Patent Description:
Arginine and other basic amino acids have been proposed for use in oral care and are believed to have significant benefits in combating cavity formation and tooth sensitivity.

Commercially available arginine-based toothpaste, such as ProClude® toothpaste or DenClude® toothpaste, for example, contains arginine bicarbonate and precipitated calcium carbonate, but not fluoride. The carbonate ion is believed to have cariostatic properties, and the calcium is believed to form in complex with arginine to provide a protective effect. <CIT> discloses an oral care composition comprising (i) basic amino acid in free or salt form, (ii) calcium carbonate, (iii) a fluoride ion source, (iv) a flavoring agent, and (v) an anionic surfactant. The invention disclosed therein relates to providing a stable oral care product comprising a basic amino acid, fluoride and calcium.

Precipitated calcium carbonate is more friable and less abrasive than natural calcium carbonate for example, and this can result in less damaging abrasion to enamel, which is good for sensitive teeth.

Accordingly, there is a need for a stable oral care product that comprising a basic amino acid and beneficial minerals such as fluoride and calcium, which moreover has an optimized abrasive system to provide effective cleaning without damaging abrasivity, particularly for people having sensitive teeth.

The invention encompasses oral care compositions and methods of using the same that are believed to be effective in inhibiting or reducing the accumulation of plaque, reducing levels of acid producing (cariogenic) bacteria, remineralizing teeth, and inhibiting or reducing gingivitis. The invention also encompasses compositions and methods to clean the oral cavity.

The invention thus comprises an oral care composition (Composition of the Invention), e.g., a dentifrice, as defined in claim <NUM>.

The composition is effective for cleaning and strengthening the teeth without damaging abrasion, e.g., in persons with sensitive teeth, for example has a good Pellicle Cleaning Ratio, e.g., at least <NUM>, and a low Radioactive Dentine Abrasivity value, e.g., less than <NUM>.

The formulation further comprises an anionic surfactant, which is sodium lauryl sulfate; and may further comprise an anionic polymer, e.g., a copolymer of methyl vinyl ether and maleic anhydride; and/or an antibacterial agent.

In particular embodiments, the Compositions of the Invention are in the form of a dentifrice comprising additional ingredients selected from one or more of water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, additional humectants (e.g., humectant in addition to glycerin), thickeners, antimicrobial agents, preservatives, flavorings, colorings and/or combinations thereof.

Without intending to be bound by a particular theory, it is believed that the presence of small particles in a formulation with arginine and calcium may help plug the microtubules responsible for hypersensitive teeth and help repair precarious lesions in the enamel and dentin.

It is moreover found that the combination of fluoride and arginine in an oral care product according to particular embodiments of the present invention produces unexpected benefits beyond and qualitatively different from what can be observed using compositions comprising effective amounts of either compound separately, in promoting remineralization, repairing pre-carious lesions, and enhancing oral health. It has moreover been found that this action can be further enhanced by addition of a small particle abrasive comprising a combination of natural calcium carbonate and precipitated calcium carbonate, which may act to help fill microfissures in the enamel and microtubules in the dentin.

The presence of a basic amino acid is also surprisingly found to reduce bacterial adhesion to the tooth surface, particularly when the basic amino acid is provided in combination with an anionic surfactant. The combination of the basic amino acid and the anionic surfactant and/or anionic polymer e.g., PVM/MA also enhances delivery of antimicrobial agents, particularly triclosan.

The invention encompasses a oral care composition as defined in the claims for use in a methods as defined in claim <NUM>.

The invention thus comprises an oral care composition (Composition <NUM>) as defined in claim <NUM> comprising a basic amino acid and a soluble fluoride salt.

The basic amino acid comprises arginine.

The compositions may comprise a salt of a di- or tri-peptide comprising the basic amino acid.

The compositions may comprise arginine having L-configuration.

The compositions may comprise the basic amino acid partially or wholly in salt form.

The compositions may comprise arginine bicarbonate as the salt form of arginine.

The compositions may comprise the salt of the basic amino acid which is formed in situ in the formulation by neutralization of the basic amino acid with an acid or a salt of an acid.

The compositions may comprise the salt of the basic amino acid which is formed by neutralization of the basic amino acid to form a premix prior to combination with the fluoride salt.

The compositions comprise arginine which is present in an amount according to claim <NUM>, the weight of arginine being calculated as free base form.

The compositions may comprise arginine in an amount of about <NUM> wt. % of the total composition weight.

The fluoride salt comprises sodium monofluorophosphate.

The compositions may have a pH between about <NUM> and about <NUM>.

The compositions may have a pH of about <NUM>, about <NUM>, or about <NUM>.

The compositions comprise precipitated calcium carbonate which may have a D<NUM> of <NUM>-<NUM> microns, a D<NUM> of <NUM> - <NUM> microns and a D<NUM> of <NUM> - <NUM> microns.

The compositions comprise precipitated calcium carbonate (PCC) which may have an average particle size of D<NUM> of <NUM>-<NUM> microns, a D<NUM> of <NUM> - <NUM> microns and a D<NUM> of <NUM> - <NUM> microns and water absorption of greater than <NUM>/<NUM>.

The compositions may comprise a small particle abrasive fraction of at least about <NUM>% having a d50 of less than about <NUM> micrometers.

The compositions may have an RDA of less than about <NUM>, e.g., about <NUM> to about <NUM>.

The compositions comprise at least one surfactant comprising sodium lauryl sulfate.

The compositions may comprise a surfactant selected from cocamidopropyl betaine, and combinations thereof.

The compositions may comprise at least one humectant in addition to glycerin.

The compositions comprise at least two polymers which comprise sodium carboxymethylcellulose and polyionic cellulose.

The compositions may additionally comprise at least one polymer selected from polyethylene glycols, polyvinylmethyl ether maleic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum), and combinations thereof.

The compositions may comprise gum strips or fragments.

The compositions may comprise flavoring, fragrance and/or coloring.

The compositions comprise purified water.

The compositions may comprise an antibacterial agent.

The compositions may comprise an antibacterial agent selected from herbal extracts and essential oils (e.g., rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract), bisguanide antiseptics (e.g., chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-<NUM>-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, metal ions (e.g., zinc salts, for example, zinc citrate, stannous salts, copper salts, iron salts), sanguinarine, propolis and oxygenating agents (e.g., hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate), phthalic acid and its salts, monoperthalic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidino derivatives, nicin preparations, chlorite salts; and mixtures of any of the foregoing. The compositions may comprise a whitening agent.

The compositions may comprise a whitening agent selected from a whitening active selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites, and combinations thereof.

The compositions may further comprise hydrogen peroxide or a hydrogen peroxide source, e.g., urea peroxide or a peroxide salt or complex (e.g., such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or persulphate salts; for example calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate, and potassium persulfate), or hydrogen peroxide polymer complexes such as hydrogen peroxide-polyvinyl pyrrolidone polymer complexes.

The compositions may comprise an antioxidant, e.g., selected from the group consisting of Coenzyme Q10, PQQ, Vitamin D, Vitamin C, Vitamin E, Vitamin A, anethole-dithiothione, and mixtures thereof.

The compositions may comprise a Zn<NUM>+ ion source, e.g., zinc citrate.

The compositions may comprise an antibacterial agent in an amount of about <NUM> to about <NUM> wt. % of the total composition weight.

The compositions may further comprise an agent that interferes with or prevents bacterial attachment, e.g., solbrol or chitosan.

The compositions may further comprise an anti-calculus agent.

The compositions further comprise at least one anti-calculus agent which comprises tetrasodium pyrophosphate, and may additionally comprise a polyphosphate, e.g., tripolyphosphate, or hexametaphosphate, e.g., in sodium salt form.

The compositions may further comprise a source of calcium and phosphate selected from (i) calcium-glass complexes, e.g., calcium sodium phosphosilicates, and (ii) calcium-protein complexes, e.g., casein phosphopeptide-amorphous calcium phosphate.

The compositions may further comprise a soluble calcium salt, e.g., selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.

The compositions may further comprise a physiologically acceptable potassium salt, e.g., potassium nitrate or potassium chloride, in an amount effective to reduce dentinal sensitivity. The compositions may comprise from about <NUM>% to about <NUM>% of a physiologically acceptable potassium salt, e.g., potassium nitrate and/or potassium chloride.

The compositions are effective upon application to the oral cavity, e.g., with brushing, as defined in claim <NUM>.

A composition obtained or obtainable by combining the ingredients as set forth in any of the preceding compositions.

The compositions are in a form as defined in claim <NUM>.

The compositions may be a toothpaste according to claim <NUM> optionally further comprising one or more of water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings, colorings and/or combinations thereof.

The compositions contain an amount of glycerin which is from <NUM> to <NUM>% by wt. (e.g., about <NUM>% by wt.

The compositions may comprise an amount of water (e.g., free water) which is from <NUM>% - <NUM>% by wt.

The compositions could not contain any sorbitol or may be substantially free of sorbitol.

Methods (Method <NUM>) for preparing an oral composition as defined in claim <NUM> may comprise.

The invention further relates to the compositions of the invention for use in the methods as defined in the claims. The compositions comprise sodium monofluorophosphate as defined in the claims, and may further comprise stannous fluoride, sodium fluoride, potassium fluoride, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof.

The compositions may additionally comprise a fluorophosphate.

The compositions comprise sodium monofluorophosphate.

The compositions comprise arginine, and may additionally comprise lysine, citrullene, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, salts and combinations thereof.

The compositions may comprise at least one basic amino acid which has the L-configuration.

The methods as defined in the claims may be carried out at room temperature and pressure.

The methods are carried out with the ingredients and their respective amounts as defined in claim <NUM>.

In another embodiment, the invention encompasses an oral care composition according to claim <NUM> for use in a method as defined in claim <NUM>.

The invention further comprises the use of arginine in the manufacture of a Composition of the Invention, e.g., for use in any of the indications set forth in claim <NUM>.

The invention further provides an oral care composition as defined in claim <NUM> for use in the treatment of at least one of demineralized teeth and enamel lesions within an oral cavity of a subject, or for enhancing the mineralization of teeth within an oral cavity of a subject.

The invention further provides the use of an oral care composition according to claim <NUM> for the manufacture of a medicament for enhancing the mineralization of teeth within an oral cavity of a subject.

It may therefore be seen by the skilled practitioner in the oral care art that a number of different yet surprising technical effects and advantages can result from the formulation, and use, of an oral care composition, for example a dentifrice, in accordance with one or more aspects of the invention, which are directed to the provision of different combinations of active components or ingredients, and preferably their respective amounts, within the composition.

Levels of active ingredients will vary based on the nature of the delivery system and the particular active. Fluoride may be present at levels of, e.g., about <NUM> to about <NUM>,<NUM> ppm, for example about <NUM> to about <NUM> ppm for a mouthrinse, about <NUM> to about <NUM>,<NUM> ppm for a consumer toothpaste, or about <NUM>,<NUM> to about <NUM>,<NUM> ppm for a professional or prescription treatment product. Levels of antibacterial will vary similarly, with levels used in toothpaste being e.g., about <NUM> to about <NUM> times greater than used in mouthrinse.

RDA: RDA is an abbreviation for radioactive dentin abrasion, a relative measure of abrasivity. Typically, extracted human or cow teeth are irradiated in a neutron flux, mounted in methylmethacrylate (bone glue), stripped of enamel, inserted into a brushing-machine, brushed by American Dental Association (ADA) standards (reference toothbrush, <NUM> pressure, <NUM> strokes, <NUM>-to-<NUM> water-toothpaste slurry). The radioactivity of the rinse water is then measured and recorded. For experimental control, the test is repeated with an ADA reference toothpaste made of calcium pyrophosphate, with this measurement given a value of <NUM> to calibrate the relative scale. See, e.g., <NPL>, and <CIT> ; <CIT>; and <CIT>.

PCR or pellicle cleaning ratio is a measure of the effectiveness of the dentifrice to remove stains, e.g. described <CIT> and <CIT>. Typically, a clear pellicle material is applied to a bovine tooth which is then stained with a combination of the pellicle material and tea, coffee, and FeCl<NUM>, which is subsequently treated with the composition, and the change in the reflectance of the tooth surface before and after treatment is the PCR value.

The basic amino acids which can be used in the compositions and methods of the invention include arginine as described in claim <NUM>, but may also include not only naturally occurring basic amino acids, such as lysine, and histidine, but also any basic amino acids having a carboxyl group and an amino group in the molecule, which are water-soluble and provide an aqueous solution with a pH of <NUM> or greater.

The basic amino acid comprises arginine, for example, L-arginine, or a salt thereof.

In some embodiments the basic amino acid comprises at least one intermediate produced in the arginine deiminase system. The intermediates produced in the arginine deiminase system may be useful in an oral care composition to provide plaque neutralization for caries control and/or prevention. Arginine is a natural basic amino acid that may be found in the oral cavity. Arginine in the mouth may be utilized by certain dental plaque bacterial strains such as S. sanguis, S. gordonii, S. parasanguis, S. milleri, S. anginosus, S. faecalis, A. naeslundii, A. odonolyticus, L. cellobiosus, L. fermentum, P. gingivalis, and T. denticola for their survival. Such organisms may perish in an acidic environment that may be present at areas close to the tooth surface where acidogenic and aciduric cariogenic strains may use sugars to produce organic acids. Thus, these arginolytic strains may break down arginine to ammonia to provide alkalinity to survive and, in addition, buffer the plaque and make a hostile environment for the cariogenic systems.

Such arginolytic organisms may catabolize arginine by an internal cellular enzyme pathway system called the "arginine deiminase system" whereby intermediates in the pathway are formed. In this pathway, L-arginine may be broken down to L-citrulline and ammonia by arginine deiminase. L-citrulline may then be broken down by ornithane trancarbamylase in the presence of inorganic phosphate to L-omithine and carbamyl phosphate. Carbamate kinase may then break down carbamyl phosphate to form another molecule of ammonia and carbon dioxide, and in the process also forms ATP (adenosine <NUM>'-triphosphate). ATP may be used by the arginolytic bacteria as an energy source for growth. Accordingly, when utilized, the arginine deiminase system may yield two molecules of ammonia.

It has been found that, in some embodiments, the ammonia may help in neutralizing oral plaque pH to control and/or prevent dental caries.

The oral care composition of some embodiments of the present invention may include intermediates produced in the arginine deiminase system. Such intermediates may include citrulline, ornithine, and carbamyl phosphate. In some embodiments, the other care composition includes citrulline. In some embodiments, the oral care composition includes ornithine. In some embodiments, the oral care composition includes carbamyl phosphate. In other embodiments, the oral care composition includes any combination of citrulline, ornithine, carbamyl phosphate, and/or other intermediates produced by the arginine deiminase system.

The oral care composition may include the above described intermediates in an effective amount. In some embodiments, the oral care composition includes about <NUM> mmol/L to about <NUM> mmol/L intermediate. In other embodiments, the oral care composition includes about <NUM> mmol/L to about <NUM> mmol/L intermediate. In other embodiments, the oral care composition includes about <NUM> mmol/L intermediate.

The compositions of the invention are intended for topical use in the mouth and so salts for use in the present invention should be safe for such use, in the amounts and concentrations provided. Suitable salts include salts known in the art to be pharmaceutically acceptable salts are generally considered to be physiologically acceptable in the amounts and concentrations provided. Physiologically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic acids or bases, for example acid addition salts formed by acids which form a physiological acceptable anion, e.g., hydrochloride or bromide salt, and base addition salts formed by bases which form a physiologically acceptable cation, for example those derived from alkali metals such as potassium and sodium or alkaline earth metals such as calcium and magnesium. Physiologically acceptable salts may be obtained using standard procedures known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.

In various embodiments, the basic amino acid is present in an amount of about for example about <NUM> wt. %of the total composition weight.

The oral care compositions further includes one or more fluoride ion sources, e.g., soluble fluoride salts, which comprises sodium monofluorophosphate. A wide variety of fluoride ion-yielding materials can be further employed as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion-yielding materials are found in <CIT>. ; <CIT> and <CIT>.

Representative fluoride ion sources include sodium monofluorophosphate as described in claim <NUM>, but may also include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In certain embodiments the fluoride ion source may include stannous fluoride, sodium fluoride as well as mixtures thereof.

Sodium monofluorophosphate is added to the compositions of the invention at a level as defined in claim <NUM>.

The Compositions of the Invention comprise precipitated calcium carbonate. In addition to precipitated calcium carbonate, the compositions of the invention may comprise a calcium phosphate abrasive, e.g., tricalcium phosphate (Ca<NUM>(PO<NUM>)<NUM>), hydroxyapatite (Ca<NUM>(PO<NUM>)<NUM>(OH)<NUM>), or dicalcium phosphate dihydrate (CaHPO<NUM> • <NUM><NUM>O, also sometimes referred to herein as DiCal) or calcium pyrophosphate. Alternatively, in addition to precipitated calcium carbonate, the compositions may also comprise natural calcium carbonate.

In addition to precipitated calcium carbonate, the compositions may include one or more additional particulate materials, for example silica abrasives such as precipitated silicas having a mean particle size of up to about <NUM> microns, such as Zeodent <NUM>®, marketed by J. Other useful abrasives also include sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof.

The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size ranging between about <NUM> and about <NUM> microns, about between <NUM> and about <NUM> microns. The silica abrasives can be from precipitated silica or silica gels, such as the silica xerogels described in <CIT> and <CIT>. Particular silica xerogels are marketed under the trade name Syloid® by the W. Grace & Co. , Davison Chemical Division. The precipitated silica materials include those marketed by the J. Huber Corp. under the trade name Zeodent®, including the silica carrying the designation Zeodent <NUM> and <NUM>. These silica abrasives are described in <CIT>.

In certain embodiments, in addition to precipitated calcium carbonate, the abrasive materials useful in the practice of the oral care compositions in accordance with the invention include silica gels and precipitated amorphous silica having an oil absorption value of about less than <NUM> cc/<NUM> silica and in the range of about <NUM> cc/<NUM> to about <NUM> cc/<NUM> silica. Oil absorption values are measured using the ASTA Rub-Out Method D281. In certain embodiments, the silicas are colloidal particles having an average particle size of about <NUM> microns to about <NUM> microns, and about <NUM> to about <NUM> microns.

In particular embodiments, the particulate or abrasive materials may comprise a large fraction of very small particles, e.g., having a d50 less than about <NUM> microns, for example small particle silica (SPS) having a d50 of about <NUM> to about <NUM> microns, for example Sorbosil AC43® (Ineos). Such small particles are particularly useful in formulations targeted at reducing hypersensitivity. The small particle component may be present in combination with a second larger particle abrasive. In certain embodiments, for example, the formulation may comprise about <NUM> to about <NUM>% SPS and about <NUM> to about <NUM>% of a conventional abrasive.

Low oil absorption silica abrasives particularly useful in the practice of the invention are marketed under the trade designation Sylodent XWA® by Davison Chemical Division of W. Grace & Co. , Baltimore, Md. Sylodent <NUM> XWA®, a silica hydrogel composed of particles of colloidal silica having a water content of about <NUM>% by weight averaging about <NUM> to about <NUM> microns in diameter, and an oil absorption of less than about <NUM> cc/<NUM> of silica is an example of a low oil absorption silica abrasive useful in the practice of the present invention. The abrasive is present in the oral care composition of the present invention at a concentration of about <NUM> to about <NUM>% by weight, in other embodiment about <NUM> to about <NUM>% by weight, and in another embodiment about <NUM> to about <NUM>% by weight.

Precipitated calcium carbonate is generally made by calcining limestone, to make calcium oxide (lime), which can then be converted back to calcium carbonate by reaction with carbon dioxide in water. Precipitated calcium carbonate has a different crystal structure from natural calcium carbonate. It is generally more friable and more porous, thus having lower abrasivity and higher water absorption. For use in the present invention, the particles are small, e.g., having an average particle size of <NUM>-<NUM> microns, and e.g., no more than <NUM>%, preferably no more than <NUM>% by weight of particles which would not pass through a <NUM> mesh. The particles may for example have a D<NUM> of <NUM> - <NUM> microns; a D<NUM> of <NUM>-<NUM> microns, and a D<NUM> of <NUM> - <NUM> microns, e.g., <NUM>-<NUM>, e.g. about <NUM> microns. The particles have relatively high-water absorption, e.g., at least <NUM>/<NUM>, e.g. <NUM>-<NUM>/<NUM>. Examples of commercially available products suitable for use in the present invention include, for example, Carbolag® <NUM> Plus from Lagos Industria Quimica.

In some embodiments, in addition to precipitated calcium carbonate, there may also be natural calcium carbonate. Natural calcium carbonate is found in rocks such as chalk, limestone, marble and travertine. It is also the principle component of egg shells and the shells of mollusks. The natural calcium carbonate abrasive of the invention is typically a finely ground limestone which may optionally be refined or partially refined to remove impurities. For use in the present invention, the material has an average particle size of less than <NUM> microns, e.g., <NUM>-<NUM> microns, e.g. about <NUM> microns. Because natural calcium carbonate may contain a high proportion of relatively large particles of not carefully controlled, which may unacceptably increase the abrasivity, preferably no more than <NUM>%, preferably no more than <NUM>% by weight of particles would not pass through a <NUM> mesh. The material has strong crystal structure, and is thus much harder and more abrasive than precipitated calcium carbonate. The tap density for the natural calcium carbonate is for example between <NUM> and <NUM>/cc, e.g., about <NUM> for example about <NUM>/cc. There are different polymorphs of natural calcium carbonate, e.g., calcite, aragonite and vaterite, calcite being preferred for purposes of this invention. An example of a commercially available product suitable for use in the present invention includes Vicron® <NUM>-<NUM> FG from GMZ.

The oral care compositions of the invention also may include an agent to increase the amount of foam that is produced when the oral cavity is brushed.

Illustrative examples of agents that increase the amount of foam include, but are not limited to polyoxyethylene and certain polymers including, but not limited to, alginate polymers.

The polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care carrier component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol ("PEG") or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of about <NUM>,<NUM> to about <NUM>,<NUM>,<NUM>. In one embodiment the molecular weight will be about <NUM>,<NUM> to about <NUM>,<NUM>,<NUM> and in another embodiment about <NUM>,<NUM> to about <NUM>,<NUM>,<NUM>. Polyox® is the trade name for the high molecular weight polyoxyethylene produced by Union Carbide.

The polyoxyethylene may be present in an amount of about <NUM>% to about <NUM>%, in one embodiment about <NUM>% to about <NUM>% and in another embodiment about <NUM>% to about <NUM>% by weight of the oral care carrier component of the oral care compositions of the present invention. The dosage of foaming agent in the oral care composition (i.e., a single dose) is about <NUM> to about <NUM> % by weight, about <NUM> to about <NUM>% by weight, and in another embodiment about <NUM> to about <NUM> % by weight.

Another agent included in the oral care composition of the invention is a surfactant or a mixture of compatible surfactants which comprises sodium lauryl sulfate. Suitable surfactants are those which are reasonably stable throughout a wide pH range, for example, anionic, cationic, nonionic or zwitterionic surfactants.

Suitable surfactants are described more fully, for example, in <CIT>; <CIT>; and <CIT>.

In certain embodiments, in addition to sodium lauryl sulfate, the anionic surfactants useful herein may further include the water-soluble salts of alkyl sulfates having about <NUM> to about <NUM> carbon atoms in the alkyl radical and the water-soluble salts of sulfonated monoglycerides of fatty acids having about <NUM> to about <NUM> carbon atoms. Sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of this type. Mixtures of anionic surfactants may also be utilized.

In another embodiment, cationic surfactants useful in the present invention can be broadly defined as derivatives of aliphatic quaternary ammonium compounds having one long alkyl chain containing about <NUM> to about <NUM> carbon atoms such as lauryl trimethylammonium chloride, cetyl pyridinium chloride, cetyl trimethylammonium bromide, di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconut alkyltrimethylammonium nitrite, cetyl pyridinium fluoride, and mixtures thereof.

Illustrative cationic surfactants are the quaternary ammonium fluorides described in <CIT> Certain cationic surfactants can also act as germicides in the compositions.

Illustrative nonionic surfactants that can be used in the compositions of the invention can be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature. Examples of suitable nonionic surfactants include, but are not limited to, the Pluronics, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.

In certain embodiments, zwitterionic synthetic surfactants useful in the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphomium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains about <NUM> to about <NUM> carbon atoms and one contains an anionic water-solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate or phosphonate. Illustrative examples of the surfactants suited for inclusion into the composition include, but are not limited to, sodium alkyl sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine and polysorbate <NUM>, and combinations thereof.

The Composition of the Invention comprises sodium lauryl sulfate.

Sodium lauryl sulfate is present in the compositions of the present invention in amounts as defined in claim <NUM>.

The oral care compositions of the invention may also include a flavoring agent. Flavoring agents which are used in the practice of the present invention include, but are not limited to, essential oils as well as various flavoring aldehydes, esters, alcohols, and similar materials. Examples of the essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange. Also useful are such chemicals as menthol, carvone, and anethole. Certain embodiments employ the oils of peppermint and spearmint.

The flavoring agent is incorporated in the oral composition at a concentration of about <NUM> to about <NUM>% by weight and about <NUM> to about <NUM>% by weight. The dosage of flavoring agent in the individual oral care composition dosage (i.e., a single dose) is about <NUM> to about <NUM>% by weight and in another embodiment about <NUM> to about <NUM> % by weight.

The oral care compositions of the invention also may optionally include one or more chelating agents able to complex calcium found in the cell walls of the bacteria. Binding of this calcium weakens the bacterial cell wall and augments bacterial lysis.

Another group of agents suitable for use as chelating agents in the present invention are the soluble pyrophosphates. The pyrophosphate salts used in the present compositions comprise tetrasodium pyrophosphate. In certain embodiments, salts may include a further tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium. The salts are useful in both their hydrated and unhydrated forms. An effective amount of pyrophosphate salt useful in the present composition is defined in claim <NUM>.

The oral care compositions of the invention also include sodium carboxymethylcellulose and polyionic cellulose, and optionally one or more further polymers, such as polyethylene glycols, polyvinylmethyl ether maleic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum). Acidic polymers, for example polyacrylate gels, may be provided in the form of their free acids or partially or fully neutralized water soluble alkali metal (e.g., potassium and sodium) or ammonium salts. Certain embodiments may include about <NUM>:<NUM> to about <NUM>:<NUM> copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, for example, methyl vinyl ether (methoxyethylene) having a molecular weight (M. ) of about <NUM>,<NUM> to about <NUM>,<NUM>,<NUM>. These copolymers are available for example as Gantrez AN <NUM>(M. <NUM>,<NUM>), AN <NUM> (M. <NUM>,<NUM>) and S-<NUM> Pharmaceutical Grade (M. <NUM>,<NUM>), of GAF Chemicals Corporation.

Other operative polymers may include those such as the <NUM>:<NUM> copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-<NUM>-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. <NUM>, M. <NUM>,<NUM> and EMA Grade <NUM>, and <NUM>:<NUM> copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-<NUM>-pyrrolidone.

Suitable generally, are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, <NUM>-benzyl acrylic, <NUM>-cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other different olefinic monomers copolymerizable with such carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water-solubility.

A further class of polymeric agents includes a composition containing homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalykane sulfonic acids such as <NUM>-acrylamide <NUM> methylpropane sulfonic acid having a molecular weight of about <NUM>,<NUM> to about <NUM>,<NUM>,<NUM>, described in <CIT>.

Another useful class of polymeric agents includes polyamino acids, particularly those containing proportions of anionic surface-active amino acids such as aspartic acid, glutamic acid and phosphoserine, as disclosed in <CIT>.

In preparing oral care compositions, it is sometimes necessary to add some thickening material to provide a desirable consistency or to stabilize or enhance the performance of the formulation. In certain embodiments, the thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as karaya, gum arabic, and gum tragacanth can also be incorporated. Colloidal magnesium aluminum silicate or finely divided silica can be used as component of the thickening composition to further improve the composition's texture. In certain embodiments, thickening agents in an amount of about <NUM>% to about <NUM>% by weight of the total composition are used.

The oral care compositions of the invention may also optionally include one or more enzymes. Useful enzymes include any of the available proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases or compatible mixtures thereof. In certain embodiments, the enzyme is a protease, dextranase, endoglycosidase and mutanase. In another embodiment, the enzyme is papain, endoglycosidase or a mixture of dextranase and mutanase. Additional enzymes suitable for use in the present invention are disclosed in <CIT>, <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>. An enzyme of a mixture of several compatible enzymes in the current invention constitutes about <NUM>% to about <NUM>% in one embodiment or about <NUM>% to about <NUM>% in another embodiment or in yet another embodiment about <NUM>% to about <NUM>%.

Water is present in the oral compositions of the invention. Water, employed in the preparation of commercial oral compositions should be deionized and free of organic impurities. The compositions comprise purified water in amounts as defined in claim <NUM>. This amount of water includes the free water which is added plus that amount which is introduced with other materials, such as with sorbitol, or any components of the invention.

Within certain embodiments of the oral compositions, it is also desirable to incorporate a humectant, in addition to the glycerin already present, to prevent the composition from hardening upon exposure to air. Certain humectants can also impart desirable sweetness or flavor to dentifrice compositions. The humectant, on a pure humectant basis, generally includes about <NUM>% to about <NUM>% in one embodiment or about <NUM>%, or about <NUM>% in other embodiments by weight of the dentifrice composition.

In addition to the already present glycerin, suitable humectants include edible polyhydric alcohols such as sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of these humectants. Mixtures of glycerin and sorbitol may be used in certain embodiments as the humectant component of the toothpaste compositions herein.

In addition to the above described components, the embodiments of this invention can contain a variety of optional dentifrice ingredients some of which are described below. Optional ingredients include, for example, but are not limited to, adhesives, sudsing agents, flavoring agents, sweetening agents, additional antiplaque agents, abrasives, and coloring agents. These and other optional components are further described in <CIT>; <CIT> and <CIT>.

The compositions of the present invention can be made using methods which are common in the oral product area.

In one illustrative embodiment, the oral care composition is made by Method <NUM>, described above, e.g., neutralizing arginine in a gel phase with an acid selected from: lactic acid, glycolic acid, citric acid, and acetic acid, and mixing to form Premix <NUM>.

Actives such as, for example, vitamins, CPC, fluoride, abrasives, and any other desired active ingredients are added to Premix <NUM> and mixed to form Premix <NUM>.

A toothpaste base, for example, dicalcium phosphate is added to Premix <NUM> and mixed. The final slurry is formed into an oral care product.

The present invention can be used in a method which involves applying to the oral cavity a safe and effective amount of the compositions described herein.

The compositions according to the invention are useful to a method to protect the teeth by facilitating repair and remineralization, in particular to reduce or inhibit formation of dental caries, reduce or inhibit demineralization and promote remineralization of the teeth, reduce hypersensitivity of the teeth, and reduce, repair or inhibit early enamel lesions, e.g., as detected by quantitative light-induced fluorescence (QLF) or electronic caries monitor (ECM).

Quantitative Light-induced Fluorescence is a visible light fluorescence that can detect early lesions and longitudinally monitor the progression or regression. Normal teeth fluoresce in visible light; demineralized teeth do not or do so only to a lesser degree. The area of demineralization can be quantified and its progress monitored. Blue laser light is used to make the teeth auto fluoresce. Areas that have lost mineral have lower fluorescence and appear darker in comparison to a sound tooth surface. Software is used to quantify the fluorescence from a white spot or the area/volume associated with the lesion. Generally, subjects with existing white spot lesions are recruited as panelists. The measurements are performed in vivo with real teeth. The lesion area/volume is measured at the beginning of the clinical. The reduction (improvement) in lesion area/volume is measured at the end of <NUM> months of product use. The data is often reported as a percent improvement versus baseline.

Electrical Caries Monitoring is a technique used to measure mineral content of the tooth based on electrical resistance. Electrical conductance measurement exploits the fact that the fluid-filled tubules exposed upon demineralization and erosion of the enamel conduct electricity. As a tooth loses mineral, it becomes less resistive to electrical current due to increased porosity. An increase in the conductance of the patient's teeth therefore may indicate demineralization. Generally, studies are conducted of root surfaces with an existing lesion. The measurements are performed in vivo with real teeth. Changes in electrical resistance before and after <NUM> month treatments are made. In addition, a classical caries score for root surfaces is made using a tactile probe. The hardness is classified on a three point scale: hard, leathery, or soft. In this type of study, typically the results are reported as electrical resistance (higher number is better) for the ECM measurements and an improvement in hardness of the lesion based on the tactile probe score.

The Compositions of the Invention are thus useful in a method to reduce early enamel lesions (as measured by QLF or ECM) relative to a composition lacking effective amounts of sodium monofluorophosphate and/or arginine.

The Compositions of the invention are additionally useful in methods to reduce harmful bacteria in the oral cavity, for example methods to reduce or inhibit gingivitis, reduce levels of acid producing bacteria, to increase relative levels of arginolytic bacteria, inhibit microbial biofilm formation in the oral cavity, raise and/or maintain plaque pH at levels of at least about pH <NUM> following sugar challenge, reduce plaque accumulation, and/or clean the teeth and oral cavity.

The compositions and methods according to the invention can be incorporated into oral compositions for the care of the mouth and teeth such as toothpastes, transparent pastes, gels, mouth rinses, sprays and chewing gum.

The compositions and methods of the invention provide particular benefits because basic amino acids, especially arginine, are sources of nitrogen which supply NO synthesis pathways and thus enhance microcirculation in the oral tissues. Providing a less acidic oral environment is also helpful in reducing gastric distress and creates an environment less favorable to Heliobacter, which is associated with gastric ulcers. Arginine in particular is required for high expression of specific immune cell receptors, for example T-cell receptors, so that arginine can enhance an effective immune response.

It is understood that when formulations are described, they may be described in terms of their ingredients, as is common in the art, notwithstanding that these ingredients may react with one another in the actual formulation as it is made, stored and used, and such products are intended to be covered by the formulations described.

The following examples further describe and demonstrate illustrative embodiments with Composition B and C lying within the scope of the present invention. Composition A is not covered by the subject-matter of the claims.

Optimized arginine toothpaste formulations are prepared using the following ingredients:.

Claim 1:
An oral care composition comprising
i. from <NUM>% - <NUM>% by wt. of arginine in free or salt form;
ii. from <NUM>% by wt. - <NUM>% by wt. of sodium monofluorophosphate;
iii. from <NUM>% - <NUM>% by wt. of precipitated calcium carbonate (PCC);
iv. from <NUM>% - <NUM>% by wt. of glycerin;
v. from <NUM>% - <NUM>% by wt. of sodium lauryl sulfate;
vi. from <NUM>% - <NUM>% by wt. of tetrasodium pyrophosphate;
vii. from <NUM>% - <NUM>% by wt. of sodium bicarbonate;
viii. from <NUM>% - <NUM>% by wt. of sodium carboxymethylcellulose and polyionic cellulose; and
wherein the composition comprises purified water in an amount of <NUM>-<NUM>% by wt of the composition.