NZ199305A

NZ199305A - Oral anticalculus composition

Info

Publication number: NZ199305A
Application number: NZ199305A
Authority: NZ
Inventors: A Gaffar
Original assignee: Colgate Palmolive Co
Priority date: 1980-12-31
Filing date: 1981-12-17
Publication date: 1984-07-31
Also published as: AU7886781A; FR2497097A1; SE448818B; AR228295A1; ES508439A0; GB2092000B; NL8105896A; NO155527C; ATA563081A; ES8302033A1; KR880001750B1; GB2092000A; FR2497097B1; AT377696B; PH18856A; NO155527B; NO814477L; PT74225B; CA1175358A; DE3151217A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 99305 1993 05 AMENDED under Section S <? <sf the PKWts Act 1953 fror/.^Al ASSIStXfjT COMMISSIONER OF PATENTS Priority Date(s): 3.\; &1 .3, VV&? . Complete Specification Fifed: Class: . Publication Date: P.O. Journal, (*Jo: .. !?-£j0. arm-iiw Patents Form No. 5 Number PATENTS ACT 1953 Dated COMPLETE SPECIFICATION ORAL COMPOSITION $We COLGATE-PALMOLIVE COMPANY of 300 Park Avenue, New York, New York 10022, United States of America, a corporation organised under the laws of the State of Delaware, United States of America do hereby declare the invention for which Ji/we pray that a Patent may be granted to ook/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - 1 993 This invention relates to oral compositions containing an anticalculus agent. Calculus is a hard, mineralized formation which forms on the teeth. Regular brushing prevents a rapid build-up of these deposits, but even regular brushing is not sufficient to remove all of the calculus deposits which adhere to the teeth. Calculus is formed on the teeth when crystals of calcium phosphates begin to be deposited in the pellicle and extracellular matrix of the dental plaque and become sufficiently closely packed together for the aggregates to become resistant to deformation. There is no complete agreement on the route by which calcium and orthophosphate ultimately become the crystalline material called hydroxyapatite (HAP). It is generally agreed, however, that at higher saturations, that is, above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate. "Amorphous calcium phosphate" although related to hydroxyapatite differs from it in atomic structure, particle morphology, and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks typical of amorphous materials, which lack the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. It is apparent therefore that agents which effectively interfere with crystalline growth of hydroxyapatite will he effective as anticalculus agents. A suggested mechanism by which the anticalculus agents of this invention inhibit calculus formation probably involves an increase of the activation energy barrier thus inhibiting the transformation of precursor amorphous calcium phosphate to hydroxyapatite. Studies have shown that there is a good correlation between the ability of a compound to prevent hydroxyapatite crystalline growth in vitro and its ability to prevent calcification in vivo. ^ ■ 199305 A substantial number of different types of compounds and compositions have been developed for use as antibacterial, and antiplague and anticalculus agents in oral compositions, including for example such cationic materials as the bisbiguanide compounds and quaternary ammonium compounds, e.g. benzethonium chloride and cetyl pyridinium chloride, disclosed in U.S. 4,110,429. Other such materials have been found to be unstable in the presence of anionic surface active agents often present in conventional oral compositions. It is an object of this invention to provide an oral anticalculus composition which will be less subject to one or more of the above deficiencies than known oral anticalculus compositions. In accordance with certain aspects, this invention relates to an oral composition comprising an orally acceptable vehicle con- 10 199305 taining in an effective amount as an anticalculus agent a copolymer consisting essentially of: a) n units having the molecular configuration of units derived from glutamicacid, b) m units having the molecular configuration of units derived from alanine, and c) p units having the molecular configuration of units derived from tyrosine, the ratio of (n + m) : p ranging from about 5 : 1 to about 9.5 : 1 and the ratio of m : n ranging from 0 : 1 to about 0.6 : 1, the molecular weight of the copolymer ranging from about 5,000 to about 150,000. The afore-mentioned copolymers may be prepared in well known manner, as for example by the procedure disclosed in Chase 15 and Williams "Immunochemistry", Vol. 2, pp 168, 169 (1978) Academic Press. In general, the copolymers are prepared by random copolymerization of the N-carboxyanhydrides of glutamic acid, tyrosine and alanine in the required molar proportions in the form of a mixture in an organic solvent such as dioxane, benzene, dimethyl formamide or N-methyl pyrrolidone and in the presenoeof an initiator such as an organic amine (e.g. trie-thylamine) or sodium methoxide. The (A) units in the copolymer may be depicted as having the structural formula: 20 25 (A) HN - CH - CH0CH_, - CO- I COOH n being a numerical value representing the number of (A) units of glutamic acid in the copolymer. 30 The (B) units in the copolymer may be depicted as having the structural formula: -4- 10 15 20 25 30 1 O Q 7 r; r i//juj (B) HN - CH - CO L m m being a numerical value representing the number of (B) units of alanine in the copolymer. The (C) units in the copolymer may be depicted as having the structural formula: (C) HN CH - CO CH, ? OH p being a numerical value representing the number of (C) units of tyrosine in the copolymer. As defined above, the ratio of (n + m) : p ranges from about 5 : 1 to about 9.5 : 1, the ratio of m : n ranges from 0 : 1 to about 0.6 : 1 and the values of m, n and p are such that the copolymer has a molecular weight of about 5,000 to about 150,000, preferably about 17,000 to about 100,000. Especially preferred copolymers are a two component copolymer containing glutamic (A) units and tyrosine (B) units in a ratio of about 9 : 1 and having a molecular weight of about 17,000 to about 21,000, and a three component copolymer containing glutamic (A) units, alanine (B) units and tyrosine (C) units in a ratio of about 6:3:1 and having a molecular weight of about 80,000 to about 100,000. It will be understood that the free acid form of the copolymers employed herein may be converted to, and employed, in their equivalent salt form by treatment with any base containing an orally acceptable cation such as alkali metal (e.g. sodium or potassium), ammonium, C1_lg mono-, di- or tri-substituted ammonium (e.g. alkanol substituted such as mono-, -5- I 9 93 0 S di- or tri-ethanolammonium), organic amines, etc. It will also be understood that when referring to these copolymers as being water soluble such copolymers should be water soluble or readily water dispersible in the concentrations employed 5 in conventional oral compositions such as mouthwashes, toothpastes and the like. The copolymers employed in accordance with this invention are peculiarly advantageous oral anticalculus agents. Bearing in mind that human saliva contains natural inhibitors of 10 calcium and phosphate precipitation including glutamic acid and tyrosine, the instant copolymers are relatively safe to use even if ingested since they are readily hydrolyzed in the stomach by chymotyprin, a proteolytic enzyme known to hydrolyze tyrosine. In contrast, other non-hydrolyzable 15 anticalculus agents when absorbed in the G.I. tract could cause changes in the bone. These copolymers are additionally advantageous in being substantive or oral surfaces. The concentration of these copolymer anticalculus agents in oral compositions can range widely, typically upwards of 20 about 0.01% by weight with no upper limit except as dictated by cost or incompatibility with the vehicle. Generally, concentrations of about 0.01% to about 10.0%, preferably about 0.1% to about 8.0%, more preferably about 0.5% to about 5.0% be weight are utilized. Oral compositions which in the ordinary 25 course of usage could be accidentally ingested preferably contain concentrations in the lower portions of the foregoing ranges. 30 t 993 Cationic nitrogen-containing antibacterial materials are well known in the art. See, for instance the section on "Quaternary Ammonium and Related Compounds" in the article on "Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia of Chemical Technology, second edition (Vol. 2, p. 632-635), incorporated herein by reference. Cationic materials which possess antibacterial activity (i.e. are germicides) are used against bacteria and have been used in oral compositions to counter plaque formation caused by bacteria in the oral cavity. Among the most common of these antibacterial "" anti-plaque quaternary ammonium compounds is benzethonium chloride, also known as Hyamine 1622 or diisobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride. In an oral preparation this material is highly effective in promoting oral hygiene by reducing formation of dental plaque and calculus, which is generally accompanied by a reduction in caries formation and perio4ontal diseases. Other cationic antibacterial agents of this type are those mentioned, for instance, in U. S. Patent Nos. 2,984,639, 3,325,402, 3,431,208 and 3,703,583 and British Patent No. 1,319,396. Other 1 antibacterial antiplaque quaternary ammonium compounds include those in which one or two of the substituents on the quaternary nitrogen has a carbon chain length (typically alkyl group) of some -7- m 10 0 7 AR I//JUJ 8 to 20, typically 10 to 18, carbon atoms while the remaining substituents have a lower number of carbon atoms (typically alkyl or benzyl group), such as 1 to 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, dodecyl dimethyl (2-phenoxy-ethyl) ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and guaternized 5-amino-l, 3-bis (2-ethyl-hexyl)-5-methyl hexa hydropyrimidine are exemplary of other typical quaternary ammonium antibacterial agents. which are desirably incorporated in oral compositions to promote oral hygience by reducing plaque formation are .the amidines such as the substituted quanidines e.g. chlor-hexidine and the corresponding compound, alexidine, having 2-ethylhexyl groups instead of chlorophenyl groups. Additional substituted guanidines are: N1-(4-chlorobenzyl)-N^-(2,4-dichlorobenzyl) biguanide; p-chlorobenzyl biguanide, 4-chlorobenzhydryl guanylurea; N-3-lauroxypropyl-N^-p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; and N-p-chlorophenyl-N^-laurylbiguanide. antibacterial and antiplaque activity. Such antibacterial agents include tertiary amines having one fatty alkyl group (typically 12 to 18 carbon atoms) and 2 poly(oxyethylene) groups attached to the nitrogen (typically containing a total of from 2 to 50 ethenoxy groups per molecule) and salts thereof with acids and compounds of the structure: where R is a fatty alkyl group containing 12 to 18 carbon atoms and x, y and z total 3 or higher, as well as salts thereof. Generally, cationic agents are preferred for their antiplaque effectiveness. Other types of cationic antibacterial agents The cationic aliphatic tertiary amines also possess (CH2CH20)yH -8- 99 305 The antibacteiial antiplaque compound is preferably one which has an antibacterial activity such that its phenol co-efficient is well over 50, more preferably well above 100, such as above about 200 or 5 more for S, aureus; for instance the phenol coefficient (A.O.A.C.) of benzethonium chloride is given by the manufacturer as 410, for S. aureus. The cationic antibacterial agent will generally be a monomeric (or possibly dimeric) material molecular weight well below 10 2,000, such as less than about 1,000. It is, however, within the broader scope of the invention to employ a polymeric cationic antibacterial agent. The cationic antibacterial is preferably supplied in the form of an orally acceptable salt thereof, such as the chloride, 15 bromide, sulfate, alkyl sulfonate such as methyl sulfonate and ethyl sulfonate, phenylsulfonate, such as p-methylphenyl sulfonate, nitrate, acetate, gluconate, etc. The nitrogen-containing cationic antibacterial 20 agents (including the tertiary amine) antibacterial agents effectively promote oral hygiene, particularly by removing plaque. However, their use has been observed * - ' ■> to lead to staining of dental surfaces or discoloration. The reason for the formation of such dental 25 stain has not been clearly established. However, human dental enamel contains a high proportion (about 95%) of + 2 -3 hydroxyapatite (HAP) which includes Ca and PO^ ions. + 2 -3 In the absence of dental plaque additional Ca and P04 particularly from saliva, can be deposited on the 30 enamel and such deposits can include color bodies which -9- 1 99305 ultimately stain the tooth enamel as a calcified deposit thereon. It cat^e that as the cationic (including the tertiary amine) antibacterial agents remove plaque they also denature protein from saliva in the oral environment and the denatured protein can then act as a nucleating agent which is deposited on and stains or discolors tooth enamel. Previously employed additives which reduced dental staining by cationic antibacterial antiplaque agents also generally reduced the activity of antibacterial antiplaque agents such as bis-biguanido compounds, as by forming a precipitate with such agents. It is a further advantage of this invention that the above-described copolymers are antinucleating agents which unexpectedly inhibit, i.e., prevent or remove, the staining of dental enamel caused by such cationic (including the tertiary amine) antibacterial agents without precipitating or substantially adversely affecting their antibacterial and antiplaque activity. In themselves (even in the absence of such antibacterial agents), these copolymer additives are effective to reduce formation of dental calculus without unduly decalcifying dental enamel, in addition to effectively inhibiting gingivitus. However, not all anti-nucleating agents are effective to prevent staining by such antibacterial agents. Victamide (also known as Victamine C) which is a condensation product of ammonia with phosphoruspentoxide, actually increases staining even in the absence of such antibacterial agents. -X- 10 1 99305 Cationic nitrogen-containing antibacterial antiplaque agents optionally employed in the practice of this invention are described above. When such agents are present they are £ typically employed in amounts such that the oral product contains 5 between about 0.001 and 15$ by weight of the agent. Preferably for desired levels of antiplaque effect, the finished oral product contains about 0.01 to about 5$, and most preferably ^ about 0.25 to 1.0$ by weight of the antibacterial antiplaque agent, referring to its free base form. 10 In certain highly preferred forms of the invention the oral composition may be substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle is typically a water-alcohol mixture desirably including a humectant as described below. Generally, the ratio of water to alcohol is 15 in the range of from about 1:1 to about 20:1, preferably about 3:1 to 10:1 and most preferably about U:1 to about 5:1 by weight. The total amount of water-alcohol mixture in this type of pre-^ paration is typically in the range of from about 70$ to about 99-9$ by weight of the preparation. The pH of such liquid and other 20 preparations of the invention is generally in the range of from about U.5 to about 9 and typically from about 5-5 to 8. The pH is preferably in the range of from about 6 to about 8.0. It is noteworthy that the compositions of the invention may be applied orally at a lower pH without substantially decalcifying dental 25 enamel. The pH can be controlled with acid (e.g. fl citric acid or benzoic acid) or base (e.g*. sodium hydroxide) or buffered (as with phosphate buffers). Such liquid oral preparations may also contain a surface active agent and/or a fluorine-providing compound. 5 In certain other desirable forms of this invention, the oral composition may be substantially solid or pasty in character such as toothpowder, a dental table't, a toothpaste or dental cream. The vehicle of such solid or pasty oral preparations generally contains polishing material. Examples of polishing 10 materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silicate, zirconium silicate, 15 silica, bentonite, and mixtures thereof. Preferred polishing materials include Dical*, colloidal silica, silica gel, complex amorphous alkali metal aluminosilicate and hydrated alumina. Alumina, particularly the hydrated alumina sold by Alcoa as C333, which has an alumina content of 64.9% by weight, a 20 silica content of 0.008%, a ferric oxide content of 0.003%, and a moisture content of 0.37%, at 110°C., and which has a specific gravity of 2.42 and a particle size such that 100% of the particles are less than 50 microns and 84% of the particles are less than 20 microns, is very effective. 25 When visually clear gels are employed, a polishing agent of colloidal silica, 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 aluminosilicate complexes are particularly useful, since they have refractive indices close 30 to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices. * Calcium dihydrogen phosphate -)*- (1 I 9 93 OS Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner, as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 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 materials. These metaphophate salts exhibit a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates. There is present therein a minor amount of soluble phosphate material as impurities, 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 metaphosphate, may be reduced by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than about 1% of the material is larger than about 37 microns. The polishing material is generally present in amounts ranging from about 10% to about 99% by weight of the oral preparation. Preferably, it is present in amounts ranging from about 10% to about 75% in toothpaste, and from about 70% to about 99% in toothpowder. In the preparation of toothpowders, it is usually sufficient to admix mecanically, e.g., by milling, the various solid ingredients in appropriate quantities and particle sizes. In pasty oral preparations the copolymer should be compatible with the other components of the preparation. Thus, in a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10% to about 90% by weight of the preparation. Glycerine, propylene glycol, sorbitol, or polyethylene glycol 400 may also be present as humectants. Particularly advantageous liquid ingredients comprise mixtures of water, glycerine and sorbitol. 199305 In clear gels where the refractive index is an . important consideration, about 3~3°# by weight of water, 0 to about 80# by weight of glycerine, and about 20-80# by „ weight of sorbitol is preferably employed. A gelling agent, such as natural or synthetic gums or gum-like materials, typically Irish moss, sodium carboxymethylcellulose, methyl cellulose, or hydroxyethyl cellulose, may be employed. Other gelling agents which may be employed include gum tragacanth, polyvinylpyrrolidone and starch. They are usually present in toothpaste in an amount up to about 10# by weight, preferably in the range of from about 0.5# to about 5#« The preferred gelling agents are methyl cellulose and hydroxyethyl cellulose. In-a toothpaste or gel, the liquids and solids arc proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible, e.g., aluminum or lead, tube. The solid or pasty oral preparation which typically has a pH measured on a 20# slurry of about ^.5 to 9, generally about 5.5 to about 8 and preferably about 6 to about 8.0, may also contain a surface active agent and/or a fluorine-providing compound. It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable' labelled packages. Thus a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash and having directions for its use; and a toothpaste will usually be in a collapsible tube, typically aluminum,; lined lead or plastic, or other squeeze dispenser for metering out the contents, having a label describing it, in substance, as i toothpaste or dental cream. 1 9 9305 The oral compositions of this invention may contain a non-soap synthetic sufficiently water soluble organic anionic or nonionic surfactant in concentrations generally ranging from about 0.05 to about 10, preferably about 0.5 to about 5> weight percent, to promote wetting, detersive and foaming properties. U.S. Pat. No. U,0Ul,1^9 discloses such suitable anionic surfactants in col. U, lines 31-38, and such suitable nonionic surfactants in col. 8, lines 30-68 and col. 9» lines 1-12, which passages axe incorporated herein by reference thereto. In certain forms of this invention a fluorine-providing compound is present in the oral preparation. These compounds may be slightly soluble in water or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by substantial freedom from reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, Ca fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or stannous chlorofluoride, barium fluoride, sodium fluorsilicate, ammonium fluorosilicate, sodium fluorqzirconate, sodium monofluorophosphate, aluminum mono-and di-fluorophosphate, and fluorinated Bodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, are preferred. The amount of the fluorine-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must -f- 199305 he a nontoxic amount. In a solid oral preparation, such as toothpaste or toothpowder, an amount of such compound which releases a maximum of about 1$ by weight of the preparation is considered satisfactory. Any suitable minimum about of such compound may be used, but it is preferably to employ sufficient compound to release about 0.005$ to 1$, and preferably about 0.1$ of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in an amount up to about 2$ by weight, based on the weight of the preparation, and preferably in the range of about 0.05$ to 1$. In the case of sodium monofluorophosphate, the compound may be present in an amount up to 7.6$ by weight, more typically about 0.76$. In a liquid oral preparation such as a mouthwash, the fluorine-providing compound is typically present in an amount sufficient to release up to about 0.13$, preferably about 0.0013$ to 0.1<|& and most preferably about 0.0013$ to 0.5$, by weight, of fluoride ion. Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds, other anticalculus agents, antibacterial antiplaque agents, and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired. In preparing the oral compositions of this invention comprising the above-defined combination of antibacterial agent and additive in an oral vehicle which typically includes water, it is highly preferred if not essential to add the additive after the other ingredients (except perhaps some of the water) are mixed or contacted with each other to avoid a tendency for said agent to be precipitated. -3^ I £ /?<?3 OS Any suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g., oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, majoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, fructose, maltose, sorbitol,xylitol, sodium cyclamate, perillartine, APM (aspartyl phenyl alanine, methyl ester), saccharin and the like. Suitably, flavor and sweetening agents may together comprise from about 0.01$ to 5$ or more of the preparation. In the practice of this invention an oral composition according to this invention such as a mouthwash or toothpaste containing the defined copolymer in an amount effective to inhibit calculus on dental surfaces is applied regularly to dental enamel, preferably from about 5 times per week to about 3 times daily, at a pH of about U.5 to about 9> generally about 5-5 to about 8, preferably about 6 to 8. The following examples are further illustrative of the nature of the present invention, but it is understood that the invention is not limited thereto. All amounts and proportions referred to herein and in the appended claims are by weight unless otherwise indicated. Example 1 fl« 21 JUL 1983 Inhibition of Crystal Growth of HAP V/f* This is evaluated by a pH Stat method. 1.0 ml of an v--C[! i aqueous solution of 1X10 to 1X10 of the anticalculus agent being tested and 0.1 M sodium dihydrogen phosphate is placed in a reaction flasK with 22 to 23 ml. of distilled water with continuous stirring in an atmosphere of nitrogen. To this is added 1 ml. of 0.1M CaCl2 and the pH adjusted to 7.ht 0.05 with NaOH (final conc. of Ca"1"*" and POj^ =UX10 ). Consumption of 0.1N NaOH is recorded automatically by a pH Stat (Radiometer). In this test, the formation of HAP occurs in 2 distinct phases. First rapid base consumption (1-U min.) then diminishes until 15-20 minutes when second rapid uptake takes place. A delay in the time of second rapid consumption or a total absence -l/- (7 /993CS 10 15 20 25 30 of the second rapid consumption indicates'an interference with the crystal growth of HAP. Agents which interfere with HAP crystal growth are effective anticalculus agents. When tested by the foregoing procedure, the following results are obtained. Table I Anticalculus Agent (conc.) Time (Min.) for Delay (Min.) for HAP Formation HAP Formation (a (b (c (d (e (f (g (h (i (j (k (1 (m Water (Control) Copolymer 9/1 (20 p.p.m.) " (21 p.p.m.) (27 p.p.m.) " (32 p.p.m.) Copolymer 6/3/1 (40 p.p.m.) Copolymer 7/3 (40 p.p.m.) Copolymer 1/1 (1 x 10 ^) Copolymer 3/7 (40 p.p.m.) Copolymer G/L/T (32 p.p.m.) .-4, 21.0 30.0 40.0 87.0 117.0 31.0 21.0 21.0 21.0 21.0 18.0 21.0 18.0 9.0 19.0 66.0 96.0 10.0 0 0 0 0 0 0 0 Glu/Tyr 1/1 (2 x 10 ) Glu/Ala/Tyr 1/1/1 (32 p.p.m.) Tyr (32 p.p.m.) The copolymers tested as above indicated were prepared by copolymerization of alpha-amino acid anhydride mixtures by the procedure described in "Immunochemistry" supra.Copolymer 9/1, illustrative of the invention, was prepared from a 9:1 molar mixture of glutamic acid and tyrosine, and was determined by centrifugation to have a molecular weight of about 19,300. Copolymer 6/3/1, also illustrative of the invention, was prepared from a 6:3:1 molar mixture of glutamic acid, alanine and tyrosine, and was determined to have a molecular weight of about 90,800. The remaining copolymers are comparative. Thus, copolymers 7/3, 1/1 and 3/7 were prepared from mixtures containing proportions of glutamic acid: tyrosine outside those required herein, i.e. in molar ratios of 7:3, 1:1 and 3:7. Copolymer G/L/T /993Q5 10 15 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 proportions of monomer components. The results shown in TABLE I plainly show the effective inhibition by the copolymers of this invention, in (b), (c), (d), (e), and (f), of crystal growth of HAP in vitro, and that the inhibition is not due to complexation or chelation of calcium since sub-stoichiometric ratios of copolymer:calcium were employed. The failure of comparative agents (g) thru (m) to inhibit HAP formation emphasizes the criticality of the instant copolymers, with respect to components and ratios of such components therein, for achieving the unexpectedly improved HAP inhibition of this invention. In the following examples illustrative of mouthwash formulations according to the invention, Pluronic F108 is a polyoxy-alkylene block polymer. 20 Example 3 25 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 Glycerine 10. 0 10. 0 10. 0 10. 0 Na Saccharin 0. 03 0. 03 0. 03 0. 03 Copolymer 6/3/1 0. 1 0. 2 0. 5 1. 0 Water q.s. to 100 100 100 100 19 93 Example 6 Toothpaste Formulation Wt. Percent Glycerin 25.0 5 Carboxymethylcellulose 1.3 Sodium benzoate 0.5 Na Saccharin 0.2 Silica ' 30.0 Sodium lauryl sulfate 1.5 10 Flavor 1.0 Copolymer 9/1 3.0 Water to make 100 15 Table II below is illustrative of mouthwash formulations according to the invention and the antistaining activity of the instant copolymer additive therein. The tooth staining characteristics of the formulations are evaluated by slurrying hydroxyapatite (Biogel), a specific salivary protein, a 2 0 carbonyl source (e.g. acetaldehyde), and a pH 7 phosphate buffer, with and without the mouthwash formulations being 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 reflectance units) determined on a 25 Garnder color difference meter. 7** Xo * ^ NOW V\V;en:O2d 1993 05 TABLE 3P MOUTHWASH FORMULATIONS Example Placebo (7) Control .J!) Ethanol Glycerine Flavor Saccharin 1 Pluronic F108 CPC2 Copolymer 9/1 Water, q.s. to pH (with IN NaOH) Reflectance Difference Kd 10 0.146 0.03 3.0 100 7.0 70.7 10# 10 0.146 0.03 3-0 0.1 100 7.0 41.8 +28.9 ./ 7.0 ■15.9/ -l'l. 2 vrlr>l;1vc l,o (:') 1. PolyoxyalkyIctie block polymer (BASF-Wyandotte) 2. Cetyl pyridinium chloride 3. Prepared by the procedure described in "Immunochemistry" supra for copolymerizing a 9:1 molar mixture of glutamic acid and tyrosine, the copolymer being determined by centrifugation to have a molecular weight of about ly,300. The above results plainly establish that the copolymer additives of the present invention substantially reduce dental staining j ordinarily produced by cationic quarternary ammonia antibacterial antiplaque agents as exemplified by CPC. Further, in vitro tests establish that the antiplaque activity of Examples 8 and 9 are substantially equal, indicating that the copolymer additives of this invention do not significantly effect i the antiplaque activity of CPC and the like. Substitution of/equivalent amounts of the following antibacterial antiplaque agents for the CPC employed in Kxamplec 3 and yield formulations also producing an unexpected reduction in dental staining.- ;> AS AMENDED TABLE K-MOUTHWASH FORMULATIONS Example Placebo (7) Control (8) (9) (10) Ethanol 105* 10# 10# 10# Glycerine 10 10 10 10 Flavor 0.146 0.146 0.146 0.146 Saccharin 0.03 0.03 0.03 0.03 ± Pluronic F108 3.0 3-0 3-0 3.0 CPC2 0.1 0.1 0.1 Copolymer 9/1^ 0.1 0.2 Water, q.s. to 100 100 100 100 pH (with IN NaOH) 7.0 7.0 7.0 7.0 Reflectance 70.7 41.8 57.7 56.0 Difference R'd — +28.9 -15.9 r el a U.i vr -14.2 (.0 (:) 1. Polyoxyalkylene block polymer (BASF-Wyandotte) 2. Cetyl pyridinium chloride 3. Prepared by the procedure described in "immunocheinistry " supra for copolymerizing a 9:1 molar mixture of glutamic acid and tyrosine, the copolymer being determined by centrifugation to have a molecular weight of about ly,300. The above results plainly establish that the copolymer additives of the present invention substantially reduce dental staining ordinarily produced by cationic quarternary ammonia antibacterial antiplaque agents as exemplified by CPC. Further, in vitro tests establish that the antiplaque activity of Examples 8 and 9 are substantially equal, indicating that the copolymer additives of this invention do not significantly effect the antiplaque activity of CPC and the like. Substitution of equivalent amounts of the following antibacterial antiplaque agents for the CPC employed in Kxainplus 9 and 10 yield formulations also producing an unexpected reduction in dental staining. 1 -1 993 05 Example 10 11 12 13 14 15 The following formulations exemplify toothpastes with antiplaque activity and reduced staining. Example (Parts) 16 17 18 Hydrated alumina 30 30 30 Glycerine 16 16 16 Sorbitol (70fo) 6 6 6 Pluronic F-108 3 3 3 Hydroxyethyl cellulose 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 q.s. to 100 100 100 Antibacterial Antiplaque Agent benzethonium chloride (DC) chlorhexidine diacetate chlorhexidine digluconate dodecyl trimethyl ammonium bromide ch2ch2oii cii2cii2oh C10 .o alkyl-N-CH2CH„NN •Lc;~±u ' * ch2ch2oh alexidine dihydrochloride ♦Prepared according to procedure described in "immunochemistry" supra for copolymerizing a 6:3:1 molar mixture of glutamic acid, alanine and tyrosine, the resulting copolymer of the invention being determined to have a molecular weight of about 90,800. It </div>

Claims

<div class="application article clearfix printTableText" id="claims"> f*S V 1 993 05 This invention has been described with respect to preferred embodiments and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be included within the spirit and purview of this application and the scope of the appended claims. /<?<5 3G5" WHAT WE CLAIM IS:

1. An oral composition comprising an orally acceptable vehicle, containing, substantially by weight, 0 to 15% of at least one cationic nitrogen-containing antibacterial antiplaque agent based on its free base form and 0.01 to 10% of a copolymer consisting essentially of: (A) n units having the molecular configuration of units derived from glutamic acid, (B) m units having the molecular configuration of units derived from alanine, and (C) p units having the molecular configuration of units derived from tyrosine, the ratio of (n + m) : p ranging from 5:1 to 9.5:1 and the ratio of m:n ranging from 0:1 to 0.6:1, the molecular weight of the copolymer ranging from 5,000 to 150,000.

2. An oral composition according to claim 1 wherein the ratio of n:m:p in the copolymer is 9:0:1 and the copolymer has a molecular weight of 17,000 to 21,000.

3. An oral composition according to claim 1 wherein the ratio .. of n:m:p in the copolymer is 6:3:1 and the copolymer has a molecular weight of 80,000 to 100,000.

4. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is present in an amount of 0.001 to 15% by weight.

5. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is present in an amount of 0.01 to 5% by weight, based on its free base form.

6. The oral composition of any one of claims 1-5 wherein said antibacterial antiplaque agent is a substituted guanidine.

7. The oral composition of claim 6 wherein said antibacterial antiplaque agent is a pharmaceutically acceptable water soluble salt of an agent selected from the group consisting of chlorhexidine and alexidine.

8. The oral composition of any one of claims 1-5 wherein said antibacterial antiplaque agent is benzethonium chloride.

9. The oral composition of any one of claims 1-5 wherein said antibacterial antiplaque agent is a quaternary ammonium compound containing 1 or 2 alkyl groups of 8 to 20 carbon atoms.

10. The oral composition of claim 9 wherein said antibacterial antiplaque agent is cetyl pyridinium chloride. iW or

11. The oral composition of any one of claims 1-10 which is a mouthwash having a pH of 4.5 to 9 comprising an aqueous-alcohol vehicle.

12. The oral composition of any one of claims 1-10 which is a toothpaste having a pH of 4.5 to 9, comprising a liquid vehicle, a gelling agent, and a dentally acceptable polishing agent.

13. The method of preparing a composition as defined in any one of claims 1-12 comprising adding the copolymer to a mixture of the other ingredients thereof optionally except for some water. 'WEST-WALKER, fflcCAEE „ /C- attorneys for T' E a i -26- </div>