SE448818B - ORAL COMPOSITION CONTAINING A DENTAL PREVENTOR - Google Patents

Description

Studies have shown that there is a good correlation between a compound's ability to inhibit the growth of hydroxyapatite crystals in vitro and its ability to prevent lime formation in vivo.

A considerable number of different types of compounds and compositions have been developed for use as antibacterial and plaque and tartar inhibitors in oral compositions, including, for example, such cationic materials as the bisbuguanide compounds and quaternary ammonium compounds, e.g. benzethonium chloride and cetylpyridine chloride, described in U.S. Patent No. 4,110,429. However, these cationic materials tend to stain the teeth in continuous use. In addition, they exert an antibacterial effect, which in an undesirable manner tends to disrupt or destroy the normal microflora of the mouth and / or digestive system. Other such materials have been found to be unstable in the presence of anionic and surfactants, which are often present in conventional oral compositions.

An object of the present invention is to provide an oral tartar-preventing composition which does not have any or any of the above-mentioned disadvantages.

Another object of the present invention is to provide an improved tartar-preventing oral composition which has relatively little or no tendency to stain the teeth.

A further object of the present invention is to provide an oral composition which prevents the conversion of amorphous calcium phosphate to the hydroxyapatite crystal structure commonly associated with tartar. Yet another object of the present invention is to provide an improved method of preventing the formation of tartar and / or staining of the teeth by means of nitrogen-containing cationic, antibacterial and tartar-preventing agents. Yet another object of the present invention is to provide an oral composition containing a nitrogen-containing cationic, antibacterial and tartar inhibitor, which composition exhibits a reduced tendency to stain the teeth.

Other objects and advantages of the invention will become apparent from the following, more detailed description.

The present invention relates to an oral composition having a pH of 4.5 to 9 comprising an orally acceptable vehicle, containing 0.01 to 10% by weight of a tartar inhibitor, and characterized in that said tartar inhibitor is a copolymer which is substantially consists of: (A) n units exhibiting the molecular structure of units derived from glutamic acid, (B) m units exhibiting the molecular structure of units derived from alanine, and (C) p units exhibiting the molecular structure of units derived from tyrosine, wherein the ratio (n + m) : p is in the range from 5: 1 to 9.5: l and the ratio mzn is in the range from 0: 1 to 0.6: l, and the molecular weight of the copolymer is in the range from 5,000 to 150,000.

Said copolymers may be prepared in a well known manner, for example according to the procedure described in "Immunochemistry" by Chase and Williams, vol 2, pages 168, 169 (1978) Academic Press.

In general, the copolymers are prepared by random copolymerization of N-carboxyhydrides of glutamic acid, tyrosine and alanine in the required molar ratios in the form of a mixture in an organic solvent such as dioxane, benzene, dimethylformamide or N-methylpyrrolidone and in the presence of an initiator such as an organic amine (eg triethylamine) or sodium methoxide.

The units (A) in the copolymer have the structural formula: co "2CH2 T ëooH l n (A) ~ - (HN - pH - CH wherein n has a numerical value representing the number of units (A) of glutamic acid in the copolymer.

The units (B) in the copolymer have the structural formula: - ~ HN - CH ~ co - ~ - ~ f- I. ê: H i '_ C 3 * (B) u- .. m and m have a numerical value representing the number of units (B) of alanine in the copolymer.

The units (C) in the copolymer have the structural formula: (C) HN - CH - CO ch? s OH p wherein p has a numerical value, which represents the number of units (C) of tyrosine in the copolymer.

Ln 10 15 20 25 30 448 818 As mentioned above, the ratio (n + m): p is in the range from approx. 5: 1 to approx. 9.5: 1, the ratio m: n can amount to approx. 0: 6: 1 and the values for m, n and p are such that the copolymer has a molecular weight of approx. 5,000 to approx. 150,000 and preferably approx. 17,000 to approx. 100,000.

Particularly preferred copolymers are a two-component copolymer containing glutamine units (A) and tyrosine units (B) in a ratio of approx. 9: 1 and with a molecular weight of approx. 17,000 to approx. 21,000 and a three-component copolymer containing glutamine units (A), alanine units (B) and tyrosine units (C) in a ratio of approx. 6: 3: 1 and with a molecular weight of approx. 80,000 to approx. 100,000.

It is understood that the free acid form of the copolymers used in the invention may be converted into and used in the equivalent salt form by treatment with any base containing an orally acceptable cation, for example of alkali metal (such as sodium or potassium), ammonium , C1-18 mono-, di- or trisubstituted ammonium (for example alkanol-substituted as mono-, di- or triethanolammonium), organic amines etc. It is also understood that when reference is made to these compounds as being water soluble, these copolymers should be water-soluble or readily dispersible in water in the concentrations used in conventional oral compositions or preparations such as mouthwashes, toothpastes and the like.

The copolymers of the present invention are remarkably advantageous oral compounds for inhibiting tartar formation. If one remembers that human saliva contains natural inhibitors against calcium and phosphate precipitation including glutamic acid and tyrosine, it is pre- LT! PJ Ul 448 818 copolymers are relatively safe to use even if swallowed, as they are rapidly and easily hydrolyzed in the stomach by chymotrypsin, a proteolytic enzyme known to hydrolyze tyrosine. In contrast, other non-hydrolyzable tartar inhibitors, when absorbed in the gastrointestinal tract, can cause changes in the bone. In addition, these copolymers are advantageous in that they are substantive to oral surfaces.

The concentration of these tartar inhibitors, of copolymers consisting of oral compositions can vary widely, typically from about 0.01% by weight with no upper limit than that dictated by cost or incompatibility with the vehicle. Usually concentrations of approx. 0.01 to about 10.0%, preferably about 0.1 to approx. 8.0% and especially approx. 0.5 to approx. 5% by weight. Oral compositions which, in normal use, may be inadvertently ingested preferably contain concentrations which are close to the lower limit of said range.

Cationic and nitrogen-containing antibacterial agents are well known in the art. See, for example, the section on "Quaternary Ammonium and Related Compounds" in the article on the Antiseptics and Disinfectant in the Kirk-Othmer Encyclopedia of Chemical Technology, 2nd edition (vol. 2, pages 632-635), the contents of which are hereby incorporated into present text.

Cationic compounds with antibacterial activity (ie germicides) have been used against bacteria and have been used in oral preparations or compositions to prevent plaque formation caused by bacteria in the oral cavity.

Among the most common of these antibacterial, plaque-preventing quaternary ammonium compounds is benzethonium chloride, also known as HYAMINE 1622 or diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride. In an oral preparation, this compound is highly effective in reducing oral hygiene by oral administration. Other cationic and antibacterial agents of this kind are, for example, those mentioned in U.S. Pat. Nos. 2,984,639, 3,325,402, 3,431,208 and 3 other cationic and antibacterial agents. 703,583 and in British Patent Specification 1,319,396.

Other antibacterial and anti-plaque quaternary ammonium compounds include those in which one or two of the substituents on the quaternary nitrogen atom have a carbon chain length (usually alkyl group) of about 8 to 20, usually 10 to 18, carbon atoms while the remaining substituents have a lower number of carbon atoms (usually alkyl or benzyl group), for example 1 to 7 carbon atoms, often methyl or ethyl groups. Dodecyltrimethylammonium bromide, dodecyldimethyl (2-phenoxyethyl) ammonium bromide, benzyldimethylstearylammonium chloride, cetylpyridine chloride and quaternized 5-amino-1,3-bis (2-ethylhexyl) -5-methyl-vanhexahydropyrimidine ammonia are examples of bacterial ammonium

Other types of cationic antibacterial compounds which can be advantageously incorporated into oral compositions to promote oral hygiene by reducing plaque formation are the amidines such as substituted guanidines, for example chlorhexidine and the corresponding compound alexidine having 2-ethylhexyl groups instead of the chlorophenyl groups, and other bisguanides such as those described in German patent application P 2 332 383 published January 10, 1974, which give the following formula: R NH m1 NH NH 1 ''. '= 1 .z .n A- (x) ZN-eNH-ë-NH (cnz) n-NH-c-NH-c-N ~ oc') z, ~ A 'LH 10 20 N Ln Jäs .. .ä GO ÖÖ ... a OD wherein A and A 'denote, depending on the circumstances, either (1) a phenyl radical, which as substituent may contain up to 2 alkyl or alkoxy groups with 1 up to approx. 4 carbon atoms, an ennitro group or a halogen atom, (2) an alkyl group containing 1 to approx. 12 carbon atoms, or (3) alicyclic groups having 4 to approx. 12 carbon atoms, X and X ', represent, depending on the circumstances, an alkylene radical having 1-3 carbon atoms, z and z' represent zero or 1, R and R 'represent hydrogen, an alkyl radical having 1 to approx. 12 carbon atoms or an aralkyl radical having 7 to approx. 12 carbon atoms, n is an integer from 2 to 12 and the polymethylene chain (CH 2) can be interrupted by up to 5 ether, thioether, phenyl or naphthyl groups, which are available as pharmaceutically acceptable salts. Additional substituted guanidines are: N '- (4-chlorobenzyl) -N5- (2,4-dichlorobenzyl) biguanide, p-chlorobenzyl biguanide, 4-chlorobenzhydrylguanyl urea, N-3-lauroxypropyl-N5-p-chlorobenzyl biguanide , 5,6-dichloro-2-guanidobenzimidazole and Np-chlorophenyl-N5-lauryl biguanide.

The cationic and aliphatic tertiary amines also possess antibacterial and anti-plaque action. Such antibacterial compounds include tertiary amines having a fatty alkyl group (usually 12 to 18 carbon atoms) and 2-poly (oxyethylene) groups attached to the nitrogen (usually containing a total of from 2 to 50 ethyleneoxy groups per molecule) and salts thereof with acids and compounds having the structural formula: 1CH 2 CH 2 O) ZHV J (CH 2 CH 2 O) XH u - 'ln / pl RN cH2cH2Nr \ (cH2cH2o) yn u- 448 818 wherein R represents a fatty alkyl group containing 12 to 18 carbon atoms and x, y and z denotes a total value of 3 or higher, as well as salts thereof. Cationic compounds are generally preferred because of their effective anti-plaque action.

The antibacterial antiplaque compound is preferably one which exhibits such antibacterial activity that its coefficient of phenol is well above 50, more preferably well above 100, for example higher than approx. 200 or more for S. aureus, and the phenolic coefficient (A.0.A.C.) for, for example, benzethonium chloride is stated by the manufacturer to be 410 for S. aureus. The cationic antibacterial compound is usually a monomeric (or possibly dimeric) material with a much lower molecular weight than 2,000, for example less than approx. 1,000. However, it is within the more general scope of this invention to use a polymeric and cationic, antibacterial compound. The cationic antibacterial compound is preferably administered in the form of an orally acceptable salt thereof, such as chloride, bromide, sulfate, alkyl sulfonate such as methyl sulfonate and ethyl sulfonate, phenyl sulfonate, such as p-methylphenyl sulfonate, nitrate, acetate, gluconate and the like.

The nitrogen-containing cationic and antibacterial compounds (including the tertiary amine) effectively promote oral hygiene, especially by removing plaque. However, their use has been observed to lead to staining of the tooth surfaces or discoloration.

The cause of such staining on the teeth has not been fully established. However, human tooth enamel contains a large amount (about 95%) of hydroxyapatite. (HAP), which includes the ions Ca2 + and PO43_. In the absence of tooth plaque, additional amounts of Ca 2+ and PO 43_, especially from saliva, 15 bd (11 448 818 10) can be precipitated on the enamel and such precipitates may contain carcasses which eventually stain the tooth enamel as a calcareous precipitate thereon. - the tertiary amine) and antibacterial compounds remove plaque, they can also denature protein from saliva in the oral environment, after which the denatured protein can act as a nucleating agent, which precipitates and stains or discolors tooth enamel.

Previously used additives which reduced the staining of the teeth by cationic, antibacterial and anti-plaque compounds also generally reduced the activity or action of antibacterial anti-plaque agents, such as bis-biguanido compounds, by forming a precipitate with these agents.

It is a further advantage of the present invention that the copolymers described above are not nucleating agents, and unexpectedly inhibit, i.e. prevents or removes, the staining of tooth enamel caused by such cationic-active (including the tertiary amine) antibacterial agents without therefore forming a precipitate or adversely affecting their antibacterial effect and anti-plaque action.

By themselves (even in the absence of such antibacterial agents), these copolymer additives are effective in reducing the formation of tartar without unduly decalcifying the tooth enamel, except that they effectively prevent gingivitis. However, not all anti-nucleating agents are effective in preventing staining caused by such antibacterial agents. VICTAMID (also known as VICTAMINE C), a condensation product of ammonia with phosphorus pentoxide, in fact increases staining even in the absence of such antibacterial agents. Cationic, nitrogenous, antibacterial and plaque inhibiting compounds, which are arbitrarily used in the practice of the present invention, are described above.

When such compounds are used, they are usually present in such amounts that the oral products contain between about 0.001 and 15% by weight of the compound. Preferably, for the desired degree of anti-plaque effect, the finished oral product contains about 0.01 to 5%, and most preferably about 0.25 to 1% by weight of antibacterial anti-plaque compound, calculated as its free base form.

In certain, particularly preferred forms of the invention, the oral preparation may be substantially liquid in its form, such as a mouthwash or rinse aid.

In such a dosage form, the carrier is usually a mixture of water-alcohol, preferably including a humectant, which is described below. Usually the ratio of water to alcohol ranges from about 1: 1 to about 20: 1, preferably about 3: 1 to 10: 1 and most preferably about 4: 1 to about 5: 1 by weight. The total amount of water-alcohol mixture in this kind of preparation is usually in the range of from about 70 to about 99.9% based on the weight of the preparation. The pH of this liquid and other dosage forms of the invention is usually in the range of from about 4.5 to about 9 and usually from about 5.5 to 8. The pH is preferably in the range of from about 6 to about 8.0. It should be noted that the compositions of the present invention can be used orally at lower pH without significantly decalcifying the tooth enamel. The pH can be controlled with acid (for example citric acid or benzoic acid), with base (for example sodium hydroxide) or can be buffered (such as with phosphate buffer). Such liquid oral formulations may also contain a surfactant and / or a fluorescent compound. According to certain other preferred embodiments of the invention, the oral composition may be substantially solid or pasty in consistency, such as a tooth powder, a tooth tablet, a toothpaste or (p) toothpaste. The carrier in such solid or pasty oral preparations usually contains polishes. Examples of polishes are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium silicon oxide, calcium silicon oxide; . Preferred polishing agents include DICAL, (calcium hydrogen phosphate), colloidal silica, silica gel, complex amorphous alkali metal aluminosilicate and hydrated alumina. Alumina, in particular the hydrated alumina sold by Alcoa as C333, having an alumina content of 64.9% by weight, a silica content of 0.008%, an iron (III) oxide content of 0.003% and a moisture content of 0.37% at 110 ° C and which has a specific gravity of 2.42 plus a particle size such that 100% of the particles are less than 50 microns and 84% of the particles less than 20 microns, is very efficient.

When visually clear gels are prepared, a colloidal silica polish such as those sold under the names SYLOID, for example SYLOID 72 and SYLOID 74, or under the name SANTOCEL as SANTOCEL 100 and the alkali metal aluminosilicate complexes are particularly valuable because they have refractive index gels. (including water and / or humectants) commonly used in dental UI preparations. Many of the so-called "water-insoluble" polishes are anionic in nature and also include small amounts of soluble material. For example, insoluble sodium metaphosphate may be prepared by any suitable means illustrated by Thorpe's Dictionary of Applied Chemistry, Vol. 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable compounds. These metaphosphate salts have a very low solubility in water and are therefore referred to as insoluble metaphosphates. In these there is a small amount of soluble phosphate materials in the form of impurities, usually a few percent such as up to 4% by weight. The amount of soluble phosphate material, which is assumed to include a soluble sodium metaphosphate in the case of insoluble sodium metaphosphate, can be reduced by washing with water if desired. The insoluble alkali metal metaphosphate is commonly used in powder form of such a particle size that no more than about 1% of the material is greater than about 37 microns.

The polish is usually present in amounts ranging from about 10% to 99% by weight of the oral preparation. Preferably it is present in amounts in the range from about 10 to 75% in toothpaste and from about 70 to 99% in tooth powder.

When preparing tooth powder, it is usually sufficient to mechanically mix, for example by rolling, the various solid constituents in suitable amounts and particle sizes.

In pasty oral preparations, the copolymer should be compatible or miscible with the other ingredients of the preparation. Thus, in a toothpaste, the liquid carrier may comprise water and humectants usually in an amount ranging from about 10% to about 90% by weight based on the formulation. Glycerol, propylene glycol, sorbitol or polyethylene glycol 400 may also be present; they as humectants. Particularly advantageous liquid constituents include mixtures of water, glycerol and sorbitol. * In clear gels, in which refractive index is an important factor to be considered, about 3-30% by weight of water, 0 to about 80% by weight of glycerol and about 20-80% by weight of sorbitol are preferably used. A gelling agent, for example natural or synthetic rubbers or rubbery materials, usually Irish moss, sodium carboxymethylcellulose, methylcellulose or hydroxyethylcellulose may be used.

Other useful gelling agents include gum tragacanth, polyvinylpyrrolidone and starch. They are usually present in a toothpaste in amounts of up to about 10% by weight, preferably in the range from about 0.5 to about 5%. The preferred gelling agents are methylcellulose and hydroxyethylcellulose. In a toothpaste or gel, the liquid and solid constituents are adapted to form a cream or gel-like mass, which can be squeezed out of a pressure vessel or from a compressible tube, for example of aluminum or lead.

The solid or creamy oral preparation, which usually exhibits a pH, measured at a 20% slurry, of about 4.5 to 9, often about 5.5 to about 8 and preferably between about 6 and about 8.0, may also contain a surfactant and / or a fluorescent compound.

It is understood that the oral preparations are usually intended to be sold or otherwise distributed in appropriately labeled packages. Thus, a bottle of mouthwash should have a label that essentially describes the agent as a mouthwash or mouthwash and with instructions for use, and a toothpaste is usually present in a compressible tube, generally made of aluminum, lined. lead or plastic, or other squeezable container for dispensing the contents, and provided with a label which essentially describes it as a toothpaste or toothpaste.

The oral compositions of the present invention may contain a non-soapy synthetic and sufficiently water-soluble, organic and anionic or nonionic surfactant in concentrations generally ranging from about 0.05 to about 10, preferably about 0. 5 to about 5% by weight in order to promote wetting, detersive and shaving properties. U.S. Patent 4,041,149 discloses such suitable anionic surfactants in column 4, lines 31-38, and such suitable nonionic surfactants in column 8, lines 30-68 and in column 9, lines 1-12, the contents of which are hereby incorporated by reference. in the present text.

In some forms of the invention there is a fluorescent compound in the oral preparation. These compounds may be slightly soluble in water or completely water soluble.

They are characterized by their ability to release fluoride ions into water and by their major absence of propensity to react with other compounds in the oral preparation. These materials include inorganic fluoride-alkaline earth metal salts and heavy metal salts, for example salts such as soluble alkali metal salts, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper (I) fluoride, zinc fluoride, a tin fluoride such as tin (IV) II) chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and difluorophosphate and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and u) tin (ID fluorides, sodium monofluorophosphate and mixtures thereof) are preferred.

The amount of fluorescent compound depends to some extent on the type of compound, its solubility and the type of oral preparation or preparation, but it must be a non-toxic amount. In a solid oral preparation, such as a toothpaste or a tooth powder, an amount of such a compound which releases a maximum of about 1% by weight calculated on the preparation is considered satisfactory. Any suitable minimum amount of such compound may be used, but it is preferred to use a sufficient amount of the compound to liberate about 0.005 to 1%, and preferably about 0.1% fluoride ion. In the case of alkali metal fluorides and stannous fluoride, this constituent is usually present in an amount of up to about 2% by weight, based on the weight of the preparation or preparation, and is preferably in the range of about 0.05 to 1%. For sodium monofluorophosphate, the compound may be present in an amount of up to 7.6% by weight, especially about 0.76%.

In a liquid oral preparation, for example a mouthwash, the fluorescent compound is usually present in an amount sufficient to release up to about 0.13%, preferably about 0.0013 to 0.1%, and most preferably about 0.0013 to 0.5% by weight of fluoride ion.

All other materials may be incorporated into the oral preparations of the invention such as whitening agents, preservatives, silicones, chlorophyll compounds, other tartar inhibitors, antibacterial antiplabs and / or ammonia-containing materials such as urea, diammonium phosphate and mixtures thereof. These adjuvants, when used, are incorporated into the compositions in amounts which do not adversely affect desired properties and characteristics.

When preparing the oral compositions of the invention comprising the above-described combination of antibacterial agent and additive in an oral carrier, which usually includes water, it is highly desirable, perhaps even necessary, to administer the additive after the the other constituents (except perhaps a certain part of the water) have been mixed or brought into contact with each other in order to avoid a tendency of this agent to precipitate.

Any flavoring or sweetening agent may also be used. Examples of suitable flavoring or sweetening agents are flavoring oils such as oils of green mint, peppermint, evergreens, sassafras, cloves, thyme, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweeteners include sucrose, lactose, fructose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, APM (aspartylphenylalanine, methyl ester), saccharin and the like. Suitably flavors and sweeteners together constitute from about 0.01 to 5% or more of the composition.

In the practice of the present invention, the oral composition of the invention, for example a mouthwash or mouthwash, containing the indicated copolymer in an amount effective to inhibit tartar on tooth surfaces, regularly on tooth enamel, preferably from about 5 times per week to about 3 times daily at a pH of about 4.5 to about 9, usually about 5.5 to about 8, and preferably about 6 to 8.

The following working examples further illustrate the nature of the present invention, but it is to be understood that the invention is not limited thereto. Every ___. -f_A ____-_: 10 15 20 448 818 18 amounts and percentages in the description and claims are calculated by weight unless otherwise indicated.

Example gel 1 Inhibition of HAP crystal growth This is calculated using a pH stat method. 1.0 ml of an aqueous solution of .1 x 10-4_M to 1 x 10-5 M of the tartar inhibitor being tested or tested, and 0.1 M of sodium dihydrogen phosphate are placed in a reaction flask with 22 - 23 ml of distilled water under continuous stirring in a nitrogen atmosphere. To this is added 1 ml of 0.1 M CaCl 2 and the pH is adjusted to 7.4 l 0.05 with NaOH (final concentration of Ca 2+ and PO 43 +; 4 x 10 -3 M). The consumption of 0.1 N NaOH is automatically recorded by means of a pH state (Radiometer). In this test, the formation of HAP takes place in two distinct phases.

First, fast base consumption (1 - 4 min) is observed, which then decreases, and after 15 - 20 minutes, a second fast uptake takes place. A delay in time with respect to the second fast consumption, or a total absence of this second fast consumption, indicates interference with the crystal growth of HAP. Agents that interfere with the crystal growth of HAP are effective tartar inhibitors. When examined according to the method described, the following results are obtained. m 10 20 30 4118 8'I8 19 Table I Tartar inhibitors Time (min) for Delay (min) (conc) HAP formation for HAP formation (a) Water (control) 21.0 - (b) Copolymer 9 / 1 (20 ppm) 30.0 9.0 (c) "(21 ppm) 40.0 19.0 (d)" (27 ppm) 87.0 66.0 (e) "(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 o (i) Copolymer 3/7 (40 ppm) 21,0 0 (j) Copolymer G / L / T (32 ppm) 21,0 0 (k) slu / 'ryš 1/1 (z x1o -4) 18.0 o (l) Glu / Ala / Tyr 1/1/1 (32 ppm) 21.0 (m) Tyr (32 ppm) 18.0 0 The copolymers tested as above were prepared by copolymerization of alpha-amino acid anhydride mixtures according to the procedure described in "Immunochemistry", indicated above. Copolymer 9/1, illustrating the invention, was prepared from a 9: 1 molar ratio of glutamic acid and tyrosine and determined by centrifugation have a molecular weight of about 19,300. The copolymer 6/3/1, also the illustrative invention, was prepared of a 6: 3: 1 molar ratio of glutamic acid, alanine and tyrosine, and was determined to have a molecular weight of about 90,800. The remaining copolymers have been included for comparative purposes. Thus, copolymers 7/3, 1/1 and 3/7 were prepared from mixtures containing proportions of glutamic acid: tyrosine outside those required by the invention, i.e. in molar ratios of 7: 3, 1: 1 and 3: 7. The copolymer G / L / T was prepared from a 1: 1: 1 molar mixture of glutamic acid, lysine and tyrosine. The agents tested in (k), (1) and (m) were monomers or monomer mixtures including glutamic acid, tyrosine and / or alanine, the mixtures containing equal molar amounts of the monomer components.

The results shown in Table I simply illustrate the effective inhibition provided by the copolymers of the invention in (b), (c), (d), (e) and (f) of the crystal growth of HAP in vitro and shows that the inhibition is not due to complex or chelating of calcium, since substoichiometric ratios of copolymer calcium were used. The failure of comparative compounds (g) to (m) to inhibit HAP formation underscores the crucial and critical importance of selecting the components and ratios thereof in the present copolymers in order to achieve the unexpectedly improved inhibition of HAP according to the invention.

In the following working examples, illustrating mouthwash compositions of the present invention, PLURONIC F 108 is a polyoxyalkylene block polymer.

Example 2 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 0.03 Copolymer 6/3/1 0.1 0.2 0.5 1.0 Water qs to 100 100 100 100 u: 10 15 20 25 30 Example 6.

Toothpaste Glycerin 21 Carboxymethylcellulose Sodium benzoate Na-saccharin Silica Sodium lauryl sulphate Flavor Copolymer 9/1 Water up to 448,818 Weight percent 25, 1, 0, 0, 30, 1, 0 3 5 2 0 5 1.0 3.0 100 The following Table II shows mouthwash according to the present invention and the inhibitory effect of the present copolymer additives. the properties are evaluated by staining, given the tooth stain of the preparation - slurrying hydroxyapatite (Biogel), a special saliva protein, a carbonyl source (for example acetaldehyde) and a phosphate buffering agent for pH 7 with or without the mouthwashes tested. The mixture is shaken at 37 ° C for 18 hours. The colored HAP powder is separated by filtration, dried and the color levels (in reflection units) are determined on a Gardner color difference meter.

Table II.

Mouthwash Placebo Control Example 7 8 9 10 Ethanol 10% 10% 10% 10% Glycerin 10 10 10 10 Flavor 0.146 0.146 0.146 0.146 Saccharin 0.03 0.03 0.03 0.03 PLURoNIc 01081 3.0 3.0 3, 0 3.0 cpcz 0.1 0.1 0.1 Copolymer 9/13 0.1 0.2 Water, qs to 100 100 100 100 pH (with 1N NaOH) 7.0 7.0 7.0 7.0 Reflection 70.7 41.8 57.7 56.0 Difference - +28.9 -15.9 -14, 2 Rd relative to (2) LJI 10 15 20 to KJ 448 818 22 1. Polyoxyalkylene copolymer (BASF-Wyandotte) 2. Cetylpyridine chloride 3. Prepared according to the procedure of "Immunochemistry", supra, for copolymerizing a mixture in a molar ratio of 9: 1 of glutamic acid and tyrosine, the molecular weight of the copolymer being determined by centrifugation to be about 19,300.

The above results simply show that the copolymer additives of the present invention significantly reduce the staining of the teeth usually caused by the cationic, quaternary, antibacterial and anti-plaque ammonium compounds exemplified by CPC.

Furthermore, in vitro tests show that the anti-plaque action of Examples 8 and 9 is substantially the same, indicating that the copolymer additives of the invention significantly affect the anti-plaque action of CPCs and similar compounds.

If equivalent amounts of the following antibacterial anti-plaque agents are allowed to replace the compound CPC, used in Examples 3 and 4, preparations are obtained which also cause an unexpected reduction in staining on the teeth.

Examples Antibacterial antiplaque compound 10 benzthonium chloride (BC) 11 chlorhexidine diacetate 12 chlorhexidine digluconate 13 dodecyltrimethylammonium bromide çH2CH2OH // CHZCHZOH 14 (11248 a1ky1-N-cH2cH2N

Exemgel (parts) 16 17 18 Hydrated alumina 30 30 30 Glycerin 16 16 16 Sorbitol (70%) 6 6 6 PLURONIC F108 3 3 3 Hydroxyethylcellulose 1,2 1,2 1,2 BC 0,5 - ~ Chlorhexidine digluconate (20%) ~ 4,725 - CPC - - ~ Copolymer 6/3/1 * 0.08 0.5 1.0 Sodium saccharin 0.17 0.17 0.17 Flavor 0.8 0.8 0.8 Water qs to 100 100 100 * Prepared according to the method described in immunochemistry "mentioned above, for copolymerizing a mixture in the molar ratio of 6: 3: 1 of glutamic acid, alanine and tyrosine, the resulting copolymer according to the invention being determined to have a molecular weight of about 90 800.

The present invention has been described with respect to preferred embodiments thereof, and it is to be understood that modifications and variations thereof, apparent to those skilled in the art, may be made without departing from the scope of the invention as set forth in the appended claims.

Claims (12)

10 15 20 25 448 818 24 P a t e n t k r a v An oral composition having a pH of 4.5 to 9 comprising an orally acceptable vehicle, containing 0.01 to 10% by weight of a tartar inhibitor, characterized in that said tartar inhibitor is a copolymer consisting essentially of of: (A) n units having the molecular structure of units derived from glutamic acid, (B) m units having the molecular structure of units derived from alanine, and (C) p units having the molecular structure of units derived from tyrosine, wherein the ratio (n + m): p is in the range from 5: 1 to 9.5: 1 and the ratio m: n is in the range from 0: 1 to 0.6: 1, and the molecular weight of the copolymer is in the range from 5,000 to 150,000. 2. A composition according to claim 1, characterized in that the ratio n: m: p in the copolymer is 9: 0: 1 and the copolymer has a molecular weight of 17,000 to 21,000. 3. A composition according to claim 1, characterized in that the ratio n: m: p in the copolymer is 6: 3: 1 and the copolymer has a molecular weight of 80,000 to 100,000. 4. A composition according to claims 1, 2 or 3, characterized in that it further contains 0.001 - 15% by weight of at least one cationic, nitrogen-containing antibacterial anti-plaque compound, based on its free base form. An oral composition according to claim 4, characterized in that the antibacterial anti-plaque compound is present in an amount of 0.01 to 5% by weight. Composition according to any one of claims 4 or 5, characterized in that the antibacterial anti-plaque compound is a substituted guanidine. Composition according to claim 6, characterized in that the antibacterial antiplaque compound is a pharmaceutically acceptable, water-soluble salt of a compound selected from the group consisting of chlorhexidine and alexidine. Composition according to any one of Claims 4 or 5, characterized in that the antibacterial compound is benzethonium chloride. 9. A composition according to any one of claims 4 or 5, characterized in that the antibacterial anti-plaque compound is a quaternary ammonium compound containing 1 to 2 alkyl groups having 8 to 20 carbon atoms. 10. A composition according to claim 9, characterized in that the antibacterial antiplaque compound is cetylpyridine chloride. 11. ll. Composition according to any one of claims 1 to 10, characterized in that it is a mouthwash with a vehicle of water-alcohol. 4-48 818 26 Composition according to any one of claims 1 to 10, characterized in that it is a toothpaste comprising a liquid vehicle, a gelling agent and a dentally acceptable polish.