Compositions of borinic acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an oral care composition having pH min. 8 or buffered so that to maintain the pH value min. 7, containing 3- hydroxypyridine-2-carbonyloxy-bis-(3-chlor-4-methylphenyl)borane in a combination or together with an orally acceptable carrier.

EFFECT: invention provides the stability, solubility and antimicrobial activity of borinic acid esters.

20 cl, 9 ex, 2 dwg

 

[0001] this application claims the priority of provisional patent application U.S. 61/183788, filed June 3, 2009, and provisional patent application U.S. 61/183792, also filed June 3, 2009, full details of which are included in the present description by reference.

BACKGROUND of INVENTION

[0002] the Present invention relates to antimicrobial compositions containing the derived porinovoi acid, for example, an ester of porinovoi acid. The present invention, in a particular embodiment, relates to oral compositions, for example, a means for cleaning the teeth, used to reduce the level of bacterial contamination of the oral cavity, for example, to suppress the formation and loosening of plaque, gingivitis and tooth decay.

[0003] Although some of the esters of porinovoi acid effective in their use as antibacterial agents, including esters of porinovoi acid compositions for the care of oral cavity encounters certain difficulties, since it is known that esters of porinovoi acid become unstable if they are added to aqueous compositions. For example, the esters of porinovoi acids can be subjected to hydrolysis and degradation, including in compositions for the care of teeth. In addition, the esters of porinovoi acid can be nerator is feasible in aqueous compositions. For example, the solubility of 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were)borane is present in the water only at a concentration of 100 ppm, and its solubility in the oils can be less than 0.5%. In this regard, there remains a need to develop appropriate compositions based on derivatives of porinovoi acid and stable ways include derivatives of porinovoi acid in the composition for the care of teeth.

A BRIEF DESCRIPTION of the INVENTION

[0004] the Present invention relates to the unexpected discovery that certain esters of porinovoi acid will be stable, soluble and will retain antimicrobial activity, if their inclusion in the composition for the care of the oral cavity, for example, in a composition for cleaning teeth or rinse composition for the oral cavity.

[0005] In one embodiment of the present invention, derivatives of porinovoi acid of the present invention are esters of porinovoi acid, for example, of the formula A:

Formula And

where R1and R2are the same or different (for example, can be the same and selected from arylalkyl, aryl, cycloalkyl or heterocycle (for example, substituted or unsubstituted aryl or heteroaryl, for example, phenyl, chlorphenyl, methylphenyl or metallorganic); and R3 denotes heteroaryl, heteroaromatic, heteroarylboronic or heteroarylboronic (for example, substituted or unsubstituted heteroaryl, for example, chinoline or hydroxyprednisolone), in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier. For example, in one embodiment of the present invention R1and R2are the same and both represent aryl, such as phenyl, chlorophenyl, were or metallorganic.

[0006] Heteroaryl represents an aryl group containing, for example, 1, 2 or 3 nitrogen atom, for example, pyridinyl, chinoline, hydroxypyridine and hydroxyquinolines. Alkyl represents, for example, With1-4alkyl. Substituents can be, for example, chlorine atoms or fluorine, or hydroxy-group1-4alkyl.

[0007] Thus, the esters of porinovoi acid used in the present invention include, for example, (i) picolinate boron, for example, picolinate derivera, such as, in particular, 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were)borane or 3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)borane, and (ii) esters of derivarives acid, for example, diphenylboron-8-hydroxyquinoline (PBHQ).

[0008] In one embodiment of the present invention, the esters of porinovoi sour whom you represent connections described in WO 2006/102604 included in the present application by reference, for example, the compounds of formula (I)

Formula 1

where

R* and R** are independently substituted or unsubstituted, aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted a heterocycle;

z is 0 or 1, provided that when z is 1, it denotes A CR10or N, and D represents N or CR12and also provided that when z is 0, D is O, S or NRl2a;

E represents hydrogen, a hydroxy-group, alkoxy, (cycloalkyl)hydroxy, (cyclogeranyl)hydroxy, carboxy or allyloxycarbonyl;

m is 0 or 1;

R12denotes hydrogen, hydroxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, carboxy, allyloxycarbonyl, aminogroup, the hydroxy-group, alkoxy, aryloxy, tigroup, alkylthio, aaltio, alkylsulfonyl, dialkylaminoalkyl, alkylaminocarbonyl, aminosulfonyl, alphagroup, cyano, halogen, the nitro-group, amino group, dialkylamino, alkylamino, arylamino, diarylamino, aralkylamines or dialkylamino;

Rl2adenotes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or asamese the hydrated cycloalkyl or substituted or unsubstituted a heterocycle; and

R9and R10independently represent hydrogen, alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, halogen, carbonyl, hydroxyamino, carboxy, allyloxycarbonyl, alkylthio, alkylsulfonyl, aaltio, dialkylaminoalkyl, alkylaminocarbonyl, aminosulfonyl, amino, alkoxy, nitro-group, alphagroup or hydroxy-group;

in free form or in the form of pharmaceutically acceptable salts.

[0009] the Terms "aralkyl and alkaryl" are sometimes used in relation to arylalkyl and alkylaryl, respectively. The alkyl or aryl portion of the fragment shown for R9, R10or R12optionally substituted, for example, hydroxy-group, halogen or1-4the alkyl.

[0010] the Alkyl preferably denotes a1-4alkyl. Cycloalkyl preferably denotes a3-7cycloalkyl. Aryl preferably denotes phenyl.

[0011] In some embodiments, implementation of the present invention, E represents a group selected from hydrogen, hydroxy or (cyclogeranyl)hydroxy, such as 2-morpholinoethoxy.

[0012] In some embodiments, implementation of the present invention, R12means (CH2)kOH (where k is 1, 2 or 3), CH2NH2CH2NH-alkyl, CH2N(alkyl)2, CO2H, CO2-alkyl, CONH2, OH, alkoxy, alloc and, SH, S-alkyl, S-aryl, SO2-alkyl, SO2N(alkyl)2, SO2NH, SO2NH2, SO3H, SCF3CN, halogen, CF3, N02, NH2, 2°-amino, 3°-amino, NH2SO2or CONH2.

[0013] In other embodiments, R9and R10independently represent hydrogen, alkyl, cycloalkyl, (CH2)nOH (n=1-3), CH2NH2CH2NH, CH2N(alkyl)2, halogen, CHO, CH=NOH, CO2H, CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N(alkyl)2, SO2NH, S02NH2, NH2, alkoxy, CF3SCF3, NO2, SO3H or OH;

[0014] the compounds of formula I can exist in the form of rotamers, and shown in the diagram connecting link (arrow) may be present or may not be present, i.e. the present invention also includes compounds in which there is coordination between the boron atom and a nitrogen or hydroxy-group in the picolinate, and compounds in which no such connection. The present invention also include compounds of formula I, in which the connecting link is formed between the boron atom and another atom in the molecule. In addition, for specialists in this field, in particular for specialists in the field of organic and medicinal chemistry is obvious that a large difference in atomic radius between carbon and boron creates the opportunity DL the formation of coordination complexes with the solvent, in which the solvent molecule, such as water, may be mounted between the boron atom and a nitrogen atom in picolinate ring. The present invention includes within its scope such adducts of compounds of formula I.

[0015] In one embodiment of the present invention, where z is 1, the compounds of formula I have the structure corresponding to the following formula:

where D is selected from N and CR12.

[0016] In another embodiment of the present invention, where z is 0, the compounds of formula I have the structure corresponding to the following formula:

where D represents a group selected from O, S and NRl2a.

[0017] In one embodiment of the present invention, R* and R** are the same value. In a more specific embodiment of the present invention, R* and R** are substituted or unsubstituted aryl. In another more specific embodiment of the present invention, R* and R** are substituted or unsubstituted phenyl, where the specified substituted or unsubstituted phenyl has the following structure:

and where each of the fragments of R4-R8represents a group selected from hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, Zam the seal aralkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, carboxy, alkylcarboxylic, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, aaltio, alkylsulfonyl, diaminoalkyl, alkylaminocarbonyl, aminosulfonyl, sulfo, cyano, halogen, nitro, amino, 2°-amino, 3°-amino, aminosulfonyl, aminoacylase (alkylamino)alkyloxy (dialkylamino)alkyloxy and cyclogeranyl. Each alkyl or aryl portion of each of the groups listed for R4-R8may be optionally substituted.

[0018] In more specific embodiments, the implementation of the present invention, according to which R* and R**, both, represent optionally substituted phenyl, as described above, each of R4-R8is a fragment selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH2)kOH (where k=1, 2, or 3), CH2NH2CH2NH-alkyl, CH2N(alkyl)2, CO2H, CO2-alkyl, CONH2, CONH, CON(alkyl)2HE, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO2-alkyl, SO2N(alkyl)2, SO2NH, SO2NH2, SO3H, SCF3CN, halogen, CF3, NO2, NH2, 2°-amino, 3°-amino, NH2SO2, OCH2 2NH25OCH2CH2NH, OCH2CH2N(alkyl)2, oxazolidin-2-yl, and alkyl, substituted oxazolidin-2-yl.

[0019] In one embodiment of the present invention, according to which R* and R**, both, represent optionally substituted phenyl, as described above, R9denotes H, z is 1, A represents CH, D is CH, E denotes OH and m is O. In a more specific embodiment, R* and R**, both represent 3-chloro-4-were. In another specific embodiment, R* and R**, both represent 2-methyl-4-chlorophenyl.

[0020] Particularly useful compounds include 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were)borane and 3 hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)borane, in free form or in the form of pharmaceutically acceptable salts.

[0021] it has been Unexpectedly found that the ether of porinovoi acid may be present in compositions in retornou form, where this form is highly dependent on pH, and where boron can be connected coordination covalent bond (connection) with the nitrogen atom in heteroaryl. Specified rotamer in which boron is non-polar in nature or associated with a hydroxy-group on picolinate fragment, predominantly or exclusively present at alkaline pH, whereas the more polar form rotamer where boron ASO is Yerevan with the nitrogen atom on the picolinate or another heterocycle, dominates in the conditions of acidic pH. For example, see the chart below:

It was also shown that nonpolar rotamer or rotamer in which boron is associated with a hydroxy-group, characterized by a greater stability in the composition. Not drawing for explaining any theoretical justification, it should be assumed that the shift in electron density that occurs in the formation of connective communication with the nitrogen makes polar isomer is more susceptible to hydrolysis by ester bonds.

[0022] In search of favorable conditions for a more stable rotamer, the authors found that for this purpose it is useful to maintain the pH of the composition at a level above 7, for example, through the use of a buffer to prevent pH drop, which could be the result of the formation of more polar rotamer, and/or maintain the pH at an even higher level, for example, in the range of 8-9,5, that is, it was unexpectedly found that the compounds are stable at a higher pH, and does not show (as expected) greater susceptibility to degradation under the action of OH ions-. This discovery provides the ability to get the drug on the basis of a more stable compositions of the considered compounds. The authors draw attention to the fact that this discovery to some extent counter the ECIT examples described in WO 2006/102604, which describes the local emulsion containing an ester of porinovoi acid in the oil phase, or even compositions with relatively low pH value, for example, 5,5.

[0023] Thus, the present invention relates to compositions 1.0, i.e. the compositions, which represents, for example, a composition for the care of an oral cavity, comprising an effective antibacterial against a number derived porinovoi acid, for example, formula A, for example, the compounds of formula (I) with a pH of at least 8, for example, in the range of 8.5-11, in particular, about 9, or which is buffered to achieve a pH of at least 7, and where the specified composition optionally also includes one or more antioxidants, surfactants and solubilizing substances.

[0024] the Present invention relates to compositions 2.0, a tool for cleaning teeth, comprising the composition of 1.0 and media to use tool for cleaning teeth, having a pH of at least 8, for example, in the range of 8.5-11, in particular, about 9, or which is buffered to pH 7, and where the specified composition optionally also includes one or more antioxidants, surfactants and/or solubilizers substances.

[0025] In another aspect, the present invention relates to the discovery of the fact that the derivative barenboimist, for example, formula A, which are often difficult to solubilize, have high solubility in polymers, including polyoxyethylene or polyoxyethylene, polyoxypropylene. Thus, the present invention in another aspect of implementation relates to compositions 3.0, compositions for the care of the oral cavity, for example, corresponding to any one of compositions 1.0-2.0, including the derived porinovoi acid, for example, formula A, in particular, the compound of formula I, and solubilizers means, for example, selected from polymers of polyoxyethylene and polyoxyethylene/polyoxypropylene.

[0026] it Was also discovered that tebufelone composition increases its stability. Accordingly, the present invention relates to compositions 4.0, oral care composition comprising an antibacterial effective amount of a derivative porinovoi acid, for example, formula A, in particular, the compound of formula (I), for example, any one of compositions 1.0 and then 3.0 and later, more fully described below, in combination with a suitable buffer, for example phosphate buffer.

[0027] the Present invention relates to a method 5.0, a method for producing an oral composition for the care of an oral cavity, comprising mixing any of compositions 1.0-4.0 orally acceptable carrier and adjusting the pH to a level at m is re 7, preferably, up to a level of at least 8, for example, in the range of 8.5-11.

[0028] the Present invention relates to a method 6.0, the way to reduce, suppress or treat microbial infections of the oral cavity, for example, reduce or inhibit formation of dental caries, treatment, attenuation or suppression of gingivitis, reduce bacteria levels in the mouth, suppressing the formation of microbial biofilms in the oral cavity, reducing the accumulation of plaque and/or cleaning of teeth and oral cavity, comprising applying the composition according to the present invention in the oral cavity of the patient, if necessary.

DESCRIPTION SONGS

[0029] In Fig. 1 shows the percentage of recovery COMPOUND 1 in two weeks at 60°C as a function of the formula pH (a) the basis of the G-series and (b) on the basis of low water content, as described in the examples.

[0030] In Fig. 2 shows the percentage of recovery COMPOUND 1 after 1 day at 70°C as a function of pH, as described in the examples.

DETAILED DESCRIPTION

[0031] In the context of the present description, the above ranges are used to reduce to specify each and any values that fall in this range. Any value in this range can be selected as the final value. In addition, all cited in the present description materials VK is uceni in it completely as references. In case of inconsistency between the definitions in the text of the present description and in the above cited materials, the option corresponding to the present invention.

[0032] Unless otherwise indicated, all information contained in the text, percentages and other quantitative data should be understood as corresponding to the percentage content by weight. Quantitative values refer to the active weight of the material.

[0033] the Oral compositions of the present invention may include means to care for your teeth, rinse for the mouth, a dental floss tool for staining teeth, dental film, candies or chocolates. Composition means for care of teeth may include toothpaste, gel or powder.

[0034] "Orally acceptable salt" is a pharmaceutically acceptable salt or additive salts of bases, which are safe for their use as a product for the care of the oral cavity, such as the means to care for the oral cavity, in quantities and concentrations corresponding to the usual practice of use of the product.

[0035] the compounds of formula (I), which can be used in the practice of implementation of the present invention include: 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were)borane (or complex 3-hydroxyphenethyl ether bis(3-chloro-4-methyl who enyl)porinovoi acid), for example, formula (II):

[0036] Thus, in one aspect of the implementation of the present invention, the Composition is 1, that is, the composition, in particular a composition for the care of the oral cavity, comprising an effective antibacterial against a number derived porinovoi acid, for example, formula A, in particular, the compound of formula (I), with a value of pH of at least 7, preferably at least 8, for example, in the range of 8.5-11, in particular, with a pH of about 9, and optionally also comprising one or more antioxidants, surface-active substances and solubilizers means includes, for example, any of the following songs:

1.1 Composition 1 comprising an ester of porinovoi acid.

1.2 1.1 Composition comprising an ester of porinovoi acid of formula 1.

1.3 Composition 1.1 or 1.2. including picolinate derivera.

1.4 Composition 1.1, 1.2 or 1.3, including 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were-borane or 3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)borane.

1.5 1.4 Composition comprising 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-were)borane.

1.6 Composition 1 comprising an ester of derivarives acid.

1.7 1.6 Composition, where an ester of derivarives acid is diphenylboron-8-hydroxyquinoline (PBHQ).

1.8 Any of compositions 1.0-1.7, in which the compound of formula (A) is present in the amount of 0.05 wt.% - 20 wt.%, for example, in amounts of from 0.1 wt.% up to 10 wt.%.

1.9 Any of the compositions 1-1 .8, including tabularasa funds to improve and maintain the pH at the right level.

1.10 1.9 Composition, where sautereau tool includes a basic amino acid in free form or in pharmaceutically acceptable salt.

1.11 1.10 Composition where the specified basic amino acid selected from arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutane acid, diaminopropionic acid and mixtures thereof, in free form or in pharmaceutically acceptable salt.

1.12 Composition 1.12, where this essential amino acid is an arginine, in free form or in pharmaceutically acceptable salt.

[0037] without drawing to explain any particular theoretical justification, it is believed that the compounds of formula A, for example, esters of porinovoi acid of the formula (I)can be oxidized by oxygen, peroxides or those peroxides that may be present in oral compositions, for example, from ethers such as reaction products of ethylene glycol with oxygen. Accordingly, oxygen and/or peroxide can interact with a complex ether of porinovoi sour what you carbon-boron communication which leads to the cleavage and formation of derivatives Bronevoy acid and phenolic derivatives, which are ineffective antibacterial agents. It should be assumed that the addition of antioxidants reduces the level of peroxides and other oxidizing agents which may be present or formed in oral compositions.

[0038] Thus, in one aspect of the implementation of the present invention, the Composition is 1.0 includes, for example, any of the following songs:

1.13 Any of compositions 1.0-1.8, which also includes antioxidant.

1.14 1.9 Composition, in which the antioxidant is selected from ascorbic acid, ascorbylpalmitate sodium, bottled hydroxytoluene (BHT), alpha-tocopherol, citric acid and mixtures thereof.

1.15 Any of the compositions 1.9-1.10, in which the antioxidant is present in an amount sufficient to inhibit oxidation of the derived porinovoi acids;

1.16 Any of the compositions 1.9-1.11, in which the antioxidant is present in an amount sufficient to prevent or inhibit the oxidation of compounds of formula (I).

[0039] In one embodiment of the present invention, the compounds of formula (I) was solubilizers in the compositions of the present invention using a solubilizer, which may include, for example, polyethylene glycol, glycerol, the copolymer is poly (ethylene glycol) and polypropylenglycol (for example, Pluraflo L4370) or triblocaltara surfactant F127. The necessary amount of solubilizer depend on the amount of compounds of formula (I) in the composition and on the nature of the specific selected a solubilizer. Thus, the present invention includes the following songs:

1.17 Any of compositions 1.0-1.12, which also includes a solubilizer.

1.18 Composition 1.13, in which the solubilizer is a non-ionic surfactant.

1.19 Composition 1.14, in which the solubilizer includes alkilany ether, for example, polyalkyleneglycol, for example, polyethylene glycol, polypropyleneglycol or their copolymers or blends.

1.20 Any of the compositions 1.13-1.15, in which the compound of the formula A was solubilisation in the solubilizer before mixing with other ingredients of the composition.

1.21 Any of the compositions 1.13-1.16, in which the solubilizer is present in amount comprising 1-30 wt.%, for example 5-10 wt.%.

[0040] Compounds of the present invention can also optionally include one or more chelating agents capable of forming a complex with calcium, present in the cell walls of bacteria, which are considered weakens the cell wall of bacteria and enhances the lysis of bacteria. Chelating agents can also emit ions that can form a complex with derivative is orinovo acid, with further destabilization. Products suitable for use as chelating agents known in the field and include di - and Tetra-acids and their salts, such as soluble pyrophosphates, polycarboxylic acid and polyaminocarboxylic acid. Used in the compositions of the present invention pyrophosphate salts can include any pyrophosphate salt of an alkali metal. In some embodiments, implementation of the present invention, these salts include pyrophosphate, Tetra-alkali metal, DIACID pyrophosphate dvuhslojnogo metal, monoacid pyrophosphate Tremeloes metal and mixtures thereof, where alkali metals are sodium or potassium. These salts can be used in their hydrated and UN-hydrated form. Effective for use in the present invention, the number pyrophosphate salt mostly considered to be a quantity sufficient to maintain the number pyrophosphate ions at the level of at least about 1 wt.%, from about 1.5 wt.% to about 6 wt.%, from about 3.5 wt.% to about 6 wt.% such ions. Used chelating agents include the pyrophosphate tetranitride, the pyrophosphate tetracene, ethylenediaminetetraacetic acid, etilenvinilatsetata acid, sodium pyrophosphate, sodium tripolyphosphate, tripolitsa the potassium, sodium hexametaphosphate sodium and citric acid. Accordingly, in another embodiment, the present invention relates to the following compositions:

1.22 Any of compositions 1.0-1.17, which also includes a chelating agent.

1.23 Composition 1.22, where the chelating agent is selected from the pyrophosphate tetranitride, the pyrophosphate tetracene, ethylenediaminetetraacetic acid, etilenvinilatsetata acid, sodium pyrophosphate, sodium tripolyphosphate, potassium tripolyphosphate, sodium hexametaphosphate and citric acid.

1.24 Any of the compositions 1.22 or 1.23, which used chelating agent supports a number pyrophosphate ions at the level of 1-6 wt.%.

[0041] In one embodiment of the present invention, this composition 2.0 of the present invention is a product for the care of the oral cavity, comprising an effective amount of a composition 1.0 and orally acceptable carrier. Acceptable carriers suitable for use in the product to care for your mouth, well-known experts in this field and can be in the form of a paste, gel or rinse for the mouth, where the specified product includes water and/or humectant, or a product can be represented in the form of a powder or a dental floss or dental setting. Components acceptable carrier can include HDMI is of 1.0. Humidifiers are known to specialists in this field and can include food polynuclear alcohols, such as glycerin, sorbitol, xylitol, allenglish, such as polyethylene glycol or polypropyleneglycol and polyols and mixtures of these humidifiers. Oral compositions of the present invention can include from about 5 wt.% to about 80 wt.% the humidifier with water and other components in the amount of correcting the level of a native.

2.1 Composition 2 in the form of a paste, gel or liquid, comprising any of the compositions 1-1 .24 in combination or in Association with water and/or humectant.

2.2 2.1 Composition in which the amount of water is less than 10%.

2.3 Composition 2.1 or 2.2, in which the number of the humidifier exceeds 50%.

2.4 Any of the compositions 2-2 .3 where the humidifier is selected from polynuclear alcohols (e.g. glycerol, sorbitol, xylitol) and alkalophiles (polyethylene glycol or propylene glycol, and other polyols and mixtures.

2.5. Any of the compositions 2-2 .4, which is a tool for care of teeth.

2.6 Composition of 2.5, which is a toothpaste.

2.7 Composition 2.5 or 2.6, which also includes abrasive tool.

2.8 2.7 Composition, which also includes a source of fluoride ion.

[0042] In another embodiment, the present invention relates to components is icii to care for the oral cavity, composition 3.0, such as any one of compositions 1.0-2.8, including derivatives of porinovoi acid, for example, formula A, for example, the compound of formula I, and at least one solubilizer selected from polymers of polyoxyethylene and/or polyoxypropylene, and includes, for example, the following composition:

3.1 Composition 3.0, in which the solubilizer comprises a copolymer of polyethylene glycol and polypropylenglycol, for example, Fluraflo L4370 (BASF).

3.2 Composition 3.0, in which the solubilizer includes poloxamer, for example, tribocorrosion formula H-(O-CH2-CH2)x-(O-CH(CH3)CH2)y-(O-CH2-CH2)z-OH.

3.3 3.2 Composition, in which the average molecular weight polyoxypropylene block in poloxamer approximately 3-4 kDa, the content of the polyoxyethylene is approximately 65-75%, and the total average molecular weight poloxamer approximately 12-13 kDa, for example, where x and z each equal to 90-110, in particular, about 101, and y is 50-65, in particular, about 56, for example, where poloxamer is poloxamer 407 (e.g., Pluronic® F-127 from BASF).

3.3 Composition 3.0, in which the solubilizer includes polyethylene glycol, for example, with a molecular weight of from 100 to 1000 daltons, such as, in particular, PEG-300 or PEG-600.

3.4 Composition 3.0, in which the solubilizer includes means is selected from copolymers of polyethylene glycol and polypropylenglycol, poloxamers, glycols and mixtures thereof.

[0043] it Was also found that the stability derivatives of porinovoi acid is significantly increased when using sautereau funds, largely at a neutral pH. In another embodiment, the present invention relates to compositions 4, which is a composition for the care of the oral cavity, which corresponds, for example, any of the above compositions 1.0-3.4 and which comprises an effective antibacterial against the derived porinovoi acid, for example, formula A, for example, the compound of formula (I), and the buffer and has a pH in the range from about 7 to about 11, in particular, a pH of about at least 8, for example, containing phosphate buffer with a pH value equal to at least 7,2.

[0044] the Composition for caring for the oral cavity according to the present invention may also contain one or more sources of fluoride ion, for example, fluoride salts, which are soluble. Preferred such fluoride salts, in which the fluoride is covalently bonded to another atom and/or proceeds from the calcium connection. In the compositions of the present invention can be used in a variety of materials, forming a fluoride ion, as sources of soluble fluoride. Representative East czniki fluoride ion include, without limitation, tin fluoride, sodium fluoride, potassium fluoride, monitoroff sodium, forcricket sodium, forcricket ammonium, amintore, ammonium fluoride, and combinations thereof. In some embodiments, implementation of the present invention, the source of fluoride ion comprises tin fluoride, sodium fluoride, monitoroff sodium, and mixtures thereof.

[0045] In some embodiments, implementation of the present invention, a composition for caring for the oral cavity according to the present invention may also contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to maintain the content of fluoride ions at the level of from about 25 ppm to about 25,000 ppm, mainly at the level of at least about 500 ppm, in particular from about 500 to about 2000 ppm, in particular from about 1000 to about 1600 ppm, in particular at about 1450 ppm

[0046] the Source of the fluoride ion can be added to the compositions of the present invention at a level from about 0.01 wt.% up to about 10 wt.%, according to one variant, or from about 0.03 wt.% to about 5 wt.%, and, according to another variant, at the level of from about 0.1 wt.% to about 1 wt.% by weight of the composition. The weight content of fluoride ions, providing the amount of fluoride ions at the right level will, of course, the var is activated depending on the weight of the counterion, available in the particular salt used.

[0047] the Oral compositions of the present invention may also include additional antibacterial agent, from a number of well-known experts in this field, such as halogen-containing diphenyl ether (triclosan), herbal extracts or essential oils, antiseptics based on biguanidine, phenolic antiseptics, hexetidine, iodine-containing povidone, delmopinol, coliflor, metal ions (e.g., zinc salts, e.g. zinc citrate), sanguinarine and propolis.

[0048] the Oral compositions of the present invention may also include desensitizing agent for teeth, from a number of well-known experts in this field, such as salt, potassium, capsaicin, eugenol, salt of strontium, zinc salts, chloride salt, or combinations thereof.

[0049] the Oral compositions of the present invention may include abrasive and/or polishing agents, such as calcium and silicon abrasives, which are known to experts in this field. Preferred calcium abrasives can include abrasive on the basis of calcium phosphate, for example, tricalcium phosphate (CA3(RHO4)2), hydroxyapatite (Ca10(PO4)6(OH)2or dihydrate dicalcium phosphate (CaHPO4•2H2About). Used abrasives based to amnia may include precipitated silica with an average particle size of about 20 microns, such as Setint® (Zeodent115®), marketed by J. M. Huber. Other commonly used abrasives include metaphosphate sodium, metaphosphate potassium, aluminum silicate, calcined alumina, bentonite or other silicon-containing materials or combinations thereof.

[0050] Suitable for use in the present invention the silicon abrasive polishing materials, as well as the other abrasives, generally have an average particle size of from about 0.1 to about 30 microns, from about 5 to about 15 microns. These silicon abrasives can be derived from silica or silica gels such as the silica xerogels, which are offered on the market under the trademark Syloid® from the company W. R. Grace & Co., Davison Chemical Division. Materials based on precipitated silica include the above products, marketed by J. M. Huber Corp. under the trademark Setint (Zeodent)comprising silicon with the name Setint (Zeodent) 115 and 119.

[0051] In some embodiments, the abrasive materials used in the practice of implementation of the present invention upon receipt of the compositions to care for the oral cavity according to the present invention include silica gels and precipitated amorphous silica with a coefficient of absorption at the level of less than 100 Centistokes/100 g silica and, in General, in the range from about 45 Centistokes/100 GDOs about 70 Centistokes/100 g silica. The absorption coefficients were measured by the method of ASTA USD-Out D281. In some embodiments, implementation of the present invention, used silica presents colloidal particles where the average particle size is from about 3 microns to about 12 microns, and from about 5 to about 10 microns.

[0052] In specific embodiments, the implementation of the present invention, abrasive materials include very small particles, for example, with the index d50 less than about 5 microns. For example, fine silica particles (SPS) with the index d50 in the range from about 3 to about 4 microns, contains, for example, the product Sorbosil AC43® (Ineos). Such small particles are especially useful in compositions used to reduce hypersensitivity. Component fine particles may be present in combination with a second abrasive material composed of larger particles. In some embodiments, for example, the composition includes from about 3 to about 8% SPS and from about 25 to about 45% of the standard abrasive.

[0053] it Was found that oral compositions containing silica and compounds of formula (I), change color from white to yellow, which is undesirable. This color change is observed even if the composition contains antioxidants (as previously described). The present invention is also based on open the AI in unexpected fact, that adding a chelating agent to the oral composition can suppress this color change and, in fact, to reverse the color change. Previously described chelating agents to prevent color change.

[0054] the Silica abrasive materials with a low coefficient of absorption, which is particularly suitable for use in the practice of implementation of the present invention, available on the market under the trademark Siladen (Sylodent) XWA® chemical division (Davison Chemical Division of the company W.R. Grace & Co., Baltimore, Md. 21203. Sylodent XWA 650®, being by silica hydrogel composed of particles of colloidal silica with a water content of about 29 wt.%, with an average diameter of from about 7 to about 10 microns and a coefficient of absorption of less than about 70 Centistokes/100 g silica, is an example of abrasive silica with a low coefficient of absorption used in the practice of implementation of the present invention. The specified abrasive is present in a composition for caring for the oral cavity according to the present invention in a concentration of from about 10 to about 60 wt.%, in another embodiment of the present invention, in an amount of from about 20 to about 45 wt.%, in one embodiment of the present invention, in an amount of from about 30 to primer is 50 wt.%.

[0055] the Composition for caring for the oral cavity according to the present invention may also include means strengthening foam when cleaning the oral cavity, and such means known to specialists in this field. Representative examples of tools that enhance the formation of foam include, without limitation, polyoxyethylene and some polymers, including, without limitation, polymers of the alginate.

[0056] the Polyoxyethylene may increase the number and thickness of the foam formed by the component carrier for oral cavity according to the present invention. Polyoxyethylene also known as polyethylene glycol ("PEG") or polyethylene oxide. Polyoxyethylene suitable for practice of the present invention have a molecular weight in the range from about 200,000 to about 7000000. In one embodiment of the present invention, the molecular weight will be from about 600,000 to about 2000000 and in another embodiment is from about to about 800000 1000000. Polyoxyethylene may be present in amount from about 1 wt.% to about 90 wt.%, in one embodiment, from about 5 wt.% to about 50 wt.%, in another embodiment, from about 10 wt.% up to about 20 wt.% from weight orally acceptable carrier in the compositions to care for the oral cavity according to the present invention. Dosage blowing means in the position to care for the oral cavity (i.e. a single dose) ranges from about 0.01 to about 0.9 wt.%, from about 0.05 to about 0.5 wt.%, in another embodiment, from about 0.1 to about 0.2 wt.%.

[0057] the Oral compositions of the present invention can also include a surfactant or a mixture of compatible surfactants known to specialists in this field. Suitable surfactants are those of them which have sufficient stability in a wide range of pH values, and include, for example, anionic, cationic, nonionic or zwitterionic surface-active substances, including mixtures thereof.

[0058] Used in the present invention the anionic surfactants include water-soluble salts of alkyl sulphates containing from about 10 to about 18 carbon atoms in the alkyl radical, and soluble salts from sulphonated of monoglycerides of fatty acids containing from about 10 to about 18 carbon atoms, for example, sodium lauryl sulfate, lauroylsarcosine sodium and sulfonates of monoglyceride sodium coconut oil. Can also be used a mixture of anionic surfactants.

[0059] Used in the present invention, cationic surfactants include derivatives of aliphatic Quaternary ammonium with the joining, containing from about 8 to about 18 carbon atoms, for example, laurillard trimethylammonium, Teilhard pyridinium, celibrated trimethylammonium chloride di-isobutyltrimethoxysilane, nitrite of alkyltrimethylammonium of coconut oil and camelford pyridinium.

[0060] non-ionic surfactants that can be used in the compositions of the present invention, can be defined as compounds produced by the condensation alkalinising groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature. Examples of nonionic surfactants used in the present invention include Pluronic (Pluronics), representing the condensation products of polyethylene oxide and alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and Ethylenediamine, condensates of ethylene oxide and aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long-chain diallylsulfide and mixtures of such materials.

[0061] Poloxamer represent a specific type of non-ionic surfactants that can be used in the present invention. Poloxamer predstavlyaet a non-ionic triblock copolymers, consisting of a Central hydrophobic chain of polyoxypropylene (poly(propylene oxide)), flanked by two hydrophobic chains of polyoxyethylene (poly(ethylene oxide)). Poloxamer also known under the trade name Pluronic (Pluronics). Because of the length units in the polymer can be adjusted accordingly, there are many different poloxamers with slightly different properties. In relation to the generic notion of "poloxamer", these copolymers are basically denoted by the letter "P" (i.e. poloxamer), followed by three digits, where the first two × 100 indicate the approximate molecular weight polyoxypropylene kernel, and the last digit × 10 indicates the percentage of polyoxyethylene (for example, P407 = Poloxamer with polyoxypropylene units with a molecular mass of 4000 g/mol and 70% polyoxyethylene). Designation copolymers brand Pluronic (Pluronic) begins with a letter that defines the physical form of a particular product at room temperature (L=liquid, P=paste, F=flake (solid)), followed by two or three digits. The first digit (two digits in a three-digit number) in the digital designation of the product, multiplied by 300, indicates the approximate molecular weight hydrophobic form; and the last digit × 10 shows the percentage of polyoxyethylene (the example L61=Pluronic with a molecular mass of polyoxypropylene equal to 1800 g/mol and 10% polyoxyethylene). In the above example, poloxamer 181 (P 181)=Pluronic L61.

[0062] Zwitterionic synthetic surfactants used in the present invention can be broadly described as derivatives of aliphatic Quaternary ammonium, fofanah and Solonevich compounds, aliphatic radicals which can be linelocations or branched, and where one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, for example, carboxylate, sulfonate, sulfate, phosphate or phosphonate. Representative examples of surfactants suitable for inclusion in the composition include, without limitation, alkylsulfate sodium, lauroylsarcosine sodium, cocamidopropylbetaine and Polysorbate 20, and combinations thereof.

[0063] the Surface-active substance or a mixture of compatible surfactants can be present in the compositions of the present invention in an amount of from about 0.1 wt.% to about 5.0 wt.%, in another embodiment, from about 0.3 wt.% % to about 3.0 wt.%, and in yet another variant, in the amount of from about 0.5 wt.% to about 2.0 wt.% the weight of the entire composition.

[0064]the Composition for caring for the oral cavity according to the present invention may also include one or more flavouring substances from a number of well-known experts in this field. Flavouring substances used in the practice of implementation of the present invention include, without limitation, essential oils, and various food aldehydes, esters, alcohols, and similar materials. Examples of essential oils include peppermint oil curly, peppermint oil, Wintergreen oil, sassafras oil, clove oil, sage oil, rosemary oil, eucalyptus oil, marjoram oil, cinnamon oil, lemon oil, lime oil, grapefruit oil and orange oil. There are also chemicals like menthol, carvon and anethole and other extracts such as green tea extract.

[0065] the Flavouring substance is included in the oral composition at a concentration of from about 0.1 to about 5 wt.% and from about 0.5 to about 1.5 wt.%. Intake of flavouring substances present in individual songs to care for the oral cavity according to the present invention (i.e., single dose) ranges from about 0.001 to about 0.05 wt.%, and in another embodiment is roughly 0.005 to about 0.015 wt.%.

[0066] the Composition for caring for the oral cavity according to the present invention also optionally include one or more polymers from a number of well-known experts in this field, such as glycols, copolymers polivinilovogo ether and maleic acid, polisher the water (for example, derivatives of cellulose, such as carboxymethyl cellulose or polysaccharide gums, for example xanthan gum or carrageenan). Acid polymers, such as polyacrylate gels can be present in the form of their free acids or in the form of partially or completely neutralized through the use of water-soluble alkali metal (e.g. potassium or sodium) or ammonium salts. Some options include copolymers of maleic anhydride or acid with another of the polymerized unsaturated ethylene monomer in a ratio of from about 1:4 to about 4:1, for example, methylviologen ether (methoxyaniline) with molecular weight (MV) of from about 30,000 to about 1000000. These copolymers are available for example as Gantrez AN 139 (MV OF 500,000), AN 119 (MV 250000) and pharmaceutical product purity S-97 (MV 70000) from GAF Chemicals Corporation. Such copolymers may enhance the antibacterial activity of the compounds of formula (I) (IR8387).

[0067] Other commonly used polymers include, in particular, such as the 1:1 copolymers of maleic anhydride with acrylate, hydroxyethylmethacrylate, N-vinyl-2-pyrrolidone or ethylene, where the latest available, for example, under the trademark of Monsanto (Monsanto) EMA No. 1103, M.V. 10,000 and EMA grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethylmethacrylate, methyl - or etelekrol is that isobutylphenyl ether or N-vinyl-2-pyrrolidone.

[0068] Another class of polymers includes a composition containing homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and their salts, in particular where such polymers based on unsaturated sulfonic acid selected from acrylamidophenylboronic acids, such as 2-acrylamide-2-methylpropanesulfonic acid with a molecular weight of from about 1000 to about 2000000, as described in U.S. patent No. 4842847, issued June 27, 1989, Zahid, where the referenced patent is incorporated into this description by reference.

[0069] Another common class of polymers includes polyaminoamide, in particular, such polyaminoamide that contain certain proportions of anionic surfactants, such as aspartic acid, glutamic acid and phosphoserine, as described in U.S. patent No. 4866161 (Sikes et al.), included in this description by reference.

[0070] Upon receipt of the compositions for the care of the oral cavity, it is sometimes necessary to add a certain amount of thickener to achieve the desired consistency or to stabilize or improve the functional properties of the composition. Such thickeners known to specialists in this field and may include carboxyvinyl polymers, carrage the Academy of Sciences, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethylcellulose and sodium-karboksimetilcelljuloza. May include natural gums such as gum karaya, Arabic gum and tragakant. Colloidal magnesium silicate-aluminum or fine silica can be used as a component of the composition of a thickening agent to further improve the texture of the composition. In some embodiments, implementation of the present invention, the thickeners are used in amounts of from about 0.5 wt.% to about 5.0 wt.% the total weight of the composition.

[0071] the Composition for caring for the oral cavity according to the present invention can also optionally include one or more enzymes from a number of well-known experts in this field. Used for these purposes enzymes include protease, glucanohydrolase, endoglycosidase, amylase, Athanasy, lipase or mucinase or a compatible mixture. In some embodiments, implementation of the present invention, this enzyme represents dextranase, endoglycosidase and athanasou. In another embodiment, the specified enzyme is a papain, endoglycosidase or mixture dextranase and atanazy. The content of the enzyme in a mixture of several enzymes of the present invention is from about 0.002% to about 2%, which according to one variant of implementation of the present invention, or from about 0.05% to about 1.5%, according to other variant, or, according to another variant, from about 0.1% to about 0.5%.

[0072] in Addition to the above components, consider the composition in some embodiments, implementation of the present invention can contain many different optional ingredients of the numbers used in the tools for teeth, some of which are described below. These optional ingredients include, for example, without limitation, adhesive materials, foaming substances, flavorings, sweeteners, additional means for plaque removal, abrasives, dyes, known to specialists in this field.

[0073] the compositions of the present invention can be obtained by conventional methods known in the production of products to care for your mouth.

[0074] the Present invention, in one aspect, relate to methods of producing, comprises introducing into the oral cavity a safe and effective amount of the compositions to care for the oral cavity according to the present invention, for example, with a brush, with the aim of (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or suppression precariously damage enamel detected, for example, by the method of quantitative induced light of fluorescence the (QLF) or electrical method for detection of caries (ECM), (iii) reduce or inhibit the demineralization and enhance remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) the reduction or suppression of gingivitis, (vi) improve healing capacity in respect of sores or cuts in the mouth, (vii) reduce levels of bacteria that form the acid (viii) to increase relative levels agrisolutions bacteria, (ix) inhibit the formation of microbial biofilms in the oral cavity, (x) raise and/or maintain the pH in the plaque on the level of at least pH 5.5 after provocation test with sucrose, (xi) reduce accumulation of plaque, (xii) reduce dry mouth, (xiii) the cleansing of the teeth and oral cavity (xiv) reduce erosion, (xv) whiten teeth, and/or (xvi) the destruction or suppression cariogenic bacteria.

[0075] the Oral compositions can also include one or more suitable solvents. The ability of any solid substance (dissolved substance) dissolved in any liquid substance (the solvent) is dependent on the physical properties of the dissolved substance and the solvent. In that case, when dissolved substances and solvents have similar physical properties, the solubility of the dissolved substance in the solvent will be higher. This situation corresponds to the well-known principle that "like dissolves under the service". Solvents may be characterized, in one extreme aspect as non-polar, lipophilic oil, while the other opposite end of the band in this classification system will correspond to the polar hydrophilic solvents. Oil solvents dissolve other nonpolar substances on the mechanism of the van der Waals interactions, while water and other hydrophilic solvents dissolve polar substances through ionic, dipole interactions, or interactions, based on the formation of hydrogen bonds. All known solvents can be listed in the form of a huge list covering connection, starting from the least polar, i.e. hydrocarbons, such as the Dean, to the polar solvent, which is water. Dissolved material will have the greatest solubility in solvents having similar polarity. Accordingly, in the case of medicines, which will have a minimal solubility in water, less polar solvents will provide increased solubility, if used, the solvent will have a polarity that is almost equivalent to that of the dissolved substance that will lead to the maximum solubility. Most drugs have an intermediate degree of polarity and, in the section communication show maximum solubility in solvents, such as propylene glycol or ethanol, which is much less polar than water. If the drug has a higher solubility in propylene glycol (e.g., 8 wt.%), than water (for example, 0.1 wt.%), the addition of water to propylene glycol will reduce the maximum amount of solute in solvent mixtures, in comparison with the use of pure propylene glycol. The addition of a solvent with low solubility to a solvent with a very good dissolving capacity will reduce the maximum solubility in the mixture, in comparison with the maximum solubility in the solvent with a very good dissolving capacity.

[0076] When the compounds included in the composition for the care of the oral cavity, the concentration of active ingredient in such compositions may be limited by the solubility of the active ingredient in the selected solvent and/or carrier. Not lipophilic drugs typically exhibit very low solubility in pharmaceutically acceptable solvents and/or carriers. For example, the solubility of some of the complexes porinovoi acid in water is less than 0,00025 wt.%. The solubility of the same complexes porinovoi acid may be less than about 2 ve is.% in propylene glycol or isopropylmyristate. In one embodiment of the present invention, for dissolving the compounds of formula I using solvent diethylene glycol-monotropy ether (DGME). It is believed that the complexes of porinovoi acid used in the present invention have a solubility of from about 10 wt.% to about 25 wt.% in DGME. In another embodiment of the present invention, use of alcohol DGME/water to dissolve the compounds of formula I. Dissolving ability DGME decreases with the addition of water; however, the system of co-solvents DGME/water can be designed in such a way as to maintain the desired concentration of active ingredient in the range of from about 0.1 wt.% to about 5 wt.%. Preferably, the active ingredient is present in an amount of from about 0.5 wt.% to about 3 wt.%, and more preferably, about 1 wt.%. This increased solubility reduces the likelihood of reducing the bioavailability caused by precipitation.

[0077] Liquid forms may include suitable aqueous or non-aqueous media together with buffers, suspendresume and crumbling agents, thickeners and the like means. Solid forms, such as creams or pastes or similar form, may include, for example, any of the following ingredients, water, oil, alcohol, or fat as a substrate, in which Oceanie with surface-active substance, polymers, such as polyethylene glycol, thickeners, solids and other Liquid or solid compositions may include improved system delivery, such as liposomes, microsome assay, microsponge etc. Additionally, these compounds can be delivered using a prolonged release system, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agent. There were various systems prolonged release materials that are well known to specialists in this field.

[0078] Below, the present invention is described using appropriate examples. These examples are given solely for the purpose of explanation and should not be construed as limiting the scope of the present invention, which is defined by the description and the claims.

EXAMPLE 1 Stability tools for cleaning teeth with a reduced water content

[0079] the Stability of the composition for cleaning teeth, containing the active ingredient, 3-hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane (COMPOUND 1)in a silica base was evaluated in the presence of different amounts of water. The composition had the following composition:

Table 1
Component (wt.%)0% added water6% added waterG series
Demineralized water6,031,367
99,0-101,0% glycerin from plants69,50753,40730,84
Silica for brushing your teeth - Zeodent 105-highly cleansing1210
Silica abrasive for care of teeth (Zeodent 115)8,5
Silica for the care of teeth, Zeodent 114 synthetic amorphous ppt silica812
Silica for care of teeth Zeodent 165-Sint. amorphous ppt silica92,5
Pyrophosphate, Tetra-sodium, finely chopped0,50,5 0,5
Sodium saccharin0,30,3
Sodium saccharin COP0,3
Sodium fluoride0,2430,2430,243
Sucralose0,150,150,15
Titanium dioxide10,750,75
Concentrate carrageenan PS-2230,4
Sodium-CMC-121
Sodium CMC, grade food 7MF0,4
Poly(vinyl pyrrolidone) (Polyclar® 10)1
Xanthan gum 0,30,5
Gantrez S-971,951,95
50% solution of sodium hydroxide1,21,2
Flavouring substance K91-65071,311
Polyethylene glycol 3006,256,726,72
Connection 10,750,750,75
Powder sodium lauryl1,71,51,5
Sodium ascorbyl phosphate0,20,2
Bottled hydroxytrol0,030,03
Vitamin E0,5

[0080] the Inclusion compound 1 in means for cleaning the teeth with a low water content increases the stability of the active ingredient, in comparison with the preparations for the care of teeth, including a higher amount of water. Such drugs with low water content have antibacterial and anti-inflammatory efficacy in vitro, which are equivalent to those for the positive control, Colgate Total® (Colgate Total®) with triclosan as an antibacterial agent.

[0081] the Difference in water content between these songs is very important. Drugs G series are characterized by the level of water activity (expressed as vapor pressure of water in the sample compared with the vapor pressure for pure water at the same temperature), equal to 0.75, whereas in the composition with 6% water content, this ratio is 0.25, and the composition without the addition of water it is 0,09. The stability of compound 1 over time in different compositions illustrated in the table below:

Table 2
Start1 month KKT1 month -40 ° C 2 months KKT2 months -40 ° C
CP1FCP1FCP1FCP1FCP1F
6%0,7211530,7110770,7011600,7412150,681041
Add.
water
(96%)ppm(94%)ppm(93%)ppm(99%)ppm(91%)ppm
0%0,6710420,7211310,6811300,72 11600,611135
Add.
water
(90%)ppm(96%)ppm(91%)ppm(96%)ppm(81%)ppm
G-0,7211440,7410260,6610760,718800,51990
series(96%)ppm(99%)ppm(93%)ppm(99%)ppm(91%)ppm

[0082] the Lowering of the water level in the medium for care of teeth has, apparently, a positive effect on the stability of compound 1 in the composition. After 2 months of storage under conditions of controlled room temperature (TCC) and at 40°C, is observed with lower % of reducible compounds 1 in compositions with a content of water is 0% and 6%, than in the standard composition G-series.

[0083] the Stability of these compounds was also evaluated by provocation option of adding hydrogen peroxide to the compound 1 in a molar ratio of 1:1. Compositions, which are characterized by sensitivity to decomposition of hydrogen peroxide, show less stability during storage. For example, the drug G-series was characterized by the reduction of compound 1 at the level of 59% after three months of storage at 40°C and at 35% recovery compound 1 after provocation with hydrogen peroxide, whereas a more stable composition used in this experiment as a positive control, showed an 87% level of recovery after three months of storage at 40°C and 85% recovery after provocation peroxide. (Note: the Positive control in this experiment was hee is automatic stable, but ineffective, according to the results of the test in vitro).

[0084] there has only been a 1% reduction in recovery connection 1 in the composition with 0% added water and 10% reduction in percent of its recovery in the composition with 6% added water. Both compositions showed a significantly reduced level of decomposition, in comparison with drugs G-series, which saw a 44% reduction reconnection 1.

[0085] based On the results of an experiment in provocation hydrogen peroxide and data in the two storage tracks, we can conclude that the decrease of water level in the medium for care of teeth improves the stability of the active component. Composition with 0% and 6% added water was investigated in the test, based on the measurement of growth inhibition A.viscosus, and it was shown that these compositions retain their antibacterial effectiveness. Composition with 0% added water was also evaluated in the test for anti-inflammatory activity by measuring the induction of PGE2, and it was shown that it is as effective as the positive control toothpaste Total® Total®) with triclosan, where the resulting value was <200 PG/ml PGE2 compared with a value of >1200 PG/ml for control, placebo, and approximately 400 PG/ml for G composition.

EXAMPLE 2 Compositions with high pH

[0086] the Composition for cleaning teeth, the content is asuu active ingredient, 3 hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane (COMPOUND 1)in a silica base was estimated at different levels of water content. It was shown that the stability of COMPOUND 1 in the means for cleaning the teeth depends on the pH of the composition. Specifically, there has been a significant increase in stability when the pH of cleaning the teeth is increased from 7 to 9, and there is no negative impact on antibacterial or anti-inflammatory efficacy of the composition.

[0087] the first composition known as the G-series, while the second composition was designated as composition with a low content of water, which corresponds to the preparations G-series, but includes 6% added water, as described in the example above. The main difference between the two compositions is the level of added water. Drugs G-series include approximately 32% of added water, while a drug with low water content includes 6% added water. In both compositions, the CONNECTION-level 1 is 0.75%. The pH was varied by adjusting the ratio of the amounts of sodium hydroxide and glycerol in the compositions described in the previous example, in order to obtain funds for brushing your teeth with pH values of 7, 8.5 and 9.

[0088] the results of the stability evaluation SOEDINENIYA under accelerated stability testing at 40°C are shown in table 2. Preparations for G-series, the percentage recovery CONNECTION 1 after three months of storage under conditions of rapid test evaluation of stability by approximately 30% higher in compositions with a pH of 8.5 and pH 9, in comparison with a composition having a pH of 7. The same trend was observed in compositions with low water content. These results demonstrate the marked improvement in the stability of COMPOUND 1 as a result of increasing pH for cleaning teeth. Although pH is a major determinant of the decline in water level, apparently, also has a positive effect on the stability of COMPOUNDS COMPOUND 1 in the composition.

[0089] After two months of storage in controlled conditions at room temperature and at 40°C, we observed less drop % recovery COMPOUND 1 in compositions with 0% and 6% added water than in the drug G-series:

Table 3
% recovery COMPOUND 1 after storage under conditions of accelerated stability testing at 40°C
Original value1 month2 months3 months
G - pH 790%88%68%61%
G - pH 8.5108%104%96%89%
G - pH 9100%97%97%90%
LW - pH 799%93%87%63%
LW - pH 8.5103%100%96%100%
LW - pH 997%97%92%97%

[0090] To further study the effect of pH on the stability of COMPOUND 1, was prepared in a series of paste-like products with pH values ranging from 5.7 to 9. The paste was kept at 60°C for two weeks to get accelerated results on the stability of compositions depending on the pH. In preparations G-series, the percentage of the recovered COMPOUND 1 decreases with decreasing pH from p 9 to pH 7.5, but increases when the change in pH from pH 7 to pH of 5.7. When using a substrate with low water content, percent recovered COMPOUND 1 decreases with the change of pH values from pH 9 to pH of 5.7. Although stability at acidic pH values is different for the two different bases in the investigated compositions, at pH 9 has the highest percentage of recovered COMPOUNDS 1 in both compositions. In addition, it was shown that the ratio of the isomers of COMPOUND 1 are also strongly depends on pH. At pH 9, the CONNECTION 1 is present only in its polar form, and the number of polar isomer increases with decreasing pH for cleaning teeth. A similar trend was observed in case of liquid funds for the care of teeth.

[0091] In Fig. 1 illustrates the percent recovery of COMPOUND 1 after two weeks of storage at 60°C as a function of the pH of the composition for drugs (a) basis consistent with the G-series, and (b) with a base containing a reduced level of water.

[0092] As a means for care of teeth contains many components, it is important to understand what is determined in this case, the observed correlation between the stability of COMPOUNDS 1 and pH: any ingredient in means for cleaning the teeth or it is a response of the CONNECTION 1 on the pH. In this regard, conducted a study of the effect of pH on OBEDINENIE 1 simple solution, including 50/50 acetonitrile/water. The result is shown in Fig. 2. In this study, produced a series of samples with pH values in the range from 9 to 6 and kept at 70°C for one day. The solution at pH 9 was characterized by the highest percentage of recovered COMPOUNDS 1. It was also shown that at pH 9 there is only one non-polar isomer and that the ratio of the nonpolar rotamer to polar rotamer decreases with decreasing pH, the same trend was demonstrated in the case of cleaning the teeth. These results indicate that non-polar rotamer COMPOUND 1 significantly less sensitive to degradation and that the ratio of nonpolar to polar isomer isomer depends on pH. Thus, the obtained results allow to explain the observed increase % recovery COMPOUND 1 in the compositions at a pH of 9 and 8.5 in comparison with a composition having a pH of 7. Differences between the stability of COMPOUND 1 at lower pH values in the two compositions with different bases reflects, apparently, the ability of the ingredients of the composition to partially stabilize the polar rotamer.

[0093] In Fig. 2 shows the percentage of recovery COMPOUND 1 in solution containing 50/50 acetonitrile/water as a function of pH, after 1-day storage at 70°C.

[0094] Protivovospalitel the capacity effect of COMPOUNDS 1, apparently unaffected by the increase in the pH of the composition. As preparations G-series, and composition with reduced water content at pH 7 and 9, are functioning well, the evaluation of suppression marker anti-inflammatory activity of PGE2. Antibacterial effect of COMPOUND 1, as measured by growth inhibition A.viscosus, comparable to those corresponding to the paste with a pH of 7, as well as commercial toothpaste high quality.

[0095] the Deposition of COMPOUND 1 on hydroxyapatite disk (HAP) significantly increases with increasing pH. Although the release of COMPOUND 1 at pH 9 is only 29%, this is equivalent to the number of CONNECTIONS 1 released from the compositions G-pH 7 and G-pH 9.

EXAMPLE 3 - the Effectiveness of the CONNECTION 1 on the inhibition of bacterial growth in the oral cavity

[0096] Determined the minimum inhibitory concentration of COMPOUND 1 against the normal bacteria of the oral cavity, which is shown in the table below. Ethanol was used as the carrier.

EXAMPLE 4 - Solubilization of Compounds 1

a. Solubilization using copolymers of ethylene glycol and propylene glycol

[0097] the Poor solubility of compound A creates certain problems in the manufacture of the composition. The solubility of this compound in water is less than 100 ppm, and solubility in pexeva the oils commonly used to solubilize the active ingredients) is less than 0.5%. The authors found that the use of copolymers of polyethylene glycol and polypropylenglycol allows to achieve solubilization of the compound 1. So, Fluraflo L4370 (BASF) solubilities 1% of compound 1 (wt.%). It is necessary to mix the solution at low heat for complete solubilization of the active ingredient. It turns a cloudy solution, which corresponds to the nature of the Fluraflo L4370. Next, a 1% solution of compound 1 in Fluraflo L4370 was diluted in the ratio 1:1 using 1.5% of LTOs in water to obtain a clear solution consisting of 0.5% AN0128, 0,75% LTOs and 50% Fluraflo L4370 in the water. Similar results were obtained when using Fluracare LI220.

[0098] Next, a solution containing 0.5% AN0128, 0,75% LTOs and 50% Fluraflo L4370 in water, were analyzed in the test for the destruction of biofilms. The resulting percentage reduction in comparison with a negative control was 65%, indicating that compound 1 retains its antibacterial activity by solubilization in Fluraflo L4370.

b. Solubilization using triblock-copolymer

[0099] the Authors also found that the triblock copolymer used as surfactants, F127 can further improve the solubilization of the compound 1. In the experimental liquid compositions funds for care of teeth (table 3), the connection 1 over time is not fully dissolved, what followed, and the evaluation results according to the method of deposition and crystallization after a certain period of time. After adding 5% F127, experimental liquid compositions funds for care of teeth (table 4) remained transparent. This means that the triblock-copolymer surfactant F127 allows more solubilisate connection 1 and, in this regard, can be used in the compositions.

Table 5
Experimental compositions not containing triblock-copolymer
A2A3
Connection 10,60,6
PEG-3001212
Propylene glycol1010
Fluraflo L43701010
Glycerin10
LTOs1,51,5
H2O3838
Only72,172,1

Table 6
Experimental compositions containing triblock-copolymer
A5A6
Connection 10,60,6
PEG-30011,411,4
Propylene glycol1010
Fluraflo L43701010
Glycerin10
LTOs1,51,5
H2About3434
Pluronic F12755
Only72,572,5

C. Solubilization using PEG

[0100] Additionally, the authors found that low molecular weight polyethylene glycol 300 (PEG 300) (Dow Chemical Company) solubilities 10% of compound 1 (wt.%). In this case, it is necessary to mix the solution at low heat for complete solubilization of the connection. The resulting solution was clear with a slightly yellow tint, which is determined by the color of the connection 1. The authors showed that PEG 600 may also solubilisate connection 1. In this regard, the authors concluded that solvents containing oligomers and/or polymers of ethylene glycol, can solubilisate connection 1 and can be used to obtain the composition.

[00101] a Solution of 2% of compound 1 in PEG 300 was diluted in the ratio 1:1 2% LTOs in water to obtain a solution consisting of 1% compound 1, 1% LTOs, 50% PEG 300 in the water, which was analyzed in the test for the destruction of biofilms. The achievable per cent decline in comparison with negative control was 76%, which indicated that compound 1 retains its antibacterial activity by solubilization in PEG 300.

[00102] the Properties of the compound 1 in combination with other excipients were additionally evaluated by dilution of a solution of compound 1 in PEG 300 other solvents, such as propylene glycol and glycerin, in different proportions. A solution containing 1% of compound 1 in 19% PEG 300 and 80% propylene glycol, was transparent. Further, this races the thief was diluted in the ratio 1:1 using 1% LTOs in water to obtain a solution, consisting of 0.5% of the compound 1, 0.5% of LTOs, and 9.5% PEG 300 and 40% propylene glycol in water, which is then analyzed in the test for the destruction of biofilms. The achievable per cent decline in comparison with negative control was 80%. The results show that compound 1 retains its antimicrobial activity in solution of a mixture of solvents. Similar results were obtained using PEG and glycerin.

EXAMPLE 5 - the Buffer composition

[00103] Received two compositions connection 1 with a pH of 7.2, one of which was prepared in phosphate buffer, and one did not contain a buffer, and determined the degree of decomposition of the compounds 1 through 14 days. Although explicit decomposition was noted in both compositions, the slope of the curve describing the rate of decomposition of compound 1 in the buffer composition was below 3.3 times than the composition without the buffer.

EXAMPLE 6 Effect of gantrez (Gantrez)

[00104], it Was shown that adding gantrez in the liquid compositions of compound 1 increases the activity of this compound, according to the test on the biofilm. The composition had the following composition:

Table 7
Liquid tooth IDG5G7
0,50,5
BHT--0,05
Gantrez--2
PEG 3004,5of 4.45
Glycerin2020
Flavouring substance11
LTOs1,51,5
NaF0,240,24
Saccharin0,30,3
Aq. buffer, pH 7.048,546,5
Only76,5476,54

[00105] the Authors determined the activity of these funds for the care of teeth in the test for inhibition of biofilm formation of A.viscosus, organism, which has been shown to be relatively resistant to compound 1, in comparison with many other plaincourault what they bacteria. The composition of the G7 had a very good efficiency, causing with this test the inhibition of the formation of biofilms on the same level as commercially available toothpaste Total® Total®) with triclosan, while the G5 was only slightly better than the control. Thus, adding gantrez (Gantrez) (copolymer metilfenidato ether and maleic acid or copolymer MVP/MK (PVM/MA)substantially increases the activity of compound A in the test for suppression film forming A. viscosus.

EXAMPLE 7 Optimization tools to care for your teeth

Table 8 describes three songs toothpaste silica containing compound 1, where the number of components is given in wt.% (w/w), the water level is so adjusted to compensate for the difference in the content of glycerol:

GHI
Connection 10,750,750,75
Sodium fluoride0,2430,243 0,243
99,0-101,0% glycerin of vegetable origin30,8420,8440,84
Demineralized waterqsqsqs
Gantrez S-97151515
Silica for brushing your teeth - Zeodent 105 - highly cleansing101010
Silica abrasive to clean teeth (Zeodent 115)8,58,58,5
Polyethylene glycol 3006,726,726,72
Silica for brushing your teeth-Zeodent 165 - Sint. amorphous ppt silica2,5 2,52,5
Sodium lauryl sulfate powder1,51,51,5
Sodium hydroxide, 50% solution1,21,21,2
Sodium-CMC-121,01,01,0
Flavoring K91-65071,01,01,0
Titanium dioxide0,750,750,75
The pyrophosphate is tetranitride,
fine
0,50,50,5
Xanthan gum0,50,5 0,5
Sodium saccharin0,30,30,3
Sodium ascorbyl phosphate or dl-α-tocopherol0,20,20,2
Sucralose0,150,150,15
Bottled hydroxytrol0,030,030,03

[00106] The compositions investigated in the test for inhibition of growth of A. viscosus within 24 hours, where the growth of the organism was assessed by a measure of the optical density at 610 nm. The specified value after 24 hours water, or the composition G without compound 1 was >1,4; it was <0.2 for the composition of G with connection 1. This indicates very good performance against that of the studied organism, the same or even better than the positive control, commercially available toothpaste Total® Total®) with triclosan. Similarly, in the test on davlenie education biofilms from different species of microorganisms, the average value of SOME of the compositions G and Total® Total®) was <2 (SD 0), in comparison with the value of 1.1×109(Standard deviation of 1.5×108demonstrating the fact that toothpaste containing compound 1, is able to inhibit the formation of biofilms.

EXAMPLE 8 - using a chelating agent

[00107] it Was observed that the means for brushing your teeth on a silica basis quickly changes its color from white to yellow when adding 0.25 to 1% of compound 1 at the final stage of preparation of the composition. This color change occurs both in the presence of an antioxidant, and in the absence of an antioxidant, such as bottled hydroxytoluene (BHT), vitamin E or vitamin C. However, the addition of small amounts of metal chelating agent returns the color specified funds for brushing your teeth to their original white color. Effective for this purpose chelating agents include 0.5% pyrophosphate is tetranitride (TSPP), and pyrophosphate is tetracene, ethylenediaminetetraacetic acid, etilenditiodiuksusnoi acid, sodium pyrophosphate, sodium tripolyphosphate, potassium tripolyphosphate, sodium hexametaphosphate, sodium and citric acid.

EXAMPLE 9 - Using antioxidants

[00108] esters of porinovoi acid can be oxidized by molecular oxygen or peroxides, which may be formed from esters, t is such as PEG, under the action of atmospheric oxygen. These highly oxidized species may act to link the carbon-boron, leading to its cleavage and formation of the respective derivatives Bronevoy acid and phenolic derivatives. The oxidation products are inactive. Adding oxygen scavengers and/or antioxidants, such as vitamin C (ascorbic acid), vitamin E (α-tocopherol) or 2,6-di-tert-butyl-4-METHYLPHENOL (bottled hydroxytoluene or BHT) removes the oxygen and reduces the level of peroxides, already present in the composition. The amount of antioxidant must not exceed the level of ester porinovoi acid used in this composition.

[00109] Compared the stability of the three compositions of compound 1, where these compositions were identical except that one song does not contain any antioxidants, the second contained α-tocopherol, and the third composition contained sodium ascorbyl phosphate. The destruction of the compounds of formula I were to be reduced significantly in the composition containing sodium ascorbyl phosphate, and an even weaker decomposition was observed in compositions containing α-tocopherol. This result shows that the use of antioxidant improves the stability of compound 1 in the composition.

1. Composition for the care of the oral cavity, having a pH of at least 8 or buffered so about what atom, in order to maintain the pH value at the level of at least 7, including 3-hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane in combination or in combination with an orally acceptable carrier.

2. The composition according to claim 1, additionally containing buffer.

3. The composition according to claim 1, additionally containing arginine, in free form or in the form of pharmaceutically acceptable salts.

4. The composition according to claim 1, additionally containing an antioxidant.

5. The composition according to claim 1, additionally containing solubilizers tool.

6. The composition according to claim 1, additionally containing a chelating agent.

7. The composition according to claim 1 with a pH of at least 8, comprising an effective antibacterial against number 3 hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane; antioxidant in the amount effective for inhibiting the oxidation of 3-hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane;
solubilizers tool and a pharmaceutically acceptable carrier.

8. The composition according to claim 1, characterized in that 3-hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane is present in amount of from 0.05 wt.% up to 20 wt.%.

9. The composition according to claim 1, characterized than that the antioxidant is selected from ascorbic acid, ascorbylpalmitate sodium
bottled hydroxytoluene (BHT), alpha-tocopherol, limnoecology or mixtures thereof.

10. The composition according to claim 1, characterized in that the specified solubilizers tool is a non-ionic surfactant.

11. The composition according to claim 1, having a pH in the range of 8.5-10.

12. The composition according to claim 1 in the form of tools for cleaning teeth, in which the orally acceptable carrier comprises water and a humectant.

13. The composition according to claim 1, characterized in that 3-hydroxypyridine-2-carbonyloxy-bis-(3-chloro-4-were)borane is in the form of an aqueous solution.

14. The composition according to claim 2, characterized in that said buffer is a phosphate buffer.

15. The composition according to item 12, optionally containing a source of fluoride ion and abrasive material.

16. The way to reduce levels of bacteria in the oral cavity, comprising applying the composition according to claim 1 on the teeth and gums of the patient.

17. The composition according to claim 1, having a pH of from 8.5 to 10.

18. The composition according to 17, further containing silicon dioxide and solubilizers agent.

19. The composition according to p in which solubilizers agent selected from the group consisting of polyethylene glycol, polypropyleneglycol and mixtures thereof.

20. The composition according to claim 19, additionally containing copolymer simple metilfenidato ether and maleic acid.



 

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