CA1175358A - Oral composition - Google Patents

Abstract

ORAL COMPOSITION

ABSTRACT OF THE DISCLOSURE

An oral composition effective to promote oral hygiene containing a copolymer of glutamic acid, tyrosine and optionally alanine and 0 to about 15% by weight of at least one nitrogen containing cationic anti-bacterial antiplaque agent based on its free base form.

Description

iL1~`~i35i~ ~

mi8 invention relates to oral composition~ containing an anticalculus agent.
C&lculus is a hard, mineralized formation which forms on the teeth. Regular brushing prevent~ a rapid build-up of these deposlts, but even regular brushlng 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 microcrystQlline calcium phosphate.
"Amorphous calcium phosphate" although related to hydroxyapatite differs ~rom it in atomic structure, particle morphology, and stoichiometry. me X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks typic~l of a~orphous materials, wh~ch lack the long-range atomic order characteristic of all crystalline materisls, including hydroxyapatite. It is apparent therefore that agents which efPectively interfere with crystalline grcwth of hydroxyapatite will be e~fective as anticalculus agents. A
suggested mechanism by which the anticalculus agents of this inven-tion inhibit calculus for~ation probably involves an increase of the activation energy barrier thus inhibiting the transformation of precursor ~morphous calcium phosphate to hydroxyapatite.
Studie~ have shown that there is a good correlation between the ability of a compound to prevent hydroxyapatite crystal line growth in vitro and its ability to prevent calcification in vivo.

-2-~a~s3s~ 1 A substantial number of different types of compounds and compositions have been developed for use as antibacterial, and ~nti-plaque and anticalculus agents in oral compositions, including for example such cationic materials as the bisbiguanide compounds and quaternary ammonium compounds, e.g. benzet~onium chloride and cetyl pyridinium chloride, disclosed in U.S. 4,110,429. These cationic materials h~wever tend to stain the teeth with continued use. Further, they exert an antibacterial function which undesirably tends to dis-rupt or destroy the normal micro~lora of the mouth and/or the digestive system. Other such materials have been found to be un-stable in the presence of anionic surface active agents often present in conventional oral compositions.
It is a ~bject of this invention to provide an oral anti-calculus composition which will not be subject to one or more of the above deficiencies.
It is another object of this invention to provide an improved anticalculus oral composition which will have relatively little or no tendency to stain the teeth.
A fu-rther ob~ect of the invention is to provide an oral composition whlch inhibits the transformation of a~orphous calcium phosphate to hydroxyapatite crystal structure normally associated with calculusO
Another object of this invention is the provision of an improvea method for inhibiting the ~ormation of calculus and/or staining of teeth by N-containing cationic antibacterial antiplaque agent~.
A still further object of the invention is the provision of an oral composition containing a nitrogen - containing cationic anti-bacterial antiplaque age m , which composition has a reduced tendency

3 to stain the teeth.
Other ob~jects and advantages will appear as the description proceeds.
In accordance with certain o~ its aspects, this invention relates to an oral composition co~prising an oralLy acceptable vehicle con-~L~753S8 taining in an effective amount at least one cationic nitrogen-containing antibacterial antiplaque agent hased on its free base form and an effective stain-inhibiting amount of a copolymer consisting essentially of ~A~ n units having the molecular configuration of unlts derived from glutamic acid, (s) 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 aforementioned copolymers may be prepared in well known manner, as for example by the procedure disclosed in Chase 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 presence of an initiator such as an organic amine (e.g. triethylamine) or sodium methoxide.
The (A) units in the copolymer may be depicted as having the structural formula:
~. _ _ (A) _ - HN - CX - CH2CH2 - CO-COOH n n being a numerical value representing the number of (A) units I of glutamic acid in the copolymer.

~A 4 -~53~8 The (B) units in the copolymer may be depicted as having the structural formula:

t N CH - CO
CH3 m :. :

~::

::

~ ~ - 4a -m being a numerical value representing the number of (1) units of alanine in the copolymer.
The ~C) units in the copolymer may be depicted as having the struc-tural formula:

(C) - ~ - CH - CO - _ OH P

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 up 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 con-taining 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 ~mderstood 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 acceptabl~ cation such as alkali metal (e.g. sodium or potassium), ammonium, Cl 18 mono-, di- or tri--substituted ammonium (e.g. alkanol substituted such as mono-, 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 in conventional oral compositions such as mouthwashes, toothpastes and the like.

~1~7535~

The copolymers employed in accordance with this invention are peculiarly advantageous oral anticalculus agents. Bearing in mind that human saliva contains natural inhibitors of calcium and phosphate precipita-tion including glutamic acid and tyrosine, the instant copolymers are rela-tively 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 anticalculus agents when absorbed in the G.I. tract could cause changes in the bone. These copolymers are addition-ally advantageous in being substantive to oral surfaces.
; 10 The concentration of these copolymer anticalculus agents in oral compositions can range widely, typically upwards of 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% by weight are utilized. Oral compositions which in the ordinary course of usage could be accidentally ingested preferably contain concentrations in the lower por-tions of the foregoing ranges.
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). 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 accom-panied by a reduction in caries formation and periodontal 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 antibacterial antiplaque quaternary ammonium compounds in-clude those in which one or two of the substituents on the quaternary nitrogen has a carbon chain length (typically alkyl group) of some ~7S358 8 to 20, typically 10 to 18, carbon atoms while the remaining substituents have a lower number o~ 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-phenoxyethyl) ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized 5-amino-1,3-bis (2-ethyl-hexyl)-5-methyl hexa hydropyrimidine are exemplary of other typical quaternary ammonium antibacterial agents.

Other types of cationic antibacterial agents which are desirably incorporated in oral compositions to promote oral hygiene by reducing plaque formation ar`e the amidines such as the substituted guanidines e.g.
chlorhexidine and the corresponding compound, alexidine, having 2-ethylhexyl groups instead o~
chlorophenyl groups and other bis-biguanides such as those described in German patent application No. P

2,332,383 published January 10, 1974, which sets forth ;

20 ~ the followlng formula:

R NH NH NH NH R ' A-~X)z~N~C~NH~C~NH(C~l2)n~NH~~~NH~C- N-(X')zlA' .
in which A and A' signify as the case may be either (1) a ~25 phenyl radical, which as substituent can contain up to 2 alkyl or alkoxy groups with 1 up to about 4C-atoms, a nitro group or a halogen atom, (2) an alkyl group which contains 1 to about 12C-atoms, or (3) alicyclic groups with 4 to about 12C-atoms, X and X' as the case may be may represent an alkylene radical with I-3C atolns, z and z' arc as the case ~7535 53 may be either zero or 1, ~ and R' as the case may be may represent elther hydrogen, an alkyl radical with 1 to about 12C-atoms or an aralkyl radical with 7 to about 12C-atoms, n is a whole number of 2 to inclusively 12 and the polymethylene chain (C~2~ can be interrupted by up to 5 ether, thioether, phenyl-~r naphthyl groups;
these are available as pharmaceutically suitable salts.
Additional substituted guanidines are: N'-(4-chlorobenzyl)-N5-(2,4-dichloroben7yl) biguanide; p-chlorobenzyl biguanide, 4-chlorobenzhydryl guanylurea;
N-3-lauroxypropyl-N5-p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; and N-p-chlorophenyl-N5-laurylbiguanide.

The cationic aliphatic tertiary ~nes also pos~e6s ~antibacterial and antiplaque activity. Such ,~ antibacterial agents include tertiary amines having one Eatty 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 ~25~ ~groups per molecule) and salts thereof with acids and compounds of the structure:.

~'" 'J /(CH2CH2O)zH /(CH2CH2O)xH

(CH2CH2O)yH

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 ~or their anl:ipl.aque e~ectivencs-..

-r~

'l'he antibactelial 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 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 catlonic antibacterial agent. The cationic antibacterial is preferably supplied in the form of an orally acceptable salt thereof, such as the chloride, lS bromide, sulfate, alkyl sulfonate such as methyl `sulfonate and ethyl sulfonate, phenylsulfonatet such as p-methylphenyl sulfonate, nitrate, acetate, gluconate, ; etc.

~ The nitrogen-containing cationic antibacterial agents (in^cluding the tertiary amine) antibacterial ; ~ agents effectively promote oral hygiene, particularly b~
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 stain has not been clearly established. However, human dental enamel contains a high proportion (about 95%) of hydroxyapatite (HAPj which includes CA~2 and PO4 3 ions.
In the absence of dental plaque ad~itional Ca~2 and PO4 3 particularly from saliva, can be deposited on the enamel and such deposits can include color bodies which ~53S~3 ultimately stain the tooth enamel as a calcified depogit thereon.
It ca~ e that as the cationic (including the tertiary amine) ant~-bacterial agents remove plaque they also denature protein from saliva in the oral environment and the denatured protein c~n then act QS 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 o~ 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-deæcribed copolymers are antinucleating agents~hich 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 affeoting their antibacterial and antiplaque activity. In themselves (even in the ab~ence of such antibacterial agents), these copolymer additives are effective to reduce formation of dental calculus without unduly decalcifying dental enamel9 in addition to effectively inhibiting gingivitus. However, not all anti-~ucleating 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.

;

~L~7S3~i8 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 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 5~0, and most preferably about 0.25 to l.O~o by weight of the antibacterial antiplaque agent, referring to its free base form.
In certain highly preferred forms of the invention the oral compositlon may be substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle is typically a water-alcohol mixture deæirably including a humectant as described below. Generally, the ratio of water to alcohol is ~ ln the~range of ~ro~ 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.
t The total amount of water-alcohol mixture in this type of pre-paration 18 typically in the range of from about 7 ~0 to about 99.9~0 ; by weight of the preparatlon. The pH of such liquid and other ; ~20 ~ ~ preparations Or the invention i: generally in the range of from about 4~.5~to about 9 and typically from about 5.5 to 8. The pH
is pre~erably in the range of from about 6 to about 8.o. It is , noteworthy that the compositions of the invention may be applied orally~a~ a lawer pH without substantially decalcifyine dental 25e~a~el. The pH ca~ be controlled with acid (e.g.

~: .

~ -12-S35~51 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.
In certain other desirable forms of this invention, the oral com-position may be substantially solid or pasty in character such as toothpowder, a dental tablet, a toothpaste or dental cream. The vehicle of such solid or pasty oral preparations generally contains polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium meta-phosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, tri-magnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silica~e, zirconium silicate, silica, bentonite, and mixtures thereof. Pre-ferred polishing materials include Dical (Calcium dihydrogen phosphate), 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 silica content of 0.008%, a ferric oxide content of 0.003%, and a moisture content of 0.37%, at llO 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.
~ hen 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 to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices.
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 ~.

117S3~3 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 metaphosphate salts exhibit a minute solubility in water, and there-fore 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 mate-rial 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 mechanically, e.g., by milling, the various solid ingredients in appro-priate quantities and particle sizes.
In pas~y 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 humec-tants. Particularly advantageous liquid ingredients comprise mixtures of water, glycerine and sorbitol.

7S3S~il ln clc.lr gcls whc~c thc rerractivc indcx is an iml)or1;arlt consideration, about 3-30y' by weight of water, O
to about ~0~0 by wei~ht of glycerines and about 20-80% by ~
weight o~ sorbitol is preferably employed. A gelling agent, such as natural or synthetic ~ums or gum-like materials, typically lrish moss, sodium carboxymethylcellulose, methyl cellulose, or hydroxyethyl cellulose a may be employed.
Other gelling ager.ts which may be employed include gum tragacanth, polyvinylpyrrolidone and starch. They are usually present in toothpaste in an amount up to abou-t 10% by weight, preferably in the range of from about 0.5~ to about 5%. The prefe~rred gelling agents are methyl cellulose and hydroxyethyl cel1ulose. In a toothpaste or ~el, the liquids and sol;ds arc I)roportioned to ~orm a creamy or gelled mass which is extrudable i`rom a pressurized container or from a collapsible 3 c.g., nluminum or lead, tube.
The solid or pasty oral preparation which typically has a pH measured on a 205' slurry of about 4.5 to 9, generally about ~,5 to about 8 and preferably about 6 2~ 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 subF,tance, as a toothpaste or dental cream.

"

:~iL17S3~

The oral compositions of this invention may contain a non-soap syn-thetic 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 foam-ing properties. U. S. Patent No. 4,041,149 discloses such suitable anionic surfactants in col. 4, lines 31-38, and such suitable nonionic surfactants in col. 8, lines 30-68 and col. 9, lines 1-12.
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 mate-rials 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 fluorosilicate, ammonium fluorosili-cate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium mono-~ fluorophosphate 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 pre-paration, but it must 131753S~3 be a nontoxic amount. In a ~olid oral prep~ration, ~uch as tooth-paste or toothpowder, an amount o~ such compound which releases a maximum of about 1~ by weight o~ the preparation iB con~idered satisfactory. Any suitable minimum about of such compound ~ay be used, but it is preferably to employ ~uf~icient compcund to release about 0.005% to 1~, and pre~erably about 0.1% o~ fluoride ion.
Typically, in the cases oP alkali metal ~luorides and stannou~
fluoride, this component is present in an amount up to about 2%
by weight, ba~ed on the weight of the preparation, and preferably ln the range Or about 0.05% to 1~. In the case of sodium mono-~luorophosphate, the compound may be present in an a~ount up to 7.6% by weight, more typically about o.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 ionO
Various other materials may be incorporated in the oral preparations o~ this invention such as whitening agents, preservatives; silicones, chlorophyll compounds, other anticalculus Qgents, antibacterial antiplaque agents, and/or ammoniated ~Qterial such as urea, dia~monium pho~phate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in a~ounts which do ', not substQntially adversely affect the properties and char~cteristics desired.
In preparing the oral ccmpositions of this invention comprising the above-defined combination of antibacterial ~gent and additive in an oral vehicle which typically includes water, it is highly preferred if not essential to add the additive after the other ingreaients (except perhaps some of the water) ~re mixed or contacted ~ith each other to avoid a tendency ~or ~aid agent to be precipitat~d.

~l~S358 Any suitable flavoring or sweetening material may al80 be e~ployed. Exa~ples of suitable ~lavoring or sweetening material may also be employed. Example9 of suitable flavoring con~tituenks are ~lavoring olls, e.g., oils of spearmint, peppermint, wintergreen, 6assafras, clove, sage, eucalyptus, major~m, cinnamon, lemon, and orange, and ~ethyl salicylate. Suitable sweetening agents include sucrose, lactose, fructose, maltose, sorbitol,xylltol~ sodium cyclamate, perillartine, APM (aspartyl phenyl alanine, ~ethyl ester), saccharin and the like. Suitably, ~lavor and sweetening ~gents 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 t~is invention such as a mouthwash or toothpaste containing the defined copolymer in an a~oNnt effective to inhibit calculus on dental sur~aces is applied regularly to dental enamel, preferably ~rom about 5 times per week to about 3 ti~es dally, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, prefer-ably about 6 to 8.
The ~ollowing 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 ~re by weight unless otherw~se indicated.
Ex~m~le Inhibition oX Crystal Groith of HAP
This is evaluated by a pH Stat method. 1.0 ~1 of an aqueous solution of IX10 4M to lX10 ~ of the antic~lculus 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 at~osphere of nitrogen. To thifi i3 added 1 ml. of O.IM
CaC12 and the pH ad~usted to 7.4+~ 0.05 with NaOH (final conc. of Ca~+
and P043 =4X10 ~ ) Consumption of O.lN NaOH is recorded automatically by ~ pH Stat (Radiometer). In thiQ te~t~ the formation o~ HAP occurs in 2 distinct phase~. First rapid base consumption (1-4 min.3 then diminishes unt~l 15-20 mlnutes when second rapid uptake take~ place.
A delay in the time o~ second rapid consu~ption or a total absence 1~535i~
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 Time ~Min.) for Delay (MinO) for (conc.) _ HAP Formation HAP Formation ~a) Water (Control) 21.0 --(b) Copolymer 9/1 (20 p.p.m.) 30.0 g.o (c) " (21 p.p.m.) 40.0 19.0 (d) " ~27 p.p.m.) 87.0 66.0 ~e) " ~32 p.p.m.) 117.0 96.0 ~f) Copolymer 6/3/1 (40 p.p.m.) 31.0 10.0 ~g) Copolymer 7/3 ~40 p.p.m.) 21.0 0 (h) Copolymer 1/1 (1 x 10 4) 21.0 (i) Copolymer 3/7 (40 p.p.m.) 21.0 0 (j) Copolymer G/L/T (32 p.p.m.) 21.0 (k) Glu/Tyr 1/1 (2 x 10 4) 18.0 0 ~1) Glu/Ala/Tyr 1/1/1 ~32 p.p.m.) 21.0 0 ~m) Tyr ~32 p.p.m.) 18.0 0 The copolymers tested as above indicated were prepared by copoly-merization 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 deter-mined 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 mix-tures containing proportions of glutamic acid: tyrosine outside those re-~L7S3S15 quired herein, i.e. in molar ratios of 7:3, 1:1 and 3:7. 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 in-cluding 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 cry-stal growth of HAP in vitro, and that the inhibition is not due to complexa-tion 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 emphasi~es the criticality of the instant copolymers, with respect to components and ratios of such components therein, for achiev-ing the unexpectedly improved HAP inhibition of this invention.
In the following examples illustrative of mouthwash formulations according to the invention, Pluronic F108 is a polyoxyalkylene block polymer.
Example :
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 Saccharin0.03 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 ~ :

*Trade Mark - 20 -75358 ,~

I~.xa~l e G
'roothpaste ~ormulation l~t. Percellt Glycerin 25.0 Carboxymethylcellulose 1.3 Sodium benzoate ~ 5 Na Saccharin 0.2 Sil1ca 30 ~

Sodium lauryl sulfate 1.5 Flavor 1.0 Copolymer 9/1 3 0 Water to make lO0 -.

~ ~ Table ~ below is illustrative of mouthwash formulations according to the invention and the antistaining activity of the instant copolymeradditive therein. The tooth staining characteristics of the : : : . :
formulations are evaluated by slurrying hydroxyapatite~20 ~ ~ (Blogel), a~pecific salivary protein, a carbonyl source (e.g. acetaldehyde), and a pH 7 phosphate buffer, with and with~ut ~the mouthwash formulations being tested.

; The ;mlxture is~ shaken at 37C. for 18 hours. The colored HAP powder is separated by filtration, dried and 25~ ~ the color levels (in reflectance units) determined on a ::
~ Gardner color difference meter.

:

.

:

,J .
S3S~

MOUTHWASH FO~ULATIONS

Placebo Control Exam~le (7~ 18~ ~9~ ~0 L ~ L _ ~thanol lO~ - lO~ lO~ lO~

Glycerine lO lO lO lO

F'lavor 00146 0.146 0.1)-~6 0.14 Saccharin 0.03 0.03 0 03 0.03 Pluronic Fl08 3.0 3.0 3.0 3.0 cpc2 0.1 .~ 0.1 Copolymer 9/13 O.l 0.2 Wa~er, q.s. to lOO lOO lOO lOO

pll (with lN Na~II? 7.0 7.0 7.0 7.0 ~eflectance 10.7 41.o 57.7 56.o ~ifference -- ~28.9 -15.9 -11l.2 d ~ v 1. l'oly:~yalkyl~lle block ~olymer (~A~l-Wyall~o~e) :: 2. Ce~yl pyrir~inium chloride ~ ~3.: Prie~ared by the procedure described in "Immunocilemistry" supra 20: ~for copolymerizing a 9:l molar mixture of glutamic .lCid al1d :~ : tyrosine, the copolymer being determined by centrilugatio11 to ~have~a molecular weight Or about 1~,300.

The above results plainly establish that the copolymer addi-tives of the present invention substantially reduce dental s~aining : ~ ~: : . .,,:
~25 -~ ;ordi~narily~produce~ by cationlc 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 antlplaque activity of CPC and the like.
Substitution of equivalent amounts of the followirln; anti- :
l1acterIal ~ntiplslque ag~el1ts for t~lc CP~ el11ployed in l~"~alllple5 3 and l yield formulations also producing an unexpected re~uction i dental stainin~.

X~ltlE~
l~enzetllolliulll cllloride (~,C) 12 chlorllexidine diacetate . chlorhexidine di~luconate 13 dodecyl trilnethyl ammonium ~romide C~2CTI2011 ~C~I2( 1I2()~I
1~ . C12 1~3 alkYl-N-C~2C~l2N ~

o 15 alexidine dihydrochloride The following formulations exemplify toothpastes with anti-plaque activity and reduced staining.

Example (Parts ?

Hydrated alumina 30 30 30 Glycerine 16 1~ lG
Sorbitol (70~) 6 6 ': Pluronic ~l-108 3 3 3 .
Hydroxyethyl cellulose 1.2 1.2 1.2 C 0.5 ; : ; Chlorhexidine-digluconate (20~ 40725 --~: I
CPC :~
~; Copolymer 6/3/1* o.o8 o. 5 1.o ~ Sodlum~saccharin~ 0.17 0.17 0.17 ~ ~ Flavor o . 8 o. 8 o. 8 ; ~
Water q.s. to 100 100 100 .
:
*Prepared accordin¢ to procedure descri~ed in "Immunvcllemis~l,y"
supra I'or copolymerizin~ a 6:3:1 molar mixture of glutamic acidg alanine and tyrosine, the resulting copolymer of the invention ~ine determined to have ~ molecular wei~ l, o.~ al~o~ 0,~3 1~ 7535~ ~ 1 ~l'his invention has been described with respect to preferred embodiments and it will be understood that modifications and variations ~hereof 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.

I
'` `' ; , ~ -24-

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An oral composition comprising an orally accept-able vehicle containing in an effective amount at least one cationic nitrogen-containing antibacterial antiplaque agent based on its free base form and an effective stain-inhibiting amount 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 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.

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

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

4. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is present in an amount of about 0.001 to about 15% by weight based on the free base form of said agent and said additive is present in an amount of about 0.01 to about 10% by weight.

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

6. The oral composition of claim 1, wherein said antibacterial antiplaque agent is a substituted guanidine.

7. The oral composition of claim 1, 2 or 3 wherein said anti-bacterial antiplaque agent is a pharmaceutically acceptable water soluble salt of an agent selected from the group consist-ing of chlorhexidine and alexidine.

8. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is a pharmaceutically acceptable water soluble salt of chlorhexidine.

9. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is benzethonium chloride.

10. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is a quaternary ammonium compound containing 1 to 2 alkyl groups of 8 to 20 carbon atoms.

11. The oral composition of claim 1, 2 or 3 wherein said antibacterial antiplaque agent is cetyl pyridinium chloride.

12. The oral composition of claim 1, 2 or 3 which is a mouthwash having a pH of about 4.5 to about 9 and an aqueous-alcohol vehicle.

13. The oral composition of claim 1, 2 or 3 which is a toothpaste hav-ing a pH of about 4.5 to about 9, a liquid vehicle, a gelling agent, and a dentally acceptable polishing agent.

14. The method of preparing a composition as defined in claim 1, 2 or 3 comprising adding the copolymer to a mixture of the other ingredients thereof.