WO2021025584A2

WO2021025584A2 - Fullerene-containing agents for comprehensive care of the oral cavity

Info

Publication number: WO2021025584A2
Application number: PCT/RU2019/000841
Authority: WO
Inventors: Елена Юрьевна БЕЛОУС; Светлана Анатольевна ЗАКИРОВА
Original assignee: Общество С Ограниченной Ответственности "Сплат Глобал"
Priority date: 2019-08-08
Filing date: 2019-11-22
Publication date: 2021-02-11
Also published as: WO2021025584A3

Abstract

The invention relates to compositions containing fullerenes for comprehensive care of the oral cavity.

Description

COMPREHENSIVE Oral Cavity Care Products Containing Fullerenes

FIELD OF TECHNOLOGY

The present invention relates to compositions containing fullerenes intended for complex oral care.

LEVEL OF TECHNOLOGY

Fullerenes are a new allotropic modification of carbon with a closed spherical shape. Fullerene occurs both in nature and can be synthesized under laboratory conditions. The biological activity of fullerenes is based, first of all, on three properties of these molecules: lipophilicity, which determines membranotropic properties; electron-withdrawing activity leading to the ability to interact with free radicals; the ability from an excited state to transfer energy to an ordinary oxygen molecule and convert it into singlet oxygen. [Sijbesma R., Srdanov G., Wudl F., Castoro J. A., Wilkins C., Friedman S. H., DeCamp D. L., Kenyon G. L. Synthesis of a fullerene derivative for the inhibition of HIV enzymes. J. Am. Chem. Soc. 1993; 115: 6510-2]. It has also been found that fullerene in a physiological environment quickly interacts with components such as proteins, lipids and other biomolecules containing hydrophobic fragments. [Belgorodsky B., Fadeev L., Ittah V., Benyamini N., Zelner S., Huppert D., Kotlyar A. B., Gozin M. Formation and characterization of stable human serum albumin-tris-malonic acid [C60] fullerene complex. Bioconjug. Chem. 2005; 16 (5): 1058-62].

At present, the most studied is the action of fullerenes of the C60 and C70 molecules. These forms are the most stable.

Fullerene is a molecular formation of carbon in the form of a truncated icosahedron and has a mass of 720 amu. e. m.In fullerene molecules, carbon atoms are located at the vertices of the hex- and pentagons, of which surface of a sphere or ellipsoid. The most studied member of the fullerene family is fullerene (C60), in which carbon atoms form a truncated icosahedron, consisting of 20 hexagons and 12 pentagons, and resembling a soccer ball (a form that is extremely rare in nature). Since each carbon atom of the C60 fullerene belongs simultaneously to two six- and one pentagon, then all atoms in C60 are equivalent, which is confirmed by the nuclear magnetic resonance (NMR) spectrum of the ¹³ C isotope - it contains only one line. [Belousov V.P., Budtov V.P., Danilov O.B., Mak A.A., "Optical journal" v. 64, Г ° 12, p. 3 (1997)].

Fullerene C70 is the next most common. It is a fullerene molecule consisting of 70 carbon atoms. It is a checkered structure with fusible rings, reminiscent of a rugby ball, made up of 25 hexagons and 12 pentagons, with a carbon atom at the vertices of each polygon and a bond along each edge of the polygon ["Rotational Dynamics in C 70 - Temperature-Dependent Infrared Studies",

Chemical Reagent S. 115 (9): 3646-3653. 2011].

The C70 molecule has the Ds _h symmetry and contains 37 faces (25 hexagons and 12 pentagons) with a carbon atom at the vertices of each polygon and a bond along each edge of the polygon. Its structure is similar to the structure of the C60 molecule (20 hexagons and 12 pentagons), but at the equator there is a belt of 5 hexagons. The molecule has eight bond lengths ranging from 0.137 to 0.146 nm. Each carbon atom in the structure is covalently bonded to 3 others ["Fullerenes, nanotubes, onions, and linked carbon structures." Materials Science and Engineering R. 15 (6): 209-262. 1995].

Fullerene C70 has a hepatoprotective effect. [Zhou Y, Li J, Ma H, et al. Biocompatible / Fullerenols: Potent Defense against Oxidative Injury Induced by Reduplicative Chemotherapy ACS Appl Mater Interfaces. 2017; 9 (41): 35539-35547]

A number of substances or, in other words, the so-called hepatoprotectors have a hepatoprotective effect. Hepatoprotectors are a group of heterogeneous drugs that prevent the destruction of cell membranes and stimulate the regeneration of hepatocytes, thereby having a positive effect on liver function. Hepatoprotectors increase the liver's resistance to pathological influences, enhance its detoxification function by increasing the activity of enzyme systems (including cytochrome P450 and other microsomal enzymes), and also contribute to the restoration of its functions in various injuries (including toxic ones) [Ivashkin V.T. and other Rational pharmacotherapy of diseases of the digestive system: a guide for practicing physicians. - Moscow: Literra, 2003 .-- S. 86-92. - Part: “Chapter 9.

Hepatoprotectors "/ Matveev A.V. Hepatoprotectors: Analysis of international studies on drugs of a group of drugs for the liver. - Simferopol: IT "ARIAL", 2013. - 384 p.]

Numerous studies of the toxicity of fullerenes, as well as a number of clinical trials, have proven the positive effect of these substances on the human and animal body. So, in particular, fullerenes can be used in the fight against allergic reactions, as a detoxification component, as protection against viruses, to stimulate immunity.

Experiments carried out on rats have shown that an aqueous dispersion of C60, prepared without the use of organic solvents, not only does not have acute toxicity in rodents, but also protects their liver from free radical damage [Gharbi N., Pressac M., Hadchouel M. et al. Fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. Nano Lett. 2005; 5: 2578-85]. In the course of the experiment, the rats were injected with toxic SCC, which caused the formation of the trichloromethyl radical CCb and serious liver damage. When reacting with oxygen, trichloromethyl peroxide CCLOO radicals are formed, which quickly initiate a chain reaction of lipid peroxidation [Slatet T. F., Cheeseman K. N., Ingold K. U. Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos. Trans. R. Soc. Lond B Biol. Sci. 1985; 311: 633-45]. The C60 molecule is capable of inactivating at once a significant amount of such radicals. Thus, histological studies have confirmed that in rats pretreated with fullerene, there is no liver damage during SCC intoxication.

Of particular interest is the "ability" of fullerene to interact with free radicals - chemical molecules with unpaired electrons. This is due to the presence of zones of increased electron density on the surface of fullerene molecules and determines the presence of reducing properties and the ability to capture free radicals, which is typical for antioxidants. [Gharbi N., Pressac M., Hadchouel M. et al. [60] fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity // Nano Letters. 2005. V. 5, No. 12. P. 2578-2585]. Results published in 1999 showed that fullerenes have potential as biological antioxidants [Rania Bakry, Rainer M Valiant, Muhammad Najam-ul-Haq, Matthias Rainer, Zoltan Szabo, Christian W. Huck, and Giinther K. Bonn Medicinal applications of fullerenes URL: https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC2676811/]. Fullerenes have a large number of conjugated double bonds and a low-lying vacant molecular orbital (LUMO), which can easily absorb an electron, making it possible for radical particles to attack. The main advantage of using fullerenes as an antioxidant is their ability to localize inside the cell in mitochondria and other parts of the cell compartment, where free radicals are formed in diseased conditions. The activity of this allotropic form of carbon depends on the properties of both the fullerene core and its chemical modification. The fullerene nucleus is hydrophobic; however, by attaching hydrophilic fragments, fullerenes become water-soluble and are able to transfer the necessary active substances for delivery to cells.

Fullerene molecule has a high lipophilicity, which ensures its ability to interact with biological membranes. The mechanism of the virucidal action of fullerene C60 depends on the form of its introduction into the medium. When fullerenes are used with, for example, polyvinylpyrrolidone (C60 / PVP), a damaging effect on the membranes of virions occurs. [Piotrovsky L.B., Kiselev O.I. Fullerenes and viruses // Fullerenes, nanotubes, and carbon nano-structures. - 2004. - Vol. 12. - P. 397-403.] Virion is a full-fledged viral particle consisting of nucleic acid and a capsid (an envelope consisting of protein and, less often, lipids) and located outside a living cell. Virions of most viruses do not show any signs of biological activity until they come into contact with the host cell, after which they form a "virus-cell" complex capable of living and "producing" new virions. When a cell is infected, the virion either introduces into the host cell only its genome (for example, bacteriophages), or penetrates the cell almost completely (most other viruses) [Kartel N.A., Makeeva E.N., Mezenko A.M. Genetics. Encyclopedic Dictionary. - Minsk: Belarusian Science, 2011 .-- 991 p. - ISBN 978-985-08-1311-4.]

So, fullerene C60 easily attaches free radicals, thereby neutralizing them. A number of previous studies have shown that this feature of fullerenes can be used to protect nerve cells from the destructive action of free radicals. The complexes of fullerene C60 with the components of oils have an adsorbing, detoxifying and antidiarrheal effect. Complexes of fullerene C60 with components of oils, absorbs pathogenic strains and their toxins in infectious diseases, such as acute dysentery, salmonellosis, viral hepatitis, typhoid fever, leptospirosis, hemorrhagic fevers, psittacosis. By binding toxins of microbial and endogenous origin, the drug reduces the load on the organs of detoxification and excretion, eliminates diarrhea in acute intestinal diseases (rotavirus gastroenteritis, cholera, staphylococcal enterotoxin poisoning).

Fullerenes, due to their properties, are able to provide protective against free radicals and viruses, antiallergic, immunostimulating effects.

Fullerenes can be used:

- to protect the body from radiation and ultraviolet radiation [Theriot SA, Casey R.C., Moore V.C., Mitchell L., Reynolds J.O., Burgoyne M., et al. (2010). Dendro [C60] fullerene DF-1 provides radioprotection to radiosensitive mammalian cells. Radiat. Environ. Biophys. 49, 437-445]; [Andrievsky G.V., Bruskov V.I., Tykhomyrov A.A., Gudkov S.V. (2009). Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostructures in vitro and in vivo. Free Radic. Biol. Med. 47, 786-793]

- to protect against viruses [Mashino T., Shimotohno K., Ikegami N., et al. (2005). Human immunodeficiency virus-reverse transcriptase inhibition and hepatitis C virus RNA-dependent RNA polymerase inhibition activities of fullerene derivatives. Bioorg. Med. Chem. Lett. 15, 1107-1109] and bacteria [Lu Z.S., Dai T.H., Huang L.Y., et al. (2010). Photodynamic therapy with a cationic functionalized fullerene rescues mice from fatal wound infections. Nanomedicine 5,1525-1533];

- to protect against allergies [Micro RNAs are involved in the regulation of tumor metastasis;]. Thus, in experiments in vivo, the introduction of fullerene derivatives inhibits anaphylaxis in mice, and no toxic effect is observed;

- as a substance that stimulates immunity [XuY.Y., ZhuJ.D., XiangK., LiY.K., SunR.H., MaJ., Etal. (2011). Synthesis and immunomodulatory activity of 60fullerene-tuftsin conjugates. Biomaterials 32, 9940-9949];

- as a powerful antioxidant [Gharbi N., Pressac M., Hadchouel M. et al. (2005). [60] Fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. Nano Lett. 5, 2578-2585], since it is an active radical scavenger. The antioxidant activity of fullerene is comparable to the action of antioxidants of the SkQ class (“ions Skulachev ") and is 100-1000 times higher than the effect of conventional antioxidants such as vitamin E, butylhydroxytoluene, b-carotene;

- as drugs for the fight against cancer [Chen Z., Ma L., Liu Y., Chen S. (2012). Applications of Functionalized Fullerenes in Tumor Theranostics. Theranostics 2, 238-250]; [Jiao F., Liu Y., Qu Y. et al. (2010). Studies on anti- tumor and antimetastatic activities of fullerenol in a mouse breast cancer model. Carbon 48, 2231-2243]

- to inhibit angiogenesis [Meng H., Xing G.M., Sun B.Y., Zhao F., Lei H., Li W., et al. (2010). Potent angiogenesis inhibition by the particulate form of fullerene derivatives. ACS Nano, 4, 2773-2783];

- to protect the brain from the harmful effects of alcohol [Tykhomyrov AA, Nedzvetsky V.S., Klochkov V.K., Andrievsky G.V. (2008). Nanostructures of hydrated C60 fullerene (C60HyFn) protect rat brain against alcohol impact and attenuate behavioral impairments of alcoholized animals. Toxicology 246,158-165]; [Grigoriev B.B., Petrova LN, Ivanova T.A., et al. and Bachurin S.O. (2011). Investigation of the neuroprotective effect of hybrid structures based on C60 fullerene. Izv. RAS Biological Series 2, 163-170]

- to stimulate hair growth [ZhouZ.G., LenkR., DellingerA., MacFarlandD., KumarK., WilsonS.R., Etal. (2009). Fullerene nanomaterials potentiate hair growth. Nanomed. Nanotechnol. Biol. Med. 5, 202-207];

- as a drug with anti-amyloid action in Alzheimer's disease [Bobylev A.G., Kornev A.V., Bobyleva L.G., Shpagina M.D., Fadeeva I.S., Fadeev R.S., et al. (2011). Fullerenolates: metallated polyhydroxylated fullerenes with potent antiamyloid activity. Org. Biomol. Chem. 9, 5714-5719].

In addition to this, fullerene can be used for the delivery of various drugs into the cell [Nanomedicine of the future: transdermal delivery using nanoparticles] and non-viral delivery of genetic vectors into the cell nucleus [Montellano A., Da Ros T., Bianco A., Prato M. (2011) ... Fullerene C (60) as a multifunctional system for drug and gene delivery. Nanoscale 3, 4035-4041]; [Kuznetsova C.A., Oretskaya T.C. (2010). Nanotransport systems for targeted delivery of nucleic acids into cells. Russian nanotechnology 5 (-N ° 9-10), 40-52].

Numerous studies have demonstrated that fullerene (C60) and its derivatives can have potential biomedical applications. It has been found that oral administration of C60 dissolved in olive oil in repeated doses to rats not only does not entail chronic toxicity, but also almost doubles the lifespan of rodents, which can be explained mainly by the weakening of age-related changes associated with oxidative stress. Pharmacokinetic studies have shown that dissolved C60 is absorbed by the gastrointestinal tract and excreted within several tens of hours. These important medical and toxicological findings open the way for many possible and anticipated biomedical applications of C60 [TAREK BAATI et al. The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. Biomaterials 33 (2012) 4936-4946; NAJLA GHARBI et al. [60] Fullerene is a Powerful Antioxidant in Vivo with No Acute or Subacute Toxicity. NanoLett, Vol. 5, No. 12, 2005].

A new mechanism of antioxidant activity of fullerene (C60) was studied based on the absorption of protons and mild uncoupling of mitochondrial respiration and phosphorylation. The hypothesis was confirmed using computer simulations based on density functional theory. The geroprotective activity of C60 was rather higher than that of the most powerful scavengers of reactive oxygen species (ROS). It is assumed that C60 has the ability to acquire a positive charge by absorbing several protons inside itself, and this complex can penetrate into mitochondria. This process allows for gentle separation of respiration and phosphorylation, which in turn leads to a decrease in the production of reactive oxygen species (ROS) [V.A. CHISTYAKOVet al. Possible Mechanisms of Fullerene C60 Antioxidant Action. BioMed Research International 2013 (3): 821498],

Studies of the effect of fullerene (C60) and its derivatives on the suppression of the allergic response have been carried out. Human mast cells (MC) and peripheral blood basophils are critical cells involved in the initiation and propagation of several inflammatory conditions, mainly type I hypersensitivity. An unexpected role of fullerenes has been reported as a negative regulator of allergic mediator release, which suppresses type I hypersensitivity triggered by Ag ions ... Human MS and peripheral blood basophils exhibited significant inhibition of IgE-dependent mediator release upon preincubation with C60. It has been demonstrated on a protein microchip that inhibition of transmitter release is associated with a profound decrease in the activation of signaling molecules involved in transmitter release and oxidative stress. Subsequent studies showed that tyrosine phosphorylation of Syk was dramatically inhibited in cells exposed to Ag, which had previously been incubated with fullerenes. Besides Moreover, preincubation with fullerene significantly inhibited the increase in IgE levels in cytoplasmic reactive oxygen species (ROS). In addition, fullerenes prevented the release of histamine in vivo and lowered the temperature in vivo using an MS-dependent model of anaphylaxis. The disclosed data indicate a new biological function of fullerenes and may represent a new way to combat MC-dependent diseases [JOHN J., RYA N. et al. Fullerene Nanomaterials Inhibit the Allergic Response. J Immunol 2007; 179: 665-672].

The inventors of the present invention have surprisingly found that oral preparations containing C60 and C70 fullerenes have a pronounced local effect.

Oral health is a major indicator of overall health, well-being and quality of life. The World Health Organization defines oral health as “a condition characterized by the absence of chronic pain in the mouth and face, mouth and throat cancer, infections and oral ulcers, periodontal (gum) disease, dental caries, tooth loss and other diseases. and health disorders that limit a person's ability to bite, chew, smile and speak and their psychosocial well-being ”(World Health Organization. World Oral Health Report 2003. Published 2003. Accessed 15 February, 2018). The 2016 Global Burden of Disease Survey estimates that at least 3.58 billion people worldwide are affected by oral diseases [GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1211-1259]. Oral diseases are among the most common noncommunicable diseases (NCDs) and affect people throughout life, causing pain and discomfort and leading to disfigurement and even death [Petersen PE, Bourgeois D, Ogawa H, Estupinan-Day S, Ndiaye C . The global burden of oral diseases and risks to oral health. Bull World Health Organ 2005; 83 (9): 661-669].

Oral diseases disproportionately affect the poor and marginalized in society. There is a very strong and consistent relationship between socioeconomic status (income, occupation and educational level) and the prevalence and severity of oral diseases. (Health issues. World Health Organization URL: https: //www.who.int/mediacentre/factsheets / fs318 / ru /). Due to the fact that social determinants have a significant impact on the health of the oral cavity, the recommendations of doctors on a balanced diet do not have the desired effect (due to the high cost of the corresponding food for a significant number of people).

The combination of antioxidant, immunostimulating and cleansing effects in a product designed for the oral cavity will solve the problem of an affordable multifunctional product. This is the body's defense against free radicals, stimulation of local immunity, elimination of toxins from the body through the oral mucosa. The introduction of fullerenes into these agents will create a multifunctional product aimed at preventing health and minimizing the incidence of oral diseases. Previously, such a solution based on fullerenes was not available to the consumer in the form of a commercial product on the market, and was also not known to the professional community from scientific publications. The following are the closest analogs known to the authors of the present invention from the prior art.

The publication of US Patent Application US2006093561A1 (publ. 05/04/2006) discloses a method of treating diseases caused by microorganisms in the oral cavity, including the stages:

1. applying the photosensitizer to periodontal pockets in the mouth;

2. application of the photosensitizer to the inner surface of the oral cavity, outer to periodontal pockets;

3. waiting for a given period of time;

4. irradiating the entire inner part of the mouth with incoherent light having a wavelength spectrum absorbed by the photosensitizer at a given light intensity and for a given period of time.

The photosensitizer is proposed to be selected from a variety of compounds, including toluidine blue, methylene blue, other molecules, as well as photoactive fullerenes such as C 16-b. The term "photosensitizer" refers to a molecule that absorbs light in order to become excited, highly reactive, which allows it to catalyze the formation of reactive oxygen species (ROS), which are capable of destroying cell membranes and DNA.

In the publication of International application WO0228222A1 (publ. 11.04.2002) discloses a brush for use in brushing teeth, containing bristles obtained from a composition containing a thermoplastic polymer resin in a mixture with an antifriction additive. Anti-friction additive for use in the disclosed invention may be any substance that will reduce the coefficient of friction experienced by the resulting floss when in contact with a tooth — when the floss is used as a bristle in a toothbrush. The antifriction additive can be a fluorinated olefin polymer, boron nitride, molybdenum disulfide, graphites, fullerene, and talc.

In the publication of International Application W02006001784A1 (publ. 01/05/2006) discloses a cosmetic composition that contains a cosmetically effective amount of fullerene clusters in combination with a cosmetically acceptable carrier. The term "cluster" refers to a small assembly of fullerene molecules held together by van der Waals forces. The size of this assembly can range from a few fullerene molecules to about a billion. The internal structure of the clusters, apparently, is close to the internal structure of molecular fullerene crystals. Various forms of clusters are possible, depending on the cluster size and interaction with the environment. Clusters can be solvated with solvent molecules, thus forming non-ideal fullerene solutions, similar in nature to stable sols and suspensions. Clusters can form donor-acceptor complexes with certain organic molecules (ligands) that are soluble in polar solvents of interest. Both solvate and complex fullerene clusters are used. It is disclosed that the clusters can be used as therapeutic or prophylactic agents with antimicrobial activity. The term "antibacterial effect" means that bacterial growth is suppressed or bacteria are destroyed. Accordingly, the invention relates to the use of fullerene clusters for preventing or treating the growth of bacteria on body surfaces such as skin, mucosal surfaces, nails or teeth.

Directly in oral care products, fullerenes form a film using, for example, oils, water or polyvinylpyrrolidone, which prevents the growth of bacteria. Also, due to the ability of fullerenes to bind free radicals, they exhibit an antioxidant effect. Fullerenes are able to reduce the body's allergic reactions due to their ability to bind food allergens contained in essential oils and other products, circulating immune complexes and bacterial antigens, which leads to an increase in the local immunity of the oral cavity and an increase in the number of T-lymphocytes, and a decrease in edema. Since the oral mucosa has a high degree of permeability to fullerenes, the effect is achieved faster. [Toxicological- hygienic characteristics of iC60 modified fullerenol. Consortium Megotrend PANATSEIA LLC 07/03/2014.

URL: http: // storagel .moguza.ru / _other / eb / 53 / eba53d7738cc523e.pdf].

The proposed solution makes a significant step in the field of oral care products due to the inclusion of fullerenes in the composition of toothpastes and other oral care products, which leads to significant effects, such as antibacterial, antioxidant and antiallergic.

SUMMARY OF THE INVENTION

The claimed product for oral hygiene containing fullerene. The tool can be designed for the care of the teeth and / or the oral cavity. The specified fullerene can be a C60 fullerene or a fullerene

C70.

Said fullerene may be present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably from about 0.0001 to about 7 wt%, more preferably from about 0.0001 to about 6 wt%, more preferably from about 0.0001 to about 5 wt%, more preferably from about 0.0001 to about 4 wt%, more preferably from about 0 0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1 wt%, more preferably from about 0.0001 to about 0.01 wt%.

The specified fullerene may be contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about

2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about

4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about

6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

The specified fullerene can be contained in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25,

1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt. The tool may additionally contain at least one bacterial lysate with therapeutic activity against bacteria in the oral cavity, and / or an extract of emblica fruit (Phyllanthus Emblica fruit extract), and / or an extract of rose hips (Rosa Canina Fruit extract), and / or an essential bergamot oil (Citrus Aurantium Bergamia essential oil) and / or grapefruit essential oil (Citrus Paradisi essential oil) and / or coniferous chlorophyll-carotene paste and / or tranexamic acid and / or dihydroquercetin and / or subtilisin or mixtures thereof ...

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin may be present in an amount of from about 0.0001 to about 10% by weight, more preferably from about 0.0001 to about 9% by weight, more preferably from about 0.0001 to about 8% wt%, more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 up to about 0.1 wt%, more preferably from about 0.0001 to about about 0.01% wt.

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin can be contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075 , about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7 , 25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about about 9.5, about 9.75, or about 10% wt.

Said at least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosehip extract (Rosa Canina Fruit extract), essential oil of bergamot (Citrus Aurantium Bergamia essential oil), essential oil of grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin can be contained in an amount of 0.0001, 0.00025, 0 , 0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1 , 25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5,

3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5,

8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

The agent can be in the form of a toothpaste, mouthwash, chewing gum for dental and oral care, foam, serum, aerosol, oral strip, ointment, irrigator fluid, tooth powder.

Also claimed is an oral hygiene product containing a combination of fullerene, totarol and bisabolol.

The tool can be designed for the care of the teeth and / or the oral cavity. The specified fullerene can be a C60 fullerene or a fullerene

C70.

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

The specified fullerene can be contained in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

Said totalarol may be present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably from about 0.0001 to about 7 wt%, more preferably from about 0.0001 to about 6 wt%, more preferably from about 0.0001 to about 5 wt%, more preferably from about 0.0001 to about 4 wt%, more preferably from about 0 0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1 wt%, more preferably from about 0.0001 to about 0.01 wt%.

The specified totalarol may be contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

The specified totalarol can be contained in the amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25,

1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

Said bisabolol may be present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably from about 0.0001 to about 7 wt%, more preferably from about 0.0001 to about 6 wt%, more preferably from about 0.0001 to about 5 wt%, more preferably from about 0.0001 to about 4 wt%, more preferably from about 0 0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1 wt%, more preferably from about 0.0001 to about 0.01 wt%.

Said bisabolol may be present in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

The specified bisabolol can be contained in the amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25,

The tool may additionally contain at least one bacterial lysate with therapeutic activity against bacteria in the oral cavity, and / or an extract of emblica fruit (Phyllanthus Emblica fruit extract), and / or an extract of rose hips (Rosa Canina Fruit extract), and / or an essential bergamot oil (Citrus Aurantium Bergamia essential oil) and / or grapefruit essential oil (Citrus Paradisi essential oil) and / or coniferous chlorophyll-carotene paste and / or tranexamic acid and / or dihydroquercetin and / or subtilisin or mixtures thereof ...

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin can be contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0, 75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5 , about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin can be contained in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0 .05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3 , 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5 , 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5,

8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

The use of fullerene for the manufacture of oral hygiene products is also claimed. The oral hygiene product can be designed to care for the teeth and / or the oral cavity. Fullerene can be C60 fullerene or C70 fullerene.

Also claimed is the use of a combination of fullerene, totalarol and bisabolol for the manufacture of oral hygiene products. The oral hygiene product can be designed to care for the teeth and / or the oral cavity. Fullerene can be C60 fullerene or C70 fullerene.

DETAILED DESCRIPTION OF THE INVENTION

The following description of a group of inventions is intended to disclose their essential aspects, taking into account the fact that a person skilled in the art can independently implement various embodiments of the claimed invention.

The term "about" means a margin of error of ± 10%. In other words, if the feature is "about 2 wt%", it covers values from 1.8 to 2.2 wt%. In a first aspect, the invention relates to an oral hygiene product containing fullerene.

The tool can be designed for the care of the teeth and / or the oral cavity.

The specified fullerene can be a C60 fullerene or a C70 fullerene or a modified C60 fullerene or a modified C70 fullerene. Fullerenes are commercially available products and can be purchased, for example, from SES Research Inc (Houston, USA) under cat numbers 600-9975, 600-998, 600-9995, 600-9999, 700-9854, 700-9999

(URL: https: //www.sesres.com/fullerene/). It should be noted that the beneficial effects of the introduction of fullerenes are due to their unique structure, which is disclosed or follows from the following illustrative examples, therefore, within the scope of the invention are fullerene C60 and its derivatives, modifications, etc. and fullerene C60 and its derivatives, modifications, and the like, where the modifications are generally due to imparting additional positive properties to the fullerene in addition to the aforementioned beneficial effects that are within the scope of the invention.

Said fullerene may be present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably from about 0.0001 to about 7 wt%, preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1 wt%, more preferably about 0 , 0001 to about 0.01% wt.

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

The specified fullerene can be contained in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8, 5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

The agent may additionally contain at least one bacterial lysate having therapeutic activity against bacteria in the oral cavity (in other words, the agent may additionally contain bacterial lysates, i.e. a mixture of lysates), and / or an extract of emblica fruits (Phyllanthus Emblica fruit extract) , and / or rosehip extract (Rosa Canina Fruit extract), and / or bergamot essential oil (Citrus Aurantium Bergamia essential oil), and / or grapefruit essential oil (Citrus Paradisi essential oil), and / or coniferous chlorophyll-carotene paste, and / or tranexamic acid and / or dihydroquercetin and / or subtilisin or mixtures thereof.

Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Citrus Paradisi essential oil, coniferous chlorophyll-carotene paste, like tranexamic acid, dihydroquercetin, subtilisin are commercially available products.

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin may be present in an amount of from about 0.0001 to about 10% by weight, more preferably from about 0.0001 to about 9% by weight, more preferably from about 0.0001 to about 8% wt%, more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt% wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1% wt., Preferably from about 0.0001 to about about 0.01% wt.

At least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Citrus Aurantium Bergamia essential oil, Grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin can be contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075 , about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2 , 25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7 , 75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

In a second aspect, the invention relates to an oral hygiene product comprising fullerene and, additionally, a combination of totarol and bisabolol.

Totarol and bisabolol are commercially available products.

2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5,

6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

Said bisabolol may be present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably from about 0.0001 to about 7 wt%, preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0.1 wt%, more preferably about 0.0001 up to about 0.01% wt.

8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

1.5. 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5,

6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

In a third aspect, the invention relates to the use of fullerene for the manufacture of an oral hygiene product.

In a fourth aspect, the invention relates to the use of a combination of fullerene, totarol and bisabolol for the manufacture of an oral hygiene product.

Thus, the invention relates to innovative oral care products containing fullerene. The present inventors have developed a series of fullerene-based products.

Rinse for oral cavity care.

The mouthwash is intended for use after brushing your teeth with a toothpaste for complex oral care. Use involves rinsing the mouth for 10-30 seconds and then spitting out.

Fullerene suitable for use in the invention can be a C60 fullerene or a C70 fullerene, where the numbers 60 and 70 indicate the number of carbon atoms. Fullerene can be contained in the mouthwash for the care of the oral cavity in an amount of 0.001-4 wt%, preferably 0.01-4 wt%, or 0.01-4 wt%, or 0.1-4 wt%., or 1-4% May., or 2-3% May., for example, in an amount of about 0.001, about 0.005, about 0.007, about 0.009, about 0.01, about 0.03, about 0.05, about 0, 1, about 0.5, about 1, about 2, about 3, or about 4 wt%.

The mouthwash may additionally contain bacterial lysates having therapeutic activity against oral bacteria. Such lysates are known to those skilled in the art and may be selected from lysates, for example B. longum, B. bifidum, B. Adolescentis, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus bulgaricus, Str.Thermophilus.

The mouthwash may further comprise mixtures of any of: bacterial lysates having therapeutic activity against oral bacteria; extract of fruit emblica (Phyllanthus emblica fhiit extract); rosehip fruit extract (Rosa Canina Fruit extract); essential oil of bergamot (Citrus aurantium bergamia essential oil); grapefruit essential oil (Citrus paradisi essential oil); coniferous chlorophyll-carotene paste; tranexamic acid; dihydroquercetin; subtilisin.

Bacterial lysates can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-5 wt%, or 0.001-5 wt%, or 0.01-5 wt%, or 0.1-5% May., or 1-5% May., or 2-4% May., in such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0, 5, 1, 2, 3, 4 or 5% May.

The emblica fruit extract can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-4 wt%, or 0.001-4 wt%, or 0.01-4 wt%, or 0.1-4 % May., or 1-4% May., or 2-3% May., in such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0 , 5, 1, 2, 3 or 4% May. Rosehip fruit extract may be contained in an amount of 0.0001-6 wt%, preferably 0.0001-5.5 wt%, or 0.001-5.5 wt%, or 0.01-5.5 wt%, or 0.1 -

5.5 wt.%, Or 1-5.5 wt.%, Or 2-4 wt.%, In an amount such as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0, 1, 0.5, 1, 2, 3, 4, 5 or 5.5% May.

Bergamot essential oil can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-2 wt%, or 0.001-2 wt%, or 0.01-2 wt%, or 0.1-2 wt%, or 1-2 wt%, in an amount such as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 2 wt% ...

The essential oil of grapefruit can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-2 wt%, or 0.001-2 wt%, or 0.01-2 wt%, or 0.1-2 % May., or 1-2% May., in such quantities as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 2% May ...

Coniferous chlorophyll carotene paste can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-5 wt%, or 0.001-5 wt%, or 0.01-5 wt%, or 0.1-5 % May., or 1-5% May., or 2-4% May., in such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0 , 5, 1, 2, 3, 4 or 5% May.

Tranexamic acid can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-3.5 wt%, or 0.001-3.5 wt%, or 0.01-3.5 wt%, or 0.1-

3.5% wt., Or 1-3.5% wt., Or 2-3% wt., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0, 1, 0.5, 1, 2, 3 or 3.5% May.

Dihydroquercetin may be contained in an amount of 0.0001-6 wt%, preferably 0.0001-1.5 wt%, or 0.001-1.5 wt%, or 0.01-1.5 wt%, or 0 ,one-

1.5 wt%, or 1-1.5 wt%, in an amount such as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 1.5% wt.

Subtilisin can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-1.5 wt%, or 0.001-1.5 wt%, or 0.01-1.5 wt%, or 0 , 1-1.5% wt., Or 1-

1.5% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 1.5% May.

Toothpaste.

The toothpaste can be for the care of the teeth and / or the oral cavity. Dental care involves the application of toothpaste to the teeth, brushing the teeth as is customary in everyday life to achieve the results usually associated with any toothpaste and tooth brushing. Getting into the cavity mouth, the components of the toothpaste inevitably come into contact not only with the surface of the teeth, but also with other parts of the oral cavity.

Fullerene suitable for use in the invention can be a C60 fullerene or a C70 fullerene, where 60 and 70 indicate the number of carbon atoms. Fullerene can be contained in the toothpaste in an amount of 0.001-4% wt., Preferably 0.01-4% wt., Or 0.01-4% wt., Or 0.1-4% wt., Or 1-4 wt%, or 2-3 wt%, for example, in an amount of about 0.001, about 0.005, about 0.007, about 0.009, about 0.01, about 0.03, about 0.05, about 0.1, about 0 , 5, about 1, about 2, about 3, or about 4 wt%.

The toothpaste may additionally contain bacterial lysates having therapeutic activity against oral bacteria. Such lysates are known to those skilled in the art and can be selected from lysates, for example B.longum, B.bifidum, B.Adolescentis, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus bulgaricus, Str. Thermophilus.

The toothpaste may additionally contain an extract of emblica fruit (INCI: Phyllanthus emblica fhxit extract), which is a commercially available product.

The toothpaste may additionally contain rosehip extract (INCI: Rosa Canina Fruit extract), which is a commercially available product.

The toothpaste may additionally contain bergamot essential oil (INCI: Citrus aurantium bergamia essentiall oil), which is a commercially available product.

The toothpaste may additionally contain grapefruit essential oil (INCI: Citrus paradisi essential oil), which is a commercially available product.

The toothpaste may further comprise a commercially available coniferous chlorophyll-carotene paste.

The toothpaste may additionally contain tranexamic acid (CAS 1197-18-8), which is a commercially available product.

The toothpaste may additionally contain dihydroquercetin (CAS 480-18-2), which is a commercially available product.

The toothpaste may additionally contain subtilisin, which is a commercially available product.

The toothpaste may additionally contain mixtures of any of:

- bacterial lysates with therapeutic activity against bacteria in the oral cavity;

- extract of emblica fruits (Phyllanthus emblica fruit extract); - rosehip fruit extract (Rosa Canina Fruit extract);

- essential oil of bergamot (Citrus aurantium bergamia essential oil);

- grapefruit essential oil (Citrus paradisi essential oil);

- coniferous chlorophyll-carotene paste;

- tranexamic acid; dihydroquercetin; subtilisin.

The emblica fruit extract can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-4 wt%, or 0.001-4 wt%, or 0.01-4 wt%, or 0.1-4 % May., or 1-4% May., or 2-3% May., in such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0 , 5, 1, 2, 3 or 4% May.

Rosehip fruit extract can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-5.5 wt%, or 0.001-5.5 wt%, or 0.01-5.5 wt%, or 0.1 -

5.5% May., Or 1-5.5% May., Or 2-4% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0, 1, 0.5, 1, 2, 3, 4, 5 or 5.5% May.

Bergamot essential oil can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-2 wt%, or 0.001-2 wt%, or 0.01-2 wt%, or 0.1-2 % May., or 1-2% May., in such quantities as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 2% May ...

Coniferous chlorophyll-carotene paste can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-5 wt%, or 0.001-5 wt%, or 0.01-5 wt%, or 0.1 -5% May., Or 1-5% May., Or 2-4% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1 , 0.5, 1, 2, 3, 4 or 5% May.

Tranexamic acid may be present in an amount of 0.0001-6 wt%, preferably 0.0001-3.5 wt%, or 0.001-3.5 wt%, or 0.01-3.5 wt%, or 0.1—

3.5% May., Or 1-3.5% May., Or 2-3% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0, 1, 0.5, 1, 2, 3 or 3.5% May.

Dihydroquercetin may be present in an amount of 0.0001-6 wt%, preferably 0.0001-1.5 wt%, or 0.001-1.5 wt%, or 0.01-1.5 wt%, or 0 ,one- 1.5% May., Or 1-1.5% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 or 1.5% May.

Subtilisin can be contained in an amount of 0.0001-6 wt%, preferably 0.0001-1.5 wt%, or 0.001-1.5 wt%, or 0.01-1.5 wt%, or 0 , 1-1.5% May., Or 1-1.5% May., In such an amount as about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0 ,five,

1 or 1.5% May.

The present invention also relates to innovative toothpastes containing a combination of fullerene, totarol and bisabolol.

As noted above, fullerene is an allotropic modification of carbon.

Totarol (CAS 511-15-9) is (4b8) -trans-8,8-trimethyl-4b, 5,6,7,8,8a, 9,10-octahydro-1-isopropylphenanthrene-2-ol - biologically active diterpene approved for use in cosmetics and personal care products. It is a commercially available product.

Bisabolol (a-bisabolol, levomenol; CAS 23089-26-1) is 6-methyl-2- (4-methylcyclohex-3-en-1-yl) hept-5-en-2-ol is a biologically active compound, approved for use in cosmetics and personal care products. It is a commercially available product.

The inclusion of a combination of fullerene, totarol and bisabolol in the toothpaste composition allows achieving the effects detailed below.

The present invention also relates to a new use of fullerene for the manufacture of oral care products such as, for example, toothpaste and mouthwash.

The present invention also relates to a novel use of a combination of fullerene, totarol and bisabolol for the manufacture of oral care products such as, for example, toothpaste and mouthwash.

EXAMPLES

The toothpaste was prepared as follows: humectants, for example, glycerin, sorbitol, polyethylene glycol, were dispersed in water with stirring in an ordinary mixer. Thickeners, surfactants, foam stabilizers, acid or base to adjust the pH, sweetener were added to the mixture. The ingredients were mixed until a homogeneous phase was obtained. Then the mixture was transferred to a high-speed vacuum mixer, in which to the mixture was added an inorganic silica thickener. Compositions of toothpastes for the studied components are presented in Table JSfel.

Table l. Toothpaste formulations for clinical trials

Clinical studies have been conducted to evaluate the effectiveness of the compositions of the invention.

Example 1.

In the experimental groups, patients used fullerene C60 or C70 with additives in the toothpaste, and the effectiveness of the complex was assessed using various indices. The common indicator is the oral hygiene index, since improper brushing of the teeth contributes to caries and a pronounced inflammatory process of the gums.

As a base for the inclusion of fullerene C60 or C70, a toothpaste with the composition given in Table Ml was used.

To determine the cleansing effect of a toothpaste containing C60 or C70 fullerene, a single-center, prospective, randomized study in 100 subjects was performed. The subjects were divided into 5 groups of 20 people each. The distribution into groups took place randomly, in accordance with the randomization list. Each group used a toothpaste with one of the formulations according to Table Ml. The toothpastes were used by volunteers on their own twice a day (morning and evening) for 28 days. After the initial examination, follow-up examinations were carried out once a week on days 7, 14 and 21 of the study. During control dental examinations, the state of hygiene of the oral cavity, hard tissues of teeth, periodontal tissues and oral mucosa were determined.

The parameter for the overall assessment of the effectiveness of plaque removal by the composition was the hygiene index (Green-Vermillion index), determined by the dentist during the visit of patients using indicator tablets by PARO. The general positive trend in the use of toothpaste with fullerene is a gentle and effective cleaning of teeth from dental plaque.

According to the Green-Vermillion hygiene index, the cleansing effect was determined by the formula:

Effect (%) = [100% x [(HGS-GPI) / IG _o]] where

IGo-average digital index of the index at the beginning of the study before the hygienic procedure;

IGP is the average digital index of the index after n-number of weeks of the study at the last examination.

For all quantitative data, the group arithmetic mean (M), median (Me), standard deviation (SD) and standard error of the mean (SEM) were calculated. The results were processed using the IBM SPSS Statistics 22.0 software (StatSoft, Russia). The likelihood of differences in the mean values at different points in time was determined using the ANOVA test for dependent samples. The likelihood of differences in mean indices in the groups was determined using the Mann-Whitney test. Differences were considered significant at a significance level of p <0.05.

Results.

4 weeks after the start of use, pronounced changes in the estimated indicator were observed. After brushing teeth with toothpastes with fullerene for 1 week, the average value of the oral hygiene index was 2.26 + 0.64 and improved compared to the initial indicator by an average of 40.68%. At the end of the use of toothpastes for 2 and 3 weeks, the average values of the oral hygiene index were 1.96 + 0.59 and 1.49 + 0.50, respectively. Thus, after 4 weeks of using toothpastes with fullerene (C60 or C70), oral hygiene improved by 68.51% in all patients. In one of the groups, there was a decrease in the index of oral hygiene by 73.56%, which indicates a pronounced cleansing effect of the studied toothpastes. Taking into account the high values of the oral hygiene indices at the initial stage of the study, it can be concluded that the tooth enamel is significantly cleared. Toothpastes are used daily, so oral hygiene will improve in the long term.

Samples B and D showed the highest cleansing effect, while the hygiene index changed positively by 3.4 times compared to the initial value of the oral hygiene index. Dental samples pastes A and C showed a 3-fold improvement in the Green-Vermillion index (Table .Ne2).

Table N ° 2. Oral hygiene index values (Green-Vermillion index)

The use of toothpastes with fullerene led to effective cleaning of tooth enamel, which indicates the removal of most of the plaque, which is a causative factor in the development of inflammation of the gums and the oral cavity in general. The base of the compositions cleared soft plaque and increased the access of fullerene to hard-to-reach periodontal joints, thereby increasing the effectiveness of the active ingredient. The compositions contain fullerene, which interacts with plaque proteins and promotes their loosening for better removal from the tooth enamel surface.

Example 2.

In the experimental groups, patients used fullerene C60 or C70 with additives in the toothpaste, and the effectiveness of the complex was assessed using the index of intensity of tooth hyperesthesia. Since in inflammatory diseases of the gums, the level of pain sensitivity to various stimuli (temperature, tactile, chemical) is increased, a decrease in the sensitivity of the gums will help to improve the course of inflammatory diseases of the oral cavity and the patient's quality of life as a whole.

As a base for the inclusion of fullerene C60 or C70, a toothpaste with the composition given in Table N ° l was used.

To determine the desensitive effect of a toothpaste containing C60 or C70 fullerene, a single-center, prospective, randomized study in 100 subjects was performed. The subjects were divided into 5 groups of 20 people each. The distribution into groups took place randomly, in accordance with the randomization list. Each group used a toothpaste with one of the formulations according to Table Nil. The toothpastes were used by volunteers independently twice a day (morning and evening) for 28 days. After the initial examination, repeated examinations were carried out once on the 7th day of the study.

The parameters for assessing the desensitive effect of the composition were the Schiff index, determined by the dentist during control dental examinations of patients, and the patient's subjective assessment of the severity of hyperesthesia in the areas of gingival recession before and at different times of the use of toothpaste with fullerene. A general positive trend in the use of toothpaste with fullerene is a decrease in the sensitivity of inflamed gums and teeth.

The Schiff air test is carried out as follows: air from a pistol of the dental unit is supplied perpendicular to the cervical surface of the tooth from a distance of 1 cm for a second (under a pressure of 40-60 psi) at a temperature of 21 degrees Celsius. Tooth sensitivity is assessed using the following criteria: 0 - no response; 1 - a feeling of discomfort, but the patient does not insist on stopping the test; 2 - discomfort accompanied by a request to stop the test; 3 - severe pain reaction with pronounced motor responses aimed at immediate termination of the test. The determination of the Schiff index was carried out in patients of the observation and comparison groups after 2 and 4 weeks.

Each patient noted their feelings after using a toothpaste with fullerene, in accordance with which subjective assessments of the severity of tooth sensitivity were given in points from 0 to 10.

Results.

An assessment of the prevalence of tooth hypersensitivity according to the Schiff index revealed that toothpastes reduced tooth sensitivity after 1 week of use by an average of 25%. According to the subjective estimates of the patients themselves, the increased sensitivity of the teeth decreased by 31%. Thus, after 4 weeks of using toothpastes with fullerene (C60 or C70), dental hyperesthesia in all patients decreased by 45% according to dental tests. The patients themselves noted reduction of tooth sensitivity by an average of 61%. In one of the groups, a decrease in tooth sensitivity by 86.1% was noted, which indicates a pronounced desensitive effect of the studied toothpastes. Desensitization of the teeth is a long-term process due to prolonged remineralization of enamel, prolonged penetration of active substances into the dentinal tubules of the tooth and a decrease in the severity of gum inflammation (Table 3).

Table N ° 3. Teeth sensitivity index values based on diagnostic tests

The use of toothpastes with fullerene led to an effective decrease in tooth sensitivity, which indicates an anti-inflammatory effect in oral diseases such as gingivitis and periodontitis. The products reduced tooth sensitivity to normal.

The base of the compositions cleared soft plaque and increased the access of fullerene to hard-to-reach periodontal joints, thereby increasing the effectiveness of the active component. Since the compositions contain fullerene with an antioxidant effect, the amount of reactive oxygen species at the site of inflammation decreased. Free radicals have the ability to lower the activation threshold of nonmyelinated sensitive C-fibers, thereby increasing pain sensitivity at the site of inflammation. Fullerene, due to its special molecular structure, has the ability to stabilize free radicals and prevent the activation of painful nerve fibers.

Example 3.

In the experimental groups, patients used fullerene C60 or C70 with additives in the toothpaste, and the effectiveness of the complex was assessed using the PMA index. Since gingivitis and periodontitis are inflammatory diseases of the gums and periodontal joints, a decrease in the severity of inflammation will help reduce pain and the quality of life of the patient as a whole.

As a base for the inclusion of fullerene C60 or C70, we used a toothpaste with the composition shown in Table Nel.

To determine the anti-inflammatory effect of a toothpaste containing C60 or C70 fullerene, a single-center, prospective, randomized study in 100 subjects was performed. The subjects were divided into 5 groups of 20 people each. The distribution into groups took place randomly, in accordance with the randomization list. Each group used a toothpaste with one of the formulations according to Table JVsl. The toothpastes were used by volunteers on their own twice a day (morning and evening) for 28 days. After the initial examination, follow-up examinations were carried out once a week on days 7, 14 and 21 of the study.

The parameter for assessing the anti-inflammatory effect of the composition was the PMA index, determined by a dentist during control dental examinations of patients. On the basis of the obtained results of PMA indices, the anti-inflammatory efficacy was determined, which indicated the nature of changes in the inflammatory process in the periodontium.

Anti-inflammatory efficacy was determined by the formula:

Anti-inflammatory efficacy (%) = [100% x (PMAo-PMA _n )] / PMAo where

PMAo - average digital index of the index before the start of the study;

PMAp - the average digital index of the index after n-number of weeks of the study, at the last examination.

A general positive trend in the use of a toothpaste with fullerene is a decrease in gum inflammation.

For all quantitative data, the group arithmetic mean (M), median (Me), standard deviation (SD) and standard error of the mean (SEM) were calculated. The results were processed using the IBM SPSS Statistics 22.0 software (StatSoft, Russia). The likelihood of differences in the mean values at different points in time was determined using the ANOVA test for dependent samples. The likelihood of differences in mean indices in the groups was determined using the Mann-Whitney test. Differences were considered significant at a significance level of p <0.05. Results.

4 weeks after the start of use, pronounced changes in the estimated indicator were observed. Assessment of the anti-inflammatory effect by the PMA index revealed that toothpastes reduced the severity of gum inflammation after 1 week of use by an average of 23.8%. After the end of the use of toothpastes for 2 and 3 weeks, the average values of the PMA index decreased on average by 35% and 52%, respectively. Thus, after 4 weeks of using toothpastes with fullerene (C60 or C70), gum inflammation in all patients decreased by an average of 78%. In one of the groups, a decrease in the sensitivity of the teeth by 90.2% was noted, which indicates a pronounced anti-inflammatory effect of the studied toothpastes (Table N ° 4).

Table X ° 4. Anti-inflammatory index values (PMA index)

The use of toothpastes with fullerene led to an effective decrease in the severity of inflammation, which indicates an anti-inflammatory effect in such diseases of the oral cavity as gingivitis and periodontitis.

The base of the toothpaste gently cleaned soft plaque and increased the access of fullerene to hard-to-reach periodontal joints, thereby increasing its effectiveness. Fullerene stabilizes reactive oxygen species at the site of inflammation during oxidative stress, contributing to the prolonged restoration of the redox balance in the gum tissue. Fullerene has zones of increased electron density on the surface of molecules, which determines the reducing properties and the ability to capture free radicals. Also, fullerene C60 has the ability to protonate and acquire a positive charge, which allows it to penetrate into the mitochondrial matrix and uncouple respiration and oxidative phosphorylation. Stabilization and reduction of free radical synthesis prevents lipid peroxidation (LPO). Reducing the severity of inflammation helps to reduce sensitivity of teeth, their bleeding and improvement of the quality of life of patients in general.

Example 4.

In the experimental groups, patients used fullerene C60 or C70 with additives in the toothpaste, and the effectiveness of the complex was assessed using the SBI bleeding index according to Muhlemann and Son. Since gingivitis and periodontitis are inflammatory diseases of the gums with visible bleeding, reducing the bleeding of the gums will help stop the inflammation and improve the patient's overall quality of life.

To determine the anti-inflammatory effect of a toothpaste containing C60 or C70 fullerene, a single-center, prospective, randomized study in 100 subjects was performed. The subjects were divided into 5 groups of 20 people each. The distribution into groups took place randomly, in accordance with the randomization list. Each group used a toothpaste with one of the formulations according to Table Nsl. The toothpastes were used by volunteers on their own twice a day (morning and evening) for 28 days. After the initial examination, follow-up examinations were carried out once a week on days 7, 14 and 21 of the study.

The parameter for assessing the hemostatic and, in general, anti-inflammatory effect of the composition was the gingival bleeding index SBI according to Muhlemann and Son, determined by a dentist during control dental examinations of patients. Based on the results of the bleeding index, the hemostatic efficiency was determined, which directly indicated the nature of the change in the inflammatory process in the periodontium.

Hemostatic efficacy was determined by the formula:

Hemostatic efficiency (%) = [100% x (IRo-IR _p )] / IRo where

IR-average digital index before the start of the study;

IR _{n is the} average digital index of the index after n-weeks of the study, at the last examination. A general positive trend in the use of a toothpaste with fullerene is a decrease in gum bleeding.

Results.

4 weeks after the start of use, pronounced changes in the estimated indicator were observed. Assessment of the haemostatic effect by the SBI index revealed that the toothpastes reduced gum bleeding after 1 week of use by an average of 23%. At the end of the use of toothpastes for 2 and 3 weeks, the average values of the SBI index decreased on average by 36% and 52%, respectively. Thus, after 4 weeks of using toothpastes with fullerene (C60 or C70), bleeding of the gums in all patients decreased on average by 77%. In one of the groups, a decrease in bleeding of the inflamed gum tissue by 91.2% was noted, which indicates a pronounced anti-inflammatory effect of the studied toothpastes. The research results correlate with the anti-inflammatory effect, which indicates the complex effect of toothpastes containing fullerene (Table M 5).

Table X ° 5. The values of the gingival bleeding index SBI according to Muhlemann and Son

The use of a toothpaste with fullerene C60 or C70 led to an effective decrease in bleeding, which indicates a hemostatic effect in inflammatory diseases of the oral cavity, for example, gingivitis and periodontitis.

The base of the compositions cleared soft plaque and increased the access of fullerene to hard-to-reach periodontal joints, thereby increasing the efficiency active component. Since the compositions contain fullerene with an anti-inflammatory effect due to stabilization and neutralization of ROS (superoxide anion radical O and hydroxide radical OH) under oxidative stress, prolonged use decreased the degree of inflammation of the oral cavity.

One of the manifestations of gum inflammation is their bleeding, therefore, to reduce the severity of inflammation, it is necessary to use compositions with a hemostatic effect.

Thus, the results obtained clearly demonstrate the effectiveness of the toothpastes according to the invention and confirm their pronounced cleansing, desensitive, anti-inflammatory and hemostatic effects.

Example 5.

A preclinical study of the antioxidant effect of fullerene toothpastes was carried out. The method of analysis is that 5 g of toothpaste was mixed with 50 ml of 95% ethanol, filtered into a 100 ml volumetric flask, brought to the mark and mixed. 10 ml of distilled water, 1 ml of 20% sulfuric acid solution, 1 ml of 0.05 M potassium permanganate solution were added to a titration glass with a capacity of 50 ml, stirred and titrated with a filtrate solution until discoloration. Thus, an indirect titration was carried out, in which the filtrate with fullerene acted as the titrant.

The calculation of the antioxidant activity (AOA), corresponding to the concentration of biologically active substances of the toothpaste of a reducing nature in terms of the sample consumed for the titration of 1 ml of 0.05 M potassium permanganate solution, mg / g, was carried out according to the formula:

AOA (mg / g) = Vi * 0, 0077125 * 1000 / m * 100 where

V, is the volume of the filtrate solution used for titration of 0.05 M potassium permanganate solution, in ml; m is the mass of the sample of toothpaste, in g;

0.008506 - the amount of biologically active substances of a toothpaste of a restorative nature, calculated per sample, corresponding to 1 ml of 0.05 M potassium permanganate solution, in g.

6.2 x 0.008506 x 1000 AOA (mg / g) = = 0.10547 (mg / g)

5.0 x 100

The calculation of the antioxidant efficiency (AOE) was carried out according to the formula:

AOE (%) = Vi х 100% / V _k , where

AOE - antioxidant effectiveness of toothpaste, expressed in%;

Vk is the volume of the sample solution used for titration of 0.05 M potassium permanganate solution, in ml;

Vi is the volume of the filtrate solution used for titration of 0.05 M potassium permanganate solution, in ml.

6.2 x 100%

AEO (%) = - = 93.93 (%)

6.6

Fullerenes in the toothpaste have a pronounced antioxidant effect due to their strong regenerative properties and a special distribution of electron density in the molecule orbitals. Toothpaste with fullerene reduces the amount of free radicals and oxidants by 93.93%, which confirms the pronounced anti-inflammatory and antioxidant effects identified in clinical trials. An antioxidant effect is essential to reduce oxidative stress and maintain oral health.

Fullerenes can also be used in the development of mouth rinses. It should be noted that fullerenes actively exhibit their antioxidant properties in combination with essential oils and oily aromas due to the solubility of the former in oils and other organic solvents.

A mouthwash is made as follows: purified water, humectants, thickeners, surfactants, foam stabilizers, an acid or base for pH adjustment, a sweetener, fullerenes, essential oils, a flavoring agent, active additives, a preservative are mixed. The specified composition is brought to a homogeneous mass by stirring on a magnetic or overhead stirrer.

The use of fullerenes in mouth rinses makes it possible, among other things, to replace activated carbon in the composition, which has properties to precipitate during storage. Fullerenes, on the other hand, have the property of being evenly distributed in mass or volume (Table Keb). Table N “6. Fullerene rinse compositions

The prepared mouth rinses were tested for the physicochemical stability of dispersions: the deposition rate of solid particles was measured by settling at room temperature, without access to light, on a flat, homogeneous surface. The comparison was made with activated carbon rinses in the composition, since activated carbon is used in rinses as an absorbent of protein deposits and a cleaning agent. Fullerene, in turn, also has cleansing properties, as well as a number of other beneficial properties, such as antioxidant, hemostatic and other effects.

After preparation, the rinses were poured into containers and left in a dark place at room temperature. Every day for two weeks, the deposition of coal and fullerenes at the bottom of the tank was monitored.

In the course of the experiment, it was revealed that the activated carbon completely settled on the bottom of the container on the seventh day, and the fullerene remained evenly distributed throughout the volume for all 14 days. This fact indicates that fullerenes can be used as an effective substitute for activated carbon in the composition of oral care products. Replacing activated carbon with fullerene will improve the quality characteristics of the corresponding products for the oral cavity, as well as make such products more attractive to the consumer in terms of aesthetics.

Thus, fullerenes have a broader spectrum of effects than activated carbon, which allows it to be used as an active ingredient in oral health care products.

Example 6. Making a paste and a rinse aid.

The toothpaste was prepared as follows: the humidifiers sorbitol 70% and glycerin were dispersed in purified water with stirring in an ordinary mixer until the mixture was homogeneous. Sodium thickeners were added to the cold mixture. carboxymethyl cellulose together with xanthan gum and heated to 50-70 ° C until complete dissolution. Next, the surfactant sodium coco sulfate, the foam stabilizer tetrasodium glutamate diacetate, the sweetener sucralose, calcium lactate, isopropylmethylphenol and titanium dioxide were added until complete uniform distribution in the base. At the very end, flavor and organic acid were added to adjust the pH. The ingredients were mixed until a homogeneous phase was obtained. The mixture was then transferred to a high speed vacuum mixer in which an inorganic silica thickener was added to the mixture. The composition of the base of toothpastes is presented in Table N “7.

Table N ° 7. Toothpaste base composition

Fullerene C60 or C70 was added to the base of the toothpaste in a certain mass ratio. Totarol and bisabolol were added to enhance the antibacterial effect. The compositions of the toothpastes for the studied components are presented in Table N? 8.

Table .N28. Toothpaste formulations for clinical trials

The mouthwash was made as follows: the humidifier sorbitol 70% and polydon A were dispersed in purified water with stirring in an ordinary mixer until the mixture was homogeneous. Then added the surfactant sodium coco-sulfate, the enzyme bromelain, the lysate of bifidobacteria "BifiLiz". Clove essential oil, menthyl lactate, natural Mint Flavor Ventos were added using NatraGem solubilizer until evenly distributed in the mixture. At the very end, organic acid was added to adjust the pH and the preservative Euxyl to maintain microbiological stability throughout the shelf life. The ingredients were mixed until a homogeneous clear solution was obtained.

As a base for the inclusion of the components, a mouthwash with the composition shown in Table L 9 was used.

Table N ° 9. Rinse Aid Base Composition

Example 7. Refinement of antioxidant action.

A preclinical study of the antioxidant effect of toothpastes with C60 and C70 fullerenes and activated carbon was carried out. The method of analysis is that 5 g of toothpaste was mixed with 50 ml of 95% ethanol, filtered into a 100 ml volumetric flask, brought to the mark and mixed. 10 ml of distilled water, 1 ml of 20% sulfuric acid solution, 1 ml of 0.05 M potassium permanganate solution were added to a titration glass with a capacity of 50 ml, stirred and titrated with a filtrate solution until discoloration. Thus, an indirect titration was carried out, in which the filtrate with fullerenes C60 and C70 or activated carbon acted as the titrant, and potassium permanganate was the titrated substance.

The redox reaction during the indirect titration of C60 fullerene can be expressed by the equation:

Cbo + 48KMP0 ₄ + 72H ₂ S0 ₄ = 6ОСО2 + 48MnS0 ₄ + 24K ₂ S0 ₄ + 72Н 0 The redox reaction during the indirect titration of C70 fullerene can be expressed by the equation:

С70 + 56КМП0 ₄ + 84H ₂ S0 ₄ = 70СО + 56MnS0 ₄ + 28K ₂ S0 ₄ + 84Н ₂ 0 The redox reaction during the indirect titration of activated carbon can be expressed by the equation:

5C + 4KMP0 ₄ + 6H ₂ S0 ₄ = 5COg + 4MnS0 + 2K ₂ S0 ₄ + 6H ₂ O Calculation of antioxidant activity (AOA), corresponding to the concentration of biologically active substances of a toothpaste of a restorative nature in terms of the sample consumed for titration of 1 ml 05 M solution of potassium permanganate, mg / g, was carried out according to the formula:

AOA (mg / g) = Vi * 0, 008506 * 1000 / w * 100 where

Vi is the volume of the filtrate solution used for titration of 0.05 M potassium permanganate solution, in ml; w is the mass of the sample of toothpaste, in g;

6.2 x 0.008506 x 1000 AOA of fullerene C60 (mg / g) = - = 0.10547 (mg / g)

5.0 x 100

7.2 x 0.008506 x 1000

AOA of fullerene C70 (mg / g) = - = 0.12249 (mg / g)

5.0 x 100

0.52 x 0.008506 x 1000

AOA of activated carbon (mg / g) = - = 0.00879 (mg / g)

5.0 x 100

Antioxidant activity corresponds to the amount of active reducing agent in the toothpaste, which reacts with the oxidizing agent in the reaction medium, with the same content of the compared substances. The higher the value of this indicator, the more oxidant ions and radical particles the sample will neutralize. Thus, the antioxidant activity of a toothpaste with activated carbon is 91.66% less than that of a toothpaste with C60 fullerene, and 92.82% less than that of a toothpaste with C70 fullerene. For the same effect, C60 fullerene can be contained in toothpaste 12 times less than activated carbon. For the same effect, fullerene C70 can be contained in toothpaste 13.94 times less than activated carbon. Fullerene contains 60 or 70 carbon atoms with reductive activity. The formation of a fullerene molecule leads to a synergistic effect: an increase in the reducing properties.

The second indicator for assessing the possibility of using reducing substances is efficiency, i.e. the degree of manifestation of any effect with the same content of substances in the means for caring for the oral cavity. The effect is determined by the concentration of the substance in the composition of the oral care product. The greatest accuracy in determining the effect is provided by in vivo study on patients, however, in vitro methods exist to determine the effectiveness with an acceptable margin of error.

The calculation of the antioxidant efficiency of toothpastes (AOE) was carried out according to the formula:

AOE (%) = Vi х 100% / V _k where

AOE - antioxidant effectiveness of toothpaste, expressed in%;

Vi is the volume of the filtrate solution used for titration of 0.05 M potassium permanganate solution, in ml;

AOE fullerene C60 (%) = 93.93 (%)

6.60

6.51 x 100%

AOE fullerene C70 (%) = = 98.63 (%)

6.60

0.52 x 100%

AOE activated carbon (%) = 7.88 (%)

6.60

The antioxidant effect is determined by active ingredients with reducing properties and is determined by the equivalent amount according to the redox reaction equation with potassium permanganate. The volumes of the filtrate solution and the sample depend on the equivalent concentrations of the active ingredients with reducing properties. Based on the results of determining the antioxidant efficiency, it was revealed that all carbon derivatives: activated carbon, fullerenes C60 and C70 have reducing properties. However, the antioxidant activity of C60 and C70 fullerenes is higher than that of activated carbon, therefore, in equal doses, the antioxidant effect of C60 and C70 fullerenes will be 91.61% and 92.01% higher (in relative terms) compared to activated carbon in toothpastes. as a control.

Fullerenes in the toothpaste have a pronounced antioxidant effect due to their strong regenerative properties and a special distribution of electron density in the molecule orbitals. Toothpaste with fullerene C60 reduces the amount of free radicals and oxidants by 93.93%, and toothpaste with fullerene C70 reduces the amount of oxidants and free radicals by 98.63%, which confirms the pronounced anti-inflammatory and antioxidant effects identified in clinical studies. An antioxidant effect is essential to reduce oxidative stress and maintain oral health.

Fullerene benefits.

Fullerenes are a quality replacement for activated carbon, which is widely used in toothpastes. Activated charcoal toothpastes have a characteristic black color, not always perceived by a person as a property of a whitening product. The addition of fullerene will avoid this characteristic, since fullerene is an active ingredient in lower concentrations in oral care products.

Activated carbon is capable of staining mucous membranes black, and the use of fullerene will make it possible to level this characteristic of the product.

Fullerene is a more stable substance and does not have the ability to absorb unpleasant odors or excess moisture, unlike activated carbon.

Activated carbon is a dry black powder that must be specially incorporated into the composition of oral care products, since due to its low solubility in water, sedimentation occurs during storage. In the case of fullerene, it is possible to obtain and use hydrated C60 fullerene - C60HyFn - a strong, hydrophilic supramolecular complex consisting of a C60 fullerene molecule enclosed in a first hydration shell containing 24 water molecules: C ₆ o (H ₂ 0) ₂₄ . Hydrogenated fullerene readily dissolves in water to form a pale yellow solution without sediment, so its use in a toothpaste will not lead to a black color.

However, the most important is the wide range of fullerene effects: a pronounced antioxidant effect, an adsorbing effect, an anti-inflammatory effect due to a decrease in the release of histamine. On average, fullerenes exceed the action of all antioxidants known before them by 100 - 1000 times, in particular, ascorbic acid, tocopherol, retinol. Also, when fullerenes are used with polyvinylpyrrolidone (PVP), a pronounced cleansing effect of tooth enamel occurs.

Claims

CLAIM

1. Means for oral hygiene containing fullerene.

2. Means according to claim 1, intended for the care of the teeth and / or the oral cavity.

3. The agent according to claim 1, wherein said fullerene is C60 fullerene or C70 fullerene.

4. The agent of claim 1, wherein said fullerene is present in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt% ., preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about 0 , 1% wt., Preferably from about 0.0001 to about 0.01% wt.

5. The agent according to claim 4, wherein said fullerene is present in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4 , 5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7, 25, about 7.5, about

7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

6. The agent according to claim 5, where said fullerene is contained in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0, 05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5,

5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10

% wt.

7. The agent according to claim 1, additionally containing at least one bacterial lysate having therapeutic activity against bacteria in the oral cavity, and / or an extract of emblica fruits (Phyllanthus Emblica fruit extract), and / or rosehip fruit extract (Rosa Canina Fruit extract ), and / or essential oil of bergamot (Citrus Aurantium Bergamia essential oil), and / or essential oil of grapefruit (Citrus Paradisi essential oil), and / or coniferous chlorophyll carotene paste and / or tranexamic acid and / or dihydroquercetin and / or subtilisin or mixtures thereof.

8. The agent according to claim 7, wherein said at least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Bergamot essential oil (Citrus Aurantium Bergamia essential oil), essential oil grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt% ., more preferably from about 0.0001 to about 0.1 wt%, more preferably from about colo 0.0001 to about 0.01% wt.

9. The agent according to claim 8, wherein said at least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Bergamot essential oil (Citrus Aurantium Bergamia essential oil), essential oil grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025 , about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1 , 25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6 , 75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

10. The agent according to claim 9, wherein said at least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Bergamot essential oil (Citrus Aurantium Bergamia essential oil), essential oil grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in the amount of 0.0001, 0.00025, 0.0005,

0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1,

1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4, 75, 5, 5.25, 5.5, 5.75, 6,

6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9, 75 or 10% wt.

11. An agent according to claim 1, in the form of a toothpaste, mouthwash, chewing gum for dental and oral cavity care, foam, serum, aerosol, oral strip, ointment, irrigator liquid, tooth powder.

12. Means for oral hygiene, containing a combination of fullerene, totarol and bisabolol.

13. Means according to claim 12, intended for the care of the teeth and / or the oral cavity.

14. The agent according to claim 12, wherein said fullerene is a C60 fullerene or a C70 fullerene.

15. The agent of claim 12, wherein said fullerene is present in an amount of from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt% ., more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about about 0.1% wt., more preferably from about 0.0001 to about 0.01% wt.

16. The agent of claim 15, wherein said fullerene is present in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4 , 5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7, 25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 % wt.

17. The agent according to claim 15, where fullerene is contained in an amount of 0.0001, 0.00025, 0.0005,

18. The agent of claim 12, wherein said totalarol is present in an amount of from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt% ., more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about about 0.1% wt., more preferably from about 0.0001 to about 0.01% wt.

19. The agent of claim 18, wherein said totalarol is contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4 , 5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7, 25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 % wt.

20. The agent according to claim 18, wherein said totalarol is contained in an amount of 0.0001, 0.00025,

0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8, 25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10

% wt.

21. The agent of claim 12, wherein said bisabolol is present in an amount of from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt% ., more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt%, more preferably about 0.0001 to about about 0.1% wt., more preferably from about 0.0001 to about 0.01% wt.

22. The agent of claim 21, wherein said bisabolol is present in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8 , 5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

23. The agent according to claim 15, wherein said bisabolol is contained in an amount of 0.0001,

0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0, 75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10% wt.

24. The agent according to claim 12, additionally containing at least one bacterial lysate with therapeutic activity against bacteria in the oral cavity, and / or an extract of emblica fruit (Phyllanthus Emblica fruit extract), and / or rosehip fruit extract (Rosa Canina Fruit extract ), and / or essential oil of bergamot (Citrus Aurantium Bergamia essential oil), and / or essential oil of grapefruit (Citrus Paradisi essential oil), and / or coniferous chlorophyll-carotene paste, and / or tranexamic acid, and / or dihydroquercetin, and / or subtilisin or mixtures thereof.

25. The agent according to claim 24, where said at least one bacterial lysate, extract of emblica fruit (Phyllanthus Emblica fhiit extract), rosehip extract (Rosa Canina Fruit extract), bergamot essential oil (Citrus Aurantium Bergamia essential oil), essential oil grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in an amount from about 0.0001 to about 10 wt%, more preferably from about 0.0001 to about 9 wt%, more preferably from about 0.0001 to about 8 wt%, more preferably about 0.0001 to about 7 wt%, more preferably about 0.0001 to about 6 wt%, more preferably about 0.0001 to about 5 wt%, more preferably about 0.0001 to about 4 wt%, more preferably about 0.0001 to about 3 wt%, more preferably about 0.0001 to about 2 wt%, more preferably about 0.0001 to about 1 wt% ., more preferably from about 0.0001 to about 0.1 wt.%, more preferably from about 0.0001 to about 0.01% wt.

26. The agent according to claim 25, wherein said at least one bacterial lysate, Phyllanthus Emblica fruit extract, fruit extract rose hips (Rosa Canina Fruit extract), bergamot essential oil (Citrus Aurantium Bergamia essential oil), grapefruit essential oil (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in an amount of about 0.0001, about 0.00025, about 0.0005, about 0.00075, about 0.001, about 0.0025, about 0.005, about 0.0075, about 0.01, about 0.025, about 0.05, about 0.075, about 0.1 , about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about

2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5 , about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7, 75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, or about 10 wt%.

27. The agent according to claim 26, wherein said at least one bacterial lysate, Phyllanthus Emblica fruit extract, Rosa Canina Fruit extract, Bergamot essential oil (Citrus Aurantium Bergamia essential oil), essential oil grapefruit (Citrus Paradisi essential oil), coniferous chlorophyll-carotene paste, tranexamic acid, dihydroquercetin, subtilisin are contained in the amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.0025, 0.005, 0.0075 , 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1,

28. An agent according to claim 12, in the form of a toothpaste, mouthwash, chewing gum for dental and oral cavity care, foam, serum, aerosol, oral strip, ointment, irrigator liquid, tooth powder.

29. The use of fullerene for the manufacture of oral hygiene products.

30. Use according to claim 29, wherein the oral hygiene agent is intended to care for the teeth and / or the oral cavity.

31. Use according to claim 29, wherein the fullerene is a C60 fullerene or a C70 fullerene.

32. Application of a combination of fullerene, totarol and bisabolol for the manufacture of oral hygiene products.

33. Use according to claim 32, wherein the oral hygiene agent is intended for the care of the teeth and / or the oral cavity.

34. Use according to claim 32, wherein the fullerene is a C60 fullerene or a C70 fullerene.