Menthol derivative compounds and using them as active systemic agents and oral agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacy and dentistry, and concerns creating new compositions of menthol derivatives. For this purpose, 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylcarbamate is suggested to be used as an antioxidant, anti-inflammatory and antimicrobial agent for local treatment of the oral cavity, e.g. periodontal diseases. That provides the basis to present the compositions containing an effective amount of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylcarbamate, and at least one excipient.

EFFECT: inventions provide treating the oral cavity ensured by an integrated effect on general mechanisms of pathogenesis.

7 cl, 7 tbl, 2 ex, 5 dwg

 

The technical field to which the invention relates.

The present invention relates to methods and compositions for providing a favorable impact on the health of the oral cavity and/or system health, including prevention of biological fixation film, anti-inflammatory, antioxidant effects, the effects of preventing bone loss, and anti-microbial benefits, containing compounds - derivatives of menthol Formula 1 or a mixture thereof, and at least one filler. In addition, the present invention relates to methods and compositions for activation and/or suppression of metabolites periodontal disease containing compounds - derivatives of menthol Formula 1 or a mixture thereof, and at least one filler.

The level of technology

Periodontal disease is an inflammation of some or all of the supporting structures of the teeth, including the gums, the cement substance of the teeth, periodontal ligament and alveolar bone. Metabolites of periodontal disease gingival crevicular fluid correspond to healthy and/or unhealthy condition of the oral cavity and make it possible differential diagnosis of oral health. Inflammation of the oral cavity usually occurs from infection of bacteria in biological the Lenk in the oral cavity soft microbial plaque that forms on teeth and is involved in the occurrence of gingivitis, periodontitis, caries and other forms of periodontal diseases and destroys the connective fibers and supporting bone that hold the teeth in place. Another factor in periodontal disease is a caused by germs oxidative damage to cells. Oxidative free radicals are used by the body as a protective system against attacks antigens. However, oxidative free radicals can also initiate an uncontrolled chain reactions that cause damage to host tissue and inflammation, such as those that occur with gingivitis mouth. Systemic oxidative cell damage, inflammation of the host tissue and loss of bone mass are carried out through similar mechanisms.

Compounds - derivatives of menthol represent a physiological cooling active ingredients, which are often used to evoke a feeling of coolness on the skin or on the mucous membrane, that is, on the mucous membrane in the oral, nasal and/or faringealni cavities by blocking calcium channels, but without any physical cooling, such that occurs, for example, by evaporation RA is the solvent, what is happening actually.

The invention

The present invention describes new applications of specific compounds - derivatives of menthol Formula 1:

,

where

X represents an oxygen atom or an NH radical; and

R represents an unsubstituted or substituted aryl or aliphatic radical.

Unobvious and unexpected result of the present invention is that the respective aryl and aliphatic radicals with appropriate regard interact with menthol to obtain compounds of the present invention, to obtain the improved characteristics of these compounds and new applications for personal care products.

In some embodiments implementing the present invention describes a new application of at least one of the compounds menthol derivatives of Formula 1 and their compositions, to methods of providing favorable effects on oral health and systemic health. In some embodiments, the implementation of a beneficial effect on oral health and systemic health includes countering biological fixation film, anti-inflammatory, antioxidant effects, the effects of preventing the loss of bone mass, and antimicrobial favorable impact the Oia.

In some embodiments implementing the present invention describes a composition for providing a favorable impact on oral health and systemic health, containing at least one compound is a derivative of menthol Formula 1 and at least one filler.

In some embodiments implementing the present invention describes a new application of at least one of the compounds menthol derivatives of Formula 1 and their compositions for methods of activation or suppression of metabolites periodontal diseases, as well as appropriate ways. In some embodiments, the implementation of metabolites periodontal diseases correspond to healthy and/or unhealthy condition of the oral cavity and make it possible differential diagnosis of oral health.

In some embodiments implementing the present invention describes a composition for activation or suppression of metabolites periodontal diseases, containing at least one compound is a derivative of menthol Formula 1 and at least one filler.

Brief description of drawings

Figure 1 shows the anti-inflammatory efficacy of the described compositions for cleaning teeth.

Figure 2 shows the antioxidant efficiency of the described compounds derived Myung-the Ola.

Figure 3 shows the antioxidant efficiency of the described compositions for cleaning teeth.

Figure 4 shows the performance impact, preventing the loss of bone mass described composition for cleaning teeth.

Figure 5 shows the antimicrobial efficacy of the described compositions for cleaning teeth.

Detailed description of the invention

As used in the present description, the ranges are used as a compact notation for describing each and every value that is within this range. Each value within the range can be selected as the extreme values of the range. In addition, all references cited in this document are thereby incorporated by reference in their entirety.

I. Methods of using compounds - derivatives of menthol

In some embodiments implementing the present invention describes a new application of specific compounds - derivatives of menthol Formula 1 and their compositions, methods of securing a favorable impact on the health of the oral cavity and/or system health. In some embodiments implementing the present invention describes a method of providing a favourable impact on oral health. In some embodiments implementing the present invention describes a method to provide the enabling impact on systemic health. In some embodiments implementing the present invention describes a method of providing at least one beneficial effect on oral health and systemic health, selected from anti attaching a biological film of the oral cavity, anti-inflammatory, anti-oxidant effects, impacts, preventing bone loss, and anti-microbial benefits. In some embodiments implementing the present invention describes a method of providing multiple favorable effects on oral health and systemic health. In some embodiments implementing the present invention describes a method of providing multiple favorable effects on oral health and systemic health, including one or more positive impacts of the following: opposition to attach a biological film in the oral cavity, anti-inflammatory, antioxidant effects, the effects of preventing bone loss, and anti-microbial benefits.

In some embodiments implementing the present invention describes a new application of specific compounds - derivatives of menthol Formula 1 and their compositions for methods of activation and/or suppression of metabolites of periodontally the disease. In some embodiments implementing the present invention describes a method of activating at least one metabolite of periodontal disease. In some embodiments implementing the present invention describes a method of suppressing at least one metabolite of periodontal disease. In some embodiments implementing the present invention describes a method of activation and/or suppression of many metabolites periodontal diseases.

A. Composition of Formula 1

In some embodiments implementing the present invention describes new applications of compounds - derivatives of menthol Formula 1:

,

where

X represents an oxygen atom or an NH radical; and

R represents an unsubstituted or substituted aryl or aliphatic radical.

In some embodiments, implementation of the X represents the oxygen atom. In some embodiments, implementation of the X represents the radical NH. In some embodiments, the implementation of the R represents an unsubstituted aryl radical. In some embodiments, the implementation of R is a substituted aryl radical. In some embodiments, the implementation of R is a monosubstituted aryl radical. In some embodiments, the implementation of R represents policemen the th aryl radical. In some embodiments, the implementation of R is an unsubstituted aliphatic radical. In some embodiments, the implementation of R is a substituted aliphatic radical. In some embodiments, the implementation of R is a monosubstituted aliphatic radical. In some embodiments, the implementation of R represents politeley aliphatic radical.

In some embodiments, the implementation of Formula 1, R represents a substituted aryl radical having up to 12 carbon atoms, where the substituents are selected from canardiere, hydroxyl radicals, amide radicals, ester radicals, amine radicals.

In other embodiments, the implementation of Formula 1, R represents a radical straight, branched or cyclic aliphatic chain, or R represents a straight, branched or cyclic gidrobiologicheskii radical, each of them has up to 10 carbon atoms.

B. a beneficial effect, preventing the fixation of a biological film in the oral cavity

1. Description a favorable impact

A biological film in the oral cavity - containing bacteria, bacterial extracellular by-products, proteins, lipids and glycolipids represent a matrix formed on the surfaces of the oral cavity, which is asgaut loci for the formation of Tartar or plaque. In some embodiments implementing the present invention describes a method of providing a favourable impact, preventing fixation of the biological film in the oral cavity. In some embodiments, the implementation of the method includes obtaining at least one compound is a derivative of menthol corresponding to Formula 1, and compositions.

In some embodiments, the implementation of a beneficial effect, preventing the fixation of a biological film in the oral cavity that is provided includes the interaction of at least one compound is a derivative of menthol Formula 1 and its compositions with bacteria in the mouth, so as not to give them the opportunity to attach to the surface of the oral cavity. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions interact with adesanmi, ligands or other residues on the surface of bacteria in the oral cavity that typically facilitate binding to the receptor or other residue on the surface of the oral cavity. In some embodiments, the implementation of a beneficial effect, preventing the fixation of a biological film in the oral cavity that is provided includes the interaction of at least one compound is a derivative of menthol Formula 1 and it is songs with the surface of the oral cavity with the formation of the protective layer, so bacteria and biological components of the film may not adhere to the surface of the oral cavity or teeth, thereby preventing the formation of the initial layer to attach on the surface of the oral cavity. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1 and its composition may effectively cover the surface of the oral cavity and to prevent the attachment of bacteria and other components of the biological matrix film.

2. Specific formula

In some embodiments implementing the present invention describes a composition for providing a favorable impact, preventing fixation of the biological film in the oral cavity containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition to provide a favourable impact, preventing the formation of plaque in the oral cavity, is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth choose from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for isdi teeth in accordance with the present invention is a toothpaste.

In some embodiments, the implementation of at least one compound is a derivative of menthol, which provides a beneficial effect, preventing the fixation of a biological film in the oral cavity, is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one compound is a derivative of menthol, which provides a beneficial effect, preventing the fixation of a biological film in the oral cavity represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol, which provides a beneficial effect, preventing the fixation of a biological film in the oral cavity represents:

In some embodiments, the implementation of at least one filler chosen from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modification of pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

3. Investigation

A beneficial effect, preventing the fixation of a biological film in the oral cavity, the compounds menthol derivatives of the present invention examined using analysis using crystal violet (SOP No. ATO-5345-00) in 384-well the tablet in the concentration range of 0.0004-2500 ppm

C. anti-Inflammatory beneficial effect

1. Description a favorable impact

A direct consequence of tissue damage is the release of certain chemical agents - i.e. histamine, serotonin and kinins, which are mediators of inflammation and cause erythema, edema, fever, pain and loss of function of tissues.

Colony-stimulating factor macrophages and granulocytes (GM-CSF) is predstavljaet a cytokine, which functions as a growth factor for white blood cells, stimulating stem cells to the production of granulocytes and monocytes. Monocytes leave the bloodstream and migrate into the tissue, at the same time they Mature to macrophages. Thus, GM-CSF is a part of the immune/inflammatory cascade by which activation of a small number of macrophages can quickly lead to an increase in their number.

Interleukin-1b (IL-1b) is a proinflammatory cytokine produced by macrophages, monocytes and dendritic cells. They form an important part of the inflammatory response of the body against infection by increasing ekspressirovali of adhesion factors on endothelial cells, making it possible to transmigration of cells, the cells that fight pathogens, infection and re-adjust thermoregulatory center of the hypothalamus, leading to increased body temperature, which in itself is expressed as fever and helps the body's immune system to fight infection.

Interleukin-6 (IL-6) is another factor which acts as a proinflammatory cytokine. It is secreted by T-lymphocytes and macrophages to stimulate immune response to trauma, in particular, burns or other tissue damage leading to inflammation. IL-6 can be released macrop is game in response to specific microbial molecules, associated with the molecules of the detection of the innate immune system present on the cell surface (or in intracellular compartments), which induce intracellular signaling cascades that give rise to the production of inflammatory cytokines.

Interleukin-8 (IL-8) is another cytokine produced by macrophages and other cell types such as epithelial cells. IL-8 is one of the major mediators of the inflammatory reaction and functions as a chemical attractant. It is also a potent angiogenic factor.

The tumor necrosis factor α (TNF-α) is another cytokine involved in systemic inflammation, and it is an element of radical cytokines, which stimulate a response in the acute phase. The main role of TNF-α is in the regulation of immune cells, with which it also can cause inflammation.

In some embodiments implementing the present invention describes a method of providing anti-inflammatory benefits. In some embodiments, the implementation of the present invention provides an anti-inflammatory beneficial effect in the oral cavity. In some embodiments, the implementation of the present invention provides a system protivovesa is sustained fashion a beneficial effect. In some embodiments, the implementation of the method includes obtaining at least one compound is a derivative of menthol corresponding to Formula 1, and compositions.

In some embodiments, the implementation of the anti-inflammatory benefit, which it turns out, includes the inhibition of at least one compound - derived menthol Formula 1, and compositions for the production and/or release of at least one chemical agent involved in inflammation. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of GM-CSF. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of IL-1b. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of IL-6. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of IL-8. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit producerof the s and/or release of TNF-α. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions provide efficiency favorable anti-inflammatory effects comparable with existing anti-inflammatory agents. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1 and its composition ensures the effectiveness of anti-inflammatory benefits, comparable with triclosan.

2. Specific formula

In some embodiments implementing the present invention describes the composition to provide anti-inflammatory benefits, containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition to provide anti-inflammatory benefits is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention is a dental p is STU. In some embodiments, the implementation of the composition for cleaning teeth, containing at least one compound is a derivative of menthol in Figure 1, ensures the effectiveness of anti-inflammatory benefits, comparable with existing anti-inflammatory drugs for brushing your teeth.

In some embodiments, the implementation of at least one compound is a derivative of menthol, providing anti-inflammatory benefits is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one compound is a derivative of menthol, providing anti-inflammatory benefits represents:

In some embodiments, implementing the Tulane at least one connection - a derivative of menthol, providing anti-inflammatory benefits represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol, providing anti-inflammatory benefits represents:

In some embodiments, the implementation of at least one filler chosen from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

3. Investigation

Anti-inflammatory study carried out in accordance with SOP No. ATO-5307-00 by measuring the percentage inhibition of PGE2.

D. Antioxidant beneficial effect

1. Description a favorable impact

Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent and can produce free radicals, which can Nhi is to iravati chain reaction of tissue damage and inflammation. Oxidative stress is the result of imbalance between production of reactive oxygen species and the ability of biological systems to easily detoxify reactive intermediate substance or repair the resulting damage, and can be an important factor in many disease States. Antioxidants are reducing agents, capable of slowing or preventing the oxidation of other molecules.

In some embodiments implementing the present invention describes a method of providing anti-oxidant benefits. In some embodiments, the implementation of the method includes obtaining at least one compound is a derivative of menthol corresponding to Formula 1, and compositions.

In some embodiments, the implementation of antioxidant beneficial effect that is obtained includes terminating the free radical chain reaction of at least one compound is a derivative of menthol Formula 1 and his compositions. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1 and its composition removes the free radical intermediate substance. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1 andhis compositions inhibit other oxidation reactions, being oxidized themselves, without generating a free radical. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions provide antioxidant efficiency benefits comparable with existing antioxidants. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions provide antioxidant efficiency benefits comparable to vitamin E.

2. Specific formula

In some embodiments implementing the present invention describes a composition for providing antioxidant benefits, containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition to provide antioxidant benefits is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention to provide the focus of a toothpaste. In some embodiments, the implementation of the composition for cleaning teeth containing compound is a derivative of menthol Formula 1 or mixtures thereof, provides antioxidant efficiency benefits comparable with existing antioxidant means for cleaning teeth.

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antioxidant benefits present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antioxidant benefits represents:

In some embodiments, the implementation of at least one of the tell - a derivative of menthol that provides antioxidant benefits represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antioxidant benefits represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antioxidant benefits represents:

In some embodiments, the implementation of at least one filler chosen from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

3. Investigation

Antioxidant activity determined using analysis of lipid peroxidase (Kamiaya Biomedical Co., Seattle, WA), which is a colorimetric method, which measures reset the establishment of cumin-hydroperoxide radicals.

E. a beneficial effect in preventing bone loss

1. Description a favorable impact

One of the main factors involved in the renewal of bone tissue during growth, development and healing, represent the matrix metalloprotease (MMP), including interstitial collagenases such as MMP-13 that degrade native interstitial collagens in several tissues. However, elevated levels of MMP observed in arthritic tissues, and degradation using MMP-13 collagen type II in cartilage is a cytokine-mediated intermediate stage in the development of rheumatoid arthritis and osteoarthritis. The expression of mRNA of MMP-13 is stimulated by parathyroid hormone (PTH), the level of which is significantly increased in response to the emergence of intermediate products of cellular signals and transcription factors, including IL-1 and TNF-α.

In some embodiments implementing the present invention describes a method of providing a favorable effect in preventing bone loss. In some embodiments, the implementation of a beneficial effect in preventing bone loss that is provided includes the suppression of at least one compound - derived menthol Formula 1, and compositions of the expression of mRNA of MMP-13. In some embodiments, the implementation of minicamera one connection - derived menthol Formula 1, and compositions inhibit the production and/or release of parathyroid hormone. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of IL-1. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions inhibit the production and/or release of TNF-α.

2. Specific formula

In some embodiments implementing the present invention describes a composition for providing a favorable impact, preventing the loss of bone mass containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition to provide a favourable impact, preventing the loss of bone mass, is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention represents subno the pasta.

In some embodiments, the implementation of at least one compound is a derivative of menthol, which provides a beneficial effect in preventing loss of bone mass, is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one compound is a derivative of menthol, which provides a beneficial effect in preventing bone loss represents:

In some embodiments, the implementation of at least one filler chosen from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents is of rest, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

3. Investigation

Activity against MMP-13, are determined by measuring the inhibition of the expression of mRNA of MMP-13, which is stimulated by parathyroid hormone (PTH).

F. Antimicrobial beneficial effect

1. Description a favorable impact

In some embodiments implementing the present invention describes a method of providing anti-microbial benefits. In some embodiments, the implementation of antimicrobial beneficial effect that is provided includes the disturbance of at least one compound - derived menthol Formula 1, and compositions of the lipid fraction in the plasma membrane of the microorganism. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1 and its composition is changing the permeability of the bacterial membrane, leading to leakage of intracellular materials and cell death. In some embodiments, the implementation of at least one compound is a derivative of menthol Formula 1, and compositions cross the microbial cell membrane, penetrate into the inner spaces of the cells and interact with intracellular sites, critical for antimicrobial activity.

2. Specific formula

In some embodiments implementing the present invention describes the composition to provide antimicrobial benefits, containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition to provide antimicrobial benefits is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth, choose from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention is a toothpaste.

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antimicrobial beneficial effect, is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol presence is there in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antimicrobial beneficial effect, represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol, providing antimikrobnaya beneficial effect, represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antimicrobial beneficial effect, represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antimicrobial beneficial effect, represents:

In some embodiments, the implementation of at least one compound is a derivative of menthol that provides antimicrobial beneficial effect, represents:

In some of the options which implement at least one connection - a derivative of menthol that provides antimicrobial beneficial effect, represents:

In some embodiments, the implementation of at least one filler is a member selected from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

3. Investigation

Antimicrobial study measured in accordance with SOP No. ATO-5308-00, to determine the minimum inhibitory concentration (MIC).

G. Regulation of metabolites periodontal disease

1. Definition

As used herein, “healthy mouth” refers to the absence of gingivitis and/or periodontal disease.

As used herein, “periodontal disease” refers to inflammation of periodontium, including gingival tissue or the tissue of the gums; the cement substance of the teeth or the outer layer of the roots of teeth; alveolar the Yu bone or bone pockets, in which are fixed teeth; periodontal ligaments, which are the connective tissue fibers that pass between the cement substance of the teeth and alveolar bone, and includes gingivitis.

2. Common metabolites

Metabolites of periodontal disease gingival crevicular fluid correspond to the healthy status of the oral cavity and/or the status of periodontal diseases of the oral cavity and make it possible differential diagnosis of oral health. Metabolites periodontal diseases can be selected from compounds generated by amino acid metabolism; a compound generated in the urea cycle; compounds generated by glutathione conversion; compounds generated during lipid metabolism; a compound generated during the metabolism of carbohydrates, the connections generated through the metabolism of nucleic acids, vitamins and co-factors.

Metabolites periodontal diseases described herein, detected using the methods of metabolic profiling. Such techniques metabolic profiling are described in U.S. patent No. 7005225 and 7329489; and applications for U.S. patent No. 11/357732; 11/301077 (publication No. 2006/0134676); 11/301078 (publication No. 2006/0134677); 11/301079 (publication No. 2006/0134678) and 11/405033 (publication No. 2007/0072203); the full content of which is enabled thereby as references.

In some embodiments implementing the present invention describes a new application of specific compounds - derivatives of menthol Formula 1 and their compositions for methods of activation or suppression of metabolites periodontal diseases. In some embodiments, the implementation of the metabolite subjected to activation or suppression represents at least one compound selected from the compounds generated by the metabolism of amino acids, the compounds generated in the urea cycle; compounds generated by glutathione conversion; compounds generated during lipid metabolism; a compound generated during the metabolism of carbohydrates, the connections generated through the metabolism of nucleic acids, vitamins and co-factors.

3. Activating

In some embodiments implementing the present invention describes a method of activating metabolites periodontal diseases. In some embodiments, the implementation of the method of activation of metabolites periodontal disease includes activating compound - derived menthol Formula 1, and compositions of at least one metabolite selected from the radicals consisting of uric acid, the restored glucat is she, oxidized glutathione, ascorbic acid and glutamine.

In some embodiments implementing the present invention describes a composition for activating metabolites periodontal diseases, containing at least one compound is a derivative of menthol corresponding to Formula 1, and at least one filler. In some embodiments, the implementation of the composition for activation of metabolites periodontal disease is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth is an element selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention is a toothpaste.

In some embodiments, the implementation of at least one compound is a derivative of menthol, activating metabolites periodontal disease, is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of the menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one filler is a member selected from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

4. Suppression

In some embodiments implementing the present invention describes a method of suppressing metabolites periodontal diseases. In some embodiments, the implementation of the method of suppressing metabolites periodontal disease involves the suppression compound - derived menthol Formula 1, and compositions of at least one metabolite selected from the radicals consisting of inosine, gipoksantina, guanosine, guanine, leucine, isoleucine, lysine methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, valine, phenylacetic acid, α-hydroxymetoprolol acid, 5-aminovaleric acid, choline, glycerol-3-phosphate and N-acetylneuraminic acid.

In some embodiments implementing the present invention describes a composition for suppressing metabolites periodontal diseases, containing at least one compound is a derivative of menthol, corresponding to the Formula 1 and at least one filler. In some embodiments, the implementation of the composition to suppress metabolites periodontal disease is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth is an element selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention is a toothpaste.

In some embodiments, the implementation of at least one compound is a derivative of menthol, the vast metabolites periodontal disease, is present in the composition in amounts of from 0.05% of the mass. up to 5% of the mass. In some embodiments, the implementation of at least one connection - ol is izvozna menthol is present in the amount of 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in the amount of 0.5% of the mass.

In some embodiments, the implementation of at least one filler is a member selected from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silicon dioxide, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof, and the like.

II. Compositions containing compounds - derivatives of menthol

A. General composition

In some embodiments, the implementation of the arrangement in accordance with the present invention provides a beneficial effect to protect the health of the oral cavity and/or system health. In some embodiments, the implementation of the present invented the e describes a composition for providing a favorable impact on oral health. In some embodiments implementing the present invention describes a composition for providing a favorable impact on systemic health. In some embodiments implementing the present invention describes the composition to provide at least one beneficial effect on oral health and systemic health, selected from anti attaching a biological film in the oral cavity, anti-inflammatory, anti-oxidant effects, impacts, preventing bone loss, and anti-microbial benefits. In some embodiments implementing the present invention describes the composition to provide many favorable effects on oral health and systemic health. In some embodiments implementing the present invention describes a composition for providing a favorable impact on oral health and systemic health, including opposition to attach a biological film in the oral cavity, anti-inflammatory, antioxidant effects, the effects of preventing bone loss, and anti-microbial benefits.

In some embodiments, the implementation of the arrangement in accordance with the present invention activates and/or inhibits at the ore one metabolite periodontal disease. In some embodiments implementing the present invention describes a composition for activating at least one metabolite of periodontal disease. In some embodiments implementing the present invention describes a composition for suppressing at least one metabolite of periodontal disease. In some embodiments implementing the present invention describes a composition for activation and/or suppression of many metabolites periodontal diseases.

In some embodiments, the implementation of the arrangement in accordance with the present invention is an oral composition suitable for use in the oral cavity. In some embodiments, the implementation of the oral composition is suitable for ingestion through the mouth. In some embodiments, the implementation of the oral composition in accordance with the present invention includes, but is not limited to, creams, gels, pastes, foams, emulsions, suspensions, aerosols, sprays, rinses mouth, pharmaceutical products, capsules, granules, pellets, tablets, pills and gum. In some embodiments, the implementation of the composition is a composition for the care of the oral cavity. In some embodiments, the implementation of the composition for oral care mouth the submitted is a composition for cleaning teeth. In some embodiments, the implementation of the composition for cleaning teeth is an element selected from toothpastes, gels, liquids for mouth rinses, dental floss, powders, adhesive cleaning strips of gum, toothbrushes, and the like. In some embodiments, the implementation of the composition for cleaning teeth in accordance with the present invention is a toothpaste.

In some embodiments, the implementation of the arrangement in accordance with the present invention is a composition for topical application suitable for use outside the body cavities. In some embodiments, the implementation of the composition for local application in accordance with the present invention includes, but is not limited to, Soaps, synthetic detergents funds, liquid preparations for a shower/bathtub, emulsions, ointments, pastes, gels, body oil, toner, balsam, serum, powder, toilet water, eau de Cologne, perfumes, waxes, sprays, products for foot care products for insect protection products against sunburn, tools, applied after sun exposure, medications, shaving or after shaving products, hair removal products for hair care, products for nail care, deodorants and/or antiperspirants and cosmetics products. In some embodiments, the implementation of the composition p is ecstasy a composition for local body care. In some embodiments, the implementation of the composition for local body care is an element selected from the ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils, and the like.

1. Composition for the care of oral cavity

In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 and at least one filler. Compounds - derivatives of menthol, suitable for use in the present invention correspond to the Formula 1:

,

where

X represents an oxygen atom or an NH radical; and

R represents an unsubstituted or substituted aryl or aliphatic radical.

In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1, where X represents the oxygen atom. In some embodiments, implementation of the X represents the radical NH. In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1, where R is predstavljaet an unsubstituted aryl radical. In some embodiments, the implementation of R is a substituted aryl radical. In some embodiments, the implementation of R is a monosubstituted aryl radical. In some embodiments, the implementation of R represents politeley aryl radical. In some embodiments, the implementation of R is an unsubstituted aliphatic radical. In some embodiments, the implementation of R is a substituted aliphatic radical. In some embodiments, the implementation of R is a monosubstituted aliphatic radical. In some embodiments, the implementation of R represents politeley aliphatic radical.

In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1, where R represents a substituted aryl radical having up to 12 carbon atoms, where the substituents are selected from canardiere, hydroxyl radicals, amide radicals, ester radicals, amine radicals.

In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1, where R is a radical with a straight, branched or cyclic aliphatic chain, or R represents a straight, branched or cyclic gidrobiologicheskii radical, each of them has up to 10 carbon atoms.

In some embodiments, the implementation of the composition for care of the oral cavity in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 in an effective amount from 0.05 wt%. up to 5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in an effective amount ranging from 0.1% of the mass. up to 1% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in an effective amount from 0.25% of the mass. up to 0.5% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in an effective amount to 0.25% of the mass. In some embodiments, the implementation of at least one compound is a derivative of menthol is present in an effective amount of 0.5% of the mass.

B. Specific compounds - derivatives of menthol

Compounds - derivatives of menthol, suitable for use in the present invention correspond to the Formula 1:

,

where

X represents an oxygen atom or an NH radical; and

R represents somaintimates or substituted aryl or aliphatic radical.

In some embodiments, implementation of the X represents the oxygen atom. In some embodiments, implementation of the X represents the radical NH. In some embodiments, the implementation of the R represents an unsubstituted aryl radical. In some embodiments, the implementation of R is a substituted aryl radical. In some embodiments, the implementation of R is a monosubstituted aryl radical. In some embodiments, the implementation of R represents politeley aryl radical. In some embodiments, the implementation of R is an unsubstituted aliphatic radical. In some embodiments, the implementation of R is a substituted aliphatic radical. In some embodiments, the implementation of R is a monosubstituted aliphatic radical. In some embodiments, the implementation of R represents politeley aliphatic radical.

In some embodiments, the implementation of Formula 1, R represents a substituted aryl radical having up to 12 carbon atoms, where the substituents are selected from canardiere, hydroxyl radicals, amide radicals, ester radicals, amine radicals.

In other embodiments, the implementation of Formula 1, R represents a radical straight, branched or cyclic aliphatic chain or R before the hat is straight, branched or cyclic gidrobiologicheskii radical, each of them has up to 10 carbon atoms.

In some embodiments, the implementation of R represents:

,

where Y represents a hydroxyl or ceanorhaditis.

In some embodiments, the implementation of R represents at least one element selected from the

In some embodiments, the implementation of R provides at least a beneficial effect, preventing the fixation of a biological film in the oral cavity, as discussed above, and may independently be selected from the

In some embodiments, the implementation of R provides a beneficial effect, preventing the fixation of a biological film in the oral cavity, through interactions with bacteria in the mouth to make them impossible to attach to the surface of the oral cavity. In some embodiments, the implementation of the R interacts with adesanmi, ligands or other residues on the surface of bacteria in the oral cavity that typically facilitate binding to the receptor or other residue on the surface of the oral cavity. In some embodiments, the implementation of R provides the benefit is realnoe impact preventing biological fixation of a film in the oral cavity, through interaction with the surface of the oral cavity with the formation of the protective layer, so that the bacteria and biological components of the film may not adhere to the surface of the oral cavity or teeth, thereby preventing the formation of primary fixing layer on the surface of the oral cavity. In some embodiments, the implementation of R can essentially cover the surface of the oral cavity and to prevent the attachment of bacteria and other components of the biological matrix film.

In some embodiments, the implementation of R provides at least antioxidant benefits as discussed above, and may independently be selected from the

In some embodiments, the implementation of R provides antioxidant beneficial effect through completion of the free-radical chain reaction. In some embodiments, the implementation of the R removes the free radical intermediate substance. In some embodiments, the implementation of the R inhibit other oxidation reactions are oxidized by itself without generating free radicals. In some embodiments, the implementation of R ensures the effectiveness of the antioxidant benefits comparable with existing antioxidant is I. In some embodiments, the implementation of R ensures the effectiveness of the antioxidant benefits comparable to vitamin E.

In some embodiments, the implementation of R provides at least favorable anti-inflammatory effects and can independently be selected from the

In some embodiments, the implementation of R provides a favorable anti-inflammatory effect by inhibiting the production and/or release of at least one chemical agent involved in inflammation. In some embodiments, the implementation of the R inhibits the production and/or release of GM-CSF. In some embodiments, the implementation of the R inhibits the production and/or release of IL-1b. In some embodiments, the implementation of the R inhibits the production and/or release of IL-6. In some embodiments, the implementation of the R inhibits the production and/or release of IL-8. In some embodiments, the implementation of the R inhibits the production and/or release of TNF-α. In some embodiments, the implementation of R ensures the effectiveness of anti-inflammatory benefits, comparable with existing anti-inflammatory agents. In some embodiments, the implementation of R ensures the effectiveness of anti-inflammatory favorable impacts the via, comparable with triclosan.

In some embodiments, the implementation of R provides at least antimicrobial beneficial effect and may independently be selected from the

In some embodiments, the implementation of R provides favorable antimicrobial effects through disturbance of the lipid fraction of the plasma membrane of the microorganism. In some embodiments, the implementation of the R changes the permeability of the bacterial membrane, leading to leakage of intracellular materials and cell death. In some embodiments, the implementation of R crosses the membrane of microbial cells, penetrating into the interior of cells, and interacts with intracellular sites, critical for antimicrobial activity.

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the composition with the accordance with the present invention contains at least one connection - derived menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one compound is a derivative of menthol Formula 1 where at least one connection is:

B. Fillers

In some embodiments, the implementation of the arrangement in accordance with the present invention contains at least one filler. Fillers suitable for use in the present invention include any compound that is commonly used in compositions for oral and/or topical application and which do not alter the effectiveness of the compound is a derivative of menthol Formula 1.

1. Compositions for oral administration

Appropriate fillers for composities oral administration in accordance with the present invention include, but not limited to, preservatives, abrasives (smoothing agents), antibacterial agents, agents inhibiting inflammation, agents, preventing irritation, agents that inhibit irritation, additional antimicrobial agents, antioxidants, binders, (mineral) fillers, buffer solutions, materials carriers, chelating agents (compounds that form chelates), cleaning agents, agents for care, surfactants, emulsification, enzymes, foaming agents, foam stabilizers, enhancers foaming agents that promote gelation, gel-forming agents, whitening agents, agents for modulation of smell and/or taste, agents that reduce odor and/or taste, agents that enhance the smell and/or taste, plasticizers, agents, cooling (mucous membrane)/skin (cooling substances), agents, soothing (mucous membrane)/leather, agents, cleansing (mucous membrane)/skin agents for care (mucous membrane)/skin agents, healing (mucous membrane)/leather, agents that protect the mucous membrane stabilizers, suspendresume agents, vitamins, colorants, agents to protect color, pigments, surfactants, electrolytes, silicone derivatives, polyols, calcium carbonate, calcium phosphate, aluminum oxide, fluorides, the Oli zinc, tin, potassium, sodium and strontium, pyrophosphates, hydroxyapatite.

a. Flavouring agents

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains a flavouring agent. In some embodiments, the implementation of the flavouring agent is a member selected from agents, cooling mucous membrane agents, warming mucous membrane agents, giving spicy flavour, sweeteners, sugar substitutes, organic or inorganic pagkikita (for example malic acid, acetic acid, citric acid, tartaric acid, phosphoric acid), bitter additives (for example quinine, caffeine, limonin, amelogenin, humulone, Lupanov, Katakolon, tannins), edible mineral salts (e.g. sodium chloride, potassium chloride, magnesium chloride and sodium phosphate), essential oils (e.g. oils of peppermint ordinary, peppermint, Wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange), menthol, carvone, anethole, and combinations thereof.

b. Abrasives

Abrasives suitable for use in the present invention include materials based on silicon dioxide and, in particular, silica and precipitiously amorphous silicon dioxide, with the magnitude of the absorption mass is less, than 100 cm3/100 g of silicon dioxide, and preferably in the range from 45 cm3/100 g to less than 70 cm3/100 g of silicon dioxide. The magnitude of the absorption oil is measured using the ASTM Rub-Out Method D281. Abrasives on the basis of silicon dioxide with a low value of the absorption oil, especially suitable for implementing the present invention, there is on the market under the trade name Sylodent® XWA (Davison Chemical Division of W. R. Grace & Co., Baltimore, Md. 21203). Sylodent® XWA 650, the hydrogel of silica, composed of particles of colloidal silica having a water content of 29 wt. -%, on average, 7 to 10 microns in diameter, and the oil absorption of less than 70 cm3/100 g of silicon dioxide, is a preferred example of the abrasive on the basis of silicon dioxide with a low value of absorption oils suitable for implementing the present invention. Other abrasive on the basis of silicon dioxide with a low value of the absorption oil, especially suitable for implementing the present invention, there is on the market under the trade name DP-105TM(J. M. Huber Chemicals Division, Havre de Grace, Md. 21078) and represents precipitiously amorphous silicon dioxide having an average size distribution of particles from 5 to 12 microns and the amount of oil absorption in the range from 50 to 70 cm3/100, Other abrasives that can be used in the implementation of this is part II of the invention, include precipitiously silicon dioxide having an average particle size up to 20 microns, such as Zeodent® 115 (J. M. Huber Chemicals Division, Havre de Grace, Md. 21078) or Sylodent® 783 (Davison Chemical Division of W. R. Grace & Company), metaphosphate sodium, metaphosphate potassium, tricalcium phosphate, digidrirovanny the dicalcium phosphate, aluminosilicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof.

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains abrasive filler. In some embodiments, the implementation of the abrasive filler is a material based on silicon dioxide. In some embodiments, the implementation of the material based on silica is a colloidal particle having an average particle size in the range of 3 microns to 12 microns. In some embodiments, the implementation of the colloidal particles have an average particle size in the range of 5 to 10 microns and a pH range from 4 to 10, preferably 6 to 9, when measured as a suspension of 5% of the mass. In some embodiments, the implementation of the material based on silicon oxide is an abrasive on the basis of silicon dioxide with a low value of the absorption oil. In some embodiments, the implementation of the abrasive on the basis of silicon dioxide with low is the magnitude of the residual oil present in the compositions to care for the oral cavity according to the present invention at a concentration of from 5% of the mass. up to 40% of the mass. In some embodiments, the implementation of the abrasive on the basis of silicon dioxide with a low value of the absorption oil is present at a concentration of from 10% of the mass. up to 30% of the mass.

In some embodiments, the implementation of the abrasive filler is a member selected from silicic acids, calcium carbonates, calcium phosphates, oxides of aluminum and/or hydroxiapatite, metaphosphate sodium, metaphosphate potassium, tricalcium phosphate, digidratirovannogo of dicalcium phosphate, aluminum silicate, calcined alumina, bentonite, and surfactants (e.g., sodium lauryl sulphate, laurylsarcosine sodium and cocamidopropylbetaine) and other siliceous materials, and combinations thereof.

In some embodiments, the implementation of the abrasive filler may be used by itself as the sole abrasive in the preparation of a composition for oral administration according to the present invention, or in combination with other known abrasives for the tools for cleaning teeth. In some embodiments, the implementation of the total number of abrasive filler, present in compositions for cleaning teeth according to the present invention is from 5% of the mass. up to 60% of the mass. In some embodiments, the implementation of the abrasive filler is present in an amount of 10% of the mass. up to 55 wt. -%, when the song for brushing your teeth is a toothpaste.

c. Antimicrobial agents

Antimicrobial agents suitable for use in the present invention include non-ionic antibacterial agents, including compounds simple halogenated diphenyl ethers, such as simple 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Triclosan) and simple 2,2'-dihydroxy-5,5'-dibromodiphenyl ether. Other usable nonionic antibacterial agents include phenolic compounds, including phenol and its homologs, mono - and polyalkyl and aromatic halogenfrei, resorcinol and its derivatives and bisphenol compounds such phenolic compounds are described more fully in U.S. patent No. 5368844, the description of which is incorporated herein by reference.

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains an antimicrobial agent. In some embodiments, the implementation of the antimicrobial agent is a member selected from triclosan, chlorhexidine and its salts (for example, acetate, gluconate or hydrochloride), peroxides, phenols and their salts, domiphen bromide (pentadecane bromide), bremgarten, Zn salts, chlorophyll, salts of Cu, Cu gluconate, chlorophyll Cu, sodium lauryl sulphate, salts of Quaternary monoamine, such as chocolatecake benzyldimethylamine chloride or pyridinium salts, such as cetylpyridinium, and their combinations.

In some embodiments, the implementation of the antimicrobial agent is a nonionic antibacterial agent. In some embodiments, the implementation of the nonionic antibacterial agent is included in the composition for cleaning teeth at a concentration of 0.10% of the mass. up to 5% of the mass. In some embodiments, the implementation of the nonionic antibacterial agent is present in amount of from 0.3% of the mass. up to 1.2% of the mass.

d. Agents against dental caries

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains the agent against dental caries. In some embodiments, the implementation of the agent against dental caries is a fluoride ion source selected from inorganic fluoride salts, such as soluble salts of alkali metal, alkaline earth metal (for example sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, copper fluoride, such as fluoride, copper(I), zinc fluoride, barium fluoride, fertilitate sodium, fertilitate ammonium, porcelanato sodium, porcelanato ammonium, monophosphate sodium, mono - and differthat aluminum, fluorinated pyrophosphate sodium-calcium and combinations thereof.

e. Media tools for cleaning teeth

In some embodiments, the implementation of the composition for oral application is in accordance with the present invention contains any orally acceptable carrier for cleaning teeth. In some embodiments, the implementation of media for cleaning teeth contains a humidifier. Humectants suitable for use in the present invention include glycerin, sorbitol, xylitol and/or propylene glycol with a molecular weight ranging from 200 to 1000. As used herein, “sorbitol” refers to a material, generally commercially available as a 70% aqueous solution. In some embodiments, the implementation of the concentration of the humidifier is 5% of the mass. up to 70% of the mass. from the composition for oral administration.

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains water. The water used in the preparation of commercially acceptable toothpastes, should preferably be deionized and does not contain organic impurities. In some embodiments, the implementation of water is present in an amount of 15% of the mass. up to 30% of the mass. from the composition for oral administration. In some embodiments, the implementation of water is present in an amount of 10% of the mass. In some embodiments, the implementation of these amounts of water include the free water which is added in addition to that which is introduced with other materials, for example, sorbitol.

f. Surfactants

Surface-active substances is STV, suitable for use in the compositions of the present invention include any material that is able to achieve increased prophylactic action and to make compositions more cosmetically acceptable. Surfactant preferably is a cleansing material which imparts cleansing and foaming properties.

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains a surfactant. In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains a combination of surfactants. In some embodiments, the implementation of the surfactant is an anionic surfactant, including higher alkyl sulphates, such as sodium lauryl sulfate. In some embodiments, the implementation of the surfactant is a surfactant that is compatible with the enzyme, selected from dianionic surfactants based on polyoxyethylene, such as Pluronic® F127, Polyoxamer 407, Steareth 30, Polysorbate 20; amphoteric surfactants, such as cocamidopropylbetaine and cocamidopropylbetaine. In some embodiments, implementing the Tulane composition for oral administration in accordance with the present invention contains a surfactant or combination of surfactants at a total concentration of surface-active substances in compositions for cleaning teeth from 2% of the mass. up to 10% of the mass. In some embodiments, the implementation of the surfactant or combination of surfactants is present in an amount of 3.5% of the mass. to 6.5% of the mass.

g. Agents against dental plaque

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains the agent against dental plaque. In some embodiments, the implementation of the agent against dental plaque is selected from pyrophosphate salts, including pyrophosphate salt with two or four atoms of alkali metals such as Na4P2O7, K4P2O7, Na2K2P2O7, Na2H2P2O7and K2H2P2O7; sodium tripolyphosphate; long-chain polyphosphates such as sodium hexametaphosphate; cyclic phosphates such as trimetaphosphate sodium. In some embodiments, the implementation of the agent against dental plaque is present in the composition for cleaning teeth according to the present invention at a concentration of 1% wt. up to 5% of the mass.

h. Thickening agents

In some embodiments, the implementation of the composition for oral administration in accordance with the present invention contains a thickening agent. In some embodiments, the implementation of the thickening agent presented yet an organic thickening agent, selected from natural and synthetic gums and colloids, including thickening agents based on cellulose, such as carboxymethylcellulose; hydroxyethylcellulose, such as hydroxypropylcellulose, hydroxyethylcellulose; resins, such as xanthan gum; polyglycols with different molecular weights, sold under the trade name PolyoxTM; polyethylene glycol. In some embodiments, the implementation of the thickening agent is an inorganic thickening agent selected from compounds of amorphous silicon dioxide, such as compounds of colloidal silica, available under the trade name Cab-o-Sil® (Cabot Corporation and sold Lenape Chemical, Bound Brook, N.J.); Zeodent® 165 (J.M. Huber Chemicals Division, Havre de Grace, Md. 21078); Sylodent® 15 (Davison Chemical Division of W.R. Grace Corporation, Baltimore, Md. 21203); natural and synthetic clays; lithium silicate-magnesium (Laponite); silicate of magnesium - aluminum (Veegum). In some embodiments, the implementation of the thickening agent is present in the composition for cleaning teeth according to the present invention in amounts from 0.1% of the mass. up to 10% of the mass. In some embodiments, the implementation of the thickening agent is present in amounts of from 0.5 wt%. to 4.0% of the mass.

i. Antioxidants

In some embodiments, the implementation of the arrangement in accordance with the present invention contains an antioxidant. In some embodiments, the implement is placed antioxidant is selected from naturally occurring Tocopherols and derivatives thereof (for example, acetate vitamin E), vitamin C and its salts and derivatives (e.g. ascorbyl palmitate, Mg ascorbylpalmitate, ascorbylpalmitate), vitamin A and derivatives (vitamin A palmitate), tocotrienols, flavonoids, alpha hydroxy acids (e.g. citric acid, lactic acid, malic acid, tartaric acid) and their salts with Na, Ka and Ca, flavonoids, quercetin, phenolic benzylamines, propylgallate, octisalate, dodecylsulfate, butylhydroxyanisole (BHA, E320), butylhydroxytoluene (BHT, 2,6-di-tert-butyl-4-METHYLPHENOL, E321), lecithins, mono - and diglycerides of edible fatty acids esterified with citric acid, carotenoids, carotenes (e.g. α-carotene, β-carotene, lycopene) and their derivatives, phytic acid, lactoferrin, EDTA, EGTA), folic acid and its derivatives, ubiquinone and original, and derivatives thereof, ferulic acid and its derivatives, zinc and its derivatives (for example, ZnO, ZnSO4), selenium and its derivatives (e.g. selenium methionine), orthophosphate and salts of Na, K and Ca and monophosphoric acids, and their constituents, extracts and their fractions isolated from plants (for example, tea, green tea, algae, grape seed, wheat germ, chamomile, rosemary, oregano) and their combinations.

2. Compositions for topical use

Suitable for use fillers to the composition places the CSOs application in accordance with the present invention include, but not limited to, solvents, preservatives, abrasives (smoothing agents), antibacterial agents, agents inhibiting inflammation, agents, preventing irritation, agents that inhibit irritation, additional antimicrobial agents, antioxidants, astringents, antistatics, binders, (mineral) fillers, buffer solutions, materials, carriers, chelating agents (compounds that form chelates), cleaning agents, agents for care, surface-active substances, deodorizing agents, emulsification, enzymes, fibres, film-forming agents, film-forming substances), fixatives, foaming agents, substances for preventing foaming, foam stabilizers, enhancers foaming agents that promote gelation, gel-forming agents, agents, preserving moisture (humectants), wetting agents, substances that retain moisture, bleaching agents, bleach (e.g., hydrogen peroxide), agents that reduce friction, lubricants, agents for modulation of smell and/or taste, agents that reduce odor and/or taste, agents that enhance the smell and/or taste, cloud emulsions, plasticizers, agents for coatings, brightening agents, silicones, agents, cooling (mucous membrane)/skin (cooling substances), soothing agents (mucous membrane)/skin, agents, cleansing (mucous membrane)/leather, agents, care (mucous membrane)/skin agents, healing (mucous membrane)/leather, agents that protect the mucous membrane, UV filters, stabilizers, suspendresume agents, vitamins, fatty oils, waxes, lubricants, phospholipids, saturated fatty acids, single or multiple unsaturated fatty acids, alpha-hydroxy acid, PHA, liquefiers, dyes, agents to protect color, pigments, surfactants, electrolytes, silicone derivatives, polyols, organic solvents, silicic acid, calcium carbonate, calcium phosphate, aluminum oxide, fluoride, zinc salts, tin, potassium, sodium and strontium, pyrophosphates, hydroxyapatite.

a. Solvents

In some embodiments, the implementation of the composition for local application in accordance with the present invention contains a solvent. In some embodiments, the implementation of the solvent is selected from the radicals consisting of, but not limited to, water or aqueous solutions; oils such as triglycerides of capric or Caprylic acid; alcohols, diols or polyols and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol and combinations thereof.

b. Thickening agents

In some embodiments, the implementation to the position in accordance with the present invention contains a thickening agent. In some embodiments, the implementation of the thickening agent is selected from calcium carbonate, titanium dioxide, silicon dioxide, talc, aluminum oxide, dicalcium phosphate, tricalcium phosphate, magnesium hydroxide, thickening agents based on cellulose, such as carboxymethylcellulose, gidroxiapathitnaya cellulose, such as hydroxypropylcellulose, hydroxyethylcellulose, gum, such as xanthan gum, polyglycols and glycol, inorganic thickening agents (for example, compounds of amorphous silicon dioxide, natural and synthetic clays, silicate lithium-magnesium and magnesium silicate-aluminum) and their combinations.

EXAMPLES

Example 1

Activity, preventing fixing bacteria selected from the carbonate radical/urethane derivatives of menthol of the present invention, are examined using analysis using crystal violet (SOP No. ATO-5345-00) in 384-well the tablet in the concentration range of 0.0004-2500 ppm Antioxidant activity carbonate/urethane derivatives of menthol according to the present invention was determined by analysis using lipid peroxides (Kamiaya Biomedical Co., Seattle, WA), which is a colorimetric method that measures the recovery of the radicals cumene hydroperoxide. Antimicrobial study implemented Aut in accordance with SOP No. ATO-5308-00 to determine the minimum inhibitory concentration (MIC). Anti-inflammatory study carried out in accordance with SOP No. ATO-5307-00 by measuring the percentage inhibition of PGE2. The results of these studies are provided below in Table 1.

Table 1
Summary of activism against attached bacteria, antioxidant, anti-inflammatory and antimicrobial activity of these compounds - derivatives of menthol
Against attached bacteriaAntioxidantAnti-inflammatoryAntimicrobial

2-hydroxypropyl 2-isopropyl-5-methylcyclohexyl carbonate

2-isopropyl-5-methylcyclohexyl 2-(phenylcarbamoyl)phenylcarbamate

2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic


2-isopropyl-5-methylcyclohexyl 2-cyanovinylene

2-(diethylcarbamoyl)phenyl 2-isopropyl-5-methylcyclohexyl carbonate

2-isopropyl-5-methylcyclohexyl 4-(prop-1-EN-2-ylamino)phenylcarbamate

2-isopropyl-5-methylcyclohexyl 4-(prop-1-EN-2-ylamino)phenylcarbamate


2-hydroxyethyl 2-((2-isopropyl-5-methylcyclohexanone)carbonyloxy)benzoate

1-(hydroxymethyl)cyclohex-3-enyl)methyl 2-isopropyl-5-methylcyclohexyl carbonate
7-hydroxymethyl-2-isopropyl-5-methylcyclohexyl carbonate

9-hydroxyaryl 2-isopropyl-5-methylcyclohexyl carbonate

Example 2

5000 ppm 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic prepared in the form of toothpaste. One percent of fragrance cool crisp mint extra used for dissolving the compound is a derivative of menthol. Placebo produced no compound - derived menthol. Composition for cleaning teeth is provided below in Table 2.

Table 2
Composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic
One hundred DiyaM/X #Ingredientswt. -%In theory-Kaya weight
1660804CP purified water22,000110,0000
06076sodium saccharin USP0,3000 1,5000
06448sodium fluoride USP0,24301,2150
20641999,0% - 101,0% synthetic glycerin20,000of 100.0000
06198titanium dioxide USP, FCC0,50002,5000
12091sorbitol - not/korichnevymi, recrystallizes20,8500104,2500
306208propylene glycol USP0,50002,5000
12212sodium CMC 2000S-12 USP1,1005,5000
00527carrageenan IOTA (LB9505)0,40002,000
406993 abrasive (Zeodent® 115) on the basis of dental silicon dioxide20,0000of 100.0000
01885thickening agent (Zeodent® 165) on the basis of dental silicon dioxide1,50007,5000
5890259Aroma cool crisp mint extra (K91-4448)1,00005,0000

2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic
0,50002,5000
06286Powder sodium lauryl NF1,50007,5000
Total % mass/mass loadof 100.0000500,0000

A. Absorption and aging

Composition for cleaning teeth of Example 2 is evaluated with respect to its absorption on the disk HAP. The results, shown below in Table 3, show that the absorption of the compound is a derivative of menthol, 2-isoprop is l-5-methylcyclohexyl 2-hydroxyphenylacetate (0.5% in the formula), much smaller than triclosan (0.3% in Colgate Total®). However, a mixed suspension of Example 2 and Total® increases the absorption of the compound is a derivative of menthol. This observation says that the polymer Gantrez®, which is missing in Example 2, but has in Total®, can improve the absorption of 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate. Gantrez® is a swelling in water, synthetic, anionic, linear copolymer of polycarboxylic used to optimize effectiveness against plaque, for linear compounds, compositions tools for cleaning teeth. Removing the compound is a derivative of menthol from the composition, with a shelf life of 3 months at room temperature, detective by HPLC, is 100%.

Table 3
The absorption of 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate
Sampleppm
0.5% of 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic15
0.25% of 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic + 0.25% polymer Gantrez®17

B. anti-Inflammatory activity

Protivovospalitel the optimum activity of 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate examined in the analysis using PGE 2and compare with Triclosan. Based on this analysis of the anti-inflammatory activity of the compound is a derivative of menthol according to the present invention is comparable with Triclosan (table 4).

Table 4
The effectiveness of the pure compounds in the analysis of PGE2
Net connectionIC50
2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic0,38 µm
Triclosanof 0.48 μm

Connection - derived menthol according to the present invention additionally assessed through analysis using the 5-plex and using Luminex. The results, shown in Table 5, demonstrate that 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic significantly inhibited the production of IL-6 and TNF-α.

Table 5
The effectiveness of the pure compounds in the analysis using the 5-plex, using Luminex (compared to unhandled control)
Net connectionGM-CSFIL-1b IL-6TNF-α
2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic6%13%33%81%
Triclosan4%13%37%58%

Anti-inflammatory activity of the composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, research analysis using PGE2and compared with the corresponding placebo and Colgate Total®. Anti-inflammatory function of a means for cleaning the teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic comparable with Total® and better than the corresponding placebo, on the basis of this analysis (see Figure 1). Composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, also demonstrates its effectiveness on other cytokines (table 6).

Table 6
The effectiveness of the composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic in the analysis using the 5-plex, using Luminex (compared to the fallow control)
Net connectionGM-CSFIL-1bIL-6IL-8TNF-α
Composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic76%6%97%21%99%
Placebo46%0%67%0%91%
Colgate Total®37%37%93%--96%
CDC12%9%83%--83%

C. Antioxidant

Connection - derived menthol 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic shows antioxidant efficacy comparable with vitamin E, in a simple solution (see Figure 2). Composition for cleaning teeth, containing 2-isopropyl-5-methylcyclohexyl the 2-hydroxyphenylarsonic, shows comparable efficacy, compared with the corresponding placebo (see figure 3).

D. Preventing bone loss

Connection - derived menthol 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic significantly suppresses mRNA MMP-13 stimulated by parathyroid hormone (PTH), within 4 hours (see Figure 4). This suggests that 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic could potentially provide a beneficial effect in preventing bone loss.

E. antimicrobial effectiveness

Connection - derived menthol 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic shows good antimicrobial efficacy in the study of the minimum inhibitory concentration (MIC) (table 7).

Table 7
Antimicrobial efficacy in vitro
ConnectionMIC (against A.v)
2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonicof 4.9 ppm
Triclosan1,9 ppm

Connection - derived menthol 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic also shows good ant the microbial efficiency on an artificial model of the oral cavity (see Figure 5).

F. Expression of metabolites

Compounds - derivatives of menthol according to the present invention, prepared in the form of toothpaste, may have the ability to activate or suppress at least one of compounds selected from compounds generated by amino acid metabolism; a compound generated in the urea cycle; compounds generated by glutathione conversion; compounds generated during lipid metabolism; a compound generated during the metabolism of carbohydrates, the connections generated through the metabolism of nucleic acids, vitamins and co-factors.

As discussed in the description and in the examples above, the contact of the mouth with 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate prepared in the form of toothpaste, can suppress the production of the following biomarkers: GM-CSF, IL-1b, IL-6, IL-8, TNF-α and MMP-13; however, the suppression of the biomarker correlates with a decrease of at least one symptom associated with periodontal disease.

Contact the oral cavity with 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate prepared in the form of toothpaste, can suppress the production of one or more of the following metabolites: inosine, gipoksantina, guanosine, guanine, leucine, isoleucine, lysine, methionine, phenylalanine, Proline is, serine, threonine, tryptophan, tyrosine, valine, phenylacetic acid, α-hydroxymetoprolol acid, 5-aminovaleric acid, choline, glycerol-3-phosphate and N-acetylneuraminic acid.

Contact the oral cavity with 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylacetate prepared in the form of toothpaste, can activate the production of one or more of the following metabolites: uric acid, reduced glutathione, oxidized glutathione, ascorbic acid and glutamine.

1. The use of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate formula:

as anti-inflammatory drugs for local treatment of the mouth, such as periodontal diseases.

2. The use of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate formula:

as an antioxidant for the local treatment of the mouth, such as periodontal diseases.

3. The use of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate formula:

as an antimicrobial agent for local treatment of the mouth, such as periodontal diseases.

4. The composition having anti-inflammatory activity for the local treatment of oral cavity, for example the PE odontalgic diseases, comprising an effective amount of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate and at least one filler.

5. Composition with antioxidant activity for the local treatment of the mouth, such as periodontal diseases, comprising an effective amount of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate and at least one filler.

6. A composition having antimicrobial activity for the local treatment of the mouth, such as periodontal diseases, comprising an effective amount of 2-isopropyl-5-methylcyclohexyl-2-hydroxyphenylacetate and at least one filler.

7. Composition according to any one of claims 4 to 6, in which at least one filler selected from surface-active agents, desensitizing agents, bleaching agents, agents for the control of dental plaque, antibacterial agents, abrasives, including silica, binders, thickening agents, detergents, adhesive agents, modulators of foaming agents for modifying pH, agents for creating a pleasant feeling in the mouth, sweeteners, flavourings, colourings, preservatives, and combinations thereof.



 

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