Compositions for oral cavity hygiene and methods

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to dentistry, and can be used for the treatment of conditions, related with the increased expression of MMP-13, selected from the group, consisting of loss of one or more teeth fixation, teeth loss, teeth mobility, formation of recesses, bone tissue loss and a combination of two and more of the said conditions. For this purpose the application of 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylcarbonate in the production of a medication for the treatment of the said conditions is claimed. A composition for teeth care, containing an orally acceptable carrier and a therapeutically effective quantity of a MMP-13 inhibitor in the form of 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylcarbonate is also claimed.

EFFECT: group of inventions provides the effective treatment of the said conditions die to effective MMP-13 suppression.

3 cl, 5 tbl, 5 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under provisional patent application U.S. No. 61/288359, filed December 21, 2009, which is incorporated in this document by reference.

PRIOR art

Matrix metalloproteinases (MMP) constitute a natural family of calcium-dependent and zinc-dependent endopeptidases, which are found in most mammals. It was suggested that increased expression and activation of MMP or the imbalance between MMP and MMP inhibitors play a role in the pathogenesis of diseases characterized by destruction of extracellular matrix or connective tissues.

The organic matrix is a major component of the periodontium (gums, cement, periodontal ligament and alveolar processes). Matrix metalloproteinases (MMP) are involved in periodontal reconstruction matrix. Destructive MMP destroy various components of the extracellular matrix in physiological and pathological conditions. Pathological over-production of destructive MMP leads to inadequate and excessive destruction of the matrix. Over-production of destructive MMP promotes resorption of bone tissue: first, due to the destruction of osteoid (not mineralized and noloop�organized bone matrix), and then the destruction of the Mature matrix, which may lead to clinical manifestations of periodontitis, including atrophy of the gingival margin, the formation of pockets, loss of fixation, tooth mobility and loss.

One of the main destructive MMP is MMP-13, which plays a role in the destruction of extracellular matrix. The expression level of MMP-13 correlated with clinical indicators of periodontitis. MMP-13 is detected in the diseased periodontal tissues and gingival fluid, but in a healthy oral mucosa of MMP-13 is missing. Uitto et al. American Journal of Pathophysiology, 152(6), 1489 (1998).

Matrix metalloproteinase-13 was identified as the enzyme responsible for bone resorption and cartilage destruction in rheumatoid arthritis and osteoarthritis. It is also known that the level of MMP-13 is elevated in gingival fluid in patients with chronic periodontitis. In addition, it is known that MMP-13 contributes to the destruction of both bone and connective tissue in patients with periodontal disease and periodontitis. Ilgenli, T. et al. Oral Diseases, 12, 573 (2006).

Currently for the treatment of diseases of the periodontium used antimicrobials, nonsteroidal anti-inflammatory drugs (NSPs), bisphosphonates and tetracyclines. These tools often fail to provide adequate relief of symptoms and, apparently, do not have a significant pliniana natural progression of the disease. In addition, most of these therapeutic modalities is associated with serious side effects. Therefore, there is a great need for safe and effective therapeutic treatment of such diseases.

Although there are many ways of treatment that are aimed at different aspects of periodontal disease, there remains a need to develop improved oral compositions containing active ingredients, which are aimed at destructive ISMS that contribute to the resorption of bone tissue and cause tissue destruction. There is a particularly urgent need to develop improved oral compositions targeting MMP-13, which contributes in bone resorption and destruction of the connective tissue.

Summary of the INVENTION

In a first aspect a method of suppressing matrix metalloproteinase MMP-13, comprising administering to the subject an effective therapeutic amount of an inhibitor of matrix metalloproteinases MMP-13, wherein the inhibitor of the matrix metalloproteinases MMP-13 is selected from the group consisting of NDM (mediasizename material) cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylamine and combinations thereof.

This method provides a new fur�change the effective suppression of matrix metalloproteinase MMP-13 and, consequently, the treatment or prevention of conditions resulting from the expression of MMP-13. The authors of the present invention unexpectedly found that the NDM from cranberry extract, acetyl-keto-β-boswellic acid (ACBK), resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexyl carbonate, and combinations thereof can effectively inhibit the matrix metalloproteinases MMP-13.

In a second aspect, the composition for oral hygiene, comprising an orally acceptable carrier and a compound selected from the group consisting of mediasizename material of cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylamine and combinations thereof, wherein the compound provided in an amount effective to suppress MMP-13.

In the third aspect - composition for oral hygiene, comprising a compound selected from the group consisting of mediasizename material of cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexyl carbonate and combinations thereof, used for the treatment or prophylaxis of conditions resulting from the expression of MMP-13.

�also provides a method for the treatment of destruction of the extracellular matrix, loss of fixation, tooth loss, tooth mobility, education, pockets and bone loss.

DETAILED description of the INVENTION

Throughout this document the ranges are used as the symbol of any size within the specified range. As the end points of the range can be set to any value within the range. In addition, all the sources cited in this document are incorporated herein by reference in its entirety content. In case of conflicting definitions between the present disclosure and the cited reference has the advantage the present disclosure.

Unless specifically stated otherwise, all percentages and amounts listed here and in other places of the description, should be understood as percentages by weight. Given the number based on the active weight of the material.

When used in this document, the term "flavor" refers to any material or mixture of materials that enhance the flavor composition.

Composition

In some embodiments, the invention provides composition comprising a therapeutically effective amount of an inhibitor of MMP-13 and orally acceptable carrier. In some embodiments, the inhibitor of MMP-13 is selected from the group�, consisting of mediasizename material of cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylamine and combinations of two or more of these substances.

In some embodiments, the inhibitor of MMP-13 is selected from the group consisting of mediasizename material of cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylamine and combinations of two or more of these substances.

In some embodiments, the composition further includes a tool against plaque, bleach, antibacterial agent, cleaning agent, flavor, sweetener, binder, surface active agent, a modulator of foam, an abrasive, a pH modifier, a humectant, a flavoring agent, a dye, a tool against the formation of Tartar (anticellulite), the source of fluoride ions, stimulates salivation, a nutrient or a combination of two or more of these substances.

Some embodiments of the invention further comprise a sweetener, alcohol, glycerin, sorbitol, propylene glycol, polyethylene glycol,a polymer, alkylpolyglycoside (APG), Polysorbate, castor oil or menthol.

In some embodiments, the sweetener is a saccharin or saccharin sodium. In some embodiments, the alcohol is an ethanol. In some embodiments, the polymer is a POLOXAMER®407 or PLURONIC®F108 (both products available from BASF Corporation). In some embodiments, the polyethylene glycol is a PEG40.

You can use any orally acceptable natural or synthetic flavoring, such as flavoring oils, flavoring aldehydes, esters, alcohols, and similar materials and combinations thereof. Flavoring agents include vanillin, sage, marjoram, parsley oil, peppermint oil curly, cinnamon oil, Wintergreen oil (methyl salicylate), peppermint oil, clove oil, Bay oil, anise oil, eucalyptus oil, citrus oils, fruit oils and essences, including derived from lemon, orange, lime, grapefruit, apricot, banana, grape, Apple, strawberry, cherry, pineapple, etc., flavorings obtained from beans and nuts, such as coffee, cocoa, Cola, peanut, almond, etc., adsorbed and encapsulated flavors or mixtures thereof. This document understood�e "flavors" are also included in the ingredients which creates in the mouth a pleasant sensation of smell and/or cause other sensory effects, including the effects of cold or heat. Such ingredients include menthol, methylacetate, Mantellate, camphor, eucalyptus oil, eucalyptol, anethole, eugenol, Cassia, Oksanen, [alpha]-irison, propylgallate, thymol, linalool, benzaldehyde, cinnamic aldehyde, N-ethyl-p-methane-3-carboxamid, N,2,3-trimethyl-2-isopropylmalonic, 3-l-methoxypropan-l,2-diol, glycerinated cinnamic aldehyde (HCA), metampicillin (MHA) and mixtures thereof. One or more fragrances can optionally be presented in a total quantity from about 0.01% to 5%, while in other embodiments (also optional) from about 0.05 to 2%, from about 0.1% to 2.5% and from about 0.1 to 0.5%.

Sweeteners useful in the present invention include dextrose, Polydextrose, sucrose, maltose, dextrin, dried invert sugar, mannose, xylose, ribose, fructose, levulose, galactose, corn syrup, partially hydrolyzed starch, hydrogenated starch hydrolysate, sorbitol, mannitol, xylitol, maltitol, isomalt, aspartame, neotame, saccharin and salts thereof, energy, intense sweeteners-based dipeptides, cyclamate, dihydrochalcone and mixtures thereof.

Means causing mouth RA�personal feelings, include materials that, when included in the composition to give it the desired structure or cause other sensations. Such means may include agglomerated particles of silicon dioxide, which are able to disintegrate under mechanical excitation, in particular a series of substances SORBOSIL®BFG (for example, BFG 10, 50 BFG, BFG 100, etc.), silica CBT60S, CBT70 or AC33/43, commercially available from PQ Corporation, Valley Forge, Pennsylvania.

Dyes useful in the present invention include pigments, paints, varnishes and agents, giving the song a special luster or reflectivity, for example mother-of-pearl tools. In various embodiments, the dyes act, creating on the surface of the teeth is white or light colored coating, that is an indicator of locations on a dental surface, which entered into effective contact with the composition, and/or modifying the appearance of the composition, especially its color and/or opacity to make it more attractive for the consumer. You can use any orally acceptable colorant, including dyes and pigments FD&C (food, drugs and cosmetics), talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminosilicate, silicon dioxide, titanium dioxide, zinc oxide, Kras�th, yellow, brown and black iron oxide, releasescontact ammonium, manganese violet pigment, ultramarine blue, titanium mica, bismuth oxychloride, and mixtures thereof. One or more dyes can optionally be present in the composition in a total amount of approximately from 0.001% to 20%, for example from about 0.01% to 10% or from about 0.1% to 5%.

In some embodiments, the composition can further comprise an optional abrasive, useful, for example, as polishing agents. You can use any orally acceptable abrasive, but the type, fineness (particle size) and amount of abrasive should be selected so that during normal use of the composition of the enamel of the teeth are not subjected to excessive abrasion. Suitable optional abrasives include silica, e.g., precipitated silica, or in a mixture with alumina, insoluble phosphates, calcium carbonate, and mixtures thereof. Among insoluble phosphates useful as abrasives include orthophosphate, polymetaphosphate and pyrophosphates. Notable examples are the dihydrate dicalcium orthophosphate, calcium pyrophosphate, tricalcium phosphate, polymetaphosphate calcium and insoluble polymetaphosphate sodium.

In some embodiments, the comp�the optional positions includes a tool against the formation of Tartar (anticellulite). Means against the formation of Tartar, useful in the present invention include salts of any of the agents of this class, for example alkali metal salts and ammonium salts: phosphates and polyphosphates (for example pyrophosphates), polyaminopropyl acid (AMPS), polyaluminosilicate, poliolefinas, diphosphonates such as azacycloheptane-2,2-diphosphonates (e.g., azacycloheptane-2,2-difosfonovoy acid), N-methylacetophenone-2,3-difosfonovoy acid, ethane-1-hydroxy-1,1-difosfonovoy acid (EHDP), ethane-1-amino-1,1-diphosphonate and phosphonocrotonate acid. Useful inorganic phosphate and polyphosphate salts include monobasic, dibasic and tribasic sodium phosphates, sodium tripolyphosphate, metropolitical, mono-, di-, tri - and tetranitro pyrophosphates, trimetaphosphate sodium, sodium hexametaphosphate and mixtures thereof.

In some embodiments, the composition optionally includes a source of fluoride ions, useful, for example, as a means against caries. You can use any orally acceptable powder source of fluoride ions, including fluoride of potassium, sodium and ammonium, as well as monophosphate, tin fluoride, fluoride India, aminofluorides, such as olaflur (N'-octadecyltrimethylammonium-N,N,N'-Tris(2-ethanol)-divergent) and mixtures thereof. One or more ion sources f�ora may not necessarily be presented in oral compositions in an amount which provides a clinically effective dose of soluble fluoride ions.

In some embodiments, the compositions optionally include a means of stimulating the production of saliva, which is useful, for example, to moisturize dry mouth. You can use any orally acceptable vehicle for the stimulation of salivation, including, without limitation, food acids such as citric, lactic, malic, succinic, ascorbic, adipic, fumaric and tartaric and mixtures thereof. One or more agents stimulating the production of saliva, can be represented in such total amount which is effective in stimulating the production of saliva.

In some embodiments, the compositions optionally comprise a nutrient. Suitable nutrients include vitamins, minerals, amino acids and mixtures thereof. Vitamins include vitamins C and D, thiamine, Riboflavin, calcium Pantothenate, nicotinic acid, folic acid, nicotinamide, pyridoxine, cyanocobalamin, para-aminobenzoic acid, bioflavonoids, and mixtures thereof. Nutritional supplements include amino acids (such as L-tryptophan, L-lysine, methionine, threonine, levocarnitine and L-carnitine), lipotropic substances (such as choline, Inositol, betaine, and linoleic acid), and mixtures thereof.

In various embodiments, the implementation�ment of the invention the oral composition according to the invention specifically does not swallow, but rather a delay in the oral cavity for a time which is sufficient for a useful target effect. In other portable embodiments (such as lozenge, mint pellet, a bead, a wafer, a liquid suitable for introduction into the oral cavity from a small portable nebulizer, liquid, intended for the insertion into the mouth of a small portable bottles with dropper, or soft chewable tablet) oral composition specially swallow optionally after a delay in the oral cavity for a time which is sufficient for a useful target effect.

Compositions for oral health in various embodiments of the invention preferably have the form of means for care of teeth. The term "means for care of teeth" when used throughout this description means paste, gel or liquid composition. Means for care of teeth can exist in any desirable form, such as a toothpaste (including pasta with deep stripes, surface stripes, multi-layer pastes, pastes having the outside gelcoat), tooth powder, granules, liquid mouthwash, mouthwash, lozenge, gel for teeth, periodontal �spruce, liquid for tinting the surface of the teeth, chewing gum, soluble, partially soluble or insoluble film or strip, wafer wet handkerchief or napkin, implant, foam, pellet, dental floss, liquid, intended for introduction into the oral cavity from a small portable nebulizer (aerosol can), liquid, intended for introduction into the oral cavity from a small portable bottles with dropper, soft chewable tablet ("gum"), or any combination of these forms. When used in this document, the term "orally acceptable carrier" refers to a material or combination of materials that are safe for use in the compositions, that is, within a reasonable ratio of benefit and risk.

When used in this document, the term "orally acceptable excipient" or "orally acceptable carrier" refers to any excipient that is useful for the preparation of any of the above described means for care of teeth. Suitable orally acceptable fillers include, for example, one or more of the following materials: solvent, an alkaline agent, humectant, thickener, surfactant, abrasive, anticellulite agent, a pigment, a flavoring agent, a dye, potassium salt, an antibacterial agent, desensibiliziruyuschee� funds tools that reduce the appearance of spots and discoloration, as well as mixtures thereof.

In some embodiments of the invention also proposes a composition selected from the group consisting of: pastilles, peppermint pellets, granules, wafers, a small portable nebulizer containing this mixture in liquid form intended for introduction into the oral cavity in the form of a spray, a small portable bottle containing this mixture in liquid form intended for introduction into the oral cavity in the form of drops, and soft chews.

Adelitasway material (NDM) from cranberry extract get from concentrate cranberry juice. Cranberry juice contains substances of high molecular weight (NDM), which inhibit the adhesion of bacteria to cells-owners, as well as coaggregation many oral bacteria. NDM from cranberry extract was obtained in accordance with the methodology described Weiss E, Lev-Dor, R., Kashmamn, Y., Goldhar, J., Sharon, N., Ofek, Itzhak, J. Am. Dent. Assoc. 129, 1719 (1998).

Acetyl-keto-β-boswellic acid (ACBK) is a useful active compound isolated from the plantBoswelliaand have antibacterial, anti-inflammatory and antioxidant activity.Boswelliais a genus of trees that produce extracts that have anti-inflammatory properties, incl�I connection Boswellia acid. Suitable extracts are produced, for example,Boswellia sacra,B. frereana,B. serrateandB. papyriferaand their subtypes.

Resveratrol (3,5,4'-trihydroxystilbene), the parent compound of a family of molecules, including carbohydrates and polymers, is a potent antagonist of AGR (aryl-hydrocarbonic receptors), as described in French patent application No. 9805673, registered on may 5, 1998, It is an antifungal agent or a phytoalexin produced by plants classified as spermatophytes, the most important representatives of which are grapes, peanuts and pine (Soleaset al., 1997,Clin Biochemistry, 30:91-113). As antagonist AGR resveratrol, the chemical name of which is 3,5,4'-trigonometrie generally useful for the prevention of the toxic effects associated with exposure to environmental ligands EPR, including, for example, halogenated and polycyclic aryl-hydrocarbons, polyaromatic hydrocarbons and polychlorinated biphenyls. In addition, it was demonstrated that resveratrol prevents the induction of proinflammatory cytokine IL-1 beta ligands AGR (Casper et al. 1999,Molecular Pharmacology, 56:784-790).

Methods of application

Some embodiments of the invention relate to methods of treating pathological conditions associated�'s with the abnormal expression of MMP-13, which consist in the introduction to the needy in this animal a therapeutically effective amount of an inhibitor of MMP-13. In some embodiments, the composition is suitable for administration in the oral cavity of the animal.

In some embodiments of the invention proposed the use of an inhibitor of MMP-13 in the manufacture of a medicine for the treatment of pathological conditions associated with abnormal expression of MMP-13.

In other embodiments, the inhibitor of MMP-13 is selected from the group consisting of NDM cranberry extract, acetyl-keto-β-Boswellia acid, resveratrol, 2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic, 4-acetamidophenyl 2-isopropyl-5-methylcyclohexylamine and combinations of two or more of these substances. In some embodiments, the pathological condition associated with the expression of MMP-13, selected from periodontal disease, destruction of the extracellular matrix, the mobility of the teeth, dental caries, loss of fixation, loss of teeth, forming pockets or bone loss.

EXAMPLES

Parathyroid hormone (PTH) stimulates the transcription of MMP-13. The experimental method uses PTH to stimulate MMP-13 in cells UMR 106-01, which are cells derived from the lines osteoblastic glue�OK rats. Cell line UMR 106-01 provides a useful model system to study the effects of PTH on osteoblastsin vitro.Cm.,for example, Qin, L.et al.Journal of Biological Chemistry, 278(22), 19723 (2003).

Material

Parathyroid hormone (rat PTH 1-34) were purchased from Sigma.

Cell culture

Cells UMR 106-01 were cultured in minimal nutrient medium eagle (EMEM) with the addition of 25 mm Hepes pH 7,4, 1% nonessential amino acids, 100 units/ml penicillin, 100 µg/ml streptomycin and 5% fetal calf serum.

Quantitative RT-PCR in real time

Cells UMR 06-01 were seeded into 12-well plates and cultured for 2-3 days in a culture medium for cell cultivation. After the merger, the cell culture medium was replaced with 1% fetal calf serum (5% fetal calf serum) for fasting cells during the night. Cells were preincubated with the active ingredient for 15 minutes and then incubated with PTH (10-8M) for 4 hours.

Total RNA from cells UMR 106-01, stimulated with or without PTH PTH, was isolated with TRIzol reagent. Total RNA (0.1 μg) back was transcribed into cDNA with a set of Superscript company Invitrogen according to the manufacturer's instructions. PCR was performed on cDNA using primers, the sequences of which are listed below. Samplefile performed adds 2.5 μl cDNA to a PCR mixture (22,5 ál) containing each primer (0.2 μm) and 12.5 µl of a mixture of Platinum SYBR Green qPCR SuperMix UDG (Invitrogen). The reaction was preincubated at 50°C for 2 minutes for the decontamination of dU-containing DNA by UDG, and then at 95°C for 2 minutes to inactivate UDG and Taq activation. The PCR program continued, performing 49 cycles of denaturation at 95°C for 15 seconds, annealing and elongation of the primers at 60°C for 30 seconds. Relative quantification of gene expression was performed using the 2-delta delta CT, with multiple changes in gene expression was determined relative to control samples. All samples were normalized to β-actin.

Primer sequences

Rat gene MMP-13

5'-GCCCTATCCCTTGATGCCATT-3' (sense)

5'-ACAGTTCAGGCTCAACCTGCTG-3 ' (antisense)

Rat β-actin

5'-AGCCATGTACGTAGCCATCC-3' (sense)

5'-ACCCTCATAGATGGGCACAG-3' (antisense)

Example 1

Was tested inhibitory effect mediasizename material (NDM) of cranberry extract against PTH stimulated the expression of MMP-13.

NDM from cranberry extract prepared by the method described by Weiss et al,J. Am. Dent. Assoc. 129(12), 1719 (1998). NDM from cranberry extract received, dialyzer cranberry juice using a cut-off dialysis bag high molecular weight. Remaining in the bag of a substance that does not come out, p�ecstasy adelitasway material (NDM).

NDM from cranberry extract in a concentration of 10 part./million, 4 part./million and 1 part./million in simple solution showed inhibitory activity against MMP-13. The multiplicity of changes in gene expression of MMP-13 relative to the control sample is shown in table 1.

Table 1
AverageStandard deviation
Negative control1,070,35
PTH72,882,01
Cranberry NDM 10 part./million0,780,32
Cranberry NDM 4 part./million1,220,15
Cranberry NDM 1 part./million2,571,41
PTH + cranberry NDM 10 part./millionOf 33.03The 11.04
PTH + cranberry NDM 4 part./million46,729,27
PTH +cranberry NDM 1 part./million 54,495,86

The results shown in table 1, show that NDM from cranberry extract reduces the gene expression of MMP-13, PTH stimulated. This suggests that NDM from cranberry extract prevents the destruction of the matrix by reducing the expression of MMP-13.

Example 2

Was tested the inhibitory effect ACBK against PTH stimulated the expression of MMP-13. ACBK bought in the Sabinsa Corporation.

ACBK at a concentration of 10 part./million in simple solution showed inhibitory activity against MMP-13 that are shown in table 2. The multiplicity of changes in gene expression of MMP-13 relative to the control sample is shown in table 2.

Table 2
AverageStandard deviation
Negative control0,890,25
PTH406,05122,16
ACBK 10 part./million1,450,62
PTH + AK�BK 10 part./million 59,7718,33

The results shown in table 2, demonstrate that ACBK reduces the gene expression of MMP-13, PTH stimulated. This suggests that ACBK prevent the destruction of the matrix by reducing the expression of MMP-13.

Example 3

Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic compound found in grapes, especially in its peel and seeds. Resveratrol was purchased in the Sabinsa Corporation.

Resveratrol at a concentration of 100 parts./million, 50 part./million, 10 part./million, 1 part./million and 0.1 part./million in simple solution showed inhibitory activity against MMP-13 (table 3). The multiplicity of changes in gene expression of MMP-13 relative to the control sample is shown in table 3.

Table 3
AverageStandard deviation
Negative control0,680,28
PTHOf 54.646,03
Resveratrol 100 frequent./million1,09 0,04
Resveratrol 50 part./million0,380,22
Resveratrol 10 part./million0,650,09
Resveratrol 1 part./million0,710,06
Resveratrol 0,1 frequent./million1,070,24
PTH + resveratrol 100 frequent./million0,650,24
PTH + resveratrol 50 part./million0,910,79
PTH + resveratrol 10 part./millionTo 1.860,69
PTH + resveratrol 1 part./million19,971,81
PTH + resveratrol of 0.1 part./million46,025.78% was established

The results shown in table 3, demonstrate that resveratrol reduces the expression of the gene of MMP-13, PTH stimulated. This suggests that resveratrol prevents the destruction of the matrix by reducing the expression of MMP-13.

Example 4

Compound A (2-isopropyl-5-methylcyclohexyl 2-hydroxyphenylarsonic) has the following characteristic structure:

Compound a at a concentration of 7 parts./million in simple solution showed inhibitory activity against MMP-13 (table 4). The multiplicity of changes in gene expression of MMP-13 relative to the control sample is shown in table 4.

Table 4
AverageStandard deviation
Negative control1,190,16
PTH445,18111,95
Compound A (7 frequent./million)7,412,65
PTH + compound A (7 frequent./million)14,6743,68

The results shown in table 4, demonstrate that compound a reduces the gene expression of MMP-13, PTH stimulated. This suggests that compound a prevents the destruction of the matrix by reducing the expression of MMP-13.

Example 5

Compound B (4-acetamidophenyl 2-isopropyl-5-methylcyclohexyl carbonate) has the following characteristic structure:

Compound B at a concentration of 10 part./million in simple solution showed inhibitory activity against MMP-13 (table 5). The multiplicity of changes in gene expression of MMP-13 relative to the control sample are shown in table 5.

Table 5
AverageStandard deviation
Negative control1,240,24
PTH257,0320,82
Compound B (10 part./million)5.78% was established1,94
PTH + compound B (10 part./million)49,8625,03

The results shown in table 5, demonstrate that the compound B reduces the gene expression of MMP-13, PTH stimulated. Because the level of MMP-13 correlated with periodontal clinical indices, we can assume that the connection B �reduviidae matrix destruction by reducing the level of MMP-13, stimulated by parathyroid hormone (PTH).

1. The use of 4-acetamidophenyl 2-isopropyl-5-methylcyclohexanone to manufacture a drug for the treatment of a condition associated with increased expression of MMP-13, which is selected from the group consisting of loss of fixation of one or more teeth, tooth loss, tooth mobility, education, pockets, bone loss, and combinations of two or more of these conditions exist.

2. Composition for care of teeth, containing a therapeutically effective amount of an inhibitor of MMP-13 and an orally acceptable carrier, where the inhibitor of MMP-13 is a 4-acetamidophenyl 2-isopropyl-5-methylcyclohexanone.

3. Composition for care of teeth according to claim 2, where the composition is presented in the form, which is selected from the group consisting of: toothpaste, toothpaste with deep strips, toothpaste surface with stripes, multi toothpaste, toothpaste with the outside gel coat, tooth powder, granules, liquid for rinsing the mouth, a dental elixir, lozenge, gel for teeth, periodontal gel, liquid for tinting the surface of the teeth, chewing gum, soluble, partially soluble or insoluble films or strips, wafers, wet handkerchief or tissue, the implant, foam, pellets, dental floss, liquid, PR�naznachennoe for introduction into the oral cavity from a small portable nebulizer, liquid intended for introduction into the oral cavity from a small portable bottles with dropper, soft chewable tablets, or a combination of two or more.



 

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FIELD: medicine.

SUBSTANCE: vaseline-lanolin (2:1) based ointment 74.0 g is added with a 40% herbal alcoholate 25 ml of the following composition (in the mixture of a herbal raw material: alcohol base - 1:5), weight fractions: nodding catchfly herb - 3 weight fractions, pot marigold blossom - 1 weight fraction, spiraea herb - 1 weight fraction, with the ointment added with clove oil 1.0 ml. The prepared ointment is applied on inflamed periodontal and oral mucosal tissues for 20 minutes 2-3 times a day for 14 days; the patient is advised not to drink or eat for 1 hour.

EFFECT: method enables increasing clinical effectiveness by combining high antimicrobial, immunomodulatory, anti-allergic and keratoplastic activity and ease of use.

3 ex

FIELD: medicine.

SUBSTANCE: on completion of the antibacterial course, sodium hyaluronate in the form of a gel is single administered by means of a syringe with a needle of 2 cm long or more under an oral mucosa along a transitory fold into the points within projections of apexes of dental roots 1.4, 2.4, 3.6, 4.6 and into a point on the mid-line of projections of apexes of anterior roots of upper and lower jaw respectively. The needle is brought under the mucosa on the lower jaw by transecting the projections of an alveolar counterfort line. On the upper jaw - by transecting the projections of the upper counterfort line. While removing the needle from the mucosa, the syringe content is squeezed out. Sodium hyaluronate is administered into both jaws in an amount of 3.0 to 4.4 ml.

EFFECT: method enables increasing the jaw bone density within counterforts, as well as soft and bone tissues of periodontium.

4 tbl, 16 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to dentistry and concerns treating chronic generalised periodontitis. Implementing the above method is ensured by a complex preparation in the form of an ointment of the following composition: Vaselin - lanolin base (1:1) - 88.5 g, 70% ipecac infusion - 5.0 g, 70% scholar tree - 5.0 g, Ecdysterone - 0.02 g; eucalyptus oil - 1.0 g. The oil is applied as a therapeutic periodontal applicate on a gingival surface following application anaesthesia with 10% lidocaine, chairside oral hygiene, drug-induced treatment of the gingival margin with 1% Iodinolum and separation of salivary glands in the oral cavity, once a day for 2 hours for 4 weeks; the patients are recommended not to eat or drink for two hours. The preparation composition particularly provides capillary-reinforcing, anti-inflammatory, reparative and anaesthetic action.

EFFECT: method of treating is easy to use, physiologically-friendly, and provides the complete recovery.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) : or a salt thereof, wherein R1 and R5 are independently selected from H, OH and alkoxy; R2-R4 and R6-R8 are independently selected from H, OH, F, Cl, Br and I; R9 and R10 are C2-C8 alkenyl; under the condition that at least one of R1, R5 and R7 is OH or alkoxy; at least one of R2-R4, R6 and R8 is F, Cl, Br or I; and R2 and R6 are Cl. The invention also relates to an antibacterial composition and treatment methods.

EFFECT: improved properties.

18 cl, 7 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: agent for treating inflammatory periodontal and oral mucosal diseases associated with Helicobacter infection contains silicone glycerohydrogel of Si(C3H7O3)4·6C3H8O3·24H2O and bismuthate tripotassium dicitrate of formula [HOC(CH2COO)2COO]2K3Bi in the following proportions, wt %: bismuthate tripotassium dicitrate 1.0-2.5; silicone glycerohydrogel - the rest up to 100. The method of treating inflammatory periodontal and oral mucosal diseases consists in a combination of systemic standard anti-Helicobacter therapy and a local effect of the above agent on the involved region. Particularly, treating periodontitis is ensured by applying the agent on the gingival surface and introducing it into the gingival pockets once a day for 10 min; the therapeutic course makes 5-6 days. The oral mucosal diseases are treated by applying the agent 0.1 mm thick with a glass spatula on the involved oral mucosa 2 times a day; the therapeutic course is 12 days.

EFFECT: formulation of the agent provides achieving the high therapeutic effect; the dosage form is easy to be applied locally.

4 cl, 2 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method includes the preparation of a carious cavity, opening the tooth cavity, creation of an access to root canals, extension of their orifice. Removal of a decayed material from the root canals and their drug treatment are carried out. After that, performed are: wide opening of the apical tooth orifice, mechanical and drug removal of periapical pathological exudative formations in the focus of periapical inflammation through the root canal. Before filling the canal with a filling material the gel "Lamifaren" is introduced into the focus of periapical destruction. Such introduction is performed three times after a day under temporary stopping. The gel "Lamifaren" is introduced inside in a dose of 50 g 2 times per day for 30 days.

EFFECT: application of the invention accelerates bone tissue regeneration due to the active release of an active substance calcium alginate, provides stable remission due to local and systemic detoxifying effect.

2 ex

FIELD: medicine.

SUBSTANCE: treatment is two-staged; at the first stage, gingival pockets are rinsed with a stream of 1.5% hydrogen peroxide in a cannula delivered through the gingival pockets around the teeth. If observing the exposed furcation of premolars and molars, the cannula is brought under the root furcation. Thereafter, the gingival pockets are similarly rinsed with an aqueous tincture of garden sage herb for 3-5 days, then with an aqueous tincture of camomile blossom for 3-5 days, an aqueous tincture of plantain leaves daily for the following 3-5 days; each rinsing procedure is followed by applications of cotton drains impregnated with the respective aqueous herbal tincture introduced by the cannula on gingival mucous membranes for 1 hour; that is combined with prescribing oral baths with the respective aqueous herbal tincture introduced by the cannula daily 5-7 times a day. The second stage involves instillations of Normoflorin-B or Bifidumbacterin in the cannula delivered through the gingival pockets around the teeth, brought under the furcation if observing the exposed furcation of premolars and molars; the gingival mucous membranes are laid with cotton drains with the above preparation for 2 hours daily for 5-10 days.

EFFECT: method enables providing the higher clinical effectiveness.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oral care agents. What is presented is using an oral care composition in the form of a mouthwash containing a fluoride ion source and a ternary polymer system consisting of xanthane gum, carboxymethyl cellulose and copovidone for dental erosion and/or wear control. This composition is also effective in dental caries control.

EFFECT: using fluoride ions in a combination with the ternary polymer system provides the better protection of the dental surface against dental erosion as compared to using fluoride ion only.

7 cl, 4 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents an agent for preventing or reducing pigmentation, containing a compound presented by the following formula (1) its stereoisomer and/or its pharmacologically acceptable salt, wherein: R1 represents a hydrogen atom or an alkyl group with a linear or branched chain having 1-4 carbon atoms; R2 represents a hydrogen atom or an unsubstituted aliphatic hydrocarbon group having 1-4 carbon atoms; R3 represents an unsubstituted aromatic group having 5-15 carbon atoms, substituted by an alkyl group having 1-6 carbon atoms, by an alkoxy group containing an alkyl chain having 1-6 carbon atoms, or by a phenyl group; R3 also represents an aromatic group having 5-15 carbon atoms; n is equal to 1 or 2, and m represents an integer falling within 0 to 3.

EFFECT: preparing the agent for preventing or reducing pigmentation.

10 cl, 10 ex, 6 tbl

Hair care product // 2553347

FIELD: cosmetology.

SUBSTANCE: hair care product is made in the form of gel, shampoo, lotion. All embodiments comprise aqueous vegetable extracts, phosphonate complex containing potassium-sodium salts of oxyethylidenebisphosphonic acid or their mixture with trisodium salt hexahydrate of phosphonformic acid and a cosmetically acceptable base.

EFFECT: hair care product is recommended for use in medicinal and cosmetic purposes for all ages for prevention and treatment of dystrophic changes in hairy part of the head.

5 cl

FIELD: cosmetology.

SUBSTANCE: cosmetic product contains an aqueous solution of trace elements in amounts close to the daily demand of the human body, succinic acid which provides a high level of energy production (ATP), and also a bioregulatory complex obtained from hair follicles of calves, which stimulates proliferation of dormant cells of hair follicles.

EFFECT: increased efficiency of cosmetic product for complete prevention of hair loss caused by a wider range of reasons, and for partial or complete restoration of hair.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of dry extract of aronia melanocarpa as hypolipidemic agent. Claimed extract is obtained by double extraction with 95% ethanol, acidified with hydrochloric acid, at heating on water bath.

EFFECT: claimed invention ensures obtaining agent with expressed ability to reduce level of triacylglycerols, total cholesterol and cholesterol in atherogenic lipoproteins of low density in blood serum.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: drops possessing antiviral and immunomodulatory effects characterised by the fact that they represent a 95% ethanol infusion of wild strawberry leaves and fruit specified in: red raspberry fruit, mountain ash fruit, bilberry fruit, blood-red hawthorn fruit, cinnamon rose fruit; 15-25 mg of the substance in 1 ml of the infusion.

EFFECT: drops possess pronounced antiviral and immunomodulatory effects.

15 tbl, 5 ex

FIELD: food industry.

SUBSTANCE: invention relates to a polyphenol grape extract, a compound for oral administration, a food product, beverage, a taste additive, a nutraceutical product, a revitalising composition and therapeutic remedy including the said grape extract. According to the invention, the grape extract contains nearly 5-15 wt % of monomers, nearly 5-20 wt % of dimers, nearly 3-10 wt % of trimers, nearly 2-10 wt % of tetramers and nearly 2-10 wt % of pentamers.

EFFECT: grape extract reduces blood pressure with patients suffering from prehypertonic condition or metabolic syndrome.

27 cl, 4 dwg, 8 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: minor amputation of the foot with the further necrectomy is performed. After the application of an antimicrobial bandage and drainage, the wound is hermetised from the environment by the creation of a negative pressure above the wound in a combination with drug treatment. The reatment is performed in two steps. At the first step the wound with the antimicrobial bandage and drainage is first hermetised from above with an adhesive film, with the creation and support of the negative pressure not lower than 80 mm Hg. Urokinase 500000 U is additionally introduced daily intravenously by drop infusion per 100 ml of physiological solution, Vessel-Due-F in a dose of 600 LU per 100 ml of physiological solution and VAP 20 - alprostadil in a dose of 40 mcg per 100 ml of physiological solution. In addition Antistax in capsules is introduced to the patient. At the second stage active 24-hour vacuum aspiration with the change of the negative pressure from 10 to 80 mm Hg within a day is carried out. Additionally introduced is Vessel-Due-F in a dose of 1 capsule with 250 LU 2 times per day between meals and Antistax. At the first and second stages Antistax is introduced in a dose of 2 capsules in the morning 30-40 minutes before meal, daily. Duration of each stage constitutes not less than 7 days.

EFFECT: increase of the treatment efficiency due to the complete and timely purification of the wound from pathological exudates, elimination of the progression of the purulent-necrotic process, increase of the regenerative activity of tissues, activation of local immunity, recovery of microcirculation and oxygenation of the affected tissues.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to nanoparticles for encapsulating biologically active compounds. The nanoparticle contains a casein matrix, a basic amino acid and a metal selected from a group including a divalent metal, a trivalent metal and combinations thereof. Disclosed is a method of producing nanoparticles, which includes preparing an aqueous solution of a casein source and a basic amino acid and adding to the prepared solution an aqueous solution of a metal selected from a group including a divalent metal, a trivalent metal and combinations thereof to obtain a suspension containing formed nanoparticles. Another version of the method of producing nanoparticles includes mixing an aqueous solution of a casein source and a basic amino acid with a solution of a biologically active compound and adding to the obtained mixture an aqueous solution of a metal selected from the group to obtain a suspension containing formed nanoparticles. Nanoparticles obtained using said methods are used in combination with a carrier to prepare food products, as well as in pharmaceutics and cosmetics.

EFFECT: invention enables to obtain nanoparticles with high stability and low polydispersity.

40 cl, 17 dwg, 13 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to a two-phase mouth wash liquid and a method for use thereof. The disclosed two-phase mouth wash liquid contains a hydrophilic phase, a hydrophobic phase, a hydrotrope and a preservative, wherein the preservative contains (i) sodium benzoate and (ii) potassium sorbate and/or methylisothiazolinone (MIT), and the hydrotrope component contains glycerine and/or propylene glycol. The mouth wash liquid contains (a) 0.05-0.11 wt % sodium benzoate and (b) 0.05-0.2 wt % potassium sorbate and/or 0.0005-0.01 wt % MIT. The hydrophilic phase of the mouth wash liquid can additionally contain cetylpyridinium chloride in amount of 0.01-0.1 wt %, wherein the disclosed method of improving oral health includes using an effective amount of said liquid in the mouth of a subject to reduce the level of cariogenic bacteria.

EFFECT: use of said combination of preservatives coupled with said hydrotrope provides good resistance to microbial contamination without any adverse effect on taste properties or appearance of the mouth was liquid.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

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