JP2005104852A - Prophylactic or treating composition for morbillivirus infectious disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition effective in prophylaxis or treatment of Morbillivirus infectious diseases. <P>SOLUTION: The prophylactic or treating composition for the Morbillivirus infectious diseases comprises a reduced form glutathione or oxidized form glutathione or a pharmacologically acceptable salt thereof. The composition comprises one or more kinds of antioxidants. In the composition, Morbillivirus is measles virus. The composition which is a medicine, a food and drink or an additive for the food and drink is provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a composition for preventing or treating morbillivirus infection.

  Mobilivirus is one of the virus genera of the Paramicrosoviridae family which is a single-stranded RNA virus. It has an envelope, and has H protein and F protein on it. F protein has membrane fusion ability, is involved in fusion with the cell membrane surface, and is said to have an important role in the early stages of infection. It is not inhibited by drugs such as actinomycin D and α-amanitin, which have an influenza virus inhibitory action, and there is no effective preventive or therapeutic drug only for acyclovir showing a weak suppressive effect.

Measles that develops due to the measles virus, a type of mobilivirus, is an important viral infection that still kills about 1 million people worldwide every year. It has become a global urgent task, especially in underdeveloped countries.
Glutathione is a tripeptide having a structure of γ-L-Glu-L-Cys-Gly, and is known as a therapeutic agent for acetoneemia caused by alcohol.

Glutathione is known to have a preventive or therapeutic effect on the influenza virus infection, which has a drug sensitivity different from that of the mobilivirus (see Patent Document 1). Is not known.
International Publication No. 98/30228 Pamphlet

  An object of the present invention is to provide a composition effective for the prevention or treatment of morbillivirus infection.

The present invention relates to the following (1) to (6).
(1) A composition for the prophylaxis or treatment of morbillivirus infection containing reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof.
(2) The composition according to (1) above, wherein the composition contains one or more antioxidants.
(3) The composition according to (1) or (2) above, wherein the morbillivirus is measles virus.
(4) The composition according to any one of (1) to (3), wherein the composition is a medicine.
(5) The composition according to (4) above, wherein the medicine is an oral preparation, an injection, a nasal aerosol, or an inhalant.
(6) The composition according to any one of (1) to (3), wherein the composition is a food or drink or a food or drink additive.

  INDUSTRIAL APPLICABILITY According to the present invention, there is provided a composition having a preventive and therapeutic effect on morbillivirus infection containing reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof.

  In the present invention, reduced glutathione represents a tripeptide having the structure of γ-L-Glu-L-Cys-Gly, and oxidized glutathione represents a glutathione dipeptide in which two reduced glutathione molecules are bound by an SS bond.

The reduced glutathione and oxidized glutathione used in the present invention may be obtained by any production method. Examples of the production method of reduced glutathione include extraction methods from microorganisms such as yeast [ Methods in Enzymology, 3 , 603 (1957)], chemical synthesis method [Bull. Chem. Soc. Jpn., 53 , 2529 (1980)], enzymatic method (JP 61-74595), etc. Production of oxidized glutathione Examples of the method include those described in [Acta Biochim. Pol., 17 , 175 (1970)].

Hereinafter, as a method for producing reduced glutathione, a chemical synthesis method and an extraction method from yeast are exemplified.
1. Chemical Synthesis Method of Reduced Glutathione Reduced glutathione can be chemically synthesized according to the method described in [Bull. Chem. Soc. Jpn., 53 , 2592 (1980)].
N-formyl-L-2-amino-4-cyanobutyric acid ethyl ester is condensed with ethyl L-cysteinyl glycinate to give (4R) -2-[(3S) -3-ethoxycarbonyl-3- ( Formylamino) propyl] -4- (ethoxycarbonylmethylcarbamoyl) -2-thiazoline, followed by saponification at about −15 ° C. in an aqueous acetone solution followed by treatment with dilute sulfuric acid (pH 4). Get glutathione. Next, the formyl group is removed by hydrolysis with 0.5 mmol / l sulfuric acid to obtain free glutathione. Purify further if necessary. In this further purification, pure glutathione can be obtained by converting free glutathione to its copper thiolate followed by treatment with hydrogen sulfide.

2. Extraction Method of Reduced Glutathione from Yeast Reduced glutathione can be extracted from yeast according to the method described in [Methods in Enzymology, 3 , 603 (1957)].
An equal weight of 10% trichloroacetic acid (TCA) is added to the yeast extract. The residue obtained by centrifugation is extracted twice more with half the initial volume of TCA. Combine the extracts and add a cadmium chloride solution in one-quarter of the volume of the extract. The pH of the solution is brought to 5 by adding 10 mol / l sodium hydroxide and then adjusted to pH 6.5 with bicarbonate. The precipitated cadmium complex is kept at 0 ° C. for 1 hour and then washed twice with ice-cold distilled water. After the precipitate is dissolved in a minimum amount of 2 mol / l sulfuric acid, 3 ml of 0.5 mol / l sulfuric acid is added per 10 mg of expected acquisition of glutathione. If necessary, the solution is filtered and the amount of glutathione present is determined in aliquots. The solution is warmed to 40 ° C. and a copper oxide suspension containing 2.5 mg of copper oxide per 10 mg of glutathione is added dropwise with gentle shaking. The resulting precipitate is left at 0 ° C. for several hours, centrifuged, and washed successively with 0.5 mol / l sulfuric acid twice, distilled water three times and methanol twice. In order to isolate free glutathione, the copper complex of glutathione is decomposed with hydrogen in an aqueous suspension, and the solution after removing the copper sulfite is dried by lyophilization.

  The composition of the present invention may be a composition containing reduced glutathione or oxidized glutathione alone, or a composition containing reduced glutathione and oxidized glutathione simultaneously.

  Moreover, the reduced glutathione and oxidized glutathione contained in the composition of the present invention may be present in the composition as pharmacologically acceptable salts thereof. As pharmacologically acceptable salts of reduced glutathione and oxidized glutathione (in the form of water-soluble, oil-soluble or dispersible products), for example, normal non-toxicity formed from inorganic acids, organic acids or bases, for example Salt or quaternary ammonium salt. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulphate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane. Sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, Bamoate, pectinate, bersulphate, 3-phenylpropionate, picrate, Bareto, propionate, can be mentioned succinates, tartrates, thiocyanates, and the like tosylate and undecanoate. Basic salts include alkali metal salts such as ammonium salt, sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, dicyclohexylamine salt, organic bases such as N-methyl-D-glucamine and the like. And salts with amino acids such as arginine and lysine.

  Basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate and dibutyl sulfate, dia May be quaternized with agents such as chlorides, bromides and iodides such as milsulphate, decyl, lauryl, myristyl and stearyl, long chain halides such as iodide, aralkyl halides such as benzyl bromide and phenethyl bromide . Other pharmacologically acceptable salts include sulfate salt ethanolate and sulfate salt.

  Furthermore, the present invention relates to a composition for the prevention or treatment of morbillivirus infection comprising reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof and one or more antioxidants.

  Antioxidants include vitamin A, vitamin E, vitamin K, copper (cupric oxide), zinc (zinc oxide), iron (ferrous salt), selenium (sodium selenate), β-carotene, polyphenols Flavonoids such as flavinoids, catechin and quercetin, flavanones such as eriodictyol, diterpenoids such as carnosic acid and carnosol, phenolic acids such as rosmarinic acid, caffeic acid, coumaric acid and cinnamic acid, coenzyme Q10, probucol And a substance selected from the group consisting of carotenoids such as astaxanthin and lycopene, α-lipoate and urate.

  In the present invention, examples of the morbillivirus include measles virus, rinderpest virus, canine distemper virus, seal distemper virus, mire camouflage virus, murine dolphin morbillivirus and the like.

The composition in the present invention can be used as a medicine, food or drink, or food or drink additive.
Examples of the medicament include oral preparations, mouth washes or gargle preparations, nasal aerosols, inhalants, drops, injections for intravenous injection or intramuscular injection, suppositories, and the like.
The oral preparation is produced by any method well known in the technical field of pharmaceutical formulation by mixing reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof together with a carrier as necessary. be able to.

When formulating oral preparations, additives such as excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, and bacterial inhibitors Can be used.
Examples of oral dosage forms include tablets, powders, granules, emulsions, syrups, capsules and the like.

  For example, if the oral dosage form is tablets, powders, granules, etc., lactose, sucrose, glucose, sucrose, saccharides such as mannitol, sorbitol, starch such as potato, wheat, corn, calcium carbonate, calcium sulfate , Inorganic substances such as sodium bicarbonate and sodium chloride, excipients such as plant powder such as licorice powder and gentian powder, starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium bicarbonate , Disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin, starch paste, etc. Binder, fat Surfactants such as esters, with the addition of plasticizer such as glycerin, can be formulated.

  When the oral dosage form is a liquid preparation such as an emulsion or syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil And preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint can be added to prepare a preparation. The concentration of reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof in the liquid preparation may be any concentration, preferably 10 to 200 mmol / l, more preferably 10 to 10 mmol / l. A concentration of 50 mmol / l can be raised. The pH of the liquid preparation may be any pH as long as reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof is stable, preferably 4.0 to 6.0. Can be raised.

  When the oral dosage form is a capsule, it can be filled into a hard capsule or encapsulated with a capsule base material and formulated as a soft capsule. As the capsule base material, gelatin can be cited. In soft capsules, glycerin or sorbitol is added to impart plasticity. Further, if necessary, a dye, titanium oxide, barium sulfate, precipitated calcium carbonate as a light-shielding agent, and paraoxybenzoic acid esters as a preservative can be added.

Mouthwash or gargle preparations include reduced glutathione or oxidized glutathione or pharmaceutically acceptable salts thereof, antibacterial agents, surfactants, co-surfactants, oils, water and other additives, It can be formulated by adding a sweetener / flavoring agent or the like known in the technical field.
The reduced glutathione or oxidized glutathione or pharmacologically acceptable salt thereof contained in the mouthwash or gargle preparation may be in any concentration, preferably 10 to 200 mmol / l, more preferably 10 A concentration of ˜50 mmol / l can be raised. The pH of the liquid preparation may be any pH as long as reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof is stable, preferably 4.0 to 6.0. Can be raised.

Nasal aerosols or inhalants can be prepared using techniques well known in the art of pharmaceutical formulation, such as benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other known in the art. Can be prepared as a physiological saline solution by using a solubilizer or dispersant, a surfactant, a jelly agent or a buffer and other stabilizers and solubilizers [Pharmaceutical
Dosage Forms and Drug Delivery Systems (6th edition, (1995)].
The volume of the solution or suspension administered as a nasal aerosol or inhaler per unit dose is preferably 5 to 400 μl, more preferably 50 to 150 μl.

  Injections for infusions, intravenous injections or intramuscular injections are well known in the technical field of pharmaceutics by dissolving reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof in an aqueous solvent. It can be produced by any method.

When formulating drops or injections, it is formulated using additives such as aqueous solvents, water-insoluble solvents, preservatives, stabilizers, soothing agents, tonicity agents, buffers and excipients. Can be
Aqueous solvents include water for injection, physiological saline, Ringer's solution, non-water soluble solvents include vegetable oils such as peanut oil, sesame oil, corn oil, olive oil and cottonseed oil, preservatives include stabilizers such as phenol and cresol As sulfites, sodium pyrosulfite and ascorbic acid, as soothing agents, as benzyl alcohol and chlorobutanol, as isotonic agents, such as sodium chloride and glucose, as buffering agents, citrate, acetate and Examples of excipients such as phosphates include sorbitol.

The administration systems for the various dosage forms described above can be dropper bottles, plastic squeeze devices, atomizers, nebulizers or pharmaceutical aerosols (unit dose or multiple dose packages).
Suppository is a suitable nonirritating agent that releases reduced or oxidized glutathione or a pharmacologically acceptable salt thereof at room temperature but is liquefied and / or dissolved in the rectal cavity to release the drug. It can be formulated by mixing with excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycol.

When the composition of the present invention is administered as a medicament to humans, the dose and frequency of administration vary depending on the dosage form, age, weight, symptoms, etc., but usually reduced glutathione or oxidized glutathione or their pharmacologically. As an acceptable salt, 1 to 10,000 mg, preferably 20 to 2000 mg, more preferably 50 to 500 mg is administered once to several times a day.
The food and drink additive of the present invention can be prepared by the same method as the oral preparation described above. The food / beverage product additive is usually processed and manufactured in the form of powder, granules, pellets, tablets, and various liquids, for example, by mixing or dissolving other food / beverage product additives as necessary.

Examples of the food and drink of the present invention include those obtained by adding reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof to the food or drink.
The food and drink of the present invention is processed and manufactured by using a general method for producing food and drink, except that reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof is added to the food or drink. can do.

  The food / beverage product of the present invention is, for example, fluidized bed granulation, stirring granulation, extrusion granulation, rolling granulation, airflow granulation, compression molding granulation, pulverization granulation, spray granulation, spray granulation, etc. Coating methods such as granulation method, pan coating, fluidized bed coating, dry coating, puff drying, excess steam method, foam mat method, expansion method such as microwave heating method, extrusion granulator or extruder etc. Can also be manufactured.

  The food and drink of the present invention are juice products, soft drinks, teas, lactic acid bacteria beverages, fermented milk, frozen desserts, butter, cheese, yogurt, processed milk, skim milk and other meat products such as ham, sausage and hamburger Fish paste products such as rice cakes, bamboo rings and deep-fried sweet potatoes, egg products such as sushi rolls, egg tofu, cookies, jelly, chewing gum, candy, candy, snacks, snacks, breads, noodles, pickles, salmon products, dried fish , Simmered, salted products, soups, seasonings, etc.

A larynx containing reduced glutathione or oxidized glutathione or a pharmaceutically acceptable salt thereof can be prepared according to US Pat. No. 3,439,089.
The food and drink of the present invention may be in the form of, for example, powdered food, sheet food, bottled food, canned food, retort food, capsule food, tablet food, liquid food, and drink.

The food / beverage products or food / beverage food additives of the present invention include food / beverage food additives generally used for food / beverage products, such as sweeteners, colorants, preservatives, thickening stabilizers, antioxidants, colorants, bleaching agents. An antifungal agent, gum base, bittering agent, enzyme, brightener, acidulant, seasoning, emulsifier, strengthening agent, manufacturing agent, fragrance, spice extract and the like may be added.
The food / beverage products of the present invention can be used as food / beverage products such as health foods or functional foods for prevention or treatment of mobivirus infection.

  The amount of reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof, or the food additive of the present invention in the food or drink of the present invention depends on the type of food or drink and the intake of the food or drink. Although it is appropriately selected depending on the expected effect and the like, it is usually 0.1 to 90% by weight, preferably 1 to 70% by weight as reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof. Particularly preferably, it is added so as to contain 5 to 50% by weight.

  The intake of the food and drink of the present invention varies depending on the intake form, the age, weight, etc. of the intake person, but is usually reduced glutathione or oxidized glutathione per day or their pharmacologically acceptable for adults. As a salt, it is 100-10000 mg, Preferably it is 100-2000 mg, Most preferably, it is 200-1000 mg, and it ingests once or several times a day. The intake period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.

The following test example shows the effect of glutathione on the inhibition of growth of morbillivirus.
Test Example 2 × 10 ⁵ B95a cells [Journal of General Virology, 83 , 1457 (2002)] were seeded in each well of a 12-well plate, and Rinderpest Virus (RPV) L strain [Journal of General Virology, 83 , 1457 ( 2002)] was infected with MOI (virus titer / cell count) = 0.05 or 0.001 for 1 hour. 2% fetal calf serum containing reduced glutathione added to a final concentration of 1, 2, 4, 10, or 30 mmol / l after removing the culture supernatant and washing the cells once with a phosphate buffer solution Cultured in RPMI 1640 medium for 4 days.

After completion of the culture, the cells in each well and the culture supernatant were collected and collected, and the supernatant obtained by freezing and thawing the cells three times and then centrifuging was used as a measurement sample. The titer of the virus in each sample was measured using the TCID50 method [Microbiology Practice Proposal 2nd edition, edited by the Alumni Institute of Medical Science, The University of Tokyo, Maruzen (1998)].
The results are shown in FIG.

By adding reduced glutathione, the virus growth-inhibiting effect was already observed from a concentration of 1 mmol / l, and at 4 mmol / l or more, virus growth was completely suppressed.
The above results indicate that reduced glutathione has a remarkable effect of suppressing the growth of mobile virus.
Examples of the present invention are shown below.

Preparation of nasal spray for treatment of morbillivirus infection containing oxidized glutathione or reduced glutathione Nasal spray containing oxidized glutathione or reduced glutathione was added to saline [0.9% (w / v) Sodium chloride aqueous solution] It is prepared by adding 3 mg of oxidized glutathione or reduced glutathione per ml and dissolving.

Preparation of reduced glutathione-containing nasal spray for treatment of morbillivirus infection A nasal spray containing the following ingredients is prepared.
Reduced glutathione 1.0g
Sodium acetate 0.3g
Methylbaraben 0.1g
Propylbaraben 0.02g
Sodium chloride Amount required for tonicity Hydrochloric acid or sodium hydroxide Amount required for pH adjustment Pure water Amount to make a total volume of 100 ml

Preparation of Nasal Spray for Treatment of Oxidized Glutathione-Containing Morbilivirus Infection A nasal spray containing the following ingredients is prepared.
Oxidized glutathione 1.0g
Sodium acetate 0.3g
Methylbaraben 0.1g
Propylbaraben 0.02g
Sodium chloride Amount required for tonicity Hydrochloric acid or sodium hydroxide Amount required for pH adjustment Pure water Amount to make a total volume of 100 ml

Preparation of reduced glutathione-containing drops (1)
Prepare a drop using the candy base and drug mixture described below.
Ame base:
Maltitol (medium particle size) 35.0kg
Corn syrup 43 ° Baume 21.0kg
Drug mixture:
Polyethylene glycol (molecular weight 6,000) 2.75kg
Reduced glutathione 5.0kg
Citric acid 60.0kg
Wild cherry imitation flavor 60.0g

The candy base is prepared as follows.
Dissolve maltitol in 5.5 liters of water, add glucose-containing corn syrup and mix well. At this point, if necessary, a dye is added to give the desired color. A dye that dissolves sufficiently is used.
The mixture is placed in a steam jacket kettle heated to 125 ° C. From there, the mixture is pumped into a storage container and fed to a continuous cooker. While the syrup passes through the coil in the cooker, it reaches a temperature of 125-150 ° C. and is then fed by a steam vacuum ejector to a receiving kettle maintained at 28-29 inches of vacuum for about 6-7 minutes. During this time, water is removed until the water content is reduced to about 1% or less to form a suitable molten candy base. The candy base is prepared by slowly cooling the molten candy base.

  Next, reduced glutathione, citric acid and a mimetic flavor (powdered) are added to polyethylene glycol to prepare a drug mixture. The mixture is then fluidized by heating at about 90 ° C. The resulting hot fluid mixture is rapidly added to the molten candy base (with the temperature lowered to about 100 ° C. or slightly below) with proper mixing. Next, after fully kneading the whole mass, it is transferred to a spinning machine and extruded into a lozenge forming die to prepare a reduced glutathione-containing drop.

Preparation of reduced glutathione-containing drops (2)
The medicinal mixture-added molten candy mass obtained in Example 4 is poured into a cooling table, solidified into a semi-solid mass on the cooling table, and then molded into any desired shape for ingesting the unit intake of reduced glutathione. By doing so, a reduced glutathione-containing drop is prepared.

Preparation of oxidized glutathione-containing drops (1)
Ame base:
Maltitol (medium particle size) 35.0kg
Corn syrup 43 ° Baume 21.0kg
Drug mixture:
Polyethylene glycol (molecular weight 6,000) 2.75kg
Oxidized glutathione 5.0kg
Citric acid 60.0kg
Wild cherry imitation flavor 60.0g

The candy base is prepared as follows.
Dissolve maltitol in 5.5 liters of water, add glucose-containing corn syrup and mix well. At this point, if necessary, a dye is added to give the desired color. A dye that dissolves sufficiently is used.
The mixture is placed in a steam jacket kettle heated to 125 ° C. From there, the mixture is pumped into a storage container and fed to a continuous cooker. While the syrup passes through the coil in the cooker, it reaches a temperature of 125-150 ° C. and is then fed by a steam vacuum ejector to a receiving kettle maintained at 28-29 inches of vacuum for about 6-7 minutes. During this time, water is removed until the water content is reduced to about 1% or less to form a suitable molten candy base. The candy base is prepared by slowly cooling the molten candy base.

  Next, oxidized glutathione, citric acid and mimetic flavor (powder) are added to polyethylene glycol to prepare a drug mixture. The mixture is then fluidized by heating at about 90 ° C. The resulting hot fluid mixture is rapidly added to the molten candy base (with the temperature lowered to about 100 ° C. or slightly below) with proper mixing. Next, after fully kneading the whole mass, it is transferred to a spinning machine and extruded into a lozenge forming die to prepare an oxidized glutathione-containing drop.

Preparation of oxidized glutathione-containing drops (2)
The drug mixture-added molten candy mass obtained in Example 6 is poured into a cooling table, solidified into a semi-solid mass on the cooling table, and then molded into any desired shape for ingesting a unit intake of oxidized glutathione. By doing so, an oxidized glutathione-containing drop is prepared.

FIG. 1 is a graph showing the effect of reduced glutathione on the growth of mobilibirvirus. The black and white columns in the graph show the results when the MOI is 0.05 and 0.001, respectively. In addition, the horizontal axis of the graph represents the concentration of reduced glutathione, and the vertical axis represents the virus titer 4 days after infection by the TCID50 method.

Claims (6)

  A composition for the prophylaxis or treatment of morbillivirus infection comprising reduced glutathione or oxidized glutathione or a pharmacologically acceptable salt thereof.   The composition of claim 1, wherein the composition comprises one or more antioxidants.   The composition according to claim 1 or 2, wherein the mobilivirus is a measles virus.   The composition according to any one of claims 1 to 3, wherein the composition is a medicine.   The composition according to claim 4, wherein the medicament is an oral preparation, an injection, a nasal aerosol, or an inhalant.   The composition according to any one of claims 1 to 3, wherein the composition is a food or drink or a food or drink additive.

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