GB2412586A - Polyaspartate to treat dental tartar - Google Patents

Abstract

There is described the use of polyaspartate to inhibit the formation of dental tartar and to inhibit the demineralisation of tooth enamel. Also described are oral care compositions comprising polyaspartate in an amount effective to inhibit dental tartar formation, the composition being substantially free of non-ionic block copolymers, in particular polyoxyethylene, polyoxypropylene block copolymers and polyoxyethylene, polyoxypropylene block copolymers of ethylene diamine.

Description

24 1 2586 1060/6611P/GB - Complete Title - Improvements Relating to Oral

Care Compositions This invention concerns improvements relating to oral care compositions, and in particular to improvements in the performance of such compositions in respect of the inhibition or prevention of the deposition of tartar upon the teeth, and/or reductions in the demineralisation of tooth enamel.

Polypeptides, in particular synthetic polyamino acids, have been known for some time to be of potential utility in oral care compositions such as dentifrices, mouth washes etc. EP-A-0305282, EP-A-0305283 and EP-A0391629 all disclose synthetic polypeptide compounds of the general formula poly (X)m(Y)n, where X and Y represent different amino acid residues. The compounds are indicated to be inhibitors of mineral formation, and to be of potential utility in a number of applications including control of dental tartar. X may represent an aspartic acid (1 amino-1,2-carboxyethane) residue, and the activity of the compounds is contrasted inter alla with that of polyaspartate, ie a polymer consisting entirely of aspartic acid residues, typically a 20-men Phosphorylation of the Y residue is indicated to increase the activity. A similar disclosure is found in WO-A-92/17194.

WO-A-92/15535 discloses that water-soluble salts of polyaspartic acid with a molecular weight range of 1000 to 5000 are effective dispersants for finely divided solid particles in aqueous suspension.

Copolymers of polyaspartic acid, and methods of their preparation, are disclosed in US-A-5408659 and US-A-5659008. The copolymers are indicated to be useful in the inhibition of dental tartar formation.

Dentifrice compositions are disclosed in WO-A-99/63961. This document is mainly concerned with improvements in the flavour of the compositions, and this is 1060/661/P/GB - Complete said to be achieved by the inclusion in the formulation of a non-ionic block copolymer such as a poloxamine or poloxomer. The document also mentions that the composition may contain any of numerous additives, including sources of polyphosphate or alternatives thereto that are known to be effective in reducing calcium phosphate mineral deposition related to calculus formation. Polypeptides are mentioned, in particular polyaspartic acid and polyglutamic acid.

WO-A-02/07690 describes dental compositions that are said to inhibit the adherence of bacteria, plaque and stains to teeth. The compositions comprise at least one poloxamer in combination with a poly-amino acid such as polyaspartate.

Guan et al (J Appl Microbiol (2003) 94: 456-461) indicates that polyaspartate reduces bacterial adhesion to hydroxyapatite surfaces, and hence that polyaspartate may be of benefit in the moderation of dental plaque development.

Dental tartar is formed by the mineralization of dental plaque, which is a mixture of organic material in the form of protein and bacteria. In general, agents for the inhibition of dental tartar formation are believed to function by preventing or inhibiting the mineralization of such organic material and its deposition in inorganic form on the tooth surface. Unfortunately, agents that are effective in preventing the deposition of inorganic material on the surface of the tooth tend also to have the effect of causing demineralisation of the teeth themselves, lo loss of inorganic material from the tooth enamel, which is clearly undesirable. Agents that are particularly effective at preventing mineralization and deposition on the tooth surface are therefore not necessarily ideal, or even acceptable, components of an oral care composition.

There thus exists a need for an agent that is effective in preventing deposition of inorganic material on the surface of a tooth, yet which does not lead to undue demineralisation of the tooth surface. Surprisingly, we have now found that polyaspartate has properties that satisfy in large measure these conflicting 1060/661/P/GB - Complete requirements and which hence render polyaspartate useful as an agent for the inhibition of dental tartar.

According to a first aspect of the present invention, there is provided the use of polyaspartate to inhibit the formation of dental tartar.

The term "polyaspartate" means in the context of the present invention polyaspartic acid (ie a polymer of aspartic acid residues) and salts thereof. Salts of polyaspartic acid are preferably water-soluble salts, and include salts of Group I and Group II metals, particularly Group I metals, and especially the sodium salt.

Preferably, the polyaspartate has an average molecular weight of up to 50, 000, preferably 2,000 to 20,000, and more preferably 2,000 to 15,000. The polyaspartate may comprise a blend of grades of polyaspartate. A particularly preferred blend comprises equal proportions of a first form of polyaspartate having an average molecular weight in the range 2,000 to 4,000, a second form of polyaspartate having an average molecular weight in the range 4,000 to 10,000 and a third form of polyaspartate having an average molecular weight in the range 10,000 to 50,000.

Suitable grades of polyaspartate are available from Donlar Corporation, 6502 South Archer Road, Bedford Park, IL 60501, USA, and from Bayer AG, Bayerwerk, D-51368 Leverkusen, Germany.

The polyaspartate preferably comprises from about 15 to about 40 aspartic acid residues, linked by either an- or ap-peptide linkages.

The polyaspartate is preferably applied to the teeth in the form of an oral care composition comprising polyaspartate and a dentally-acceptable carrier.

1060/661/P/GB - Complete The polyaspartate is preferably present in the compositions at a level of between 0.0005 and 0.5% w/w, more preferably 0.001 to 0.1% w/w, and most preferably 0.005 to 0.05% w/w of the total composition.

As noted above, the compositions are beneficial in that they are useful in inhibiting the formation of dental tartar, and certain such compositions are believed to be novel. Thus, according to a further aspect of the invention there is provided an oral care composition comprising polyaspartate in an amount effective to inhibit dental tartar formation, the composition being substantially free of non-ionic block copolymers, in particular polyoxyethylene, polyoxypropylene block copolymers and polyoxyethylene, polyoxypropylene block copolymers of ethylene diamine.

The compositions according to the invention are advantageous primarily in that they inhibit or prevent the formation of dental tartar, while at the same time not leading to excessive demineralisation of the tooth enamel.

By "substantially free" is meant that the composition contains an amount of the ingredient in question, eg non-ionic block copolymers, that is nil or is so low as to have no significant effect on the properties of the composition. The concentration of such an ingredient may therefore be less than 0. 1% w/w, or less than 0.01% w/w, or less than 0.001% w/w.

According to another aspect of the invention there is provided a method for inhibiting or preventing the formation of dental tartar, which method comprises the administration to the teeth of a human or animal subject susceptible to tartar formation of an oral care composition comprising polyaspartate in an amount effective to inhibit dental tartar formation. Similarly, there is provided the use of polyaspartate in the manufacture of a composition for inhibiting the formation of dental tartar.

1060/661/P/GB - Complete As also noted above, the compositions according to the invention are further beneficial in that their use does not lead to excessive demineralisation of the tooth enamel. In a further aspect, the invention thus provides the use of polyaspartate to inhibit the demineralisation of tooth enamel. Similarly, there is provided the use of polyaspartate in the manufacture of a composition for inhibiting the demineralisation of tooth enamel.

As used herein, an "oral care composition" is any composition suitable and intended for administration to the buccal cavity for the purpose of improving the appearance of the teeth. The composition may, for instance, be formulated as a toothpaste, mouthrinse, toothgel, tooth paint or a dental gel.

The compositions according to the invention may, as appropriate, contain further components which are well known to those skilled in the art of oral care compositions, such as, for example, humectants, surfactants, abrasives, fluoride sources, desensitizing agents, flavourings, colourings, sweeteners, antimicrobial agents to act as preservatives, bactericides and/or anti-plaque agents, structuring agents, chelating agents, whitening agents, vitamins and any other therapeutic actives. The choice and amount of additives for any particular form of composition will be evident to, or readily determined by, those skilled in the art.

Suitable humectants for use in dentifrice compositions include polyhydric alcohols such as xylitol, sorbitol, glycerol, propylene glycol and polyethylene glycols.

Sorbitol, and mixtures of glycerol and sorbitol or sorbitol and xylitol, are particularly effective. A humectant helps to prevent dentifrice compositions from hardening on exposure to air, and may also provide a moist feel, smooth texture, flowability, and a desirable sweetness in the mouth. Suitably, such humectants may comprise from about 0-85%, preferably from about 20-80% by weight of the composition.

1060/661/P/GB - Complete Suitable surfactants for use in dentifrices, mouthwashes etc. are usually water-soluble organic compounds, and may be anionic, non-ionic, cationic or amphoteric species.

Anionic surfactants include the water-soluble salts of C10-C18 alkyl sulphates (eg sodium lauryl sulfates), water soluble salts of C10-C18 ethoxylated alkyl sulphates, water soluble salts of C1 0-C18 alkyl sarcosinates, the water-soluble salts of sulfonated monoglycerides of C10C18 fatty acids (eg sodium coconut monoglyceride sulfonates), alkyl aryl sulfonates (eg sodium dodecyl benzene sulfonate), sodium salts of the coconut fatty acid amide of N-methyltaurine and sodium salts of long chain olefin sulfonates (eg sodium C14-C16 olefin sulfonates).

Non-ionic surfactants suitable for use in oral compositions include the products of the condensation of alkylene oxide groups with aliphatic or alkylaromatic species, and may be for example, polyethylene oxide condensates of alkyl phenols, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures thereof. Alternatives include ethoxylated sorbitan esters such as those available from ICI under the trade name "Tween".

Cationic surfactants are generally quaternary ammonium compounds having one C8-C18 alkyl chain and include, for example, lauryl trimethylammonium chloride, cetyl trimethylammonium bromide, cetyl pyridinium chloride, diisobutylphenoxyethoxyethyidimethylbenzylammonium chloride, coconut alkyl trimethylammonium nitrite and cetyl pyridinium fluoride.

Also useful are benzyl ammonium chloride, benzyl dimethyl stearylammonium chloride, and tertiary amines having one C1-C18 hydrocarbon group and two (poly)oxyethylene groups.

1060/661/P/GB - Complete Amphoteric surfactants may be aliphatic secondary and tertiary amines comprising aliphatic species which may be branched or unbranched, and in which one of the aliphatic species is a C8- C18 species and the other contains an anionic hydrophilic group, for example, sulfonate, carboxylate, sulfate, phosphonate or phosphate. Examples of quaternary ammonium compounds are the quaternized imidazole derivatives available under the trade name 'Miranol' from the Miranol Chemical Company. Other amphoteric surfactants that may be employed are fatty acid amide alkyl betaines where one alkyl group is commonly C10-C12 such as cocamido propyl betaine, for example Tego Betain supplied by T H Goldschmidt.

Flavouring agents may be added to increase palatability and may include, for example, menthol, oils of peppermint, spearmint, wintergreen, sassafras and clove. Sweetening agents may also be used, and these include D-tryptophan, saccharin, dextrose, aspartame, levulose, acesulfam, dihydrochalcones and sodium cyclamate.

Colouring agents and pigments may be added to improve the visual appeal of the composition. Suitable colourants include dyes and pigments. A suitable and commonly used pigment is pigment grade titanium dioxide, which provides a strong white colour.

Suitably, as described above, the compositions of the invention may include a further antimicrobial agent as a preservative, antibacterial and/or anti-plaque agent. Suitable antimicrobial agents include water soluble sources of certain metal ions such as zinc, copper and silver such as zinc citrate and silver chloride, cetyl pyridinium chloride, the bis-biguanides (such as chlorhexidine), aliphatic amines, phenolics such as bromochlorophene and triclosan, salicylanilides and quaternary ammonium compounds. Optionally, the formulations may also contain enzymes that will disrupt the pellicle or interfere with bacterial intercellular polysaccharides. Examples include proteases such as papain and bromelain or 1060/661/P/GB - Complete dextranases. Natural enzymatic biocidal systems such as a system comprising lactoperoxidase and glucose oxidase may also be employed.

In addition to the polyaspartate, the composition may also comprise one or more further anti-tartar agents. Suitable anti-tartar agents include zinc salts such as zinc citrate and zinc chloride, polyphosphates and pyrophosphates. Suitable pyrophosphates include the sodium and potassium pyrophosphates, preferably disodium pyrophosphate, dipotassium pyrophosphate, tetrasodium pyrophosphate and tetrapotassium pyrophosphate. A preferred source of pyrophosphate is a mixture of tetrasodium pyrophosphate and tetrapotassium pyrophosphate.

Suitable polyphosphates include sodium tripolyphosphate.

Preferably, however, the polyaspartate is the only anti-tartar agent present in the composition, the composition being substantially free of other anti-tartar agents.

Structuring (gelling) agents may be required in, for example, dentifrices and gums to provide desirable textural properties and "mouthfeel". Suitable agents include natural gum binders such as gum tragacanth, xanthan gum, gum karaya and gum arable, seaweed derivatives such as Irish moss and alginates, smectite clays such as bentonite or hectorite, carboxyvinyl polymers and water-soluble cellulose derivatives such as hydroxyethyl cellulose and sodium carboxymethyl cellulose.

Improved texture may also be achieved, for example, by including colloidal magnesium aluminium silicate.

Suitable vitamins for inclusion in the oral care compositions of the present invention include vitamins A, B5, B6, C and E. The composition may also comprise a polymer to enhance delivery and retention of the active ingredients to the tooth surface. Suitable polymers may include PVM/MA (poly(vinylmethylether/maleic acid)) copolymers eg Gantrez S-97 from IS P. PVP (polyvi nyl pyrrolidone) or PVP/VA (polyvi nyl pyrrol idone/vi nyl acetate) 1060/6611P/GB - Complete copolymers, eg Plasdone S-630 from ISP, and similar materials from other suppliers.

Where the composition contains any of the further ingredients or excipients mentioned above, the concentrations of such ingredients may be generally similar to those conventional in dental compositions of the corresponding form.

The efficacy of the compositions according to the invention in the inhibition of tartar formation, and of tooth demineralisation, may be demonstrated by the following methods, in which the results obtained using polyaspartate are contrasted with those obtained using sodium pyrophosphate, an established anti- tartar agent.

Method A - Anti-tartar activity This method utilises the following reaction to model the deposition of mineral and hence tartar formation in the mouth: 5Ca + 3HPO42-+ H20 Ca5 (PO4)30H +4H+ HAP represents hydroxyapatite, which mimics the behaviour of enamel mineral in the mouth, and acts as a "seed" for crystal growth. In the following experiments, an artificial saliva formulation is used as the source of free Ca2+.

Crystal growth inhibition is determined by mixing calcium and phosphate ions in the presence of hydroxyapatite, filtering after a predetermined time, and measuring the remaining calcium concentration in the filtrate.

Matenals 1060/661/P/GB - Complete Polyaspartate (1:1:1 blend of polyaspartates of molecular weights 3,000, 5,000 and 30,000 - Donlar Corporation, USA) Sodium pyrophosphate Hydroxyapatite crystals (surface area 18m2/g) Na2HPO4 - 93.6mM EDTA Na4- 0.5M NaOH - 1 M Artificial Saliva - having the composition set out in Table 1

Table 1.

Material Concentration Calcium Chloride 2.0mM Magnesium Chloride 4.2mM Sodium Chloride 4.0mM Sodium Thiocyanate 1.3mM Sodium Fluoride 15pM Potassium iodide 8.0nM Potassium Bicarbonate 5.0mM Potassium Dihydrogen 6. 0mM Phosphate Potassium Chloride 10.0mM Urea 3.2mM Glucose 0.55mM Lactoferrin 5.4 mg/l Lysozyme 0.264 g/l a-Amylase 0.38 g/l Lactoperoxidase 2.0 mg/l Serum Albumin 2.2 g/l 1060/661/P/GB - Complete Test solutions are prepared in delonised water at 1 Ox the required final concentrations.

Method 1. All solutions were prepared to the concentrations given above. Solutions of the test reagents (Oppm, 50ppm, 100ppm and 200ppm polyaspartate, and 10,000ppm sodium pyrophosphate for comparative purposes) were prepared at 1 Ox the required final concentrations in the Na2HPO4 solution.

2. 0.19 hydroxyapatite (HA) crystals was accurately weighed into test tubes, which were then placed in a water bath at 37 C.

3. 1 ml Na2HPO4 test solution was added to each of the tubes containing hydroxyapatite.

4. 9 ml of artificial saliva (as the free Ca 2+ source) was added by pipette into clean test tubes and these were also placed in the water bath.

5. Both sets of tubes were allowed to thermally equilibrate.

6. The artificial saliva was then added to the tubes containing the HA and test solutions (to) 7. After 30 minutes, each tube was removed from the water bath, a 1 Oml aliquot of the suspension was removed and filtered through a 451lm Whatman syringe filter.

8. 5ml of the filtrate was added to 5ml 0.5M EDTA Na4 in a labelled tube.

9. The filtrate was analysed for calcium content using Inductively Coupled Plasma Spectroscopy calibrated with an appropriate range of Ca2+ standards prepared in artificial saliva.

Results The results are shown in Figure 1. As can be seen, the concentration of Ca2+ in the solutions containing polyaspartate is comparable to that of the solution containing sodium pyrophosphate.

1060/661/P/GB - Complete Method B - Demineralisation activity This method utilises the following equation to model the demineralisation potential of anti-tartar agents: Ca5(PO4)3OH + 4H+ 5Ca2+ + 3HPO42- + H2O Materials Hydroxyapaptite crystals (surface area 18m2/g) EDTA Na4 - 0.5M Artificial Saliva - as for Method A (see Table 1) Test solutions are prepared in delonised water at 10x the required final concentrations (50, 100, 200 and 400ppm polyaspartate and 10,000ppm sodium pyrophosphate).

Method 1. 27ml of artificial saliva was added by pipette to a beaker and the beaker placed in a water bath at 37 C.

2. 3ml of test solution was added and the solution allowed to thermally equilibrate.

3. 0.3g of hydroxyapatite (HA) crystals was added to the beaker (to) and shaken. The beaker was covered in parafilm to prevent evaporation. (Note: beakers were shaken constantly during the course of the experiment).

4. At t=120 minutes sample aliquots were removed and filtered using a 45, um Whatman syringe filter.

5. 5ml of the filtrate was added to 5ml 0.5M EDTA Na4 in a labelled tube.

1060/661/P/GB - Complete 6. Samples were analysed for calcium content using Inductively Coupled Plasma Spectroscopy calibrated against an appropriate range of Ca2+ standards prepared in artificial saliva.

Results The results are shown in Figure 2. As can be seen, the concentration of Ca2+ present in the filtrate showed a general decrease with increasing concentration of polyaspartate, and was substantially lower that that measured when the polyaspartate was replaced by sodium pyrophosphate.

The invention will now be described in greater detail, by way of illustration only, with reference to the following non-limiting Examples:

Example 1

Anti-tartar toothpaste with anti-olaque anent Material % w/w Sorbitol (70% sole) 25.00 Silica abrasive 6.67 Silica thickener 10.00 Sodium carboxymethyl cellulose 0.90 Sodium fluoride 0.22 Titanium dioxide 0.50 Sodium saccharin 0.20 Bromochlorophene 0.1 0 Sodium polyaspartate (40% sole) 0.125 PEG-32 1.39 Sodium lauryl sulphate 1.50 Flavour 1.00 Water To 100% Method of preparation 1060/661/P/GB - Complete Sodium fluoride, sodium saccharin, PEG-32 and sodium polyaspartate are added to water and stirred to dissolve. Sorbitol (70% sole) is added and mixed until homogenous. Silica abrasive, silica thickener, sodium carboxymethyl cellulose, titanium dioxide and sodium lauryl sulphate are added under vacuum and the bulk mixed until homogeneous. Bromochlorophene is dissolved in flavour and added to bulk and mixed until homogenous.

Example 2

Anti-tartar mouthwash Material % w/w Sorbitol (70%) 10.00 Cetylpyridinium chloride 0.05 Sodium fluoride 0.055 Sodium saccharin 0.04 Ethanol (96%) 7. 40 PEG-40 hydrogenated castor oil 0.15 Polysorbate 20 0.15 Sodium polyaspartate (40% sole) 0.0125 Flavour 0.1 5 Colour As required Water To 100% Method of preparation Sodium fluoride, sodium saccharin and sodium polyaspartate are dissolved in water with stirring. Sorbitol (70%) is added. Flavour is mixed with PEG-40 hydrogenated castor oil and polysorbate 20 and mixed until fully dissolved.

Ethanol is added to flavour premix and mixed. Flavour/alcohol mix is added to bulk and stirred until homogeneous.

Claims (18)

1060/661/P/GB - Complete Claims 1. The use of polyaspartate to inhibit the

formation of dental tartar.

2. Use as claimed in Claim 1, wherein the polyaspartate is a salt of polyaspartic acid.

3. Use as claimed in Claim 2, wherein the salt is a sodium salt.

4. Use as claimed in any preceding claim, wherein the polyaspartate has a molecular weight of up to 50,000, preferably 2,000 to 20,000, and more preferably 2,000 to 15,000.

5. Use as claimed in any preceding claim, wherein the polyaspartate comprises from about 15 to about 40 aspartic acid residues, linked by either on- or op-peptide linkages.

6. Use as claimed in any preceding claim, wherein the polyaspartate is applied to the teeth in the form of an oral care composition comprising polyaspartate and a dentally acceptable carrier.

7. Use as claimed in Claim 6, wherein the polyaspartate is present at a level of between 0.001 and 1% w/w, more preferably 0.005 to 0.5% w/w, and most preferably 0.01 to 0.1% w/w of the total composition.

8. Use as claimed in any preceding claim, wherein the composition has the form of a toothpaste, mouthrinse, toothgel, tooth paint or a dental gel.

9. An oral care composition comprising polyaspartate in an amount effective to inhibit dental tartar formation, the composition being substantially free of non-ionic block copolymers, in particular polyoxyethylene, polyoxypropylene block 1060/661/P/GB - Complete copolymers and polyoxyethylene, polyoxypropylene block copolymers of ethylene Famine.

10. A composition as claimed in Claim 9, which comprises one or more further components selected from humectants, surfactants, abrasives, fluoride sources, desensitizing agents, flavourings, colourings, sweeteners, antimicrobial agents to act as preservatives, bactericides and/or anti-plaque agents, structuring agents, chelating agents, whitening agents, vitamins and any other therapeutic actives.

11. A composition as claimed in Claim 9 or Claim 10, wherein the polyaspartate is the only anti-tartar agent present in the composition, the composition being substantially free of other anti-tartar agents.

12. A method for inhibiting or preventing the formation of dental tartar, which method comprises administering to the teeth of a human or animal subject susceptible to tartar formation of an oral care composition comprising polyaspartate in an amount effective to inhibit dental tartar formation.

13. The use of polyaspartate in the manufacture of a composition for inhibiting the formation of dental tartar.

14. A method as claimed in Claim 12 or a use as claimed in Claim 13, wherein the composition is a composition as claimed in any one of Claims 9 to 11.

15. The use of polyaspartate to inhibit the demineralisation of tooth enamel.

16. A use as claimed in Claim 15, wherein the polyaspartate is applied in the form of a composition as claimed in any one of Claims 9 to 11.

17. The use of polyaspartate in the manufacture of a composition for inhibiting the demineralisation of tooth enamel.

1060/661/P/GB - Complete

18. A use as claimed in Claim 17, wherein the composition is a composition as claimed in any one of Claims 9 to 11.