JP7350304B2 - Allergic rhinitis symptom suppressant - Google Patents

Description

The present invention relates to an allergic rhinitis symptom suppressant.

In recent years, the number of allergic patients has been increasing year by year due to changes in the natural environment, dietary habits, and increased stress. The onset mechanisms of allergies are generally classified into four types, from type I to type IV, and mixed types of these types also exist. Type I allergies, such as hay fever, allergic rhinitis, atopic dermatitis, bronchial asthma, and urticaria, are called immediate allergies because their symptoms appear within a short time after the antigen acts on them.

The mechanism of action of type I allergy is characterized by the induction of IgE antibodies and the release (degranulation) of chemical mediators such as histamine and leukotrienes from mast cells and basophils. First, allergens (pollen, indoor dust, dust mites, mold, etc.) that invade from the outside world are presented to T cells by antigen-presenting cells such as dendritic cells and macrophages, in which part of the allergens are bound to MHC class II molecules. and Th2 cells are activated and differentiated. Th2 cytokines (IL-4, IL-5, IL-9, IL-13, etc.) released by Th2 cells induce class switching of B cells, and IgE antibodies are produced. Binds to FcεRI on the surface of basophils in the blood. During the next invasion, the allergen is recognized by IgE antibodies bound to the surface of mast cells and basophils, and crosslinks are formed between the IgE antibodies, and this stimulation triggers mast cells and basophils to release chemical mediators ( As a result of degranulation, various allergic symptoms occur. For example, in allergic rhinitis (including hay fever), histamine released from mast cells and basophils in the nasal mucosa causes vasodilation and increased vascular permeability, resulting in sneezing, watery rhinorrhea, and nasal congestion ( Nasal congestion) and other unpleasant symptoms of rhinitis appear. So far, drugs that suppress and improve allergic symptoms mediated by IgE antibodies and chemical mediators include, for example, chemical mediator release inhibitors that weaken the activity of mast cells and suppress the release of chemical mediators, and drugs that inhibit the release of chemical mediators from histamine H1 receptors. A histamine H1 antagonist that inhibits the function of histamine by binding competitively to leukotriene receptors, a leukotriene antagonist that inhibits the function of leukotriene by binding competitively to leukotriene receptors, and suppresses the production and action of thromboxane. In addition to anti-allergic agents such as thromboxane inhibitors/antagonists and Th2 cytokine inhibitors that suppress the production of IL-4 and IL-5, there are also steroid agents that reduce inflammation by weakening immune responsiveness. Furthermore, among antihistamines, second- or third-generation antihistamines that have both histamine antagonism and suppressive action on the release of chemical mediators from mast cells are sometimes called antiallergic drugs in Japan. However, to date, the above drugs have not been sufficiently effective in treating allergic symptoms, and they also cause side effects such as drowsiness and fatigue, and are contraindicated for use in patients with other diseases. There are problems such as: Furthermore, the long-term use of the above-mentioned drugs also poses a heavy medical economic burden. Therefore, there is a need for the development of next-generation antiallergic agents that are highly therapeutic, safe, and inexpensive.

On the other hand, in order to deal with the above-mentioned problems such as side effects, food-derived anti-allergic materials are being used instead of pharmaceuticals such as anti-allergic agents and steroids to suppress and improve symptoms and diseases caused by type I allergic reactions. Exploration and utilization are being studied. For example, the enlarged underground stem of the lotus plant is edible as lotus root, and it has long been known to have excellent nutritional and tonic properties, and in recent years it has also been found to have anti-allergic properties. An anti-allergic agent containing a ground lotus product or extract, or a combination thereof (Patent Document 1), an anti-allergy drug containing a ground lotus product and/or extract and lactic acid bacteria (Patent Document 2), etc. have been reported. . It has also been reported that when lotus root nodule extract is used in combination with the antihistamine drug epinastine, allergic symptoms such as allergic rhinitis are significantly suppressed compared to using the antihistamine drug alone (Patent Document 3 ). Furthermore, various plant-derived polyphenols have been confirmed to have the effect of suppressing allergic symptoms mainly through in vitro tests, such as apple polyphenols, cacao polyphenols, and tea polyphenols. In particular, the catechins contained in green tea are known to have various effects such as suppressing blood pressure increases, lowering blood cholesterol, antioxidant, antibacterial/antiviral, and anticancer effects, and antiallergic effects are one of them. It is one. For example, Patent Document 4 discloses that a composition containing non-polymer non-epi catechins and non-polymer epi catechins in a specific ratio is effective in improving sneezing attacks and rhinorrhea symptoms. is disclosed. However, the composition contains a total of eight types of catechins, four types of non-epi type catechins and four types of epi type catechins, and it is not clear which ingredients were effective.

Japanese Patent Application Publication No. 2006-151811 Patent No. 3947778 Japanese Patent Application Publication No. 2017-048161 Japanese Patent Application Publication No. 2007-145830

As mentioned above, antihistamines are typical antiallergic agents for allergic symptoms such as allergic rhinitis and hay fever. However, increasing the dosage may cause side effects and increase costs.

Therefore, an object of the present invention is to provide a drug containing food-derived ingredients that exhibits the same excellent suppressive effect as antihistamines on allergic rhinitis symptoms, has no side effects, is safe, and is inexpensive. .

As a result of extensive research to solve the above problems, the present inventors confirmed that the antiallergic substance in lotus root joints is a proanthocyanidin polymer with a specific structure, and found that The present inventors have discovered that when proanthocyanidins are used in combination with epigallocatechin gallate, a green tea component, allergic rhinitis symptoms are more significantly suppressed than when used alone, leading to the completion of the present invention.

（式中、Ｒ_２及びＲ_４はそれぞれ独立に水素原子又は水酸基、Ｒ_１及びＲ_３は水酸基を示し、ｎは０以上の整数を示す。）
（２）前記鼻炎症状が、くしゃみ、水性鼻漏、又は鼻の腫れ若しくは発赤である、（１）に記載のアレルギー性の鼻炎症状の抑制剤。
（３）前記プロアントシアニジンの一日の投与量が、患者の体重１ｋｇあたり０．２～１０ｍｇである、（１）又は（２）に記載のアレルギー性の鼻炎症状抑制剤。
（４）前記エピガロカテキンガレート含有物質が緑茶抽出物である、（１）～（３）のいずれかに記載のアレルギー性の鼻炎症状抑制剤。 That is, the present invention includes the following inventions.
(1) An agent for suppressing allergic rhinitis symptoms, which is represented by the following general formula (I) and contains proanthocyanidin derived from lotus root joints and epigallocatechin gallate or an epigallocatechin gallate-containing substance as active ingredients.

(In the formula, R ₂ and R ₄ each independently represent a hydrogen atom or a hydroxyl group, R ₁ and R ₃ represent a hydroxyl group, and n represents an integer of 0 or more.)
(2) The agent for suppressing allergic rhinitis symptoms according to (1), wherein the rhinitis symptoms are sneezing, watery rhinorrhea, or nasal swelling or redness.
(3) The agent for suppressing allergic rhinitis symptoms according to (1) or (2), wherein the daily dose of the proanthocyanidin is 0.2 to 10 mg per 1 kg of patient's body weight.
(4) The agent for suppressing allergic rhinitis symptoms according to any one of (1) to (3), wherein the epigallocatechin gallate-containing substance is a green tea extract.

According to the present invention, an allergic rhinitis suppressant containing proanthocyanidins derived from lotus root joints and epigallocatechin gallate, which is a green tea component, is provided. Since the allergic rhinitis suppressant of the present invention contains as an active ingredient ingredients contained in natural products such as edible lotus roots and green tea, it has no side effects even when used on a daily basis and is highly safe. Therefore, it can be safely used in medicines, health foods, etc. Furthermore, since lotus root is a material that is inexpensive and easily available, the cost burden of allergy treatment is reduced.

Figure 1 shows the results of C18 column chromatography analysis of the thiol-decomposed product of the proanthocyanidin fraction contained in lotus root extract powder (P1: gallocatechin, P2: epigallocatechin, P3: catechin, P4: epicatechin, P5: ( +)-Gallocatechin thiol derivative (Gallocatechin thiol 1), P6: (-)-Gallocatechin thiol derivative (Gallocatechin thiol 2), P7: Epigallocatechin thiol derivative, P8: Catechin thiol derivative, P9: Epicatechin thiol derivatives). FIG. 2 shows a schematic diagram of the structure of a proanthocyanidin polymer purified from lotus root extract powder. FIG. 3 shows the schedule for creating a TDI-sensitized nasal hypersensitivity model rat. Figure 4 shows proanthocyanidins (LR) derived from lotus root extract powder administered alone, epigallocatechin gallate (EGCG) alone administered, and proanthocyanidins (LR) derived from lotus root extract powder and epigallocatechin gallate (EGCG) administered to TDI-sensitized nasal hypersensitivity model rats. The number of sneezes after the combined administration of EGCG) is shown (Control: Test group where ethyl acetate solution was applied instead of TDI on the same schedule as sensitization and seizure induction by TDI, TDI: TDI sensitized nasal hypersensitivity model rat. Test area without drug administration (positive control), LR14: LR14mg/kg/day administration group, LR28: LR28mg/kg/day administration group, EGCG: EGCG45mg/kg/day administration group, Mix14: LR14mg/kg/day+EGCG45mg /kg/day administration group, Mix28: LR28mg/kg/day+EGCG45mg/kg/day administration group. Statistically significant difference compared to TDI (positive control) by Dunnett's t-test: **p<0.01). Figure 5 shows proanthocyanidins (LR) derived from lotus root extract powder administered alone, epigallocatechin gallate (EGCG) alone administered, and proanthocyanidins (LR) derived from lotus root extract powder and epigallocatechin gallate (EGCG) administered to TDI-sensitized nasal hypersensitivity model rats. EGCG) (Control: Test group where ethyl acetate solution was applied instead of TDI on the same schedule as TDI sensitization and seizure induction, TDI: TDI sensitized nasal hypersensitivity model rat Test group in which no drug was administered (positive control), LR14: LR14mg/kg/day administration group, LR28: LR28mg/kg/day administration group, EGCG: EGCG45mg/kg/day administration group, Mix14: LR14mg/kg/day + EGCG45mg/ kg/day administration group, Mix28: LR28mg/kg/day + EGCG45mg/kg/day administration group. Statistically significant difference from TDI (positive control) by Dunnett's t test: *p<0.05, **p<0.01 ).

The present invention will be explained in detail below.
The allergic rhinitis symptom suppressant of the present invention contains proanthocyanidins derived from lotus root nodes and epigallocatechin gallate or an epigallocatechin gallate-containing substance as active ingredients.

(Proanthocyanidins derived from lotus root joints)
Proanthocyanidin, which is an active ingredient of the allergic rhinitis symptom suppressant of the present invention, is a polymer having flavan-3-ol as a constituent unit, represented by the following general formula (I).

（式中、Ｒ_２及びＲ_４はそれぞれ独立に水素原子又は水酸基、Ｒ_１及びＲ_３は水酸基を示し、ｎは０以上の整数を示す。）

(In the formula, R ₂ and R ₄ each independently represent a hydrogen atom or a hydroxyl group, R ₁ and R ₃ represent a hydroxyl group, and n represents an integer of 0 or more.)

The structural feature is that the gallocatechin type in which R ₂ and R ₄ are hydroxyl groups is more common than the catechin type in which R ₂ and R ₄ are hydrogen atoms, and R ₂ is OH:H = 65 to 85:15. ~35, R ₄ is OH:H=75~85:15~25. Further, proanthocyanidins include stereoisomers, and the hydroxyl groups of R ₁ and R ₃ can take the α type and β type in different ratios.

The above-mentioned proanthocyanidins are obtained by extracting a proanthocyanidin fraction from lotus root nodes, and further extracting and purifying a dimer or higher proanthocyanidin (gallocatechin) polymer excluding gallocatechin and catechin. It can also be obtained by chemical synthesis methods. The degree of polymerization of the proanthocyanidins is not limited, but the estimated degree of polymerization is preferably 3 to 5.

A specific example of the method for preparing the proanthocyanidins using lotus root joints as a material is shown below.

In the present invention, the lotus root (Lotus root) refers to the enlarged underground stem of the lotus (Nelumbo nucifera), and in the present invention, the term "Lotus root node" refers to the node or the area near the node within 1 cm from the end of the node. . Examples of lotus root varieties (production areas in parentheses) include Bicchu (produced in Naruto, Tokushima Prefecture, Ishii Prefecture), Ojiro (produced in Kawauchi, Tokushima Prefecture), and Lotus (produced in Sendai, Tokushima Prefecture), but the varieties and production areas vary. It is not particularly limited to these.

The method for extracting the proanthocyanidin fraction from lotus root joints is not particularly limited, but can be carried out by stirring or column extraction using water, hot water, or a mixed solvent of water and an organic solvent. Examples of organic solvents include water-soluble organic solvents, such as lower alcohols or water-containing lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, and isobutanol, and polyvalent alcohols such as propylene glycol, 1,3-butylene glycol, and glycerin. Examples include alcohol or water-containing polyhydric alcohol, acetone, ethyl acetate, or a mixed solvent of two or more thereof. Among these solvents, the solvent used in the present invention is preferably water, hot water, or ethanol, and more preferably hot water. There is no particular limitation on the amount of solvent to be used; for example, it may be at least 3 times, preferably at least 6 times, the lotus root joint part (dry weight), but it may be necessary to perform concentration or isolation after extraction. For convenience of operation, it is preferably 100 times or less. The extraction temperature and time depend on the type of solvent used, but for example, when water is used as a solvent, the temperature is 10 to 120°C, preferably 20 to 100°C, for 10 minutes to 24 hours, preferably 30 minutes to 5 hours. can be exemplified.

After removing insoluble matter from the extract by centrifugation, it is pulverized by processes such as concentration to dryness, spray drying, and freeze drying to obtain lotus root extract powder. The obtained lotus root extract powder was treated as a proanthocyanidin fraction (the fraction contains proanthocyanidins with different degrees of polymerization, and the content of the mixture thereof is estimated to be about 6% (w/w)). The proanthocyanidin fraction is subjected to filtration treatment using a filter with a pore size of 0.1 to 2.0 μm, and the permeate containing the low molecular weight fraction is collected. By subjecting it to a purification treatment such as the above, it is possible to obtain a proanthocyanidin oligomer mainly composed of proanthocyanidins having a low degree of polymerization, for example, a degree of polymerization of 3 to 5. In addition, since lotus root extract powder contains contaminant components such as polyphenol glycosides and esters other than proanthocyanidins, in order to improve the purity of proanthocyanidins, hydrolytic enzymes are It is preferable to remove the contaminant components by processing the aglycone in advance to form an aglycone.

To explain the purification process specifically, as an adsorbent treatment method, for example, adsorbents such as modified dextran gel (Sephadex LH-20 etc.), polystyrene resin, polyamide, reverse phase silica gel, hydrophilic vinyl polymer, etc. After adsorbing the proanthocyanidin fraction, it is washed with water and eluted with an eluent (polar solvent) for fractionation.Membrane separation methods include, for example, fractionation using a reverse osmosis membrane or an ultrafiltration membrane. A method for separating a fraction with a molecular weight of 1,000 to 100,000 and a solvent fractionation method include, for example, partition extraction with ethyl acetate, dehydration of the ethyl acetate layer, and fractional precipitation with a nonpolar solvent such as chloroform. An example is a method in which the sample is separated. In the method using the above adsorbent, examples of the eluent used to elute the adsorbed fraction include ethanol, methanol, propanol, and acetone. The main component of the adsorbed fraction is proanthocyanidin oligomers, which are mainly composed of proanthocyanidins with a degree of polymerization of 3 to 5, extracted from lotus root nodes in the extraction process. The adsorbed fraction containing proanthocyanidin oligomers may be further subjected to treatments such as concentration, drying, and powdering.

In the present invention, the estimated degree of polymerization of proanthocyanidins is determined by reacting a fraction containing proanthocyanidins with a nucleophile (such as phloroglucinol) and acid hydrolyzing the product, and then determining the concentration of each reaction product by HPLC analysis. The total number of moles of the reaction product is calculated from the standard curve of the reaction product, and then the total number of moles of the reaction product is calculated from the number of flavan-3-ols (gallocatechin, epigallocatechin, catechin, epicatechin) that constitute the terminal part of proanthocyanidins. It can be calculated by dividing by the total number of moles.

(Epigallocatechin gallate)
Epigallocatechin gallate (EGCG) is a major component of green tea polyphenols. The epigallocatechin gallate used in the present invention is not particularly limited, and may be commercially available, such as chemically synthesized or extracted and purified from various plants including tea leaves. Tea leaves include unfermented teas such as sencha, bancha, hojicha, gyokuro, tencha, and kettle tea made from tea leaves obtained from the evergreen tea tree (scientific name: Camellia sinensis(L)O.Kuntze) of the Camellia family. green tea, semi-fermented oolong tea (Tieguanyin, Golden Gui, Wuyiyan tea, etc.) made from the above-mentioned tea leaves through a semi-fermentation or fermentation process, or fermented black tea (Darjeeling, Assam, Java tea, etc.) Examples include. These tea leaves may be used alone or in combination of two or more. Among them, green tea containing a large amount of epigallocatechin gallate is preferred.

Extraction of catechins including epigallocatechin gallate from tea leaves can be performed using known methods such as stirring extraction (batch extraction), column extraction, and countercurrent extraction (drip extraction) using water, hot water, or a mixed solvent of water and an organic solvent. This can be done by the following method. As the organic solvent, alcohols, ethers, esters, etc. can be used, but water-soluble organic solvents such as ethanol, methanol, acetone, etc. are preferable. There is no particular limitation on the amount of solvent used; for example, it may be at least 10 times, preferably at least 20 times, the amount of tea leaves (dry weight), but operations when concentrating or isolating after extraction For convenience, it is preferably 100 times or less. Further, the extraction temperature and time depend on the type of solvent used, but may be, for example, 10 to 100°C, preferably 30 to 90°C, 30 minutes to 24 hours, preferably 1 to 10 hours. In addition, the tea leaf extract may be used as an extracted solution, but if necessary, it may be further concentrated (concentrated using an organic solvent, vacuum concentration, membrane concentration, etc.), diluted, or It may be used after treatment such as filtration, decolorization with activated carbon, deodorization, and ethanol precipitation. Furthermore, the extracted solution may be subjected to treatments such as concentration to dryness, spray drying, freeze drying, etc., and used as a dried product.

As shown in the Examples below, proanthocyanidins derived from the lotus root nodules obtained as above can be administered in combination with epigallocatechin gallate to improve rhinitis symptoms in TDI-sensitized nasal hypersensitivity model rats compared to each alone. can also be significantly suppressed. Therefore, proanthocyanidins derived from lotus root joints can be used as an "allergic rhinitis symptom suppressant" together with epigallocatechin gallate as they are, or by adding a suitable carrier and formulating them into a desired form.

The allergic rhinitis symptom suppressant of the present invention may be composed of separate preparations of proanthocyanidins derived from lotus root nodules and epigallocatechin gallate, or a mixture of proanthocyanidins derived from lotus root nodules and epigallocatechin gallate. It may also consist of a single formulation containing:

The method for administering the allergic rhinitis symptom suppressant of the present invention may be a method in which proanthocyanidins derived from lotus root nodules and epigallocatechin gallate are administered substantially simultaneously, for example, proanthocyanidins derived from lotus root nodules and epigallocatechin gallate are administered at the same time. Epigallocatechin gallate may be administered to subjects completely simultaneously or may be administered sequentially within a short period of time (preferably within a few minutes). Furthermore, in order to maximize the effect, it is preferable to administer a preparation in which proanthocyanidins derived from lotus root nodules and epigallocatechin gallate are thoroughly mixed together in advance. Therefore, the dosage form of the allergic rhinitis symptom suppressant of the present invention includes, for example, (a) administration of a single preparation obtained by simultaneously formulating proanthocyanidins derived from lotus root nodes and epigallocatechin gallate; (b) Simultaneous administration of two formulations obtained by separately formulating proanthocyanidins derived from lotus root nodules and epigallocatechin gallate, (c) Proanthocyanidins derived from lotus root nodules and epigallocatechin gallate, and (c) Proanthocyanidins derived from lotus root nodules and epigallocatechin gallate. Administration of two preparations obtained by separately formulating catechin gallate and catechin gallate via the same administration route at different times (for example, administration of proanthocyanidins derived from lotus root nodules and epigallocatechin gallate in the order, or administration in the reverse order) (d) simultaneous administration of two formulations obtained by separately formulating proanthocyanidins and epigallocatechin gallate derived from lotus root nodules, and (e) simultaneous administration by different administration routes of lotus root nodules. This includes an administration mode in which two types of preparations obtained by separately formulating proanthocyanidins derived from the above and epigallocatechin gallates are administered at different administration routes at different times.

The content of proanthocyanidins and epigallocatechin gallate derived from the lotus root joints in the above preparation varies depending on the purpose and dosage form, and is not particularly limited, but the solid content of proanthocyanidins derived from the lotus root joints is based on the total weight of the preparation. In terms of weight, it is preferably 1.0 to 30% by weight, more preferably 1.5 to 20% by weight, and epigallocatechin gallate is preferably 1.6 to 50% by weight, more preferably 2.4 to 35% by weight. . Regarding the method of adding the active ingredient during formulation, it may be added in advance or added during the manufacturing process, and may be selected as appropriate in consideration of workability.

The allergic rhinitis symptom suppressant of the present invention can be incorporated into compositions such as pharmaceuticals, food and drink, etc., along with appropriate additives within a range that does not impair the effects of the present invention. Note that the pharmaceutical products of the present invention include drugs used for animals, that is, veterinary drugs.

The pharmaceutical product of the present invention functions as a preventive drug that suppresses the onset of allergic rhinitis symptoms and/or as a therapeutic drug that improves or alleviates the symptoms.

Examples of allergic rhinitis symptoms include allergic rhinitis, hay fever, runny nose, stuffy nose, sneezing, itching in the nasal cavity or pharynx, and the like. Among these, preferred is nasal hypersensitivity, particularly allergic nasal hypersensitivity caused by increased expression of IL-9 via the calcineurin/NFAT signal transduction system. Here, "allergic nasal hypersensitivity" refers to an allergic disease characterized by symptoms such as repeated sneezing, watery rhinorrhea, and nasal congestion.

Since the active ingredient of the pharmaceutical of the present invention is derived from natural products, it is highly safe and has no side effects. It can be administered orally or parenterally to mammals such as dogs and cats in a wide range of dosages.

The pharmaceutical products of the present invention are prepared by mixing the above-mentioned allergic rhinitis symptom suppressant with pharmacologically and pharmaceutically acceptable additives, and formulating the mixture into various formulations suitable for application to the affected area. be able to. Pharmacologically and pharmaceutically acceptable additives include pharmaceutical bases, carriers, excipients, diluents, binders, lubricants, and coatings selected as appropriate depending on the dosage form and use. agent, disintegrant or disintegration aid, stabilizer, preservative, preservative, filler, dispersant, wetting agent, buffer, solubilizer or dissolution aid, tonicity agent, pH regulator, propellant , a coloring agent, a sweetener, a flavoring agent, a flavoring agent, etc. may be added as appropriate, and various formulations that can be administered orally or parenterally systemically or locally may be prepared by various known methods. When the pharmaceutical of the present invention is provided in each of the above forms, it can be manufactured by a manufacturing method commonly used by those skilled in the art, such as the manufacturing method shown in the Japanese Pharmacopoeia's General Preparations [2] Preparation Monograph.

Formulations for oral administration include excipients such as, for example, starch, glucose, sucrose, fructose, lactose, sorbitol, mannitol, crystalline cellulose, magnesium carbonate, magnesium oxide, calcium phosphate, or dextrin; carboxymethylcellulose, calcium carboxymethylcellulose, Disintegrants or disintegration aids such as starch or hydroxypropylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic, or gelatin; lubricants such as magnesium stearate, calcium stearate, or talc. Coating agents such as hydroxypropyl methylcellulose, white sugar, polyethylene glycol, or titanium oxide; Bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used; It is not limited to these.

The form of the pharmaceutical of the present invention is not particularly limited, but includes, for example, tablets, sugar-coated tablets, capsules, troches, granules, powders, liquids, pills, emulsions, syrups, suspensions, and elixirs. oral preparations, injection preparations (e.g. subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drops, nasal drops, eye drops, suppositories, ointments, lotions, Examples include parenteral preparations such as sprays, transdermal absorption agents, transmucosal absorption agents, and patches. It may also be a dry product that is redissolved before use, or, in the case of injectable preparations, presented in unit-dose ampoules or multi-dose containers. These formulations can be prepared by conventional pharmaceutical methods.

The dosage of the pharmaceutical of the present invention can be appropriately determined depending on the type of disease, the age, sex, body weight, symptoms, administration route, administration schedule, formulation form, etc. of the subject. For example, when orally administered to a patient (adult), the daily dose of proanthocyanidins derived from lotus root nodes is 0.2 to 10 mg, preferably 0.3 mg, per 1 kg of the patient's body weight in terms of solid content. -9 mg, more preferably 0.4-8 mg, and epigallocatechin gallate 0.3-16 mg, preferably 0.5-14.5 mg, more preferably 0.6-13 mg.

Furthermore, the allergic rhinitis symptom suppressant of the present invention can be incorporated into food and drink products. The food/beverage products of the present invention can be used as functional foods for the purpose of prevention or treatment for patients suffering from the above-mentioned allergic rhinitis symptoms. In the present invention, foods and beverages include not only general foods and beverages, but also foods other than pharmaceuticals that can be taken for the purpose of maintaining or promoting health, such as health foods, functional foods, foods with health claims, or foods for special purposes. It is used in a meaning that includes. Health foods include foods provided under the names of nutritional supplements, health supplements, supplements, etc. Foods with health claims are defined by the Food Sanitation Law or the Food Promotion Law, and are foods for specified health uses and foods with nutritional function claims that can claim specific health effects, functions of nutritional ingredients, reduction of disease risk, etc., as well as foods with nutritional claims based on scientific evidence. This includes foods with functional claims that can be labeled with the functionality that has been reported to the Commissioner of the Consumer Affairs Agency. In addition, foods for special uses include foods for the sick, foods for the elderly, foods for infants, foods for pregnant women, etc. that are labeled as being suitable for specific subjects or patients with specific diseases. The food or drink may be in any form suitable for eating, such as solid, liquid, granule, granule, powder, capsule, cream, or paste.

Types of food and beverages include breads, noodles, confectionery, dairy products, processed seafood and livestock foods, fats and oils and processed foods, seasonings, and various beverages (soft drinks, carbonated drinks, nutritional drinks, fruit drinks, milk drinks). etc.), concentrated stock solutions of the beverages, powders for preparation, etc., but are not limited thereto.

The food/beverage products of the present invention may appropriately contain commonly used additives depending on the type thereof. Any additive can be used as long as it is acceptable in terms of food hygiene; for example, sweeteners such as glucose, sucrose, fructose, high-fructose corn syrup, aspartame, and stevia; citric acid, malic acid, Acidulants such as tartaric acid; Excipients such as dextrin and starch; Binders, diluents, fragrances, colorants, buffers, thickeners, gelling agents, stabilizers, preservatives, emulsifiers, dispersants, suspensions Examples include preservatives and preservatives. In addition to the above-mentioned essential ingredients, foods may contain materials and additives commonly used in foods (e.g., excipients, disintegrants, emulsifiers, stabilizers, lubricants, buffers) to the extent that they do not impair the effects of the present invention. , fragrance, etc.) may be appropriately blended as necessary.

The content of the allergic rhinitis symptom suppressor in the food and drink products of the present invention may be any amount that can exert the suppressing effect on the allergic rhinitis symptoms, and may be based on the general intake of the food or drink, the form of the food or drink, It may be determined as appropriate in consideration of taste, palatability, cost, etc., but for example, it can be blended in an amount of 0.1 to 99.0% by weight based on the entire food or drink.

When ingesting the food and drink products of the present invention for the purpose of preventing or improving the symptoms of allergic rhinitis, the intake amount varies depending on the condition of the subject to be ingested, the form of intake, the amount of food consumed, etc. , proanthocyanidins derived from lotus root nodules are 0.2 to 10 mg, preferably 0.3 to 9 mg, more preferably 0.4 to 8 mg, and epigallocatechin gallate is 0.3 per kg of patient body weight in terms of solid content. -16 mg, preferably 0.5-14.5 mg, more preferably 0.6-13 mg. The above amount may be taken at one time, or may be taken in several divided doses (2 to 4 times). It is preferable that the food/beverage products of the present invention are packaged or filled in a container such as a bag or a bottle, so that the amount of food/beverage products to be ingested at one time is used as a guideline for intake.

(Example 1) Production of proanthocyanidins derived from lotus root joints (1) Preparation of lotus root extract powder 793 kg of lotus root joints produced in Tokushima Prefecture (mainly Bichu variety) were ground with a food cutter, 2382 kg of water was added to this, Extraction was carried out with stirring at 95°C or higher for 1 hour. After adding 1588 kg of water at room temperature to the extract and lowering the temperature to 50°C, 0.476 kg of Protease M "Amano" was added and enzyme treatment was performed for 1 hour. After heating to 95° C. or higher to deactivate the enzyme activity and filtering through a 100 mesh filter, the solid content was separated and removed by centrifugation, and the extract was clarified by diatomaceous earth filtration. The obtained filtrate was concentrated to 710 kg using a vacuum concentrator. Add and dissolve dextrin to the concentrate so that the solid content in the concentrate is 80% (W/W) and the solid content of dextrin added is 20% (W/W), and powder it by spray drying. 75.6 kg of lotus root extract powder was collected.

(2) Purification of proanthocyanidins from lotus root extract powder 60.89 g of lotus root extract powder prepared in (1) was dissolved in 6000 g of 0.5M sodium chloride aqueous solution. This solution was filtered through a 0.2 μm filter. The filtrate was divided into two equal parts, and the two equal parts were continuously loaded onto a 50 x 200 mm column filled with Sephadex LH-20 (GE Healthcare Japan Co., Ltd.) swollen with purified water, and proanthocyanidins were extracted. It was adsorbed. Subsequently, the column was washed with a 0.5M aqueous sodium chloride solution, and 6000 g of purified water was passed through the column to remove sodium chloride. Thereafter, the components adsorbed on the column were eluted with a 50% (V/V) acetone aqueous solution. This eluate was concentrated by removing acetone using a vacuum concentrator and powdered by freeze-drying. After two column treatments, 2.0085 g of lyophilized powder was recovered.

Weighed out 1.809g of the above freeze-dried powder, dissolved it in purified water, and further added ethanol to make a 90% (V/V) ethanol aqueous solution with a powder concentration of 0.25% (W/V). . This ethanol aqueous solution was filtered through a 0.45 μm filter. The filtrate was divided into two equal parts, and the two equal parts were sequentially loaded onto a 50 mm x 150 mm column packed with Sephadex LH-20 resin swollen with ethanol. Subsequently, the column was thoroughly washed with ethanol to obtain an unadsorbed fraction. Thereafter, the column adsorbed components were eluted with a 50% (V/V) acetone aqueous solution to obtain an adsorbed fraction. The collected unadsorbed fraction and adsorbed fraction were subjected to vacuum concentration treatment to remove the organic solvent, and freeze-dried to powder, and 82.07 mg of unadsorbed fraction and 1.7996 g of adsorbed fraction were collected.

(3) Structural analysis of proanthocyanidins derived from the joints of lotus root extract The adsorbed fraction obtained in (2) was dissolved in methanol and treated with benzyl mercaptan (Sigma-Aldrich) under acidic conditions for thiol decomposition treatment. Ta. As a result of analyzing this decomposed solution using a C18 column (ODS-3 manufactured by GL Sciences), it was found that the component consisted of nine types of components (P1 to P9) (Figure 1). These nine components were determined by NMR analysis, P1 is gallocatechin, P2 is epigallocatechin, P3 is catechin, P4 is epicatechin, P5 is (+)-gallocatechinthiol derivative (gallocatechinthiol 1), P6 It was confirmed that P7 is an epigallocatechin thiol derivative, P8 is a catechin thiol derivative, and P9 is an epicatechin derivative. The concentration of each component was measured, and the composition ratio and estimated degree of polymerization (total number of moles of the components)/(total number of moles of the terminal portion) were analyzed. The results are shown in Table 1.

The proanthocyanidins contained in the adsorbed fraction were dimer or higher polymers, and the estimated degree of polymerization was 3.8. Furthermore, a schematic diagram of the structure of the proanthocyanidin polymer contained in the adsorbed fraction is shown in FIG.

(Example 2) Test for suppressing allergic rhinitis symptoms using a combination of proanthocyanidins derived from lotus root nodules and epigallocatechin gallate Allergy caused by a combination of proanthocyanidins derived from lotus root nodules and purified epigallocatechin gallate (Nagara Science Co., Ltd.) The effect of suppressing the symptoms of rhinitis was evaluated using nasal hypersensitivity model rats. In this test, the Sephadex-adsorbed fraction containing the proanthocyanidin polymer purified from the lotus root extract powder in Example 1 was used as the proanthocyanidin derived from lotus root joints.

1. Test method (1) Creation of nasal hypersensitivity model rat
Six-week-old Brown-Norway male rats (200 g, SLC, Hamamatsu, Japan) were used. Animals were kept at room temperature at 22±1°C with a 12-hour day/night cycle. Rats were sensitized with TDI (toluene 2,4-diisocyanate) using a modified method of Kitamura et al. (Acta Otolaryngol. 2004, 124, 1053-1058). That is, 10 μL of a 10% TDI-ethyl acetate solution was applied to the bilateral nasal vestibules of male Brown-Norway rats twice every day for 5 days using a very fine otorhinolaryngal swab (TDI sensitization). After a one-week period without treatment, seizures were induced by applying a 10% TDI-ethyl acetate solution to the nasal vestibule. Figure 3 shows the schedule for creating a TDI-sensitized nasal hypersensitivity model rat. In addition, a control model rat (positive control) was created by applying an ethyl acetate solution instead of TDI using the same schedule as the sensitization and seizure induction using TDI described above.

Proanthocyanidins (LR) derived from lotus root extract powder (14 mg/kg/day and 28 mg/kg/day) were administered to TDI-sensitized nasal hypersensitivity model rats once a day during the preparation process. Epigallocatechin gallate (EGCG) (Nagara Science Co., Ltd.) (45 mg/kg/day), and their combinations Mix14 (LR 14mg/kg/day+EGCG 45mg/kg/day, 1:3.2) and Mix28 (LR 28mg/kg/day+EGCG 45mg/kg/day, 1:1.6) was orally administered for 3 consecutive weeks.

(2) Evaluation of the number of allergic sneezes On the final day of oral administration, the number of "sneezes" was measured for 10 minutes and the number was recorded.

(3) Evaluation of nasal hypersensitivity symptoms (water-soluble rhinorrhea, nasal swelling and redness) On the final day of oral administration, “water-soluble rhinorrhea” and “nasal swelling and redness” were evaluated as nasal hypersensitivity symptoms. It was evaluated and scored using the indicators shown in Table 2.

2. Test Results The results of the number of sneezes are shown in Figure 4, and the results of nasal hypersensitivity symptoms (nasal symptom score) are shown in Figure 5.
The number of allergic sneezes was determined in the 28mg/kg administration group (Mix28) in TDI-sensitized nasal hypersensitivity model rats (positive control) administered with a combination of proanthocyanidins derived from lotus root extract powder and epigallocatechin gallate. significantly decreased compared to the single administration groups (LR14, LR28, EGCG). Furthermore, no significant decrease in the number of sneezes was observed in the 14 mg/kg administration group (Mix 14), which is a low dose administration group. In addition, a significant decrease in nasal symptom score was observed in the 28 mg/kg administration group (Mix28) compared to TDI (positive control).

These results revealed that allergic sneezing symptoms can be suppressed by combining proanthocyanidins (LR) derived from lotus root extract powder and epigallocatechin gallate (EGCG) in a specific ratio.

INDUSTRIAL APPLICABILITY The present invention can be used in the field of manufacturing food and drink products such as pharmaceuticals, health foods, and functional foods for preventing or improving allergic rhinitis symptoms, particularly sneezing symptoms.

Claims (6)

A composition for suppressing symptoms of allergic rhinitis, which contains proanthocyanidins derived from lotus root joints and epigallocatechin gallate or an epigallocatechin gallate-containing substance represented by the following general formula (I) as active ingredients.

(In the formula, R ₂ and R ₄ each independently represent a hydrogen atom or a hydroxyl group, R ₁ and R ₃ represent a hydroxyl group, and n represents an integer of 0 or more.) The composition for suppressing allergic rhinitis symptoms according to claim 1, wherein the rhinitis symptoms are sneezing, watery rhinorrhea, or nasal swelling or redness. The composition for suppressing allergic rhinitis symptoms according to claim 1 or 2, wherein the daily dose of the proanthocyanidin is 0.2 to 10 mg per kg of patient body weight. The composition for suppressing allergic rhinitis symptoms according to any one of claims 1 to 3, wherein the epigallocatechin gallate-containing substance is a tea leaf extract. The composition for suppressing allergic rhinitis symptoms according to any one of claims 1 to 4, which is in the form of a pharmaceutical. The composition for suppressing allergic rhinitis symptoms according to any one of claims 1 to 4, which is in the form of a food or drink.

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