0005] For these reasons, the idea of ​​suppressing the onset of allergic symptoms through daily eating habits is spreading, and there is a demand for food-derived ingredients and foods containing them that are intended to suppress the onset of allergies and alleviate symptoms.

[0006] From such a viewpoint, various studies have been conducted. Non-Patent Document 3 reports that administration of puerarin contained in Kakkonto reduces allergic symptoms. However, with the ingestion of puerarin, Foxp3-positive CD4-positive T cells and CD103-positive CD11c-positive dendritic cells increase in the intestinal tract, and immune tolerance is induced, so there is concern about a decrease in the acquired immune system in the intestinal tract and a decrease in immune response to pathogens.

[0007] Non-Patent Document 4 reports that equol, an intestinal bacterial metabolite of soy isoflavone, induces an increase in immunoglobulin E (IgE), which is the starting point of allergic diseases, and exacerbates allergic symptoms.

[0008] Non-Patent Documents 5 and 6 report that omega-3 fatty acids 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid reduce allergic symptoms without inducing immune tolerance. However, since both 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid are polyunsaturated fatty acids, they are easily oxidized, and there are concerns that oxidation may reduce activity or cause odor. Non-Patent Documents 5 to 7 report that allergic diseases are reduced by ingesting flaxseed oil, which is rich in α-linolenic acid, a type of omega-3 fatty acid. However, α-linolenic acid, the main component of flaxseed oil, is a polyunsaturated fatty acid, and there are similar concerns.

[0009] In light of the above-mentioned background, there is a demand for food-derived ingredients or foods containing such ingredients that can suppress the onset of allergies or reduce allergic symptoms, and compositions that have characteristics that make them easy for consumers to use, such as being highly stable, capable of being stored for a long time, and being easily soluble in water.

[0010] Lignans, on the other hand, are a type of phenolic compound with a 2,3-dibenzylbutane skeleton. They are formed by the coupling of monomer units called precursors (e.g., cinnamic acid, caffeic acid, ferulic acid, coumaric acid, and gallic acid). Lignans are widely distributed in plants and are found in various plant parts such as roots, leaves, stems, seeds, and fruits. In seeds and fruits, lignans exist as glycosidic conjugates bound to fiber components. In mammals, lignan precursors (glycosidic conjugates) are provided by the ingestion of grain-derived products.

[0011] Linseed (flaxseed) is the seed (kernel) of Linum usitatissimum, a flax plant native to the Mediterranean region of Europe, and is sometimes called flaxseed. Linseed is known to be an edible plant that contains a high concentration of lignans, one of which is secoisolariciresinol diglucoside (SDG). Plant lignans such as secoisolariciresinol diglucoside are converted by intestinal bacteria into secoisolariciresinol (SECO), 2,3-bis(3,4-dihydroxybenzyl)butene-1,4-diol, and further to enterodiol (ED) or enterolactone (EL).

[0012] Lignans are known to have estrogen-like effects and are also called "phytoestrogens". In particular, enterolactone is known to have properties that are useful and can be used in the treatment of many beneficial diseases. For example, it has been shown that phytoestrogens are useful for breast cancer (Non-Patent Document 8) and hypercholesterolemia (Non-Patent Document 9). It is also known that menopausal symptoms are improved in postmenopausal women by ingesting a diet containing flaxseed (Non-Patent Document 10). Enterolactone is thought to exert a preventive or ameliorative effect on such estrogen-dependent diseases by binding to estrogen receptor α or inhibiting steroid metabolism aromatase.

[0013] Anhydrosecoisolariciresinol (AHS) is a type of lignan derivative obtained by treating SDG, secoisolariciresinol monoglucoside (SMG) or SECO with acid. Non-Patent Document 11 reports that AHS has an antioxidant effect, and Non-Patent Document 12 reports that AHS has an inhibitory effect on breast cancer cell proliferation. AHS is expected to be a lignan derivative that exerts physiological activity in the body. However, the effect of AHS on allergies and its use have not been clarified.

[0014] As described above, it is widely known that lignans and their derivatives have useful health-promoting or health-maintaining functions. However, it has not been known that they have effects such as suppressing the onset of allergic diseases, alleviating symptoms, or improving symptoms. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Tokyo Metropolitan Government Bureau of Social Welfare and Public Health Survey on the Actual Conditions of Hay Fever Patients 2016, p.39, 5-2 Estimated Prevalence of Cedar Pollen Allergy in Tokyo [Non-Patent Document 2] Galli SJ et al., Nat Med., 2012 May 4;18(5):693-704. [Non-Patent Document 3] Yamamoto et al., Biochem Biophys Res Commun., 2019 Aug 27;516(3):626-631. [Non-Patent Document 4] Sakai et al., J Nutr Sci Vitaminol (Tokyo), 2010;56(1):72-6. [Non-Patent Document 5] Sawane et al., Nutrients, 2019 Nov 22;11(12). [Non-Patent Document 6] Kunisawa et al., Sci Rep., 2015 Jun 11;5:9750. [Non-Patent Document 7] Hirakata et al., FASEB J., 2019 Mar;33(3):3392-3403. [Non-Patent Document 8] Ingram D et al., Clin Endocrinol (Oxf), 2002 Mar;56(3):321-8. [Non-Patent Document 9] Zhang W et al., Br J Nutr., 2008 Jun;99(6):1301-9. [Non-Patent Document 10] Tarpila S et al., Eur J Clin Nutr., 2002 Feb;56(2):157-65. [Non-Patent Document 11] Ping Lan et al., J Agric Food Chem., 2019 Dec 26;67(51):14152-14159. [Non-Patent Document 12] Abdelali Lehraiki et al., J Med Food., 2010 Aug;13(4):834-41. Summary of the Invention [Problem to be solved by the invention]

[0016] In view of the above-mentioned circumstances, the present invention aims to provide an anti-allergy composition that is highly safe and can suppress allergic symptoms without inducing immune tolerance, and further, an anti-allergy composition that is highly stable and highly soluble in water. [Means for solving the problem]

[0017] As a result of intensive research conducted to solve the above problems, the present inventors discovered that phytoestrogens having a benzylbutane skeleton, mammalian lignans derived from said phytoestrogens, and dehydrated condensates of said phytoestrogens have the effect of suppressing allergic diseases, thereby completing the present invention.

[0018] That is, the present invention includes the following. (1) An anti-allergic composition comprising, as an active ingredient, one or more selected from the group consisting of phytoestrogens having a benzylbutane skeleton, mammalian lignans derived from said phytoestrogens, and dehydrated condensates of said phytoestrogens, or a salt thereof, or a prodrug thereof. (2) The antiallergic composition according to (1), wherein the phytoestrogen is secoisolariciresinol and / or its glycoside. (3) The antiallergic composition according to (1) or (2), wherein the mammalian lignan is one or more selected from the group consisting of enterodiol, enterolactone, enterodiol conjugates, and enterolactone conjugates. (4) The antiallergic composition according to any one of (1) to (3), wherein the dehydrated condensate is anhydrosecoisolariciresinol. (5) A composition for suppressing degranulation of mast cells and basophils, comprising the antiallergic composition according to any one of (1) to (4). (6) An antiallergic food or drink comprising the antiallergic composition according to any one of (1) to (4). (7) An antiallergic drug comprising the antiallergic composition according to any one of (1) to (4). Effect of the Invention

[0019] The antiallergic composition according to the present invention is highly safe because the active ingredient is derived from flax, which is a common dietary ingredient, and can reduce allergic symptoms without inducing immune tolerance. Furthermore, the active ingredient of the antiallergic composition according to the present invention is highly stable and can be stored for a long time, and is water-soluble, so it can be easily ingested in daily life. [Brief description of the drawings]

[0020] [Figure 1] This paper outlines a method for evaluating the effect of secoisolariciresinol diglucoside (SDG) on allergic diseases using a mouse model of allergic rhinitis. [Diagram 2] 1 is a graph showing the suppression of rhinitis symptoms by administration of SDG using a mouse model of allergic rhinitis. [Diagram 3] FIG. 1 is a graph showing plasma ovalbumin (OVA)-specific IgE (OVA-IgE), OVA-specific IgG1 (OVA-IgG1), and OVA-specific IgG2a (OVA-IgG2a) concentrations after administration of SDG in a mouse model of allergic rhinitis. [Figure 4] 1 is a graph showing the results of a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells, regarding the effects of phytoestrogens and mammalian lignans on allergic diseases. [Diagram 5] 1 is a graph showing the results of a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells, regarding the effect of phytoestrogens on allergic diseases. [Figure 6] 1 is a graph showing the results of a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells, regarding the effects of mammalian lignan aglycones and conjugates on allergic diseases. [Figure 7] 1 is a graph showing the results of a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells, regarding the effect of flaxseed extract or flaxseed acid decomposition product on allergic diseases. [Figure 8] 1 is a graph showing the results of a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells, regarding the effect of anhydrosecoisolariciresinol (AHS) on allergic diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention will be described in detail below.

[0022] The antiallergic composition according to the present invention (hereinafter referred to as "the composition according to the present invention") contains, as an active ingredient, one or more selected from the group consisting of phytoestrogens having a benzylbutane skeleton, mammalian lignans derived from the phytoestrogens, and dehydrated condensates of the phytoestrogens, or their salts or prodrugs. The composition according to the present invention can prevent, treat or improve allergic diseases such as hay fever, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, contact dermatitis, food allergies, and bronchial asthma. Therefore, the composition according to the present invention can also be used as an agent for preventing, treating or improving allergic diseases. Furthermore, the composition according to the present invention has a degranulation inhibitory effect and can also be used as a composition for inhibiting degranulation of mast cells and basophils.

[0023] In the present invention, the phytoestrogens, which are the active ingredients, refer to a group of compounds contained in plants and having estrogenic activity. Lignans and isoflavones are known as such phytoestrogens. Lignans are a group of polyphenolic substances having a dibenzylbutane skeleton, which are produced by dimerization of substituted cinnamic alcohols known as monolignols (oxidative condensation between the β-positions of the side chains of substituted cinnamic alcohols) starting from phenylalanine, and are widely distributed in plants. Some lignans are classified as phytoestrogens based on their chemical structure and physiological activity, but not all lignans have estrogenic activity. Therefore, lignans having estrogenic activity can be referred to as "phytoestrogens having a benzylbutane skeleton". In the present invention, lignans having estrogenic activity will be simply referred to as "phytoestrogens", but this term is not intended to include plant-derived components having estrogenic activity that are not classified as lignans such as isoflavones (not having a benzylbutane skeleton).

[0024] Known phytoestrogens include sesamin, hydroxymatairesinol, matairesinol, secoisolariciresinol (SECO), syringaresinol, arctigenin, lariciresinol, pinoresinol, anhydrosecoisolariciresinol, and the like, as well as their glycosides (for example, in the case of secoisolariciresinol, secoisolariciresinol diglucoside (SDG) and secoisolariciresinol monoglucoside (SMG)). These are found in seeds of flax, pumpkin, sunflower, peanut, soybean, etc.; grains such as wheat, rye, barley, oats, etc.; fruits such as blackberries, cranberries, strawberries, etc.; green and yellow vegetables such as broccoli, etc. In particular, flaxseed, which is the seed of the flax plant (scientific name: Linum usitatissimum), is rich in secoisolariciresinol diglucoside, and contains small amounts of matairesinol, pinoresinol, isolariciresinol, and their glycosides, etc.

[0025] The method for producing lignans from flaxseed is not particularly limited as long as it is a known method. For example, flaxseed is pulverized with a pulverizer such as a mixer or homogenizer, and the pulverized product is degreased with a fat-soluble organic solvent such as n-hexane to prepare a defatted linseed pulverized product. Lignans are extracted from the defatted linseed pulverized product using a lower alcohol (ethanol, methanol, n-propanol, isopropanol, n-butanol, etc.) or a water-containing alcohol thereof, and if necessary, saponification and neutralization are performed, and secoisolariciresinol diglucoside can be obtained by fractionation and purification using octadecyl silica, silica gel, etc. as an adsorbent. Alternatively, an oil extraction by-product obtained by extracting linseed oil by a cold press method or the like may be used instead of the defatted linseed pulverized product.

[0026] As the flaxseed lignans, in addition to flax itself, a flaxseed extract extracted from flaxseed by a known method may be used, or a product obtained by purification may be used. Furthermore, flaxseed containing a large amount of lignans may be used as it is or after processing. For example, flaxseed contains about 100 mg of SDG per 10 g, so it can be crushed and added to the composition. In the present invention, flaxseed can be used regardless of the place of origin (domestic or foreign), the variety for cultivation, or the variety for oil extraction, and can be used as a raw material regardless of whether it is roasted or not. In addition, flaxseed meal produced in the oil extraction process may be used as a raw material.

[0027] In the present invention, the phytoestrogen is not particularly limited and may be any known phytoestrogen, preferably secoisolariciresinol and / or its glycoside. Secoisolariciresinol diglucoside is more preferable from the viewpoints of preservation and diversification of intake forms due to its high stability and high solubility in water.

[0028] On the other hand, with regard to mammalian lignans, which are active ingredients in the present invention, phytoestrogens themselves do not play an estrogenic role, but are converted to enterodiol, enterofuran or enterolactone via intermediate metabolites such as secoisolariciresinol and 2,3-bis(3,4-dihydroxybenzyl)butene-1,4-diol by the metabolism of intestinal bacteria, and exert estrogenic effects. In general, metabolites that are metabolized by intestinal bacteria and have estrogenic effects are called "mammalian lignans". In the present invention, the mammalian lignans are not particularly limited, and may be metabolites of phytoestrogenic origin and have estrogenic effects, and are preferably enterodiol (ED), enterofuran (EF), enterolactone (EL) or conjugates thereof.

[0029] The dehydration condensation product of phytoestrogens, which is the active ingredient in the present invention, is a five-membered cyclic ether formed by dehydration condensation of the hydroxyl groups at the γ-position of the benzylbutane skeleton side chain, such as anhydrosecoisolariciresinol (AHS).

[0030] The method for obtaining the dehydration condensation product of phytoestrogens is not particularly limited as long as it is a known dehydration condensation method. For example, when secoisolariciresinol diglucoside (SDG), secoisolariciresinol monoglucoside (SMG), or secoisolariciresinol (SECO) is used as the starting material, the AHS in which SECO is etherified into a five-membered ring can be obtained by heating and stirring under acidic conditions, resulting in the elimination of sugar and dehydration condensation. In addition, a product extracted from linseed or defatted linseed ground material containing SDG, SMG, or SECO using a lower alcohol (ethanol, methanol, n-propanol, isopropanol, n-butanol, etc.) or a water-containing alcohol thereof may be used. Alternatively, an oil extraction by-product obtained by extracting linseed oil by a cold press method or the like may be used instead of the defatted linseed ground material.

[0031] Mammalian lignans can be administered parenterally, such as by intraperitoneal injection or intravenous injection, in addition to oral administration, but are preferably administered orally as oral preparations. In addition to directly ingesting mammalian lignans, foods containing phytoestrogens such as sesamin, hydroxymatairesinol, matairesinol, secoisolariciresinol (SECO), secoisolariciresinol diglucoside (SDG), syringaresinol, arctigenin, lariciresinol, pinoresinol, and anhydrosecoisolaiciresinol can be orally ingested to increase the amount of mammalian lignans in the body through metabolism by intestinal bacteria.

[0032] The dehydrated condensate of phytoestrogens can be taken orally or parenterally, for example, by intraperitoneal injection or intravenous injection, but is preferably administered as an oral preparation.

[0033] Phytoestrogens, mammalian lignans and dehydrated condensates of phytoestrogens are understood to include any mixture of geometric isomers or stereoisomers or isomers (e.g., racemates) of these compounds. Salts, adducts and complexes of these compounds are also understood to be included in this term. In addition, dehydrated condensates of phytoestrogens (e.g., AHS) produced during the processing of natural products containing phytoestrogens (e.g., flaxseed containing SDG, SMG, and SECO) can be ingested as is or after processing such as extraction.

[0034] As the salts of phytoestrogens, mammalian lignans, and dehydrated condensates of phytoestrogens, pharma- ceutically acceptable salts are preferred, and examples thereof include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid, etc., or organic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid), amino acids (e.g., glutamic acid), etc., alkali metal salts such as sodium salts and potassium salts, lysine salts, and arginine salts.

[0035] The water-soluble substance forming the mammalian lignan conjugate may be one or more selected from glucuronic acid, sulfuric acid, glutathione, and amino acids. The amino acids may be amino acids present in the body, such as essential amino acids. The bond molar ratio of mammalian lignan:water-soluble substance is preferably 1:1 to 1:3, more preferably 1:1 to 1:2, and even more preferably 1:1.

[0036] Prodrugs of phytoestrogens, mammalian lignans, and dehydrated condensates of phytoestrogens or their salts refer to any compound that, when administered to a biological system, produces phytoestrogens, mammalian lignans, dehydrated condensates of phytoestrogens, or their salts as a result of a spontaneous chemical reaction or by catalyzing an enzymatic or metabolic reaction.

[0037] The phytoestrogens, mammalian lignans, dehydrated condensates of phytoestrogens or their salts or their prodrugs may be provided in the form of pharmaceutical preparations, dietary supplements, nutritional preparations for clinical use or functional foods.

[0038] The composition according to the present invention may further contain, as an optional component, a component known to have an allergic disease suppressing effect, such as α-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, and other ω3 highly unsaturated fatty acids, triterpenes, dietary fiber, edible microorganisms, polyphenols, and derivatives thereof.

[0039] As the ω3 highly unsaturated fatty acid, preferred are α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. These can be isolated and blended alone or used as a mixture, and fats and oils containing a large amount of these can be used as they are. α-linolenic acid is contained in large amounts in seed-derived oils such as perilla oil, rapeseed (canola) oil, soybean oil, and linseed oil, and is preferably added as edible linseed oil. Edible linseed oil can be obtained, for example, by squeezing the raw material linseed by a low-temperature compression method, and then passing through a refining process to remove impurities such as moisture, gums, free fatty acids, pigments, and odors. Examples of edible fats and oils containing a large amount of eicosanepentaenoic acid and docosahexaenoic acid include fish oil. The fats and oils to be blended can also be used alone or in mixtures.

[0040] The composition according to the present invention can be formulated together with an auxiliary agent into any form to produce a pharmaceutical product that can be administered orally or parenterally. For example, the dosage form for oral administration includes solid dosage forms such as tablets, oral fast disintegrating tablets, capsules, caplets, lozenges, powders, granules, and fine granules, and liquid dosage forms such as elixirs, emulsions, syrups, and suspensions. For parenteral administration, the dosage form includes nasal drops, injections, eye drops, patches, suppositories, and skin topical preparations. In addition, pharmaceutical products also include quasi-drugs.

[0041] In the case of a solid dosage form, various additives used in the manufacture of general pharmaceutical preparations may be contained in appropriate amounts, such as excipients, binders, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, pH adjusters, surfactants, etc.

[0042] When the pharmaceutical is formulated into a liquid dosage form, it can be formulated in a conventional manner in the presence of a pH adjuster, a buffer, a solubilizer, a suspending agent, an isotonic agent, a stabilizer, a preservative, etc., as necessary.

[0043] The form of the skin external preparation is not particularly limited, and may be, for example, a pharmaceutical product such as an ointment, cream, or external liquid. In addition to the above-mentioned components, components usually used in pharmaceutical skin external preparations, such as whitening agents, moisturizing agents, various skin nutrient components, ultraviolet absorbers, antioxidants, oily components, surfactants, thickeners, alcohols, coloring agents, water, preservatives, and fragrances, may be appropriately blended as necessary.

[0044] In one embodiment, in the case of an agent for preventing, treating or ameliorating allergic rhinitis, the composition according to the present invention is preferably administered intranasally as a nasal drop.

[0045] Also, in one embodiment, the medicament (or pharmaceutical formulation) is preferably an oral formulation.

[0046] Although the dosage range of a pharmaceutical containing the composition of the present invention varies depending on the age, weight, sex, severity of symptoms, and administration form of the patient or subject (human) to be administered, the amount of the active ingredient, phytoestrogens, mammalian lignans and / or dehydrated condensates of phytoestrogens or salts thereof, or prodrugs thereof, is about 1 mg / day to about 6000 mg / day per adult, preferably about 10 mg / day to about 600 mg / day per adult, or about 0.01 mg / day to about 10000 mg / day per adult, preferably about 0.1 mg / day to about 1000 mg / day per adult, and more preferably about 1 mg / day to about 100 mg / day per adult.

[0047] The composition according to the present invention may be prepared as a functional food, a health food, a food for specified health uses, a food with nutritional function claims, or the like, a food for special uses (e.g., food for the sick), a dietary supplement, a supplement, or the like. For example, the composition according to the present invention can be used in a functional food labeling claim that indicates "suppresses allergic diseases," "reduces eye and nose discomfort," or the like. As a supplement, it can be in the form of, for example, a tablet, a pill, a capsule (including a hard capsule, a soft capsule, and a microcapsule), a powder, a granule, a fine granule, a lozenge, or a liquid (including a syrup, milk, or suspension) together with various additives used in the manufacture of general supplements.

[0048] The composition of the present invention can be added to food and drink.The food and drink that can be added is not particularly limited, but includes, for example, confectionery such as candy, gummy candy, chewing gum, etc.; confectionery such as cookies, crackers, biscuits, chocolate, pudding, jelly, snacks, rice crackers, buns, yokan, etc.; cold desserts such as ice cream, ice candy, sorbet, gelato, etc.; bakery foods such as donuts, cakes, bread, French bread, croissants, etc.; noodles such as udon, soba, Chinese noodles, Kishimen, etc.; rice dishes such as white rice, red rice, pilaf, etc.; sauces such as curry, stew, dressing, etc.; paste products such as ham, sausage, kamaboko, chikuwa, fish sausage, etc.; various side dishes such as tempura, croquette, hamburger, etc.; beverages such as juice, tea, etc.

[0049] Typical foods containing the composition according to the invention are in particular functional foods, food supplements, nutritional supplements, pharma foods, nutraceuticals, health foods, designer foods or any food.

[0050] Although it varies depending on the age, weight, sex, severity of symptoms, and intake form of the patient or subject (human) to be ingested, the intake amount of the food and drink containing the composition of the present invention is preferably 1 to 6000 mg, more preferably 20 to 300 mg, or preferably 0.01 to 10000 mg, more preferably 1 to 1000 mg, and even more preferably 20 to 300 mg per day for adults as the amount of the active ingredient, phytoestrogens, mammalian lignans, and / or dehydrated condensates of phytoestrogens, or their salts, or their prodrugs. For children, the amount of the active ingredient, phytoestrogens, mammalian lignans, and / or dehydrated condensates of phytoestrogens, or their salts, or their prodrugs, per day is preferably 1 to 3000 mg, more preferably 2 to 150 mg, or preferably 0.01 to 3000 mg, more preferably 0.1 to 300 mg, and even more preferably 2 to 150 mg.

[0051] The composition according to the present invention can be incorporated into pet food. Pet food refers to food for pet mammals such as dogs, cats, hamsters, and squirrels. In the present invention, the form of the pet food is not particularly limited, and examples thereof include dry type, wet type, semi-moist type, biscuit type, sausage type, jerky type, powder, granule, capsule, and the like.

[0052] The effect of the composition according to the present invention can be evaluated, for example, in an allergic rhinitis model mouse in which allergic rhinitis is reproduced by administration of ovalbumin (J Immunol. 2007 Nov 1;179(9):5897-906.). For example, the composition according to the present invention is orally administered to the allergic rhinitis model mouse, and the number of sneezes (a symptom of allergic rhinitis) in a specific period of time is counted. If the number of sneezes is significantly reduced compared to a control group not administered the composition according to the present invention, it can be determined that the composition according to the present invention suppresses allergic rhinitis.

[0053] The effect of the composition according to the present invention can be evaluated, for example, by the inhibitory effect on degranulation (β-hexosaminidase release) in a β-hexosaminidase assay measurement test using rat-derived basophilic RBL-2H3 cells (J Nutr. 2013 May;143(5):632-9.). For example, Anti-DNP-IgE is added to rat-derived basophilic RBL-2H3 cells to sensitize the cells, and then the composition according to the present invention is added and cultured. Then, DNP-BSA is added, cultured, and the amount of β-hexosaminidase released in the culture supernatant is measured. If the amount of β-hexosaminidase released is significantly reduced compared to a control group to which the composition according to the present invention is not added, it can be determined that the composition according to the present invention has a degranulation inhibitory effect and suppresses allergies.

[0054] On the other hand, in accordance with the description of the composition of the present invention above, the present invention also relates to a method for suppressing an allergic disease, or a method for preventing, treating or ameliorating an allergic disease, which comprises administering or ingesting the composition of the present invention to a patient or subject (human). EXAMPLES

[0055] The present invention will be described in more detail below using examples, but the technical scope of the present invention is not limited to these examples.

[0056] [Example 1] Effects of phytoestrogens, mammalian lignans, and dehydrated condensates of phytoestrogens on allergic diseases 1. Materials and Methods <Method of Extracting and Purifying Secoisolariciresinol Diglucoside (SDG) from Linseed> SDG was obtained by the method described in JP 2006-347978 A. That is, linseed seeds were crushed and defatted with n-hexane, and then refluxed with aqueous methanol. The extract was saponified and neutralized, and the SDG fraction was purified using octadecyl silica and silica gel as adsorbents.

[0057] <Preparation of Amanilic Acid Decomposition Product> Linseed acid decomposition products were obtained by acid decomposition of linseed extract. Linseed extract was dissolved in 1N hydrochloric acid aqueous solution and reacted at 90℃ for 3 hours. The reaction solution was collected in a separatory funnel, and the reaction vessel was washed with an equal amount of ethyl acetate, and collected in the same separatory funnel. After the separation operation, the ethyl acetate layer was collected and the solvent was removed with an evaporator. The obtained fraction was used as linseed acid decomposition products in the subsequent experiments.

[0058] <Preparation of Anhydrosecoisolariciresinol (AHS)> AHS was obtained with reference to Non-Patent Documents 11 and 12. First, 300 mg of SDG was dissolved in 25 ml of 1N hydrochloric acid solution and reacted at 90°C for 3 hours. The reaction solution was collected in a separatory funnel, and the reaction vessel was washed with an equal amount of ethyl acetate and collected in the same separatory funnel. After the separation operation, the ethyl acetate layer was collected and mixed with an equal amount of water again to perform a separation operation. The ethyl acetate layer was collected and the solvent was removed using an evaporator. The obtained residue was dissolved in a solvent of hexane / ethyl acetate 2:3 and subjected to silica gel column chromatography. Column separation was performed with a developing phase of hexane / ethyl acetate 2:3, and the fraction containing AHS was collected and concentrated under reduced pressure. It was confirmed that the obtained fraction contained only AHS by a single spot of thin layer chromatography, and was used in subsequent experiments.

[0059] <Preparation of mammalian lignan conjugates> Enterodiol glucuronide (ED-Glu) and enterolactone glucuronide (EL-Glu), which are mammalian lignan conjugates, were prepared with reference to Brian Dean et al., Arch Biochem Biophys. 2004 Sep 15;429(2):244-51. Standards of enterodiol (ED) and enterolactone (EL) were obtained from Sigma-Aldrich. 0.15 M Tris-HCl buffer containing 1.25 mM uridine 5'-diphosphoglucuronic acid, 10 mM D-saccharic acid 1,4-lactone, 10 mM (±)-dithiothreitol, 10 mM magnesium chloride, and 0.02% Triton-X100 was prepared, and ED or EL was added to 100 μM. The mixture was incubated at 37°C for 1 hour, and the reaction was stopped by adding an equal volume of methanol. The supernatant was collected by centrifugation and mixed with chloroform / methanol / water (reaction solution) in a ratio of 2:1:1 for liquid-liquid partitioning. The upper layer was collected, concentrated, and subjected to preparative HPLC to separate the peaks corresponding to ED-Glu or EL-Glu. The separated fractions were concentrated to dryness, redissolved in PBS or HBSS, and used in subsequent experiments.

[0060] <Allergy evaluation test using mice> The effects on allergic diseases were evaluated using the following method, as outlined in Figure 1. Seven-week-old female Balb / c mice (Japan SLC) were purchased and pre-fed with AIN93G diet for one week. After that, in parallel with feeding with AIN93G diet, 200μl of SDG solution suspended in distilled water at a concentration of 10mg / ml was orally administered to the mice three times a week. Distilled water was orally administered to the control group. Oral administration of SDG and distilled water was continued until the end of the study.

[0061] Four weeks after the start of oral administration, an ovalbumin (OVA)-induced allergic rhinitis model was applied. A suspension of 10 μg of OVA and 1 mg of aluminum hydroxide in PBS was injected twice intraperitoneally to sensitize the mice. One week after the final sensitization, a solution of 250 μg of OVA in 20 μl of PBS was administered intranasally to the mice to induce allergic rhinitis. 20 μl of PBS was administered to the group in which rhinitis was not induced. The severity of allergic symptoms was evaluated by counting the number of sneezes within 5 minutes immediately after administration. Nasal administration was continued for 7 consecutive days.

[0062] On the seventh day, the mice were intranasally administered the drug again, and blood was collected from the mice in the presence of heparin 5 minutes after administration. The blood was centrifuged to collect plasma, which was then frozen and stored until use. The concentration of OVA-specific IgE (OVA-IgE) in plasma was measured using a DS Mouse IgE ELISA kit (DS Pharma). In addition, the concentrations of OVA-specific IgG1 and IgG2a (OVA-IgG1, OVA-IgG2a) in plasma were measured by the method described in Non-Patent Document 4.

[0063] <Allergy evaluation test using β-hexosaminidase assay> The effects of phytoestrogens, mammalian lignans, mammalian lignan conjugates, linsecoisolariciresinol, and linsecoisolariciresinol on allergic diseases were evaluated by a β-hexosaminidase assay using rat-derived basophilic RBL-2H3 cells.

[0064] RBL-2H3 cells were plated in a 24-well plate at 2.5 × 10 5The cells were seeded at 1 cell / well, cultured for 24 hours (5% carbon dioxide, 37°C), washed twice with PBS, and then 500 μl of HBSS buffer containing Anti-DNP-IgE (50 ng / ml) was added and cultured for 2 hours to sensitize the cells. The Anti-DNP-IgE solution was removed, and the cells were washed twice with HBSS buffer. HBSS buffer containing 0.1% ethanol containing 100 μM of either standard or preparation of secoisolariciresinol (SECO), enterodiol (ED), enterolactone (EL), enterodiol glucuronide (ED-Glu), enterolactone glucuronide (EL-Glu), and anhydrosecoisolariciresinol (AHS) was prepared, and 400 μl was added to each well. 400 μl of HBSS buffer containing 0.1% ethanol was added to the negative control and positive control. These were cultured for 10 minutes in a 37°C, 5% carbon dioxide incubator. HBSS solution was added to the negative control, and 100 μl of DNP-BSA solution (1 μg / ml) was added to the other controls, mixed well, and cultured for 30 minutes in a 37°C, 5% carbon dioxide incubator.

[0065] After the reaction, the culture supernatant was collected and used as the Supernatant. 500 μl of 0.1% Triton X-100 solution was added to the remaining cells, and the cells were left to stand on ice for 5 minutes to dissolve, which was used as the cell lysate. 50 μl each of the Supernatant and Cell lysate were placed in a 96-well microplate and pre-incubated at 37°C for 5 minutes. 100 μl of p-nitrophenyl-2-acetamido-2-deoxy-β-D-glucopranosid (3.3 mM) was added to each well, mixed well, and then incubated at 37°C for 30 minutes. 100 μl of 2 mM glycine buffer was added, mixed well, and the absorbance at 405 nm was measured using a microplate reader. Since the added sample may have absorption at 405 nm, the supernatant and cell lysate were collected separately, and the absorbance was measured simultaneously when the reaction stop solution was added followed by the substrate solution. The β-hexosaminidase release rate (%) was calculated using the following formula, and the release rate (%) at the time of sample addition was calculated when the control was taken as 100% release rate.

[0066] β-Hexosaminidase release rate (%) = 100 × [(S - Sc) / {(S - Sc)+(CL - CLc)}] CL: absorbance of cell lysate CLc: Absorbance of cell lysate when reaction stop solution was added followed by substrate solution S: Supernatant absorbance Sc: Absorbance of Supernatant when reaction stop solution was added followed by substrate solution

[0067] 2. Results and Discussion <Allergy assessment: Effect of SDG on the number of sneezes in mice> When the number of sneezes was measured, the number of sneezes was reduced in the SDG-administered group compared to the distilled water-administered group, and allergic symptoms were alleviated (Figure 2). At this time, no difference was observed in the plasma OVA-IgE concentration between the two groups, and no difference was observed in OVA-IgG1 or OVA-IgG2a between the two groups (Figure 3). From the above, it was thought that SDG can be used as an ingredient to alleviate allergic symptoms without inducing immune tolerance.

[0068] <Allergy assessment: Effects of phytoestrogens and mammalian lignans on β-hexosaminidase release rate> The β-hexosaminidase release rate (%) was calculated, and the release rate was decreased when secoisolariciresinol (SECO), enterodiol (ED), enterodiol glucuronide (ED-Glu), enterolactone (EL) and enterolactone glucuronide (EL-Glu) were added (Figures 4-6). From the above, it was found that phytoestrogens (secoisolariciresinol), mammalian lignans (enterodiol and enterolactone) and mammalian lignan conjugates have degranulation inhibitory effects and exert antiallergy effects. In addition, it was found that the aglycones of mammalian lignans reduced the β-hexosaminidase release rate more effectively than mammalian lignan conjugates (Figure 6).

[0069] <Allergy evaluation: Effect of linseed oil hydrolysate on β-hexosaminidase release rate> When the degranulation inhibitory activity was evaluated using RBL-2H3, 100 μg / ml flaxseed extract did not inhibit the β-hexosaminidase release rate (%), but the release rate was inhibited when the same concentration of flaxseed acid decomposition product was added (Figure 7). This suggests that the products obtained by acid decomposition of flaxseed extract contain some substance with degranulation inhibitory activity.

[0070] <Allergy evaluation: Effect of AHS on β-hexosaminidase release rate> Alcohol extracts of flaxseed contain SDG, which is known to be converted to AHS by acid decomposition. From this, it was speculated that AHS exerts anti-allergy activity. When AHS was added, it exerted a degranulation inhibitory effect (Figure 8). From the above, it was found that AHS, which is generated by acid decomposition of SDG contained in flaxseed, has a degranulation inhibitory effect and exerts an anti-allergy effect.

Claims

1. An anti-allergic composition comprising, as an active ingredient, one or more selected from the group consisting of phytoestrogens having a benzylbutane skeleton, mammalian lignans derived from said phytoestrogens, and dehydrated condensates of said phytoestrogens, or their salts or prodrugs.

2. 2. The antiallergic composition according to claim 1, wherein the phytoestrogen is secoisolariciresinol and / or its glycoside.

3. 3. The antiallergic composition according to claim 1 or 2, wherein the mammalian lignan is one or more selected from the group consisting of enterodiol, enterolactone, enterodiol conjugates and enterolactone conjugates.

4. The antiallergic composition according to any one of claims 1 to 3, wherein the dehydrated condensate is anhydrosecoisolariciresinol.

5. A composition for suppressing degranulation of mast cells and basophils, comprising the antiallergic composition according to any one of claims 1 to 4.

6. An antiallergic food or drink comprising the antiallergic composition according to any one of claims 1 to 4.

7. An antiallergic drug comprising the antiallergic composition according to any one of claims 1 to 4.

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