JP2023063145A - virus inactivator - Google Patents

Abstract

To provide a virus inactivator that can inactivate virus in an environment.SOLUTION: A virus inactivator comprises at least one compound selected from mugor, linalyl formate, cis-6-nonenal, cinnamyl formate, vertoliff, 3,5,5-trimethyl hexanol, citronellyl formate, γ-valerolactone and melonal as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to virus inactivating agents that inactivate viruses.

Viral infections are diseases that cause severe symptoms such as cold symptoms, pneumonia, hepatitis, encephalitis, and the like, and are an everlasting threat to mankind. In recent years, influenza viruses have raged all over the world, and in some cases, outbreaks of new strains of influenza with altered antigenicity have caused pandemics. In 2019, SARS coronavirus-2 (SARS-CoV-2) emerged and caused a pandemic, affecting not only life and health but also economic activities and social functions.

Vaccines and antiviral agents have been developed to deal with such situations, but the development of vaccines and therapeutic agents takes time and is not necessarily successful.
When the virus is brought into the living space by an infected person, the infection spreads directly from the patient or through the environment including clothing, various instruments/members, walls and equipment such as air conditioners. Therefore, it is recommended to remove viruses and inactivate viruses by washing and disinfecting hands, clothes, various instruments and parts that viruses can attach to, and inactivating viruses that are splashed in living spaces and viruses that are floating in the air as aerosols. It is considered effective to prevent the spread of infection.

Conventionally, ethanol, sodium hypochlorite, chlorine dioxide, glutaraldehyde, etc. have been used for the purpose of inactivating viruses. However, these general antiseptics are highly irritating to mucous membranes and skin, and their use is limited due to safety concerns. Spraying chlorine dioxide has also been devised as a method of chemically inactivating viruses in space, but its effectiveness is uncertain.

Essential oils and their fragrant components are used as fragrances in cosmetics and various other products. For example, there are many essential oils and fragrance compounds that have antiviral activity against viruses (eg, Patent Document 1, Non-Patent Document 1, Non-Patent Document 2).

JP-A-5-306217

Swamy et al., Evid Based Complement Alternat Med. 2016:3012462. Hayashi K, et al., Planta Medica, 01 Jun 1995, 61(3):237-241

The present invention relates to providing a virus-inactivating agent capable of inactivating viruses present in the environment.

The present inventors have found that certain fragrance compounds have the effect of inactivating influenza viruses and are useful as virus inactivating agents.

That is, the present invention relates to the following 1) and 2).
1) A virus whose active ingredient is one or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone and melonal. Inactivating agent.
2) One or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, vertolif, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone and melonal, or a composition containing the same A virus inactivation method in which a substance is applied to a subject for which virus contamination is a concern.

According to the virus inactivating agent of the present invention, it is possible to inactivate viruses adhering to hard and soft surfaces in the living environment, viruses splashed in the living space, viruses floating in the space as aerosols, etc., and spread of infection by the virus. can be prevented or reduced.

Influenza virus inactivation effect (gas phase). Influenza virus inactivation effect (liquid phase).

Mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, vertolif, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone and melonal (hereinafter also referred to as "compounds of the present invention") of the present invention are All of them are compounds used as fragrances and are commercially available as follows.
・Mugol (alias: 3,7-dimethylocta-4,6-dien-3-ol): International Flavors & Fragrances ・Linalyl formate (alias: 3,7-dimethylocta-1,6-diene-3-ol) yl): Sigma-Aldrich ・cis-6-nonenal (alias: (Z)-6-nonenal): Sigma-Aldrich ・cinnamyl formate (alias: 3-phenylprop-2-enyl formate): Sigma-Aldrich Bertlif (a mixture of 3,6-dimethylcyclohex-3-ene-1-carbaldehyde and 4,6-dimethylcyclohex-3-ene-1-carbaldehyde): International Flavors & Fragrance Co. 3,5, 5-trimethylhexanol (alias: 3,5,5-trimethyl-1-hexanol): Tokyo Chemical Industry Co., Ltd., Fujifilm Wako Pure Chemical Industries, Ltd. Citronellyl formate (alias: 3,7-dimethyl formate-6-octene-1- yl): Fujifilm Wako Pure Chemical Co., Ltd. γ-valerolactone (alias: 5-methyloxolan-2-one): Sigma-Aldrich, Tokyo Chemical Industry Co., Ltd. Melonal (alias: 2,6-dimethylhepta-5 -enal): Sigma-Aldrich

Such compounds may be used alone or in combination of two or more.

Among the compounds of the present invention, cinnamyl formate, linalyl formate, beltliff, cis-6-nonenal, 3,5,5-trimethylhexanol, mugol, odor intensity and quality are preferred from the viewpoint of virus inactivation effect. , from the viewpoint of volatility, mugol, linalyl formate, comprehensively mugol, linalyl formate, cis-6-nonenal, cinnamyl formate.

The compound of the present invention can be used in either a liquid phase state or a gas phase state, but is preferably used in a gas phase state from the viewpoint of virus inactivation effect.

Viruses to which the virus inactivating agent of the present invention is applied include all types of viruses, regardless of the types of nucleic acids (RNA, DNA) and the presence or absence of envelopes.
SARS coronavirus; SARS coronavirus-2; respiratory syncytial virus; mumps virus; Lassa virus; dengue virus; human herpes virus; vaccinia virus; hepatitis B virus, etc., having DNA.
In addition, non-enveloped viruses include norovirus, poliovirus, echovirus, hepatitis A virus, hepatitis E virus, rhinovirus, astrovirus, rotavirus, coxsackievirus, enterovirus, and sapovirus. , adenovirus, which has DNA as the nucleic acid; B19 virus; papovavirus; human papillomavirus, and the like.

Among them, viruses having an envelope are preferred, viruses having an envelope and having RNA as a nucleic acid are more preferred, and influenza virus, human coronavirus, SARS coronavirus, and SARS coronavirus-2 are more preferred.
SARS coronavirus-2 (Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is a SARS-related coronavirus that causes acute respiratory disease (COVID-19).

In the present invention, virus inactivation means the action of reducing or eliminating virus activity and eliminating the ability to infect host cells.
The virus-inactivating action can be confirmed by, for example, contacting the test article with the virus, infecting the host cell with the virus, and measuring the virus infectivity. Here, the host cell may be any cell in which the target virus can proliferate. In the case of influenza virus, for example, canine kidney cells (MDCK), African green monkey kidney epithelial cells (Vero), duck embryonic stem cell-derived cells. Cell line (EB66), human coronavirus, human ileocecal adenocarcinoma cell line (HCT-8), African green monkey kidney epithelial cell line (VeroE6), human liver cancer-derived cell line line (Huh7) can be done.

As shown in the examples below, the compound of the present invention impregnated in a cotton ball is placed in a glass bottle and filled with the dried influenza virus, and then the compound and the virus are brought into contact with each other in the gas phase at room temperature. , the viral infectious titer is reduced by more than 97.7%.
Accordingly, the compounds of the present invention can be virus-inactivating agents, preferably virus-inactivating agents that inactivate viruses in the gas phase. Alternatively, the compounds of the invention can be used to produce virus-inactivating agents, preferably virus-inactivating agents that inactivate viruses in the gas phase.
The compounds of the invention can also be used to inactivate viruses, preferably in the gas phase.

The virus inactivating agent of the present invention may be in the form of using the compound of the present invention alone, or in the form of a composition (e.g., antiviral composition, sanitary product composition, etc.) containing the compound of the present invention. good too. That is, the virus inactivating agent of the present invention can be used as an antiviral composition exhibiting a virus inactivating effect, a sanitary product composition exhibiting an antiviral effect, or as a material or formulation to be blended therein.

The antiviral composition includes those used in liquid phase or gas phase. In addition to the compound of the present invention, the antiviral composition used in a liquid phase includes hypochlorous acid, hydrogen peroxide, antibacterial substances such as silver ion compounds, cationic antibacterial agents (benzethonium chloride, etc.), sterilization agents (triclosan, isopropylmethylphenol, etc.), ethanol, surfactants, etc., chelating agents, moisturizers, lubricants, builders, buffers, abrasives, electrolytes, bleaching agents, fragrances, dyes, foaming It is prepared by appropriately blending additives such as control agents, corrosion inhibitors, essential oils, thickeners, pigments, gloss enhancers, enzymes, detergents, solvents, dispersants, polymers, silicones, and hydrotropic substances. The form of such a composition may be liquid, milky lotion, cream, lotion, paste, gel, sheet (carrying a substrate), oil, etc., but is not limited thereto.
The antiviral composition is used by appropriately blending with various cleaning agents (clothing cleaning agents, household cleaning agents, dish cleaning agents, hair washing agents, hand cleaning agents, whole body cleaning agents, etc.), disinfectants, etc. be able to.

The antiviral composition used in the gaseous state (for example, a composition for removing viruses in space) may be in the form of a liquid or a gel, and preferably in the form of a liquid. In addition to the compound of the present invention, the composition contains a base material and various additives (polyols (dipropylene glycol, propylene glycol, etc.), surfactants, ultraviolet absorbers, antioxidants, preservatives, deodorants, natural extracts, silicones, thickeners, dyes, pigments, pigments, oils, perfumes, etc.). Here, as the base, water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dimethyl ether, liquid propane, petrolatum, lanolin, castor oil, paraffinic hydrocarbons (for example, , liquid paraffin, etc.), which can be used alone or in combination of two or more.
In the case of forming a gel formulation, for example, a water-soluble gelling agent such as carrageenan and gellan gum, a metal soap, an oil-soluble gelling agent such as aluminum octylate, a natural gelling agent or a synthetic gelling agent are conventionally known. It can be prepared by appropriately adding according to the method of .

Examples of the sanitary composition include lotions, creams, shampoos, hair conditioners, hand soaps, shampoos, body shampoos, facial cleansers, bath salts, foams, antiperspirants, deodorants, anti-armpit odor agents, oral hygiene products ( mouthwash, toothpaste, mouth freshener, gargle, etc.) and the like.
The composition contains a carrier (e.g., diluent, dispersant, buffer, pH adjuster, dispersant, emulsifier, surfactant, preservative, stabilizer, antioxidant, colorant, etc.) acceptable as a cosmetic or the like. , moisturizing agents, thickeners, bactericides, perfumes, etc.) can be appropriately combined and prepared by a conventional method.

The content of the active ingredient in the aspect of using the virus inactivating agent of the present invention as a composition can be appropriately determined according to the form of the composition. For example, the content of the compound of the present invention relative to the total amount of the composition is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, and even more preferably 0.1% by mass or more. Moreover, it is preferably 99.999% by mass or less, more preferably 50% by mass or less, and even more preferably 10% by mass or less. Also, it is preferably 0.001 to 99.999% by mass, more preferably 0.01 to 50% by mass, even more preferably 0.1 to 10% by mass.

According to the virus inactivating agent of the present invention, it is possible to inactivate viruses that have adhered to the skin or mucous membranes of animals contaminated with viruses or hard or soft surfaces of inanimate objects, and to inactivate viruses that have splashed into living spaces. becomes. Here, the surface of an inanimate object includes, for example, hard surfaces such as counters, sinks, restrooms, toilets, bathtubs, shower stands, floors, windows, doorknobs, walls, sewers, and pipes in homes and business facilities; Hard surfaces such as kitchen utensils, furniture, various appliances such as telephones and toys, tools, miscellaneous goods; and soft surfaces such as textile products (carpets, area rugs, curtains, cloth furniture, clothing, etc.). In addition, as a living space, there are general households such as dining kitchen rooms, bedrooms, children's rooms, bathrooms, and toilets, facilities such as shops, restaurants, inns, hospitals, workshops, factories, and vehicles such as automobiles, trains, and aircraft. Among them, semi-closed spaces (lockers, storerooms, closets, etc.) are included.

In the virus-inactivating agent of the present invention, the compound of the present invention or a composition containing the same is applied to a subject that is concerned about virus contamination, but the aspect is not particularly limited. Alternatively, it may be brought into contact with or reacted with the virus in a liquid phase. As a method of contacting the compound of the present invention with a virus in a liquid phase, a method of applying the compound of the present invention or a composition containing the same to an object to be treated as it is, or a method of spreading the compound of the present invention or a composition containing the same. or a method of wiping the target surface with a sheet, gauze, towel, wet towel, tissue, wet tissue, etc. impregnated with the compound of the present invention or a composition containing the same.
In addition, the compound of the present invention or a composition containing the same is filled into a container or device for atomization or diffusion, such as a pressurized liquid atomizer, a pressurized air atomizer, a diffuser, a nebulizer, etc. It can be used by spraying in the form of a mist in the space where the virus exists. As a result, the volatilization rate can be increased, and the virus inactivation effect can be rapidly exhibited, and this mode of use is preferred in the present invention. Similar effects can also be obtained by using the compound of the present invention or a composition containing it in the form of an aerosol, mist spray, or the like.

As a method for contacting or reacting the compound of the present invention or a composition containing the same with a virus in the gas phase, the compound of the present invention may be naturally volatilized or forced to volatilize. In the volatilization form, the virus existing in the space can be inactivated simply by leaving it in the living space, and the virus in the space can be easily removed (virus removal). is preferred.
When the virus inactivating agent of the present invention is used for the purpose of natural volatilization, for example, the compound of the present invention or a composition containing the same is soaked into a core rod, filter paper, etc. to volatilize, or using a permeable membrane. A conventionally known method such as a volatilization method can be applied. Alternatively, the compound of the present invention or a composition containing the same may be kneaded with a resin for use. Examples of resins that can be kneaded include natural, petroleum, and synthetic waxes, rosin resins, ethylene-vinyl acetate copolymers, ethylene-vinyl alcohol copolymers, polyesters, polyolefins, and acrylic resins. The above kneaded product can be used as it is, or can be supported on a porous carrier, formed into a sheet, or formed into a laminate from the sheet. Examples of porous carriers include natural polymers such as cellulose and chitosan, synthetic resins described above, inorganic porous substances such as calcium silicate, and the like, which are formed into arbitrary shapes such as granules and sheets. The above-mentioned kneaded product or laminate can be used, for example, by installing it in air conditioning equipment, toilets, bathrooms, living rooms, hospital rooms, hospital waiting rooms, dust boxes, etc., and gradually volatilizing the compound of the present invention. In addition, the compound of the present invention or a composition containing it can also be used by supporting it on a product made of paper, non-woven fabric, etc. (air purifier filter, etc.).
When the compound of the present invention is forcibly volatilized and used, such means include, for example, a method of volatilizing using a fan or the like, a method of volatilizing by heating using a heater or the like, a method of volatilizing by ultrasonic waves, and the like.

In the case of spatial virus removal treatment, the amount of the compound of the present invention or the composition containing it can be appropriately adjusted depending on the mode of treatment, the spatial environment such as temperature and humidity, the vapor pressure of each compound, etc. The concentration of the compound of the present invention in the space can be higher than the saturation concentration of the compound, but for example, the concentration of the compound of the present invention in the target space is 0.1% or more, preferably 1% or more of the saturation concentration of the compound in the space. It is preferably 5% or more, more preferably 10% or more, preferably 100% or less, more preferably 50% or less, and more preferably 25% or less.
The concentration of the compound of the present invention in the target space can be detected by measuring the concentration of the compound in the gas sampled from the space. Examples thereof include a method of determination using gas chromatography or gas chromatography/mass spectrometry in combination with a collection tube or the like.

The following aspects are further disclosed in this invention regarding embodiment mentioned above.
<1> One or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, vertolif, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone, and melonal as an active ingredient virus inactivator.
<2> Selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone, and melonal for producing a virus inactivating agent Use of one or more compounds that are
<3> 1 selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone, and melonal for inactivating viruses Use of more than one species of compound or composition containing same.
<4> One or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone, and melonal, or containing the same A virus inactivation method, comprising applying a composition to a subject suspected of virus contamination.
<5> In <1> to <4>, the virus is preferably an enveloped RNA virus.
<6> In <1> to <4>, the virus is preferably influenza virus or coronavirus.
<7> In <1> to <6>, virus inactivation is preferably virus inactivation in the gas phase.
<8> In <1> to <7>, the content of the compound with respect to the total amount of the composition in the composition containing the compound is preferably 0.001% by mass or more, more preferably 0.01% by mass. % or more, more preferably 0.1 mass % or more, and preferably 99.999 mass % or less, more preferably 50 mass % or less, still more preferably 10 mass % or less, or preferably 0.001 mass % ~99.999% by mass, more preferably 0.01 to 50% by mass, still more preferably 0.1 to 10% by mass.
<9> the compound or the composition containing the same, wherein the concentration of the compound in the target space is 0.1% or more, preferably 1% or more, more preferably 5% or more of the saturation concentration of the compound in the space; The method of <4> is more preferably 10% or more, preferably 100% or less, more preferably 50% or less, and more preferably 25% or less.

EXAMPLES Hereinafter, the present invention will be described more specifically by showing examples.
Example 1 Inactivation of Influenza Virus in Vapor Phase by Fragrance Compounds 1 . Methods Influenza virus type A (A/Puerto Rico/8/1934, H1N1) strain was used as the test virus strain. A cotton ball was impregnated with 75 μL of the compound shown in Table 1 below or mineral oil, and the cap of a 15 mL glass bottle (Maruem Co., Ltd.) was sealed with double-sided tape and filled for 30 minutes. 1.5 μL (8.3×10 ⁵ FFU) of influenza virus was allowed to dry on the lid of a cryovial (Thermo Fisher Scientific) for 30 minutes. The virus-attached vial lid was placed in a glass bottle, and the compound was allowed to react with the virus at room temperature (approximately 23° C.) for 30 minutes. At that time, the compound was placed on the lid of the bottle, and the virus was placed on the bottom of the bottle, so that the compound and the virus did not come into direct contact with each other. After the reaction, the virus was recovered with Hybridoma-SFM medium (Thermo Fisher Scientific), inoculated into MDCK cells (derived from canine kidney tubular epithelial cells) previously cultured in a 12-well plate, and placed at 37°C in 5% CO. After culturing for about 18 hours under _{the two} conditions, the number of foci formed was measured, and the virus infection titer was determined. The virus-inactivating activity of each compound was calculated based on the infectious titer when reacted with the control mineral oil as 100%. The test was performed 3 times.

2. Results As shown in FIG. 1, compounds 1-9 reduced the detectable viral load by 2.34%, ≤0.001%, 0.05%, ≤0.001%, and 0%, respectively, compared to the mineral oil control. 0.001%, 0.06%, 0.04%, 0.10%, 0.45%.

Example 2 Inactivation of Influenza Virus in Liquid Phase by Fragrance Compounds 1 . Methods Influenza virus type A (A/Puerto Rico/8/1934, H1N1) strain was used as the test virus strain. The compounds shown in Table 1 were dissolved in Hybridoma-SFM medium (Thermo Fisher Scientific) containing 1% (v/v) dipropylene glycol as a solvent so that the final concentration was 0.1% (v/v). . Compound solution or 1% (v/v) dipropylene glycol solution and influenza virus solution (8.3 × 10 ⁵ FFU) using medium as solvent (60 µL each) were added to a 96-well plate and incubated at room temperature (approximately 23°C). React for 30 minutes. After the reaction, the virus was diluted with a medium, inoculated into MDCK cells (derived from canine renal tubular epithelial cells) previously cultured in a 48-well plate, and cultured at 37°C, 5% _CO2 for about 18 hours. The number of foci formed was measured and the virus infection titer was determined. The virus infection titer of each compound was calculated by setting the infection titer when reacted with the control 1% (v/v) dipropylene glycol solution as 100%. The test was performed 3 times.

2. Results As shown in FIG. 2, compared to the control 1% dipropylene glycol solution, compounds 1-2 and 4-9 reduced the amount of virus detected by 77.0%, 75.1%, 39.9%, respectively. Although it decreased to 60.0%, 58.2%, 84.3%, 75.0% and 68.4%, compound 7 had no virus inactivating effect.

Claims (5)

Virus inactivation containing as an active ingredient one or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone and melonal agent. The virus-inactivating agent according to claim 1, wherein the virus is an enveloped RNA virus. 3. The virus inactivating agent according to claim 1 or 2, wherein the virus is influenza virus or coronavirus. The virus inactivating agent according to any one of claims 1 to 3, which inactivates viruses in the gas phase. One or more compounds selected from mugol, linalyl formate, cis-6-nonenal, cinnamyl formate, beltliff, 3,5,5-trimethylhexanol, citronellyl formate, γ-valerolactone and melonal, or a composition containing the same A virus inactivation method applied to a subject where virus contamination is a concern.

Images