Antimicrobial composition for oral use and prevent the formation of plaque and connection


(57) Abstract:

The invention relates to medicine, namely dentistry. The composition for oral administration contains insoluble in water vacationy antibacterial phenol containing an alkyl or cycloalkyl group, preferably tert-butyl, in the second position relative to the hydroxyl group and the substituents in the 4-th or 5-th position (or both), one of which may be phenyl, or 2'3'- or 4'-substituted alkyl, or cyclofenil, or one of the 4-th and 5-th deputies (or both of these substituent may be alkyl or cycloalkyl, one is tert-bootrom or phenanthrene containing hydroxyl Deputy in the 2nd or 3rd position and alkyl or cycloalkyl, preferably tert-butylene substituents in other positions, other than the 2nd and 3rd, and at least one other of the rings, as well as new antibacterial alkylated phenols. Composition reduces plaque, and also has a high antimicrobial activity. 7 S. p. f-crystals, 10 PL.

The invention relates to antibacterial compositions for oral administration against the formation of plaque; and to compositions containing ionic antibacterial alkilirovanie connection phenol, which is described in more detail below; and to the selected group of such compounds, which are new.

Plaque is a soft Deposit that forms on the teeth as opposed to Tartar, which is hard calcinatory deposition on the teeth. Unlike plaque plaque may form on any part of the tooth surface, including, in particular, the edge of the gums. Therefore, being invisible, he is guilty in the occurrence of gingivitis.

In this regard, it is highly desirable to include in the composition for oral administration of antimicrobial (antibacterial) agents, which are known to reduce the formation of plaque.

Cationic antibacterial materials such as chlorhexidine, benzoylchloride and cetylpyridinium, have been extensively studied as antibacterial agents against the formation of plaque. However, they are usually ineffective when used with anionic materials. On the other hand, nicotianae antibacterial materials can be compatible in the compositions for oral administration with anionic components.

However, compositions for oral administration are usually a mixture on the effectiveness of these compositions.

As antibacterial agents in compositions for oral administration are very effectively used such halogenated hydroxyproline esters as triclosan. However, it is desirable to have the possibility of using non-halogenated agents, which would be highly effective and possibly even more effective than triclosan.

Phenol and alkyl substituted phenols are well known and widely used antimicrobial agents. Thymol (2-isopropyl-5-METHYLPHENOL) is the active antimicrobial agent used in preparations for mouthwash, produced in industry, but its antimicrobial activity is relatively low and may be insufficient, for example, its activity is only a small part of the activity of triclosan. To date, drugs, alternative triclosan, with significantly higher activity against the formation of dental plaque than thymol or monoalkylphenol, and comparable or higher activity than the activity of triclosan is not available.

The purpose of this invention to provide a composition for oral administration with significant efficacy against plaque containing nationalnogo application (AA) as drugs, alternative to triclosan. Another object of the invention is ALKYLPHENOLS AA, which is wholly hydrocarbons, with the exception of one OH group, and have oral antimicrobial activity, 100 or more times greater than the activity of thymol, for example the same as the activity of triclosan, or more. Another object of the invention to provide such AA that are available or in the presence of which in nature can be assumed, for example, plant material, etc. Another object of the invention is the new AA. Other objects and advantages of the invention will be clear from the description.

In accordance with some aspects, the invention relates to compositions against plaque for oral administration, comprising suitable for oral administration filler and effective against the formation of plaque quantity of at least one essentially water-insoluble negativnogo monohydroxy AA, having one of the following formulas:

< / BR>

< / BR>

< / BR>
where R1is (1) C1-8n-alkyl, optionally partially or completely replaced by3-6cycloalkyl or C1-7lateral alkyl chains is mi chains or C3-6cycloalkyl;

ring and R6the formula I are used interchangeably substituents of ring A of formula I in 4 and 5-positions, and R6is H or R1;

(1) R2and R3formulas are interchangeable substituents in the 4' and 5' positions of the ring In formula I and formula II, the substituents in the 4 and 5 positions; R2is R1and R3is H or R1; or

(2) in the ring R3in the 5'-position is H, R2in the 4'-position is R7, R8independently is H or R1in positions 2' and/or 3', and n=2;

R4in the formula II is (1) tert-bootrom or C3-8n-alkyl, optionally partially or completely replaced by 3-6cycloalkyl, or C1-7lateral alkyl chains, or (2) C3-6cycloalkyl, optionally partially or fully substituted C1-7lateral alkyl chains or C3-6cycloalkyl; and

R8in the formula III is independently H, or R1in positions 5, 6, 7 and/or 8 and m=4.

In addition, it was found that in the vast majority of cases the agents AA one of the above formulas, including tert-butyl as at least one, and preferably two (or even more) of R This invention is based, at least in part, on the following discoveries:

1. Substituting tert-bootrom on ortopilot unsubstituted phenol may enhance antimicrobial activity 10 times.

2. Second tert-botilony the substituent in the 4 (para-) position orthotamine tert-bootrom phenol (formula II) may enhance antimicrobial activity 10 times.

3. Substituting tert-bootrom in the side phenyl group phenylphenol (formula I), for example, substituting 2-tert-butyl-5-phenylphenol with obtaining 2-tert-butyl-5-(4'-tert-butylphenyl)-phenol similarly enhances the activity of another 10 times.

Thus, for example, 3-phenylphenol (3-hydroxybiphenyl) has activity, slightly less than the activity of thymol against A. viscoscus, the normal component of dental plaque. On the other hand, the observed activity of 2-tert-butyl-5-phenylphenol (3-hydroxy-4 - tert-butylbiphenyl) 50 times higher than the activity of thymol, and the observed activity of 2-tert-butyl-5-(4'-tert-butylphenyl)phenol (3-hydroxy-4,4'-di-tert-butylphenyl) 100 times higher activity of thymol.

As described here, other ALKYLPHENOLS AA also possess high antibacterial effect, preventing or reducing obrashau activity of thymol.

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< / BR>
< / BR>
< / BR>
where (4) R10= -C(CH3)3(tert-butyl)

(5) R10= phenyl

(6) R10= -C(CH3)2CH2CH3(1,1-dimethylpropyl)

(7) R10= -C(CH3)2CH2CH2CH3(1,1 - dimethylbutyl)

(8) R10= -C(CH3)2C(CH3)3(1,1,2,2-TETRAMETHYLBUTYL)


< / BR>
The level of activity of phenols, below 100 times greater than the level of activity of thymol. This is the level of activity of triclosan.

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< / BR>
< / BR>
< / BR>
Above AA compounds (1) to(13) are included in the scope of the AA agents defined by formulas I, II and III; and it is clear that the compounds comprising these options by nature, the number and positions of the substituents R1-R4and R6-R8can be used as AA agents, for example:




2,4-aminobutiramida 5-phenylphenol,






2-(1-cyclopropylmethyl)-4 is,













2-tert-butyl-3-hydroxy-10, 10-di-tert-butyl-9, 10-dihydrophenazine,

2-(1,1-dimethylpropyl-3-hydroxy-10, 10-DICYCLOHEXYL-9, 10-dihydrophenazine.

Although 2-tert-butyl-5-phenylphenol (3-hydroxy-4-tert-butyl - biphenyl) known in the literature no reports on its use as an antimicrobial agent. The same applies to many other compounds described above formulae, such as formulae I and II. As described below, many of the AA agents are new compounds.

Enhancement of antimicrobial activity attained in accordance with this invention, generally, includes the use of branched chains, in preference to linear selectively located deputies, increased the number of substituents and/or content of ugly into account the indication to the contrary in the prior art. For example, in C. M. Suter, Chem. Rev. 28, 269-299 (1941) when discussing the phenol coefficients of ALKYLPHENOLS v.B.typhosus and Staph.aureus indicated: (a) position of the alkyl group does not matter", and (b) ortho - and para-Deut-butylphenol have a phenol coefficient 28, and the lateral branching of the carbon chain such as tertbutylphenol, reduces the efficiency to about 20" (page 272), and (C) "common is that primary alkyl phenols with linear chains more efficient than their isomers" (page 273), (g) "concluded that isobutylene connections are probably less effective than their n-butylene isomers", and (d) "as ALKYLPHENOLS, branching carbon chain reduces their effectiveness" (page 275). The microorganisms used in the above studies are different from those that usually accumulate in the mouth.

Evans and others, J. Calls. 48, 156-162 (1977), in the article "Effect antiseptic phenols against the formation of dental plaque in vitro indicate "found that 3,5,4 - tribromaniline is effective against A. viscosus, A. naeslundii, S. mutans and S. sanguis, for dibromosalicylic found that it is effective against A. viscosus. Other phenols (hexylresorcinol, thymol, phenylphenol and phenolsulfonate zinc) do not inhibit row compositions for oral administration of the present invention use C1-7and C1-8side chains and n-alkyla from methyl to heptyl and Attila and C3-6cycloalkyl from zipeprol to cyclohexyl. AA usually have a molecular weight (M. C.) of from about 175 to 500, preferably from about 190 to 350, more preferably from about 210 to 310. In the compositions of this invention for oral administration use AA in non-toxic, effective against plaque number is usually in the range of about 0.003 to 5%, preferably about 0.005 to 3%, more preferably about 0.02 to 1%. the pH of the compositions of this invention for oral administration may vary approximately from 4.0 to 9.0.

To improve the stability and even greater antibacterial activity of AA in the composition for oral administration can include agent, reinforcing antibacterial action (AEA). The use of AEA in combination with water-insoluble sectionname antibacterial compounds known in practice, for example in U.S. patent N 5188821 and 5192531. Agent AEA is an organic substance that contains the group, improve delivery, and the group, increasing retention. Used here is a group that improves the delivery refers to the groups through which the AEA and the Bo other way with surfaces in the mouth (for example, with teeth and gums), giving thus to the data surfaces of the active connection. Organic group, increase retention, usually hydrophobic, attaches or otherwise associates with AA AEA, promotora thus holding AA in AEA and indirectly on the surfaces of the mouth. Increased retention of AA on the surfaces of the mouth increases the slowdown in the growth of plaque on these surfaces.

AEA is preferably an anionic polymer comprising a main chain or skeleton containing repeating units each of which preferably contains at least one carbon atom and preferably at least one directly or indirectly attached to a monovalent group that improves the delivery, and at least one directly or indirectly attached monovalent group, increase retention, attached to the atoms in the chain, preferably carbon gemenele, related or otherwise, which is less preferable.

AEA may be a simple compound, preferably a polymerizable monomer, more preferably a polymer, including, for example, oligomers, homopolymers, copolymers of two or more monomers, ionomer, block copolymers, in which m, water-insoluble or preferably soluble in water (saliva) or swelling (gidratirutmi forming hydrogel) with an average molecular weight from about 100 to 5000000, preferably from about 1000 to 1000000, more preferably from about 25000 to 500000.

In the case of polymer AEA to maximize the delivery and retention of AA on the surfaces of the mouth, it is desirable that the repeating unit in the polymer chain or the main chain, containing acid groups, increasing the delivery was at least about 10%, preferably at least about 50%, more preferably at least about 80% to 95% or 100% by weight of the polymer.

Usually AEA contains at least one group that improves the delivery, which is preferably an acid group such as sulfonic, phosphinic or more preferably phosphonic or carboxylic or salt, such as alkali metal salt or ammonium, and at least one group, increase retention, typical groups have the formula -(X)n-R, where X represents O, N, S, SO, SO2, P, PO or Si and the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocycle or its derivatives with which usually are dehydrofolate and did not significantly affect the desired function of the AEA to improve the delivery AA and hold it on the surfaces of the oral cavity. Such substituents include halogen, for example Cl, Br, I, carboxypropyl and the like. Examples of such groups are shown in table. 1.

Preferably, the AEA was natural or synthetic anionic polymeric polycarboxylates with a molecular weight of from about 1000 to 5000000, preferably from about 30,000 to 5000000.

Usually use a synthetic anionic polymeric polycarboxylate in the form of free acid or preferably in the form of partially or more preferably fully neutralized water soluble alkali metal salts (e.g. potassium and preferably sodium) or ammonium. Preferred are copolymers of from 1:4 to 4:1 of maleic anhydride or acid with another polymerizable ethyleneamines monomer, preferably metilidinovy ether/maleic anhydride with a molecular weight (M. C.) for about 3000-100000, most preferably about 30000-500000. These copolymers can be obtained, for example as Gantrez, AN139 (M. C. 500000), AN119 (M. C. 250000); and preferably pharmaceutical S-97 Pharmaceutical Grade (M. C. 70000) from GAF Corporation.

Other polymeric polycarboxylate containing groups, increase retention, or modified by such groups and apply the-methacrylate, N-vinyl-2 - pyrrolidone or ethylene (the latter, for example, available from Monsanto EMAN 1103, M. C. 10000 and Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethylmethacrylate, methyl - or acrylate, isobutylacetate, isobutylparaben ether or N-vinyl-2-pyrrolidone.

Additional polymer polycarboxylate containing groups, increase retention, or modified by such groups used in the practice of this invention include copolymers of maleic anhydride with styrene, isobutylene or ethylvanillin ether, polyacrylic, polietilenovoi and polimolekuly acids and sulfonanilide the oligomers with M. C. below 1,000 available as UniroyalND-2.

Suitable for use in the present invention are polymerized carboxylic acid, reinstatement or Ethylenediamine, containing activated carbon-carbon olefinic double bond which readily polymerize due to its presence in the monomer molecule, alpha - or beta-position to the carboxyl group, or as part of the final methylene group. Examples of such acids are acrylic, methacrylic, etakrinova, alfilaria, Mukanova, Takanawa, Tarakanova, musicanova, glucagonoma, konitova, alpha phenylacrylate, 2-benzylacrylamide, 2-cyclohexylaniline, angelic, umbilicata, fumaric, maleic acid and their anhydrides. Various other olefinic monomers, copolymerizes with carboxylic monomers include vinyl acetate, vinyl chloride, dimethylmaleic and the like. The copolymers contain enough group of salts of carboxylic acids for solubility in water.

Useful in the practice of the present invention are also so-called carboxyvinyl polymers. They are available commercially, for example, under the trademarks Carbopol934, 940 and 941 from B. F. Goodrich, these products consist of colloidal water-soluble polymer of polyacrylic acid crosslinked by about 0.75-2.0% of polyallylamine or polyaryletheretherketone as a cross-linking agent, often with M. C. up to 4-5 million or more.

Examples AEA containing phosphine and/or sulfonic acid groups, improving delivery, are polymers and copolymers containing units or parts obtained by the polymerization of vinyl - or allyl-phosphine and/or sulfonic acids, substituted, if necessary, 1 or 2, île defined above. You can use a mixture of these monomers and their copolymers with one or more inert polymerized Ethylenediamine monomers such as monomers mentioned above in the description of suitable synthetic anionic polymer polycarboxylate.

Examples of the polymer containing the repeating unit, in which one or more phosphonic acid groups, improving delivery, connected to one or more carbon atoms in the polymer chain is poly(phosphonic acid) containing units of the formula

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which can be AEA, even if does not contain a group that improve retention. However, the group of the latter type will be present in poly(1-phosphonopropyl) with links in formulas

< / BR>
The preferred polymer containing phosphonic acid, for use in this invention is poly(beta-staroletova acid) containing units of the formula

< / BR>
where Ph is a phenyl, phosphonic group, improve delivery, and phenyl group, increase retention, attached to adjacent carbon atoms in the chain or a copolymer of beta-stratopoulos acid with vinylphosphonate having units of the formula C, alternating or randomly with the mules

< / BR>
in which groups that enhance the delivery and retention are integral in the chain.

These polymer stratstone acids and their copolymers with other inert Ethylenediamine monomers typically have a molecular weight in the range of from about 2000 to 30,000, preferably from about 2500 to 10000.

Other polymers containing phosphonic groups, include, for example, vospominanii ethylene with links in formulas

E. -[(CH2)14CHPO3H2]n-

where n can be, for example, integer, or to have a value giving the molecular weight of the polymer, for example, about 3000; and sodium[butene-4,4-diphosphonate)], with units of the formula

< / BR>
and poly[allyl-bis-(phosphonoethyl)amine] with links in formulas

< / BR>
Other Vospominanie polymers, for example poly(allylphosphonate), vospominanii polymethacrylate and others, and gemenele diphosphopyridine polymers disclosed in the published European patent 0321233, are also useful in the practice of the present invention, it is necessary to ensure the presence of the above organic groups, improving retention, or modify them accordingly.

Polysiloxane containing groups, which improves on the example diphenyl - or di(C1-C4) alkylpolyglucoside and especially dimethylpolysiloxane, can also be used in the practice of the present invention.

Effective in this case are also ionomer containing groups that enhance the delivery and retention, or modified accordingly. Ionomer described on pages 546-573 in Kirk Othmer Encyclopedia of Chemical Technology, 3rd edition, supplementary volume, John Wiley & Sons, Inc. copyright 1984, which is incorporated here by reference. Effective in this case are also polyesters, polyurethanes and synthetic and natural polyamides, including proteins and protein materials, such as collagen, polyalanine and other polymerized amino acids containing groups that enhance the delivery and retention, or modified accordingly.

Applied AEA includes in the composition of the present invention in weight amounts of from about 0.05 to 5%, preferably from about 0.1 to 3%.

Linear digidrirovannye polyphosphate salt can optionally be used in this invention as agents against the formation of dental calculus. They are well known and are typically used in the form of their wholly or partially neutralized in the Yessei. Examples of such salts include sodium hexametaphosphate, sodium tripolyphosphate, trickily nonantibiotic, likely dinitropropane, sour trinatriyfosfat, tetrahydrofolate, the corresponding potassium salts and the like. In the present invention can be used in compositions for oral administration in a weight amount of about 0.1-3%, usually 1-2,5%, more typically 1.5 to 2%, in particular 2%.

Especially desirable agents against the formation of dental calculus are Tetra - (alkali metal pyrophosphates, such as tetranitro and terkaly-pyrophosphates and mixtures thereof.

In compositions for oral administration, when there are both AEA and the pyrophosphate, the weight ratio of AEA and pyrophosphate ions is typically about 1.6: 1 to 2.7:1, preferably about 1.7:1 to 2.3:1, more preferably about 1.9:1 to 2:1.

It may also be desirable for inclusion in a composition for oral administration of the present invention, the fluoride ion, which is an effective multifunctional agent, providing anticaries action or increase the hardness of the teeth, and not necessarily in conjunction with AEA, the inhibition of hydrolysis by enzymes in saliva polyphosphate Agay the source of fluoride ions or component, providing a fluorine may be such to provide from about 25 to 5000 million D. fluoride ion.

These compounds can be laboratorii in water or completely water soluble. They differ in their ability to release fluoride ions in water at essentially complete absence of adverse reactions with other compounds of the composition for oral administration. These materials include inorganic salts fluorides, such as soluble salts of alkaline and alkaline-earth metals, for example sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, fluoride monovalent copper, zinc fluoride, barium fluoride, monitoroff sodium, mono - and di-perforat aluminum and perforat sodium-calcium. Preferred fluorides of alkali metals and tin, such as the fluorides of sodium and divalent tin, monitoroff sodium (MFP), and mixtures thereof.

The number of connections that provide fluoride to some extent depends on the type of compound, its solubility, and the type of composition for oral administration, but it must be non-toxic amount, usually from 0.0005 to 3% in the preparative form. You can use any suitable minimum amount of such connection, but predpochtiteljno 800-1500 million D.

Usually, in the case of using the alkali metal fluorides, this component is present in an amount up to 2 wt.% by weight of the composition and preferably in an amount of about 0.05 to 1%, typically about 0.2 to 0.35 percent for sodium fluoride. In the case of monophosphate compound may be present in an amount of about 0.1 to 3%, typically about 0,76 wt.%.

The composition for oral administration of the present invention may be a solution ingredients, such as the solution to rinse the mouth, or it may be semi-solid preparation, such as toothpaste or gel for brushing your teeth, which can contain from 0 to 75% of a polishing agent, or chewing gum, or solid tablet, or similar.

Gel preparations for oral administration contain silicon polishing material comprising crystalline silicon dioxide with a particle size of approximately 5 microns, silica gel, colloidal silica or a complex amorphous alkali metal aluminosilicate.

When used visually transparent or opaque gels, especially useful polishing agent of colloidal silica, such as solid agents under the trademark Syloxfor example Sylox 15, or under the Zeodent 113, or complex silicates of alkali metals (silicon dioxide containing in its matrix alumina), as they are compatible with gel-like texture and have an index of refraction close to the index of refraction systems "gelling agent - liquid (including water and/or humectant), usually used in the means for brushing your teeth.

In the framework of the present invention, in which the composition for oral administration is a gel or paste that is suitable for oral administration filler, including a water-phase with humectant, which is preferably glycerine or sorbitol, or alkalophiles, such as polyethylene glycol or propylene glycol, and water is typically present in an amount of about 15-40 weight. % and glycerin, Corbin and/or allenglish (preferably propylene glycol) usually together constitute 20-75 wt.% by weight of the composition for oral administration, more typically, about 25-60%.

When the composition for oral administration is, essentially, a semi-solid or paste, such as toothpaste (dental cream), filler means for cleaning teeth includes suitable for teeth polishing material such as sodium bicarbonate and is, digidrirovanny the dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, calcium carbonate, aluminum silicate, hydrated aluminum oxide, silicon dioxide, bentonite and mixtures thereof with each other and with small amounts of solid polishing material, such as calcined aluminum oxide and zirconium silicate. Preferred polishing materials include silicon dioxide, insoluble metaphosphate sodium, dicalcium phosphate, calcium pyrophosphate and hydrated aluminum oxide, and sodium bicarbonate.

The polishing material is generally present in the compositions of gels, creams or pastes in weight concentrations of about 10-75%, preferably about 10-30% in the gel and about 25-75% in the cream or paste.

Toothpaste or cleaning of the teeth in the form of a cream, as a means in the form of a gel, typically contain a natural or synthetic thickener or gelling agent in an amount of about from 0.1 to 10%, preferably 0.5 to 5%.

Suitable thickeners or gelling agents include Irish moss (Irish moss), ι-Karagan, Kappa-Karagan, tragakant, starch, polyvinylpyrrolidone, hydroxyethylmethylcellulose, hydroxyethylmethylcellulose, hypromellose, who azizia for oral administration is, essentially, liquid, such as a means for washing or rinsing of the mouth, the media is usually Vodopyanova mixture. Usually the weight ratio of water and alcohol is from about 3:1 to 10:1 and preferably from about 4:1 to 6:1. Alcohol is a non-toxic alcohol, ironically as ethanol or isopropanol. There may be a humectant, such as glycerin, sorbitol or allenglish, such as polyethylene glycol or preferably propylene glycol, in an amount of about 10-30 wt.%. Preparations for mouthwash usually contain approximately 50-85% water, about 0-20 wt.% non-toxic alcohol and about 10-40 wt.% the humidifier.

In the compositions of the present invention use organic surface-active agents to achieve increased prophylactic action, ensuring a thorough and complete dispersion of AA in the oral cavity and obtaining the compositions more suitable from the cosmetic point of view. Organic surface-active material is preferably anionic, nonionic or apoliticism material in nature, it is preferable to use as surface-active agent, a detergent, which gives the composition of the surface-actiniaria salt monoglycerides of higher fatty acids, such as sodium salt monoculturing monoglyceride fatty acids, hydrogenated coconut oil, higher alkyl sulphates, such as sodium lauryl sulfate, alkylarylsulfonate, such as dodecylbenzenesulfonate sodium higher alkyl sulphonates, esters of higher fatty acids and 1,2-dihydroxydiphenylsulfone, and substantially saturated higher aliphatic acylamide compounds of lower aliphatic aminocarbonyl acids, such as compounds having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals and allylthiourea and the like. Examples of the last mentioned amides and turato are N-lauroylsarcosine and salts of sodium, potassium and ethanolamine N-lauroyl-, N-myristoyl - or N-palmitoylcarnitine, which, in essence, must not contain soap, or similar compounds of higher fatty acids, and N-methyl-N-Cocoyl(or oleoyl-, or Palmitoyl-)taurine. The use of sarcosinates in the compositions of the present invention for oral administration is often advantageous since these materials exhibit a prolonged and marked effect in the inhibition of acid generation in the oral cavity due to the destruction of carbohydrates, in addition to the effect of reducing the on-active agents are the condensation products of ethylene oxide with various reactive compounds, containing hydrogen and having long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), condensation products ("autocamera") contain hydrophilic polyoxyethylene parts, such as condensation products of polyethylene oxide with fatty acids, fatty alcohols, fatty inorganic salts, polyhydric alcohols (for example, and polypropyleneoxide (for example, materials Pluronic).

Examples of poloxamers used in the present invention include block copolymers of polyoxyethylene and polyoxypropylene with an average molecular weight from about

3000 to 5000 and preferably with an average molecular weight of from about 3500 to 4000, containing about 10-80% hydrophilic polyoxyethylene groups by weight of the copolymer. The preferred poloxamers used in the present invention is Pluronic F127 (trade mark), a block copolymer of polyoxyethylene and polyoxypropylene with a molecular weight of about 4000.

You can also use any suitable aromatic and sweetening materials. Examples of suitable aromatic agents are aromatic oils, e.g. oil of spearmint, peppermint, gresivaudan agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, peralatan, methyl ether of aspartylphenylalanine, saccharin and the like. A suitable quantity of flavouring and sweetening agent (each or both) is about 0.1-5% or more by weight of the drug.

Agents used to reduce tooth sensitivity, such as strontium chloride, potassium nitrate and potassium citrate can also be included in compositions of the present invention for oral administration in concentrations of about 0.1-10 wt.%.

In the composition of the present invention for oral administration can also include various other materials, including bleaching agents, such as urea peroxide and hydrogen peroxide, preservatives such as sodium benzoate, compound chlorophyll and/or ammoniaand materials such as urea, diammonium phosphate and mixtures thereof. In the presence of these additives include them in the composition in amounts that do not materially inappropriate action on the required properties and characteristics.

Compositions of the present invention for oral administration can be obtained with a suitable mixing of the ingredients. For example, upon receipt of solutions for rinsing the mouth AA di is billaut and mix salt, such as sodium fluoride and potassium phosphate, and flavoring. After the ingredients are mixed in a vacuum within 15-30 minutes. Then pack up the resulting solution. Cleaning teeth is prepared in a similar manner, optionally adding a thickening agent and a polishing agent on the preliminary or final stages.

In the preferred application of the compositions of the present invention for oral administration, such as means for cleaning the teeth, it systematically during the life of the clean tooth enamel with a brush every second or third day, preferably 1-3 times a day at a pH of 4.5 to 10, generally about 5.5 to 9, preferably about 6 to 8, for at least 2 weeks and up to 8 weeks or more. After each application of the tool for cleaning teeth removed usually by rinsing with water. Liquid mouth rinse to remove or rinse in the same way.

The compositions of this invention can be incorporated in tablets, or in chewing gum or other products, for example, by mixing in warm rubber base or coating the outer surface of the rubber base, examples of which is jelutone, rubber latex, vinylite resin, etc. , gelatine, or carbohydrates such as glucose, sorbitol and the like.

Filler or carrier in tablet or wafer is nicaraguensis solid water-soluble polyhydric alcohol (polyol) such as mannitol, xylitol, sorbitol, malic, hydrogenated starch hydrolysate, Lisitzin, gidrirovanny glucose, hydrogenated disaccharides or hydrogenated polysaccharides in an amount of about 90-98% of the total weight of the composition. Solid salts such as sodium bicarbonate, sodium chloride, potassium bicarbonate or potassium chloride, can completely or partially replace paleology media.

In preparation for tablets or wafers you can include lubricating agents in a small amount, about 0.1-5 wt.%, in order to facilitate the manufacturing process as tablets and wafers. Suitable lubricating agents include vegetable oils, such as coconut oil, magnesium stearate, aluminum stearate, talc, starch and Carbowax.

Drugs those capsules contain approximately 2% of the resin as a barrier agent to provide a shiny surface as opposed to tablets that have smooth edges. Suitable nicaraguense resin include Capa-Karagan, carboxymethylcellulose, hydrox is it special material, such as waxes, shellac, carboxymethyl cellulose, copolymer of polyethylene/maleic anhydride or Capa-Karagan, to further increase the time during which the tablet or capsule dissolves in the mouth. Coated tablets or pellets dissolve slowly, providing a gradual release of active ingredients in 3-5 minutes. As a consequence, the composition of solid dosage tablets and wafers of the present invention provides a relatively longer period of contact of the teeth in the oral cavity with the active ingredients.

In table. 10 lists the categories AA agents. Category I includes AA, which, as shown, 100 or more times more active than thymol. That is, they are comparable with triclosan effectiveness against the formation of plaque or even more effective. Category II includes AA with lower activity, such as 10-50 times greater activity of thymol.

Another aspect of this invention relates to compounds category I, which differ in that they have one of the following formulas:

< / BR>

< / BR>
where R1is (1) C1-8n-alkyl, partially or completely substituted C3-6cycloalkyl or C1-7lateral alkyl chains is mi chains or C3-6cycloalkyl; and

R3independently is hydrogen or R1provided that when R3in the ring A of formula IV is hydrogen, at least one R3the ring is R1.

The preferred compound of formula III is 2-tert-butyl-3-hydroxy-10, 10-di-tert-butyl - 9, 10-dihydrophenazine. Preferred compounds of formula IV are the following:


2,4-di-tert-butyl-5-phenylphenol and


General methods of synthesis used in this invention alkyl phenolic antibacterial agents.

AA agents of the present invention, some of which can be found in nature, synthetically obtained by alkylation reaction according to the Friedel-Crafts in accordance with the General synthetic methods of organic chemistry. Thus, phenolic compounds such as phenol, 3-phenylphenol, 4-phenylphenol or 9,10-dihydro-3-hydroxy-10, 10-dimethylphenanthrene handle RX, where R represents the alkyl part, and X is a halogen or other suitable leaving group, in the presence of a suitable catalyst for Friedel-such as the chloride is the IDA, the carbon disulfide or nitrobenzene. Processing of phenolic compounds with one equivalent of the RX gives mainly monoalkylamines in anthopology relative to the hydroxyl phenol. Processing of phenolic compounds with two equivalents RX gives di - or polyalkylphenol. Can also be carried out stepwise multiple alkylation. Asymmetrically substituted polyalkylphenol can be obtained, based on 3-alkylphenol. It should be noted that when dialkylamino of biphenylene surround alkilani, for example tert-bootrom, the first alkyl give orthopaedie relatively hydroxyl, while the second substitution is alkyl side phenyl. These methods are illustrated by the synthesis of 2-tert-butyl-5-phenylphenol and 2-tert-butyl-5-(4-tert-butylphenyl)phenol below as examples 1 and 2, respectively.

To obtain 2,4-di-tert-butyl-5-phenylphenol, 3-nitrophenylthio alkylate two moles of tert-butyl chloride in accordance with the method described above. The nitro-group is obtained 2,4-di-tert-butyl-5-nitroaniline removed by catalytic hydrogenation and subsequent diazotization and restoration of diazonium salts aniline (see N. Porowska, W. Polaczkowa and S. Kwiatkowska, Rocz. Chem., 44 (2), 375 (1970)).

The R X, where R' is one methylene group is shorter than the required alkyl chain R, and reacts with magnesium to form the corresponding Grignard reagent R MgX. It reacts with ortho-, meta - or para-anise aldehyde, giving 2-hydroxyestradiol. Hydroxyl group is removed by hydrogenation over palladium-on-coal in a fluidized cyclohexene, receiving n-alkyl-substituted anisole. The desired n-alkyl-substituted phenol is produced by cleavage of a methyl group from anisole handling tribromide boron (J. Weinstock and others, J. Med.Chem., 30, 1166 (1987)).

Similar alkylation can be performed, replacing the RX in the previous description of a suitable olefin.

To determine the ability of active substances to kill in a short period of time (for example, 2 minutes) apply the test SIKT (Short Interval Kill "Test"), referenced in the examples, simulating the conditions of the mouthwash solution against the formation of plaque. In this test, which is described in U.S. patent N 5275805, column 11, lines 10-28, the description of which is included here, the control and test samples are mixed with preexisting inoculate S. sanguis, S. mutans and S. viscosus (106-107colony forming units (CFU/ml), providing 2 minutes of contact, then the system is neutralized, dapolito on the tablet (plate count methodology). The reduction in the number of "some" relative to water control is the basis for the expression of the antibacterial activity of the tested agents, namely % destruction compared with the corresponding placebo or control.

In the test MIC (minimum inhibition concentration) referenced in the Examples, determines the minimum concentration in million D. mm or agent AA, in which the growth of bacteria (the same 3 species contained in plaque used in the test SIKT) completely inhibited by AA. Investigate antibacterial activity at concentrations of AA is smaller and more MICK. This MIC test is also described in U.S. patent N 5275805, column 11, lines 54-68, the description of which is included here.

The following additional examples illustrate the nature of the present invention, but it is clear that the invention is not limited to them. All amounts and proportions that are referenced in the description and in the appended claims, are by weight, unless stated differently.

Example 1

2-tert-butyl-5-phenylphenol (3-hydroxy-4-butyl-biphenyl)

A suspension of 0.8 g of aluminium chloride in 50 ml of anhydrous methylene chloride is stirred in an atmosphere of anhydrous nitrogen at 5-15%, add drop by drop is live in 2 hours then leave to stand at room temperature for 12 hours. The reaction mixture is poured onto 150 g of ice/water and shake. The organic phase is separated and the aqueous residue extracted twice with 50 ml of methylene chloride. The combined organic solutions are washed twice with portions of water, 50 ml, 50 ml saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. The residue is placed in 150 ml of hexane. After standing at room temperature for 3-hydroxy-4-tert-butylphenyl crystallizes from solution. Select the filtration, and then recrystallized from 100 ml of pentane until until its melting point will not become permanent. Get the substance in the form of a white crystalline compound with a yield of 6.8 g, so pl. 86-87oC. Source hexane, the filtrate after several precrystallization from pentane also give a collection of crystals: 1.1 g of 2-tert-butyl-5-(4'- tertbutylphenyl) phenol, I. pl. 143-145oC. Additional 1.12 g of the substance obtained by chromatography of the residues mother liquor.

Example 2


A mixture of 25 g of 3-phenylphenol (SRR) in 100 ml of tert-butyl chloride is stirred in an atmosphere of anhydrous Asai portion. After 1.5 hours, add a portion of 15 ml of tert-butyl chloride followed by the addition of 0.8 g of aluminum chloride. The mixture is stirred for 45 minutes at boiling under reflux, then add a portion of 200 ml of chloroform. The solution is poured into 200 ml of water and the mixture shaken. The organic layer is separated and the aqueous layer was extracted with 100 ml of chloroform. The combined organic layers (300 ml), washed successively with 100 ml each, 6 N. hydrochloric acid (2x), water, 5% aqueous sodium bicarbonate, water and saturated aqueous solution of sodium chloride. The organic solution was dehydrated over sodium sulfate, filtered and evaporated in vacuum. The residue is placed in 150 ml of boiling hexane. The solution is cooled until, until the end of crystallization. The mixture is filtered and the crude product washed with cold hexane and left to dry in the air, receiving 29 g of a white solid. The crude product was again recrystallized from hexane, receiving 22.3 g of analytically pure 2-tert-butyl-5(4'-tert-butylphenyl)phenol as a white crystalline compounds with the release, so pl. 145-147oC.

Elemental analysis:

calculated: C 85.06%, H 9.28%;

found: C 84.74%, H 9.55%.

IR spectroscopy and proton NMR confirmed the Drago cleaning of the teeth are given in table. 3.

This MIC test drug of the present invention (example 3) shows antibacterial activity equal to the activity of the drug triclosan (example 4) with respect to S. sanguis and S. mutans and two times greater than the activity of placebo with respect to S. sanguis.

The results SIKT for the liquid cleaning of the teeth are given in table. 4.

To control the number of bacteria present is equal to 104cells/ml When comparing the presence of 10-15 cells is considered as 100% defeat. SIKT tests show that the antibacterial activity of the drug of the present invention (example 3) provides 100% of defeat and drug activity of triclosan (example 4), essentially the same.

Example 5

The preparation for oral administration containing 3 - hydroxy-4,4'-di-tert-butylbiphenyl (2-tert-butyl-5(4'- tertbutylphenyl)phenol) (see tab. 5).

Example 6

Toothpaste containing 3-hydroxy-4,4'-di-tert-butylbiphenyl (see tab. 6).

Such medication can be modified by replacing a certain amount or entirely Zeodent 115, a polishing agent based on silicon dioxide and a thickening agent based on silicon dioxide Sylodent 15 sodium bicarbonate, insoluble metaphosphate sodium, decalcifies the 8 and 9 tests carried out in concentrated solutions of the active agent of AA in 98.5% ethanol (EtOH), which does not show antibacterial properties when tested concentrations.

Example 7

Test results minimum inhibitory concentration (MIC) (see tab. 7).

In this test found that 2,4-di-tert-butylphenol is many times greater than the thymol significantly exceeds triclosan against S. mutans and a little less active than triclosan, against A. viscosus and S. sanguis.

Example 8

Test 2-tert-butyl-5-phenol and 2-tert-butyl-5-(4'-tert-butylphenyl)phenol in vitro against some strains of bacteria, typical, as found, for plaque person. Experimental test results minimum inhibitory concentration (MIC) is shown in table. 8.

This test shows that the agent is (1) significantly more active than any other agent, and the agent (2) is significantly more active than triclosan, relative to S. sanguis and S. mutans and many times exceeds the thymol against all three strains.

Example 9

The results SIKT test (undiluted solution of 3-hydroxy-4,4'-di-tert-butylbiphenyl = 2-tert-butyl-5-(4'- tert-butylphenyl) phenol) with respect to A. viscosus. (see tab. 9).

Each AA compound prepared in 98.5% EtOH. At concentrations in the final test the ohms, which does not contain active agents, such as EtOH. These tests show that the proposed AA has two times greater antibacterial activity relative to A. viscosus compared to triclosan.

In table. 10 lists the preferred AA of the present invention in two categories. Specified predicted values MICK mm, and for some of them contain values found. In addition, the values for MICK thymol and triclosan.

The prediction values of MIC based on the above references authors on the results of their research and other criteria, including the types, sizes, number and position of the substituents, their structure (linear, branched, cyclic, alkali), and other Compounds listed in category I are new compounds of formulas III and IV, falling in the scope of the invention, and are predicted antibacterial activity 100 times more activity of thymol and values MICK lower by about 0.4 mm. The compounds listed in category II, some of which are known, have predicted antibacterial activity in 10-50 times greater than the activity of thymol and values MICK above about 0.4 mm. The experimental values MICK ("found") for one from AA to the fact, equal to or much less (for example, 0.0022 against 0.038 in categories 1 and 0.043 versus 0.12 in categories (II) and, therefore, these agents are even much more antibacterial active against A. viscosus than predicted. In table. 10 shows also that all these AA are significantly smaller MICK (predicted and found) than thymol, and found that the value MICK connection category II 2-tert-butyl-4(4'-tert-butylphenyl)phenol is approximately one-tenth of the corresponding values for triclosan, and that the predicted values MICK 2,4-di-tert-butyl-5-phenylphenol and 2-tert-butyl-4-(1,1-dimethylpropyl)-5-phenylphenol even lower than the corresponding value of 2-tert-butyl-4-(4-tert-butylphenyl)phenol and comparable to the size of the MIC of triclosan.

The invention is disclosed with regard to its preferred options, it is clear that for a specialist obvious variations and modifications are to be included in the scope of this application and appended claims.

1. Antimicrobial composition for oral administration to prevent the formation of plaque, including suitable for oral administration filler and effective against the formation of plaque if the) formula

< / BR>
where R2is C3-6cycloalkyl, optionally partially or fully substituted C1-7alkyl side chains or C3-6cycloalkyl;

R4is (1) tert-bootrom or C3-8n-alkyl, optionally partially or fully substituted C3-6cycloalkyl or C1-7alkyl side chains, or (2) C3-6cycloalkyl, optionally partially or fully substituted C1-7alkyl side chains or C3-6cycloalkyl;

R3is H or R2.

2. Antimicrobial composition for oral administration to prevent the formation of plaque, including suitable for oral administration filler and effective against the formation of plaque number of 2-tert-butyl-5-(4'-tert-butylphenyl)phenol.

3. Antimicrobial composition for oral administration to prevent the formation of plaque, including suitable for oral administration filler and effective against the formation of plaque number, at least one essentially water-insoluble nikotinovoi antibacterial agent (AA) formula

< / BR>
where R10wysopal), -C(CH3)2CH2CH2CH3(1,1-dimethylbutyl) and C(CH3)2(CH3)3(1,1,2,2,-TETRAMETHYLBUTYL).

4. The connection representing a 2-tertbutyl-5-(4'-tert-butylphenyl)phenol.

5. A connection represents a 2,4-di-tert-butyl-5-phenylphenol.

6. The connection representing a 2-tert-butyl-4(1,1-dimethylpropyl)-5-phenylphenol.

7. The connection representing a 2-tert-butyl-3-hydroxy-10,10-dimethyl-9,10-dihydrogenated.


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Tooth paste // 2246931

FIELD: medicine, stomatology.

SUBSTANCE: the present innovation deals with preventing diseases and hygiene of mouth cavity. The suggested tooth paste contains chalk, sodium carboxymethylcellulose, glycerol and/or sodium laurylsulfate, vitamin additive, biologically active components of plant origin, functional additives and water, moreover, as vitamin additive it contains vitamin C, as biologically active components it contains lavender and eucalyptus oils and, additionally, it contains menthol. Components should be taken at a certain quantitative ratio. The suggested tooth paste has mint-plant odor with a scent of lavender and eucalyptus and refreshening taste by protecting teeth and parodontium tissues.

EFFECT: better sanitation and prophylactic action.

4 cl, 3 ex