WO2021047971A1 - Method for remineralizing and/or reducing sensitivity of teeth - Google Patents

Method for remineralizing and/or reducing sensitivity of teeth Download PDF

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Publication number
WO2021047971A1
WO2021047971A1 PCT/EP2020/074413 EP2020074413W WO2021047971A1 WO 2021047971 A1 WO2021047971 A1 WO 2021047971A1 EP 2020074413 W EP2020074413 W EP 2020074413W WO 2021047971 A1 WO2021047971 A1 WO 2021047971A1
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WIPO (PCT)
Prior art keywords
ceramic
bioactive
phosphate
composition
mixtures
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PCT/EP2020/074413
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French (fr)
Inventor
Huanjun ZHOU
Meili Zhang
Weining LIU
Yuekui SUN
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Unilever Ip Holdings B.V.
Unilever Global Ip Limited
Conopco, Inc., D/B/A Unilever
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Publication of WO2021047971A1 publication Critical patent/WO2021047971A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/25Silicon; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the present invention relates to tooth remineralization and/or the treatment of tooth hypersensitivity.
  • the invention relates to the use of bioactive ceramics, or compositions comprising bioactive ceramics, for remineralizing and/or reducing sensitivity of teeth of an individual.
  • Teeth comprise dentin overlaid with an outer layer of enamel. Teeth are under constant attack from chemical and physical forces, including bacteria-derived acids and mechanical wear, resulting in demineralization and weakening of enamel and the underlying dentin.
  • Tooth hypersensitivity is a temporary induced pain sensation that affects up to 20% of the adult population. It is associated with tooth demineralization and the loss of either enamel or cementum to expose underlying dentin.
  • the dentin of the tooth generally contains channels, called tubules, which provide for an osmotic flow between the inner pulp region of the tooth and the outer root surfaces.
  • the cause of tooth hypersensitivity may be related to demineralization giving rise to increased exposure of tubules and permeability of the dentine.
  • the most common causes of demineralization of the enamel or dentine are attrition, abrasion, gingival recession and erosion. When root surfaces are exposed, dentinal tubules are also exposed.
  • tooth hypersensitivity is the hydrodynamic theory, based on the belief that open exposed dentinal tubules allow fluid flow through the tubules. This flow excites the nerve endings in the dental pulp.
  • Clinical replica of sensitive teeth viewed in a SEM (scanning electron microscopy) reveal varying numbers of open or partially occluded dentinal tubules.
  • Efforts have been made over the years to treat tooth hypersensitivity.
  • One approach is to reduce the excitability of the nerve in a sensitive tooth by using “nerve-depolarising agents” comprising strontium ions, potassium salts such as potassium nitrate, potassium bicarbonate, potassium chloride and the like. These nerve-depolarising agents function by interfering with neural transduction of the pain stimulus to make the nerve less sensitive.
  • tubule blocking agents that fully or partially occlude tubules such as polystyrene beads, apatite, polyacrylic acid, mineral hectorite clay and the like. These tubule blocking agents function by physically blocking the exposed ends of the dentinal tubules, thereby reducing dentinal fluid movement and reducing the irritation associated with the shear stress described by the hydrodynamic theory.
  • Bioactive ceramics are used in bone repair applications and are being developed for tissue engineering applications. Such materials are called “bioactive” because interfacial bonds form between the material and surrounding tissues.
  • Ca-P ceramics typically, hydroxyapatite (HAP) and b-tricalcium phosphate (b-TCP) ceramics are widely used for bone tissue replacement and regeneration due to their generally good biocompatibility and similar chemical composition with biological apatite in bone tissues.
  • HAP hydroxyapatite
  • b-TCP b-tricalcium phosphate
  • Other elements like magnesium (Mg) or silicon (Si) have been incorporated into Ca-P bioactive ceramics to enhance their bioactivity.
  • CN 1623952 A (Shanghai Institute of Ceramics, Chinese Academy of Sciences) discloses a preparation method and use of bredigite (Ca7MgSUOi6).
  • the bioactive ceramic can be used as bone hard tissue repair and implant materials.
  • CN 102584203 A (Shanghai Institute of Ceramics, Chinese Academy of Sciences) discloses a preparation method of a bioactive ceramic material nagelschmidtite (Ca 7 Si 2 P 2 0 16 ) that can support adherence and proliferation of bone marrow stromal cells. Compared with traditional b-tricalcium phosphate ceramics, the bioactive ceramic can better promote osteogenic differentiation of the bone marrow stromal cells and has higher degradability.
  • a publication (C.Wu, J. Chang, W. Zhai, S. Ni, “A novel bioactive porous bredigite (Ca7MgSUOi6) scaffold with biomimetic apatite layer for bone tissue engineering”, J Mater Sci Mater Med, 2007, 18, pp. 857-864) discloses a novel bioactive, degradable and cytocompatible bredigite (Ca7MgSUOi6) scaffold with biomimetic apatite layer for bone tissue engineering.
  • the present inventors have surprisingly found that bioactive ceramics or compositions comprising bioactive ceramics can be used to treat tooth hypersensitivity by occluding the open dentinal tubules and to remineralize teeth by rebuilding the enamel layer.
  • “Dentifrice” for the purposes of the present invention means a paste, powder, liquid, gum or other preparation for cleaning the teeth or other surfaces in the oral cavity.
  • Tooth paste for the purpose of the present invention means a paste or gel dentifrice for use with a toothbrush. Especially preferred are tooth pastes suitable for cleaning teeth by brushing for about two minutes.
  • Particle size for the purpose of the present invention means D50 particle size.
  • the D50 particle size of a particulate material is the particle size diameter at which 50 wt% of the particles are larger in diameter and 50 wt% are smaller in diameter.
  • Refractive index is quoted at a temperature of 25°C and a wavelength of 589 nm.
  • “Soluble” and “insoluble” for the purpose of the present invention means the solubility of a source (e.g., like calcium salts) in water at 25°C and atmospheric pressure.
  • “Soluble” means a source that dissolves in water to give a solution with a concentration of at least 0.1 moles per litre.
  • “Insoluble” means a source that dissolves in water to give a solution with a concentration of less than 0.001 moles per litre.
  • “Remineralization” for the purpose of the present invention means in situ (i.e. in the oral cavity) generation of calcium phosphate on teeth (including layers on teeth from 10 nm to 20 microns, and preferably from 75 nm to 10 microns, and most preferably, from 150 nm to 5 microns thick including all ranges subsumed therein) to reduce the likelihood of tooth sensitivity, tooth decay, regenerate enamel and/or improve the appearance of teeth by whitening through the generation of such new calcium phosphate.
  • the present invention is directed to a bioactive ceramic or a composition comprising a bioactive ceramic for use in remineralizing and/or reducing sensitivity of teeth of an individual.
  • the present invention is directed to non-therapeutic use of a bioactive ceramic or a composition comprising a bioactive ceramic for remineralizing and/or reducing sensitivity of teeth of an individual.
  • the present invention is directed to use of a bioactive ceramic or a composition comprising a bioactive ceramic in the manufacture of a medicament in remineralizing and/or reducing sensitivity of an individual.
  • the present invention is directed to a method for remineralizing and/or reducing sensitivity of teeth of an individual comprising the step of applying a bioactive ceramic or a composition comprising a bioactive ceramic to at least one surface of the teeth of the individual.
  • the method is preferably for non-therapeutic benefits.
  • Bioactive materials usually include ceramics, glasses and glass-ceramics, which can attach directly to bone tissue via a biologically active carbohydroxyapaptite layer that provides the interfacial bonding.
  • Bioactive glasses have an amorphous structure, whereas glass-ceramics are crystallized glasses, consisting of a composite of a crystalline phase and a residual glassy phase.
  • Bioactive ceramics have a fully crystalline structure.
  • Bioactive ceramics are an important subset of bioactive materials. Bioactive ceramics range in biocompatibility from the ceramic oxides, which are inert in the body, to the other extreme of resorbable materials, which are eventually replaced by the body after they have assisted repair.
  • Bioactive ceramics refers to ceramic materials comprising calcium oxide (CaO), silicon dioxide (S1O2), magnesium oxide (MgO) or phosphorous oxide (P 2 O 5 ) which possess good biocompatibility and bioactivity.
  • the bioactive ceramic suitable for use in this invention is Ca, P, Si, or Mg-containing ceramic.
  • the bioactive ceramic is a Ca, Si and P- containing ceramic, a Ca, Si and Mg- containing ceramic or mixtures thereof.
  • Illustrative yet non-limiting examples of the bioactive ceramic that may be used in this invention include, for example, bredigite (Ca7MgSUOi6), merwinite (CasMgShOs), akermanite (Ca2MgSi2C>7), diopside (CaMgShOe), monticellite (CaMgSiCL), nagelschmidtite (Ca7Si2P20i6), silicocarnotite (Ca 5 SiP 2 0i 2 ), mixtures thereof or the like.
  • the bioactive ceramic is bredigite (Ca7MgSUOi6), nagelschmidtite (Ca 7 Si 2 P 2 0i 6 ) or mixtures thereof.
  • the bioactive ceramic may further comprise one or more elements selected from Zn, Cu, Sn, Na, Li, K, B, Sr, Ti, Al, N, Ag or F.
  • Bioactive ceramics are typically made by sol-gel process. Suitable preparation methods for bioactive ceramics are described, for example, in C. Wu, W. Fan, Jiang. C, M. Zhang, Y. Xiao, J. Am. Ceram. Soc., 2013, 96, 3, pp. 928-934, C.Wu, J. Chang, W. Zhai, S. Ni, J Mater Sci” Mater Med, 2007, 18, pp. 857-864, and W. Lu, W. Duan, Y. Guo, C. Ning, J Biomater. AppL, 2012, 26, pp. 637-650.
  • the bioactive ceramic is particulate which allows for maximum surface area for contact with dental tissue.
  • the bioactive ceramic used in this invention has a particle size from 100 nm to 50 microns, preferably from 500 nm to 30 microns, more preferably from 700nm to 20 microns, most preferably from 1 micron to 15 microns.
  • a composition comprising the bioactive ceramic as described above is also included in the present invention.
  • the composition is an oral care composition.
  • the oral care composition comprises from 0.1 to 80% by weight of the bioactive ceramic, more preferably from 0.2 to 50% and most preferably from 1 to 30%, based on total weight of the oral care composition and including all ranges subsumed therein.
  • An oral care composition typically has a pH ranging from 5.5 to 10.0, preferably from 6.0 to 10.0, which helps maintain a healthy mouth and protect the teeth.
  • a lower pH may induce the enamel to demineralize and a higher pH may cause mucosa irritation.
  • the phosphate source that may be used in this invention is limited only to the extent that the same may be used in a composition suitable for use in the mouth.
  • Illustrative examples of the phosphate source suitable for use in this invention include trisodium phosphate, monosodium dihydrogen phosphate, disodium hydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, tripotassium phosphate, monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, mixtures thereof or the like.
  • the phosphate source is preferably one which is water soluble.
  • the phosphate source is trisodium phosphate, monosodium dihydrogen phosphate or a mixture thereof.
  • the phosphate source is trisodium phosphate and monosodium dihydrogen phosphate at a trisodium phosphate to monosodium dihydrogen phosphate weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1, and most preferably, from 1:2 to 2:1, including all ratios subsumed therein.
  • the phosphate source When used, the phosphate source typically makes up from 0.5 to 40%, and more preferably, from 1 to 30%, and most preferably, from 2 to 20% by weight of the oral care composition, based on total weight of the oral care composition and including all ranges subsumed therein.
  • the oral care composition preferably comprises the bioactive ceramic and the phosphate source in a weight ratio from 1:10 to 30:1, more preferably from 1:5 to 20:1, most preferably from 1:3 to 15:1.
  • the oral care composition of the present invention typically comprises a physiologically acceptable carrier.
  • the carrier preferably comprises at least surfactant, thickener, humectant or a combination thereof.
  • the oral care composition comprises a surfactant.
  • the composition comprises at least 0.01% surfactant by weight of the composition, more preferably at least 0.1% and most preferably from 0.5 to 7%.
  • Suitable surfactants include anionic surfactants, such as the sodium, magnesium, ammonium or ethanolamine salts of Cs to Ci 8 alkyl sulphates (for example sodium lauryl sulphate), Cs to Cis alkyl sulphosuccinates (for example dioctyl sodium sulphosuccinate), Cs to Cis alkyl sulphoacetates (such as sodium lauryl sulphoacetate), Cs to Cis alkyl sarcosinates (such as sodium lauryl sarcosinate), Cs to Cis alkyl phosphates (which can optionally comprise up to 10 ethylene oxide and/or propylene oxide units) and sulphated monoglycerides.
  • anionic surfactants such as the sodium, magnesium, am
  • Suitable surfactants include nonionic surfactants, such as optionally polyethoxylated fatty acid sorbitan esters, ethoxylated fatty acids, esters of polyethylene glycol, ethoxylates of fatty acid monoglycerides and diglycerides, and ethylene oxide/propylene oxide block polymers.
  • suitable surfactants include amphoteric surfactants, such as betaines or sulphobetaines. Mixtures of any of the above described materials may also be used.
  • the surfactant comprises or is anionic surfactant.
  • the preferred anionic surfactants are sodium lauryl sulphate and/or sodium dodecylbenzene sulfonate.
  • the surfactant is sodium lauryl sulphate, sodium coco sulfate, cocamidopropyl betaine, sodium methyl cocoyl taurate or mixtures thereof.
  • Thickener may also be used in this invention and is limited only to the extent that the same may be added to a composition suitable for use in the mouth.
  • Illustrative examples of the types of thickeners that may be used in this invention include, sodium carboxymethyl cellulose (SCMC), hydroxyl ethyl cellulose, methyl cellulose, ethyl cellulose, gum tragacanth, gum arabic, gum karaya, sodium alginate, carrageenan, guar, xanthan gum, Irish moss, starch, modified starch, silica based thickeners including silica aerogels, magnesium aluminum silicate (e.g., Veegum), Carbomers (cross-linked acrylates) and mixtures thereof.
  • SCMC sodium carboxymethyl cellulose
  • hydroxyl ethyl cellulose hydroxyl ethyl cellulose
  • methyl cellulose methyl cellulose
  • ethyl cellulose gum tragacanth
  • gum arabic gum karay
  • xanthan gum and/or sodium carboxymethyl cellulose and/or a Carbomer is/are preferred.
  • a Carbomer those having a weight-average molecular weight of at least 700,000 are desired, and preferably, those having a molecular weight of at least 1,200,000, and most preferably, those having a molecular weight of at least about 2,500,000 are desired. Mixtures of Carbomers may also be used herein.
  • the Carbomer is Synthalen PNC, Synthalen KP or a mixture thereof. It has been described as a high molecular weight and cross-linked polyacrylic acid and identified via CAS number 9063-87-0. These types of materials are available commercially from suppliers like Sigma.
  • the sodium carboxymethyl cellulose (SCMC) used is SCMC 9H. It has been described as a sodium salt of a cellulose derivative with carboxymethyl groups bound to hydroxy groups of glucopyranose backbone monomers and identified via CAS number 9004-32-4. The same is available from suppliers like Alfa Chem.
  • the thickener is xanthan gum.
  • Thickener typically makes up from 0.01 to about 10%, more preferably from 0.1 to 9%, and most preferably, from 0.1 to 5% by weight of the oral care composition, based on total weight of the composition and including all ranges subsumed therein.
  • the oral care composition of this invention is a toothpaste or gel
  • the same typically has a viscosity from about 30,000 to 180,000 centipoise, and preferably, from 60,000 to 170,000 centipoise, and most preferably, from 65,000 to 165,000 centipoise.
  • Suitable humectants are preferably used in the oral care composition of the present invention and they include, for example, glycerin, sorbitol, propylene glycol, dipropylene glycol, diglycerol, triacetin, mineral oil, polyethylene glycol (preferably, PEG-400), alkane diols like butane diol and hexanediol, ethanol, pentylene glycol, or a mixture thereof. Glycerin, polyethylene glycol, sorbitol or mixtures thereof are the preferred humectants.
  • the humectant may be present in the range of from 10 to 90% by weight of the oral care composition. More preferably, the carrier humectant makes up from 25 to 80%, and most preferably, from 30 to 60% by weight of the composition, based on total weight of the composition and including all ranges subsumed therein.
  • the oral care composition may further comprise abrasives.
  • Preferred abrasives include silicas, aluminas, calcium carbonates, dicalcium phosphates, calcium pyrophosphates, hydroxyapatites, trimetaphosphates, insoluble hexametaphosphates or mixtures thereof, including agglomerated particulate abrasives. Calcium carbonate and silica are particularly preferred, especially silica.
  • the abrasives may be present in the range of from 0.01 to 60%, more preferably from 0.1 to 30%, and most preferably from 1 to 15% by weight of the oral care composition, based on total weight of the composition and including all ranges subsumed therein.
  • the oral care composition of the present invention may contain a variety of other ingredients which are common in the art to enhance physical properties and performance. These ingredients include opacifying agents, colouring agents, anti-microbial agents, anti inflammatory agents, anti-caries agents, plaque buffers, vitamins, plant extracts, desensitizing agents, anti-calculus agents, biomolecules, flavours, proteinaceous materials, preservatives, pH-adjusting agents, sweetening agents, polymeric compounds, buffers and salts to buffer the pH and ionic strength of the compositions, and mixtures thereof.
  • these ingredients include opacifying agents, colouring agents, anti-microbial agents, anti inflammatory agents, anti-caries agents, plaque buffers, vitamins, plant extracts, desensitizing agents, anti-calculus agents, biomolecules, flavours, proteinaceous materials, preservatives, pH-adjusting agents, sweetening agents, polymeric compounds, buffers and salts to buffer the pH and ionic strength of the compositions, and mixtures thereof.
  • Such ingredients typically and collectively make up less than 20% by weight of the composition, and preferably, from 0.0 to 15% by weight, and most preferably, from 0.01 to 12% by weight of the composition, including all ranges subsumed therein.
  • the oral care composition may be in any form common in the art, preferred forms are tooth pastes, gels, mouthwashes and whitening serums/gels.
  • the composition will be packaged.
  • tooth paste or gel form the composition may be packaged in a conventional plastic laminate, metal tube or a single compartment dispenser. The same may be applied to dental surfaces by any physical means, such as a toothbrush, fingertip or by an applicator directly to the sensitive area.
  • liquid mouthwash form the composition may be packaged in a bottle, sachet or other convenient container.
  • the composition can be effective even when used in an individual’s daily oral hygiene routine.
  • the composition may be brushed onto the teeth.
  • the composition may, for example, be contacted with the teeth for a time period of one second to 20 hours. More preferably from 1 s to 10 hours, more preferably still from 10 s to 1 hour and most preferably from 30 s to 5 minutes.
  • the composition may be used daily, for example for use by an individual once, twice or three times per day.
  • Human dentine discs were eroded by 6% citric acid for 2 mins, then they were treated with different slurries via brushing following the same protocol.
  • the discs were then soaked in simulated oral fluid (SOF) for 3 ⁇ 4 hours under the condition of a shaking water bath at 37°C and 60.0 rpm. After that, the dentine discs were brushed with the slurry by machine using the same procedure as in the first step. The brushing was repeated three times for one day, then the dentine discs were kept in SOF overnight (>12 hours) in a shaking water bath at 37°C to mimic oral environment.
  • the dentine samples were characterized by scanning electron microscopy (SEM, Hitachi S-4800, Japan) after 3 brushings.
  • a square (with a size of 4mm x 4mm) is selected and one image is captured under 50x magnification. Within this square, five spots (each with a size of 150 pm x 150 pm, one in the middle, and one in every corner) are selected and observed under 1000x magnification.
  • the blockage of tubules is accessed following the standards described in Table 3. The measurement is carried out for the two dentine discs of each test group. TABLE 3
  • the enamel blocks were brushed with the slurry by machine using the same procedure as in the first step.
  • the brushing was repeated three times for one day, then the enamel blocks were kept in SOF overnight (>12 hours) in a shaking water bath at 37°C to mimic oral environment.
  • the enamel blocks were characterized by SEM (Hitachi S-4800, Japan) after 3 brushings.

Abstract

Disclosed are uses and methods for remineralizing and/or reducing sensitivity of teeth of an individual comprising the step of applying a bioactive ceramic or a composition comprising a bioactive ceramic to at least one surface of the teeth of the individual.

Description

METHOD FOR REMINERALIZING AND/OR REDUCING SENSITIVITY OF TEETH
Technical Field of the Invention
The present invention relates to tooth remineralization and/or the treatment of tooth hypersensitivity. In particular, the invention relates to the use of bioactive ceramics, or compositions comprising bioactive ceramics, for remineralizing and/or reducing sensitivity of teeth of an individual.
Background of the Invention
Teeth comprise dentin overlaid with an outer layer of enamel. Teeth are under constant attack from chemical and physical forces, including bacteria-derived acids and mechanical wear, resulting in demineralization and weakening of enamel and the underlying dentin.
Tooth hypersensitivity is a temporary induced pain sensation that affects up to 20% of the adult population. It is associated with tooth demineralization and the loss of either enamel or cementum to expose underlying dentin. The dentin of the tooth generally contains channels, called tubules, which provide for an osmotic flow between the inner pulp region of the tooth and the outer root surfaces. The cause of tooth hypersensitivity may be related to demineralization giving rise to increased exposure of tubules and permeability of the dentine. The most common causes of demineralization of the enamel or dentine are attrition, abrasion, gingival recession and erosion. When root surfaces are exposed, dentinal tubules are also exposed.
The currently accepted theory for tooth hypersensitivity is the hydrodynamic theory, based on the belief that open exposed dentinal tubules allow fluid flow through the tubules. This flow excites the nerve endings in the dental pulp. Clinical replica of sensitive teeth viewed in a SEM (scanning electron microscopy) reveal varying numbers of open or partially occluded dentinal tubules.
Efforts have been made over the years to treat tooth hypersensitivity. One approach is to reduce the excitability of the nerve in a sensitive tooth by using “nerve-depolarising agents” comprising strontium ions, potassium salts such as potassium nitrate, potassium bicarbonate, potassium chloride and the like. These nerve-depolarising agents function by interfering with neural transduction of the pain stimulus to make the nerve less sensitive.
Another approach is to use “tubule blocking agents” that fully or partially occlude tubules such as polystyrene beads, apatite, polyacrylic acid, mineral hectorite clay and the like. These tubule blocking agents function by physically blocking the exposed ends of the dentinal tubules, thereby reducing dentinal fluid movement and reducing the irritation associated with the shear stress described by the hydrodynamic theory.
Bioactive ceramics are used in bone repair applications and are being developed for tissue engineering applications. Such materials are called “bioactive” because interfacial bonds form between the material and surrounding tissues. For example, Ca-P ceramics, typically, hydroxyapatite (HAP) and b-tricalcium phosphate (b-TCP) ceramics are widely used for bone tissue replacement and regeneration due to their generally good biocompatibility and similar chemical composition with biological apatite in bone tissues. Other elements like magnesium (Mg) or silicon (Si) have been incorporated into Ca-P bioactive ceramics to enhance their bioactivity.
CN 1623952 A (Shanghai Institute of Ceramics, Chinese Academy of Sciences) discloses a preparation method and use of bredigite (Ca7MgSUOi6). The bioactive ceramic can be used as bone hard tissue repair and implant materials.
CN 102584203 A (Shanghai Institute of Ceramics, Chinese Academy of Sciences) discloses a preparation method of a bioactive ceramic material nagelschmidtite (Ca7Si2P2016) that can support adherence and proliferation of bone marrow stromal cells. Compared with traditional b-tricalcium phosphate ceramics, the bioactive ceramic can better promote osteogenic differentiation of the bone marrow stromal cells and has higher degradability.
A publication (C.Wu, J. Chang, W. Zhai, S. Ni, “A novel bioactive porous bredigite (Ca7MgSUOi6) scaffold with biomimetic apatite layer for bone tissue engineering”, J Mater Sci Mater Med, 2007, 18, pp. 857-864) discloses a novel bioactive, degradable and cytocompatible bredigite (Ca7MgSUOi6) scaffold with biomimetic apatite layer for bone tissue engineering. The present inventors have surprisingly found that bioactive ceramics or compositions comprising bioactive ceramics can be used to treat tooth hypersensitivity by occluding the open dentinal tubules and to remineralize teeth by rebuilding the enamel layer.
Tests and Definitions
Dentifrice
“Dentifrice” for the purposes of the present invention means a paste, powder, liquid, gum or other preparation for cleaning the teeth or other surfaces in the oral cavity.
Tooth Paste
“Tooth paste” for the purpose of the present invention means a paste or gel dentifrice for use with a toothbrush. Especially preferred are tooth pastes suitable for cleaning teeth by brushing for about two minutes.
Particle Size
“Particle size” for the purpose of the present invention means D50 particle size. The D50 particle size of a particulate material is the particle size diameter at which 50 wt% of the particles are larger in diameter and 50 wt% are smaller in diameter.
Refractive Index
Refractive index is quoted at a temperature of 25°C and a wavelength of 589 nm. Solubility
“Soluble” and “insoluble” for the purpose of the present invention means the solubility of a source (e.g., like calcium salts) in water at 25°C and atmospheric pressure. “Soluble” means a source that dissolves in water to give a solution with a concentration of at least 0.1 moles per litre. “Insoluble” means a source that dissolves in water to give a solution with a concentration of less than 0.001 moles per litre. “Slightly soluble”, therefore, is defined to mean a source that dissolves in water to give a solution with a concentration of greater than 0.001 moles per litre and less than 0.1 moles per litre.
Viscosity
Viscosity of a tooth paste is the value taken at room temperature (25 °C) with a Brookfield Viscometer, Spindle No.4 and at a speed of 5 rpm. Values are quoted in centipoises (cP=mPa.s) unless otherwise specified. Remineralization
“Remineralization” for the purpose of the present invention means in situ (i.e. in the oral cavity) generation of calcium phosphate on teeth (including layers on teeth from 10 nm to 20 microns, and preferably from 75 nm to 10 microns, and most preferably, from 150 nm to 5 microns thick including all ranges subsumed therein) to reduce the likelihood of tooth sensitivity, tooth decay, regenerate enamel and/or improve the appearance of teeth by whitening through the generation of such new calcium phosphate.
Miscellaneous
Except in the examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties of materials and/or use may optionally be understood as modified by the word “about”.
All amounts are by weight of the final oral care composition, unless otherwise specified.
It should be noted that in specifying any ranges of values, any particular upper value can be associated with any particular lower value.
For the avoidance of doubt, the word “comprising” is intended to mean “including” but not necessarily “consisting of’ or “composed of”. In other words, the listed steps or options need not be exhaustive.
The disclosure of the invention as found herein is to be considered to cover all embodiments as found in the claims as being multiply dependent upon each other irrespective of the fact that claims may be found without multiple dependency or redundancy.
Where a feature is disclosed with respect to a particular aspect of the invention (for example a composition of the invention), such disclosure is also to be considered to apply to any other aspect of the invention (for example a method of the invention) mutatis mutandis.
Summary of the Invention
In a first aspect, the present invention is directed to a bioactive ceramic or a composition comprising a bioactive ceramic for use in remineralizing and/or reducing sensitivity of teeth of an individual. In a second aspect, the present invention is directed to non-therapeutic use of a bioactive ceramic or a composition comprising a bioactive ceramic for remineralizing and/or reducing sensitivity of teeth of an individual.
In a third aspect, the present invention is directed to use of a bioactive ceramic or a composition comprising a bioactive ceramic in the manufacture of a medicament in remineralizing and/or reducing sensitivity of an individual.
In a fourth aspect, the present invention is directed to a method for remineralizing and/or reducing sensitivity of teeth of an individual comprising the step of applying a bioactive ceramic or a composition comprising a bioactive ceramic to at least one surface of the teeth of the individual. The method is preferably for non-therapeutic benefits.
All other aspects of the present invention will more readily become apparent upon considering the detailed description and examples which follow.
Detailed Description
Bioactive materials usually include ceramics, glasses and glass-ceramics, which can attach directly to bone tissue via a biologically active carbohydroxyapaptite layer that provides the interfacial bonding. Bioactive glasses have an amorphous structure, whereas glass-ceramics are crystallized glasses, consisting of a composite of a crystalline phase and a residual glassy phase. Bioactive ceramics have a fully crystalline structure.
Bioactive ceramics are an important subset of bioactive materials. Bioactive ceramics range in biocompatibility from the ceramic oxides, which are inert in the body, to the other extreme of resorbable materials, which are eventually replaced by the body after they have assisted repair.
It is reported that Si is located at active calcification sites in the bones and directly involves the mineralization process of bone growth. Due to its significant function in human bones, Si has been widely incorporated into bioactive ceramics to enhance their bioactivity. Mg is also one of the most important elements in the human body which is closely associated with mineralization of calcined tissues and indirectly influences mineral metabolism. Bioactive ceramics, as used herein, refers to ceramic materials comprising calcium oxide (CaO), silicon dioxide (S1O2), magnesium oxide (MgO) or phosphorous oxide (P2O5) which possess good biocompatibility and bioactivity.
The bioactive ceramic suitable for use in this invention is Ca, P, Si, or Mg-containing ceramic. The bioactive ceramic is a Ca, Si and P- containing ceramic, a Ca, Si and Mg- containing ceramic or mixtures thereof. Illustrative yet non-limiting examples of the bioactive ceramic that may be used in this invention include, for example, bredigite (Ca7MgSUOi6), merwinite (CasMgShOs), akermanite (Ca2MgSi2C>7), diopside (CaMgShOe), monticellite (CaMgSiCL), nagelschmidtite (Ca7Si2P20i6), silicocarnotite (Ca5SiP20i2), mixtures thereof or the like. Preferably, the bioactive ceramic is bredigite (Ca7MgSUOi6), nagelschmidtite (Ca7Si2P20i6) or mixtures thereof. The bioactive ceramic may further comprise one or more elements selected from Zn, Cu, Sn, Na, Li, K, B, Sr, Ti, Al, N, Ag or F.
Bioactive ceramics are typically made by sol-gel process. Suitable preparation methods for bioactive ceramics are described, for example, in C. Wu, W. Fan, Jiang. C, M. Zhang, Y. Xiao, J. Am. Ceram. Soc., 2013, 96, 3, pp. 928-934, C.Wu, J. Chang, W. Zhai, S. Ni, J Mater Sci” Mater Med, 2007, 18, pp. 857-864, and W. Lu, W. Duan, Y. Guo, C. Ning, J Biomater. AppL, 2012, 26, pp. 637-650.
It is preferable that the bioactive ceramic is particulate which allows for maximum surface area for contact with dental tissue. Preferably the bioactive ceramic used in this invention has a particle size from 100 nm to 50 microns, preferably from 500 nm to 30 microns, more preferably from 700nm to 20 microns, most preferably from 1 micron to 15 microns.
A composition comprising the bioactive ceramic as described above is also included in the present invention. Preferably, the composition is an oral care composition. Typically, the oral care composition comprises from 0.1 to 80% by weight of the bioactive ceramic, more preferably from 0.2 to 50% and most preferably from 1 to 30%, based on total weight of the oral care composition and including all ranges subsumed therein.
An oral care composition typically has a pH ranging from 5.5 to 10.0, preferably from 6.0 to 10.0, which helps maintain a healthy mouth and protect the teeth. A lower pH may induce the enamel to demineralize and a higher pH may cause mucosa irritation. To obtain a pH within the acceptable range, it is preferable to compound a phosphate source in the oral care composition.
The phosphate source that may be used in this invention is limited only to the extent that the same may be used in a composition suitable for use in the mouth. Illustrative examples of the phosphate source suitable for use in this invention include trisodium phosphate, monosodium dihydrogen phosphate, disodium hydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, tripotassium phosphate, monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, mixtures thereof or the like. The phosphate source is preferably one which is water soluble.
In a preferred embodiment, the phosphate source is trisodium phosphate, monosodium dihydrogen phosphate or a mixture thereof.
In an especially preferred embodiment, the phosphate source is trisodium phosphate and monosodium dihydrogen phosphate at a trisodium phosphate to monosodium dihydrogen phosphate weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1, and most preferably, from 1:2 to 2:1, including all ratios subsumed therein.
When used, the phosphate source typically makes up from 0.5 to 40%, and more preferably, from 1 to 30%, and most preferably, from 2 to 20% by weight of the oral care composition, based on total weight of the oral care composition and including all ranges subsumed therein. The oral care composition preferably comprises the bioactive ceramic and the phosphate source in a weight ratio from 1:10 to 30:1, more preferably from 1:5 to 20:1, most preferably from 1:3 to 15:1.
The oral care composition of the present invention typically comprises a physiologically acceptable carrier. The carrier preferably comprises at least surfactant, thickener, humectant or a combination thereof.
Preferably the oral care composition comprises a surfactant. Preferably the composition comprises at least 0.01% surfactant by weight of the composition, more preferably at least 0.1% and most preferably from 0.5 to 7%. Suitable surfactants include anionic surfactants, such as the sodium, magnesium, ammonium or ethanolamine salts of Cs to Ci8 alkyl sulphates (for example sodium lauryl sulphate), Cs to Cis alkyl sulphosuccinates (for example dioctyl sodium sulphosuccinate), Cs to Cis alkyl sulphoacetates (such as sodium lauryl sulphoacetate), Cs to Cis alkyl sarcosinates (such as sodium lauryl sarcosinate), Cs to Cis alkyl phosphates (which can optionally comprise up to 10 ethylene oxide and/or propylene oxide units) and sulphated monoglycerides. Other suitable surfactants include nonionic surfactants, such as optionally polyethoxylated fatty acid sorbitan esters, ethoxylated fatty acids, esters of polyethylene glycol, ethoxylates of fatty acid monoglycerides and diglycerides, and ethylene oxide/propylene oxide block polymers. Other suitable surfactants include amphoteric surfactants, such as betaines or sulphobetaines. Mixtures of any of the above described materials may also be used.
More preferably the surfactant comprises or is anionic surfactant. The preferred anionic surfactants are sodium lauryl sulphate and/or sodium dodecylbenzene sulfonate. Most preferably the surfactant is sodium lauryl sulphate, sodium coco sulfate, cocamidopropyl betaine, sodium methyl cocoyl taurate or mixtures thereof.
Thickener may also be used in this invention and is limited only to the extent that the same may be added to a composition suitable for use in the mouth. Illustrative examples of the types of thickeners that may be used in this invention include, sodium carboxymethyl cellulose (SCMC), hydroxyl ethyl cellulose, methyl cellulose, ethyl cellulose, gum tragacanth, gum arabic, gum karaya, sodium alginate, carrageenan, guar, xanthan gum, Irish moss, starch, modified starch, silica based thickeners including silica aerogels, magnesium aluminum silicate (e.g., Veegum), Carbomers (cross-linked acrylates) and mixtures thereof.
Typically, xanthan gum and/or sodium carboxymethyl cellulose and/or a Carbomer is/are preferred. When a Carbomer is employed, those having a weight-average molecular weight of at least 700,000 are desired, and preferably, those having a molecular weight of at least 1,200,000, and most preferably, those having a molecular weight of at least about 2,500,000 are desired. Mixtures of Carbomers may also be used herein.
In an especially preferred embodiment, the Carbomer is Synthalen PNC, Synthalen KP or a mixture thereof. It has been described as a high molecular weight and cross-linked polyacrylic acid and identified via CAS number 9063-87-0. These types of materials are available commercially from suppliers like Sigma. In another especially preferred embodiment, the sodium carboxymethyl cellulose (SCMC) used is SCMC 9H. It has been described as a sodium salt of a cellulose derivative with carboxymethyl groups bound to hydroxy groups of glucopyranose backbone monomers and identified via CAS number 9004-32-4. The same is available from suppliers like Alfa Chem.
In another especially preferred embodiment, the thickener is xanthan gum.
Thickener typically makes up from 0.01 to about 10%, more preferably from 0.1 to 9%, and most preferably, from 0.1 to 5% by weight of the oral care composition, based on total weight of the composition and including all ranges subsumed therein.
When the oral care composition of this invention is a toothpaste or gel, the same typically has a viscosity from about 30,000 to 180,000 centipoise, and preferably, from 60,000 to 170,000 centipoise, and most preferably, from 65,000 to 165,000 centipoise.
Suitable humectants are preferably used in the oral care composition of the present invention and they include, for example, glycerin, sorbitol, propylene glycol, dipropylene glycol, diglycerol, triacetin, mineral oil, polyethylene glycol (preferably, PEG-400), alkane diols like butane diol and hexanediol, ethanol, pentylene glycol, or a mixture thereof. Glycerin, polyethylene glycol, sorbitol or mixtures thereof are the preferred humectants.
The humectant may be present in the range of from 10 to 90% by weight of the oral care composition. More preferably, the carrier humectant makes up from 25 to 80%, and most preferably, from 30 to 60% by weight of the composition, based on total weight of the composition and including all ranges subsumed therein.
The oral care composition may further comprise abrasives. Preferred abrasives include silicas, aluminas, calcium carbonates, dicalcium phosphates, calcium pyrophosphates, hydroxyapatites, trimetaphosphates, insoluble hexametaphosphates or mixtures thereof, including agglomerated particulate abrasives. Calcium carbonate and silica are particularly preferred, especially silica. The abrasives may be present in the range of from 0.01 to 60%, more preferably from 0.1 to 30%, and most preferably from 1 to 15% by weight of the oral care composition, based on total weight of the composition and including all ranges subsumed therein. The oral care composition of the present invention may contain a variety of other ingredients which are common in the art to enhance physical properties and performance. These ingredients include opacifying agents, colouring agents, anti-microbial agents, anti inflammatory agents, anti-caries agents, plaque buffers, vitamins, plant extracts, desensitizing agents, anti-calculus agents, biomolecules, flavours, proteinaceous materials, preservatives, pH-adjusting agents, sweetening agents, polymeric compounds, buffers and salts to buffer the pH and ionic strength of the compositions, and mixtures thereof.
Such ingredients typically and collectively make up less than 20% by weight of the composition, and preferably, from 0.0 to 15% by weight, and most preferably, from 0.01 to 12% by weight of the composition, including all ranges subsumed therein.
The oral care composition may be in any form common in the art, preferred forms are tooth pastes, gels, mouthwashes and whitening serums/gels. Typically the composition will be packaged. In tooth paste or gel form, the composition may be packaged in a conventional plastic laminate, metal tube or a single compartment dispenser. The same may be applied to dental surfaces by any physical means, such as a toothbrush, fingertip or by an applicator directly to the sensitive area. In liquid mouthwash form the composition may be packaged in a bottle, sachet or other convenient container.
The composition can be effective even when used in an individual’s daily oral hygiene routine. For example, the composition may be brushed onto the teeth. The composition may, for example, be contacted with the teeth for a time period of one second to 20 hours. More preferably from 1 s to 10 hours, more preferably still from 10 s to 1 hour and most preferably from 30 s to 5 minutes. The composition may be used daily, for example for use by an individual once, twice or three times per day.
The following examples are provided to facilitate an understanding of the present invention. The examples are not provided to limit the scope of the claims. Examples
Example 1
This example was conducted to investigate the effect of bioactive ceramics on blockage of dentinal tubules. All ingredients are expressed by amount of the total formulation, and as level of active ingredient.
TABLE 1
Figure imgf000012_0001
a. Bredigite (CayMgSLO- ), commercially available from Kunshan Chinese Technology New Materials Co., Ltd. b. Nagelschmidtite (CayS^O- ), made in house following the protocol described in Y. Zhou, C. Wu, Y. Xiao. “The stimulation of proliferation and differentiation of periodontal ligament cells by the ionic products from CayS^O- bioceramics’’, Acta Biomaterialia, 8, 2012, pp 2307-2316.
Methods pH Measurement pH is quoted at atmospheric pressure and a temperature of 25°C. 0.75 g powder was mixed with 10 mL de-ionised (Dl) water for 30 seconds, and then immediately testing the pH with indicator or a pH meter within 3 mins.
Brushing Protocol
To evaluate the blockage efficacy of dentinal tubules, fresh slurries were prepared by mixing powder with Dl water or sodium phosphate solution for 20 seconds and used immediately.
Human dentine discs were eroded by 6% citric acid for 2 mins, then they were treated with different slurries via brushing following the same protocol. Eight human dentine discs were separated into four groups (n=2). The dentine discs were brushed with the slurry under a tooth brushing machine equipped with toothbrushes. The load of the tooth brushing was 170 g +/-5 g and the automatic brushing operated at a speed of 150 rpm. After brushing for 1 min, the dentine discs were soaked in slurry for 1 min. Then the dentine discs were placed in 50 mL Dl water and agitated on a flatbed shaker at 150 rpm for 10 strokes. The discs were then soaked in simulated oral fluid (SOF) for 3~4 hours under the condition of a shaking water bath at 37°C and 60.0 rpm. After that, the dentine discs were brushed with the slurry by machine using the same procedure as in the first step. The brushing was repeated three times for one day, then the dentine discs were kept in SOF overnight (>12 hours) in a shaking water bath at 37°C to mimic oral environment. The dentine samples were characterized by scanning electron microscopy (SEM, Hitachi S-4800, Japan) after 3 brushings.
Simulated oral fluid was made by combining the ingredients in Table 2:
TABLE 2
Figure imgf000013_0001
Scoring Standard for Tubules Blockage
Regardless of the original shape of the dentine discs, a square (with a size of 4mm x 4mm) is selected and one image is captured under 50x magnification. Within this square, five spots (each with a size of 150 pm x 150 pm, one in the middle, and one in every corner) are selected and observed under 1000x magnification. The blockage of tubules is accessed following the standards described in Table 3. The measurement is carried out for the two dentine discs of each test group. TABLE 3
Figure imgf000014_0001
Results pH values of the samples were measured after fresh preparation. The values were reported in Table 4.
TABLE 4
Figure imgf000014_0002
An oral care composition with a pH range from 5.5 to 10.0 is taken as acceptable. The results showed that the addition of phosphate salts reduced the pH of sample 2 and sample 4 to the acceptable range.
After 3 brushings, SEM images of the dentine discs were taken. The images were analyzed and scored. The results are summarized in Table 5 (error represents standard error for duplicate measurements).
TABLE 5
Figure imgf000014_0003
The SEM images clearly showed that the dentinal tubules of dentine discs treated with samples 1 to 4 were fully blocked.
Example 2
This example was conducted to investigate the deposition on tooth surfaces by using bioactive ceramics. Samples used here were samples 1 to 4 as listed in Example 1.
Methods
The same protocol was used to evaluate the deposition on tooth surfaces, fresh slurries were prepared by mixing powder with Dl water or sodium phosphate solution for 20 seconds and used immediately.
Bovine enamel blocks were treated with different slurries via brushing following the same protocol. Eight enamel blocks were separated into four groups (n=2). The enamel blocks were brushed with the slurry under a tooth brushing machine equipped with toothbrushes. The load of the tooth brushing was 170 g +/-5 g and the automatic brushing operated at a speed of 150 rpm. After brushing for 1 min, the enamel blocks were soaked in slurry for 1 min. Then the enamel blocks were placed in 50 ml_ Dl water and agitated on a flatbed shaker at 150 rpm for 10 strokes. The enamel blocks were then soaked in SOF for 3~4 hours under the condition of a shaking water bath at 37°C and 60.0 rpm. After that, the enamel blocks were brushed with the slurry by machine using the same procedure as in the first step. The brushing was repeated three times for one day, then the enamel blocks were kept in SOF overnight (>12 hours) in a shaking water bath at 37°C to mimic oral environment. The enamel blocks were characterized by SEM (Hitachi S-4800, Japan) after 3 brushings.
Results
After 3 brushings, SEM images of the enamel block surfaces were taken. From the top view of the SEM images, it showed that samples 1 to 4 all gave good and dense deposition on tooth surfaces. The corresponding cross-section SEM images further showed that a new layer was formed on the surface of the enamel blocks after treatment with samples 1 to 4. EDX (Energy Dispersive X-ray Spectroscopy) further identified the elements of Ca, P, and O within the new layer, indicating the bioactive ceramic deposited on tooth surfaces and induced remineralization.

Claims

1. A bioactive ceramic comprising a Ca, Si and Mg-containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof, or a composition comprising a bioactive ceramic wherein the bioactive ceramic is a Ca, Si and Mg-containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof for use in remineralizing and/or reducing sensitivity of teeth of an individual.
2. Non-therapeutic use of a bioactive ceramic comprising a Ca, Si and Mg-containing ceramic or a Ca, Si and P-containing ceramic or mixtures thereof or a composition comprising a bioactive ceramic wherein the bioactive ceramic is a Ca, Si and Mg- containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof for remineralizing and/or reducing sensitivity of teeth of an individual.
3. Use of a bioactive ceramic comprising a Ca, Si and Mg-containing ceramic or a Ca, Si and P-containing ceramic or mixtures thereof or a composition comprising a bioactive ceramic wherein the bioactive ceramic is a Ca, Si and Mg-containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof in the manufacture of a medicament in remineralizing and/or reducing sensitivity of teeth of an individual.
4. A method for remineralizing and/or reducing sensitivity of teeth of an individual comprising the step of applying a bioactive ceramic comprising a Ca, Si and Mg- containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof or a composition comprising a bioactive ceramic wherein the bioactive ceramic is a Ca, Si and Mg-containing ceramic, a Ca, Si and P-containing ceramic or mixtures thereof to at least one surface of the teeth of the individual.
5. Use or a method according to any of the preceding claims, wherein the bioactive ceramic comprises a Ca, Si and Mg-containing ceramic selected from the group consisting of bredigite (Ca7MgSLOi6), merwinite (CasMgShOs), akermanite (Ca2MgSi2C>7), diopside (CaMgShOe), monticellite (CaMgSiCU) or mixtures thereof.
6. Use or a method according to any one of the preceding claims, wherein the bioactive ceramic comprises a Ca, Si and P-containing ceramic selected from the group consisting of nagelschmidtite (Ca7Si2P20i6), silicocarnotite (CasSiP20i2) or mixtures thereof.
7. Use or method according to any of the preceding claims, wherein the bioactive ceramic is bredigite (Ca7MgSUOi6), nagelschmidtite (CayShPaOie) or mixtures thereof.
8. Use or method according to any of the preceding claims, wherein the level of the bioactive ceramic is from 0.1 to 80%, preferably from 0.2 to 50% by weight of the composition.
9. Use or method according to any of the preceding claims, wherein the composition comprising a bioactive ceramic additionally comprises a phosphate source.
10. Use or method according to claim 9, wherein the phosphate source is trisodium phosphate, monosodium dihydrogen phosphate, disodium hydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, tripotassium phosphate, monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate or a mixture thereof.
11. Use or method according to claim 10, wherein the phosphate source is trisodium phosphate, monosodium dihydrogen phosphate or a mixture thereof.
12. Use or method according to claim 11 , wherein the trisodium phosphate and the monosodium dihydrogen phosphate at a trisodium phosphate to monosodium dihydrogen phosphate weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1.
13. Use or method according to any one of claims 9 to 12, wherein the level of phosphate source is from 0.5 to 40%, preferably from 1 to 30% by weight of the composition.
14. Use or method according to any of the preceding claims, wherein the composition comprising a bioactive ceramic has a pH from 5.5 to 10.0, preferably from 6.0 to 10.0.
15. Use or method according to any of the preceding claims, wherein the composition comprising a bioactive ceramic additionally comprises a silica abrasive.
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