JP2022132181A - Inhibitors of coronavirus invasion into cells - Google Patents

Abstract

To provide agents that inhibit coronavirus invasion into cells by effectively inhibiting an infection factor on a human (host) side and are useful for preventing or suppressing coronavirus infection.SOLUTION: The invention provides an inhibitor of the invasion of coronavirus into cells, where the inhibitor contains at least one ingredient selected from tetradecene sulfonate, lauryl sulfonate, lauroylmethyl taurine salt, aluminum lactate, potassium nitrate, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, coconut oil fatty acid amidopropyl betaine, lauroyl sarcosine salt, tranexamic acid, epsilon-aminocaproic acid and copper gluconate.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a coronavirus cell entry inhibitor.

Since the oral cavity can be an infection route for upper respiratory tract infections, including the new coronavirus infection (COVID-19), daily oral care behaviors such as toothbrushing may help prevent infection. So far, it has been reported that ingredients contained in oral care products such as toothpaste and mouthwash act on the new coronavirus and reduce its infectivity by destroying the functions of the virus (non-patent literature). 1 and 2).

On the other hand, in the oral cavity, core factors related to intracellular infection of the new coronavirus on the human (host) side such as receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed. (Non-Patent Document 3), it is believed that the oral cavity can be an infection route for the new coronavirus (promotion of infection to the upper respiratory tract due to invasion into the body and an increase in the number of viruses).

Patent Document 1 describes that tranexamic acid has anti-influenza virus activity as an antiviral agent containing ingredients contained in oral care products such as dentifrices and mouthwashes.

WO2004/032915

“Brief Report: The Virucidal Efficacy of Oral Rinse Components Against SARS-CoV-2 In Vitro,” https://doi. org/10.1101/2020.11.13.381079 "Antiviral Activity of Reagents in Mouth Rinses against SARS-CoV-2" J Dent Res 2020 Oct 22;22034520967933. "Existence of SARS-CoV-2 Entry Molecules in the Oral Cavity" Int J Mol Sci 2020 Aug 20;21(17):6000

Although research has been conducted focusing on the effects of the ingredients contained in oral care products such as toothpaste and mouthwash on the virus itself, infection on the human (host) side, which is important for the prevention of persistent infection with coronavirus, is being conducted. The effect of oral care ingredients on factors has not been clarified.

An object of the present invention is to provide a viral cell entry inhibitor that can exert an effective inhibitory action or inhibitory action against infectious agents on the human (host) side and is useful for inhibiting, preventing, or suppressing coronavirus infection.

The present invention provides the following [1] to [13].
[1] Tetradecenesulfonate, Lauryl Sulfate, Lauroyl Methyl Taurate, Aluminum Lactate, Potassium Nitrate, 2-Alkyl-N-Carboxymethyl-N-Hydroxyethylimidazolinium Betaine, Coconut Fatty Acid Amidopropyl Betaine, Lauroyl Sarcosine A coronavirus cell entry inhibitor comprising at least one selected from salts, tranexamic acid, epsilon-aminocaproic acid, and copper gluconate.
[2] The agent of [1], which inhibits the formation of a bond between a coronavirus spike protein and a cell surface receptor.
[3] 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, coconut oil fatty acid amidopropyl betaine, tetradecenesulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, gluconic acid The agent according to [2], which contains at least one selected from copper and lauroyl sarcosine salts.
[4] The agent of [1], which inhibits activation of spike protein bound to cell surface receptors by transmembrane serine protease 2 (TMPRSS2).
[5] The agent of [4], wherein the inhibition of spike protein activation is inactivation of transmembrane serine protease 2 (TMPRSS2).
[6] containing at least one selected from lauroyl methyl taurate, tetradecene sulfonate, tranexamic acid, epsilon-aminocaproic acid, lauryl sulfate, aluminum lactate, potassium nitrate, copper gluconate, and lauroyl sarcosinate, [4 ] or the agent according to [5].
[7] the agent of any one of [2] to [6], wherein the receptor is angiotensin converting enzyme 2;
[8] The agent of [1], which inhibits expression of transmembrane serine protease 2 (TMPRSS2).
[9] The agent of [8], which contains lauryl sulfate.
[10] The agent according to any one of [1] to [9], which is for prevention of coronavirus infection, or suppression or alleviation of symptoms.
[11] The agent according to any one of [1] to [10], wherein the coronavirus is SARS-CoV-1, CoV-NL63, or SARS-CoV-2.
[12] The agent according to any one of [1] to [11], which is a mucosal external preparation.
[13] The agent according to any one of [1] to [12], which is an oral, nasal, or ophthalmic agent.

INDUSTRIAL APPLICABILITY According to the present invention, a cell entry inhibitor capable of exerting an effective inhibitory action on core factors involved in infection on the human (host) side and useful for preventing or suppressing coronavirus infection is provided.

[1. Active ingredient]
The agent of the present invention includes tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, coconut oil fatty acid amidopropyl betaine. , lauroyl sarcosine salt, tranexamic acid, epsilon-aminocaproic acid, and copper gluconate.

Tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, and lauroyl sarcosine salt may be each pharmacologically acceptable salt. Pharmaceutically acceptable salts include, for example, base addition salts and amino acid salts. Specific examples thereof include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts and diisopropylammonium salts; arginine salts and the like. and basic amino acid salts of Among them, inorganic base salts are preferred, respective alkali metal salts (eg, sodium salts, potassium salts) or ammonium salts are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred.

The agent of the present invention may contain one or more of the above active ingredients, and preferably contains any one of A to E below.
A) 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, coconut oil fatty acid amidopropyl betaine, tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, copper gluconate , and at least one selected from lauroyl sarcosine salts;
B) at least one selected from lauroyl methyl taurate, tetradecene sulfonate, tranexamic acid, epsilon-aminocaproic acid, lauryl sulfate, aluminum lactate, potassium nitrate, copper gluconate, and lauroyl sarcosinate;
C) at least one selected from tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, copper gluconate, and lauroyl sarcosinate;
D) 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, coconut oil fatty acid amidopropyl betaine, tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, copper gluconate , and at least one selected from lauroyl sarcosine salts, and at least one combination selected from tranexamic acid and epsilon-aminocaproic acid;
E) At least one selected from 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine and coconut oil fatty acid amidopropyl betaine, lauroylmethyltaurate, tetradecenesulfonate, tranexamic acid, epsilon - at least one combination selected from aminocaproic acid, lauryl sulfate, aluminum lactate, potassium nitrate, copper gluconate and lauroyl sarcosinate; and F) lauryl sulfate.

When the active ingredient is A above, it is possible to inhibit the formation of a bond between the coronavirus spike protein (S protein) and the receptor ACE2. Being B can inhibit TMPRSS2 activity that contributes to the activation of the S protein coupled to the receptor ACE2. Any combination of C to E can inhibit formation of a bond between the coronavirus S protein and the receptor ACE2 and inhibit TMPRSS2 activity that contributes to the activation of the S protein bound to the receptor ACE2. can. Being F can suppress the expression of TMPRSS2.

[2. Content of active ingredient]
The agent of the present invention may be in the form of a so-called composition containing other optional ingredients as necessary. Optional components will be described later. When the agent of the present invention contains optional ingredients, the content of the active ingredient (the amount relative to 100% by mass of the agent) varies depending on the type of active ingredient. Using about 1 g or more (dentifrice) or about 10 mL or more (eg, liquid toothpaste) each time:

- Content of tetradecene sulfonate -
The amount of tetradecene sulfonate is preferably 0.007% by mass or more or 0.01% by mass or more, more preferably 0.02% by mass or more, and still more preferably 0.03% by mass or more or 0.1% by mass. That's it. The upper limit is preferably 25% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.01% by mass to 25% by mass, more preferably 0.02% by mass to 10% by mass, still more preferably 0.03% by mass to 5% by mass.

-Content of lauryl sulfate-
The amount of lauryl sulfate is preferably 0.01% by mass or more or 0.02% by mass or more, more preferably 0.05% by mass or more, and still more preferably 0.5% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 2% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.01% by mass to 10% by mass, more preferably 0.02% by mass to 5% by mass, still more preferably 0.05% by mass to It is 2% by mass.

-Content of lauroyl methyl taurine salt-
The amount of lauroyl methyl taurate salt is preferably 0.01% by mass or more or 0.03% by mass or more, more preferably 0.05% by mass or more, and still more preferably 0.08% by mass or more or 0.1% by mass or more. is. The upper limit is preferably 25% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibition of activation of S protein bound to the receptor, preferably 0.03% by mass to 25% by mass, more preferably 0.05% by mass to 10% by mass, still more preferably 0.08% by mass to 5% by mass.

-Content of aluminum lactate-
The amount of aluminum lactate is preferably 0.02 mass % or more or 0.05 mass % or more, preferably 0.1 mass % or more or 0.2 mass % or more, more preferably 0.3 mass % or more or 0.05 mass % or more. It is 5% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less or 3% by mass or less, and even more preferably 2.5% by mass or less or 2% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.02% by mass to 10% by mass, more preferably 0.05% by mass to 5% by mass, still more preferably 0.1% by mass to 2.5% by mass.

-Content of potassium nitrate-
The amount of potassium nitrate is preferably 0.01% by mass or more or 0.02% by mass or more, more preferably 0.1% by mass or more or 0.5% by mass or more, and even more preferably 1% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 2% by mass or less. From the viewpoint of inhibition of binding between S protein and receptor, preferably 0.01% to 10% by mass, more preferably 0.5% to 5% by mass, still more preferably 1% to 2% by mass. is. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.02% by mass to 10% by mass, more preferably 0.1% by mass to 10% by mass, still more preferably 0.5% by mass to 5% by mass.

-Content of 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine-
The amount of 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine is preferably 0.05% by mass or more, more preferably 0.09% by mass or more, and still more preferably 0.15% by mass or more. be. The upper limit is preferably 6% by mass or less, more preferably 3% by mass or less, and even more preferably 1.2% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the .2 mass %.

- Content of coconut oil fatty acid amidopropyl betaine -
The amount of coconut fatty acid amidopropyl betaine is preferably 0.025% by mass or more, more preferably 0.08% by mass or more, and still more preferably 0.4% by mass or more. The upper limit is preferably 8% by mass or less, more preferably 4% by mass or less, and even more preferably 1.6% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the .6 mass %.

-Content of lauroyl sarcosine salt-
The amount of lauroyl sarcosine salt is preferably 0.01% by mass or more or 0.03% by mass or more, more preferably 0.05% by mass or more, and still more preferably 0.07% by mass or more or 0.12% by mass or more. be. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 2% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.01% by mass to 10% by mass, more preferably 0.03% by mass to 5% by mass, still more preferably 0.12% by mass to It is 2% by mass.

-Content of tranexamic acid-
The amount of tranexamic acid is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, and still more preferably 0.015% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.005% by mass to 10% by mass, more preferably 0.01% by mass to 5% by mass, still more preferably 0.015% by mass to It is 1% by mass.

-Content of epsilon-aminocaproic acid-
The amount of epsilon-aminocaproic acid is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, and even more preferably 0.015% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.005% by mass to 10% by mass, more preferably 0.01% by mass to 5% by mass, still more preferably 0.015% by mass to It is 1% by mass.

-Content of copper gluconate-
The amount of copper gluconate is preferably 0.004% by mass or more, or 0.008% by mass or more, more preferably 0.01% by mass or more, or 0.02% by mass or more, and still more preferably 0.05% by mass. or more, or 0.09% by mass or more. The upper limit is preferably 10% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less. From the viewpoint of inhibiting the formation of binding between S protein and receptor, the % by mass. From the viewpoint of inhibiting the activation of the S protein bound to the receptor, preferably 0.004% by mass to 10% by mass, more preferably 0.01% by mass to 2% by mass, still more preferably 0.05% by mass to It is 1% by mass.

[3. Cell invasion inhibitory action]
The agent of the present invention can suppress cell invasion of coronavirus. As used herein, "inhibiting cell entry" means inhibiting, removing, or reducing the activity of at least one factor involved in virus entry into cells. The outline of the process of coronavirus cell entry is as follows. After the S protein, which is a membrane protein of coronavirus, binds to a receptor on the human cell surface (on the cell membrane) to form an S protein-receptor bond, the S protein is activated by TMPRSS2 on the human cell membrane. (Cleavage of part of the S protein protrudes the fusion site to the human cell membrane) to induce membrane fusion. The agent of the present invention preferably inhibits at least one factor involved in the above process, inhibiting the formation of a bond between the S protein and the receptor, inhibiting the activation of the S protein bound to the receptor (preferably TMPRSS2 inactivation), and inhibition of TMPRSS2 expression, and a combination of two or more selected from these, that is, an S protein-receptor binding inhibitor, an S protein activation inhibitor (preferably, TMPRSS2 inactivating agents) and TMPRSS2 expression inhibitors. As a result, it is possible to prevent or suppress coronavirus infection because it is possible to suppress the invasion of viruses into cells.

Examples of receptor proteins on cell membranes include angiotensin converting enzyme 2 (ACE2), aminopeptidase N (CD13), dipeptidyl peptidase 4 (DPPIV, CD26), and O-acetylated sialic acid, with ACE2 being preferred.

Examples of coronaviruses include, for example, SARS-CoV1, CoV-NL63, SARS-CoV2, and other ACE2-receptor coronaviruses; CoV-OC43, CoV-HKU1, and other CD13-receptor coronaviruses; MERS - DPPIV-receptor coronaviruses such as CoV, preferably ACE2-receptor coronaviruses, and more preferably SARS-CoV-2.

[4. dosage form]
Dosage forms include, for example, liquid (solution), syrup (syrup), cream, paste, tablets (tablets, tablets), capsules (capsules), powder (granules, fine granules), and soft capsules. (soft capsules such as gelatin bases) and hard capsules (hard capsules), which may be appropriately selected according to the dosage form.

[5. Administration method/subject]
Methods of administering the agent include, for example, oral administration (e.g., buccal administration, sublingual administration), parenteral administration (e.g., transdermal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, pulmonary administration, Among these, less invasive dosage forms are preferred, transdermal administration (external use) and oral administration (internal use) are more preferred, and mucosal administration (external use to the mucosa) is even more preferred.

The subject of administration may be any animal including humans, and is usually a human. The administration subject may be a healthy subject, but may be a person infected or suspected to be infected with a coronavirus infection (preferably SARS-CoV-1, CoV-NL63, or SARS-CoV-2) . Examples of animals other than humans include mammals such as mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

[6. Optional component]
When the agent of the present invention is in the form of a so-called composition containing other optional ingredients, the other ingredients include, for example, a medicinal ingredient, a buffering agent, a solubilizing agent, a tonicity agent, a stabilizer, a chelating agent, pH adjusters, preservatives, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, coloring agents, coloring agents, corrigents (acidifiers, flavors, sweeteners), antioxidants, enhancers agents, swelling agents, thickeners, surfactants, abrasives, humectants, moisturizing agents, cooling agents, abrasives, binders, astringents, plant extracts, UV absorbers, aqueous solvents, preservatives, seasonings Ingredients other than the above active ingredients, such as food ingredients and food ingredients (including food additives). The type and content of optional ingredients may be selected according to the application of pharmaceuticals, quasi-drugs, food compositions, cosmetics, dosage forms, administration methods, etc., and may be one or two. A combination of the above may also be used.

- Medicinal Ingredients -
Examples of medicinal ingredients include enzymes such as dextranase, mutanase, amylase, protease, and litek enzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and tin fluoride; allantoin, glycyrrhizinate (e.g., glycyrrhizin dipotassium salt), glycyrrhetinic acid, glycyrrhetic acid derivatives (e.g., stearyl glycyrrhetinate), anti-inflammatory agents such as allantoin chlorohydroxyaluminum, azulene, dihydrocholesterol; metal salts such as zinc salts, copper salts, tin salts; condensed phosphoric acid anticalculus agents such as salt and ethane hydroxydiphosphonate; blood flow promoters such as vitamin E (e.g., tocopherol acetate); hypersensitivity inhibitors such as strontium chloride; coating agents such as hydroxyethyl cellulose dimethyl diallyl ammonium chloride; C (e.g., ascorbic acid or a salt thereof), lysozyme chloride, astringents such as sodium chloride; water-soluble copper compounds such as copper chlorophyll; anticalculus agents; amino acids such as alanine, glycine, proline; plant extracts such as hamamelis; calopeptides; polyvinylpyrrolidone and the like. Other examples include decongestants, antiphlogistic agents, astringents, antihistamines, vitamins, amino acids, bactericides, local anesthetics, ingredients other than the active ingredients of the present invention that have the effect of suppressing invasion of coronavirus into cells, Combinations of two or more selected from these are also included. Examples of decongestants include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate. Examples of anti-inflammatory and astringent agents include neostigmine methyl sulfate, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, bromelain, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, and azulene sulfonic acid. Sodium, chamomile, cromoglycate sodium. Antihistamines include, for example, iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate. Examples of vitamins include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, vitamins A (e.g. retinol acetate, retinol palmitate), vitamins E (tocopherol acetate (e.g. d-α-tocopherol acetate) Examples of amino acids include potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc. Examples of fungicides include cetylpyridinium chloride, chlorhexidine gluconate, dequalinium chloride, Benzalkonium chloride, benzetrium chloride, iodine, potassium iodide, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, isopropylmethylphenol, hinokitiol. Examples of anesthetics include lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and chlorobutanol.The respective medicinal ingredients may be used singly or in combination of two or more.The content of the medicinal ingredients is determined according to a conventional method. An effective amount can be set appropriately.

-Surfactant-
Surfactants can be blended with anionic surfactants, nonionic surfactants, and amphoteric surfactants.

Anionic surfactants include, for example, alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfate, and lauryl sulfoacetate. Alkyl groups and acyl groups may be linear or branched, saturated or unsaturated, and usually have 10 to 20 carbon atoms, preferably 12 to 18 carbon atoms, more preferably 12 to 14. Salts may be selected from pharmacologically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and amino acid salts. Specific examples thereof include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts and diisopropylammonium salts; arginine salts and the like. and basic amino acid salts of Among them, inorganic base salts are preferred, alkali metal salts (eg, sodium salts, potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred. Alkyl sulfates include, for example, myristyl sulfate. Acyl amino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate and palmitoyl glutamate; acylglycinates such as N-lauroyl-N-methylglycinate and cocoylglycinate; N-lauroyl-β- Alanine salt, N-myristyl-β-alanine salt, N-cocoyl-β-alanine salt, N-lauroyl-N-methyl-β-alanine salt, N-myristoyl-N-methyl-β-alanine salt, N-methyl - acyl alanine salts such as N-acyl alanine salts; and acyl aspartates such as lauroyl aspartate. Acyl taurine salts include, for example, N-methyl-N-acyl taurine salts and N-cocoyl methyl taurine salts. Examples of anionic surfactants also include, for example, hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate.

Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (eg, polyoxyethylene sorbitan monostearate), alkylolamide , polyoxyethylene fatty acid ester, polyoxyethylene alkenyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester (eg, maltose fatty acid ester), sugar alcohol fatty acid ester (eg, maltitol fatty acid ester, lactitol fatty acid ester), fatty acid diethanolamide (eg, lauric acid mono- or diethanolamide), polyoxyethylene-polyoxypropylene copolymers, and polyoxyethylene-polyoxypropylene fatty acid esters. The number of carbon atoms in the alkyl chain of the polyoxyethylene alkyl ether is generally 14-18, and the average number of moles of ethylene oxide added is generally 5-30 mol. The average mole number of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is generally 20 to 100 mol, preferably 20 to 60 mol. The number of carbon atoms in the fatty acid of the sorbitan fatty acid ester is usually 12-18. The number of carbon atoms in the fatty acid of the polyoxyethylene sorbitan fatty acid ester is generally 16-18, and the average number of moles of ethylene oxide added is generally 10-40 mol. The alkyl chain of the alkylolamide usually has 12-14 carbon atoms.

Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (eg, lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine; N-fatty acid acyl-N-carboxymethyl- imidazoline-type amphoteric surfactants such as N-hydroxyethylethylenediamine salts and coconut oil fatty acid imidazolinium betaine; and alkylbetaines such as lauryldimethylaminoacetate betaine.

When a surfactant is included, the content of each of the anionic, nonionic, and amphoteric surfactants is usually 0.01 to 10% by mass, preferably 0.1 to 5% by mass, more preferably 0% of the total agent. .2 to 3% by mass.

-Abrasive-
The abrasive may be, for example, either an inorganic abrasive or an organic abrasive. Examples of inorganic abrasives include abrasive silica such as precipitated silica, aluminosilicate, zirconosilicate, crystalline zirconium silicate, and titanium-bonded silica; Calcium phosphate compounds such as tribasic calcium phosphate and calcium pyrophosphate; calcium carbonate abrasives such as calcium carbonate; calcium hydroxide, calcium sulfate and other calcium-based abrasives other than carbonate/phosphate; aluminum oxide, aluminum hydroxide, Aluminum-based materials such as alumina; Silicic acid-based materials such as silicic anhydride, zeolite, and zirconium silicate; Magnesium-based materials, such as magnesium carbonate and magnesium triphosphate; Apatite-based materials, such as hydroxyapatite, fluoroapatite, and calcium-deficient apatite Materials; Titanium-based materials such as titanium dioxide, titanium mica, and titanium oxide; and minerals such as bentonite. Examples of organic abrasives include polymethyl methacrylate and synthetic resin abrasives. Among these, abrasive silica and calcium phosphate compounds are preferred, and silicic anhydride is more preferred. The amount of abrasive is preferably 50% by mass or less, more preferably 8 to 50% by mass, based on the total amount of the agent.

-wetting agent-
Wetting agents include, for example, sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol (PEG); and reduced starch saccharification products. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The content of the wetting agent is usually 40% by mass or less, preferably 1 to 30% by mass, based on the entire agent.

-Binder-
As the binding agent, any suitable conventionally known organic binding agent such as polysaccharides, cellulose-based binding agents (e.g., carboxymethylcellulose (CMC), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cationic cellulose, etc.), other polysaccharide thickeners (e.g., xanthan gum, guar gum, gellan gum, tragacanth gum, karaya gum, gum arabic, locust bean gum, carrageenan, sodium alginate), synthetic water-soluble polymers (e.g., sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol alginate). Furthermore, inorganic binders such as thickening silica and aluminum silicate can also be contained. The content of the organic binder is preferably 0 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total agent. The content of the inorganic binder is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

- Buffer -
Examples of buffering agents include citric acid or salts thereof (e.g., sodium citrate), phosphoric acid or salts thereof (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate). , tartaric acid or its salts (e.g. sodium tartrate), gluconic acid or its salts (e.g. sodium gluconate), acetic acid or its salts (e.g. sodium acetate), carbonic acid or its salts (e.g. sodium bicarbonate), trometamol, Amino acids (eg, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), combinations of two or more thereof.

－Solubilizer－
Solubility aids include, for example, propylene glycol, polyethylene glycol, and combinations of two or more thereof.

- Tonicity agent -
Tonicity agents include, for example, sodium chloride, potassium chloride, glycerin, combinations of two or more thereof.

-Stabilizer-
Stabilizers include, for example, sodium edetate, cyclodextrins, sulfites, citric acid or salts thereof, dibutylhydroxytoluene, ascorbic acid, combinations of two or more thereof.

- Chelating agent -
Chelating agents include, for example, sodium edetate, sodium citrate, and combinations thereof.

-moisturizer-
Humectants include, for example, glycerin, concentrated glycerin, sugar alcohols (eg, sorbitol, xylitol, maltitol, mannitol, reduced starch syrup, reduced palatinose, erythritol, lactitol, isomalt), and combinations of two or more thereof.

-Flavoring agent-
Flavoring agents include, for example, sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, stevioside, paramethoxycinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, asparatylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose , maltitol, sorbitol, mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, artificial sweeteners such as lactitol, etc.), fragrances (e.g. anise oil, cassia oil, wintergreen oil, mastic oil, neroli oil (orange flower oil ), lemongrass oil, jasmine oil, rose oil, iris oil, clove oil, sage oil, cardamom oil, rosemary oil, laurel oil, chamomile oil, basil oil, marjoram oil, lemon oil, orange oil, lime oil, yuzu oil, nutmeg oil, lavender oil, paracress oil, vanilla oil, cinnamon oil, pimento oil, cinnamon oil, perilla oil, wintergreen oil, peppermint oil, lychee oil; menthol, carvone, cinnamic aldehyde, anethole, Natural essential oils such as methyl salicylate, eugenol, linalool, limonene, menthone, menthyl acetate, citral, decanal, camphor, borneol, pinene, spilanthol, n-decyl alcohol, citronellol, α-terpineol, citronellyl acetate, ethyl linalool, vanillin, etc. Perfume ingredients contained in: Ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methyl phenylglycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, N-ethyl-p-menthane-3 - fragrance ingredients such as carboxamide, menthyl lactate, ethylene glycol-l-menthyl carbonate; -8277-T, dry coat matcha #421), acidulants (eg, citric acid, tartaric acid, malic acid), green tea powder.

- Oily component -
Oily components include, for example, fatty acid esters (e.g. glycerin fatty acid esters), hydrocarbons (e.g. paraffin, liquid paraffin, ceresin, squalane, vaseline, microcrystalline wax), higher fatty acids (e.g. lauric acid, myristic acid, olein acids, fatty acids with 8 to 22 carbon atoms such as isostearic acid), higher alcohols (for example, alcohols with 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol), plants Oils and fats (eg, vegetable oils such as olive oil, castor oil, and coconut oil; fatty acid esters such as isopropyl myristate), beeswax, and combinations of two or more thereof.

-Preservative-
Examples of antiseptics include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben, and butylparaben; alcohol derivatives such as phenylethyl alcohol, benzyl alcohol, phenol, and acrinol; sorbic acid and salts thereof (potassium sorbate, etc.); ), benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, alkylpolyaminoethylglycine, combinations of two or more thereof.

-wetting agent-
Wetting agents include, for example, sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol (PEG); and reduced starch saccharification products. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The amount of the wetting agent is generally 40% by mass or less, preferably 1 to 35% by mass, based on the total agent.

-coloring agent-
Examples of coloring agents include natural pigments such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, monascus pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cacao pigment, spirulina blue pigment, tamarind pigment, Legal pigments such as Red No. 2, Red No. 3, Red No. 104, Red No. 105, Red No. 106, Red No. 227, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, riboflavin, sodium copper chlorophyllin, Titanium dioxide etc. are mentioned. When a coloring agent is included, its content is preferably 0.00001 to 3% by mass with respect to the entire agent.

-pH adjuster-
Examples of pH adjusters include organic acids such as phthalic acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid, salts thereof (sodium citrate), and inorganic acids such as phosphoric acid (orthophosphoric acid). Acids or salts thereof (eg, potassium salts, sodium salts, and ammonium salts), and hydroxides such as sodium hydroxide and potassium hydroxide. Examples of inorganic acid salts include disodium hydrogen phosphate and sodium dihydrogen phosphate. The content of the pH adjuster can be adjusted so that the pH of the agent after addition is usually 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value after 3 minutes at 25°C from the start of measurement. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

-solvent-
Examples of the solvent include water (purified water) and ethanol, with water being preferred. A solvent may be used individually by 1 type, or may be used in combination of 2 or more type.

-Excipient-
Excipients include, for example, celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, methylethylcellulose, low-substituted hydroxypropylcellulose, and pharmacologically acceptable derivatives thereof; polyvinylpyrrolidone, Synthetic polymers such as partially saponified polyvinyl alcohol; Polysaccharides such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, and xanthan gum; Starches such as corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch, and their Pharmacologically acceptable derivatives; lactose, lactose granules, fructose, glucose, sucrose, granulated sugar, hydrous glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose , reduced starch syrup, powdered reduced maltose starch syrup, maltitol; inorganic excipients such as magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (another name: anhydrous silicic acid, fine silicon dioxide), titanium oxide, aluminum hydroxide gel, etc. and combinations of two or more of these.

-Disintegrant-
Examples of disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, cross-linked insoluble polyvinylpyrrolidone, and hydroxypropyl starch. , partially pregelatinized starch, corn starch, combinations of two or more thereof.

-Binder-
Binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, dextrin, starch, pregelatinized starch, combinations of two or more thereof.

-lubricant-
Lubricants include, for example, calcium stearate, magnesium stearate, sucrose fatty acid esters, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and combinations of two or more of these.

-Other optional ingredients-
Examples of optional components other than the above include polyisobutylene, polybutadiene, urethane, silicon, and natural rubber. The content of these other optional components can be appropriately set within a range that does not impair the effects of the present invention.

[Dosage form, application site]
The agent of the present invention can be used as pharmaceuticals, quasi-drugs, cosmetics, and foods. The dosage form is not particularly limited and includes, for example, liquids, sprays, solids, semi-solids, liquids, powders, and granules. Examples of application sites for pharmaceuticals and quasi-drugs include the oral cavity, nasal cavity, and eyes. For the oral cavity, for example, dentifrice (e.g., toothpaste, gel toothpaste, wet toothpaste, liquid toothpaste), mouthwash, tongue polish, oral spray, oral tablet, gum, mouth freshener, gargle tablets, buccal pastes, gels, and ointments. For the nasal cavity, for example, nasal drops and nasal washes can be mentioned. For the eyes, for example, eye drops (e.g., general eye drops, eye drops for contact lens users), eye washes (general eye wash, eye wash for contact lens users), contact lens agents (e.g., contact lens preservatives, contact lens cleaning agents, contact lens cleaning agents).

As cosmetics, for example, it can be used in dosage forms such as creams, milky lotions, packs, gels, aerosols, and sheets. Specifically, for example, skin cosmetics such as lotion, serum, whitening agent, moisturizer, face mask, milky lotion, foundation, eye shadow, mascara, eyebrow, eyeliner, cheek powder, lipstick, lip balm; hair rinse , hair conditioners, hair treatments, hair lotions, hair tonics, hair packs, hair creams, conditioning mousses, hair mousses, hair sprays, shampoos, leave-on treatments, hair dyes, and hair cosmetics.

Foods (food compositions) include, for example, health foods, functional foods, health supplements (supplements), dietary supplements, foods for specified health uses, functional nutritional foods, medical foods, foods for the sick, foods for infants, Food compositions with uses such as food for nursing care and food for the elderly can be mentioned.

〔Production method〕
The method for producing the agent of the present invention may be determined according to the dosage form, application, and application site. For example, when it is used as a toothpaste, a method of preparing a component that dissolves in a solvent, mixing other insoluble components, and defoaming (for example, reducing pressure, etc.) as necessary. Another example is dispersing and dissolving the active ingredient and optionally other ingredients in an aqueous solvent (for example, water such as purified water and sterilized water) to prepare a composition, (For example, glass, resin, etc.). As for the container, for example, a container for an oral agent includes a laminated tube, and resin such as polyethylene, polypropylene, polyethylene terephthalate, and nylon can be used as the material. In the case of a spray, a container equipped with an atomizing means (for example, a trigger-type, pump-type, or aerosol-type container) may be selected. The obtained toothpaste can be put into a container to be used as a product. The shape and material of the container are not particularly limited, and containers commonly used for oral compositions can be used.

〔how to use〕
The method of using the agent of the present invention may be, for example, administering the agent to the application site. The number of administrations per day is not particularly limited, but may be, for example, 1 to 6 times or more. In the case of oral preparations, put an appropriate amount of the agent on the toothbrush and brush the surface of the teeth, then rinse with water after use (dentifrice), or spit out after gargling with an appropriate amount of the agent in the mouth (mouthwash). According to

Examples 1-16 and Comparative Examples 1-4
For each evaluation sample shown in Table 1, the inhibition rate of S protein-ACE2 binding and the inhibition rate of TMPRSS2 activity were evaluated.

The rate of inhibition of S protein-ACE2 binding and the rate of inhibition of TMPRSS2 activity were evaluated using the following evaluation systems (Tables 2 and 3).

<S protein-ACE2 binding evaluation system>
Spike S1 (SARS-CoV-2): ACE2 Inhibitor Screening Colorimetric Assay Kit (Cat#.79954, BPS Bioscience) [https://bpsbioscience. com/pub/media/wysiwyg/Other/79954_2. pdf], the experiment was carried out according to the following procedure. (Control, blank, each concentration of each evaluation sample were all performed in triplicate)

50 μL/well of Spike S1 solution was added to a 96-well plate for coating with Spike S1 and incubated at 4° C. overnight. After removing the reaction solution, the cells were washed three times with 100 μL/well of 1×Immuno Buffer, 100 μL/well of Blocking Buffer was added, and the cells were incubated at room temperature for 1 hour with shaking.

After washing three times with 2.1×Immuno Buffer, 20 μL/well of 1×Immuno Buffer was added, and then 10 μL/well of evaluation sample solution was added. To the control and blank wells, only PBS was added instead of PBS in which the evaluation sample was dissolved. It was then incubated for 1 hour at room temperature with shaking.

3. 20 μL/well of ACE2-Biotin (1 ng/μL) was added to each well except blanks. 20 μL/well of 1×Immuno Buffer was added to the blank. Incubated for 1 hour at room temperature with shaking.

4. After removing the reaction solution, the cells were washed three times with 100 μL/well of 1×Immuno Buffer.

5. 100 µ/well of Blocking Buffer was added and incubated at room temperature for 10 minutes.

6. A Streptavidin-HRP solution was added at 100 μL/well, and incubated with shaking at room temperature for 1 hour.

7. After the reaction, the cells were washed three times with 100 μL/well of 1×Immuno Buffer.

8. 100 µ/well of Blocking Buffer was added and incubated at room temperature for 10 minutes.

9. After removing the blocking buffer, 100 μL/well of Colorimetric HRP substrate was added and incubated at room temperature until the control wells turned blue.

10. After the color changed, 100 μL/well 1N HCl was added to stop the reaction. The absorbance of each well was measured with a plate reader at a wavelength of 450 nm.

11. A value obtained by subtracting the absorbance of the blank well from the absorbance of the well of the control and each evaluation sample was used as the measured value of the control and each evaluation sample.

The inhibition rate was calculated by the following formula.
Inhibition rate (%) = (measured value of control - measured value of evaluation sample) / measured value of control x 100

<TMPRSS2 evaluation system>
Based on the following references, an evaluation method was formulated and implemented. (Control, blank, each concentration of each evaluation sample were all performed in triplicate)
Hoffmann et al. : Version 1. bioRxiv. Preprint. 2020 Aug (https://www.biorxiv.org/CONTENT/10.1101/2020.08.05.237651v1)
Shrimp et al. : Version 2. bioRxiv. Preprint 2020 Jun 23
(https://www.biorxiv.org/content/10.1101/2020.06.23.167544v1.full)

1. Assay was performed on a 384-well black plate with a solution of 10 μL/well.

2. First, Recombinant Human TMPRSS2 (N-terminus 6xHis, aa106-492; manufactured by LifeSpan Biosciences) was added to a 384-well black plate with a buffer (50 mM Tris-HCl pH 8.0, 154 mM NaCl) to a final concentration of 4 μg/mL. The adjusted one was added. To the blank wells, only the above buffer was added.

3. To the above (2.) 384-well black plate, evaluation samples dissolved in phosphate buffer (PBS) were added to each final concentration. To the control and blank wells, only PBS was added instead of PBS in which the evaluation sample was dissolved.

4. A substrate (Boc-Gln-Ala-Arg-MCA (manufactured by Peptide Institute)) was added to the above (3.) 384-well black plate at a final concentration of 10 μM.

5. Reacted for 60 minutes at room temperature.

6. Fluorescence values were measured at an excitation wavelength of 380 nm and an emission wavelength of 460 nm using a microplate reader (SpectraMax M5; manufactured by Molecular Devices).

7. A value obtained by subtracting the fluorescence value of the blank well from the fluorescence value of the well of the control and each evaluation sample was used as the measurement value of the control and each evaluation sample.

The inhibition rate was calculated by the following formula.
Inhibition rate (%) = (measured value of control - measured value of evaluation sample) / measured value of control x 100

In Comparative Example 1, no inhibitory effect on S protein-ACE2 binding was observed, whereas in Examples 1 to 9, concentration-dependent inhibitory effects were observed (Table 2). Further, in Comparative Example 2, no inhibitory effect on TMPRSS2 activity was observed, whereas in Examples 10 to 18, an inhibitory effect was observed, and the higher the addition concentration, the greater the inhibition rate (Table 3). ). Sodium lauroyl methyl taurate, sodium tetradecene sulfonate, sodium lauryl sulfate, aluminum lactate, potassium nitrate, sodium lauroyl sarcosinate, copper gluconate showed inhibitory effects on both S protein-ACE2 binding and TMPRSS2 activity (Example 3-9, 10, 11, 14-18).

These results indicate that the agent of the present invention exhibits an inhibitory effect on cell invasion of coronavirus, and is useful as an agent for preventing coronavirus infection, or suppressing or alleviating symptoms.

Example 19
The evaluation samples having the composition shown in Table 4 were evaluated for the expression of TMPRSS2.

<TMPRSS2 expression evaluation system>
Expression of TMPRSS2 was evaluated by the following procedure.

1. From the subjects who brushed their teeth with the evaluation sample, saliva was collected with Sarivet cotton (manufactured by Sarstedt) before toothbrushing, 1 hour and 3 hours after toothbrushing.

2. The protein concentration of saliva was measured using BCA Protein Assay Kit (manufactured by Takara Bio Inc.), and the protein concentration of each sample was matched with UPW (ultra-pure water).

3. A sample buffer (NuPAGE (registered trademark) LDS Sample Buffer, manufactured by Thermo Fisher) and a reducing agent (NuPAGE (registered trademark) Sample Reducing Agent, manufactured by Thermo Fisher) were added to the above (2.), and incubated at 95°C for 5 minutes. heated with

4. The sample of (3.) above was added to a Bolt (registered trademark) Bis-Tris Plus gel (manufactured by Thermo Fisher) and electrophoresis was performed.

5. The proteins in the gel in (4.) above were transferred to a membrane (Transblot Turbo (registered trademark) transfer pack PVDF, Bio-Rad).

6. After blocking the membrane of (5.) above with TBS-T (Tris Buffered Saline with Tween (registered trademark) 20) containing 5% skimmed milk for 1 hour, a primary antibody (Anti-TMPRSS2 antibody [EPR3861], manufactured by Abcam) was applied. was reacted overnight at 4°C.

7. A secondary antibody (Anti-rabbit IgG, HRP-linked Antibody, manufactured by Cell Signaling Technology) was reacted at room temperature for 1 hour.

8. A detection reagent (ECL Prime Western Blotting Detection Reagent, manufactured by Cytiva) was added, and an imager (Amersham (registered trademark) ImageQuant (registered trademark) 800, manufactured by Cytiva) was used to obtain a TMPRSS2 protein band.

9. The band signal intensity (expression level) of the TMPRSS2 protein was analyzed using the attached imager software in (8.) above.

10. Taking the expression level before tooth brushing as 1, the expression level after 1 hour and 3 hours after tooth brushing was calculated (Table 5).

Comparative example 3
In Example 19, instead of the subjects who brushed their teeth in the evaluation samples of Table 5, the subjects who did not brush their teeth and were at rest were collected and evaluated at the same time points.

Compared with Comparative Example 3, in Example 19, the TMPRSS2 expression level was decreased after toothbrushing (Table 5).

Comparative example 4
An evaluation sample obtained by diluting a blank formulation from Table 5 with sodium lauryl sulfate excluding sodium lauryl sulfate with purified water assuming dentifrice was evaluated by <TMPRSS2 evaluation system>, and the inhibitory effect on TMPRSS2 activity was evaluated. I was not able to admit.

These results indicate that the agent of the present invention inhibits the formation of binding between the coronavirus spike protein and its cell surface receptor, inhibits the activation of the spike protein bound to the cell surface receptor by TMPRSS2, and inhibits the expression of TMPRSS2. It has been shown that it can exert each action such as inhibition and is useful as an agent for preventing coronavirus infection, or suppressing or alleviating symptoms.

Claims (13)

Tetradecene Sulfonate, Lauryl Sulfate, Lauroyl Methyl Taurate, Aluminum Lactate, Potassium Nitrate, 2-Alkyl-N-Carboxymethyl-N-Hydroxyethylimidazolinium Betaine, Coconut Fatty Acid Amidopropyl Betaine, Lauroyl Sarcosinate, Tranexam A coronavirus cell entry inhibitor containing at least one selected from acid, epsilon-aminocaproic acid, and copper gluconate. 2. The agent of claim 1, which inhibits the formation of a bond between the coronavirus spike protein and a cell surface receptor. 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, coconut oil fatty acid amidopropyl betaine, tetradecene sulfonate, lauryl sulfate, lauroyl methyl taurate, aluminum lactate, potassium nitrate, copper gluconate, and 3. The agent according to claim 2, comprising at least one selected from lauroyl sarcosine salts. 2. The agent according to claim 1, which inhibits the activation of cell surface receptor-bound spike protein by transmembrane serine protease 2 (TMPRSS2). 5. The agent of claim 4, wherein the inhibition of spike protein activation is inactivation of transmembrane serine protease 2 (TMPRSS2). Claim 4 or 5, containing at least one selected from lauroyl methyl taurate, tetradecene sulfonate, tranexamic acid, epsilon-aminocaproic acid, lauryl sulfate, aluminum lactate, potassium nitrate, copper gluconate, and lauroyl sarcosinate The agent described in . The agent according to any one of claims 2 to 6, wherein the receptor is angiotensin-converting enzyme-2. 2. The agent according to claim 1, which inhibits expression of transmembrane serine protease 2 (TMPRSS2). 9. The agent of claim 8, comprising lauryl sulfate. The agent according to any one of claims 1 to 9, which is for prevention of coronavirus infection, or suppression or alleviation of symptoms. The agent according to any one of claims 1 to 10, wherein the coronavirus is SARS-CoV-1, CoV-NL63, or SARS-CoV-2. The agent according to any one of claims 1 to 11, which is a mucosal external agent. The agent according to any one of claims 1 to 12, which is an oral, nasal, or ophthalmic agent.