Antiviral food product

Abstract

The present invention relates, in a first aspect, to an oral antiviral product, characterised in that it comprises black grape extract. Preferably, this oral product has the grape extract encapsulated in a capsule selected from the group consisting of a capsule with maltodextrin, a capsule with gelatin and a combination of the two. The invention also relates to the use of an oral product comprising black grape extract as an antiviral agent.

Description

[0001] ANTIVIRAL FOOD PRODUCT

[0002] TECHNICAL SECTOR

[0003] The present invention falls within the food products sector and, in particular, relates to an oral product capable of reducing and / or eliminating viral load in the mouth. Therefore, this invention also falls within the field of microbiology, and specifically, in the field of viral infections and antiviral compositions.

[0004] BACKGROUND OF THE INVENTION

[0005] Viral transmission is one of the most important factors considered in the study of infectious diseases. Most viruses are transmitted orally. When a person coughs, speaks, or sneezes, they exhale a series of saliva particles or droplets into the environment, which are highly infectious.

[0006] Several studies show that ambient temperature and relative humidity are factors that greatly influence the evaporation process. In turn, evaporation time depends on particle size; therefore, the smaller the diameter, the shorter the evaporation time required. Furthermore, it is known that these very small particles are capable of remaining suspended in the air for between 60 and 70 seconds, which allows them to travel a certain distance. (Computational characterization of the behavior of a saliva droplet in a social environment. Ainara Ugarte-Anero, Unai Fernandez-Gamiz, Koldo Portal-Porras, Ekaitz Zulueta & Oskar Urbina-Garcia. Scientific Reports volume 12, Article number: 6405 (2022)).

[0007] Based on this, it seems reasonable to think that microparticles that an individual has in their mouth can move and be capable of infecting other individuals.

[0008] It is well known that, due to their very nature, viruses are transmitted through these saliva droplets or aerosols, but also through contact with oral and nasal mucous membranes, infecting a subject upon entering the nasal or respiratory tract.

[0009] Viruses are known to be primarily responsible for the most common diseases affecting the human population annually. There are approximately 219 species of viruses capable of infecting humans, and three to four new ones are discovered each year. The most common are rhinoviruses, parainfluenza viruses, influenza A and B (both belonging to the Orthomyxoviridae family), HIV, viruses from the paramyxovirus family, hepatitis A and B viruses, poliovirus, and SARS-CoV-2. These microorganisms are responsible for common illnesses and infections such as the common cold, flu, and warts. However, they are also responsible for very serious diseases such as HIV, Ebola, AIDS, and COVID-19, which is responsible for the pandemic that began in 2020.

[0010] Therefore, in parallel with the development of effective treatments for these viral diseases, various methodologies are also being developed to intervene in the transmission process, thereby preventing a subject from becoming ill.

[0011] Reducing viral load in the mouth and esophagus has been seen as a possible option. In fact, various products are known in the state of the art aimed at reducing viral load in the oral cavity.

[0012] Among them, a nostril-applicating spray against COVID-19 was developed by a research group at the Spanish National Research Center (CSIC-Spain). It should be noted that the active ingredient in this spray is hypromellose (hydroxypropyl methylcellulose, HPMC), which, along with citric acid, sodium citrate, and benzanconium chloride, acts against SARS-CoV. Also known is an antiviral gum developed by the German laboratory Clevergum GmbH. This product contains essential oils such as cinnamon bark, mint, and lemon; ginseng; quercetin; zinc; and other ingredients such as ginger extract, vitamin D3, sucralose, spermidine (wheat germ extract), xylitol, medicinal gum base, natural coloring, and natural flavoring.

[0013] These products comprise a combination of acids, including acetic acid, which acts on the virus's outer lipid capsid and other components that interfere with coronavirus spores, thereby inactivating the virus's infectious activity.

[0014] Also known in the state of the art is international patent application W02022241010A1, which describes a composition and method for reducing viral load in the oral cavity, particularly Coronaviruses such as SARS-CoV-2 and Influenza viral loads, comprising a trapping molecule that has binding affinity for a protein, glycan or other molecule on the surface of a virus or microorganism.

[0015] However, consumers of these products report that their taste is very bitter, which is why these products are ultimately rejected by end consumers.

[0016] Therefore, there is a need to discover new edible products designed to effectively reduce and even eliminate viral load in the oral and esophageal cavities, in order to prevent the transmission of viral pathogens, while also providing a pleasant taste for the end consumer.

[0017] DESCRIPTION OF THE INVENTION

[0018] BRIEF DESCRIPTION OF THE INVENTION

[0019] In a first embodiment, the invention relates to an antiviral oral product characterized in that it comprises black grape extract, where the grape extract is in free form and / or encapsulated in a capsule of the type selected from the group consisting of capsule with maltodextrin, capsule with gelatin and a combination of the two, and where said oral product is presented in a soluble or chewable form inside the oral cavity.

[0020] In a second embodiment, the invention relates to an oral product for use as an antiviral agent.

[0021] In further embodiments, the composition of the invention is described for use in the prevention and / or treatment of coronavirus infection.

[0022] In another embodiment, the composition of the invention is described for use in reducing viral load in the mouth.

[0023] In this document, when grape extract is indicated, it refers to black grape extract.

[0024] Furthermore, in this document, all percentages described refer to percentages by weight with respect to the total weight.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] To complement the description being made and in order to help better understand the characteristics of the invention, a set of drawings is attached as an integral part of said description, in which the following has been represented for illustrative and non-limiting purposes:

[0027] Figure 1. Example 1 - Experiment 1. Cell viability, determined by MTT, of MRC-5 cells treated with the composition under study comprising different concentrations (7.81-1000 pg / ml) of grape extract with the presence (black line and dots) or absence (grey line and dots) of a 229E inoculum. The dashed line marks the mean viability of infected MRC-5 cells without any treatment. CCso: mean maximum cytotoxic concentration; ECso: mean maximum effective concentration.

[0028] Figure 2. Example 1 - Experiment 2. Cell viability, determined by MTT, of MRC-5 cells treated with the composition under study comprising different concentrations (0.781-100 pg / ml) of grape extract with the presence (black line and dots) or absence (grey line and dots) of a 229E inoculum. The dashed line marks the mean viability of infected MRC-5 cells without any treatment. CCso: mean maximum cytotoxic concentration; ECso: mean maximum effective concentration.

[0029] Figure 3. Example 1 - Cell viability, determined by MTT, of MRC-5 cells treated with different concentrations of chloroquine with the presence (black line and dots) or absence (gray line and dots) of a 229E inoculum. The dashed line marks the mean viability of infected MRC-5 cells without any treatment. CCso: mean maximum cytotoxic concentration; ECso: mean maximum effective concentration. Figure 4. The linear regression between Absorbance and ppm of black grape extract is shown.

[0030] Figure 5. Result showing the absorbance, obtained using the spectrophotometric method, of the saliva extracts obtained from chewing gum at different chewing times. PO: 2 minutes; P1: 5 minutes; P2: 10 minutes; P3: 18 minutes; P4: 30 minutes.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] In a first aspect, the present invention provides an antiviral oral product comprising black grape extract and wherein said oral product is presented in a form selected from the group consisting of soluble or chewable form in the mouth.

[0033] The object of the present invention is therefore an antiviral oral product characterized in that it comprises black grape extract, where the grape extract is in free form and / or encapsulated in a capsule of the type selected from the group consisting of a capsule with maltodextrin, a capsule with gelatin and a combination of the two.

[0034] In a preferred embodiment, the oral product is in a soluble or chewable form.

[0035] After numerous studies, the inventors have developed an oral product that remains in the oral cavity and is chewed or sucked. It releases, in a controlled manner, significantly reduced amounts of an active ingredient, black grape extract, capable of inhibiting and even eliminating a viral microorganism. In preferred embodiments, this viral organism is the coronavirus.

[0036] In the context of the present invention, a soluble form is a product whose components are dissolved in a liquid medium to be incorporated into said liquid medium.

[0037] In the context of the present invention, a chewable form is a product that can be chewed, or in other words, can be crushed with the teeth, palate and tongue to release its components into the oral cavity.

[0038] In particular embodiments of the present invention, the antiviral oral product comprises black grape extract, where the grape extract is in free form and / or encapsulated in a capsule of the type selected from the group consisting of capsule with maltodextrin, capsule with gelatin and a combination of the two.

[0039] In particular embodiments of the present invention, the black grape extract comprising the oral product object of the invention is characterized in that in the total polyphenol analysis it presents 100% of Catechin equivalents in an OD 280nm analysis. In a particular embodiment of the invention, the grape extract is characterized in that in the total polyphenol analysis it presents 70% of gallic acid equivalents in a Folin-Ciacalteu analysis. In another particular embodiment of the invention, the grape extract is characterized in that in the total polyphenol analysis it presents 2% of anthocyanin (cyanidin-3-O-glucoside) equivalents in an HPLC-DAD analysis.

[0040] In the context of the present invention, catechin is a polyphenolic antioxidant. The term catechin is commonly used to refer to the flavonoid family and the flavan-3-ol subgroup.

[0041] Furthermore, in the context of the present invention, gallic acid is a phenolic compound found in various natural sources such as plants, fruits and vegetables.

[0042] Finally, in the context of the present invention, anthocyanin is a pigment found in many red berries, such as grapes, among others.

[0043] The black grape extract comprising the oral product comprises, in turn, a combination of anthocyanin and one or more polyphenols. In a preferred embodiment, the at least one polyphenol comprising the grape extract is selected from the group consisting of phenolic acid, stilbene, lignan, phenolic alcohol, flavonoid, or a combination thereof.

[0044] In more preferred embodiments of the present invention, the phenolic acid comprising the black grape extract is an acid derived from hydroxy benzoic acid or hydroxycinnamic acid.

[0045] In a preferred embodiment, the oral product comprises free black grape extract in an amount of 0.0006-9% by weight relative to the total oral product. In a more preferred embodiment, 0.06-4.5% by weight relative to the total oral product.

[0046] In other particular embodiments of the present invention, the oral product comprises the grape extract in an amount of 0.06%, 0.07%, 0.08%, 0.09%, 0.1% 0.2% 0.3%, 0.4% 0.5% 0.6%, 0.7% 0.8% 0.9% or 1%. In preferred embodiments of the present invention, the oral product comprises the grape extract in an amount of 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2% by weight with respect to the total.

[0047] In other particular embodiments of the present invention, the oral product comprises the grape extract in an amount of 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5% or 9% by weight with respect to the total.

[0048] In preferred embodiments of the present invention, the oral product object of the invention comprises the grape extract encapsulated in a capsule of the type selected from the group consisting of capsule with maltodextrin, capsule with gelatin and a combination of the two.

[0049] In another preferred embodiment, the oral product comprises the grape extract encapsulated in a capsule containing maltodextrin. In the context of the present invention, the grape extract encapsulated in a capsule containing maltodextrin is referred to as a type A capsule.

[0050] In a more preferred embodiment of the present invention, the oral product comprises a grape extract encapsulated in a type A capsule, and comprises the following components and amounts:

[0051] Table 1. Components and quantities of type A capsules. In an even more preferred embodiment, the oral product comprises the black grape extract encapsulated in a type A capsule having the following composition:

[0052] • 38.46% Black grape extract

[0053] • 26.92% Gum Arabic

[0054] • 7.7% Modified starch

[0055] • 26.92% Maltodextrin

[0056] The inventors have been able to verify that the presence of maltodextrin influences the solubility of the grape extract, and therefore, directly influences the release of the grape extract into the oral cavity when the oral product is tasted or chewed.

[0057] In the present invention, different types of maltodextrin comprising the type A capsule are used, depending on the level of hydrolysis of the dextrose chains provided by the starch, so it can come from corn, potato, sweet potato, tapioca... etc. According to the level of hydrolysis, the maltodextrin can have a Dextrose Equivalent (DE) of 2, 6, 12, 19. The higher the dextrose equivalent, the greater the hydrolysis of the maltodextrin. In a more preferred embodiment of the present invention, the Dextrose equivalent is DE = 19.

[0058] The presence of maltodextrin influences the release because maltodextrin, due to its own chemical nature, dissolves easily in water.

[0059] In another preferred embodiment, the oral product comprises the black grape extract encapsulated in a gelatin capsule. The grape extract encapsulated in a gelatin capsule, which, in the context of the present invention, is referred to as a type B capsule, is less soluble than the maltodextrin capsule. In a more preferred embodiment of the present invention, the oral product comprises a grape extract encapsulated in a type B capsule and comprises the following components and amounts:

[0060] In an even more preferred embodiment, the oral product comprises the black grape extract encapsulated in a type B capsule having the following composition:

[0061] • 44.29% Black grape extract

[0062] • 33.22% Gum Arabic

[0063] • 11.42% Modified starch

[0064] • 11.07% Gelatin

[0065] Gelatin can have different gel strengths. In the context of the present invention, gel strength is measured by the Bloom degree. The higher the Bloom degree, the greater the gel strength and therefore the lower the hydrolysis. Bloom degrees typically range from about 80° Bloom to about 380° Bloom, with a preference of 250° Bloom.

[0066] Therefore, the oral product described here has the surprising effect of constantly and controlledly releasing a minimum effective amount of black grape extract that allows the viral load found in the oral cavity to be eliminated, without the need to reach high doses that may be toxic to the individual ingesting the oral product object of the invention.

[0067] In particular embodiments of the present invention, the grape extract found in a type A encapsulation is released at a higher rate compared to the grape extract found in a type B encapsulation. In particular embodiments of the invention, the inventors have been able to verify that the encapsulated grape extract is released more slowly than the grape extract in free form when the oral product object of the invention is ingested, being even more preferred, a constant and progressive release when the oral product is a gum and this is chewed.

[0068] Thanks to numerous studies, the inventors have been able to verify that, in the preferred embodiment, in which the oral product is a chili pepper containing black grape extract encapsulated in type A and type B capsules, after 30 minutes of chewing, the gum continues to release enough black grape extract to eliminate viral microorganisms. Furthermore, beyond those 30 minutes, and up to a maximum of 60 minutes, black grape extract was detectable in the tested area, demonstrating that the gum remains effective for a time longer than the average time users typically chew gum.

[0069] In a particular embodiment of the invention, the oral product is a confectionery product selected from the group consisting of a chewing gum, a lozenge, a gummy, a gel, and a candy.

[0070] In the context of the present invention, chewing gum is understood to mean a flavored, non-swallowable chewable product with a gum-like texture, which releases a substance during chewing.

[0071] In the context of the present invention, a tablet is understood to mean a very small portion of hard paste composed mainly of sugar and some substance that is pleasant to the taste.

[0072] In the context of the present invention, gummy candy is understood to mean a portion of a given size of soft paste composed mainly of sugar, glucose syrup, gelling agents, humectants, flavorings, colorings, which make this product pleasant to the taste.

[0073] In the context of the present invention, gel is understood to mean a portion of paste which adopts a colloidal dispersion material when coagulated.

[0074] In the context of the present invention, a candy is understood to mean a small portion of a generally rounded medicinal material coated with a layer of palatable substance and which, in the present invention, comprises an effective amount of the antiviral composition. In preferred embodiments of the present invention, the candy is a lollipop, which, in the context of the present invention, is a candy arranged at the end of a stick. This type of product has the advantage that the stick prevents the candy from being swallowed, thus avoiding choking.

[0075] In a preferred embodiment of the present invention, the oral product is chewing gum, and in preferred embodiments, it is a chewing gum. In the context of the present invention, a chewing gum is a chewing gum tablet comprising a central chewing gum core and a coating over its entire surface.

[0076] In particular embodiments of the present invention, the oral product is a chewing gum and has the following composition:

[0077] Coating: 30% by weight of the total gum and which in turn includes:

[0078] - 86.84% Policies;

[0079] 9.29% 45% solution of Gum Arabic in water;

[0080] 0.13% artificial sweeteners;

[0081] 1.59% aromas;

[0082] 1.59% acids;

[0083] 0.56% brighteners.

[0084] Chewing gum center 70% by weight with respect to the total chewing gum and which in turn includes:

[0085] 52.48% policies

[0086] 35.00% gum base

[0087] 5.65% aromas

[0088] 3.12% acids

[0089] 0.60% Intensive sweeteners

[0090] 0.15% Emulsifiers

[0091] 1.00% Free Black Grape Extract

[0092] 1.00% PP ENOCAPSUL A: Fast-dissolving encapsulated black grape extract

[0093] 1.00% PP ENOCAPSUL B: Slow-dissolving encapsulated black grape extract

[0094] In another preferred embodiment of the present invention, the oral product is a chewing gum object of the invention, comprising:

[0095] 62.33% Policies, preferred, sorbitol, maltitol syrup and mannitol;

[0096] 27.00% Gum base;

[0097] 3.00% Humectant, preferably: glycerin;

[0098] 2.45% Aromas;

[0099] 2.60% Acids, preferred: citric acid and malic acid;

[0100] 0.60% Free black grape extract;

[0101] 0.60% PP ENCAPSUL A: fast-release encapsulated black grape extract;

[0102] 0.60% PP ENCAPSUL B: slow-release encapsulated black grape extract;

[0103] 0.72% Sweetener, preferred, aspartame, sucralose and acesulfame K;

[0104] 0.10% Emulsifier, preferred: sunflower lecithin.

[0105] In a preferred embodiment of the present invention, the oral product is a hard candy comprising the following composition:

[0106] 100.00

[0107] Table 3. Table describing the amounts in which each of the components are comprised for a preferred embodiment, a more preferred embodiment and an even more preferred embodiment where the oral product is a standard hard candy.

[0108] In a particular embodiment of the present invention, where the oral product is a hard candy, the sum of the different components is 100%. The adjustment to 100% of the total weight of the oral product is made in all combinations with sugar and / or polyols and syrups, maintaining the proportions established for them. Typically, the combinations of sugar-polyols / glucose syrups-maltitol syrups are usually between 50 / 50 and 60 / 40. In this type of confectionery product, combinations of the three black grape extracts, combined in different %, or only the free extract, can be used. It should be noted that since it is a hard candy, which gradually dissolves in the mouth, only free black grape extract would be sufficient to progressively release the black grape extract in the mouth during the dissolution time of the candy.

[0109] 100.00

[0110] Table 4. Table describing the amounts in which each of the components are comprised for a preferred embodiment, a more preferred embodiment and an even more preferred embodiment where the oral product is a chewable candy.

[0111] In this particular embodiment, the sum of the different components is 100%. The adjustment to 100% of the total weight of the oral product is made in all combinations with sugar and / or the polio and syrups, maintaining the established proportions for them. In this type of confectionery product, combinations of the three black grape extracts, combined in different %, or only the free extract, can be used.

[0112] It should be noted that, as it is a chewy candy, which remains in the mouth for a certain amount of time while being chewed, only free black grape extract would be sufficient to progressively release the black grape extract into the mouth during the dissolution time of the candy.

[0113] In a preferred embodiment of the present invention, the oral product is a gummy:

[0114] 100.00 Table 5. Table describing the amounts in which each of the components are comprised for a preferred embodiment, a more preferred embodiment and an even more preferred embodiment where the oral product is a gummy.

[0115] In all cases, the sum of the different components is 100%. The adjustment to 100% of the total weight of the oral product is made in all combinations with sugar and / or polyphenols and syrups, maintaining the established proportions. In this type of confectionery product, combinations of the three black grape extracts, combined in different percentages, or just the free extract can be used. It should be noted that since this is a gummy candy, which is chewed for a period of time, only the free black grape extract would be sufficient to progressively release the black grape extract in the mouth during chewing and swallowing.

[0116] In a preferred embodiment of the present invention, the oral product is a chewing gum:

[0117] Table 6. Table describing the amounts in which each of the components are comprised for a preferred embodiment, a more preferred embodiment and an even more preferred embodiment where the oral product is a chewing gum.

[0118] In particular embodiments of the present invention, the oral product comprises at least one additive selected from the group consisting of milk, cream, fruit juices, cremogenates and licorice extract, or a combination thereof.

[0119] In other particular embodiments, the oral product comprises polishes, waxes, sugars or acids on its surface, in order to give shine to the surface of the product and prevent different pieces of the product from sticking together.

[0120] In preferred embodiments, the oral product is a sugar-free product and comprises at least one sweetener, which is referred to in the prior art as the "majority sweetener in the formula" and which is selected from the group consisting of sorbitol, maltitol, xylitol, somaltose, mannitol, lactitol, erythritol, maltitol syrup, and a combination thereof. In preferred embodiments, the sweetener is present in an amount of between 40-85% by weight relative to the total. In a more preferred embodiment, the sweetener is present in an amount of between 50-75% by weight relative to the total. In more preferred embodiments, the sweetener is present in an amount of between 54-65% by weight relative to the total.

[0121] In other preferred embodiments, the oral product is a sugar-free product and may comprise at least one intensive sweetener selected from the group consisting of aspartame, acesulfame K, sucralose, neohesperidin dihydrochalcone (NHDC), thaumatin, neotame, advantame, sodium and calcium saccharin, steviol glycosides, aspartame salt, acesulfame, and a combination thereof. In preferred embodiments, the intensive sweetener is present in an amount of 0.005-0.5% by weight relative to the total. In more preferred embodiments, the intensive sweetener is present in an amount of 0.01-0.1%, and is even more preferred, 0.05-0.09%.

[0122] In preferred embodiments, the oral product is a sugar product and comprises at least one sweetener selected from the group consisting of sucrose, dextrose, maltose, lactose, glucose syrup, and a combination thereof. In preferred embodiments, the sweetener is present in an amount of 40-75% by weight relative to the total. In a more preferred embodiment, the sweetener is present in an amount of 50-75%. In more preferred embodiments, the sweetener is present in an amount of 54-65% by weight relative to the total.

[0123] In particular embodiments of the present invention, the oral product comprises gum base, which, in the context of the present invention, is a hydrogenated microcrystalline wax composed mostly of branched-chain hydrocarbons, preferably with a high iso-paraffin content, and which gives it a high degree of plasticity. In preferred embodiments, the amount of gum base comprising the oral product is between 15% and 40%. In more preferred embodiments, the amount of gum base comprising the oral product is between 20% and 32%. In even more preferred embodiments, the amount of gum base comprising the oral product is 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31% or 32%.In particular embodiments of the present invention, the oral product comprises other ingredients, also referred to herein as additives and selected from the group consisting of flavorings, acids, gum arabic, water, brightener, modified starch, emulsifier, gelatin, or a combination thereof. In preferred embodiments, the amount of additives comprising the oral product is between 8% and 12%. In more preferred embodiments, the amount of additives comprising the oral product is 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, or 12%.

[0124] In preferred embodiments of the present invention, when the oral product is a candy, the grape extract is in free form, such that the extract is released from the first moment the candy is sucked. In preferred embodiments of the present invention, when the oral product is a candy, the grape extract in its free state is released over a period of time between 5 and 15 minutes, which is the average time it takes for a candy weighing 4 to 5 g to dissolve in the mouth. In more preferred embodiments, the grape extract in its free state is released over a period of time between 5 and 10 minutes, with 7 to 9 minutes being even more preferred.

[0125] In a preferred embodiment of the invention, the oral product is a chewing gum, wherein the chewing gum further comprises a gum base and, optionally, one or more excipients selected from plasticizers, elastomers, softeners, fillers and bulking agents, or wherein the oral product is a lozenge, wherein the lozenge further comprises one or more excipients selected from sweetening and flavoring agents.

[0126] In particular embodiments, when the oral product is a candy or a lollipop, the grape extract is in a free state.

[0127] In particular embodiments, when the oral product is a chewing gum, the grape extract is free and encapsulated in type A and type B.

[0128] In particular embodiments of the present invention, the oral product is a chewing gum comprising one or more excipients selected from the group consisting of polyphenols, gum base, flavorings, coating agents and stabilizers, acids, encapsulated acids, intensive sweeteners, brighteners, emulsifiers, and combinations thereof. In an even more preferred embodiment of the present invention, the oral product is a chewing gum having the following composition: Table 7. Composition of a particular embodiment of coated chewing gum, according to the present invention

[0129] Table 8. Composition of a particular embodiment of one-piece chewing gum, according to the present invention.

[0130] The weights described are in percentage with respect to the total.

[0131] In particular embodiments of the present invention, the oral product of the present invention is a chewing gum and comprises at least one polyol. In preferred embodiments of the present invention, the at least one polyol is selected from the group consisting of sorbitol, maltitol, mannitol, xylitol, somaltose, lactitol, erythritol, maltitol syrup or a combination thereof. In even more preferred embodiments, the at least one polyol is selected from the group consisting of sorbitol, maltitol, maltitol syrup or a combination thereof. Within the scope of the present invention, the polyols are hydrogenated sugars and have the technical advantage that they do not ferment inside the oral cavity. Therefore, these products maintain a pH in the mouth above the critical value for the wear of tooth enamel. As long as the enamel protects the tooth, caries bacteria cannot affect the teeth since they cannot act.Likewise, polyphenols also offer the advantage over sugars in that they provide fewer calories to the consumer. That is, polyphenols provide around 2.4 cal / g, while sugar, which is sucrose, provides 4 cal / g, compared to 9 cal / g for fat and 7 cal / g for alcohol.

[0132] In particular embodiments of the present invention, the oral product of the present invention comprises at least one aroma that is selected from the group consisting of fruit aromas, mint, chamomile, vanilla, violet, cinnamon or a combination of the above.

[0133] In preferred embodiments, the fruity aroma is selected from the group consisting of red fruits, citrus fruit, strawberry, apple, banana, pear, cherry, pineapple, mango, passion fruit, pomegranate, lychee, custard apple, currant, raspberry, blackberry, watermelon, melon, grape, peach, or a combination thereof. In more preferred embodiments, the citrus aroma is selected from the group consisting of orange, lemon, grapefruit, mandarin, or a combination thereof.

[0134] In more preferred embodiments, the mint aroma is selected from the group consisting of peppermint, spearmint, chlorophyll, menthol, and combinations thereof.

[0135] In particular embodiments of the present invention, the oral product comprises at least one coating agent that is selected from the group consisting of carnauba wax, beeswax, candelilla wax and shellac, or a combination thereof.

[0136] In particular embodiments of the present invention, the oral product comprises at least one acid selected from the group consisting of citric acid, malic acid, tartaric acid, acetic acid, lactic acid, ascorbic acid, phosphoric acid, and a combination thereof. In more preferred embodiments, the oral product comprises at least one acid selected from the group consisting of citric acid, malic acid, and a combination thereof.

[0137] In preferred embodiments of the present invention, the oral product is a chewing gum and comprises at least one encapsulated acid. In preferred embodiments of the present invention, the at least one encapsulated acid is encapsulated by fats with different melting points. In more preferred embodiments, these fats are stearins with a high or very high melting point, preferably between 60°C and 70°C, or more. In other preferred embodiments, the acid is coated by other coating materials selected from the group consisting of gum arabic, modified starches, or a combination of the foregoing. The technical effect of these types of materials is that they allow the slow release of the acid during chewing. This causes the acidic note in the chewing gum to extend over time, giving that acidic effect a longer duration. In sour flavors, the acidic note enhances the flavor of the fruit in the chewing gum.

[0138] In particular embodiments of the present invention, the oral product comprises at least one intensive sweetener selected from the group consisting of aspartame, acesulfame K, sucralose, neohesperidin dihydrochalcone (NHDC), thaumatin, neotame, advantame, sodium and calcium saccharin, steviol glycosides, aspartame salt, acesulfame and combination of the above.

[0139] In particular embodiments of the present invention, the oral product comprises at least one polish selected from the group consisting of carnauba wax, white and yellow beeswax, candelilla wax, microcrystalline wax, shellac, or a combination thereof.

[0140] In particular embodiments of the present invention, the oral product comprises at least one emulsifier selected from the group consisting of soy lecithin, sunflower lecithin, mono and diglycerides of fatty acids and combinations thereof.

[0141] In particular embodiments of the present invention, the oral product comprises at least one humectant selected from the group consisting of glycerol or glycerin, sorbitol, and a combination thereof. In preferred embodiments, the humectant is glycerin.

[0142] In particular embodiments of the present invention, the oral product comprises at least one modified starch that is selected from the group consisting of sodium starch octenylsuccinate, acetylated starch, acetylated distarch adipate, hydroxypropylated starch, hydroxypropylated distarch phosphate, and combinations thereof.

[0143] In particular embodiments of the present invention, the oral product comprises at least one anti-adherent selected from the group consisting of talc, sugar, mannitol, starches, somaltose, and a combination thereof. More preferably, the anti-adherent is talc, which is used to prevent the gum from sticking to surfaces during the rolling, cutting, and packaging process.

[0144] In particular embodiments of the present invention, the oral product comprises at least one gelling agent selected from the group consisting of pork gelatin, cow gelatin, fish gelatin, agar-agar, pectin and a combination of the foregoing.

[0145] In a second aspect, the invention relates to the use of an oral product comprising black grape extract as an antiviral agent. In a preferred embodiment, the invention relates to the use of the oral product for reducing and / or eliminating viral load in the oral cavity, the respiratory tract, preferably the upper respiratory tract, and exhaled air.

[0146] In the context of the present invention, viral load is understood as the quantification of the virus infection which is calculated by estimating the amount of viral particles in body fluids.

[0147] In a preferred embodiment of the present invention, said viral load is a viral load of a coronavirus virus, preferably, cold coronavirus 229E.

[0148] In another preferred embodiment, the invention relates to the use of the oral product where said oral product is kept inside the oral cavity for a time between 5 to 60 minutes.

[0149] Likewise, the invention also relates to the oral product according to the first aspect of the invention, for use in preventing a coronavirus infection.

[0150] In a preferred embodiment of the present invention, the inventors have been able to verify that the use of this oral product has surprisingly reduced the viral load of the 229E cold coronavirus, obtaining an extremely positive result of inhibition and / or destruction of said virus with the oral product object of the invention which comprises very small amounts of black grape extract.

[0151] In a preferred embodiment of the invention, the oral product is held in the oral cavity for chewing or sucking, or for dissolving within the oral cavity. In more preferred embodiments of the present invention, the oral product is held within the oral cavity for a time between 1 and 60 minutes. In preferred embodiments, the time is between 5 and 30 minutes, and in another more preferred embodiment, the time is between 10 and 30 minutes, and more preferably, between 10 and 15 minutes.

[0152] In particular embodiments, the oral product is a chewing gum comprising black grape extract in three forms: free or unencapsulated, and encapsulated. The free form is released very quickly as the chewing gum hydrates with saliva. Therefore, the free grape extract begins to be detected within the first minute of chewing, which in more particular embodiments is 0.5 to 1 minute, and up to a maximum of 2 to 5 minutes. After this time, the grape extract released is the encapsulated grape extract. Therefore, in particular embodiments, where the chewing gum comprises grape extract in both types of encapsulations, after the free extract is released, the grape extract encapsulated in the type A capsule, which contains maltodextrin, is released.The grape extract encapsulated in the type B capsule, which contains gelatin, is then released. In preferred embodiments, the release lasts for more than 15 minutes. After the first 15 to 30 minutes of chewing, we can consider that the black grape extract has already released more than enough extract to eliminate the virus.

[0153] Based on the above, when the oral product is a chewing gum, the release time of the grape extract will range from 0 to more than 30 minutes, even 45 minutes or 60 minutes.

[0154] In other preferred embodiments, when the oral product is a hard candy weighing about 10 grams, the release time of the grape extract will be between 0 and 15 minutes, preferably between 5 and 15 minutes, which is the time that must elapse for the candy to be completely dissolved.

[0155] In other preferred embodiments, when the oral product is a chewy candy or a gummy bear, the release time of the grape extract will range from 0 to about 2 to 5 minutes. In preferred embodiments, the chewy candy dissolves faster than a hard candy. In other embodiments, the gummy bear dissolves even faster than the candy, since it breaks into small pieces when chewed, causing it to dissolve even faster than the candy.

[0156] Following numerous studies, the inventors have been able to verify that this oral product, which includes grape extract, is surprisingly effective in inhibiting and even eliminating viral load in the oral cavity in very small amounts. This is thanks to the design of the oral product described in this document, where a very small amount of grape extract is strategically released during chewing, in the preferred case of chewing gum, or during the ingestion of a gel, candy, or lozenge.

[0157] Gum base, in the context of the present invention, is a substance designed to be chewed without being swallowed, to which other components are usually added to market it as chewing gum with different flavors and colors, which gives it a pleasant appearance for the consumer.

[0158] The term "effective amount," as used herein, means an amount of an active agent high enough to achieve the desired benefit, but low enough to avoid serious side effects within the scope of sound medical judgment.

[0159] After extensive testing, researchers have developed an oral antiviral product that inhibits the infectivity of coronaviruses, particularly HuCov-229E, a common cold coronavirus.

[0160] Throughout the description and claims, the word "comprises" and its variations are not intended to exclude other features, additives, components, or technical steps. Additional objects, advantages, and characteristics of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. Furthermore, the present invention encompasses all possible combinations of particular and preferred embodiments described herein.

[0161] EXAMPLES

[0162] The purpose of the examples indicated below is illustrative and is not intended to limit the scope of the invention in any way.

[0163] Example 1. Determination of the inhibitory potential of a grape extract on the infectivity of a human coronavirus (229E)

[0164] Objective of the study

[0165] In this study, the ability of the product object of the invention to inhibit the infectivity of human coronavirus 229E was determined. To this end, different concentrations of grape extract were incubated with a defined concentration of the virus of interest for 30 minutes. Exposure of host cells to the virus causes the virus to replicate within the cells, producing a cytopathic effect on the cells that is quantified using a cell viability assay 5 days after exposure. Thus, it was assessed whether the grape extract had an inhibitory effect on the infectivity of the virus of interest; cells treated with the test substance-virus mixture did not see their cell viability reduced.

[0166] The black grape extract that was tested is characterized by comprising:

[0167] 100% total polyphenol equivalents of Catechin in an OD 280nm analysis;

[0168] 70% gallic acid equivalents in a Folin-Ciacalteu analysis; and

[0169] 2% anthocyanin equivalents (cyanidin-3-O-glucoside) in a HPLC-DAD analysis.

[0170] Cell cultures and viruses

[0171] The MRC-5 cell line (lung-derived fibroblasts) from the American Type Culture Collection (ATCC) (CCL-171) was used. Cells were maintained at 37°C and 5% CO2 in Eagle's minimum essential medium (EMEM) supplemented with 10% fetal bovine serum (FBS) and antibiotics, and trypsinized every 3–4 days until reaching 90% confluence. Coronavirus 229E was obtained from ATCC (VR-740) and amplified in MRC-5 cells according to the ATCC protocol.

[0172] 229E infectivity inhibition assays

[0173] For 229E infectivity inhibition assays, MRC-5 cells were seeded in 96-well plates at a density of 5000 cells / well, 48 hours prior to treatments.

[0174] Two experiments were carried out, with different concentration ranges of the test substance:

[0175] Experiment 1

[0176] A stock solution of the test substance was prepared in dimethyl sulfoxide (DMSO) at 100 mg / ml. From this stock solution, a 2 mg / ml solution in phosphate buffer saline (PBS) was prepared, followed by serial 1 / 2 dilutions up to 0.015625 mg / ml. Next, 0.25 ml of each dilution was mixed with 0.25 ml of a 229E inoculum diluted in EMEM 2% FBS medium, leaving the inoculum at an infective concentration of 1000 TCID50 / ml and the maximum concentration of the extract at 1 mg / ml (range of concentrations analyzed in the medium: 7.81-1000 pg / ml). The test substance-inoculum mixture was incubated for 30 min at room temperature. The medium was aspirated from the wells, and 0.1 ml of each test substance-inoculum mixture was added in quadruplicate. The mixture was incubated for 4.5 h at 35°C and 5% CO2 to allow virus adsorption by the MRC-5 cells.The cell medium was then aspirated, 2% FBS EMEM medium was added and the cells were incubated for 5 days at 35°C and 5% CO2.

[0177] In all treatments, the final concentration of DMSO in the medium during the 4.5h of treatment was 1%.

[0178] Experiment 2

[0179] Because in experiment 1 the minimum effective amount of black grape extract against the virus could not be defined, another experiment was carried out with amounts less than 8 pg / ml in order to define the minimum amount of grape extract necessary to inactivate the virus.

[0180] For this purpose, a stock solution of the test substance in dimethyl sulfoxide (DMSO) was prepared at 50 mg / ml. From the stock solution, a 200 pg / ml solution in PBS was prepared, followed by 1 / 2 dilutions up to 1.5625 pg / ml. Next, 0.25 ml of each dilution was mixed with 0.25 ml of a 229E inoculum diluted in EMEM 2% FBS medium, leaving the inoculum at an infective concentration of 1000 TCID50 / ml and the maximum concentration of the extract at 1 mg / ml (concentration range analyzed in medium: 0.78125 pg / ml - 100 pg / ml). The test substance-inoculum mixture was incubated for 30 min at room temperature. The medium was aspirated from the wells, and 0.1 ml of each test substance-inoculum mixture was added in quadruplicate. The cells were incubated for 4.5 h at 35°C and 5% CO2 to allow virus adsorption by the MRC-5 cells. The medium was then aspirated from the cells, EMEM medium with 2% FBS was added, and the cells were incubated for 5 days at 35°C and 5% CO2.

[0181] In all treatments, the final concentration of DMSO in the medium during the 4.5h of treatment was 0.2%.

[0182] Toxicity controls were performed on all concentrations of the test substance and chloroquine by mixing 0.25 ml of each concentration with 0.25 ml of virus-free 2% FBS EMEM medium to determine the toxicity associated with the test substance.

[0183] As a positive control for the experiments, chloroquine (Sigma C6628) was used, following the same procedure described for the test substance, and with a final concentration range in the medium of 0.0625 - 256 pg / ml.

[0184] In both experiments, 5 days post-infection, differences in cell viability associated with the cytopathic effect of the virus or the toxicity of the treatments were analyzed using the MTT assay. The MTT assay is a colorimetric assay that measures the activity of enzymes that transform the MTT molecule (Methylthiazolyldiphenyl-tetrazolium bromide) into formazan, a purple color. Briefly, the medium from the wells was aspirated and 0.1 ml of 1 mg / ml MTT solution in EMEM was added to each well, and the mixture was incubated at 37°C for 2 h. The MTT solution was then aspirated, the formazan crystals were dissolved in 0.1 ml of DMSO, and the absorbance was read at 570 nm (660 nm as reference). The average of the absorbance values ​​of the uninfected controls was considered 100% cell viability.

[0185] Calculation of the results.

[0186] In order to evaluate the results, the following variables were calculated:

[0187] • CC50: Half maximal cytotoxic concentration, which is the concentration of the compound of interest that causes 50% toxicity. Lower CC50 values ​​indicate greater toxicity.

[0188] • EC50: Half maximal effective concentration, which is the concentration of the compound of interest that inhibits 50% of the toxicity caused by the viral infection. Lower EC50 values ​​indicate greater inhibition.

[0189] • SI: Selectivity index, calculated by dividing the CC50 by the EC50. The higher the SI, the better the relationship between toxicity and effect of the compound.

[0190] The CCso and ECso values ​​were obtained through nonlinear regressions, using GraphPad Prism 9.0.1 software.

[0191] Analysis of the results

[0192] In the first experiment, which tested a range of grape extract doses from 7.81 to 1000 pg / ml, an inhibitory effect on the infectivity of HuCov-229E was observed at all doses of the extract tested. No decrease in cell viability was seen in its cytotoxicity control (without 229E virus), since no decrease in cell viability associated with viral infection was observed at any dose. A decrease in cell viability was observed both in cells treated with the extract alone and in those treated with both the virus and the extract, starting at 500 pg / ml, with almost total toxicity at a concentration of 1000 pg / ml. This made it possible to establish the CC50 (theoretical concentration of the extract that causes 50% toxicity) of the extract at 529.3 pg / ml. (Figure 1).

[0193] Since no toxicity associated with viral infection was observed in the first experiment at low doses of the extract and in order to establish the minimum concentration at which inhibition occurred and the EC50 (theoretical effective concentration that inhibits 50% of the toxicity associated with viral infection) of the extract, a second experiment was carried out with a lower dose range of the grape extract: 0.781-100 pg / ml. This experiment confirmed that from 1.56 pg / ml of grape extract in the medium, there is some inhibition of the cytopathic effect of the HuCov-229E virus, with total inhibition from 6.25 pg / ml, and allowed the EC50 to be established of 2,634 pg / ml (Figure 2).

[0194] Regarding the results of the antiviral positive control used in this study, chloroquine, a clear antiviral effect was observed starting at 16.5 pg / ml, with an ECsode of 5.96 pg / ml. No significant toxicity was observed at any dose within the dose range used (0.06–264 pg / ml), so the ECso of chloroquine was greater than 264 pg / ml (Figure 3).

[0195] In summary, the ECso and CCso values ​​indicated in Table 9 were obtained for chloroquine and grape extract. From these values, the selectivity index (SI) of each compound was calculated, indicative of the ratio between toxic concentration and effective concentration. Thus, the grape extract showed a good SI for the conditions tested, since the CCso was 200 times higher than the ECso, which means that the effective antiviral concentrations are far from toxic concentrations. It is interesting to note that the grape extract showed antiviral effectiveness at lower doses than chloroquine, a well-known drug used as a treatment against malaria, which has shown antiviral activity in vitro against coronaviruses such as SARS-CoV, MERS-CoV, HCoV-OC43 and HuCov-229E and was proposed as a treatment against SARS-CoV-2 infection in the initial stages of the pandemic.

[0196] Conclusions of the study

[0197] The results of this study demonstrated a clear antiviral effect of the tested grape extract, with complete inhibition of the cytopathic effect of HuCoV-229E infection starting at 6.25 pg / ml. The extract demonstrated antiviral effectiveness at lower doses than chloroquine, a drug with known antiviral properties.

[0198] It should be noted that the concentrations determined in the present study are effective for the in vitro conditions described, in which antiviral effectiveness was tested against an infectious dose of 100 TCID50 / reaction, and that higher concentrations of the virus could require higher concentrations of the grape extract to have the same effectiveness. The present study shows at what concentrations the grape extract exhibits inhibitory activity against the infectivity of HuCoV-229E. Once the minimum concentrations to obtain an antiviral effect have been determined, as possible future steps, it would be interesting to determine the percentage reduction in the infectious load of one or two specific doses, such as 25 or 50 pg / ml, exposing the grape extract to a higher viral concentration -106 TCID50- and determining the percentage inhibition of infectivity.These additional studies would provide further insight into the antiviral effects of grape extract, which could be used as a starting point for obtaining more solid scientific evidence for the potential use of this natural ingredient as a strategy to help prevent viral infections or as a complementary therapy once an infection has already occurred.

[0199] Example 2. Preparation of a linear regression table between absorbance and concentration (ppm) of black grape extract.

[0200] Objective of the study

[0201] To determine the relationship between absorbance and concentration in ppm of grape extract. To do this, a table with grape extract samples is created using a standard procedure, and the sample's absorbance is then measured to construct the linear regression line showing the correlation between absorbance and concentration of black grape extract, as represented in Figure 4.

[0202] The results are also shown in the following table:

[0203] Table 10. Linear regression table between Absorbance and grape extract concentration (PPm).

[0204] According to this graph, it is known that with only 2 ppm of black grape extract, we already have an absorbance result of 0.158. Furthermore, the increase in absorbance is correlated with the increase in ppm of black grape extract. The graph shows a good correlation between ppm of black grape extract and absorbance.

[0205] On the other hand, according to the virological study carried out with coronavirus 229E, it has been shown that 6.25 ppm of black grape extract completely inactivates the coronavirus 229E population.

[0206] Therefore, extrapolating from the correlation graph between absorbance and concentration of ppm of black grape extract, 6.25 ppm of black grape extract would correspond to approximately an absorbance of 0.263, which would correspond to the minimum amount of ppm of black grape extract necessary to completely inactivate the population of coronavirus 229E.

[0207] Example 3. Analysis of the amount of black grape extract released into the oral cavity by chewing a chewing gum.

[0208] Objective of the study

[0209] To know the quantity of black grape extract released by the oral product, and in this case, a sugar-coated chewing gum as described in this document and in particular in table 7 (AOM 20220922- PA1- sugar-coated chewing gum 1.4 gr).

[0210] Seven samples of repetitions of each sample were analyzed according to the European Pharmacopoeia, in order to subsequently carry out the statistical study.

[0211] For this analysis, the chewing gum described in Table 7 of this document was used. A chewing test simulating chewing within the oral cavity was performed. To this end, the chewing protocols and machinery established in European Pharmacopoeia 7.4 Vol. 04 / 2012:20925 were followed. Preferably, the machinery described in this protocol, Chapter 2.9.25 - Type B machinery - was used.

[0212] The conditions under which this test was carried out are as follows:

[0213] • Solvent used: Phosphate buffer pH=6

[0214] • Solvent volume 20 ml

[0215] • Chewing medium temperature 37.0±0.5 °C

[0216] • Number of chews: 60 chews / min

[0217] • Sampling time 2, 5, 10, 18 and 30 minutes

[0218] The solvent used to carry out the study had the following composition:

[0219] • Na2HPO4.12H20: 28.6520g

[0220] • C12H25NaO4S: 1.0049 g

[0221] The following table 11 shows the total weight of each of the samples evaluated in the analytical study that included 2 pellets and the solvent:

[0222] Table 11. Descriptive table indicating the weight in grams of the samples evaluated for this analytical study and the weight of the solvent.

[0223] Results

[0224] Figure 5 shows that after 2 minutes of chewing time, the absorbance already has a value of 1.78. In this regard, it should be noted that an absorbance of 0.263, equivalent to 6.25 ppm of black grape extract, is sufficient to inactivate the virus. Therefore, it is concluded that, after 2 minutes, or very likely sooner, the amount of black grape extract released from the gum during chewing is already much higher than that needed to eliminate the entire population of coronavirus 229E in the mouth and retronasal cavity. That is, we have approximately 42.3 ppm of black grape extract, while 6.25 ppm already eliminates the entire coronavirus population.

[0225] In the chewing period after the initial 2 minutes, and according to the 30-minute maximum chewing test, throughout the entire chewing period, the amount of black grape extract in the mouth remains much higher than that needed to completely inactivate the coronavirus.

[0226] Given the results of this test, shown in the graph, it can be concluded that even if the gum were chewed for over 30 minutes, the amount of black grape extract would still be high enough to fully protect against the coronavirus studied.

Claims

CLAIMS 1. An oral antiviral product characterized in that it comprises black grape extract.

2. The oral antiviral product according to claim 1, wherein the grape extract is encapsulated in a capsule selected from the group consisting of a capsule with maltodextrin, a capsule with gelatin, and a combination of the two.

3. The antiviral oral product according to claim 1, wherein the oral product comprises an amount of 0.0006 - 9% of black grape extract, by weight with respect to the total.

4. The antiviral oral product according to claim 1 or 2, wherein the capsule with maltodextrin comprises an amount comprised from 9 to 42% of maltodextrin, as a percentage by weight with respect to the total.

5. The oral antiviral product according to claim 1 or 2, wherein the gelatin capsule comprises an amount of 4 to 20% gelatin, as a percentage by weight with respect to the total.

6. The antiviral oral product according to any one of claims 1 to 5, wherein the oral product is selected from the group consisting of a chewing gum, a pill, a gummy, a gel, and a candy.

7. The antiviral oral product according to any one of claims 1 to 6, wherein the oral product is a chewing gum and comprises other excipients selected from the group consisting of policies, gum base, flavors, coating agents and stabilizers, acids, residual water, encapsulated acids, intensive sweeteners, brightener, emulsifiers and combination of the above.

8. Use of an oral product comprising black grape extract as an antiviral agent.

9. Use according to claim 8, for the reduction and / or elimination of the viral load in the oral cavity, in the respiratory tract, preferably in the upper respiratory tract, and in exhaled air.

10. Use according to claim 9, wherein said viral load is a viral load of a coronavirus virus, preferably cold coronavirus 229E.

11. Use according to any one of claims 8 to 10, wherein the oral product is kept inside the oral cavity for a time between 5 to 60 minutes.

12. The oral antiviral product according to any one of claims 1 to 7, for use in preventing a coronavirus infection.

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