Antibacterial 3,5-disubstituted 2,4-dihydroxybiphenyls, derivatives thereof and related methods

FIELD: medicine.

SUBSTANCE: invention refers to dentistry, namely to an oral antiplaque composition, containing an orally acceptable carrier and an antibacterial effective amount of compound of formula (I). The tooth-paste or gel composition containing at least one moistening agent and at least one abrasive compound, and the oral antiplaque composition. Method of inhibiting bacterial growth in an animal's oral cavity by applying the antibacterial composition including the compound of formula (I) on the surface of the animal's oral cavity.

EFFECT: declared composition shows high antibacterial efficiency.

25 cl, 1 ex

 

Link to close application

This application claims priority from provisional patent application U.S. 60/662991 filed March 18, 2005, the contents of which are incorporated into this description by reference.

The level of technology

Many painful conditions associated with bacteria in the mouth. Plaque is a soft Deposit which forms on the tooth surface as a by-product of bacterial growth. It is usually assumed that the cause of gingivitis, an inflammation or infection of the gums and alveolar bone plaque is caused by bacteria and toxins, which are formed as by-products of the bacteria. In addition, plaque provides a nidus for the formation of Tartar or dense deposits. Periodontitis, as generally believed, occurs when if not removed, plaque hardens into Tartar (deposition), which affects the periodontal ligament. With the growth of plaque and deposits gums begin to recede, which can lead to continuous infection and potentially the loss of teeth.

To prevent or treat these pathological condition, to care for the oral cavity, such as toothpaste and liquid for mouthwash or rinses include bactericidal additives. The use of antimicrobial compounds in the oral cavity have the t tends to slow down the formation of plaque and close oral infections.

Effective against plaque of antibacterial compounds in the composition for cleaning teeth depends on many factors, including the presence of other ingredients that can interfere with its effects. For example, certain cationic antibacterial compounds and certain non-ionic antibacterial compounds lose its effectiveness when produced with certain anionic surfactants or other anionic active ingredients such as phosphates, preventing the deposition of Tartar. In many samples it is preferable to use an antibacterial composition, which does not take adverse interaction with anionic components.

Extracts from Magnolia officinalis ("Magnolia") and especially from the bark contain biphenylene antibacterial compounds that include honokiol and tetrahydrocannabinol. It has been found that the extracts have antibacterial effectiveness when introduced, for example, in the formulation of toothpaste.

Extracts prepared from natural sources, such as Magnolia, are variable in composition and contain many compounds other than certain active substances for which the extract is prepared. Activity of compounds of the extract is not characterized by Danimarca, so it is impossible to predict how changes in the structure of any of the compounds of the extract would affect its antibacterial effectiveness. In addition, the composition of the extracts can vary from season to season and depends on geographic area. In the antibacterial activity of the extracts in vivo is far from optimal.

Description of the invention

Derivatives of 3',5-disubstituted 2,4'-dihydroxy - and-dialkoxy-1,1'-biphenyl show inhibitory activity against a number of bacteria that are normally found in the oral cavity. Connections are used as protivoraketnyi and/or antibacterial components of the means for cleaning the teeth and other oral compositions. The invention provides various oral compositions containing the compounds according to the invention and an orally acceptable carrier. In different embodiments of the invention provided with antibacterial and protivoraketnyi oral composition in the form of a toothpaste or gel, tooth powder, liquid for washing or mouth rinses, lozenges, chewing gum, food strips, etc. Antibacterial compounds are conveniently synthesized using conventional reaction combinations, alkylation, recovery and demethylation, although you may use any means of synthesis known or developed in the technology.

The invention provides the characteristic disubstituted 2,4'-definaly and derivatives, represented by the formula:

except honokiol and tetrahydrocannabinol. R1and R2means independently hydrogen or lower C1-4-alkyl and R3and R4means independently of alkenyl or alkyl having from 1 to 20 carbon atoms, provided that R3and R4not mean at the same time 2-propanol or n-propyl, when R1and R2each signify hydrogen. Preferably, R contains from 1 to 8 carbon atoms.

Proposed protivoraketnyi oral compositions which contain an orally acceptable carrier and an antibacterial effective amount of at least one of the compounds of formula (I). In various embodiments, the compositions contain from about 0.001 to about 10 wt.% the compounds of formula (I). Without limitation, orally acceptable carrier may be a liquid carrier, a powder carrier or carrier which dissolves after contact with saliva and other components of the oral environment. In other embodiments, the carrier may include the type of the resin. Proposed various oral compositions in the form of a toothpaste or gel dentifrice, rinse the mouth, lozenges, chewing gum and food strips. Other forms of the composition include, without limitation liquid suitable for painting a dental surface, the wafer wiping the sludge is a napkin implant thread for cleaning the teeth and forms that are eaten or Joutsa small mammals, such as dogs or cats.

In other embodiments, the invention provides a toothpaste or gel compositions which contain at least one moisturizer, at least one abrasive material and an antibacterial effective amount of at least one of the compounds of formula (I). In various embodiments, toothpaste or gel compositions additionally include means against plaque, such as phosphate, alternative combined with synthetic anionic polycarboxylates. In the example embodiment of toothpaste or gel composition includes

of 0.001-5 wt.% the compound (I);

1-70 wt.% moisturizer;

1-70 wt.% abrasive compounds;

0.5 to 2.5 wt.% tetrahydrofolate (TNPF); and

1-10 wt.% nutritionista (NTPF).

In other embodiments, the invention provides a method of inhibiting the growth of bacteria in the oral cavity of the animal, whether or not a human, comprising applying to the surface of the oral cavity antibacterial composition for an animal comprising at least one compound of formula (I). In various embodiments, the method includes brushing and rinsing compositions containing the compound of formula (I). As is mentioned above, the method can be carried out by applying the antibacterial composition in various forms, such as toothpastes, tooth gels, tooth powder, rinsing the mouth, tinted gels, soluble or edible strips, chewing gum, lozenges, etc. In different variants of embodiment of the invention, the surface treatment of oral antibacterial compositions containing the compounds of formula (I), leads to the reduction or removal of coatings for the prevention or treatment of gingivitis, to improve bad breath and to the prevention of periodontal disease.

In various embodiments, the antibacterial compounds are selected from derivatives of 3',5-disubstituted-2,4'-dihydroxy-1,1'-biphenyl represented by formula (II):

where R3and R4independently represent alkenyl or alkyl with 1-20 carbon atoms, provided that R3and R4are not both 2-propanole or n-propylene. Formula (II) corresponds to the formula (I), when R1and R2each signify hydrogen.

In some embodiments of formulas (I) and (II), R3and R4each represent alkyl groups. In other embodiments, R3and R4each mean alkeneamine group. In the following embodiments, one of the groups R3and R4means alkyl, and the other means of alkenyl. In the versions of hypoxia group, R 3and R4are the same. In various embodiments, oral compositions containing the compounds of formula (I) and/or (II), shows antibacterial efficacy, comparable with the efficiency of formulations containing triclosan.

The size and nature of the alkyl or alkenyl groups R3and R4choose in order to achieve the desired combination of solubility and bioavailability of the compounds of formulas (I) and (II). Compounds of formula (I) and (II) tend to be soluble in fats; the distribution of compounds between the fat and water phases is reflected by the value of log P, is well known to specialists in this field. In various embodiments, the log P value of 3 to 5 is preferred. In General, the more groups R3and R4(that is, the greater the number of carbon atoms in the alkyl or alkenyl groups), the higher the solubility in fat and lower solubility in water. The size of the groups R3and R4also affects the molecular weight and thus on the molar amount of the compounds (I) or (II)supplied in one dose. In a preferred embodiment, the group R3and R4are chosen so that the solubility of the compounds (I) in water is 1 mln or more, preferably 5 mln or more and more preferably 10 mln or more.

Compounds described herein may synthesize the I by any known means, including developed in the field of technology. Obtaining the compounds (I) and (II) for options, where R1and R2mean hydrogen or methyl, shown in the following diagram

Dibromsalan intermediate compound (III) to alkylate dimethylselenide intermediate compounds (IV), which will demetrious with obtaining the compounds (V). Compounds (IV) and (V) in the reaction scheme correspond to the formulas (I) and (II), respectively, according to the invention. Dibromsalan intermediate compound can be alkylated, for example, in the normal conditions of the Grignard reaction, as shown. R-X represents alkyl or alkenylamine, where R is defined above for R3and R4and X represents halogen, preferably bromine. When the Grignard reaction is used only halide, synthesize variant of the compounds (I) and (II)in which R3and R4the same. If desirable, may be used a mixture of halides to obtain the variants of the compounds (I) and (II)in which R3and R4different. In various embodiments, a full or partial dealkylation (shown as full demethylation) of the resulting structures (IV) proceeds by known methods, is shown in the diagram, by mixing with tribromide boron in dimethylaniline at -10°C. the Initial products (III) can be easily Sint is optimized. In a non-limiting example, para-iodoanisole combined with 2-methoxy-phenylboronic acid to obtain an intermediate product, which bromilow with the formation of compound (III). In the example of obtaining the reaction mix is carried out in the presence of palladianatravertin, potassium carbonate and a catalyst phase transfer, such as tetrabutylammonium. Bromination product of combination reaction proceeds easily, for example, with Br2in ethylene dichloride at 0°C.

According to one alternative scheme for the synthesis dibromsalan intermediate compound 10 is introduced into the reaction alkenylamine (shown alternative 2-bromopropene 20a and brothelbased 20b) to produce alkenylamine 30a and 30b, where R1and R2each represent methyl. As shown, alkenylamine 30a and 30b can be recovered by obtaining the appropriate alkylamine 40a and 40b with optional subsequent dialkylammonium (shown as demethylation) diol in 50. According to another scheme of synthesis dibromsalan intermediate compound 10 is converted into an intermediate dialdehyde 60 with subsequent condensation type Clausena with ketone (shown acetone) to produce another intermediate connection 70 with chetyrehmagnitnoy chain. You can use other ketones to obtain circuits with more than 4 carbons. Dual link is b and oxoprop side chain intermediate compound then establish a connection 80 with saturated alkyl chains for R 3and R4. Alkyl groups (shown as a methyl group) can be removed by obtaining 2,4'-dihydroxytoluene 40b.

Antibacterial compound according to the invention is administered in a composition together with an orally acceptable carrier to provide oral compositions having different shapes, such as mentioned above. Depending on the form of the composition orally acceptable carrier may be a liquid carrier, powder carrier, soluble solid carrier, a resin, a film-forming polymer or polymers, and so forth.

Various compositions according to the invention contain an orally acceptable carrier and an antibacterial effective amount of the compounds of formula (I). An effective amount of antibacterial agent is provided by either a single compound or mixture of compounds represented by formula (I). The blend of compounds can be obtained, for example, by intentionally adding a separately synthesized compounds or a reaction product containing a mixture of compounds with different substituents R1, R2, R3and R4.

As used here, the term "media" refers to the components of the individual oral compositions in which the antibacterial compound or compounds of formula (I) is introduced into the composition as an active ingredient. In the ranks embodiments, the media covers all the components of the oral composition except for the antibacterial compound (I). In other aspects, the term refers to the components, such as inactive ingredients, carriers, binders, etc. that, as usually understood as specialists in this field of technology, functioning as a carrier, filler or other relatively inert ingredient. In other words, the term media is used in different ways depending on the context. Depending on the context, the oral compositions include other components in addition to the active compound (I) and the media. However, in all contexts, the components of the oral compositions according to the invention can be divided into media components and antibacterial compounds (I).

As a non-limiting example in the case of toothpastes media can represent the system water/moisturizer, which provides a large mass fraction composition. Alternatively, the carrier in the composition of the toothpaste can be a water, moisturizer and other functional components in addition to antibacterial system. Regardless of context, a specialist in the art will understand that the composition of toothpaste contains both antibacterial compound (I)and orally acceptable carrier for the composition.

In the case of a rinse for the mouth, the media, as generally believed, is a water-alcohol liquid component is, which is dissolved or dispersed antibacterial compound (I). The soluble toffee media, as generally understood, includes a solid matrix material that dissolves slowly in the mouth on the surfaces of the oral cavity. Chewing gum carrier includes a base resin, while in the edible strip carrier includes one or more film-forming polymers.

In all the above examples, the oral composition in any form includes antibacterial compound (I), a suitable carrier in an appropriate form and other additives or functional materials that are required to obtain oral compositions with desirable properties. Additional active substances and functional materials described below.

In addition to the biologically acceptable carrier for oral compositions according to the invention contain an antibacterial effective amount of the compound (I). In various embodiments, an antibacterial effective amount is from about 0,001% to about 10% calculated on the total weight of the oral composition, such as from 0.01% to about 5% or from about 0.1% to about 2%. The effective amount will vary depending on the form of the oral composition. For example, in toothpastes, tooth gels and tooth powders effective amount of SOS is to place typically at least about 0.01%, and more preferably at least about 0.05%. In some preferred embodiments, the compound (I) is present in toothpaste, gel or powder at the level of 0.1% or more to achieve the desired level of antimicrobial activity. Typically, the compound (I) is administered in an amount of 5% or less, preferably about 2% or less and more preferably about 1% or less. The maximum concentrations of these limits can be used, but sometimes they are less preferred for economic reasons. In various embodiments, the optimal efficiency is achieved when from about 0.1% to about 1%, particularly from about 0.1% to about 0.5%, or from about 0.1% to about 0.3 percent, all percentages calculated by weight of the total oral composition.

The number used in tooth gels, tooth powders, chewing gums, edible strips, etc. comparable with that used in toothpastes.

In liquids for washing and rinsing the mouth with an antibacterial effective amount of the compound (I) is usually in the lower region of the above-mentioned intervals. Typically, the compound (I) used at the level of from about 0,001% (or 10 mlns) to approximately 1% or less. Preferably, the compound (I) is about 0.5% or less, or about 0.2% or less. Prefer the LNA compound (I) is about 0.01% (100 mlnc) or more. In various embodiments, the compound (I) is present in amount of from 0.03 to 0.12 wt.%.

Presented here provisions for structure (I) is also applicable to structures (II), which illustrates a variant or a variant of structure (I), where R1and R2each mean hydrogen atoms. In addition to the antibacterial compound (I) many of the active ingredients and functional materials include a variety of compositions according to the invention. Such materials include, without limitation, abrasives, humectants, surfactants, anti-Tartar, thickeners, viscosity modifiers, anticaries tools, odorants, coloring tools, additional bactericidal additives, antioxidants, anti-inflammatories, and so forth. They are added to toothpastes, gels, rinses, gum, tablets, strips and other forms of oral compositions according to the invention according to known methods.

In various embodiments, an existing invention, where the carrier composition for oral care mouth - solid or paste, the oral composition preferably includes acceptable to the teeth with an abrasive material, which is used to Polish tooth enamel or to provide a whitening effect. Non-limiting examples include kremnezemnyi abrasives, such as silicagel and precipitated oxides of silicon. Commercial options include ZEODENT® 115, sold by Haber (J. M. Huber), and SYLODENT® XWA, SYLODENT® 783 or SYLODENT® XWA 650 from Damianovskogo Chemical Division of Grace (Davison Chemical Division of W. R. Grace and Co.). Other useful abrasive cleaning teeth include, without limitation, metaphosphate sodium, metaphosphate potassium, tricalcium phosphate, dicalcium phosphate dihydrate, aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof.

The abrasive is present in an effective amount. In embodiments where the oral composition is in solid or pasty form, the abrasive material is generally present in an amount of from about 10% to about 99% of the oral composition. In certain embodiments of the polishing material is present in amounts ranging from about 10% to about 75% (e.g., from about 10% to about 40%, or from about 15% to about 30%) in toothpaste, and from about 70% to about 99% in a tooth-powder.

In yet another embodiment, the composition according to the invention includes at least one moisturizer, useful, for example, to prevent hardening of tooth paste when exposed to air. Any orally acceptable moisturizer can be used, including, without limitation, a lot of the languid spirits, such as glycerin, sorbitol, xylitol and low molecular weight polyethylene glycol. Most moisturizers also functions as sweeteners. One or more moisturizers optionally present in a total amount from about 1% to about 70%, for example from about 1% to about 50%, from about 2% to about 25% or from about 5% to about 15 wt.% structure.

In yet another embodiment, the composition according to the invention includes at least one surfactant, providing, for example, compatibility with other components of the composition and thus resulting in increased stability, facilitating cleaning of the tooth surface by washing steps and provide the foam with stirring, for example, during brushing with a composition for cleaning teeth according to the invention. Can be any orally acceptable surfactant, most of which is anionic, nonionic or amphoteric. Suitable anionic surfactants include, without limitation, water-soluble salts

With8-20-alkylsulfonyl, sulfated monoglycerides of fatty8-20acids, sarcosinate, taurate etc. Illustrative examples of these and other classes include nutriceutical is at, nitrosulfonic of monoglycerides coconut nutriceuticals, acrylourethane, acrylourethane and nutrimedical-bansilalpet. Suitable nonionic surfactants include, without limitation, surfactants, polymers, esters polietilenoksidnye, ethoxylated fatty alcohols, ethoxylated alkyl phenols, oxides of tertiary amines, tertiary phosphine oxide, diallylsulfide etc. Suitable amphoteric surfactants include, without limitation derivatives of secondary and tertiary aliphatic C8-20amines having the anionic group such as carboxylate, sulfate, sulfonate, phosphate or phosphonate. A good example are the betaines of propylamide acids of coconut oil. One or more surfactants randomly present in a total amount from about 0.01% to about 10%, for example from about 0.05% to about 5% or from about 0.1% to about 2 wt.% structure.

In another embodiment, the composition includes orally acceptable vehicle against Tartar. Can be one or more of these components. Suitable means against Tartar include, without limitation phosphates and polyphosphates (for example pyrophosphates), polyaminopolycarboxylic the (PAPS), the citrate trihydrate zinc, polypeptides, such as poliasparaginovaya and polyglutamine acid, polyaluminosilicate, poliolefinas, diphosphonates, such as azacycloheptane-2,2-diphosphonates (e.g., azacycloheptane-2,2-diphosphonic acid), N-methylethanolamine-2,3-diphosphonic acid, ethane-1-hydroxy-1,1-diphosphonic acid (EGDF) and ethane-1-amino-1,1-diphosphonate, phosphonocrotonate acid and salts of these components, for example their melodramatycheskye and ammonium salt. Useful inorganic phosphates and polyphosphates illustrative include monobasic, dibasic and trekhosnovnye nativespace, nutritionist (NTPF), metropolitical, mono-, di-, tri - and tetrahydrofolate, distritofederal, nutritionalist, nutrigenetic, etc. in which the sodium may be replaced by potassium or ammonium. Other useful anti-Tartar include polycarboxylate polymers. They include polymers or copolymers of monomers containing carboxyl groups such as acrylic acid, methacrylic acid and maleic acid or anhydride. Non-limiting examples include copolymers of poly(vinylethylene ether/maleic anhydride (PVME/MA), such as copolymers available under the brand name GANTREZ® from ISP, Wayne, New Jersey, USA. However, other useful tools against subneg the stone include connection linking metal ion in the chelate complex comprising hydroxycarbonate acids such as citric, fumaric, malic, glutaric, and oxalic acids and their salts, and aminopolycarboxylate acids such as ethylenediaminetetraacetic acid (EDTA). One or more anti-Tartar optionally present in the composition in a quantity effective against plaque, typically from about 0.01% to about 50%, for example from about 0.05% to about 25% or from about 0.1% to about 15 wt.%.

In various embodiments, the composition against plaque includes a mixture of nutritionista (NTPF) and tetrahydrofolate (TNPF). In various embodiments, the ratio TPF/NTPF varies from about 1:2 to about 1:4. In a preferred embodiment, the first ingredient, active against Tartar, TNPF, is present in an amount of from about 1 to about 2.5%, and the second ingredient, active against Tartar, NTPF, is present in an amount of from about 1 to about 10%.

In various embodiments, the composition against Tartar further includes a synthetic anionic polycarboxylate polymer. In one embodiment, the synthetic anionic polycarboxylate is present in an amount of from about 0.1% to about 5%. Drugom variant synthetic anionic polycarboxylate is present in amount from about 0.5% to about 1.5%, most preferably in amount of about 1% of the oral care mouth. In one embodiment according to the present invention means against plaque includes a copolymer of maleic anhydride and methylvinylether simple ester, such as, for example, the product GANTREZ® S-97, discussed above.

In various embodiments, the ratio TPF/NTPP/synthetic anionic polycarboxylate varies from approximately 5:10:1 to about 5:20:10 (or 1:4:2). In one embodiment, the tool against plaque composition for the care of the oral cavity includes TNPF, NTPF and polycarboxylate, such as a copolymer of maleic anhydride and methylvinylether ether in the ratio of approximately 1:7:1. In a non-limiting embodiment, the tool against Tartar contains TNPP in the amount of from about 0.5% to about 2.5%, NTPF in the amount of from about 1% to about 10%, and the copolymer of maleic anhydride and methylvinylether ether in an amount of from about 0.5% to about 1.5%.

In yet another embodiment, the composition according to the invention includes at least one thickener, useful, for example, to give the composition the desired consistency and/or sensation when chewing. Can be any orally acceptable thickening agent, including, without limitation, carbomer, also known as carboxyvinyl polymer clay is s, carragenan, also known as Irish moss and more particularly ι-carrageenan (ι-carrageenan), cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (CMC) and their salts, such as sodium CMC, natural resins, such as karaya, xanthan gum, gum Arabic and tragakant, colloidal aluminum silicate-magnesium, colloidal silica, etc. One or more optional thickeners are present in a total amount from about 0.01% to about 15%, for example, from about 0.1% to about 10%, or from about 0.2% to about 5 wt.% structure.

In yet another embodiment, the composition according to the invention includes at least one viscosity modifier is useful, for example, slow sucks or separation of ingredients or to support the re-dispersion with stirring of the liquid composition. Can be any orally acceptable viscosity modifier, including, without limitation, mineral oil, petrolatum, clay and organomodified clay, silica, etc. One or more of the optional viscosity modifier is present in a total amount from about 0.01% to about 10%, for example from about 0.1% to about 5 wt.% structure.

In another embodiment, the composition includes orally acceptable source of fluoride ions. Can prisutstwu shall be one or more of such sources. Suitable sources of fluoride ions include salt, fluoride, monitoroff and forcricket and amine fluorides, including olaflur (N'-octadecylamine-diamine-N,N,N'-Tris(2-ethanol)divergent). Any such salt, which is orally acceptable, may be used, including, without limitation, salts of alkali metal (e.g. potassium, sodium, ammonium, tin(2) and India etc. are Commonly used water-soluble fluoride-releasing salt. One or more fluoride-releasing salts optionally present in an amount to provide a total of from about 100 to about 20000 mlnc, from about 200 to about 5000 mln, or from about 500 to about 2500 mln fluoride ions. When sodium fluoride is the only fluoride-releasing salt, in the illustrative composition may contain from about 0.01% to about 5%, from about 0.05% to about 1% or from about 0.1% to about 0.5 wt.% sodium fluoride.

Other components include, without limitation, odorants, coloring agents and other active ingredients such as antioxidants and anti-inflammatories. Components injected into the oral compositions according to known procedures.

Toothpastes and gels contain a large amount of moisturizers and usually abrasive connection of the giving or compounds for cleaning teeth. They entered into a composition with various active ingredients, such as anticaries tools, connections against plaque, anti-inflammatory agents, etc. in addition to the antibacterial compound (I).

Rinsing liquid for rinsing the oral cavity contain the active compound (I) in a liquid medium such as water or water/ethanol. In General, the compositions contain a large amount of solvent, up to 98 or 99 wt.%. The active compound (I) is not necessarily enter into the composition of surfactants, coloring agents, fragrances and other active ingredients.

Orally acceptable diluent or carrier in the toffee, bead or tablet is necrogenic, solid, water-soluble polyhydric alcohol (polyol)such as mannitol, xylitol, sorbitol, malic, hydrolyzed hydrogenated starch, gidrirovanny glucose, hydrogenated disaccharides, hydrogenated polysaccharides and the like in an amount of from about 85% to about 95% of the total composition. Emulsifiers such as glycerin and lubricant for tableting, in small quantities from about 0.1 to 5%, can be included in a tablet, bead or lozenges to ease the preparation of tablets, pastilles and lozenges. Suitable lubricants include vegetable oils, such as coconut is the new oil, magnesium stearate, aluminum stearate, talc, starch and carbowax. Suitable nicaraguense chewing gum include Kappa-carrageenan, carboxylmethylcellulose, hydroxyethyl cellulose, etc.

The toffee, bead or tablet may not necessarily be covered with coating material, such as waxes, shellac, carboxylmethylcellulose, copolymer of polyethylene/maleic anhydride or Kappa-carrageenan to further increase the time it takes for the tablet or the toffee to dissolve in the mouth. Uncoated tablet or toffee dissolves slowly, providing delayed the release rate of the active ingredients in approximately 3-5 minutes. Accordingly, the solid dosage forms such as tablets, pastilles and lozenges under this option, provide a relatively longer period of time of contact of the teeth in the mouth with an antibacterial substance and remedy against Tartar according to the present invention.

The chewing gum formulations usually contain the basis of chewing gum, one or more softeners, at least one sweetening means and at least one flavoring in addition to the antibacterial composition (I). Preferably, the gum does not contain sugar.

Materials fundamentals of gum known in the art and include natural or SYN is eticheskie basis. Representatives of natural gums or elastomers include chicle, natural rubber, jelutong, Balata, guttapercha, Lechi Caspi, sorva (sorva), Gattaca (guttakay), resin crown and Perilla or mixtures thereof. Representatives synthetic resins or elastomers include copolymers of butadiene and styrene, polyisobutylene and copolymers of isobutylene and isoprene. The basis of the gum include in the finished chewing gum in a concentration of from about 10% to about 40% and preferably from about 20% to about 35%.

Plasticizing/softening tools include, without limitation, gelatin, waxes and mixtures thereof in amounts from about 0.1% to about 5%. Sweetening the tool used in the practice of this invention may be selected from a wide range of materials and includes the same artificial and polyol as one sweeteners used in the preparation of tablets, pastilles and lozenges. Polyol as one sweeteners, such as sorbitol and malic, are present in the chewing gum composition of the present invention in amounts from about 40% to about 80% and preferably from about 50% to about 75%. In a non-limiting embodiment, the artificial sweetener agent is present in the chewing gum composition of the present invention in amounts from arr is siteline 0.1% to about 2% and preferably from about 0.3% to about 1%.

The invention has been described above, various preferred options. Further, the invention is illustrated in the examples, not limiting the description.

EXAMPLES

Example 1. Synthesis of 3',5-dibutil-2,4'-dimethoxy-1,1'-biphenyl and 3',5-dibutil-2,4'-dihydroxy-1,1'-biphenyl

At 120°C p-iodoanisole enter into reaction with 2-methoxyflavone acid in the presence of palladianatravertin, potassium carbonate and a catalyst phase transfer, tetrabutylammonium, obtaining 2,4'-dimethoxybiphenyl (66%), which is then bromilow at 0°C in dichloromethane to obtain 5,5'-dibromo-2,4'-dimethoxybiphenyl with 80%yield. N-butylbromide is introduced into reaction with dibromsalan promezhutochnym compound in the presence of magnesium and copper iodide(1) at -10°C with 3',5-dibutil-2,4'-dimethoxy-1,1'-biphenyl with 50%output. Demethylation by tribromide boron gives 3',5-dibutil-2,4'-dihydroxy-1,1'-biphenyl (yield 17%).

1. Oral composition against plaque, comprising orally acceptable carrier; and an antibacterial effective amount of the compounds of formula (I)

in which R1and R2each independently signify hydrogen or lower With1-4-alkyl, and R3and R4each independently mean of alkenyl or alkyl having from 1 to 20 carbon atoms, provided that R3and R4od is vremenno not mean 2-propanol or n-propyl, when R1and R2simultaneously denote hydrogen.

2. The composition according to claim 1, comprising 0.001 to 10 wt.% the compounds of formula (I).

3. The composition according to claim 1, in which the carrier is a liquid carrier.

4. The composition according to claim 1, in which the carrier is a powder carrier.

5. The composition according to claim 1, in which the carrier is dissolved upon contact with the intraoral environment.

6. The composition according to claim 1, which is in the form selected from a toothpaste, gel, rinse the mouth, tooth powder, lozenges, chewing pallette, chewing gum and food strips.

7. The composition according to claim 1, where R1and R2mean hydrogen.

8. The composition according to claim 1, where R3and R4mean alkyl.

9. The composition according to claim 1, where R3and R4independently have 1 to 8 carbon atoms.

10. The composition according to claim 1, where R3and R4independently have from 4 to 8 carbon atoms.

11. The composition of the toothpaste or gel that includes at least one moisturizing agent; at least one abrasive compound; and oral composition against plaque according to claim 1.

12. The composition according to claim 11, additionally comprising an effective amount of anti-plaque, comprising at least one phosphate compound.

13. The composition according to claim 11, in which the tool against Tartar includes tetrahydrofolate and Trina is tripolyphosphate.

14. The composition according to claim 11, in which the tool against Tartar include synthetic anionic polycarboxylate.

15. The composition according to 14, in which the synthetic anionic polycarboxylate includes a copolymer of maleic anhydride with methylviologen ether.

16. The composition according to claim 11, including
0.01 to 5 wt.% the compounds of formula (I):

1-70 wt.% at least one moisturizer;
1-70 wt.% at least one abrasive compounds;
0.5 to 2.5 wt.% tetrahydrofolate (TNPF); and
1-10 wt.% nutritionista (NTPF).

17. The composition according to item 16, in which the mass ratio of TNPP:NTPF is approximately 1:7.

18. The composition according to item 16, additionally comprising anionic polycarboxylate.

19. The composition according to p where TPF:NTPF:polycarboxylate is approximately 1:7:1.

20. Method of inhibiting the growth of bacteria in the oral cavity of an animal, comprising applying to the surface of the oral cavity of the animal an antibacterial composition comprising a compound of formula (I):

in which R1and R2each independently signify hydrogen or lower C1-4-alkyl, and R3and R4each independently mean of alkenyl or alkyl having from 1 to 20 carbon atoms, provided that R3and R4at the same time does not mean the 2-propanol or n-propyl, when R1and R2simultaneously denote hydrogen.

21. The method according to claim 20, in which the deposition is carried out by brushing with a brush.

22. The method according to claim 20, in which the deposition is carried out by rinsing the surfaces of the oral cavity a composition for rinsing the oral cavity, comprising a compound of formula (I).

23. The method according to claim 20, in which the antimicrobial composition is a toothpaste or gel.

24. The method according to claim 20, in which the antimicrobial composition is a rinse for the mouth.

25. The method according to claim 20, in which an animal selected from a mammal, horses, dogs, cats and people.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly cosmetics. An antiperspirant composition contains emulsion "water-in-oil" containing a continuous oil phase and a dispersed aqueous phase. The oil phase contains: cyclomethicone(-s) with an ignition point 100°C or less, a silicone surface-active substance, a non-siliconised organic solubiliser of flavouring agents. The aqueous phase contains glycine-containing antiperspirant active salt or aluminium, or aluminium and zirconium provided that metal/Cl ratio in salt is within 0.9-1.3:1, glycine/Zr ratio is > 1.2, and peak-5/peak-3 ratio is > 1.0; and if aluminium salt is used, then the molar ratio of aluminium to chloride is within 0.5-2.5:1, and the molar ratio of glycine/A1 is within 0.05-0.26:1; the ratio calculated by formula: (area of peak-5)/(total area for peaks 2+3+4+5) makes at least 0.50. The composition represents a transparent emulsion and does not contain elastomers, borate cross-linking agents, saponification agents, gelling agents and auxiliary water-soluble surface-active substances.

EFFECT: invention provides effective antiperspirant action and does not leave white and sticky traces.

27 cl, 3 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: external skin preparation contains as active components a ferrous compound and a compound chosen from 5-aminolevulin acid, salt of 5-aminolevulin acid, ester of 5-aminolevulin acids, ester of salt of 5-aminolevulin acids, N-acyl-5-aminolevulin acids, salts of N-acyl-5 aminolevulin acid and ester of N-acyl-5-aminolevulin acid. The ferrous compound is chosen from iron (II) citrate, sodium-iron citrate, ammonium-iron citrate, iron acetate, iron oxalate, iron (II) succinate, sodium-iron succinate and citrate, iron (II) pyrophosphate, iron (III) pyrophosphate, heme iron, iron dextrane, iron lactate, iron (II) gluconate, sodium-iron diethylene triaminepentaacetate, ammonium-iron diethylene triaminepentaacetate, ethylenediaminetetraacetate sodium-iron ethylene aminpentaacetate, ammonium-iron ethylene aminpentaacetate, iron triethylene tetraamine, sodium-iron dicarboxymehtyl glutamate and ammonium-iron dicarboxymehtyl glutamate.

EFFECT: improved skin look, prevention or reduction of roughness, dryness, wrinkles, flabbiness, and pigment spots, efficient for atopic dermatitis.

16 cl, 2 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: paste for oral cleansing contains: silicon dioxide, glycerine, PEG 400, xylite, disodium EDTA, papain, lysozyme, lactulose, sodium carboxymethyl cellulose, Carbomer, ribonuclease, Lydasa, sodium lauroyl sarcosinate, sodium lauroyl sulphate, cocamidopropyl betaine, reduced glutathione, camomile extract, parsley extract, grapeseed extract, glycospheres (liposomes), tetrapotassium pyrophosphate, tetrasodium pyrophosphate, disodium pyrophosphate, sodium saccharinate, citric acid, sodium citrate, spruce extract, sage extract, chondroitin sulphate, betaine, aminofluoride, sodium fluoride, sodium methyl paraben, sodium propyl paraben, the titanium dioxide, an aromatiser, polyvinylpyrrolidone, demineralised water in the certain ratio.

EFFECT: high-effective product prevents development of herpetic stomatitis, moistens oral cavity, restores damaged parodentium tissues, and reduces formation of dental deposit on the tooth surface.

9 tbl, 5 ex

Protective cream // 2380088

FIELD: medicine.

SUBSTANCE: invention concerns cosmetology and represents a protective cream containing soap, a mineral vehicle, a preserving agent and water, differing that it contains potassium phytogenesis soap, kaolin or talc as said mineral vehicle and in addition, natural saturated and unsaturated higher fatty acids, cetyl or cetearyl alcohol, low-molecular organic acid and a biologically-active additive. The ingredients of the cream are taken in certain proportions.

EFFECT: invention provides reduction of negative effect of the cream on hand skin by reducing its pH to the level close to physiological pH of skin, and given cream can stimulate the regenerative function of skin and protect skin from other harmful non-chemical factors.

7 cl, 33 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology and represents a cosmetic composition for lips, containing at least one first polyester which can be produced by reaction of at least one polyol, containing 3 to 12 carbon atoms and 3 to 6 hydroxyl groups, at least one nonaromatic branched monocarboxyl acid chosen from the group, at least one aromatic monocarboxylic acid, chosen from the group and at least one polycarboxyl acid containing at least 2 carboxyl groups COOH, and/or cyclic anhydride of such polycarboxyl acid containing 3 to 18 carbon atoms; and at least one second polyester which can be produced by reaction of at least one polyol, containing 3 to 12 carbon atoms and 3 to 6 hydroxyl groups, at least one nonaromatic linear monocarboxyl acid chosen from the group, at least one aromatic monocarboxyl acid, chosen from the group and at least one polycarboxyl acid containing at least 2 carboxyl groups COOH, and/or cyclic anhydride of such polycarboxyl acid containing 3 to 18 carbon atoms. The first and second polyesters are in the composition in certain mass ratio.

EFFECT: invention provides stability and improved shine of deposited film.

10 cl, 9 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, more specifically to a soft aqueous composition for hair and skin cleaning that contains: i) medium-chain alkylethoxysulfosuccinate, ii) amphoteric surface-active substance, iii) long-chain alkylethoxysulfosuccinate, where long-chain alkylethoxysulfosuccinate component iii) is found in the composition in amount 0.1% to 6% of total medium-chain alkylethoxysulfosuccinate component i).

EFFECT: invention allows producing storage-stable soft cleaning compositions for hair and skin providing moistening and conditioning action.

9 cl, 6 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, more specifically to a soft aqueous composition for hair and skin cleaning that contains: i) medium-chain alkylethoxysulfosuccinate, ii) amphoteric surface-active substance, iii) long-chain alkylethoxysulfosuccinate, where long-chain alkylethoxysulfosuccinate component iii) is found in the composition in amount 0.1% to 6% of total medium-chain alkylethoxysulfosuccinate component i).

EFFECT: invention allows producing storage-stable soft cleaning compositions for hair and skin providing moistening and conditioning action.

9 cl, 6 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention concerns cosmetology and represents a cosmetic composition containing at least one silicone-polyamide copolymer, at least one volatile alcohol and, at least one thickener, where said copolymer contains at least one fragment (III) or (IV).

EFFECT: invention provides production of lubrication free or lubrication resistant compositions, as well as ensures improvement of keratinised tissue and provides improved by-touch characteristics in application and shows water resistance.

35 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns cosmetology and represents a cosmetic composition containing at least one silicone-polyamide copolymer, at least one volatile alcohol and, at least one thickener, where said copolymer contains at least one fragment (III) or (IV).

EFFECT: invention provides production of lubrication free or lubrication resistant compositions, as well as ensures improvement of keratinised tissue and provides improved by-touch characteristics in application and shows water resistance.

35 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns cosmetic industry, particularly to an oral care composition. The oral care composition containing propolis extract, a nonionic antibacterial substance representing halogenated diphenyl ester, an active compound for oral care chosen from: a cationic antibacterial substance, an adhesion preventing substance, a substance decomposing biological films or an antiinflammatory substance, and a fluorine ion source.

EFFECT: composition effectively prevents development of oral diseases.

24 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely dentistry, particularly to paediatric dentistry. The composition for prevention and treatment of oral diseases contains, wt %: glyderinine sodium salt 0.3-0.5, mineral-vitamin laminaria concentrate 4.0-6.0, fluoric sodium 2.0-4.0, polyvinylpyrrolidone 5.0-6.0, sodium lauryl sulfate 2.0-4.0, antiseptic preservatives (sodium benzoate or propyl or methyl ester of paraoxybenzoic acid) 0.6-1.2, odorant 1.0-1.7, calcium dihydrogen phosphate 20.0-40.0, water - the rest. The offered composition does not contain alcohol, therefor it is recommended for paediatric dentistry. The composition expresses mineralising action, and antiinflammatory and cleansing properties, provides accelerated maturing of dental enamel.

EFFECT: application of the composition during permanent eruption stimulates the teething processes with decreased inflammatory effects in erupting teeth.

3 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely dentistry, and can be used for microorganism control in oral cavity. That is ensured by introduction in the oral cavity of a composition that creates active particles under exposure to light, and then using of an electric tooth brush with a head comprising a light-emitting element. Said light-emitting element is located on a back surface of the tooth brush head, and its back surface contains one or more flanges. An output signal from the light-emitting element is directed to the part of oral soft tissues during a period of time sufficient to create active particles of said composition.

EFFECT: invention allows for effective oral care with simultaneous clearing and microorganism control.

11 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dentistry, and aims at treating peri-implantitis that is ensured by introduction of mesenchymal stem self-cells recovered from bone marrow. It is preceded by cultivation thereof within 14 days. The cells are introduced on 16-18th day of the integrated surgical and therapeutic treatment, intravenously, at 1 million cells per 1 kg of the patient's body weight.

EFFECT: invention allows restoring number of osteocytes within inflammatory resorption, ensures formation of an adequate bone tissue in the postoperative period that leads to fast recovery of the dental implant capacity.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dentistry, and can be used for treating the patients with atrophy of alveolar process in osteopenic syndrome. That is ensured by preoperative diagnostics of alveolar bone remodelling imbalance in the patients with hyperfunctioning or hypofunctioning thyroid gland. Then preoperative therapy follows. If hyperfunctioning thyroid gland is observed, an antiresorptive preparation, e.g. Miacalcic, and an active metabolite of vitamin D, e.g. alphacalcidol, are prescribed for three months. In hypofunctionining thyroid gland, therapy involves an osteogenic preparation, e.g. osteogenon, and an active metabolite of vitamin D within three months. The operation is also followed with therapy. In the first phase of reparative regeneration, an antiresorptive preparation is prescribed for all the patients within 18 days. The second phase of reparative regeneration involves an osteogenic preparation for lower jaw within 3 months, for upper jaw within six months.

EFFECT: invention allows improving osteoplasty results ensured by stabilisation of bone metabolism and bone improvement within operative intervention.

7 cl, 13 tbl, 2 ex, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dentistry. It involves preparing two applicators by filling two nonwoven fabric enclosures with homogenised medical mud of Tambukan lake containing (wt %): crystal skeleton 15.0-25.0, colloid complex 10.0-20.0 and mud solution - the rest. The applicators are enclosed with a supplementary light- and gas-tight case and heated to temperature 42 - 45°C. Then the applicators are pulled out of said supplementary light- and gas-tight case. One applicator is inserted into vestibule of oral upper jaw, and the other - into vestibule of oral lower jaw. The applicators are kept with teeth clenched during 10-15 minutes.

EFFECT: method improves gingival microcirculation, reduces venous-limphatic congestion and extends an active capillary surface that leads to reduction of interstitial edema, and terminates horizontal and vertical bone resorption, reduces dental mobility and gingival haemorrhage.

4 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention is related to medicine, namely to stomatology, and is intended for treatment of periodontitis. For this purpose mesenchyme stem autocells extracted from bone marrow are introduced to patients. Previously cells are cultivated for 14 days. Introduction of cells is done on 16-18th day from the beginning of complex surgical and therapeutical treatment, intravenously, 1 mln. cells per 1 kg of patient weight.

EFFECT: invention makes it possible to restore number of osteocytes in area of inflammatory resorption, assists in formation of healthy bone tissue in postoperational period, which results in fast recovery of functional activity of teeth.

2 ex

FIELD: medicine.

SUBSTANCE: invention is related to chemical-pharmaceutical industry, and to medicine, namely to stomatology, and may be used as local agent in complex conservative therapy in treatment of inflammatory diseases of periodontium, in particular periodontitis in light, medium and severe form, and also in postoperational period in case of surgical procedure on periodontium. Agent is suggested for treatment of inflammatory diseases of periodontium on the basis of gelatin, which contains glycerin and water, and either of the following medicinal components - lincomycin, metronidazole, lidocaine and dexamethasone. Suggested agent has high medicinal properties due to active components (anti-inflammatory, antibacterial, anesthetic ones). Besides gelatin base provides for strong fixation on surface due to its own adhesion when wet, and the same property of gelatin brings ability to absorb pathological exudate in combination with haemostatic effect.

EFFECT: high viscosity of agent assists in durable release of dosage forms, which reduces number of agent intakes.

5 ex

FIELD: medicine.

SUBSTANCE: invention is related to medicine, namely to stomatology, and may be used for prophylaxis of milk teeth caries in children with formed milk occlusion. For this purpose content of calcium, phosphor, lactobacteria and PH level are identified in mouth fluid of patient. If content of lactobacteria is higher than the norm and/or pH is lower than the norm, and content of calcium and phosphor is within the norm limits, "Enamel-sealing liquid" is applied onto surface of teeth as preparation for deep fluoridation. If content of lactobacteria is higher than the norm and/or pH is lower than the norm, and content of calcium and phosphor is lower than the norm - then "Gluftored" is applied.

EFFECT: method makes it possible to increase efficiency of prophylaxis due to selection of preparation depending on individual picture of caries aetiological factors intensity.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for treatment of inflammatory diseases of parodentium. The agent for treatment of inflammatory diseases of parodentium contains interferon alpha and Bactisubtil as reactants, and as adjuvants it contains calcium carbonate, kaolin, sodium carboxymethyl cellulose and purified water in certain component ratio.

EFFECT: agent is effective antiviral and enteroantiseptic agent, characterised by prolonged action, well fixed on gums and uniformly distributed on mucous surface, applicable and hygienic.

2 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dentistry and can be used for local treatment of inflammatory parodentium diseases. That is ensured by removal of dental deposit with using an ultrasonic device "Ultrastom". Gingival pockets are irrigated with 0.05% miramistine. Then a gingival bandage containing mixed 2% calcium chloride, juice kalanchoe and great nettle, glucosamine hydrochloride, dimethyl sulphoxide and fused polyethylene PEO-400 and PEO-4000 with glycerine as a gel base is applied. Through the gingival bandage, parodentium tissues are exposed to low-frequency magnetic field of intensity 12-17 MTl of the device "Polus-1" within 20 minutes.

EFFECT: optimal relation of medicinal substances in the gingival bandage combined with magnetic field exposure ensures high therapeutic effect and reduced time of treatment of inflammatory parodentium diseases.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly cosmetics. An antiperspirant composition contains emulsion "water-in-oil" containing a continuous oil phase and a dispersed aqueous phase. The oil phase contains: cyclomethicone(-s) with an ignition point 100°C or less, a silicone surface-active substance, a non-siliconised organic solubiliser of flavouring agents. The aqueous phase contains glycine-containing antiperspirant active salt or aluminium, or aluminium and zirconium provided that metal/Cl ratio in salt is within 0.9-1.3:1, glycine/Zr ratio is > 1.2, and peak-5/peak-3 ratio is > 1.0; and if aluminium salt is used, then the molar ratio of aluminium to chloride is within 0.5-2.5:1, and the molar ratio of glycine/A1 is within 0.05-0.26:1; the ratio calculated by formula: (area of peak-5)/(total area for peaks 2+3+4+5) makes at least 0.50. The composition represents a transparent emulsion and does not contain elastomers, borate cross-linking agents, saponification agents, gelling agents and auxiliary water-soluble surface-active substances.

EFFECT: invention provides effective antiperspirant action and does not leave white and sticky traces.

27 cl, 3 tbl, 25 ex

Up!