KR20150086928A - Composition for prevention or treatment of influenza virus infection comprising curcuminoid and licorice extracts or fraction thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, a food composition, a quasi-drug composition, a feed additive, a beverage additive, a feed and a drinking water for preventing, improving or treating influenza virus infection including a compound represented by chemical formula 1 or a salt thereof and extracts of Glycyrrhiza uralensis Fisch. or fraction thereof as active ingredients. In the present invention, provided is a method for preventing, improving or treating influenza virus by using the composition, feed additive, beverage additive, feed or drinking water.

Description

The present invention relates to a composition for prevention or treatment of an influenza virus infection comprising a glucuronide-based compound, a glucuronide-based compound, and a licorice extract or a fraction thereof.

The present invention relates to a pharmaceutical composition, a food composition, a quasi-drug composition, a feed additive, a drinking water additive, a food additive, a food additive, a food additive, Feed and drinking water.

The present invention also relates to a method for preventing, ameliorating or treating an influenza virus infection using the composition, feed additive, drinking water additive, feed or drinking water.

Influenza virus is a highly contagious virus that causes acute respiratory illness and is one of the viruses causing severe respiratory symptoms to children, elderly people, and cardiopulmonary patients by causing group infections in the whole world. Influenza viruses belong to Orthomyxovirus , which is taxonomically classified into three types of A, B, and C.

Surface antigens of viruses cause mutations in the same subtype, and new antigenic mutants appear each year. Especially, avian influenza virus, which is a serious problem among influenza viruses, is infected with various kinds of birds such as chickens, turkeys, ducks, and wild birds due to feces. More than 80% Is a viral disease that pose a great deal of damage and threat to the poultry industry and its ripple effect is not limited to the poultry industry but it is reported to cause diseases to humans due to infection to human body.

Inhibition of adsorption to epithelial cells, inhibition of invasion into cells, inhibition of transcription and replication of genes, inhibition of protein synthesis, inhibition of release from cells and the like can be considered as methods for preventing and treating infection of such viruses. Each is the target of an antiviral.

Conventionally, substances such as Amatadine, Rimatadine, Zanamivir and Oseltamivir have been approved by the US Food and Drug Administration (FDA) for the treatment of diseases caused by influenza virus . However, amantadine and rimantadine, two of the M2 inhibitors that block the uncoating of the virus by interrupting the ion channel of the M2 protein, a membrane protein essential for viral replication, are only effective against influenza virus type A, It has been reported that a virus with resistance is generated during use and that serious side effects occur in the nervous system and gastrointestinal tract (Bantia, S. et al. Antiviral Research 69 , 39, 2006).

In addition, since 1999, it has been recognized that new medicines such as zanamivir and oseltamivir, which play an important role in the proliferation of viruses and have a low incidence of resistance and are stably present in both influenza A and B viruses, (Ryan, DM et al., Antimicrob . Agents) have been reported to be effective in the treatment of viral infections, Chemother ., 39, 2583, 1995), and oseltamir has a side effect of severe vomiting.

The antiviral agents developed so far have severe side effects and require a great deal of attention to their application. In addition, the development of a vaccine has a problem of low efficacy when the virus type of the prevalent virus is not matched with the virus of the vaccine, and thus there is an increasing need for the development of a new influenza virus infection therapeutic agent having excellent infection control effect and excellent stability. In addition, in order to treat an object substantially infected with influenza virus, it is necessary to develop a substance exhibiting excellent antiviral effect throughout the whole body of an individual.

Under these circumstances, the inventors of the present invention conducted a study on a new influenza virus infection therapeutic agent. When the compound represented by the formula (1) and the licorice extract are used together, the synergistic effect between these components is exerted, And virucidal efficacy are remarkably improved, and there is no side effect. Therefore, it has been found for the first time that an influenza virus infection, particularly a highly pathogenic influenza virus infection, can be effectively prevented and treated even with a small amount of use.

It is an object of the present invention to provide a pharmaceutical composition, food composition, quasi-drug composition, feed additive (s) for preventing, improving or treating influenza virus infection comprising the compound represented by the formula (I) or a salt thereof and a licorice extract or a fraction thereof as an active ingredient , A drinking water additive, a feed and drinking water.

It is another object of the present invention to provide a method for preventing, ameliorating or treating an influenza virus infection by using the composition, feed additive, drinking water additive, feed or drinking water.

In one embodiment of the present invention, there is provided a compound represented by the following general formula (1) or a salt thereof; And a composition for preventing, ameliorating or treating an influenza virus infection comprising the licorice extract or a fraction thereof as an active ingredient.

[Chemical Formula 1]

Wherein R ¹ and R ² are each independently hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group, and n and m are ₁ ? N? 5 and 1? M? 5.

When the compound represented by the above formula (1) and the licorice extract or its fractions are used together, the synergistic effect between these components is exerted. As compared with the case of using them alone, the present inventors have found that an influenza virus Inhibitory effect, in particular inhibiting the proliferation of H5N1, a highly pathogenic influenza virus.

In a specific example of the present invention, the case where the compound represented by the formula (1) (the curcumin is specifically used in this example) and the licorice extract are individually treated after MDCK cells are inoculated with the highly pathogenic influenza virus H5N1, When the curcumin and licorice extracts of the present invention were treated together, the number of plaques formed was observed. As a result, it was found that when curcumin and licorice extracts were treated together, they were treated in a much smaller amount than those treated with each of them, (Experimental Example 1).

In the present invention, the compound represented by the general formula (1) is a concept including all of its salts, hydrates, solvates, isomers and derivatives within the range having the same efficacy. The compound represented by Formula 1 may be chemically synthesized or isolated from natural materials, and may be purchased from domestic and overseas chemical companies. When the compound represented by the formula (1) of the present invention is isolated from a natural substance, it may be a concept including the extract of a natural product or a fraction thereof, as long as it contains the compound represented by the formula (1).

In the present invention, when the compound represented by Formula 1 is isolated from a plant, the type of the plant is not particularly limited, but may be preferably a plant belonging to Curcuma sp .

The plants belonging to the above-mentioned kyokyu group include onion ( Curcuma Wenyujin , YH Chen et C. Ling), Autumn Ulgum ( Curcuma longa Linne), spring corn ( Curcuma longa Salisb.), purple wool ( Curcuma zedoaria), Guangxi ahchul (based turmeric) (Curcuma kwansiensis, SG Lee et Liang CF), ahchul (noksa turmeric) (Curcuma aeruginosa), rods ahchul [Curcuma phaeocaulis Val. (ginger and Zingiberaceae)], Curcuma domestica ), but are not limited thereto.

In the present invention, it is more preferable that the kyocyparis obtuse plant for isolating the compound represented by the formula (I)

In the present invention, the term " Turmeric " means a root part or a root part of a root of a plant belonging to the root of Cucurbitaceae. The term "root root" is also referred to as a tuber root, "Rootstock" is the root of the plant, where the stem of the plant grows like a root and extends to the ground. It is also called rootstock.

In the present invention, the gilt-roots are preferably roots or rootstocks of autumn gull, or they are steamed and dried.

In the present invention, those obtained by various methods such as those cultivated and marketed can be used.

In the present invention, the compound represented by the above formula (1) may be in a form contained in the ganoderma extract or a fraction thereof.

The term "extract" used in the present invention refers to an extract obtained by extracting a natural substance, a diluted solution or a concentrate of the extract, a dried product obtained by drying the extract, a preparation or a purified product of the extract, , The extract itself and extracts of all the formulations that can be formed using the extract.

The extract can be extracted from various organs of natural products, hybrids or varieties thereof. For example, in the case of an extract of a plant, the extract may be applied to the roots, the top parts, the stems, the leaves, the flowers, the bodies of the fruits, But also from plant tissue culture.

The method for producing the extract is not particularly limited, and may be extracted according to a method commonly used in the art. Examples of the extraction method include hydrothermal extraction method, ultrasonic extraction method, filtration method, reflux extraction method, immersion extraction method, high temperature and high pressure steam extraction method, etc. These methods can be performed alone or in combination of two or more methods have.

The kind of the extraction solvent used for extracting the natural substance in the present invention is not particularly limited, and any solvent known in the art can be used. Particular examples of the extraction solvent is water, alcohol, or and the like, mixed solvents of the foregoing, when using an alcohol as a solvent is preferably to more preferably an alcohol, a C ₁ to C ₄ C ₁ to C ₂ < / RTI > lower alcohols.

Turmeric the dry product obtained by the turmeric extract is preferably crushed roots of the foreign substances removed by cleaning and dried turmeric in the present invention water, C ₁ To C ₄ alcohol or a mixed solvent thereof, more preferably an extract of C ₁ to C ₄ alcohol, and most preferably an extract of methanol or ethanol. At this time, the extraction solvent is preferably 2 to 20 times the dry weight of the koi. For example, it is possible to obtain an alcoholic extract by placing the crude warts in an extraction container, adding a lower alcohol of C ₁ to C ₄ or a mixed solvent thereof, preferably methanol or ethanol, allowing to stand at room temperature for a certain period of time, . At this time, the extraction is preferably allowed to stand at room temperature for 1 week, and thereafter, a method such as concentration or freeze-drying may further be carried out.

The term "fraction " as used herein means a product obtained by performing fractionation to separate a specific component or a specific component group from a mixture containing various components.

The fractionation method for obtaining the fraction in the present invention is not particularly limited and may be carried out according to a method commonly used in the art. As a non-limiting example of the above-mentioned fractionation method, there can be mentioned a method in which a fraction obtained from the extract is obtained by treating a predetermined substance with an extract obtained by extracting a natural substance.

The kind of the fraction solvent used for obtaining the fraction in the present invention is not particularly limited, and any solvent known in the art can be used. Non-limiting examples of the fraction solvent include polar solvents such as water and alcohol; And non-polar solvents such as hexane, ethyl acetate, chloroform and dichloromethane. These may be used alone or in combination of two or more. When alcohols are used in the fraction solvent, C ₁ to C ₄ alcohols can be preferably used.

In the present invention, the uroguanthes fraction may preferably be a hexane fraction, an ethyl acetate fraction or a water fraction obtained by suspending a herbal extract in water and then fractionating it with hexane and / or ethyl acetate, respectively.

The compounds of formula (I) of the present invention may be used in the form of their pharmaceutically, pharmacologically or pharmacologically acceptable salts.

As the salt, an acid addition salt formed by a pharmaceutical, foodstuff or quasi-free acid is useful. Acid addition salts can be prepared in a conventional manner, for example, by dissolving the compound in an excess amount of an aqueous acid solution and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It is also possible to heat an equimolar amount of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water, and then evaporate the mixture to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, an inorganic acid or an organic acid can be used. The inorganic acid may be, for example, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. These may be used alone or in admixture of two or more. Non-limiting examples of the organic acid include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, The present invention also relates to the use of a compound of formula (I) as an acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillyric acid, hydroiodic acid and the like. These may be used alone or in combination of two or more.

In addition, the compound represented by the formula (1) can be prepared by using a base to produce a pharmacologically, pharmacologically or pharmacologically acceptable metal salt. The alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. As the metal salt, it is preferable to produce sodium, potassium or calcium salt in particular, but it is not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The pharmaceutically, pharmacologically acceptable or pharmacologically acceptable salts of the compound represented by the formula (1) may include all salts of an acidic or basic group which may exist in the compound represented by the formula (1) have. For example, the pharmaceutically, pharmacologically or pharmacologically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the like, as well as other pharmacokinetic, pharmacologically or pharmacologically acceptable salts of amino groups (Mesylate) and p-toluenesulfonate (e. G., Toluenesulfonate), such as hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, Salt), and the like, which can be produced through a method for producing a salt known in the art.

In the present invention, the compound represented by Formula 1 is a curcuminoid compound, preferably curcumin, Demethoxycurcumin of Formula 3, Bisdemethoxycurcumin of Formula 4, Or a mixture thereof.

(2)

(3)

[Chemical Formula 4]

The compound represented by the formula (1) of the present invention may be more preferably the curcumin of the formula (2).

In the present invention, the "licorice" is one of the plants belonging to rosewood and soybean.

In the present invention, the licorice may be used as dried licorice as it is, or may be used in dry form as it is, or may be used in dried dry form by steaming it. The dried licorice may be powdered and used in powder form.

In the present invention, the licorice extract is not particularly limited, but may be an immersion extract extracted by an immersion extraction method using an organic solvent or an extract form extracted by a high-temperature and high-pressure steam extraction method. The licorice extract may be obtained by using commercially available ones or by extracting and extracting from natura liquorice, which has been harvested or cultivated in nature.

In one specific embodiment of the present invention, the Northeast Licorice Extract Extract is used as the licorice extract. The Northeast licorice extract may be an extract prepared by extracting Northeast licorice from the market with a known extraction method.

In the present invention, the licorice extract may be obtained by extracting with water, C ₁ to C ₄ lower alcohols or a mixed solvent thereof. As a specific example, water or ethanol with a volume of about 2 to 10 times, preferably 2 to 5 times the weight of the licorice, with a lower alcohol such as methanol, preferably with ethanol at 20 ° C to 50 ° C, The mixture is extracted twice or three times with stirring at 25 ° C to 30 ° C by ultrasonic extraction, hot water extraction at 100 ° C, and the like, followed by filtration through a filter paper. The filtrate is removed with a rotary vacuum concentrator and the residue is subjected to vacuum freeze drying , And the licorice extract can be obtained through hot air drying.

In the present invention, when the compound represented by the formula (1) is used in the form of a plant extract or a fraction thereof (preferably a herbal extract or a fraction thereof), the mixture ratio of the herbal extract or its fractions and the licorice extract or its fractions May be appropriately selected depending on the desired effect, an individual to be administered, etc., but preferably the herbal extract or the fraction thereof: licorice extract or its fractions may be mixed at a weight ratio of 1:10 to 1: 150, Preferably 1:50 to 1: 120, and more preferably about 1: 100.

In the present invention, the compound represented by Formula 1 or a salt thereof; And a licorice extract or a fraction thereof as an active ingredient may be prepared by a method including the steps of:

a) a first composition comprising the compound represented by the formula (1) or a salt thereof as an active ingredient; And a second composition comprising the licorice extract or a fraction thereof as an active ingredient; And

b) treating the mixture obtained in step a) with a microwave.

In the present invention, the mixing ratio of the first composition and the second composition is not particularly limited, but preferably the weight ratio of the first composition to the second composition is 1: 1 to 1: 15, more preferably 1: : 50 to 1: 12O, more preferably about 1: 100

The method of treating the microwaves can be, but is not limited to, microwave ovens (including both for general household use and synthesis only). It is preferable that the microwave is treated at 600 W to 800 W for 1 minute to 20 minutes, more preferably at 650 W to 750 W for 10 minutes to 20 minutes in a general domestic microwave oven, Preferably, the treatment is carried out at 700 W for 15 minutes. The microwaves may be treated in a microwave oven for synthesis for 1 minute to 100 minutes at 50 W to 300 W, preferably at 140 W to 240 W for 1 minute to 20 minutes. More preferably, the treatment is carried out at 160 W to 220 W for 6 minutes to 12 minutes, and still more preferably at 180 W to 200 W for 7 minutes to 10 minutes.

The number of times of the microwave treatment is not limited, but is preferably two or more times. When the microwave treatment is repeated twice or more, it is preferable to add the step of cooling the mixture after microwave treatment to the mixture once.

In the present invention, the mixture may be further subjected to ultrasonic treatment before microwave treatment. In addition, in the case of ultrasonic treatment, more soluble formulations can be obtained.

In the present invention, the influenza virus is preferably a highly pathogenic influenza virus for the purpose of the present invention, more preferably a highly pathogenic influenza virus H5N1, but is not limited thereto. In addition, the influenza virus can cause flu, cold, sore throat, bronchitis, pneumonia and the like, and may cause bird flu, swine flu, chlorine flu and the like.

The term "prophylactic, " as used herein, refers to any act of inhibiting or delaying an influenza virus infection by administering the composition of the present invention to an individual.

As used herein, the term "improvement" means any action that at least reduces the degree of symptom associated with the condition being treated.

As used herein, the term "treatment" refers to any act that causes the influenza virus infection symptom to be improved or improved by administering the composition of the present invention to the individual.

In one embodiment of the present invention, the compound represented by Formula 1 or a salt thereof; And a composition for preventing, improving or treating an influenza virus infection comprising the licorice extract or a fraction thereof as an active ingredient may be a pharmaceutical composition.

In the pharmaceutical composition of the present invention, the compound represented by Formula 1 or a salt thereof, and the licorice extract or a fraction thereof may be contained in an amount of 0.00001% by weight to 99.99% by weight based on the total weight of the pharmaceutical composition, May be contained in an amount of 1% by weight to 99.99% by weight, more preferably 10% by weight to 99.99% by weight, and even more preferably 50% by weight to 99.99% by weight, and may be included in the total content of the pharmaceutical composition.

The pharmaceutical composition of the present invention comprises a compound represented by the general formula (1) or a salt thereof; And a licorice extract or a fraction thereof, as an active ingredient, may further comprise a pharmaceutically acceptable carrier.

In the present invention, the above-mentioned "pharmaceutically acceptable" means that it is commonly used in the pharmaceutical field, which does not disturb the biological activity and properties of the compound administered, without irritating the organism upon administration thereof.

The pharmaceutical composition of the present invention may be formulated together with the carrier to be used as food, medicines, feed additives, drinking water additives, and the like.

In the present invention, the type of the carrier is not particularly limited and any carrier conventionally used in the art can be used. Examples of the carrier include, but are not limited to, saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, . These may be used alone or in combination of two or more.

In addition, the pharmaceutical composition of the present invention may be supplemented with other pharmaceutically acceptable additives such as excipients, diluents, antioxidants, buffers or bacteriostats, and may be used as fillers, extenders, wetting agents, disintegrants, , A binder, a lubricant, and the like may be additionally used.

The pharmaceutical composition of the present invention may be formulated into various formulations suitable for oral administration or parenteral administration.

Non-limiting examples of such oral dosage forms include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs .

In order to formulate the pharmaceutical composition of the present invention for oral administration, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; Excipients such as dicalcium phosphate and the like; Disintegrating agents such as corn starch or sweet potato starch; Magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax, and the like. Sweetening agents, fragrances, syrups, and the like may also be used.

Furthermore, in the case of capsules, in addition to the above-mentioned substances, liquid carriers such as fatty oils can be further used.

Non-limiting examples of the parenteral preparation include injections, suppositories, respiratory inhalation powders, aerosol preparations for spraying, ointments, powder for application, oils, creams and the like.

In order to formulate the pharmaceutical composition of the present invention for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and external preparations may be used. Examples of the non-aqueous solutions and suspensions include propylene glycol, polyethylene Glycerol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.

More specifically, when the pharmaceutical composition of the present invention is formulated into an injection, the composition of the present invention is mixed with water or a stabilizer or buffer in water to prepare a solution or suspension, which is then mixed with an ampoule or a vial Unit dosage form. In addition, when the pharmaceutical composition of the present invention is formulated into an aerosol formulation, a propellant or the like may be added together with the additive such that the water-dispersed concentrate or the wet powder is dispersed.

When the pharmaceutical composition of the present invention is formulated into an ointment, cream, or the like, it is possible to use an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, a polyethylene glycol, a silicone, a bentonite, Or the like can be used as a carrier.

The pharmaceutical composition of the present invention may preferably be for oral administration.

The pharmaceutically effective amount and the effective dose of the pharmaceutical composition of the present invention may be varied depending on the formulation method, administration method, administration time and / or route of administration of the pharmaceutical composition, Including, but not limited to, the type and severity of the disease, the type of subject being treated, the age, body weight, general health, severity or severity of the disease, sex, diet, excretion, Can be varied according to various factors and similar factors well known in the medical field, and those skilled in the art can easily determine and prescribe effective dosages for the desired treatment.

In the dosage for the more preferable effect of the pharmaceutical composition of the present invention, the compound represented by Formula 1 is preferably administered at a dose of 0.0001 mg / kg to 100 mg / kg, more preferably 0.001 mg / kg to 10 mg / kg, and when the compound represented by the formula (1) is administered in the form of a ganoderma extract or fraction thereof containing the compound, the dose is preferably 0.0001 mg / kg to 100 mg / kg per day, Is preferably administered at a dose of 0.001 mg / kg to 100 mg / kg.

Accordingly, the effective dose of the pharmaceutical composition of the present invention including the compound represented by the formula (1) or a salt thereof is not particularly limited, but for the more preferable effect, the compound represented by the formula (1) The dose of the licorice extract can be controlled by adjusting the dose ratio of the compound represented by the formula (1) and the licorice extract to the weight ratio of the compound of the formula (1) May be adjusted depending on the dosage.

The pharmaceutical composition of the present invention may be administered once a day or divided into several doses. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

The pharmaceutical compositions of the present invention may be administered alone, in combination with methods of using surgery, hormone therapy, drug therapy and biological response modifiers, for the prevention, amelioration, or treatment of influenza virus infections, especially highly pathogenic influenza virus infections .

The route of administration and the mode of administration of the pharmaceutical composition of the present invention may be independent of each other, and the method is not particularly limited, and any route of administration and administration method may be used as long as the pharmaceutical composition can reach the desired site You can follow. The pharmaceutical composition may be administered orally or parenterally.

The parenteral administration may be, for example, intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration or subcutaneous administration, and a method of applying, spraying or inhalation the composition to a diseased site may also be used But are not limited to.

In one embodiment of the present invention, when the pharmaceutical composition is orally administered to chickens, it has been confirmed that the virus and the antiviral effect to survive not only in the organs but also in the cecum of the cecum are maintained. The composition of the present invention is preferably administered orally .

According to another embodiment of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a pharmaceutical composition for preventing or treating an influenza virus infection comprising an extract of licorice or a fraction thereof as an active ingredient.

The term "individual" as used herein refers to all animals, including mammals including rats, livestock, humans, and the like.

According to another embodiment of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a food composition for preventing or ameliorating an influenza virus infection comprising the licorice extract or a fraction thereof as an active ingredient.

The food composition of the present invention is not particularly limited and includes a health functional food composition.

When the health functional food composition of the present invention is used as a food additive, the composition may be added as it is or may be used together with other food or food ingredients, and may be appropriately used according to a conventional method.

The kind of the food is not particularly limited, and includes food in a conventional sense. Non-limiting examples of the food to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice creams, , A drink, an alcoholic beverage, and a vitamin complex.

When the health functional food composition of the present invention is a beverage composition, various flavoring agents, natural carbohydrates, and the like may be contained as additional components such as ordinary beverages. Non-limiting examples of such natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Natural sweetening agents such as dextrin, cyclodextrin; Synthetic sweetening agents such as saccharin and aspartame, and the like. The proportion of the additional component added may be appropriately determined by a person skilled in the art.

In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the health functional food composition of the present invention may contain pulp for the production of natural fruit juice, fruit drink or vegetable drink. These components may be used independently or in combination of two or more. The ratios of these additives can also be suitably selected by those skilled in the art.

According to another embodiment of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a fragrance extract of licorice or a fraction thereof as an active ingredient. The present invention also provides a quasi-drug composition for preventing or ameliorating an influenza virus infection.

The term "quasi-drug product" used in the present invention means products that are less active than drugs, among the products used for diagnosing, treating, improving, alleviating, treating or preventing diseases of human or animal. For example, Quasi-drugs are products that are used for the purpose of treating or preventing diseases of humans or animals, products that are mild or have no direct action on the human body.

The compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof; When the licorice extract or its fractions are used as a quasi-drug additive, they can be added as they are, or they can be used together with other quasi-drugs or quasi-drugs, and can be suitably used according to conventional methods. The mixing ratio with other ingredients used together can be suitably determined according to the purpose of use (for example, prevention, improvement or therapeutic treatment).

The quasi-drug composition of the present invention may be manufactured by a formulation such as disinfectant cleaner, shower foam, gauze, soap, wet tissue, hand wash, humidifier filler, ointment, cream, lotion, essence, spray, filter filler, no.

According to another embodiment of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a feed additive or a drinking water additive for preventing or ameliorating an influenza virus infection comprising the licorice extract or a fraction thereof as an active ingredient.

The feed additive or the water-soluble additive of the present invention is a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof; And a licorice extract or a fraction thereof as an active ingredient is separately prepared in the form of a feed additive or a drinkable water additive and is mixed with a feed or drinking water, or a composition comprising the compound represented by the above formula 1 or a pharmaceutically acceptable salt thereof ; And a composition containing the licorice extract or a fraction thereof as an active ingredient may be directly added to the feed or drinking water in the preparation thereof.

The feed additive or drinking water additive of the present invention may be in a liquid or dry state, preferably in the form of a dried powder. The drying method for preparing the feed additive or the additive for drinking water of the present invention in the form of a dried powder is not particularly limited and a method commonly used in the art can be used. Non-limiting examples of the drying method include air drying, natural drying, spray drying, and freeze drying. These may be used alone or in a manner that uses two or more methods together.

The feed additive or the drinking water additive of the present invention may further include other additives as required. Non-limiting examples of the above-mentioned usable additives include binders, emulsifiers, preservatives and the like which are added to prevent deterioration of feed or drinking water quality; A non-protein nitrogenous compound, a silicate, a buffer, a coloring agent, an extracting agent or an oligosaccharide to be added for the purpose of increasing the efficiency of feed or drinking water, In addition, a feed mixture or the like may be further included. These may be used alone or two or more of them may be added together.

According to another aspect of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a licorice extract or a fraction thereof as an active ingredient for preventing or ameliorating an influenza virus infection.

The feed or drinking water may be prepared by adding the feed additive or the drinking water additive of the present invention to feed or drinking water, or a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof; And a composition containing the licorice extract or a fraction thereof as an active ingredient may be directly added.

In the present invention, the type of the feed is not particularly limited, and feeds conventionally used in the art can be used. Non-limiting examples of such feeds include vegetable feeds such as cereals, muscle roots, food processing busines logistics, algae, fibers, pharmaceutical buses, oils, fats, pastes or grain by-products; Animal feeds such as proteins, inorganic substances, fats, oils, fats, oils, monocellular proteins, animal plankton or foods. These may be used alone or in combination of two or more.

In the present invention, the type of the drinking water is not particularly limited, and drinking water commonly used in the related art can be used.

According to another embodiment of the present invention, there is provided a method of preventing or improving an influenza virus infection comprising administering to the subject the food composition, quasi-drug composition, feed or drinking water additive, or feed or drinking water.

In the method for preventing or improving influenza virus infection according to the present invention, description of each composition, feed or drinking water additive, feed or drinking water, and dosage, route of administration, Are the same as those described above in connection with the above pharmaceutical composition.

A compound represented by the formula (1) of the present invention or a salt thereof; A composition for preventing, improving or treating an influenza virus infection comprising the licorice extract or a fraction thereof as an active ingredient, a feed or drinking water additive, and a feed or drinking water comprising a compound represented by the above formula (1) or a salt thereof; And the licorice extract or fractions thereof, exhibit remarkably excellent virulence and antiviral activity even with a small amount of use compared with the case of using them individually.

In addition, the present invention can be effectively used to prevent, ameliorate, or treat an influenza virus infection, particularly a highly pathogenic influenza virus infection because of its high absorption rate in the body and no side effects.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these examples and experimental examples are only for illustrative purposes of the present invention, and thus the scope of the present invention should not be construed as being limited by these examples and experimental examples.

Example 1: Preparation of koi extract

The ginseng used in the present invention is generally available in the market of Chinese medicinal herbs or on the market. Dried ginseng root of Curcuma longa Linne is intact and then dried to obtain the powder of the present invention. . 1.5 kg of 100% ethanol was added to 1.6 kg of water, and the mixture was allowed to stand at room temperature for 5 days, filtered through a filter paper, and concentrated to obtain 170 g of uroguanic acid ethanol extract.

Example  2: Kool  From the extract Kool Fraction  And Cucuminoid system  Separation and purification of compounds

To 170 g of the ethanol extract of the urogus obtained in Example 1, 1 L of water was added to suspend it. This was put in a separating funnel and fractionated using n-hexane and ethyl acetate in order to obtain n-hexane soluble extract (23 g), ethyl acetate soluble extract (85 g) and water soluble extract (34 g).

85 g of the ethyl acetate soluble extract obtained above was purified by silica gel column chromatography [silica gel 500 g, 70-230 mesh (silica gel) using chloroform, methanol and a mixed solvent thereof (80: 1 to 1: 1 (v / v) (Fr. 1-15) by performing the following procedure. The sixth fraction (Fr.6, 16 g) was further purified by silica gel column chromatography (30 g, 230 [mu] g) using a mixed solvent of n-hexane: ethyl acetate To 400 mesh) was performed to obtain five fractions (Fr.6-1 to 6-5).

Among them, Fr.sup.6-2 and 6-3 fractions (11 g) were subjected to silica gel column chromatography using chloroform, methanol and a mixed solvent thereof (80: 1 to 4: 1 (v / v)) as a mobile phase The obtained fractions were developed by preparative TLC (preparative TLC) method [(n-hexane: ethyl acetate = 4: 1 (v / v)] to obtain pure compound 1 (8 g) (Fr.8, 14 g) was dissolved in a mixed solvent of n-hexane: ethyl acetate (20: 1 to 1: 1 (v / v)) and chloroform: methanol (80: 1-20: (30 g, 230-400 mesh) was repeated to obtain compound 2 (0.4 g) and compound 3 (0.2 g).

Example 3: Structural analysis of a cucuminoid compound

The molecular weight and molecular formula of the glucuronide compound obtained in Example 2 were determined using a VG high resolution GC / MS spectrometer (VG high resolution GC / MS spectrometer, Election Ionization MS, Autospec-Ultima). The molecular structure was also determined using 1 H-NMR, 13 C-NMR, and 2D NMR spectroscopy data through nuclear magnetic resonance (NMR) analysis (Bruker AM 500).

As a result of analyzing the above apparatus analysis results, the compounds 1 to 3 were confirmed by curcumin, demethoxy curcumin and bisdemethoxy curcumin, respectively, represented by the following Chemical Formulas 2 to 4 (Food Chem 265- Proc Nat. Prod. 1227-1231, 2002; J. Nat. Prod. 1531-1534, 1998; J. Agric. Food Chem. 3668-3672, 2002). The results of the analysis are as follows.

Compound 1: Curcumin ( Curcumin )

(2)

1) Properties: Bright orange powder (m.p. 183 ° C)

2) Molecular weight: 368.3

3) Molecular formula: C ₂₁ H ₂₀ O ₆

4) 1 H-NMR (acetone-d 6, 500 MHz)? 7.62 (2H, d, J = 15.80 Hz, H- H-6 '), 6.83 (2H, d, J = 8.3, 1.9 Hz, H-10, H-10' 8.15 Hz, H-9, H-6 '), 5.99 (1H, s, H-1). ≪ 13 > C-NMR (acetone-d6, 125 MHz) [delta] 56.72, 102.01, 111.95, 116.64, 122.72, 124.25, 128.58, 141.81, 149.20, 150.44, 184.94.

Compound 2: Demethoxy curcumin ( Demethoxycurcumin )

(3)

1) Physical properties: orange powder (m.p. 220 ° C)

2) Molecular weight: 338

3) Molecular formula: C ₂₀ H ₁₈ O ₅

4) 1 H-NMR (acetone-d 6, 500 MHz)? 7.62-7.55 (4H), 7.34 (1H), 7.18 (1H), 6.89 (3H), 6.70 (2H), 5.97 13C-NMR (acetone-d6, 125 MHz)? 56.38, 101.79, 111.53, 116.30, 116.89, 122.12, 122.35, 123.98, 127.77, 128.24, 131.06, 141.13, 141.48, 148.87, 150.13, 160.64, 184.66.

Compound 3: Bisdemethoxy curcumin ( Bisdemethoxycurcumin )

[Chemical Formula 4]

1) Properties: Orange powder (m.p. 224 캜)

2) Molecular weight: 308

3) Molecular formula: C ₁₉ H ₁₆ O ₄

4) 1 H-NMR (acetone-d 6, 500 MHz)? 7.62-7.56 (6H), 6.91-6.87 (4H), 6.68-6.65 (2H), 5.98 (1H). 13C-NMR (acetone-d6, 125 MHz)? 101.82, 116.87, 122.11, 127.79, 131.06, 141.12, 160.58, 184.62.

Example  4: Preparation of licorice extract

In this example, Northeast licorice extract extract was used as licorice extract.

Example  5: licorice Fraction  Produce

590 g of the licorice extract of Example 4 was suspended in 1 liter of water. The mixture was extracted with n-hexane, chloroform and ethyl acetate in order and extracted with n-hexane soluble extract (5.5 g), chloroform soluble extract (180 g), ethyl acetate soluble extract (140 g) and water A soluble extract was obtained.

90 g of the chloroform-soluble extract obtained above was purified by silica gel column chromatography (silica gel, 500 g, 70 to 230 mesh) using 100% chloroform, acetone and a mixed solvent thereof (40: 1 to 1: 1 (v / v) ) Were separated into 10 fractions (Fr.1 to 10).

Example  5: Curcumin  And licorice extract

The curcumin isolated in Examples 1 to 3 and the licorice extract of Example 4 were mixed in a weight ratio of curcumin: licorice extract of about 1: 100 to prepare a mixture of curcumin and licorice extract.

Experimental Example  One: Curcumin  And in vitro toxicity of a mixture of licorice extract H5N1  Validation of influenza virus proliferation inhibition

For confirmation of the plaque reduction assay efficacy of the highly pathogenic influenza virus H5N1 of the curcumin isolated in Examples 1 to 3, the licorice extract of Example 4, and the curcumin and licorice extract prepared in Example 5, Respectively.

First, 200 ㎕ of highly pathogenic influenza virus H5N1 (10 ^3.0 EID ₅₀ / mL) was inoculated into MDCK cells and incubated for 40 minutes. Thereafter, the sample was diluted with 2 × MEM medium for each concentration, incubated for 40 minutes, and then the inoculated highly pathogenic influenza virus was removed. Then, the medium containing the sample was mixed with 1% agarose and concentration, Respectively. Finally, plaques formed after incubation in a 37 ° C incubator for 2 days were observed to determine the presence or absence of influenza virus and viral titers. The results are shown in Table 1 below.

Curcumin Licorice extract Curcumin and licorice extract mixture Material concentration
(쨉 g / mL) plaque number Material concentration
(쨉 g / mL) plaque number Material concentration
(쨉 g / mL) plaque number 40 69 60 94 25 13 32 91 30 152 20 88 25 122 15 181 15 123 Positive control group 184 Positive control group 188 Positive control group 194 EC ₅₀ 33.4 / / mL EC ₅₀ 73.2 / / mL EC ₅₀ 16.2 / / mL

As shown in Table 1, the inhibitory effect of the mixture of curcumin and licorice extract on the highly pathogenic virus H5N1 proliferation was remarkably superior to that of curcumin and licorice extract alone.

Therefore, it has been confirmed that the mixture of the curcumin and licorice extract of the present invention can be usefully used for the prevention of infections of highly pathogenic influenza virus H5N1 or for the treatment after infection.

Experimental Example  2: Curcumin  And a mixture of licorice extract SPF  Verification of antiviral activity using chicken animal model

In order to examine the in vivo antiviral activity of a mixture of curcumin and licorice extract which confirmed the antiviral effect through Experimental Example 1, the following experiment was conducted.

The animal used in Experimental Example 2 was a 3-week-old specific pathogen free (SPF) chicken. The concentration of the curcumin and licorice extract mixture of the present invention was 10 mg / kg, and the highly pathogenic influenza virus H5N1 It tested the antiviral activity to attack inoculated _{^{(10 4.5 EID 50/100)}} .

First, a mixture of curcumin and licorice extracts was orally administered once a day (2 ml / chichen / day) for 7 days after the attack, 7 days before the H5N1 attack. Attack Inoculation Positive and negative control groups were orally administered with PBS in the same manner as the above mixture administration group. Influenza viruses were measured by real-time RT-PCR in oral and total excreta on days 1, 2, 3, 4, 5 and 7 after H5N1 challenge. The efficacy of the combination of curcumin and licorice extracts for the prevention of the highly pathogenic influenza virus was evaluated by observing clinical symptoms and reducing the mortality rate for 10 days after the inoculation. The experimental results are shown in Table 2 below.

group density
(mg / kg) ^A inoculation
Head Attack results PI ₁₀ ^F Clinical symptoms Our company Sick ^B MTO
(day) ^C Dead ^D MDT
(day) ^E Curcumin alone One 10 10/10 One 9/10 2.8 1.9 Curcumin and
Licorice extract mixture 10 10 10/10 One 8/10 2.6 1.8 Positive control group PBS 10 10/10 One 10/10 5.5 2.0 Negative control group PBS 10 0/10 - 0/10 - -

^A Dose: 2 ml per day / chichen; Duration of administration: From 7 days before attack to 7 days after attack.

^B Clinical manifestations / number of inoculation.

^C The average number of days that clinical symptoms develop.

^D Our head / Inoculation head.

^E The average number of days of death.

^F Pathogenicity index (PI): 0 for normal, 1 for fever, 1 for eyelid or hair, 2 for our company.

Next, influenza virus emissions were verified in oral and total excreta after challenge with the highly pathogenic influenza virus.

Table 3 below shows the results of measurement of influenza virus release in oral cavity.

Treatment live / total ^A Positive rate ^B Ct value ^C Mean SD Curcumin alone treatment 10/10 5/10 35.59 2.32 Curcumin and
Licorice extract mixture 10/10 7/10 34.87 2.89 Positive control group 10/10 4/10 33.65 3.61

^A Survival Number / Test Number.

^B Positive head / survival head.

^C Mean and standard deviation of cycle threshold (Ct) values of oropharyngeal swab samples positive by real-time RT-PCR.

As shown in Table 3, when curcumin alone was used, the incidence of highly pathogenic influenza virus in the oral cavity was lower than when curcumin and licorice extract were used together. When curcumin and licorice extract were used together, It was confirmed that the absorption rate in the body was higher than that in the case of using.

Table 4 below shows the results of measurement of influenza virus emissions in total excrement.

Treatment live / total ^A Positive rate ^B Ct value ^C Mean SD Curcumin alone treatment 10/10 3/10 36.57 0.89 Curcumin and
Licorice extract mixture 10/10 1/10 33.68 - Positive control group 10/10 0/10 - -

^A Survival Number / Test Number.

^B Positive head / survival head.

^C Mean and standard deviation of cycle threshold (Ct) values of oropharyngeal swab samples positive by real-time RT-PCR.

As shown in Table 4, when the curcumin and licorice extracts were used together, the virus isolation rate in the total excreta was lower than that in the case of using the curcumin and licorice extract together. It was confirmed that the absorption rate in the body was higher than that in the case of using alone.

Specifically, in the group administered with curcumin alone, the virus re-segregation rate and the mean titer decreased in the oral cavity. However, when the mixture of the curcumin and licorice extracts of the present invention was administered, the virus re- And the mean titer was not significantly lower than that of the positive control.

Table 5 below shows the test results of influenza viruses in total excreta on the second day of the inoculation.

Treatment live / total ^A Positive rate ^B Ct value ^C Mean SD Curcumin alone treatment 8/10 7/8 32.34 1.92 Curcumin and
Licorice extract mixture 6/10 3/6 35.10 3.27 Positive control group 10/10 2/10 35.60 1.18

^A Survival Number / Test Number.

^B Positive head / survival head.

^C Mean and standard deviation of cycle threshold (Ct) values of oropharyngeal swab samples positive by real-time RT-PCR.

From the above results, it was confirmed that when the mixture of curcumin and licorice extract was orally administered to an animal model, not only the virus in the organism but also the virus in the cecum one way, Showed that the virus had an antiviral effect on the entire body part of the infected individual.

Therefore, the mixture of curcumin and licorice extract of the present invention exhibits remarkable antiviral efficacy and bioavailability enhancement effect against highly pathogenic H5N1 influenza virus by the synergy effect of curcumin and licorice extract, so that curcumin and licorice extract are used alone And exhibited remarkably superior live virus and antiviral efficacy as compared with the case of the control.

Experimental Example  4: Cucuminoid system  Acute toxicity test of compound

The following experiment was carried out in order to examine the acute toxicity of the composition of the present invention to a carmucinoid compound as an active ingredient.

6-week-old SPF C57BL / 6J mice were divided into four groups of 12 mice each (male and female). The animals were housed in an animal room at a temperature of 22 ± 3 ° C, humidity of 55 ± 10%, and illumination of 12L / 12D. Mice were purified for a week before being used in the experiment. Feeds for laboratory animals (mouse and rats, Cheil Jedang Co., Seoul, Korea) and drinking water were sterilized and fed free.

The compounds of Formulas 2 to 4 prepared in Example 2 were each adjusted to a concentration of 50 mg / mL in 0.5% Tween 80, and then 0.04 mL (100 mg / kg) and 0.2 mL 500 mg / kg) and 0.4 mL (1,000 mg / kg). The samples were orally administered once, and the following side effects or deaths were observed for 7 days after administration. That is, on the day of administration, changes in general symptoms and presence or absence of dead animals were observed at 1 hour, 4 hours, 8 hours, 12 hours after the administration, and 1 day at the morning and at the afternoon from the next day to 7 days after administration.

As a result of the above acute toxicity test, no clinical symptoms were observed in all of the mice to which the sample was administered, no dead mouse was observed, and toxicity was not observed even in weight change, blood test, blood biochemical test, I did.

Thus, were the invention increases kyumi cannabinoid-based compound did not show any toxic change in all mice to 1,000 mg / kg, the were found to be orally administered minimum lethal dose (LD ₅₀₎ is 1,000 mg / kg or more safe substance, licorice extract also Actual sweeteners and nutritional supplements, KFDA is a safe substance that is used by permission, a compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof; And a composition for preventing, improving or treating an influenza virus infection comprising the licorice extract or its fraction as an active ingredient can be safely used for the treatment of an influenza virus infection, particularly a highly pathogenic influenza virus H5N1 infection.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. More variations are possible within a range that does not. Accordingly, the present invention may be embodied in other ways than those specifically described and illustrated herein, and it may be understood by those skilled in the art.

Claims (16)

Claims [1] A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a licorice extract or a fraction thereof, as an active ingredient, for preventing or treating an influenza virus infection.
[Chemical Formula 1]

Wherein R ¹ and R ² are each independently hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group, and n and m are ₁ ? N? 5 and 1? M? 5.
The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is a compound represented by any one of the following formulas (2) to (4), or a mixture thereof.
(2)

(3)

[Chemical Formula 4]

The pharmaceutical composition according to claim 1, wherein the weight ratio of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: licorice extract or its fraction contained in the pharmaceutical composition is 1:10 to 1: 150.
The pharmaceutical composition according to claim 1, wherein the compound represented by Formula 1 is isolated from Turmeric.
The pharmaceutical composition according to claim 1, wherein said influenza virus is a highly pathogenic influenza virus H5N1.
2. The pharmaceutical composition according to claim 1,
a) a first composition comprising, as an active ingredient, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a second composition comprising the licorice extract or a fraction thereof as an active ingredient; And
b) treating the mixture obtained in step a) with a microwave.
7. The pharmaceutical composition of claim 6, wherein step b) further comprises treating the mixture with ultrasound prior to microwave treatment.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for oral administration.
9. A method for the prevention or treatment of an influenza virus infection comprising administering a pharmaceutical composition according to any one of claims 1 to 8 to a subject other than a human.
Claims 1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a licorice extract or a fraction thereof as an active ingredient.
[Chemical Formula 1]

Wherein R ¹ and R ² are each independently hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group, and n and m are ₁ ? N? 5 and 1? M? 5.
The food composition according to claim 10, wherein the compound represented by the formula (1) is a compound represented by any one of the following formulas (2) to (4), or a mixture thereof.
(2)

(3)

[Chemical Formula 4]

Claims [1] A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a licorice extract or a fraction thereof as an active ingredient.
[Chemical Formula 1]

Wherein R ¹ and R ² are each independently hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group, and n and m are ₁ ? N? 5 and 1? M? 5.
13. The quasi-drug composition according to claim 12, wherein the compound represented by the formula (1) is a compound represented by any one of the following formulas (2) to (4), or a mixture thereof.
(2)

(3)

[Chemical Formula 4]

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a feed additive or a drinking water additive for preventing or ameliorating an influenza virus infection comprising an licorice extract or a fraction thereof as an active ingredient.
[Chemical Formula 1]

Wherein R ¹ and R ² are each independently hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group, and n and m are ₁ ? N? 5 and 1? M? 5.
The feed additive or the additive for drinking water according to claim 14, wherein the compound represented by the formula (1) is a compound represented by any one of the following formulas (2) to (4), or a mixture thereof.
(2)

(3)

[Chemical Formula 4]

A feed or drinking water comprising the feed additive or the additive for drinking water of claim 14 or 15.