DK159372B - FOOT CARE AGENT - Google Patents

Description

DK 159372B

in

The invention relates to a mouthpiece containing as a tartaric antagonist 0.01-10% by weight of a carboxyl-containing phosphonic acid in an acceptable carrier.

Tartar is a hard mineralized formation on the teeth.

5 Regular brushing prevents the rapid build-up of these deposits, but even regular brushing is not sufficient to remove all the tartar deposits that stick to the teeth. Tartar is formed on the teeth as crystals of calcium phosphates begin to deposit 10 in the brain and extracellular matrix of the dental plaque and become sufficiently tightly packed to make the aggregates resistant to deformation. There is no complete consensus on the way in which calcium and orthophosphate eventually become the crystalline material called hydroxyapatite (HAP). In general, however, it is agreed that at higher saturations, i.e. above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate. "Amorphous calcium phosphate" is similar to hydroxyapatite, but differs from this in its atomic structure, particle morphology and stoichiometry. X-ray diffraction patterns of amorphous calcium phosphate show broad peaks typical of amorphous materials lacking the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. Therefore, it seems that agents that effectively generate the crystalline growth of hydroxyapatite will be effective as anti-tartar agents. A proposed mechanism whereby the anti-tartar agents included in the oral care agent of the invention inhibit tartar formation, likely implies an increase in the activation energy limit, thereby preventing the conversion of precursor amorphous calcium phosphate to hydroxyapatite.

Studies have shown that there is a good correlation between a compound's ability to prevent hydroxyapatite crystal growth in vitro and its ability to prevent calcification in vivo.

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Cationic nitrogen-containing antibacterial materials are well known. See, for example, the section on "Quaternary ammonium and related compounds" in the article on "Spirit Antiseptic Disinfectants" in the Kirk-Othmer Encyclopedia of 5 Chemical Technology, 2nd Edition (Vol. 2, pp. 632-635). Cationic materials having antibacterial activity (i.e., germicides) are used against bacteria and have been used in oral care agents to counteract plagiarism caused by bacteria in the oral cavity.

Among the most common of these antibacterial anti-plague quaternary ammonium compounds are benzethonium chloride, also known as Hyamine 1622, or diisobutyl = phenoxyethoxyethyldimethylbenzylammonium chloride. In an oral care agent, this material is very effective in promoting oral hygiene by reducing the formation of dental plague and tartar, which is generally accompanied by a reduction in caries formation and periodontal disease. Other cationic antibacterial agents of this type are those mentioned, for example, in U.S. Pat.

20,984,639, 3,325,402, 3,431,208 and 3,703,583, and British Patent Nos. 1,319,396.

Other antibacterial antiplague quaternary ammonium compounds include those in which one or two of the substituents on the quaternary nitrogen have a carbon chain length (typically alkyl group) of approx. 8-20, typically 10-18 carbon atoms, while the remaining substituents have a lower number of carbon atoms (typically alkyl or benzyl group) such as 1-7 carbon atoms, typically methyl or ethyl groups. Dodecyltrimethylammonium bromide, dodecyldimethyl (2-phenoxy = 30) ammonium bromide, benzyldimethylstearylammonium chloride, cetylpyridium chloride and quaternized 5-amino-1,3-bis (2-ethylhexyl) -5-methylhexahydropyrimidine are examples of other typical ammonium examples,

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Other types of cationic antibacterial agents which may be conveniently incorporated into oral care agents to promote oral hygiene by reducing plaque formation are the amidines such as the substituted guanidines, for example, chlorhexidine and the corresponding compound, alex = idine, which has 2-ethylhexyl chlorophenyl groups, and other bis-biguanides such as those described in German Patent Application No. P. 2,332,383, published January 10, 1974, which states the following formula: 10 R NH NH NH NH R * A- (X ) -NC-NH-C-NH (CHO) -NH-C-NH-C- N- (X ')', -A 'z 2. nz where A and A' denote either (1) a phenyl radical which as a substituent may contain up to 2 alkyl or alkoxy groups having 1 and up to 4 C atoms, a nitro group or a halogen atom, (2) an alkyl group containing 1 - about

12 C atoms, or (3) alicyclic groups having from 4 to approx. 12 C atoms, X and X 'may be an alkylene radical having 1-3 C atoms, z and z' may be either 0 or 1, R and R 1 may represent either hydrogen, an alkyl radical having from 1 to approx. 12 20 C atoms or an aralkyl radical of 7 - approx. 12 C atoms, n is an integer from 2 incl. to 12, and the polymethylene chain (CH 2) n may be interrupted by up to 5 ether, thioether, phe = nyl or naphthyl groups. These are available as pharmaceutically suitable salts. Other substituted guanidines are: Ν '- (4-chlorobenzyl) -N - (2,4-dichlorobenzyl) biguanide, p-chlorobenzylbiguanide, 4-chlorobenzhydryl guanylurea, 5N-3-lauroxypropyl-N-p-chlorobenzylbiguanide, 5, 6-dichloro-2-guanidobenzimidazole and Nβ-chlorophenyl-Nβ-lauryl biguanide.

The long chain tertiary amines also have antibacterial activity and antiplaque action. These antibacterial agents include tertiary amines having a fatty alkyl group (typically 12-18 carbon atoms) and 2 poly (oxyethylene) groups bonded to the nitrogen (typically containing from 2 to 50 etheneoxy groups per molecule) and salts thereof with 35 'acids and compounds with the structure: 4

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(CH2CH2O) zH2 (CH2CH2O) χΗ R-] i-CH2CH2N

^ (CH2CH20) y H

wherein R is a fatty alkyl group containing 12 to 18 carbon = atoms, and x, y and z are in total 3 or more, and salts thereof. In general, cationic agents are preferred because of their plaque effectiveness.

The antibacterial antiplaque compound is preferably one which has such an antibacterial effect that its phenol coefficient is slightly above 50, preferably slightly above 100, such as above ca. 200 or more for S.aureus. For example, the phenol coefficient (A.O.A.C.) of benzethonium chloride is stated by the manufacturer as 410 to S. aureus. The cationic antibacterial agent will generally be a monomeric (or optionally dimeric) material having a molecular weight slightly below 2,000 such as less than about 2,000. 1000. However, it is within the scope of the invention to use a polymeric cationic antibacterial agent. The cationic antibacterial agent is preferably administered in the form of an orally acceptable salt thereof such as the chloride, bromide, sulfate, alkyl sulfonate such as methylsulfonate and ethyl = sulfonate, phenylsulfonate such as p-methylphenylsulfonate, nitrate, acetate, gluconate etc.

The nitrogenous cationic antibacterial agents and antibacterial long chain tertiary amines effectively promote oral hygiene, especially by removing plaque. However, use of them 25 has been observed to lead to staining of dental surfaces or discoloration.

The reason for the formation of such dental staining has not been clearly established. However, human tooth enamel contains a high amount (about 95%) of hydroxyapatite (HAP) which contains + 2 -3 30 containing Ca and PO. ions. In the absence of dental plaque +24 -3. e, additional Ca and PO ^, especially from saliva, can be deposited on

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5 the enamel, and these deposits may contain color bodies which eventually discolor the tooth enamel as a calcified deposit thereon. It can be seen that as cationic or long-chain tertiary amine antibacterial agents remove 5 plaques, they also denature protein from saliva in the mouth, and the denatured protein can then act as a nucleating agent on and discolor tooth enamel.

Previously used additives which reduced tooth staining 10 with cationic antibacterial anti-plaque agents generally also decreased the activity of antibacterial antiplaque agents such as bis-biguanido compounds, for example, by forming a precipitate with such agents.

15 from DE Publication No. 2,332,383 discloses a mouth pie agent containing, together with a bis-biguanide compound, a phosponoethane or phosphonoethene compound containing two carboxyl groups, and from US patent 4,118,476 an oral care agent 20 is known. containing as a means of counteracting discoloration a phosphone compound see having 1 phosphone group and 3 carboxyl groups, but in which all the latter groups are vicinal, ie in positions 2, 3, 4 or 1, 2, 3.

The oral care agent according to the invention is characterized in that the carboxylic group-containing phosphonic acid is a 2-phosphonobutane butyrate.

1,2,4-tricarboxylic acid compound (PBTA) of Formula I

0 ch2-cooh

«HMI

P-C-C00H

Or H0 ch2-ch2-cooh or an orally acceptable salt thereof, wherein the agent optionally contains 0-15% of at least one normally staining nitrogen-containing anti-bacterial anti-plaque agent based on the free base form of the agent.

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The said compound has been found to give a better effect in comparison with hydroxylapatite formation in vitro and to prevent tartar formation in vivo compared to related compounds.

5

The compound of formula I and the process for its preparation are described in U.S. Pat. Nos. 3,886,204 and 3,886,205.

The concentration of the PBTA compound (or salt) in the oral care agents may vary between ca. 0.01% by weight and approx. 10% by weight and preferably approx. 0.1 - approx. 6% by weight. Oral care products which could be accidentally ingested during conventional use preferably contain lower concentrations of the PBTA compound. Thus, a mouthwash liquid according to the invention preferably contains less than approx. 2% by weight of the PBTA compound, preferably approx. 0.1 - approx. 1.5% by weight. Other dentifrices, topical solutions and prophylactic pastes to be professionally administered may preferably contain approx. 0.1 - approx. 3% by weight of the PBTA compound.

The PBTA compound is an anti-nucleating agent and oral care agents of the invention containing it are effective in reducing the formation of tartar without decalcifying tooth enamel 2g too much, and in contrast to the nitrogen-containing antibacterial antiplaque agents described above, such PBTA compounds have and -Means little or no tendency to stain teeth, as well as effectively prevent gingivitis.

It is a further advantage of the invention that these anti-nucleating anti-tartar PBTA compounds unexpectedly inhibit, i.e. prevents or removes, discoloration of tooth enamel caused by the aforementioned nitrogen-containing antibacterial anti-plaque agents without precipitation or, substantially damaging their antibacterial and antiplaque action. Not all anti-nucleating agents are effective in preventing discoloration caused by such antibacterial agents. Actually, Victamide (also known as Victamin C), a condensation product of ammonia with phosphorus pentoxide, increases the discoloration, even in the absence of such antibacterial agents.

When present, these usually staining antibacterial anti-plaque agents are typically used in normally effective amounts, for example, so that the oral care agent contains between 0.001 and 15% by weight thereof. To achieve the desired degree of anti-plague effect, the finished mouthpiece preferably contains about 0.01 - approx. 5% by weight and most conveniently approx. 0.25 - 1.0 weight of the antibacterial antiplaque agent, referring here to the free base form. Most suitably, the PBTA compound is present in a molar excess relative to the amount of antibacterial anti-plaque agent (based on the free base form) to best reduce, inhibit or prevent staining.

In certain very preferred embodiments, the mouth care agent of the invention may be of a substantially liquid nature, such as a mouthwash or rinse liquid. In such a composition, the carrier is typically a water / alcohol mixture which conveniently contains a moisture-binding agent as described below.

Generally, the ratio of water to alcohol is in the range of about 1: 1 to approx. 20: 1, preferably approx. 3: 1 to approx. 10: 1 and most conveniently approx. 4: 1 to approx. 5: 1 by weight. The total amount of water / alcohol in this type of preparation 30 is typically in the range of from approx. 70 to approx. 99.99% by weight of the composition. The pH of such a liquid or other compositions of the invention is generally in the range of from about.

4.5 to approx. 9 and typically from ca. 5.5 to approx. 8. The pH value is preferably in the range of from approx. 6 to approx. 8. It is worth noting that the compositions of the invention can be used orally at 8

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a pH below 5 without substantially decalcifying dental enamel. The pH can be controlled with acid (e.g. citric or benzoic acid) or base (e.g., sodium hydroxide) or buffer (such as with phosphate buffers). Such liquid oral care compositions may also contain a surfactant and / or a fluorine-providing compound.

In certain other convenient embodiments of the invention, the oral care agent may be substantially solid or paste-like in character such as a tooth powder, a dental tablet, a toothpaste or a toothpaste. The carrier in such solid or paste-like mouthpieces generally contains polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnium phosphate, calcium carbonate, aluminum oxide, aluminum oxide, aluminum oxide, hydrated alumina, hydrated alumina, hydrated alumina. Preferred polishing materials include silica gel or colloidal silica = 20 cium dioxide, complex amorphous alkali metal aluminum silicate and hydrated alumina.

Alumina, in particular the hydrated alumina marketed by Alcoa as C333, which has an alumina content of 64.9% by weight, a silica content of 0.008%, a ferric oxide content of 0.003% and a moisture content of 0.37% at 110 ° C, which has a density of 2.42 and such a particle size that 100% of the particles are less than 50 microns and 84% of the particles are less than 20 microns, is particularly effective.

When visually clear anti-tartar gels are used, a colloidal silica polish such as those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100, and alkali metal aluminum silicate complexes are particularly useful.

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has a refractive index close to the refractive index of the gelling and liquid systems (including water and / or moisture-binding agent) commonly used in dentifrices. For similar reasons, alkali metal aluminum = 5 silicate complexes are particularly useful as a polishing agent in visually clear gels containing the PBTA compound in combination with the described nitrogenous antibacterial anti-plaque agents.

Many of the so-called "water-insoluble" polishes 10 are of anionic nature and also contain small amounts of soluble material. Insoluble sodium metaphosphate. can thus be formed in any suitable manner as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pages 510-511. The forms of insoluble sodium = 15 metaphosphate, called Madrell's salt and Kurrol's salt, are other examples of suitable materials. These metaphosphate salts exhibit very little solubility in water and are therefore commonly referred to as insoluble metaphosphate salts. There is a minor amount of soluble phosphate material as impurities therein, usually a few percent such as up to 4% by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium = trimetaphosphate, in the case of insoluble meta = phosphate, can be reduced by washing with water if desired.

The insoluble alkali metal metaphosphate is typically used in powder form with a particle size such that no more than about 1% of the material is greater than approx. 37 microns.

The polishing material is usually found in amounts ranging from approx. 10 to approx. 99% by weight of the oral care product. Preferably, it is present in amounts ranging from ca. 10 to approx.

75% in toothpaste and from about, 70 to approx. 99% in tooth powder.

In the manufacture of dental powders, it is usually sufficiently mechanical to mix, for example, by grinding, the various solid components in appropriate amounts and in pairs.

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particle sizes.

In paste-like mouth care agents, the PBTA compound must be compatible with the other components of the preparation. Thus, in a toothpaste, the liquid carrier may comprise water and moisture-binding agent, typically in an amount ranging from approx. 10 to approx. 90% by weight of the composition. Glycerin, propylene = glycol, sorbit or polyethylene glycol 400 may also be present as moisture-binding agents or binders. Particularly advantageous liquid ingredients include mixtures 10 of water, glycerine and sorbit.

In clear gels where the refractive index is important, 3-30 wt% water, 0-80 wt% glycerine and 20-80 wt% sorbit are preferably used. A gelling agent such as natural or synthetic rubbers or rubbery materials, typically Irish moss, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl = cellulose, the carbopoles (e.g. 934, 940 and 941), tragacanth, polyvinylpyrrolidone or the like or starch or the like in toothpaste in a 20 amount up to approx. 10% by weight, preferably in the range of about 0.5 to approx. 5% by weight. In a toothpaste or gel, the amounts of liquids and solids are adjusted to form a creamy or gelled mass which can be extruded from a pressure vessel or from a compressible tube, for example aluminum or lead.

The solid or paste-like oral care agent, which typically has a pH value of 20% solution of 4.5 - 9, generally approx. 5.5 - approx. 8 and preferably approx. 6 -ca. 8 may also contain a surfactant and / or a fluorine-releasing compound.

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It will be appreciated that the oral care agents - as is customary - must be sold or otherwise distributed in appropriately labeled packages. Thus, a glass with mouthwash will have a label describing it as a mouthwash or mouthwash and having instructions for use, and a toothpaste will usually be in a compressible tube, typically of aluminum, lined lead or plastic or in a second container for squeezing and measuring the contents, which has a label describing it as a toothpaste paste or a toothpaste.

Organic surfactants are used in the compositions of the invention to achieve increased prophylactic effect, help to achieve thorough and complete dispersion of the PBTA agent in the oral cavity and make the present agents cosmetically more acceptable. The organic surfactant is preferably anionic, nonionic or ampholytic in nature, and it is preferred to use as a surfactant a purifying material which imparts the scavenging and foaming properties of the agent. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfate such as the sodium salt of monosulfated monoglyceride of hydrogenated coconut oil, fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl ether sulfate acetate, dihydroxypropane sulfonate and the substantially saturated higher aliphatic acyl amides of lower aliphatic aminocarboxylic acid compounds such as those having 12 to 16 carbon atoms in the fatty acid, alkyl or acyl radicals and the like. Examples of the latter amides are N-lauroylsarcosine and the sodium, potassium and ethanolamine salts of the N-layroyl, N-myristoyl or N-palmitoylsarcosine, which must be substantially free of soap or similar higher fatty acid material. The use of these sarcosinate compounds in dentifrices of the invention is particularly advantageous, as these materials exhibit a great advantage.

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prolonged and pronounced action to inhibit acid formation in the oral cavity due to carbohydrate degradation, while exerting some reduction in the solubility of tooth enamel in acid solutions.

Examples of water-soluble nonionic surfactants are ethylene oxide condensation products with various reactive hydrogen-containing compounds which are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12-20 carbon atoms), which condensation products ("ethoxamers" ") contains hydrophilic polyoxyethylene molecules such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g., sorbitan monostearate) and polypropylene oxide (i.e.

15 Pluronic materials).

In certain embodiments of the invention, a fluorine-releasing compound is present in the oral care agent. These compounds may be slightly soluble in water or may be completely water soluble. They are characterized by their ability to release fluoride ions in water and by being essentially free of reaction with other compounds in the mouth care agent. Among these materials are inorganic fluorides such as soluble alkali metal, alkaline earth metal and heavy metal salts, e.g. sodium monofluorophosphate, aluminum mono- and difluorophosphate, and fluorinated sodium calcium = 30 pyrophosphate. Alkali metal and tin fluorides such as sodium and stannofluorides, sodium monofluorophosphate and mixtures thereof are preferred.

The amount of the fluorine-providing compound depends to some extent on the type of compound, its solubility and type 13

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of mouthwash, but it must be a non-toxic amount.

In a solid mouthpiece such as a toothpaste or a toothpaste, an amount of such a compound which releases a maximum of approx. 1% by weight of the composition, for satisfactory. Any suitable minimal amount of such a compound can be used, but it is preferred that sufficient compound be used to release 0.005 - 1% and preferably about 0.1% fluoride ion.

In the case of alkali metal fluorides 10 and stannofluoride, this component is typically present in an amount of up to approx. 2% by weight, based on the weight of the composition, and preferably in the range of 0.05 to 1%.

In the case of sodium monofluorophosphate, the compound can be found in an amount up to 7.6% by weight, more typically about 15% by weight. 0.76%.

In a liquid oral care agent such as a mouthwash liquid, the fluorine-providing compound is typically present in an amount sufficient to release up to about 5 0.13 wt%, preferably 0.0013 - 0.1 wt and most conveniently 0.0013 - 0.5 wt% fluoride ion.

Various other materials may be incorporated into the oral care compositions of the invention such as whitening agents, preservatives, silicones, chlorophyll compounds, other antitumor agents, antibacterial anti-plaque agents and / or ammoniated materials such as urea, diammonium = phosphate and mixtures thereof. When such additives are present, they are incorporated into the compositions in amounts which have no significant detrimental effect on the desired properties. Any suitable flavoring or sweetening material may also be used. Examples of suitable aromatics are aromatizing oils, for example, oil of garden mint, peppermint, evergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange as well as methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbit, xylite, na = 14

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triacyclamate, perillartin, APM (aspartylphenylalanine = methyl ester), saccharin and the like. Conveniently, flavoring and sweetening agents comprise from 0.01 to 5% or more of the composition.

In the preparation of the mouth care compositions of the invention it is preferred, but it is not essential to add PBTA after the other ingredients (except perhaps some of the water) are mixed or brought into contact with one another to avoid a tendency for the PBTA to precipitate .

For example, a mouthwash or mouthwash may be prepared by mixing ethanol and water with the aromatized oil, surfactant, moisturizing agent, optionally antibacterial antiplaque agent such as cetylpyridium chloride, benzethonium chloride or chlorhexidine, sweetening agent and sweetening agent, compound, followed by additional water as desired.

A toothpaste can be prepared by forming a gel with wetting agent, rubber, thickener or gelling agent such as hydroxyethyl cellulose, sweetening agent and adding polish, flavor, optionally antibacterial antiplaque agent, additional water, and then the PBTA compound defined above. If sodium carboxymethyl cellulose is used as a gelling agent with a bis-biguanide antibacterial antibody, the method of either U.S. Pat. U.S. Patent No. 3,843,779 or U.S. Pat. Patent No. 3,842,168, modified by the inclusion of the PBTA connecting ice.

The oral care agent of the invention, such as a mouthwash or toothpaste, is preferably applied to tooth enamel from 1 to 3 times 30 times at a pH of about 4.5 - approx. 9, generally approx. 5.5 - approx. 8, preferably 6-8.

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The following examples further illustrate the nature of the invention. All quantities disclosed therein and in the claims are by weight, unless otherwise stated.

EXAMPLE 1.

Crystal Growth Inhibition 'by HAP.

This is assessed by a pH Stat method. 1.0 ml of an aqueous 10 solution of 1 x 10 4 M - 1 x 10 5 M of the anti-tartar agent being tested and 0.1 M sodium dihydrogen phosphate are placed in a reaction flask with 22 to 23 ml of distilled water while still stirring in an atmosphere of nitrogen. . To this is added 1 ml of 0.1 M CaCl 3 and the pH is adjusted to 7.4-0.05 with NaOH (final concentration of Ca and 3- -3 PO 2 = 4 x 10 M). Consumption of 0.1 N NaOH is automatically detected by a pH Stat (radiometer). In this test, the formation of HAP occurs in two distinct phases. First, fast base consumption (1-4 minutes), which is then reduced to 20 15 _ 20 minutes, during which another rapid recording occurs.

A delay in the timing of the second fast consumption or a complete absence of another fast consumption shows an interference with the crystal growth of HAP. Agents that interfere with the HAP crystal growth are effective antitumor agents.

25 When PBTA is tested by the previous method, the following results are obtained.

TABLE I ·.

30 Antenna surfactant Time for Delay of (wife) HAP formation HAP formation

Water (control) 15 minutes PBTA (4 ppm) 25 minutes 10 minutes 35 PBTA (8 ppm) 75 minutes 60 minutes PBTA (10 ppm) 129 minutes 114 minutes PBTA (20 ppm) 33.8 hours

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The above results show that PBTA effectively inhibits the crystal growth of HAP in vitro and that the inhibition is not due to complex formation or chelation of calcium, as sub-stoichiometric ratios are used PBTA: calcium.

5 in the following examples which illustrate mouthwash preparations according to the invention, Pluronic F108 is a polyalkylene = oxide block polymer.

EXAMPLES 2 3 4 5

Flavor 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

Na Saccharin 0.03 0.03 0.03 0.03 PBTA 0.1 0.2 0.5 1.0 15 Water 100 100 100 100 pH (with NaOH) 7.4 7.4 7.4 7.4 , 4

Appearance Clear Clear Clear Clear

The following example illustrates an anti-toothpaste toothpaste of the invention.

EXAMPLE 6

Silicon dioxide 30

Glycerin 16

Sorbit (70%) 6

Pluronic F108 3 25 Hydroxyethyl cellulose 1.2 PBTA 2

Sodium saccharin 0.17

Aroma 0.8

Water q.s. to Table 30 below illustrates mouthwash compositions according to the invention and the anti-color effect of the preferred PBTA

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17 additives therein. The staining properties of the compositions are assessed by suspending hydroxyapatite (Biogel), a specific salivary protein, a carbonyl source (e.g., acetaldehyde) and a pH 7 phosphate buffer with and without the mouthwash preparation being examined. The mixture is shaken at 37 ° C for 18 hours. The colored HAP powder is separated by filtration, dried, and the color levels (in reflectance units) determined on a Gardner color difference meter.

TABLE II.

Clear mouthwashes.

EXAMPLES 7 8 9 10 11 12 13

Ethanol 10% 10% 10% 10% 10% 10% 10% 15 Glycerin 10 10 10 10 10 10 10

Pluronic F1081 3.0 3.0 3.0 3, 0 3.0 3.0 3.0

Aroma 0.146 0.146 0.146 0.146 0.146 0.146 0.146

Saccharin (Na) 0.03 0.03 0.03 0.03 0.03 0.03 0.03 CPC2 0.1 0.1 0.1 0.1 0.1 0.1 PBTA 0.1 0 , 2 0.3 0.5 1.0

Water 25 g.s. to 100% 100% 100% 100% 100% 100% 100% pH (with 1N NaOH) 7.0 7.0 7.0 7.0 7.0 7.0 7.0

Reflected 56.8 39.6 42.1 43.6 46.2 47.8 55.9 30

Difference - +17.2 -2.5 - 4.0 - 6.6 - 8.2 -16.3 j Compared to Example 8 -> | 1. Polyalkylene oxide block polymer.

2. Cetylpyridinium chloride.

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18

The above results clearly show that PBTA significantly reduces the tooth discoloration usually induced by antibacterial anti-plaque agents exemplified by CPC. A PBTA concentration of approx. 1.0% seems to give excellent results. Such additives also reduce or inhibit gingivitis and do not appreciably reduce the antiplaque action of the antiplaque agents shown.

Use of equivalent amounts of the following antibacterial anti-plaque agents instead of the CPC used in Examples 9-13 provides preparations which also produce an unexpected reduction in tooth discoloration and tartar.

EXAMPLES Antibacterial Antiplaque 14 Benzethonium Chloride (BC) 15 Chlorhexidine Diacetate 15 16 Chlorhexide Indigluconate 17 Dodecyltrimethylammonium Bromide ch2ch2oh .ch2ch2oh

18 C12_18alkyl-Å-CH2CH2IJ

^ CH2CH2PH

19 Alexidine dihydrochloride 20 The following compositions exemplify toothpastes having antiplaque effect and reduced discoloration and tartar formation.

19

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EXAMPLES (parts) 2Ό · 21 22

Hydrated aluminum hydroxide 30 30 30

Polyethylene glycol 600 22 22 22

Pluronic F108 333 5

Hydroxypropyl methylcellulose 1.2 1.2 1.2 BC 0.5

Hibitan. - 4.725 CPC - - 0.5 PBTA 1.0 1.0 1.0 10

Sodium saccharin 0.17 0.17 0.17

Aroma 0.8 0.8 0.8

Water, e.g. to 100 100 100 15 Comparative Example 1

The in vitro formation of hydroxylapatite (HA) was investigated by A. Gaffars Method according to J. Dent. Res. 64, 6-10, using as a starting solution a 0.1 molar CaCl 2 solution and a 0.1 molar NaH 2 PO 4 solution in distilled water.

To 23 ml of water was added 1 ml of a phosphate stock solution containing the inhibitor at various concentrations. Then, 1 ml of the calcium starting solution was added and the reaction time determined. The initial concentration of the calcium-25 µm and phosphate solutions was 4 mmol. The experiments were carried out at a pH of 7.4 under nitrogen and the base consumption was determined automatically with a 0.1 n NaOH solution. At room temperature, the time for HA formation and delay was determined. The inhibitors were as follows: 30

Compound Structural Formula

PFA Phosphonic formic acid H2O3P-COOH

PAA Phosphonic acetic acid H2O3P-CH2-COOH

PPT 1 phosphonopropane 1,2,3-tri carboxylic acid Η203Ρ-0Η (000Η) 0Η (000Η) 0Η2000Η 20

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PBTA 2-phosphonbutane-1,2,4-

tricarboxylic acid CH2 (C00H) C (PO3H2) (C00H) -CH2CH2-C00H

PAPA Polyallyl phosphonoacetate [CH2-CH] n 0 0

I II II

5 CH2-O-C-CH2-P-OH

OH

PVPA Polyvinylphosphonic acid -f-CH2-CH2 * n H0-P = 0

10 I

OH

MA Malonic acid. C00H-CH2-C00H

0 0 II II

PPI pyrophosphate Η0-Ρ-0-Ρ-0Η

15 OH OH

This results in the results given in Table III.

Table III

20

Molar Concentration HA Formation

Inhibitor tration x 1Q ~ 5 min. _

None 0 18 - PFA 13.0 37 19 25 PAA 28.0 96 77 PPT 6.2 62 44 PBTA 3.0 78 60 PVPA 15.0 30 12 PAPA 27.0 48 30 MA 20.0 18 No PPI 10, 0 66 48

The above values show that in the use of the invention of PBTA, the longest time for HA formation is obtained at the smallest concentration of the inhibitor and the greatest delay at the smallest concentration of the inhibitor.

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21

Comparative Example 2

Crystal growth of HA or inhibition thereof was investigated by analogy with the method of Moreno et al. in Dissue Res.

24, 47/57, using a supersaturated HA solution of 5 250 ml of KH2PO4 and CHCl2, and all solutions containing a 50 mmol boiling salt concentration to mimic saliva. The complete inhibition of crystal growth was determined over 5 hours for a 10 "molar solution, yielding the values listed in Table IV.

Table IV

-6

Concentration in 10 mol / liter to completely inhibit growth Inhibitor_in 5 hours_ PFA 30 15 PAA 1.3 PPT 2.0 PBTA 0.2 PAPA 0.7

Comparative Example 3 20 Tartar formation was investigated in animal experiments with rats with topically applied inhibitors in a 1 wt% solution. The decrease in tartar formation was measured as a percentage. The values are listed in Table V.

Table V

25 Inhibitor_Tarsten's reduction PPT 29.6 PBTA 33.0 PAPA 27.6 PVPA 16.0 30 These values show that PBTA causes a significantly increased inhibition of tartar.

Claims (11)

An oral care agent containing as tartaric antagonist 0.01-10% by weight of a carboxyl group-containing phosphonic acid in an acceptable carrier, characterized in that the carboxylic group-containing phosphonic acid is a 2-phosphonobutane-1,2,4-tri-carboxylic acid compound (PBTA). ) of formula I 0 CH2-COOH «M1 I PC-C00H (I) 'I HO I CH2-CH2-C00H or an orally acceptable salt thereof, wherein the agent optionally contains 0-15% of at least one normally staining nitrogen-containing antibacterial antiplaque agent based on the free base form of the agent. DK 159372 B Oral care agent according to claim 1, characterized in that the antibacterial anti-plaque agent is cationic and is present in an amount of at least approx. 0.001% by weight. Mouthpiece according to claims 1-2, characterized in that the compound (I) is present in an amount of approx. 0.1 - approx. 6% by weight. Oral care agent according to claims 1-3, characterized in that the antibacterial antiplaque agent is a substituted guanidine. The mouth care agent according to claim 4, characterized in that the antibacterial anti-plaque agent is a pharmaceutically usable water-soluble salt of an agent selected from the group consisting of chlorhexidine and -alexidine. Oral care agent according to claims 1-3, characterized in that the antibacterial anti-plaque agent is benzethonium chloride. Oral care agent according to claims 1-3, characterized in that the antibacterial antiplaque agent is a quaternary ammonium compound containing 1-2 alkyl groups of 8-20 carbon atoms. The mouth care agent according to claims 1-3, characterized in that the antibacterial anti-plaque agent is cetylpyridinium chloride. 9. Oral care agent according to claims 1-8, characterized in that the carrier is an aqueous alcohol and that the agent is a mouthwash liquid having a pH of approx. 4.5 - approx. 9th A mouth care agent according to claims 1-8, characterized in that the carrier comprises a liquid carrier and a gelling agent and that a dental acceptable polishing material 24 DK 159372 B is present and that the agent is a toothpaste having a pH of approx. 4.5 - approx. 9th 10 Inhibitor_Dimension of tartar formation PFA 33.4 PAA 50.0 PBTA 84.0 15 Patent claims. Mouthpiece according to claims 1-10, characterized in that it contains approx. 0.01 - approx. 5.0% by weight of said agent.