CH651204A5 - AGENT TO PROMOTE ORAL HYGIENE. - Google Patents

Description

The present invention relates to an agent for promoting oral hygiene and to a method for the production thereof. - The agent according to the invention contains a copolymer which is effective against tartar formation.

Tartar is a hard mineralized deposit that forms on the teeth. Regular brushing prevents these deposits from building up quickly, but even regular brushing is not enough to remove all tartar deposits on the teeth. Tartar forms on the teeth when calcium phosphate crystals begin to deposit in the cuticles and the extracellular matrix of the plaque and accumulate sufficiently tightly to form aggregates that are resistant to deformation. There is no complete agreement on the manner in which calcium and orthophosphate ultimately form the crystalline material called hydroxyapatite (HAP). However, there is agreement that at higher degrees of saturation, i.e. an amorphous or microcrystalline calcium phosphate is above the critical saturation limit of the precursors for crystalline hydroxyapatate. “Amorphous calcium phosphate”, which is related to hydroxyapatite, differs from it in its atomic structure, particle morphology and stoichiometry. X-ray diffraction on amorphous calcium phosphate shows broad maxima that are typical of amorphous materials that do not have the large atomic distances that are characteristic of crystalline materials, including hydroxyapatite. As a result, agents that effectively interfere with crystal growth of hydroxyapatite are effective anti-tartar agents. A presumed mechanism by which the tartar formation inhibitor according to the invention inhibits tartar formation is presumably to increase the activation energy threshold, thereby preventing the conversion of the amorphous calcium phosphate to hydroxyapatite.

Research has shown that there is a good correlation between the ability of a compound to prevent crystal growth of hydroxyapatite in vitro and its ability to inhibit tartar formation in vivo.

A variety of different types of compounds and preparations have been developed for use as antibacterial, plaque and tartar preventive in oral compositions, including, for example, such cationic materials as bisbiguanide compounds and quaternary ammonium compounds, e.g. Benzethonium chloride and cetylpyridinium chloride, described in U.S. Patent 4,110,429. However, these cationic materials lead to discoloration of the teeth when used continuously. In addition, their antibacterial effect means that the normal mi-kroflora in the mouth and / or in the digestive system is adversely affected or destroyed. Other such materials have been found to be inconsistent in the presence of anionic surfactants, which are often found in conventional oral preparations.

The subject of the invention is oral preparations which prevent tartar formation and which do not have one or more of the disadvantages described above. These preparations stain the teeth only relatively little or not at all. They inhibit the conversion of the amorphous calcium phosphate to crystalline hydroxyapatite, the formation of which is normally associated with the formation of tartar.

The agent for promoting oral hygiene according to the invention is characterized in that it contains an orally acceptable carrier and 0.01 to 10% by weight of a copolymer which consists of

A) n units with the molecular configuration of units,

which are derived from glutamic acid

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3rd

651 204

B) m units with the molecular configuration of units derived from alanine and

C) p units with the molecular configuration of units derived from tyrosine,

wherein the ratio (n + m): p is 5: 1 to 9.5: 1, the ratio m: n is from 0: 1 to 0.6: 1 and the molecular weight of the copolymer is 5,000 to 150,000.

The agent according to the invention preferably contains 0.001 to 15% by weight of at least one cationic nitrogen-containing antibacterial anti-fouling agent, based on the free base form.

The copolymers mentioned can be prepared in a known manner, e.g. according to the method described by Chase and Williams in “Immunochemistry”, Volume 2, pages 168/169 (1978), Aacademic Press. In general, the copolymers are obtained by any copolymerization of N-carboxyanhydrides of glutamic acid, tyrosine and alanine in the required molar ratios in an organic solvent such as dioxane, benzene, dimethylformamide or N-methylpyrrolidone in the presence of an initiator such as an organic amine, e.g. Triethylamine or sodium ethylate produced.

The (A) units in the copolymer have the following structural formula:

(A)

ÎIN - CH - CH2CH2 - CO-COOH

n where n indicates the number of (A) units of glutamic acid in the copolymer.

The (B) units in the copolymer have the structural formula:

(B)

HN - CH - CO ■

Cll:

■ J m in which m represents the number of (B) units of alanine in the copolymer.

The (C) units in the copolymer have the structural formula:

(C)

HN

- OH - CO-

I.

in which p indicates the number of (C) units of tyrosine in the copolymer.

As already mentioned, the ratio (n + m): p is 5: 1 to 9.5: 1, the ratio m: n up to 0.6: 1 and m, n and p have values such that the copolymer is a Molecular weight of 5000 to 150,000, preferably from 17,000 to 100,000.

Particularly preferred copolymers consist of two components with glutamic acid units (A) and tyrosine units (C) in a ratio of 9: 1 and a molecular weight of 17,000 to 21,000 and from three components with glut-5 aynic acid units (A), alanine units (B) and tyrosine units (C) in a ratio of 6: 3: 1 and a molecular weight of 80,000 to 100,000.

It goes without saying that the free acid groups of the copolymers used with bases have been converted into salts and can be used as such. Suitable bases with an orally acceptable cation are in particular those which contain an alkali metal, e.g. Sodium or potassium, the ammonium group, CW8 mono- or tri-substituted ammonium groups such as alkanol-substituted ammonium groups, e.g. Have mono-, di- or triethanolammonium groups, organic amines etc. If these copolymers are referred to as water-soluble in the present case, this means that the copolymers in the concentrations which are usually present in oral preparations, e.g. Mouth water, toothpastes and the like, are used, are soluble in water or are easily dispersible.

The copolymers contained in the agent according to the invention are particularly advantageous agents against tartar formation. If one takes into account that human food contains natural inhibitors against precipitation of calcium and phosphate, including glutamic acid and tyrosine, the copolymers present are relatively safe in their Use because, even if swallowed, they are easily hydrolyzed in the stomach by chymotrypsin, a proteolytic enzyme that hydrolyzes tyrosine. In contrast, other non-hydrolyzable anti-calculus agents, when absorbed in the gastrointestinal tract, can lead to changes in the bones. The copolymers contained in the agent according to the invention have the further advantage that they are substantive to the surface of the mouth.

The concentration of the copolymers in the oral preparations varies within a wide range, namely from 0.01 to 10% by weight. Theoretically, this upper limit could be 40 higher, but is dictated by the cost or incompatibility with the carrier. The agent according to the invention preferably contains 0.1 to 8.0% by weight and in particular 0.5 to 5.0% by weight. Oral preparations, which could accidentally be swallowed if used normally, usually have concentrations in the lower ranges.

Cationic nitrogen-containing antibacterial agents are well known, cf. e.g. the section “Quaternary Ammonium and Related Compounds” under “Antiseptics 50 and Disinfectans” in Kirk-Othmer Encyclopedia of Chemical Technology, 2nd edition, Volume 2, pages 632 to 635, to which reference is made here. Cationic substances that have antibacterial activity, i.e. Germicides are used against bacteria and are generally used in oral preparations to counteract the build-up of bacteria in the oral cavity.

Among the most common of these antibacterial quaternary ammonium compounds, which act against deposit formation, is benzethonium chloride, which is also known as Hyamine 1622 or diisobutylphenoxyethoxyethyl-dimethyl-benzyl-ammonium chloride. In a preferred oral preparation, this compound is extremely effective in promoting oral hygiene by reducing the formation of teeth and reducing tartar, which is generally associated with a reduction in tooth decay and gum disease. Other cationic antibacterial agents of this type are e.g. In U.S. Patents 2,984,639; 3,325,402;

651 204

4th

3,431,208 and 3,703,583 and in British Patent 1,319,396.

Further preferred antibacterial, plaque-preventing quaternary ammonium compounds are those in which one or two of the substituents on the quaternary nitrogen atom have a carbon chain, typically an alkyl group with 8 to 20, in particular 10 to 18, carbon atoms, while the other substituents have a smaller number of carbon atoms , e.g. 1 to 7 carbon atoms typically have alkyl or benzyl groups, especially methyl or ethyl groups. Examples of these quaternary antibacterial ammonium compounds are dodecyl trimethyl ammonium bromide,

R NH NH

1 it

A- (X) z -N-C-NH-C-NH (CH2

in which A and A 'are either (1) a phenyl radical which, as substituents, can contain up to two alkyl or alkoxy groups with 1 to 4 C atoms, a nitro group or a halogen atom, (2) an alkyl group with 1 to 12 C -Atoms or (3) alicyclic groups with 4 to 12 carbon atoms, X and X 'are alkylene radicals with 1 to 3 carbon atoms, z and z' are either 0 or 1, R and R 'are hydrogen, alkyl radicals with 1 to 12 carbon atoms or aralkyl radicals with 7 to 12 carbon atoms mean n is an integer from 2 to 12 and the polymer group (CH2) n is interrupted by up to 5 ether, thioether, phenyl or naphthyl groups can be. These compounds are available as pharmaceutically acceptable salts. Other preferred substituted guanidines are: N '- (4-chlorobenzyl) -N5 - (2,4-dichlorobenzyl) -biguanide, p-chlorobenzyl-biguanide, 4-chlorobenzhydryl-guanylurea, N-3-lauroxypropyl-N5-p-chlorobenzyl -biguanide, 5,6-di-chloro-2-guanidobenzimidazole and Np-chlorophenyl-Ns-laurylbiguanide.

Cationic, aliphatic tertiary amines also have antibacterial and anti-coating effects. These antibacterial compounds mainly comprise tertiary amines with a fatty alkyl group, which typically contains 12 to 18 carbon atoms, and 2 polyoxyethylene groups on the nitrogen atom, which typically have a total of 2 to 50 ethylene oxy groups per molecule, and their salts with acids. The structural formula of these compounds is as follows:

^ (CH2CH20) ^ H ^ (CH2CH20) xH R-N-CH-jCH-N

2. 2 v

\ (CH2CH20) yH

in which R is a fatty alkyl group with 12 to 18 carbon atoms and x, y and z together represent three or more, and their salts. In general, cationic compounds are preferred for their anti-fouling activity.

The antibacterial compound with an anti-coating effect which is preferably contained in the agent according to the invention is preferably one with such an antibacterial activity that its phenol coefficient is well above 50 and in particular well above 100, e.g. B. about 200 or more compared to S. aureus. For example, the phenol coefficient of benzethonium chloride according to the manufacturer is 410 compared to S. aureus. The cationic antibacterial agent is generally

Dodecyl-dimethyl- (2-phenoxyethyl) ammonium bromide, benzyl-dimethyl-stearyl-ammonium chloride, cetyl-pyridium chloride and quatanized 5-amino-1,3-bis (2-ethylhe-xyl) -5-methyl-hexahydropyrimidine .

Other types of cationic antibacterial compounds that are advantageously incorporated into oral formulations to promote oral hygiene and reduce fouling are amidines, e.g. substituted guanidines, such as chlorhexidine and the corresponding compound alexidine with 2-ethylhexyl groups instead of the chlorophenyl groups and other bis-biguanides, such as those described in German patent application P 2 332 383 with the following formula:

NH • NH R '

I I I

-NH-C-NH-C- N- (X '), -A'

2nd

my monomeric or possibly dimer with a molecular weight of well below 2000, e.g. B. less than about 1000. However, polymeric cationic antibacterial compounds can also be contained in the agent according to the invention. The cationic antibacterial compound is preferably used in the form of an orally acceptable salt, e.g. as chloride, bromide, sulfate, alkyl sulfonate such as methyl sulfonate, ethyl sulfonate, phenyl sulfonate, e.g. p-methylphenyl sulfonate, nitrate, acetate, gluconate and the like.

The nitrogen-containing cationic antibacterial agents, including the tertiary amines, effectively promote oral hygiene, particularly by removing dental plaque. However, their use leads to the formation of spots on the tooth surface or to discoloration.

The reason for the formation of these spots has not yet been fully elucidated. However, human tooth enamel contains a high proportion of approximately 95% hydroxyapatite (HAP) which has CA + 2 and P04 ~ 3 ions. In the absence of plaque, additional Ca "1" 2 and P04 ~ 3, especially saliva, can be deposited on the enamel and these deposits can include dyes that ultimately discolour the enamel in the form of a calcified deposit. It is possible that the cationic antibacterial agents, including the tertiary amines, also denature protein from the saliva in the oral cavity when the plaque is removed, and the denatured protein can then act as a nucleating agent that will be deposited and cause staining or discoloration of the tooth enamel leads.

The additives used hitherto, which reduced staining on the tooth enamel by cationic antibacterial anti-scaling agents, also generally reduced the effectiveness of the antibacterial anti-scaling agents, such as bis-biuanido compounds, by forming a precipitate with these agents.

The copolymers contained in the agent according to the invention counteract and inhibit core formation, i.e. surprisingly prevent or remove the stains from the tooth enamel caused by cationic and bacterial compounds, including tertiary amines, without precipitating them or without significantly impairing their antibacterial and anti-plaque activity. Even in the absence of such antibacterial agents, the copolymeric additives effectively reduce the formation of tartar without unduly decalcifying the tooth enamel. They also effectively prevent gingivitis. However, not all are capable of counteracting a core formation

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60

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to effectively prevent discoloration by antibacterial agents. Victaraide, also known as Victamine C, a condensation product of ammonia and phosphorus pentoxide, actually increases staining even in the absence of such antibacterial agents.

Cationic nitrogen-containing antibacterial anti-fouling agents, which are optionally used in the agent according to the invention, are described above. When these compounds are present, they are typically used in amounts such that the oral product contains between 0.001 and 15% by weight of the compound. The finished product preferably contains 0.01 to 5% and in particular 0.25 to 1.0% by weight of the antibacterial anti-coating agent in the form of the free base for the desired anti-coating effect.

For certain preferred embodiments of the invention, the composition for oral use may be substantially liquid, e.g. in the form of a mouthwash. In these preparations, the carrier typically consists of a water-alcohol mixture, which advantageously contains a humectant of the type described below. In general, the ratio of water to alcohol is in the range from 1: 1 to 20: 1, preferably from 3: 1 to 10: 1 and in particular from 4: 1 to 5: 1 by weight. The total amount of the water-alcohol mixture in these preparations is generally 70 to 99.9% by weight of the preparation. The pH of these liquid and other preparations according to the invention is generally in the range from 4.5 to 9 and in particular from 5.5 to 8. The preferred pH range is 6 to 8.0. It is noteworthy that the preparations according to the invention can be used orally at lower pH values without substantially decalcifying the tooth enamel. The pH can be adjusted with acids, e.g. Citric acid or benzoic acid or with bases, e.g. Sodium hydroxide or with buffers, e.g. Phosphate buffers can be set. The liquid preparations for oral use may also contain a surface active agent and / or a fluorine-providing compound.

Other desired embodiments according to the invention may be in substantially solid or pasty form, e.g. B. as tooth powder, tooth tablets, toothpastes or toothpastes. The carrier for such solid or pasty oral preparations generally contains a polishing agent. Examples of polishing agents are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, aluminum oxide, hydrated aluminum oxide, aluminum silicate, zirconium silicate, silicon dioxide, silicon dioxide, silicon dioxide, silicon dioxide and silicon dioxide, silicon dioxide, silicon dioxide and silicon dioxide, silicon dioxide, silicon dioxide and silicon dioxide, silicon dioxide and silicon dioxide. Preferred polishes include dical (calcium dihydrophosphate), colloidal silica, silica gel, complex amorphous alkali metal aluminosilicate and hydrated alumina.

Aluminum oxide, in particular the hydrated aluminum oxide sold by Alcoa as C333 with an aluminum oxide content of 64.9% by weight, a silicon dioxide content of 0.008%, an iron (III) oxide content of 0.003% and a moisture content of 0.37% at 110 ° C, which has a specific gravity of 2.42 and a particle size such that 100% of the particles are less than 50 µm and 84% of the particles are less than 20 µm, is particularly effective.

If e.g. B. visually clear gels are used, polishing agents made of colloidal silicon dioxide, such as those under the trademark SYLOID, e.g. B. Syloid 72 and Syloid 74 and those under the trademark Santocel, e.g. Santocel 100 ver651 204

and alkali metal aluminosilicate complexes are particularly useful because they have refractive indices that are close to the refractive indices of the gel-forming agent and liquid systems (including water and / or humectant) commonly used in dentifrices.

Many of the so-called «water-insoluble» polishing agents are anionic and also contain small amounts of soluble material. For example, insoluble sodium metaphosphate can be prepared in any suitable manner, such as in Thorpe's Dictionary of Applied Chemistry, vol. 9.4. Edition, pages 510 to 511. The forms of insoluble sodium metaphosphate known as Madrell's and Kur-Rol's salts are further examples of suitable materials. These metaphosphate salts have minimal solubility in water and are therefore usually referred to as insoluble metaphosphates. They contain less soluble phosphate material than impurities, usually a few percent, e.g. up to 4% by weight. The amount of soluble phosphate material which is believed to include soluble sodium trimetaphosphate in the case of the insoluble metaphosphate can, if desired, be reduced by washing with water. The insoluble alkali metal metaphosphate is usually used in powder form of such a particle size that no more than about 1% has a particle size above about 37 (xm).

The polishing agent is generally used in amounts of 10 to 99% by weight of the oral preparation. Preferably, its amount is 10 to 75% in toothpaste and 70 to about 99% in tooth powder.

In the manufacture of tooth powders, it is usually sufficient to mechanically mix the various solid components in appropriate amounts and particle sizes, e.g. by grinding.

In pasty oral preparations, the copolymer should be compatible with the other components of the preparation. In a toothpaste, for example, the liquid carrier can make up water and a humectant, typically in amounts of 10 to 90% by weight of the formulation. Glycerin, propylene glycol, sorbitol or polyethylglycol 400 can also be present as humectants. Mixtures of water, glycerol and sorbitol are particularly advantageous liquid components

In clear gels, in which the refractive index is an important factor, 3 to 30% by weight of water, 0 to 80% by weight of glycerol and 20 to 80% by weight of sorbitol are preferably used. Gel-forming agents, such as natural or synthetic rubber or rubber-like materials, in particular Irish moss, sodium carboxymethyl cellulose, methyl cellulose or hydroxyethyl cellulose, can be used. Other preferred gel-forming agents are gum tragacanth, polyvinylpyrrolidone and starch. They are usually contained in the toothpaste in an amount of up to about 10% by weight, preferably from 0.5 to 5%. The preferred gelling agents are methyl cellulose and hydroxyethyl cellulose. In a toothpaste or gel, the liquid and solid components are used in such proportions that a cream-like or gel mass is obtained which can be obtained from a pressurized container or from a compressible tube, e.g. made of aluminum or lead.

The solid or pasty oral formulations, the pH of which is usually 4.5 to 9, generally 5.5 to 8, and preferably 6 to 8.0, as measured on a 20% slurry, may also be a surfactant and / or contain fluorine-providing compound.

5

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6

Oral formulations according to the invention may contain a synthetic, non-soap organic anionic or nonionic surfactant which is sufficiently soluble in water in concentrations which are usually about 0.5 to about 10 and preferably about 0.5 to about 5% by weight to promote the wetting, cleaning and foaming properties. Such suitable anionic surfactants are described in U.S. Patent 4,041,149, column 4, lines 31 to 38, and suitable nonionic surfactants in column 8, lines 30 to 68 and column 9, lines 1 to 12, which are expressly referred to herein Reference is made.

In certain embodiments of the invention, a fluorine-providing compound is included in the oral formulations. These compounds can be slightly or completely soluble in water. They are characterized by the property of releasing fluoride ions in water and essentially not reacting with the other compounds of the oral formulation. These substances include primarily inorganic fluoride salts such as soluble alkali metal, alkaline earth metal and heavy metal salts, e.g. Sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride, such as copper (I) fluoride, zinc fluoride, tin fluoride, such as tin (IV) fluoride or tin (II) chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorofluoronate , Aluminum mono- and difluorophosphate as well as fluorinated sodium calcium pyrrophosphate. The alkali metal and tin fluorides such as sodium and tin (II) fluoride, sodium monofluophosphate and mixtures thereof are preferred.

The amount of the fluorine-providing compound depends to some extent on the type of compound, its solubility and the type of oral formulation, but it must not be toxic. In a solid oral formulation, such as in toothpastes or tooth powders, an amount of this compound is generally considered satisfactory that releases a maximum of about 1% by weight, based on the formulation. Any suitable minimum amount of this compound can be used, but it is preferred to use a sufficient amount to release about 0.005 to 1%, and especially about 0.1%, of fluoride ions. In the case of the alkali metal fluorides and the stannous fluoride, these compounds are generally present in an amount of up to about 2% by weight based on the weight of the formulation and preferably in an amount of about 0.05 to 1%. In the case of sodium monofluorophosphate, this can be present in an amount of up to 7.6% by weight and in particular of about 0.76%.

In liquid, oral formulations, such as in mouthwashes, the fluorine-providing compound is typically contained in an amount sufficient to be up to about 0.13%, preferably about 0.0013 to 0.1%, and most preferably about 0.0013 to release up to 0.5% by weight of fluoride ions.

Various other substances can be incorporated into the oral formulations according to the invention, such as whitening agents, preservatives, silicone, chlorophyll compounds, other anti-calculus agents, antibacterial anti-scaling agents and / or ammoniated materials such as urea, diammonium phosphate and the like

Mixtures. These auxiliaries are, if they are present, incorporated into the formulations in such amounts that they do not significantly impair the desired properties.

5 When producing preferred oral formulations according to the invention, which contains the abovementioned combination of antibacterial agent and polymer additive in an oral carrier, typically including water, it is very desirable, if not essential, that the io additive be mixed after the other ingredients, except perhaps some water, to prevent breakdown.

Any suitable flavoring or sweetening agent can also be used. Examples of suitable 15 flavors are flavoring oils, e.g. B. spearmint oils, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage oil, eucalyptus oil, marjoram oil, cinnamon oil, lemon oil, orange oil and methyl salicylate. Suitable sweeteners include sucrose, lactose, fructose, maltose, 20 sorbitol, xylitol, sodium cyclamate, perillartin, aspartylphenylalanine methyl ester (APM), saccharin and the like. The flavoring and sweetening agents together suitably make up about 0.01 to 5% or more of the formulation.

25th

The orally applicable preferred formulations according to the invention, such as mouthwashes or toothpastes, which contain the copolymer mentioned in an amount which effectively prevents tartar formation, are generally applied regularly to the enamel, preferably about 5 times a week to about 3 times a day pH from 4.5 to 9, generally from 5.5 to 8 and in particular from 6 to 8.

The following examples illustrate the invention. In them 35, all quantities and ratios relate to the weight, unless stated otherwise.

40 Example 1

Inhibition of the crystal growth of hydroxyapatite It is determined by pH measurements. 1.0 ml of an aqueous solution of 1 x 10 ~ 4M to 1 x 10 ~ 5M of the tartaring agent to be examined, 45 and 0.1 M sodium dihydrophosphate are placed in a reaction flask with 22 to 23 ml of distilled water under constant stirring under nitrogen given. Then 1 ml of 0.1 M CaCl2 is added and the pH is adjusted to 7.4 + 0.05 with NaOH (final concentration of the Ca + + and the PO ,, 3- = 4 x 10-3M). The consumption of 0, IN NaOH is automatically recorded by a pH radiometer. In this test, the formation of the hydroxyapatite takes place in two distinct phases. The first quick base consumption (1 to 4 minutes) decreases until a second quick consumption occurs after 15 ss to 20 minutes. A delay until the second rapid consumption time or a complete absence of the second rapid consumption indicates an impairment of the crystal growth of the hydroxyapatite. Substances that interfere with the crystal 60 growth of hydroxyapatite are effective anti-calculus agents. Using the above procedure gave the following results:

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Table I

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Anti-tartar remedies, minutes to delay until

Concentration HAP formation HAP formation, min.

(a)

Water (control)

21.0

-

(b)

Copolymer 9/1 (20 ppm)

30.0

9.0

(c)

Copolymer 9/1 (21 ppm)

40.0

19.0

(d)

Copolymer 9/1 (27 ppm)

87.0

66.0

(e)

Copolymer 9/1 (32 ppm)

117.0

96.0

(f)

Copolymer 6/3/1 (40 ppm)

31.0

10.0

(G)

Copolymer 7/3 (40 ppm)

21.0

0

(H)

Copolymer 1/1 (1 x 10 ~ 4)

21.0

0

(i)

Copolymer 3/7 (40 ppm)

21.0

0

(j)

Copolymer G / L / T (32 ppm)

21.0

0

(k)

Glu / Tyr 1/1 (2 x 10 ~ 4)

18.0

0

0)

Glu / Ala / Tyr 1/1/1 / (32 ppm)

21.0

0

(m)

Tyr (32 ppm)

18.0

0

The copolymers investigated were obtained by copolymerization of a-amino acid anhydride mixtures according to the loc.cit in Immunochemistry. described method produced. The copolymer 9/1 was obtained from a 9: 1 molar mixture of glutamic acid and tyrosine.

Its molecular weight, determined by centrifugation, was approximately 19,300. The copolymer 6/3/1 was produced from a 6: 3: 1 molar mixture of glutamic acid, alanine and tyrosine. Its molecular weight was about 90,800. The other copolymers were obtained in the same way. For example, copolymers 7 / 3.1 / 1 and 3/7 were prepared from mixtures with the corresponding glutamic acid: tyrosine ratios, i.e. those with the molar ratios 7: 3.1: 1 and 3: 7. The copolymer G / L / T was obtained from a 1: 1: 1 molar mixture of glutamic acid, lysine and tyrosine. The agents listed under (k), (1) and (m) consisted of monomers or monomer mixtures of glutamic acid, tyrosine and / or alanine in the corresponding molar ratios of the monomers.

The results of Table 1 clearly show the inhibitory effect of the copolymers according to the invention on the crystal growth of the hydroxyapatite in vitro, compare under (b), (c), (d), (e), and (f), furthermore that the inhibitory effect does not result from complexation or chelation of the calcium, since sub-stoichiometric ratios of copolyme-30 rem to calcium were used. The ineffectiveness of the comparison substances (g) to (m) with regard to the inhibition of HAP formation shows that the components and their ratios are critical in the copolymers according to the invention if the unexpectedly improved inhibition of crystal growth of hydroxyapatite is to be achieved.

The following examples list formulations for mouthwashes according to the invention.

example

Flavoring

0.22%

0.22%

0.22%

0.22%

Ethanol

15.0

15.0

15.0

15.0

Pluronic F108 *

3.0

3.0

3.0

3.0

Glycerin

10.0

10.0

10.0

10.0

Saccharin-Na

0.03

0.03

0.03

0.03

Copolymer 6/3/1

0.1

0.1

0.1

0.1

Water to

Filling up

100

100

100

100

* Polyoxyalkylene block polymer

Example 6 Toothpaste

% By weight

Glycerin

25.0

Carboxymethyl cellulose

1.3

Sodium benzoate

0.5

Saccharin-Na

0.2

Silicon dioxide

30.0

Sodium lauryl sulfate

1.5

Flavoring

1.0

Copolymer 9/1

3.0

Water to fill up

100

Table II below shows formulations according to the invention for mouthwashes and the effectiveness of the copolymer additive in preventing stains. The tooth-staining properties of the 60 formulations were determined in such a way that hydroxyapatite (Biogel), a specific saliva protein,

a carbonyl source, e.g. Acetaldehyde and a phosphate buffer of pH 7 with and without the mouthwash formulations to be investigated slurried. Mixtures 65 were shaken at 37 ° C for 18 hours. The colored HAP powder was filtered off and dried. The color values, in reflection units, were determined using a Gardner color difference meter.

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Table II Mouthwash Formulations

example

placebo

(7)

control

(8th)

(9)

(10)

Ethanol

10%

10%

10%

10%

Glycerin

10th

10th

10th

10th

Flavoring

0.146

0.146

0.146

0.146

Saccharin

0.03

0.03

0.03

0.03

Pluronic F1081

3.0

3.0

3.0

3.0

CPC2

0.1

0.1

0.1

Copolymer 9/13

0.1

0.2

Water to fill up

100

100

100

100

pH adjusted with IN NaOH

7.0

7.0

7.0

7.0

reflection

70.7

41.8

57.7

56.0

difference

Rd

-

+ 28.9

-15.9

-14.2

1. Polyoxyalkylene block polymer (BASF-Wyandotte)

2. Cetyl pyridinium chloride

3. Made according to the procedure in «Immunochemistry» loc.cit. from a 9: 1 molar mixture of glutamic acid and tyrosine. Molecular weight of the copolymer determined by centrifugation is approximately 19,300.

The above results make it clear that the copolymer additions according to the invention significantly reduce tooth stains, which are usually caused by cationic quaternary ammonium compounds with antibacterial and anti-plaque effects, such as cetylpyridinium chloride.

with respect to (8)

Furthermore, the in vitro tests show that the anti-fouling effectiveness of the formulations of Examples 8 and 9 is essentially the same, which indicates that the copolymer additives according to the invention do not significantly impair the anti-fouling effectiveness of Ce-25 tylpyridinium chloride and similar compounds.

Instead of the cetyl-pyridinium chloride used in Examples 3 and 4, equivalent amounts of the following antibacterial anti-scaling agents can be used, where a surprising reduction in tooth discoloration is also achieved.

example

Antibacterial anti-tipping agent

10th

11

12

13

14

15

Benzethonium chloride (BC)

Chlorhexidine diacetate

Chlorhexidine digluconate

Dodecyl trimethyl ammonium

bromid ch2ch2oii

/

.CH2CII20H

C12-i8 alkyl-N-CH2CH2N \

CII2CH20iI Alexidine dihydrochloride

The following is a list of formulations for toothpastes that have an anti-deposit effect and lead to less discoloration.

16

Example, parts 17 18

Hydrated alumina

30th

30th

30th

Glycerin

16

16

16

Sorbitol, 70%

6

6

6

Pluronic F-108

3rd

3rd

3rd

Hydroxyethyl cellulose

1.2

1.2

1.2

Benzethonium chloride

0.5

-

Chlorhexidine digluconate, 20%

-

4,725

-

Cetylpyridinium chloride

-

-

-

Copolymer 6/3/1 *

0.08

0.5

1.0

Saccharin-Na

9.17

0.17

0.17

Flavors

100

100

100

Water to fill up

100

100

100

Manufactured according to the procedure described in «Immunochemistry» from a 6: 3: 1 molar mixture of glutamic acid, alanine and tyrosine. Molecular weight of the copolymer about 90,800.

s

Claims (13)

651 204 1. Means for promoting oral hygiene, characterized in that it contains an orally acceptable carrier and 0.01 to 10 wt.% Of a copolymer consisting of A) n units with the molecular configuration of units derived from glutamic acid B) m units with the molecular configuration of units derived from alanine and C) p units with the molecular configuration of units derived from tyrosine, the ratio (n + m): p 5: 1 to 9.5: 1, the ratio m: n from 0: 1 to 0, 6: 1 and the molecular weight of the copolymer is 5,000 to 150,000. 2. Composition according to claim 1, characterized in that the ratio n: m: p in the copolymer 9: 0: 1 and the molecular weight of the copolymer is 17,000 to 21,000. 2nd PATENT CLAIMS 3. Composition according to claim 1, characterized in that the ratio n: m: p in the copolymer 6: 3: 1 and the molecular weight of the copolymer is 80,000 to 100,000. 4. Composition according to one of claims 1 to 3, characterized in that it additionally contains 0.001 to 15 wt .-% of at least one cationic nitrogen-containing antibacterial anti-fouling agent, based on the free base form. 5. Composition according to claim 4, characterized in that the antibacterial anti-fouling agent is present in an amount of 0.01 to 5 wt .-%, based on the free base. 6. Composition according to one of claims 4 and 5, characterized in that the antibacterial anti-fouling agent consists of a substituted guanidine. 7. Composition according to claim 6, characterized in that the antibacterial anti-fouling agent consists of a pharmaceutically acceptable water-soluble salt of chlorhexidine or alexidine. 8. Composition according to one of claims 4 and 5, characterized in that the antibacterial anti-fouling agent consists of benzethonium chloride. 9. Composition according to one of claims 4 and 5, characterized in that the antibacterial anti-fouling agent consists of a quaternary ammonium compound with 1 to 2 alkyl groups, each containing 8 to 20 carbon atoms. 10. Composition according to claim 9, characterized in that the antibacterial anti-fouling agent consists of cetylpyridium chloride. 11. Agent according to one of claims 1 to 10, characterized in that it is in the form of a mouthwash with a pH of 4.5 to 9 with an aqueous alcohol carrier. 12. Composition according to one of claims 1 to 10, characterized in that it is in the form of a toothpaste with a pH of 4.5 to 9, which contains a liquid carrier, a gel-forming agent and a dental-acceptable polishing agent. 13. A process for the preparation of the agent according to any one of claims 1 to 12, characterized in that the copolymer is added to a mixture of the other ingredients.