CH652023A5 - ESSENTIAL WATER-FREE ORAL CARE AGENT AGAINST TARTAR. - Google Patents

Description

The present invention relates to a substantially water-free oral care product which is essentially free of stain-forming antibacterial anti-plaque agents and which is effective against tartar.

Tartar is a hard, mineralized deposit that forms on the teeth. Regular brushing prevents these deposits from building up quickly, but regular brushing is also not enough to remove all the tartar deposits that adhere to the teeth. Tartar is formed on the teeth when calcium phosphate crystals begin to be deposited in the cuticle and the extracellular matrix of the plaque or plaque and are so densely packed that the aggregates can no longer be deformed. There is no complete agreement on how calcium and orthophosphate ultimately form the crystalline material known as hydroxylapatite (HAP). However, there is agreement that at higher levels of saturation, i.e. above the critical saturation limit, amorphous or microcrystalline calcium phosphate is the precursor for crystalline hydroxylapatite. Although "amorphous calcium phosphate" is related to hydroxyapatite, it differs from it in terms of atomic structure, particle morphology and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks that are typical of amorphous material, which lacks the regular atomic arrangement typical of all crystalline materials, including hydroxyapatite. According to a proposed mechanism of action by means of which the non-toxic oral tartar agents which act against tartar prevent the formation of tartar, these agents presumably bind the amino groups in the matrix system of the oral cavity at physiological pH values and temperatures and also crosslink the protein.

Numerous different compounds and preparations have been developed as antibacterial agents and against plaque and tartar in oral care products, for example cationic materials such as bisbiguanide compounds and quaternary ammonium compounds, for example the benzethonium chloride and cetylpyridine chloride described in US Pat. No. 4,080,441. However, these cationic materials tend to stain the teeth when used regularly.

It is an object of the invention to develop an improved oral hygiene agent which works against tartar and which does not or only slightly discolors the teeth.

Another object of the invention is to develop an oral care product that prevents the conversion of amorphous calcium phosphate to the hydroxyapatite crystal structure that is normally associated with tartar formation.

Further objects and advantages of the invention will appear from the description below.

To achieve the object, an essentially water-free oral care agent is proposed according to the invention, which is essentially free of stain-forming antibacterial anti-plaque agents, which is characterized by a content of an orally acceptable carrier and as an agent against tartar, an effective amount of at least one bis (o carboxy-phenyl) ester of an aliphatic dicarboxylic acid having 2 to 8 carbon atoms. This agent can be applied to the teeth.

The anti-calculus agents contained in the agent according to the invention can exist in the form of their free acid of the following formula:

o oc — eoo

ÇpCCOH HOOC- | ^ j in which the radicals R are preferably independently of one another H or alkyl groups having 1 to 4 carbon atoms and preferably H, and in which n is an integer value from 0 to 6, preferably 2, the preferred being against tartar corresponding agent is bis (o-carboxy-phenyl) succinate (BOCS). However, if n = 0, the - (CRR) n group can be a single bond, as in the bisesters of oxalic acid, or it can be an alkylene or alkylene group with 1 to 6 C atoms, i.e. straight chain or branched, saturated or unsaturated, with O- or S-containing chain, C 1-4 alkoxy substituted or the like. If the -CRR group is part of an ethylenic radical, one or both radicals can be zero, i.e. be replaced by a valence bond. Below are some examples of aliphatic dicarboxylic acids whose bis- (o-carboxyphenyl) esters are suitable for use in the tartar agent according to the invention.

Oxalic acid (ethanedicarboxylic acid)

Malonic acid (propanedicarboxylic acid)

Succinic acid (butanedicarboxylic acid)

Glutaric acid (pentanedicarboxylic acid)

Adipic acid (hexanedicarboxylic acid)

Pimelic acid (heptanedicarboxylic acid)

Suberic acid (octanedicarboxylic acid)

Maleic acid (1,2-ethylenedicarboxylic acid HOOCCHrCH-COOH)

Itaconic acid (methylene succinic acid HOOCC (: CH2-COOH)

Isosuccinic acid (2-methylpropane dicarboxylic acid) muconic acid (2,4-hexadiene dicarboxylic acid HOOCCH: CHCH: CH-COOH)

Dihydromuconic acid (HOOCCH2CH2CH: CHCOOH) Dihydroitaconic acid (methyl succinic acid) 3-ethylhexanedicarboxylic acid

Furthermore, one or both phenyl moieties in this

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Agents with one or more C, _4-alkyl or alkoxy groups such as methyl or isobutoxy groups or halogens such as chlorine, bromine, iodine or fluorine may be nucleus-substituted.

Suitable methods for the preparation of these anti-calculus agents are described in US Pat. No. 4,080,441. Another improved manufacturing process is described below in Example 1.

It will be appreciated that the free acid tartar agents can also be converted to their corresponding salts and used as such by reacting with any base containing an orally acceptable cation such as an alkali metal (e.g. sodium, potassium ), an alkaline earth metal (e.g. calcium, magnesium), a metal, ammonium, mono-, di- or tri-C 1-6 alkyl or alkanol-substituted ammonium or organic amine (with, for example, methyl, ethyl, hydroxyethyl substituents) contains.

The anti-tartar agents prevent the formation of crystallization nuclei, and the oral care agents containing them reduce the formation of tartar without excessively removing lime from the tooth enamel and, in contrast to the above-mentioned cationic antibacterial agents which act against plaque and tartar, have little or no tendency , stain the teeth and are also suitable for effectively combating or preventing gingivitis.

The concentration of the anti-calculus agents in the oral preparation can vary within wide limits, it is normally above 0.01% by weight, the usable amount, apart from the costs involved or the incompatibility with the carrier, not being subject to an upper limit. In general, concentrations of 0.01 to 10% by weight are used, preferably 0.05 to 8% by weight and more preferably 0.1 to 4% by weight. Oral preparations which, when used normally, may be swallowed by chance should preferably contain concentrations within the ranges given below.

Although the anti-calculus agents vary in water solubility depending on their molecular weight, identity and the proportion of their salt-forming cations, etc., they are sufficiently soluble in aqueous media such as the oral cavity at the low concentrations used in the agent of the invention to be described as water-soluble. Unexpectedly, however, it turned out

that oral care products containing such products in an aqueous medium are subject to considerable hydrolysis or other decomposition during storage. Accordingly, an essentially water-free oral care agent is provided according to the invention, which contains, for example, 0 to less than 0.2 mole of water per mole of the anti-calculus agent.

If the oral care composition according to the invention is in liquid, pasty or cream-like form, such as in mouthwash and dishwashing detergents, toothpastes and toothpastes, a water-miscible (preferably water-soluble), organic, generally liquid, orally acceptable carrier is preferably used. Such carriers are e.g. B. water-soluble monohydroxy and polyhydroxyalkanes with 2 to 4 carbon atoms and their C, .4-alkyl ethers such as ethanol, ethylene glycol, their methyl, ethyl and butyl ether (methyl, ethyl and butyl cellosolve), propylene glycol , Tetramethyl-glycol and glycerin and water-soluble poly (ethylene glycols) such as diethylene glycol and their methyl, ethyl, diethyl and butyl ether (methyl, ethyl, diethyl and butyl carbitol), triethylene glycol, low-polyethylene glycols Molecular weight of, for example, 400, 600 and mixtures thereof. Polyhydroxyl compounds of the group mentioned, in particular propylene glycol, glycerol and the low molecular weight polyethylene glycols, generally also act as humectants which form desirable components of the oral care compositions according to the invention.

Other preferred water-miscible carriers are polar aprotic solvents such as dimethylformamide and sulfoxide, N-methylpyrrolidone, sulfolane, tetramethylsulfone, acetonitrile and preferably ethylene and propylene carbonate.

Substantially water-immiscible organic liquid carriers can also be used; Examples include oily hydrocarbons, fatty acids and fatty acid esters such as mineral oil, tetradecane, pentane, caproic acid, oenanthic acid, methylcaproate and laurate, ethylene glycol dicaprylate and the like.

Mixtures of the same type and / or different liquid carrier types of the type described above can of course be used.

The proportion of the liquid carrier used in the oral care products depends primarily on the desired level of liquid or viscosity and can easily be determined in individual cases according to routine procedures. In general, liquid preparations such as mouthwashes or detergents contain 70 to about 99.9% by weight and toothpastes and toothpastes 10 to 80% by weight of such a liquid carrier, of which 10 to 100% can be a humectant. Solid humectants such as sorbitol can also normally be included.

The oral care products according to the invention generally have an aqueous medium, i.e. in the oral cavity or in the form of a 20% aqueous slurry or solution, a pH of 3.5 to 8, preferably from 4 to 7 and more preferably from 4 to 6. Such a pH value can be obtained by adding the required amounts of acidic substances such as citric or benzoic acid, basic substances such as sodium hydroxide and / or buffering agents such as sodium citrate, benzoate, bicarbonate or carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures the same can be set.

In solid or pasty compositions such as tooth powders, tablets, tooth pastes or tooth creams, the carrier generally contains a polishing agent. Examples of suitable polishing agents are water-insoluble sodium metaphosphate (IMP), potassium metaphosphate, tricalcium phosphate, anhydrous, monohydrated and dihydrated calcium and dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, magnesium and calcium carbonate and sulfate, aluminum oxide, aluminum hydrated aluminum hydroxide and alkaline earth metal aluminosilicates, zirconium silicate, silicon oxide, bentonite and mixtures thereof. Preferred polishing agents include crystalline and colloidal silicon oxides, silica gel, complex amorphous alkali metal aluminosilicates, hydrated aluminum oxide and IMP.

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

Are z. B. optically clear gels are used as a polishing agent, especially colloidal silicon oxide, at 5

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for example the Syloids 72, 74 or 244 offered under the trade name SYLOID or the Santocel 100 sold under the trade name SANTOCEL as well as alkali metal aluminosilicate complexes, since they have refractive indexes that are similar to those of gel-forming solid-liquid systems, as are usually used in dentifrices to come close.

Many of the so-called «water-insoluble» polishing agents have an anionic character and also contain small amounts of soluble material. Insoluble sodium metaphosphate can be prepared in any suitable manner, for example according to Thorpe's Dictionary of Applied Chemistry, volume 9.4. Edition, pages 510 to 511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are also suitable polishing agents. These metaphosphate salts show very low solubility in water and are therefore generally referred to as insoluble metaphosphates. They contain small amounts of soluble phosphates as impurities, usually amounts of a few percent, for example up to 4% by weight. The amount of soluble phosphate, which in the case of insoluble metaphosphate can also include a soluble sodium trimetaphosphate, can be reduced by washing with water if desired. The undissolved alkali metal metaphosphate is usually used in powder form with a particle size which is such that no more than about 1% of the material has a grain size of more than 37 μm.

The polishing agent is generally present in the oral care composition according to the invention in amounts in the range from 20 to 99% by weight. It is preferably present in amounts from 20 to about 75% by weight in toothpastes and from 70 to 99% in tooth powders.

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

In a toothpaste, cream or gel, the liquids and solids are present in such a ratio that a creamy or gelled mass is formed which can be extruded from a pressurized container or from a compressible tube. Thickening of the product to the desired level of viscosity or liquid can be facilitated or achieved by using a binding, thickening or gelling agent such as natural or synthetic gums or rubber-like materials, typically Irish moss, Pluronics, sodium carboxymethyl cellulose and carboxyethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose , Hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, Laponit CP or Laponit SP (synthetic hectorites from La-porte Industries Ltd.), viscarin, gelatin, glucose, sucrose, carbopole (e.g. 934, 940, 941), karaya gum, gum arabic, tragacanth gum, polyvinylpyrrolidone Polyvinyl alcohol or starch can be incorporated. They are generally present, individually or in groups, in an amount of up to 10% by weight, preferably in the range from about 0.5 to about 5% by weight. Preferred gel-forming agents are Pluronics and hydroxypropyl cellulose. Pluronics such as F 108 and F 127 are polyoxypropylene-polyoxyethylene block polymers that also act as nonionic surfactants.

The oral care composition according to the invention can be a sufficiently water-soluble, non-soap-like, organic, anionic or nonionic, synthetic surfactant in concentrations which generally range from about 0.05 to about 10% by weight, preferably from 0.5 to about

5% by weight are included to promote both the wetting and the cleaning and foaming properties. In US Pat. No. 4,041,149, such suitable anionic surfactants are described in column 4, lines 31 to 38 and in column 8, lines 30 to 68 and in column 9, lines 1 to 12, suitable nonionic surfactants.

In an advantageous embodiment of the invention, the oral care products contain a fluorine-providing compound. Such compounds can be slightly or completely soluble in water. They are characterized by their properties of releasing fluoride ions or ions containing fluorine in water and essentially not reacting with other compounds of the oral care product. These compounds include in particular 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, copper fluorides 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 fluorozirconate, sodium fluoride, sodium fluoride, sodium fluoride, sodium fluoride -phosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, for example sodium and tin II fluorides, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of fluorine-providing compound used depends to a certain extent on the type of the compound, and also on its solubility and on the type of oral care product, and the amount added must in principle be non-toxic. In a thickened or solid oral care product, such as a toothpaste or a tooth powder, such an amount of the fluorine-providing compound is considered sufficient that preferably releases a maximum of about 1% by weight, based on the total amount of the preparation, of fluoride ions. Any suitable minimum amount of such a compound can be used, but it is preferred to use an amount of the compound sufficient to release 0.005 to 1%, preferably about 0.1%, of fluoride ions. Alkali metal fluorides and stannous fluoride are generally used in an amount of up to about 2% by weight, preferably in the range from about 0.05 to 1% by weight, based on the total weight of the preparation. Sodium monofluorophosphate can be present in an amount up to 7.6% by weight, but usually about 0.5 to about 1% by weight.

In a liquid oral care composition according to the invention, for example a mouthwash, the fluorine-providing compound is usually present in an amount which is sufficient to be about 0.0005 to about 0.2% by weight, preferably about 0.001 to about 0.1% by weight and in particularly preferably to release about 0.0013% by weight of fluoride ions.

Various other materials such as bleaching agents, preservatives, silicones, chlorophyll compounds, other anti-calculus agents, antibacterial anti-plaque agents and / or nitrogen-containing materials such as urea, diammonium phosphate and mixtures thereof can also be incorporated into the oral care agent according to the invention. If these auxiliary substances are present, they are incorporated into the preparations in such quantities that they do not significantly adversely affect the properties and the desired characteristics of the preparation in question.

Any flavoring or sweetening agent can also be used. Examples of suitable flavorings are flavoring oils, e.g. B. spearmint oil, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage oil, eucalyptus oil, marjoram oil, cinnamon oil, lemon and orange oil, menthol, eugenol, cineol and methyl salicylate.

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Suitable sweeteners include sucrose, fructose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartin, aspartylphenylalanine methyl ester (APM) and saccharin. Flavoring and sweetening agents can be present in the preparation in an amount of about 0.01 to 5% by weight or more.

In the manufacture of the oral care products according to the invention, it is a preferred but not decisive procedure to add the anti-calculus agent after the other ingredients have been mixed or brought into contact with one another in order to prevent this agent from precipitating out.

The use of the oral care products according to the invention, such as mouthwashes or toothpastes, which contain the described anti-calculus agent in sufficient quantity to prevent calculus on the tooth surfaces, takes place regularly, preferably one to three times a day, in the oral cavity, in particular on the tooth enamel.

The following examples serve to illustrate the invention, but without restricting it to the examples. The quantities and parts given relate to the weight and the temperatures to ° C, unless expressly stated otherwise.

example 1

A. To prepare bis (o-carboxyphenyl) succinate (BOCS), 0.4 mole of salicylic acid (55.2 g), 0.4 mole of pyridine (31.2 ml), 0.2 mole of succinyl chloride ( 31.0 g) used.

The salicylic acid and pyridine were dissolved in 90 ml of acetone. To the clear solution obtained, the succinyl chloride in 90 ml of acetone was added with stirring at a rate such that acetone reflux was maintained for half an hour. During this addition, the desired BOCS product began to separate and the mixture turned dark purple. The reaction mixture was further stirred for half an hour after all of the succinyl chloride had been added. Then 200 ml of water were added, the acetone was evaporated from the slurry in a rotary evaporator at 35 ° C. and the desired BOCS product was collected on a suction filter, washed with water and dried in vacuo at 60 ° C.

Yield: 66.5 g (93%)

Mp 177-177.5 ° C

Neutral equivalents 179.9 *

Saponification equivalents 186.8 *

* Calculated for CI8H1408

B. The BOCS thus obtained was incorporated into a toothpaste of the following composition which prevented tartar:

Parts by weight

Propylene glycol

42.0

Hydroxypropyl cellulose

1.0

Polyethylene glycol 600

10.0

Sodium saccharin

0.2

Ti02

0.4

Insoluble in water

Sodium metaphosphate (IMP)

28.0

Colloidal silicon oxide (Syloid 244)

12.0

Sodium lauryl sulfate

1.5

Flavorings

3.0

BOCS

3.0

Examples 2 to 4 The formulations given below, in parts by weight, show tartar-preventing mouthwashes according to the invention.

example

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Flavorings

0.22

0.22

0.22

Ethanol

15.0

15.0

15.0

Pluronic F108

3.0

3.0

3.0

Glycerin

10.0

10.0

10.0

Sodium saccharin

0.03

0.03

0.03

BOCS

0.05

0.50

1.0

The listed mouthwash formulations of Examples 2 to 4 can be used either in their original form or after 2 to 4-fold dilution of their volume with water, i.e. in a volume ratio of formulation to water of 1: 2 to about I: 4 in the oral cavity.

Examples 5-13 The following bisester-containing compounds can be used in the formulations according to Examples 2 to 4 instead of the BOCS, and formulations which prevent tartar can also be obtained in this way:

Example Bisester containing compound

5 bis (2-carboxy-4-butoxyphenyl) oxalate

6 bis (2-carboxy-4-propyl-6-chlorophenyl) glutarate

7 bis (2-carboxy-4-methyl-6-bromophenyl) adipate

8 bis (2-carboxy-4-iso-6-ethoxyphenyl) suberate

9 bis (2-carboxyphenyl) pimelate

10 bis (2-carboxy-5-methoxyphenyl) malonate

11 bis (2-carboxy-6-butylphenyl) maleate

12 bis (2-carboxyphenyl) itaconate

13 bis (2-carboxy-4-fluorophenyl) muconate

COMPARATIVE EXPERIMENT In this experimental set-up, a water placebo and a 0.1% BOCS solution in dimethyl sulfoxide, pH 7.10, as a test mouthwash against tartar were tested for their effectiveness against tartar formation in 24 rats over a period of 30 days. Fully developed Osborne-Mendel hatchlings were used. They were inoculated intraorally on the 21st and 22nd day with Streptomyces mutans (Strep-mutans), Actinomyces viscosus and faeces from caries-active Osborne-Mendel rats, on a diet that favored tartar formation and was enriched with 0.2% P as Na2P04 (580F) and the placebo and the test mouthwash were applied to the molars in 12 animals over a period of 30 days on Mondays and Fridays twice a day and on Saturdays and Sundays once a day. The animals were weighed at the start and end of the study to ensure that their condition was otherwise normal. At the end of the trial, tartar formation was determined using routine procedures and the following results were obtained:

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Number Medium Medium Signi

Animals terminal dental calculus

Increase weight units

Placebo (water) 12 128 g 17.9 mouthwash

(0.1% BOCS) 12 135 g 14.8 0.01 * 20 units are considered a risk limit.

The results indicate a significant effectiveness in reducing the tartar build-up (at the + 99% level) of BOCS in 0.1% concentration when applied topically.

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Claims (6)

652 023 1. Essentially anhydrous oral care product. which is essentially free of stain-forming antibacterial anti-tiplaom agents, characterized in that it is an orally acceptable carrier and, as an anti-tartar agent, an effective amount of at least one bis (o-car-boxy-phenyl) ester of an aliphatic dicarboxylic acid with 2 contains up to 8 carbon atoms. 2. Oral care product according to claim 1, characterized in that the anti-calculus agent is bis (o-carboxy-phenyl) succinate. 2nd PATENT CLAIMS 3. Oral care agent according to claims 1 or 2, characterized in that it contains the anti-calculus agent in an amount of 0.01 to 10 wt.%. 4. Oral care agent according to claims 1 or 2, characterized in that it contains the anti-calculus agent in an amount of 0.05 to 5 wt.%. 5. Oral care product according to claims 1 or 2, characterized in that it is an M and detergent containing a liquid carrier and has a pH of 3.5 to 8 in an aqueous medium. 6. Oral care product according to claims 1 or 2, characterized in that it is a toothpaste containing a liquid carrier, a gelling agent and a dental acceptable polishing agent and has a pH of 3.5 to 8 in an aqueous medium.