Concealment of hypomineralised lesions

Abstract

To provide new or improved methods and kits for reducing the visibility of and / or forming a barrier to hypomineralised dental surfaces or subsurfaces.SOLUTION: The present invention relates to a method for reducing the visibility of hypomineralised dental surfaces or subsurfaces, the method comprising the steps (i) contacting the hypomineralised dental surface or subsurface with a liquid composition comprising at least 40% w / v of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of less than or equal to pH 6; and (ii) subsequently to (i), raising the pH of the liquid composition applied to the hypomineralised dental surface or subsurface to equal to, or greater than, about 9, thereby forming a gel in and / or on the hypomineralised dental surface or subsurface, thereby reducing visibility of a hypomineralised dental surface or subsurface.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Australian Provisional Application No. 2019900833 and Australian Provisional Application No. 2019903860, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to compositions and uses for reducing the visibility of hypomineralized tooth surfaces or subsurfaces, particularly tooth enamel. [Background technology]

[0003] White spots on teeth are porous lesions in the tooth enamel / dentin that can result from caries (white spot lesions), hypomineralization (e.g. fluorosis lesions and other developmental disorders), or other demineralization processes (e.g. erosion lesions). Typically, they indicate the early stages of caries formation, where the affected surface appears intact to gentle probing. Other common causes of insufficient mineralization and associated white spot lesions include trauma, xerostomia, and arrested caries with only partial remineralization around fixed orthodontic appliances that may provide a harbor for bacteria or prevent normal remineralization.

[0004] This porous tissue in enamel and dentin has a different refractive index than the translucent enamel and dentin, and therefore porous lesions appear as milky white lesions against a translucent background. These lesions are not only a cosmetic problem, but also increase the risk of exacerbating caries / erosion and hypersensitivity.

[0005] Current treatment of these lesions prior to cavity preparation involves remineralization with fluoride with or without calcium phosphate, but remineralization is a slow process that takes several months to change the appearance of the lesion, which often does not disappear completely. Alternative treatments include invasive or at best microinvasive restorations involving infiltration with methacrylate-based resins. These restorative methods are expensive, time-consuming, and since the natural repair of the white spots (remineralization with calcium and phosphate) does not occur, problems of discoloration of the restorative material or caries under the restoration due to insufficient sealing may occur later.

[0006] The best treatment for repairing porous white spots and reducing dentin sensitivity is to treat the lesion with CPP-ACP (commercially available as Recaldent™) with or without fluoride ions to allow for remineralization with hydroxyapatite or fluorohydroxyapatite. However, current treatment methods using this technology still require several weeks of treatment at best to achieve an improvement in the appearance of the lesion and a reduction in dentin sensitivity. This can result in poor patient outcomes due to poor compliance and insufficient remineralization. Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need to provide new and improved methods of reducing the visibility of and / or forming a barrier on or under the surface of hypomineralized teeth.

[0008] Any reference in this specification to any prior art is made with the understanding that this prior art forms part of the common general knowledge in Australia or any other jurisdiction and that this prior art would be expected to be identified, understood and regarded as relevant by a person skilled in the art. It is not, and should not be construed as, an admission or any form of suggestion that such a claim may be appropriate. [Means for solving the problem]

[0009] In one aspect, the present invention provides a method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: contacting the surface or subsurface of a hypomineralized tooth with a liquid composition comprising at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 5 or more but not exceeding 9; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The present invention provides a method comprising:

[0010] Preferably, the pH of the liquid composition is at least pH 6 but not greater than pH 8, such as at least pH 7 but not greater than pH 8.

[0011] In a further aspect, the present invention provides a method for forming a protective layer on a tooth surface, comprising: contacting the tooth surface with a liquid composition comprising at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 5 or more but not exceeding 9; thereby forming a protective layer on the tooth surface; The present invention provides a method comprising:

[0012] Preferably, the pH of the liquid composition is at least pH 6 but not greater than pH 8, such as at least pH 7 but not greater than pH 8.

[0013] In a further aspect, the present invention provides a method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: contacting the tooth surface with a liquid composition having a pH of at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and a pH of at least 5 but not more than 9 to contact the exposed dentinal tubules; thereby treating or preventing dentin hypersensitivity in a subject in need thereof; The present invention provides a method comprising:

[0014] Preferably, the pH of the liquid composition is at least pH 6 but not greater than pH 8, such as at least pH 7 but not greater than pH 8.

[0015] Preferably, a heat source is applied to the liquid composition after it contacts the tooth surface or subsurface.

[0016] In one aspect, the present invention provides a method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (i) contacting the surface or subsurface of a hypomineralized tooth with a liquid composition having a pH of 6 or less, the liquid composition comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP); (ii) following (i), increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The present invention provides a method comprising:

[0017] In a further aspect, the present invention provides a method of forming a gel in and / or on a tooth surface or subsurface lesion, comprising: (i) contacting the tooth surface or subsurface lesion with a liquid composition comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of pH 6 or less; (ii) subsequent to (i), increasing the pH of the liquid composition applied to the tooth surface or subsurface lesion to greater than about 9; thereby forming a gel in and / or on the tooth surface or subsurface lesion; The present invention provides a method comprising:

[0018] In a further aspect, the present invention provides a method for reducing surface or subsurface visibility of hypomineralized teeth, comprising: (i) mixing (a) a liquid composition having a pH of 6 or less, comprising at least 40% w / v of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and (b) a further composition having an alkaline pH, thereby forming a mixed composition having a pH of about 9 or more; (ii) contacting the mixed composition with the surface or subsurface of the hypomineralized tooth, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The present invention provides a method comprising:

[0019] In a further aspect, the present invention provides a method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: (i) contacting the exposed dentinal tubules with a liquid composition comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of pH 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the exposed dentinal tubules; thereby treating or preventing dentin hypersensitivity in a subject in need thereof; The present invention provides a method comprising:

[0020] In a further aspect, the present invention provides a method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: (i) mixing (a) a liquid composition having a pH of 6 or less, comprising at least 40% w / v of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and (b) a further composition having an alkaline pH, thereby forming a mixed composition having a pH of about 9 or more; (ii) contacting the exposed dentinal tubules with the mixed composition, thereby forming a gel in and / or on the exposed dentinal tubules; thereby treating or preventing dentin hypersensitivity in a subject in need thereof; The present invention provides a method comprising:

[0021] In a further aspect, the present invention provides a method for forming a protective layer on a tooth surface, comprising: (i) applying to the tooth surface at least 40% w / v of phosphopeptide (PP) stabilized amorphous lipid; with a liquid composition having a pH of 6 or less comprising amorphous calcium fluoride phosphate (ACCP) and / or amorphous calcium fluoride phosphate (ACFP); (ii) subsequent to (i), increasing the pH of the liquid composition applied to the tooth surface to about 9 or greater; thereby forming a protective layer on the tooth surface; The present invention provides a method comprising:

[0022] In a further aspect, the present invention provides a method for forming a protective layer on a tooth surface, comprising: (i) mixing (a) a liquid composition having a pH of 6 or less, comprising at least 40% w / v of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and (b) a further composition having an alkaline pH, thereby forming a mixed composition having a pH of about 9 or more; (ii) contacting the tooth surface with the mixture composition; thereby forming a protective layer on the tooth surface; The present invention provides a method comprising:

[0023] In any embodiment of the present invention, the pH of the liquid composition applied to the tooth surface or subsurface lesion is raised to about 9 or above, preferably 10 or above.

[0024] In any aspect of the invention, the tooth surface is preferably tooth enamel. In one embodiment, the tooth surface is a lesion in the enamel, such as a lesion caused by caries, acid erosion, or fluorosis. Typically, the lesion is a white spot lesion.

[0025] In any aspect of the invention, the tooth surface is dentin, for example exposed dentin, hi one embodiment, the exposed dentin is, for example, the root of a tooth resulting from recession.

[0026] In any embodiment of the present invention, the mixed composition is contacted with the tooth surface less than 20 minutes, less than 15 minutes, less than 14 minutes, less than 13 minutes, less than 12 minutes, less than 11 minutes, less than 10 minutes, less than 9 minutes, less than 8 minutes, less than 7 minutes, less than 6 minutes, less than 5 minutes, less than 4 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute after formation of the mixed composition.

[0027] In any embodiment of the present invention where an increase in pH of the liquid composition applied to the tooth surface or subsurface is required, this can be done by contacting the liquid composition applied to the tooth surface or subsurface with an additional composition having an alkaline pH. This additional composition may also be in liquid form and may also be referred to herein as an additional liquid composition. The alkaline pH of this additional composition may be a pH of about 9, 10, 11, 12, 13, or 14. Preferably, the additional composition has an alkaline pH of about 9 or greater.

[0028] In any of the aspects described herein, the liquid composition may further include fluoride ions, preferably free fluoride ions. The fluoride ions may be present in the liquid composition at a concentration within the range of about 200 ppm to 50,000 ppm. In a preferred embodiment, the fluoride ions are present at a concentration within the range of about 2,600 ppm to about 10,000 ppm. In a more preferred embodiment, the fluoride ions are present in the liquid composition at a concentration of about 8,200 ppm or about 6,500 ppm. The fluoride ions may be present in the liquid composition at any of the ppm or higher concentrations described herein, particularly in the Examples. In another embodiment, fluoride ions are present at a concentration of about 5,200 ppm for 40% w / v CPP-ACP, about 5,850 ppm for 45% w / v CPP-ACP, about 6,500 ppm for 50% w / v CPP-ACP, about 8,200 ppm for 63% w / v CPP-ACP, or about 9,900 ppm for 75% CPP-ACP. In another embodiment, fluoride ions are present at a concentration of about 5,200 ppm for 40% w / w CPP-ACP, or about 7,800 ppm for 60% w / w CPP-ACP. The fluoride ions are present in a concentration of 0.1 to 1.0% by weight. The fluoride ions may be from any suitable source. The fluoride ion source may include free fluoride ions or fluoride salts. Examples of fluoride ion sources include, but are not limited to, sodium fluoride, sodium monofluorophosphate, stannous fluoride, sodium silicofluoride, silver fluoride, silver diammine fluoride, and amine fluorides. They may be provided in a solution (typically an aqueous solution) or in a suspension.

[0029] In any aspect of the invention, steps (i) and (ii), or any step in which a composition is applied to the tooth surface or subsurface, may include or be followed by a step of heating the tooth surface or subsurface or lesion. In one embodiment, the method may include a step of heating the hypomineralized tooth surface or subsurface or lesion simultaneously with or following contacting the hypomineralized tooth surface or subsurface or lesion with a liquid composition having a pH of pH 6 or less comprising at least 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP. In another embodiment, the method may include a step of heating the hypomineralized tooth surface or subsurface or lesion simultaneously with or following raising the pH of the liquid composition applied to the hypomineralized tooth surface or subsurface to about 9 or greater. In another embodiment, the method may comprise heating the hypomineralized tooth surface or subsurface, or lesion, simultaneously with or subsequent to contacting the hypomineralized tooth surface or subsurface, or lesion, with a liquid composition comprising at least 60% w / w phosphopeptide (PP) stabilized ACP and / or ACFP and having a pH of at least pH 5 but not more than pH 9.

[0030] In any aspect of the invention, the method comprises the step of heating the surface or subsurface of the tooth or lesion to a temperature of 40°C or more, 45°C or more, 50°C or more, 55°C or more, 60°C or more, or 65°C or more.

[0031] In any aspect of the invention, the method comprises the step of heating the surface or subsurface of the tooth or lesion to a temperature greater than 37°C but less than or equal to 65°C, greater than 40°C but less than or equal to 65°C, greater than 45°C but less than or equal to 65°C, greater than 50°C but less than or equal to 65°C, greater than 55°C but less than or equal to 65°C, or greater than 60°C but less than or equal to 65°C.

[0032] In any aspect of the invention, the liquid composition comprises greater than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP, greater than 45% w / v, greater than 50% w / v, greater than 55% w / v, greater than 60% w / v, greater than about 65% w / v, greater than about 70% w / v, or greater than about 75% w / v. In one embodiment, the liquid composition comprises 63% w / v stabilized ACP and / or ACFP.

[0033] In any embodiment of the invention, the liquid composition comprises greater than 40% w / w phosphopeptide (PP) stabilized ACP and / or ACFP, greater than 45% w / w, greater than 50% w / w stabilized ACP and / or ACFP, greater than 55% w / w stabilized ACP and / or ACFP, greater than 60% w / w stabilized ACP and / or ACFP, greater than about 65% w / w stabilized ACP and / or ACFP, greater than about 70% w / w stabilized ACP and / or ACFP, or greater than about 75% w / w stabilized ACP and / or ACFP.

[0034] In any embodiment of the invention, the liquid composition comprises more than 40% w / v of phosphopeptide (PP) stabilized ACP and / or ACFP, more than 40% w / v of stabilized ACP and / or ACFP but less than 80% w / v of stabilized ACP and / or ACFP, more than 45% w / v of stabilized ACP and / or ACFP but less than 80% w / v of stabilized ACP and / or ACFP, stabilized ACP and / or ACFP, greater than 50% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 55% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 60% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 65% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 70% w / v but less than 80% w / v stabilized ACP and / or ACFP, or greater than 75% w / v but less than 80% w / v stabilized ACP and / or ACFP.

[0035] In any embodiment of the invention, the liquid composition comprises more than 40% w / w of phosphopeptide (PP) stabilized ACP and / or ACFP, more than 40% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 45% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 50% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 55% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 60% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 65% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, more than 70% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP, or more than 75% w / w of stabilized ACP and / or ACFP but less than 80% w / w of stabilized ACP and / or ACFP.

[0036] In any aspect of the invention, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for a time period that allows the liquid composition to penetrate the tooth surface, subsurface, or lesion. In one embodiment, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for up to 20 minutes, after which the pH of the liquid composition applied to the hypomineralized tooth surface or subsurface is increased to about 9 or higher. In one embodiment, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for at least about a few seconds to at least about 5 minutes, preferably at least about 5 minutes to about 20 minutes.

[0037] In any aspect of the invention, the method further comprises the step of etching, preferably acid etching, the hypomineralized surface, subsurface, or lesion, e.g., prior to contact with the liquid composition in (i). Acid etching can be performed by any method known in the art. Typically, acid etching can be performed by contacting the hypomineralized surface, subsurface, or lesion with a composition comprising about 30% phosphoric acid or about 15% HCl. Preferably, a resin barrier, e.g., a rubber dam or liquid rubber dam, is applied to protect the soft tissue prior to acid etching.

[0038] In either embodiment, the formation of the protective layer can be facilitated by a further step of heating as described herein and / or etching as described herein.

[0039] As used herein, stabilized ACP and / or ACFP are phosphopeptide stabilized. Preferably, the phosphopeptide is a casein phosphopeptide (as defined below). Preferably, the ACP or ACFP is in the form of a casein phosphopeptide stabilized ACP or ACFP complex.

[0040] In a preferred embodiment, the phosphopeptide stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes provide tightly bound calcium and At pH 7.0, the ACP or ACFP complex has loosely bound calcium and the tightly bound calcium in this complex is less than the tightly bound calcium in the ACP or ACFP complex formed at pH 7.0. Typically, the ACP or ACFP is predominantly in the base form.

[0041] In a preferred embodiment, the calcium ion content of the stabilized ACP or ACFP complex is in the range of about 30 to about 100 moles of calcium per mole of PP, more preferably, the calcium ion content is in the range of about 30 to about 50 moles of calcium per mole of PP.

[0042] In any aspect or embodiment described herein, the stabilized ACP and / or ACFP can be present in a formulation with additional calcium phosphate. Typically, the formulation includes at least an equal weight amount of calcium phosphate with the PP stabilized ACP and / or ACFP complex.

[0043] In a preferred embodiment, the PP-stabilized ACP and / or ACFP is in the form of a casein phosphopeptide-stabilized ACP and / or ACFP complex.

[0044] Preferably, the phase of the ACP is predominantly a basic phase, and the ACP is predominantly Ca. 2+ , PO4 3- , and OH - The basic phase of ACP has the general formula [Ca3(PO4)2] x [Ca2(PO4)(OH)], where x≧1. Preferably, x=1-5. More preferably, x=1. Preferably, the two components in the above formula are present in the same ratio. Thus, in one embodiment, the basic phase of ACP is represented by the formula Ca3(PO4)2Ca2(PO4)(OH).

[0045] Preferably, the phase of the ACFP is a predominantly basic phase, and the ACFP is predominantly Ca 2+ , PO4 3- , and F -The basic phase of ACFP has the general formula [Ca3(PO4)2] x [Ca2(PO4)F] y where x≧1 when y=1, or y≧1 when x=1. Preferably, y=1 and x=1-3. More preferably, y=1 and x=1. Preferably, the two components in the above formula are present in the same ratio. Thus, in one embodiment, the basic phase of ACFP is represented by the formula Ca3(PO4)2Ca2(PO4)F.

[0046] In one embodiment, the ACP complex consists essentially of phosphopeptide, calcium, phosphate, and hydroxide ions, and water.

[0047] In one embodiment, the ACFP complex consists essentially of phosphopeptide, calcium, phosphate, fluoride, and hydroxide ions, and water.

[0048] In a further aspect of the invention there is provided a method for remineralising dental lesions comprising the steps of: (i) contacting the dental lesion with a liquid composition comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of pH 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the dental lesion to about 9 or greater, thereby forming a gel in and / or on the dental lesion; thereby remineralizing the dental lesion; A method is provided that includes:

[0049] In a further aspect of the invention there is provided a method for remineralising dental lesions comprising the steps of: At least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate ( a liquid composition having a pH of 5 or more but 9 or less, comprising: thereby remineralizing the dental lesion; A method is provided that includes:

[0050] Preferably, the pH of the liquid composition is at least pH 6 but not greater than pH 8, such as at least pH 7 but not greater than pH 8.

[0051] Preferably, the dental lesion is present in the enamel or dentin. Typically, the dental lesion is selected from the group consisting of one or more of: white spot lesions, fluorosis lesions, caries lesions; or lesions caused by dental erosion.

[0052] In any aspect or embodiment of the invention described herein, the liquid composition and the further composition, or the mixed composition, described herein, is applied to the mouth, tooth, or lesion by the subject in need of treatment or by a dental health care professional.

[0053] In one embodiment, the tooth surface is in need of such treatment. Thus, in another aspect, the present invention includes, in addition to the steps of any method described herein, a step of identifying a subject suffering from fluorosis, caries, dentin hypersensitivity or tartar, white spot lesion, fluorosis lesion, caries lesion, or lesion caused by dental erosion. In particular, the tooth surface requiring the formation of a protective layer may be exposed dentin, which typically causes dentin hypersensitivity in the subject. The exposed dentin may be exposed dentinal tubules.

[0054] Typically, the tooth surface may be a surface that has been identified as being affected by the surface layer, for example because of its high potential for demineralization.

[0055] The present method of forming a protective layer on a tooth surface finds particular use in sealing exposed dentin, particularly exposed dentin having exposed dentinal tubules.

[0056] The tooth surface may be a cavity, whereby the methods of the invention described herein may be used in the cavity, whereby a gel or protective layer may be formed. A dental restorative material, such as a composite or glass ionomer cement, may then be added over the gel or protective layer.

[0057] In a further aspect, the present invention provides a method for repairing a cavity, comprising the steps of: (i) forming a gel or protective layer in the cavity by any method described herein; (ii) attaching a dental restoration; thereby repairing the cavity. The present invention provides a method comprising:

[0058] The present invention provides a liquid composition having a pH of less than or equal to pH 6 for use in surface or subsurface mineralisation of teeth comprising at least 40% w / v phosphopeptide (PP)-stabilised amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and a further composition having an alkaline pH, which is applied to the surface or subsurface of the teeth after the first composition, thereby forming a gel.

[0059] The present invention relates to Formation of a layer on the surface of the teeth, Formation of a gel in and / or on the tooth surface or subsurface lesions; Treatment or prevention of dentin hypersensitivity, Reduced visibility of the hypomineralized tooth surface or subsurface; or Remineralization of the tooth surface or subsurface, The present invention provides a liquid composition comprising at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of at least pH 5 but not more than pH 9 for use in

[0060] Preferably, the pH of the liquid composition is at least pH 6 but not greater than pH 8, such as at least pH 7 but not greater than pH 8.

[0061] In a further aspect, there is provided a method for the treatment or prevention of one or more of each of dental caries, dental caries, dental erosion, fluorosis, and white spot lesions, comprising: (i) contacting the tooth surface or subsurface with a liquid composition comprising at least 40% by weight of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the dental lesion to about 9 or greater, thereby forming a gel from the first composition; A method is provided that includes:

[0062] Topical administration of the composition is preferred. The method preferably comprises administration of the complex in a formulation as described above.

[0063] In a further aspect, there is provided the use of a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) in the manufacture of a product comprising a liquid composition for reducing the surface or subsurface visibility of hypomineralized teeth, the liquid composition comprising at least 40% w / v of said phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and having a pH of less than or equal to pH 6, Use is provided in which the liquid composition is applied to the surface or subsurface of the hypomineralized tooth, followed by raising the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth.

[0064] In a further aspect, the use of a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) in the manufacture of a product comprising a liquid composition for forming a gel in and / or on a tooth surface or subsurface lesion, the liquid composition comprising at least 40% w / v of said phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and having a pH of less than or equal to pH 6, Use is provided in which the liquid composition is applied to a tooth surface or subsurface lesion, followed by increasing the pH of the liquid composition applied to the tooth surface or subsurface lesion to about 9 or greater, thereby forming a gel in and / or on the tooth surface or subsurface lesion.

[0065] In a further aspect: Formation of a layer on the surface of the teeth, Formation of a gel in and / or on the tooth surface or subsurface lesions; Treatment or prevention of dentin hypersensitivity, Reduced visibility of the hypomineralized tooth surface or subsurface; or Remineralization of the tooth surface or subsurface, In the manufacture of a product comprising or consisting of a liquid composition for the preparation of a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate Use of the ACFP, Use is provided, wherein said liquid composition comprises at least 40% w / w of said phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and has a pH of at least 5 but not more than 9. In one embodiment, the product is a cosmetic product.

[0066] In a further aspect, there is provided the use of a base in the manufacture of a composition to reduce the visibility of hypomineralised tooth surfaces or subsurfaces in a subject receiving a liquid composition having a pH of 6 or less comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) on the hypomineralised tooth surfaces or subsurfaces.

[0067] In a further aspect there is provided the use of a base in the manufacture of a composition for forming a gel in and / or on a dental surface or subsurface lesion in a subject who has received a liquid composition having a pH of 6 or less comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) on the dental surface or subsurface lesion.

[0068] In a further aspect, there is provided the use of a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and a base in the manufacture of a product comprising a liquid composition and a further composition, wherein the liquid composition comprises at least 40% w / v of said phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and has a pH of 6 or less, and the further composition comprises said base, the liquid composition and the further composition are used to reduce the visibility of the surface or subsurface of a hypomineralized tooth, and the further composition is applied to the surface or subsurface of a hypomineralized tooth after the liquid composition, thereby increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth, thereby reducing the visibility of the surface or subsurface of the hypomineralized tooth. In one embodiment, the product is a cosmetic product.

[0069] In a further aspect, there is provided the use of a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and a base in the manufacture of a product comprising a liquid composition and a further composition, wherein the liquid composition comprises at least 40% w / v of said phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and has a pH of 6 or less, and the further composition comprises said base, and the liquid composition and the further composition are used to form a gel in and / or on a tooth surface or subsurface lesion, and the further composition is applied to the tooth surface or subsurface lesion after the liquid composition, thereby raising the pH of the liquid composition applied to the tooth surface or subsurface lesion to about 9 or more, thereby forming a gel in and / or on the tooth surface or subsurface lesion.

[0070] In a preferred embodiment, the phosphopeptide-stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex in the composition has tightly bound calcium and loosely bound calcium, and the bound calcium in the complex is less than the tightly bound calcium in the ACP or ACFP complex formed at pH 7.0. Optionally, the ACP or ACFP is predominantly in a base form.

[0071] In a preferred embodiment, the calcium ion content of the stabilized ACP or ACFP complex in the composition is in the range of about 30-100 moles of calcium per mole of PP. More preferably, the calcium ion content is in the range of about 30 to about 50 moles of calcium per mole of PP.

[0072] In any embodiment, the ACP and / or ACFP in the composition may be in the form of a casein phosphopeptide stabilized ACP and / or ACFP complex.

[0073] In another aspect, the present invention provides a liquid composition comprising at least 40% w / v stabilized ACP and / or ACFP. Preferably, the liquid composition comprises 45% w / v or more stabilized ACP and / or ACFP, 50% w / v or more stabilized ACP and / or ACFP, 55% w / v or more stabilized ACP and / or ACFP, 60% w / v or more stabilized ACP and / or ACFP, 65% w / v or more stabilized ACP and / or ACFP, 70% w / v or more stabilized ACP and / or ACFP, or 75% w / v or more stabilized ACP and / or ACFP. In one embodiment, the liquid composition comprises 63% w / v stabilized ACP and / or ACFP. Preferably, the liquid composition further comprises fluoride ions as described herein.

[0074] In this aspect of the invention, the liquid composition comprises more than 40% w / v stabilized ACP and / or ACFP but less than 80% w / v stabilized ACP and / or ACFP, more than 45% w / v stabilized ACP and / or ACFP but less than 80% w / v stabilized ACP and / or ACFP, more than 50% w / v stabilized ACP and / or ACFP but less than 80% w / v stabilized ACP and / or ACFP, more than 55% w / v stabilized ACP and / or ACFP but less than 80% w / v stabilized ACP and / or ACFP. The liquid composition may comprise a stabilized ACP and / or ACFP, greater than 60% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 65% w / v but less than 80% w / v stabilized ACP and / or ACFP, greater than 70% w / v but less than 80% w / v stabilized ACP and / or ACFP, or greater than 75% w / v but less than 80% w / v stabilized ACP and / or ACFP. Preferably, the liquid composition further comprises fluoride ions as described herein.

[0075] In either embodiment, the liquid composition is degassed. Degassing may be by any method that creates a negative pressure above the liquid composition. Exemplary methods include a vacuum pump or system, such as a venturi vacuum water system.

[0076] Any of the compositions described herein can be used in any one of the methods described herein, which is a physiologically acceptable composition as described herein.

[0077] In any method or use of the invention described herein, the method or use is for cosmetic purposes to mask or conceal the appearance of hypomineralised surface or subsurface.

[0078] In another aspect, the present invention relates to a method or process for preparing a liquid composition comprising at least 40% w / v of PP-stabilized ACP and / or ACFP, comprising: mixing a solvent with a powder comprising or consisting of a PP-stabilized ACP and / or ACFP; maintaining the pH at less than 7; Preferably, the pH is maintained below 6, preferably the pH is maintained below 5.5.

[0079] In another aspect, the present invention provides a composition comprising at least 40% w / v PP stabilized ACP and / or A method or process for preparing a liquid composition comprising an ACFP, comprising: mixing a solvent with a powder comprising or consisting of a PP-stabilized ACP and / or ACFP; reducing the pH to less than 7; Preferably, the pH is lowered to below 6, preferably below 5.5. Typically, the pH is maintained below 7, more preferably the pH is maintained below 6, even more preferably below 5.5.

[0080] In either embodiment, the step of mixing the solvent with the powder comprising or consisting of the PP-stabilized ACP and / or ACFP comprises adding the solvent to the powder, or alternatively, the step comprises adding the powder to the solvent.

[0081] In any method or process for preparing a liquid composition described herein, the method or process further comprises the step of degassing the liquid composition. Degassing can be accomplished by any method that creates a negative pressure above the liquid composition, such as the methods described herein.

[0082] In any of the methods or processes for preparing a liquid composition described herein, the method or process further comprises the step of mixing the liquid composition with a solution comprising fluoride ions.

[0083] In another aspect, the present invention provides a method or process for preparing a liquid composition comprising at least 40% w / v PP-stabilized ACP and / or ACFP, comprising or consisting of the steps described in Example 1 herein.

[0084] In any embodiment, the present invention provides a method for preparing a powder comprising or consisting of a PP-stabilized ACP and / or ACFP, comprising: mixing one or more solutions comprising phosphopeptides, calcium ions, phosphate ions, hydroxide ions, and optionally fluoride ions while maintaining a pH at about 7.0 or greater, preferably about 9, to form a solution comprising stabilized ACP and / or ACFP; Drying the solution containing the PP-stabilized ACP and / or ACFP; thereby forming a powder comprising or consisting of a PP-stabilized ACP and / or ACFP; Preferably, the drying is spray drying or freeze drying.

[0085] In one embodiment, the method or process comprises: The method further includes filtering the solution containing the PP-stabilized ACP and / or ACFP prior to drying to form a retentate, which is then dried to form a powder containing or consisting of the PP-stabilized ACP and / or ACFP.

[0086] In another aspect, the present invention relates to a method or process for preparing a liquid composition comprising at least 40% w / w of PP-stabilized ACP and / or ACFP, comprising: mixing a solvent with a powder comprising or consisting of a PP-stabilized ACP and / or ACFP; reducing the pH to less than 8; Preferably the solvent comprises a fluoride.

[0087] In this embodiment, the method further comprises the step of stirring the liquid composition after lowering the pH. Preferably, the stirring is for at least 5, 10, 15, 20, 25, or 30 minutes.

[0088] In this embodiment, the liquid composition is degassed, preferably by placing the solution under reduced pressure, most preferably for 24 hours, to remove any trapped air bubbles.

[0089] In another aspect, the present invention provides a method or process for preparing a liquid composition comprising at least 40% w / w, preferably 60% w / w, of PP-stabilized ACP and / or ACFP, comprising or consisting of the steps described in Example 11 herein.

[0090] In any method or process for preparing a liquid composition containing 40% w / v or more than 40% w / w stabilized ACP and / or ACFP, the solvent is water.

[0091] In any method or process for preparing a liquid composition containing 40% w / v or more than 40% w / w stabilized ACP and / or ACFP, the pH is lowered or maintained using 1-10 M HCl, or 11 M HCl.

[0092] In any embodiment, the method or process for preparing a liquid composition comprising at least 40% w / v of PP-stabilized ACP and / or ACFP may be for preparing a liquid composition comprising 45% w / v or more, 50% w / v or more, 55% w / v or more, 60% w / v or more, 65% w / v or more, 70% w / v or more, or 75% w / v or more (or any other % w / v described herein) of stabilized ACP and / or ACFP.

[0093] In any method or process for preparing a liquid composition comprising at least 40% w / v PP-stabilized ACP and / or ACFP, the PP-stabilized ACP or ACFP is a CPP-ACP or CPP-ACFP described herein.

[0094] In any method or process for preparing a liquid composition comprising at least 40% w / v PP-stabilized ACP and / or ACFP, the liquid composition is for use in any dental treatment method, preferably the methods described herein (e.g., reducing surface or subsurface visibility of hypomineralized teeth).

[0095] In another aspect, the present invention provides a liquid composition comprising at least 40% w / v of a PP-stabilized ACP and / or ACFP prepared by a method or process described herein.

[0096] The present invention also relates to a kit for the treatment or prevention of one or more of dental caries, fluorosis, dental erosion, and white spot lesions, comprising: (a) a liquid composition with a pH of 6 or less, comprising at least 40% by weight of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP); and (b) an additional composition, preferably as described herein, with an alkaline pH, which is applied to the surface or subsurface of the tooth after the liquid composition, and a gel is formed from the liquid (or first) composition by the additional (or second) composition. Desirably, the kit further comprises instructions for their use for mineralizing the surface of the teeth of a patient in need of treatment, preferably for use in any of the methods described herein. The instructions may describe the use of the kit for the treatment or prevention of one or more of dental caries, dental caries, dental erosion, fluorosis, and white spot lesions, respectively. In one embodiment, the liquid (or first) composition and the additional (or second) composition are present in an amount suitable for treating a patient. Preferably, the phosphopeptide (described below) is Zein phosphopeptide. Preferably, the PP-stabilized ACP or ACFP is in the form of a casein phosphopeptide-stabilized ACP or ACFP complex.

[0097] In one embodiment, the invention provides any of the kits described herein for use, or when used, in a cosmetic method for masking or concealing the appearance of hypomineralized surface or subsurface. Typically, the kit may further comprise written instructions for use in the cosmetic method described herein.

[0098] The kit of the present invention can further include a free fluoride ion source. Examples of free fluoride ion sources include, but are not limited to, sodium fluoride, stannous fluoride, silver fluoride, amine fluoride, or any metal ion fluoride salt. These fluoride ion sources are provided in a solution (typically an aqueous solution) or suspension.

[0099] In one aspect, the present invention provides: (a) a first composition comprising a powder of phosphopeptide-stabilized ACP and / or ACFP; (b) a second composition having a pH of 6 or less comprising a solution of fluoride; (c) a third composition at an alkaline pH; and Also provided is a kit comprising or consisting of:

[0100] Preferably, the alkaline pH of the third composition may be a pH of about 9, 10, 11, 12, 13, or 14. Preferably, the third composition has an alkaline pH of about 9 or greater. Preferably, the first composition comprises an amount of phosphopeptide stabilized ACP and / or ACFP that, when mixed with the second composition, forms a liquid composition comprising at least 40% w / v phosphopeptide stabilized ACP and / or ACFP.

[0101] In one embodiment, the kit comprises: (a) 5g CPP-ACP and / or CPP-ACFP; (b) 5 ml of 0.73 M NaF in 1.146 M HCl; (c) 1.5 M NaOH; It comprises or consists of:

[0102] Preferably, the kit further comprises two microbrushes.

[0103] Preferably, the kit further comprises written instructions for using the kit in any of the methods described herein. [Brief description of the drawings]

[0104] [Figure 1] Masking of a vitiligo lesion with a 45% w / v CPP-ACP pH 5.5 solution followed by a 1 M NaOH solution. Left: treated lesion, right: control. [Diagram 2]Masking of a vitiligo lesion using a pH 5.5 solution (not degassed) of 63% w / v CPP-ACP and 8,200 ppm F as NaF, followed by a 1 M NaOH solution. Left: treated lesion, right: control. [Diagram 3] Using the dental kit described in Example 3, part (a) is added to part (b) and mixed thoroughly. This mixture is then applied to the left white spot lesion using one microbrush (see image in (A) showing the lesion before application). After a few seconds / minutes at 37°C, solution (c) is then applied to the left white spot lesion using a second microbrush. Within 15 minutes, a reaction occurs within the white spot forming a gel, concealing the white spot (see image in (B)). [Figure 4] Masking of a vitiligo lesion using a pH 5.5 solution of 75% w / v CPP-ACP and 9,880 ppm F as NaF, followed by a 2 M NaOH solution. Left: treated lesion, right: control. [Diagram 5] Masking of vitiligo lesions using a mixed composition formed from a liquid composition (degassed) of 63% w / v CPP-ACP and 8,000 ppm F at pH 5.5 and a solution of 1.5 M NaOH. Left: treated lesion, right: control. [Figure 6] Treatment of demineralized dentin with a mixed composition formed from a liquid composition of 63% w / v CPP-ACP and 8,000 ppm F at pH 5.5 and a solution of 1.5 M NaOH. Left: Treated lesion, right: Control. [Figure 7] (A and B) Representative transverse microradiography (TMR) images showing the formation of a protective layer on demineralized dentin using a mixed composition formed from a liquid composition of 63% w / v CPP-ACP and 8,000 ppm F at pH 5.5 and a solution of 1.5 M NaOH. This TMR image was taken approximately 20 minutes after application of the mixed composition. [Figure 8]Representative scanning electron microscope (SEM) images showing the formation of a protective layer on demineralized dentin in (A) and control dentin with exposed dentinal tubules in (B) using a mixed composition formed from a liquid composition of 63% w / v CPP-ACP and 8,000 ppm F at pH 5.5 and 1.5 M NaOH. [Figure 9] Representative scanning electron microscope (SEM) image showing deliberate cracking due to dehydration of the protective layer from Figure 8 in (A) and elemental analysis by SEM-EDS of the protective layer in (B). [Figure 10] Microradiographic images showing the formation of a protective layer on root dentin treated with premixed CPP-ACFP and 2 M NaOH and incubated at 37° C. for 48 hours. [Figure 11] Microradiographic images showing the formation of a protective layer on etched enamel surfaces treated with premixed CPP-ACFP and 2 M NaOH and incubated at 37° C. for 48 h. [Figure 12] Masking of vitiligo lesions using the composition of 60% w / w CPP-ACP pH 7.8 containing 7,800 ppm F (75% w / v CPP-ACP pH 7.8 containing 10,000 mg / L F) described in Example 11. (a) Before treatment, (b) 40 seconds after curing, (c) 15 minutes after curing, (d) 23 hours after curing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0105] Further aspects of the invention, and further embodiments of the aspects described in the preceding paragraphs, will become apparent from the following description, given by way of example and referring to the accompanying drawings, in which: It will be understood that the invention disclosed and defined herein extends to any and all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings, all of which constitute various alternative aspects of the invention.

[0106] Reference will now be made in more detail to specific embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that it is not intended that the invention be limited to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0107] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention, and it is in no way intended that the present invention be limited to the methods and materials described.

[0108] All patents and publications cited herein are incorporated by reference in their entirety.

[0109] For the purposes of describing this specification, terms used in the singular will also include the plural and vice versa.

[0110] As used herein, unless the context requires otherwise, the term "comprise" and variations of that term, such as "comprising," "comprises," and "comprised," are not intended to exclude additional additives, ingredients, integers, and steps. As used herein, unless the context requires otherwise, "comprise" and "include" can be used interchangeably.

[0111] One aspect of the present invention is based on several surprising discoveries, the first of which is that compositions containing high concentrations of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous fluorinated calcium phosphate (ACFP) can remain in a liquid state (i.e., do not form a gel). Prior to the present invention, it was believed that high concentrations of phosphopeptide-stabilized ACP and / or ACFP would result in a composition that would form a gel or paste, and all liquid compositions described to date have had relatively low concentrations of phosphopeptide-stabilized ACP and / or ACFP. The second surprising discovery is that increasing the pH of an acidic liquid composition can cause the composition to change into a gel form, which can occur on the tooth surface, subsurface, or in and / or on the lesion. Without being bound by any theory or mechanism of action, it is believed that the increase in pH destabilizes the PP-ACP and / or PP-ACFP complexes, forming an amorphous, immature hydroxyapatite or fluorohydroxyapatite gel. A third surprising discovery is that the formation of this gel occurs rapidly after the pH of the composition is increased, for example by applying an additional composition having an alkaline pH. A fourth surprising discovery is that the gel that is formed changes the refractive index, reducing the visibility of the hypomineralized surface, subsurface, or lesion by making the hypomineralized surface, subsurface, or lesion translucent. One advantage of the present invention is that it masks or conceals visible hypomineralized lesions, substantially improving their appearance and reducing their visibility, i.e., changing the surface to translucent, within minutes in an oral surgery during a single patient visit. Moreover, this is done with calcium and phosphate (with or without fluoride). This represents a substantial improvement in current surgical dental treatments, for example of white spot lesions. At the same time as providing a cosmetic benefit, the gel becomes a reservoir of high concentrations of calcium, phosphate, and optionally fluoride for remineralizing the surface, subsurface, or lesion.

[0112] Liquid compositions containing high concentrations of phosphopeptide-stabilized ACP and / or ACFP typically have a pH of 6 or less and can be combined or mixed with an additional liquid composition of alkaline pH prior to application to a dental surface. A further surprising discovery is that the resulting combined or mixed composition containing high concentrations of phosphopeptide-stabilized ACP and / or ACFP and having a pH of about 9 or greater remains in a state that is ready for application to a dental surface. In other words, the combined or mixed composition exists in liquid form for a period of time, such as 1-2 minutes, that can be applied to a dental surface.

[0113] Yet another surprising discovery is that compositions containing high concentrations of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) can remain in a liquid state (i.e., do not form a gel) and do so at near neutral pH. The compositions do not need to be prepared in a specialized oral surgeon at the physical location where the individual is treated. The liquid compositions can then be used to reduce the visibility of white spot lesions, reduce dentin hypersensitivity, and other uses described herein.

[0114] The subsurface of the tooth is typically a hypomineralized lesion, so the first The composition and the second composition, or the mixed composition, pass through any surface layers, i.e., pellicle and / or plaque, and pass through the porous tooth surface to the area that needs mineralization.Preferably, the PP-stabilized ACP or ACFP is in the form of a casein phosphopeptide-stabilized ACP or ACFP complex.The tooth surface is preferably tooth enamel.The tooth surface may be a lesion in enamel, such as a lesion caused by dental caries, dental erosion, or fluorosis.

[0115] The reduced visibility of the hypomineralized surface, subsurface, or lesion can be determined by simple visual inspection with the human eye. The reduced visibility can be any level of reduction that makes the hypomineralized surface, subsurface, or lesion less visible. Reduced visibility can give the hypomineralized surface, subsurface, or lesion a translucent appearance, such that it appears little or not different from the surrounding normal mineralized tooth surfaces when examined by the human eye.

[0116] Surface, subsurface, or lesion visibility may also be determined as follows: Chroma Surface reflectance can be recorded using a Minolta ChromaMeter CR241, Minolta, Japan. Surface reflectance measurements are based on the L * a * b * The measurements are related to human color perception in three color dimensions (Commision Internationale de L'Eclaige (1978). Recommendations on uniform color spaces, color difference equations and psychometric color terms. Paris: Bureau Centrale de la DIE Suppl. 2:15.). * The value represents the color gradient from white to black, and a * The value represents the color gradient from green to red, and b * The value represents the color gradient from blue to yellow (Commision Internationale de L'Eclaige, 1978). *Only the measured value of the color reflectance L can be used, with whiter colors having larger measurements and darker colors having smaller measurements. To ensure reproducible positioning of the test specimens in the Chroma Meter, wax casts of each specimen were made and stored. All specimens were allowed to air dry using a dental triplex syringe for 60 seconds before each measurement. Individual test specimens could be repositioned 10 times both before and after treatment, and the color reflectance L was measured. * The values ​​were recorded.

[0117] Dentin hypersensitivity occurs when the protective enamel or cementum that covers the dentin is lost. Typically, cementum is more easily destroyed than enamel because it is thinner and more easily corroded by acids. However, destruction of cementum cannot occur until gingival recession is present and the root surface is exposed to the oral environment. Individuals with destroyed cementum and dentin hypersensitivity often feel pain when the exposed areas of the tooth come into contact with cold air, hot and cold liquids, sweet or sour foods, or when they touch metal objects. Patients with tooth hypersensitivity have a higher number of open dentin tubules and / or larger diameter tubules than normal.

[0118] One of the advantages of one aspect of the present invention is the formation of a protective layer. This layer typically has the same or similar composition as hydroxyapatite or fluoroapatite. It can be formed on enamel or dentin and can be used to seal or occlude dentinal tubules, thereby reducing dentin hypersensitivity.

[0119] Such a layer can be characterized as having a calcium:phosphate ratio similar to that of conventional apatite, preferably about 1.5 to 2: 1. The layer ideally contains a calcium content of about 20% by weight.

[0120] Preferably, this layer contains carbon, oxygen, phosphate, and calcium, and optionally fluoride.

[0121] The method of the present invention of sealing exposed dentin reduces tooth sensitivity and reduces the risk of caries, for example, caries of the root surface. Furthermore, the present invention finds particular application prior to the use of restorative materials, such as compositions containing glass ionomer cements, since dental restorative materials can shrink and form micro-voids with the tooth surface. The gel or protective layer then acts as a gap sealant, reducing the formation of micro-voids.

[0122] The word "treat" or "treatment" refers to a therapeutic procedure that aims to slow down (reduce) an undesirable physiological change or disease. For purposes of the present invention, beneficial or desirable clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of a disease state, a stable (i.e., not worsening) state of a disease state, a delay or slowing of progression of a disease state, amelioration or palliation of a disease / symptom, and remission (partial or complete), whether detectable or not. Treatment may not necessarily result in the complete elimination of detectable symptoms of a disease state, but may reduce or minimize complications and side effects of the disease state. Success of treatment or the like may be monitored by a physical examination of the individual or by response to any thermal, tactile, or chemical treatment described herein. When the method of the present invention is used to treat dentin hypersensitivity or hypersensitivity in a subject, preferably, the subject experiences a reduction in the severity of pain or a reduction in the occurrence of pain over time. Methods for identifying subjects with different degrees of dentin hypersensitivity and for measuring successful treatment or prevention are described herein, including those outlined in Med Oral Patol Oral Cir Bucal. 2008 Mar1;13(3):E201-6. Treatment of a subject can be determined by comparing the degree of pain experienced when exposed to any of the stimuli described herein before and after treatment, whereby a reduction in pain after treatment indicates a reduction in hypersensitivity.

[0123] The words "prevent" and "prevention" generally refer to preventative or prophylactic measures that prevent or inhibit the progression of a condition or symptom, such as hypersensitivity, in an individual who does not have the condition or symptom, such as hypersensitivity. Individuals who may be in need of prevention are those who undergo dental procedures, particularly dental procedures that expose dentin.

[0124] In any aspect of the invention, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for a period of time that allows the liquid composition to penetrate the tooth surface, subsurface, or lesion. Typically, the liquid composition is applied for a period of time that allows the liquid composition to penetrate the pores of the hypomineralized tooth surface or subsurface or lesion. This can then reduce the visibility of the hypomineralized tooth surface or subsurface or lesion when the liquid composition is delivered into those pores, increasing the pH of the liquid composition in the pores, thereby forming a gel. This gel can thus be formed in the subsurface or lesion, or in and on the subsurface or lesion. In one embodiment, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for up to 20 minutes, after which the pH of the liquid composition applied to the hypomineralized tooth surface or subsurface is increased to about 9 or higher. In one embodiment, the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for at least about a few seconds to about 5 minutes, preferably at least about 5 minutes to about 20 minutes.

[0125] Typically, the gel forms anywhere from about 5 to about 20 minutes after the additional composition is applied. Thus, in one embodiment, the additional composition is applied to raise the pH of the first composition, and about 5 to about 20 minutes may pass before the additional composition is applied or treated on the tooth surface, subsurface, or lesion.

[0126] As used herein, % w / v can be interpreted as equivalent to g / 100 ml.

[0127] In either aspect, the dental surface is in need of such treatment. Thus, in another aspect, the invention includes, in addition to the steps of any method described herein, the step of identifying a subject suffering from fluorosis, caries, dentin hypersensitivity or tartar, white spot lesions, fluorosis lesions, caries lesions, or lesions caused by dental erosion.

[0128] A further composition of alkaline pH is a composition that contains a base or a compound capable of generating a base and has a pH greater than 7. A base is defined as a compound that can accept a hydrogen cation (proton) or, more generally, can donate a valence electron pair. The composition may contain compounds that are not necessarily normally considered to be bases (e.g., polypeptides with multiple acidic and basic residues) but that can nevertheless raise the pH of the composition to greater than 7, preferably to a pH of about 9 or greater. Non-limiting examples of bases suitable for use in the present invention include hydroxides, borates, phosphates such as hydrogen phosphates, amines, and any salt form thereof, such as alkali metal salt forms. In particular, non-limiting examples of suitable pharma- ceutically acceptable bases include ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, sodium hypochlorite, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, or urea. In one embodiment, the further composition comprises sodium hydroxide, preferably at a concentration of 1 or 2 M or higher.

[0129] Any pharma- ceutically acceptable compound described as a base is suitable for use in the present invention. Typically, the base is suitable for oral use. Preferably, the compound functions as a base, i.e., only releases hydroxide ions or donates electrons in the presence of acid. The base may be in free base form or in the form of a pharma-ceutically acceptable salt. Non-limiting examples of bases suitable for use in the present invention include hydroxides, borates, phosphates such as hydrogen phosphates and dihydrogen phosphates, citrates, carbonates, bicarbonates, hypochlorites, amines, and any of their salt forms, such as alkali metal salt forms. More specifically, non-limiting examples of suitable pharma- ceutically acceptable bases include ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine. Hypofluorites capable of functioning as bases as described herein are also useful in the present invention as agents for increasing or maintaining pH. Suitable hypofluorites react in situ to produce fluoride ions and hydroxide (or other base) ions. As one skilled in the art will appreciate, fluoride ions can substitute for hydroxide in the crystal structure of apatite to form fluoroapatite.

[0130] Any heat source can be used in the method or use of the present invention to heat or cure the surface or subsurface of the tooth. Heat sources suitable for use in light or radiation extraction, dental applications are well known in the art. Specific examples include dental curing lights, such as 10W high power blue LEDs, such as X-Cure by Guilin Woodpecker Medical Instrument Co. Ltd. In any method or use of the present invention, heating of the liquid composition after contacting the liquid composition with the surface or subsurface of the tooth can be performed. A further step of heating or curing may be performed. Heating or curing may be performed for a time of at least 30 seconds, at least 40 seconds, at least 50 seconds, at least 60 seconds, at least 2 minutes, or at least 5 minutes. Heating or curing may rapidly increase the temperature (for patient comfort) to 45-50°C. Heading or curing may be performed for any time or at any temperature described herein, including the examples.

[0131] Any of the compositions described herein can be applied to the tooth surface, subsurface, or lesion using any technique known in the art or described herein. An exemplary application technique is the use of a microbrush.

[0132] Additionally, any resin barrier, such as a rubber dam, can be used to protect the soft tissues in the oral cavity from the application of any of the compositions described herein.

[0133] As used herein, "stabilized ACP or ACFP" and "stabilized ACP or ACFP complex" are used interchangeably.

[0134] A stabilized ACP or ACFP complex as described herein may be a "closed" complex as shown in FIG. 2 of Cross et al., 2007.

[0135] Stabilized ACP or ACFP complexes as referred to herein include stabilized ACP or ACFP complexes as described in WO 2006 / 056013 (PCT / AU2005 / 001781), the contents of which are incorporated by reference.

[0136] In a preferred embodiment, the phosphopeptide-stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex has tightly bound and loosely bound calcium, in which the bound calcium is less than the tightly bound calcium in the ACP or ACFP complex formed at pH 7.0. Optionally, the ACP or ACFP is predominantly in the base form.

[0137] Stabilized ACP or ACFP complexes as referred to herein include stabilized ACP or ACFP complexes formed at a pH less than 7.0. Preferably, the complexes are formed at a pH in the range of about 5.0 to less than 7.0. More preferably, the complexes are formed at a pH range of about 5.0 to about 6.0. In a preferred embodiment, the complexes are formed at a pH of about 5.0 or about 5.5. Preferably, the ACP or ACFP in the complex is predominantly in the base form.

[0138] Stabilizing ACP: (i) obtaining a solution comprising at least one phosphopeptide; (ii) mixing a solution containing calcium ions, phosphate ions, and hydroxide ions while maintaining a pH of about 5.5 to 9; The composition can be produced by a method comprising the steps of:

[0139] In one embodiment, the pH is maintained at or below 7.0.

[0140] Stabilized ACFP is: (i) obtaining a solution comprising at least one phosphopeptide; (ii) mixing a solution containing calcium ions, phosphate ions, hydroxide ions, and fluoride ions while maintaining a pH of about 5.5 to 9; The composition can be produced by a method comprising the steps of:

[0141] In one embodiment, the pH is maintained at or below 7.0.

[0142] Hydroxide ions can be titrated into the solution to maintain a substantially constant pH. Calcium and phosphate ions can be titrated into the phosphopeptide solution with constant mixing and at a rate that avoids the formation of calcium phosphate precipitates.

[0143] A phosphopeptide-stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex is formed in which the ACP in the complex has tightly bound calcium and loosely bound calcium, or in which the tightly bound calcium in the complex is less than the tightly bound calcium in the ACP or ACFP complex formed at pH 7.0, and the ACP or ACFP is primarily in the base form: a) mixing a first solution containing calcium ions, a second solution containing phosphate ions, and optionally a third solution containing fluoride ions with a solution containing a phosphopeptide and a solvent at a pH of about 5 to less than 7; b) maintaining the pH of the solution at about 5.0 to less than 7.0 during mixing by adding hydroxide ions; and may include cases where the method is obtainable or obtainable by.

[0144] "Tightly" and "loosely" bound calcium and phosphate can be measured using analytical ultrafiltration. Briefly, a solution of mixed phosphopeptide, calcium, phosphate, and optionally fluoride, while maintaining a pH of about 7.0 or less, can be first filtered through a 0.1 micron filter to remove free calcium and phosphate that are not associated with complexes. This free calcium and phosphate is present in the filtrate and is discarded. Any free calcium or phosphate that is not associated with any complexes is not bioavailable, i.e., cannot be delivered to the tooth by the phosphopeptide. The retentate obtained from the 0.1 micron filtration can be further analyzed by centrifugation at 1,000 g for 15 minutes through a 3000 mw cutoff filter. The resulting filtrate contains calcium and phosphate that are loosely bound or associated with complexes. At this centrifugal force, calcium and phosphate that are not tightly bound to complexes are released and move into the filtrate. The tightly bound Ca and Pi in the complexes are retained in the retentate. The amount of tightly bound Ca and Pi in the retentate can then be determined by subtracting the amount of Ca and Pi in the filtrate from the total amount of Ca and Pi in the retentate from the 0.1 micron filtration.

[0145] Stabilized ACP or ACFP complexes as referred to herein include stabilized ACP or ACFP complexes as described in WO 2006 / 135982 (PCT / AU2006 / 000885), the contents of which are incorporated by reference.

[0146] "Superloaded" phosphopeptide or phosphoprotein (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes. The complexes can be formed at any pH (e.g., 3-10). Preferably, the phosphopeptide comprises the sequence -ABC-, where A is a phosphoamino acid, preferably phosphoserine, B is any amino acid, such as a phosphoamino acid, and C is glutamic acid, aspartic acid, or a phosphoamino acid. The phosphoamino acid may be phosphoserine. The PP is superloaded with calcium and phosphate ions. The calcium ions may be in the range of 30-1000 moles Ca per mole PP, or in the range of 30-100 or 30-50 moles Ca per mole PP. In another embodiment, the number of moles Ca per mole PP is at least 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, , 45, or 50.

[0147] The present invention includes amorphous calcium phosphate or amorphous calcium fluoride phosphate complexes stabilized with phosphopeptides or phosphoproteins (PP) having a calcium ion content greater than about 30 moles of calcium per mole of PP. In a preferred embodiment, the calcium ion content is in the range of about 30-100 moles of calcium per mole of PP. More preferably, the calcium ion content is in the range of about 30-50 moles of calcium per mole of PP.

[0148] The present invention relates to: (i) obtaining a solution containing calcium, inorganic phosphate, and fluoride (optional); (ii) mixing (i) with a solution containing PP-ACP; Also provided is a phosphopeptide or phosphoprotein (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex produced by a method comprising:

[0149] In a preferred embodiment, the PP is a casein phosphopeptide (CPP).

[0150] In a further aspect, the present invention also includes the use of a blend of PP-stabilized ACP and / or ACFP complex with at least an equal weight amount of calcium phosphate. Preferably, the calcium phosphate is CaHPO4 or calcium lactate or any other soluble calcium phosphate compound. Preferably, the calcium phosphate (e.g., CaHPO4) is dry blended with the PP-stabilized ACP and / or ACFP complex. In a preferred embodiment, the ratio of PP-ACP and / or PP-ACFP complex:calcium phosphate is about 1:1-50, more preferably about 1:1-25, more preferably about 1:5-15. In one embodiment, the ratio of PP-ACP and / or PP-ACFP complex:calcium phosphate is about 1:10.

[0151] Oral care formulations containing phosphopeptide or phosphoprotein (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) complexes having a calcium ion content of greater than about 30 moles of calcium per mole of PP when used in the oral cavity: (i) obtaining a powder comprising a PP-ACP and / or PP-ACFP complex; (ii) dry blending with an effective amount of calcium phosphate; (iii) formulating an oral care formulation from the dry blended PP-ACP and / or PP-ACFP and calcium phosphate mixture; The composition can be produced by a method comprising the steps of:

[0152] Preferably, the form of calcium phosphate for dry blending is any soluble calcium phosphate, including but not limited to CaHPO4, Ca2HPO4, and calcium lactate.

[0153] The compositions described herein can further comprise free fluoride ions. Fluoride ions can be derived from any suitable source. Fluoride ion sources can include free fluoride ions or fluoride salts. Examples of fluoride ion sources include, but are not limited to, sodium fluoride, sodium monofluorophosphate, stannous fluoride, sodium silicofluoride, and amine fluorides. They can be provided as a solution (typically an aqueous solution) or a suspension.

[0154] Fluoride ion is preferably present in the composition in an amount of more than 1 ppm. More preferably, the amount is more than 3 ppm. In another embodiment, the amount is preferably more than 10 ppm. In the following exemplary embodiment, the amount can be hundreds or thousands of ppm. Fluoride content is typically measured as ppm in oral compositions by the method generally used in the art. When fluoride is obtained from a source with stabilized ACP, ppm refers to the fluoride concentration in that source, which is typically a solution or suspension of bioavailable fluoride.

[0155] Tin-associated ACP or ACFP complexes described herein include any of those described in International Publication No. PCT / AU2014 / 050447, the contents of which are incorporated by reference in their entirety.

[0156] The compositions described herein for use in the methods of use of the invention can include a stannous associated ACP or ACFP complex. The compositions can include 2% CPP-ACP and 290 ppm fluoride, including 220 ppm as stannous fluoride and 70 ppm fluoride as sodium fluoride.

[0157] In any aspect or embodiment described herein, the stabilized ACP and / or ACFP is phosphopeptide (PP) stabilized. Preferably, the phosphopeptide is a casein phosphopeptide (as defined below). Preferably, the ACP or ACFP is in the form of a casein phosphopeptide stabilized ACP or ACFP complex.

[0158] "Phosphopeptide" in the context of the present description means an amino acid sequence in which at least one amino acid is phosphorylated. Preferably, a phosphopeptide comprises one or more amino acid sequences -ABC-, where A is a phosphoamino residue, B is any aminoacyl residue, including a phosphoamino residue, and C is selected from a glutamyl residue, an aspartyl residue, or a phosphoamino residue. Any phosphoamino residue may independently be a phosphoseryl residue. B is desirably a residue whose side chain is neither relatively large nor hydrophobic. It may be Gly, Ala, Val, Met, Leu, Ile, Ser, Thr, Cys, Asp, Glu, Asn, Gln, or Lys. Preferably, at least two phosphoamino acids in the sequence are adjacent. Preferably, the phosphopeptide comprises the sequence ABCDE, where A, B, C, D, and E are independently phosphoserine, phosphothreonine, phosphotyrosine, phosphohistidine, glutamic acid, or aspartic acid, and at least two, preferably three, of A, B, C, D, and E are phosphoamino acids. In a preferred embodiment, the phosphoamino acid residues are phosphoserine, most preferably three consecutive phosphoserine residues. It is also preferred that D and E are independently glutamic acid or aspartic acid.

[0159] In one embodiment, the ACP or ACFP is stabilized by casein phosphopeptides (CPPs), which are in the form of intact casein or fragments of casein, and the complex formed preferably has the formula [CPP(ACP) 8]nor [(CPP)(ACFP)8]n, where n is 1 or more, e.g., 6. The complex formed may be a colloidal complex, the core particles of which aggregate to form large (e.g., 100 nm) colloidal particles in water. Thus, PP may be a casein protein or a phosphopeptide.

[0160] PP may be obtained from any source and may exist in the context of a larger polypeptide, including full-length casein polypeptides, and may be prepared by trypsin or other enzymatic or chemical digestion of casein or another phosphoamino acid-rich protein, such as phosphitin, or by chemical or recombinant synthesis. The nucleic acid sequence may be isolated by the above-mentioned procedure, provided that it contains the sequence -ABC- or ABCDE. The sequence flanking this core sequence may be any sequence. However, α s1 (59 79), beta (1-25), alpha s2 (46-70), and α s2 Flanking sequences in (1-21) are preferred. The flanking sequences may optionally be modified by deletion, addition, or conservative substitution of one or more residues. The amino acid composition and sequence of the flanking region are not critical.

[0161] The phosphopeptides can be selected from those described in any of WO 2006 / 056013, WO 2006 / 135982, or US Pat. No. 5,015,628.

[0162] Examples of conservative substitutions are shown in Table 1 below.

[0163] [Table 1]

[0164] The flanking sequences may also include residues of unnatural amino acids. Commonly encountered amino acids that are not encoded by the genetic code include: 2-aminoadipic acid (Aad) for Glu and Asp; 2-aminopimelic acid (Apm) for Glu and Asp; 2-aminobutyric (Abu) acid in the case of Met, Leu, and another aliphatic amino acid; 2-aminoheptanoic acid (Ahe) in the case of Met, Leu, and another aliphatic amino acid; 2-aminoisobutyric acid (Aib) in the case of Gly; cyclohexylalanine (Cha) in the cases of Val and Leu and Ile; homoarginine (Har) for Arg and Lys; 2,3-diaminopropionic acid (Dpr) for Lys, Arg, and His; N-ethylglycine (EtGly) for Gly, Pro, and Ala; N-ethylasparigine (EtAsn) for Asn and Gln; hydroxylysine (Hyl) in the case of Lys; allohydroxylysine (AHyl) in the case of Lys; 3-(and 4) hydroxyproline (3Hyp, 4Hyp); Alloisoleucine (Alle) in the cases of Ile, Leu, and Val; ρ-amidinophenylalanine for Ala; N-methylglycine (MeGly, sarcosine) for Gly, Pro, and Ala. N-methylisoleucine (MeIle) for Ile; Norvaline (Nva) in the case of Met and another aliphatic amino acid; norleucine (Nle) in the case of Met and another aliphatic amino acid; Ornithine (Orn) for Lys, Arg and His; citrulline (Cit) and methionine sulfoxide (MSO) in the case of Thr, Asn, and Gln; In the case of Phe, N-methylphenylalanine (MePhe), trimethylphenylalanine, halo (F, Cl, Br and I) phenylalanine, triflourylphenylalanine.

[0165] In one embodiment, PP is α s1 (59-79)[1], beta(1-25)[2], alpha s2 (46-70)[3] and α s2 (1-21)[4] is one or more phosphopeptides selected from the group consisting of: [1] Gln 59 -Met-Glu-Ala-Glu-Ser(P)-Ile-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ile-Val-Pro-Asn-Ser(P)-Val-Glu-Gln-Lys 79 (SEQ ID NO:1) α s1 (59-79) [2] Arg 1 -Glu-Leu-Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-Ile-Val-Glu-Ser(P)-Leu-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-Ile-Thr-Arg 25 (SEQ ID NO:2) β(1-25) [3] Asn 46 -Ala-Asn-Glu-Glu-Glu-Tyr-Ser-Ile-Gly-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser(P)-Ala-Glu-Val-Ala-Thr-Glu-Glu-Val-Lys 70 (SEQ ID NO:3) α s2 (46-70) [4] Lys 1 -Asn-Thr-Met-Glu-His-Val-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-Ile-Ile-Ser(P)-Gln-Glu-Thr-Tyr-Lys 21 (SEQ ID NO: 4) α s2 (1-21).

[0166] In some preferred forms of the invention, the liquid composition may be a mouthwash, rinse, spray, or the like. In such preparations, the vehicle is typically a water-alcohol mixture, preferably containing a humectant. In general, the weight ratio of water to alcohol is in the range of about 1:1 to about 20:1. The total amount of the water-alcohol mixture in this type of preparation is typically in the range of about 70 to about 99.9% by weight of the preparation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.

[0167] As is conventional, it will be appreciated that oral preparations will typically be sold or otherwise distributed in suitable labeled packaging, so a bottle of mouthrinse will have labelling substantially stating that it is a mouthrinse or mouthwash and describing its use.

[0168] Prior to application of the liquid composition, the tooth surface, subsurface, or lesion may be prepared (e.g., cleaned) with a preparation composition. Such compositions may include the following ingredients: Organic surfactants may be used in the composition to increase the prophylactic action, promote thorough and complete distribution of the actives throughout the oral cavity, and make the composition more cosmetically acceptable. Organic surfactant materials are preferably anionic, nonionic, or amphoteric. and preferably does not interact with the active agent. It is preferred to use as the surfactant a cleaning material that imparts cleaning and foaming properties to the composition. Suitable examples of anionic surfactants include water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of monosulfated monoglyceride of hydrogenated coconut oil fatty acid, higher alkyl sulfates, such as sodium lauryl sulfate, alkylaryl sulfates, such as sodium dodecylbenzene sulfate, higher alkyl sulfoacetates, higher fatty acid esters of 1,2-dihydroxypropanesulfonate, and substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl group, or acyl group. An example of the last mentioned amide is N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine, which should be substantially free of soap and similar higher fatty acid materials. The use of these sarconite compounds in the oral compositions of the present invention is particularly advantageous since these materials show a long-term and significant effect in inhibiting acid formation in the oral cavity, due to the decomposition of carbohydrates in addition to a certain degree of reducing the solubility of dental enamel in acid solutions. Examples of water-soluble nonionic surfactants suitable for use are the condensation products of ethylene oxide with various reactive hydrogen-containing compounds that have long hydrophobic chains (e.g., aliphatic chains of about 12 to 20 carbon atoms) and are reactive therewith; these condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as the condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g., sorbitan monostearate), and polypropylene oxide (e.g., Pluronic materials).

[0169] Various other materials may be incorporated into the oral preparations of the present invention, such as whitening agents, preservatives, silicones, chlorophyll compounds, and / or ammoniated materials, e.g., urea, diammonium phosphate, and mixtures thereof. When present, these adjuvants are incorporated into the preparations in amounts that do not substantially adversely affect the desired properties and characteristics. Any suitable flavoring or sweetening material may be used. Examples of suitable flavoring ingredients are flavor oils, such as spearmint oil, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage oil, eucalyptus oil, marjoram oil, cinnamon oil, lemon oil, and orange oil, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenylalanine methyl ester), saccharin, and the like. Suitably, the flavoring and sweetening agents, each or combined, may constitute from about 0.1% to more than 5% of the preparation.

[0170] Further compositions at alkaline pH can further include additional ingredients to enhance gel formation, such as the addition of stannous, zinc, magnesium, or other metal ions or other chemicals to promote cross-linking of the phosphopeptide-stabilized ACP or ACFP to enhance gelation.

[0171] Although the present specification refers specifically to human application, it will be clearly understood that the invention is also useful for veterinary purposes, and thus in all aspects the invention is useful for farm animals such as cattle, sheep, horses and poultry, companion animals such as cats and dogs, and zoo animals.

[0172] The invention will now be further described with reference to the following non-limiting examples.

[0173] Example 1 Preparation of high-concentration liquid CPP-ACFP and CPP-ACP solutions Just before precipitation or gelation (usually about 78 mM Ca 2+and 48 to 76 mM A stock solution of 3.25 M CaCl2 and 1.25 M NaH2PO4 (pH 5.5) was added in approximately 30 aliquots to a tryptic digest of 10-15% w / v casein (resulting in a final concentration of inorganic phosphate of 100 mM NaCl). The solutions were added slowly (i.e., less than about 1% volume per minute) with thorough mixing. One aliquot of the phosphate solution was added first, followed by one aliquot of the calcium solution. The pH of the bulk solution was maintained at 9.0 with 1-10 M NaOH with thorough mixing. Sodium hydroxide solution was added automatically by a pH stat, usually with hydroxide ion added after each addition of calcium ion. After the addition of calcium, phosphate, and hydroxide ions was completed, the solution was filtered through a 0.1 micron filter and concentrated 1-2 fold. The retentate was then washed with 1-2 volumes of water to remove salts and inactive (and bitter) peptides. The prepared CPP-ACP solution was then spray-dried or freeze-dried to obtain a white powder. This dried powder was then added to water to form a 45% w / v CPP-ACP solution at pH 5.5 by adding 1-10 M HCl, or NaF was added to produce 8,200 ppm F and 1-10 M HCl to produce a 63% w / v CPP-ACP solution at pH 5.5.

[0174] A 75% w / v solution was prepared by adding 75 g of CPP-ACP powder to 20 ml of water, each addition being made at a small amount of powder (0.5 g / min) and maintaining the pH at 5.5 by simultaneous addition of 10 M HCl. The solution was mixed thoroughly after each addition to ensure dispersion. A concentrated NaF (0.95 M) solution was added along with the 10 M HCl to provide a final addition of 52 mmol of F. The CPP-ACP powder, NaF, and HCl were added over 2-3 hours with water to a final volume of 100 ml. This produced a liquid composition of 75% w / v CPP-ACP, 9,880 ppm F, and pH 5.5.

[0175] Example 2 Masking of vitiligo lesions using CPP-ACP and alkaline solution A 45% w / v liquid solution of CPP-ACP pH 5.5 was applied with a microbrush (for a few seconds) to the surface of the enamel block containing the white spot lesion. The enamel block was then incubated for 20 minutes at 37° C. A 1M NaOH solution (approximately pH 14) was then applied with a microbrush (for a few seconds) and the enamel block was then incubated for an additional 20 minutes at 37° C.

[0176] Figure 1 shows a comparison of a white lesion (T) after treatment and a control lesion (C) derived from the same lesion (i.e., the enamel block was cut in two). Compared to the control sample, where the white lesion was still clearly visible, the white lesion in the treated sample was essentially masked by the treatment by making the lesion translucent.

[0177] Example 3 Masking of vitiligo lesions with 63% w / v CPP-ACP, free fluoride, and alkaline solution A pH 5.5 liquid solution of 63% w / v CPP-ACP and 8,200 ppm F as NaF was applied with a microbrush (for a few seconds) to the surface of the enamel block containing the white spot lesion. The enamel block was then incubated for 20 minutes at 37° C. A 1M NaOH solution was then applied with a microbrush (for a few seconds) and the enamel block was then incubated for an additional 20 minutes at 37° C.

[0178] Figure 2 shows a comparison of a treated white spot lesion on the left (T) and a control lesion on the right (C) derived from the same lesion (i.e., the enamel block was cut in two). Compared to the control sample where the white spot lesion was still clearly visible, the white spot lesion in the treated sample was essentially masked by the treatment by making the lesion translucent.

[0179] Example 4 In a dental office, a patient needing to reduce the surface or subsurface visibility of hypomineralized tooth enamel can be treated using the following steps: 1. Apply a rubber dam and perform an acid etch of the vitiligo [this step is optional and not necessary in the case of very porous (active) lesions]. This may require a standard liquid rubber dam (a resin barrier to protect the soft tissue) and acid etching technique (e.g. 30% phosphoric acid or 15% HCl). 2. A highly concentrated (>40% w / v) acidic solution (e.g., pH <6) of stabilized CPP-ACP or CPP-ACP / F is applied to the vitiligo using a microbrush and then left on for 5-20 minutes. Optionally, heat can be applied by using a high intensity LED curing light (e.g., 10W high power blue light) to rapidly raise the temperature to 45-50°C (while the patient is comfortable). 3. Apply a concentrated base (e.g. 4% w / v NaOH) with a microbrush, then leave for 5-20 minutes. Optionally, heat can be applied by using a high intensity LED curing light (e.g. 10W high power blue light) to rapidly raise the temperature (while the patient is comfortable) to 45-50°C.

[0180] Example 5 Exemplary Dental Kit A dental kit comprising or consisting of three parts: (a) 5 g of CPP-ACP powder, preferably prepared as described herein; (b) 5 ml of 0.73 M NaF in 1.146 M HCl, and (c) 1.5 M NaOH containing two microbrushes.

[0181] Part (a) was added to part (b) and mixed thoroughly. This mixture was then applied with one microbrush to the vitiligo lesion on the left side (see image in FIG. 3(A) showing the lesion before application). After a few seconds / minutes at 37° C., solution (c) was then applied with a second microbrush to the vitiligo lesion on the left side. Within 15 minutes, a reaction occurred in the vitiligo, forming a gel and concealing the vitiligo (see image in FIG. 3(B)).

[0182] Example 6 Masking of vitiligo lesions with 75% w / v CPP-ACP, free fluoride, and alkaline solutions A pH 5.5 liquid of 75% w / v CPP-ACP and 9,880 ppm F as NaF was applied with a microbrush (for a few seconds) to the surface of the enamel block containing the white spot lesion. The enamel block was then incubated for 10 minutes at 37°C. A 2M NaOH solution was then applied with a microbrush (for a few seconds) and the enamel block was then incubated for an additional 20 minutes at 37°C.

[0183] Figure 4 shows a comparison of the white spot lesion after treatment on the left and a control lesion on the right, both derived from the same lesion (i.e., the enamel block was cut in two). Compared to the control sample, where the white spot lesion was still clearly visible, the white spot lesion in the treated sample was essentially masked by the treatment by making the lesion translucent.

[0184] Example 7 Masking white spot lesions by forming a mixed composition prior to application to the tooth surface Prior to application to the tooth surface, a degassed 63% w / v CPP-ACP / 8,000 ppm F liquid composition at pH 5.5 was mixed with a solution of 1.5 M NaOH. This mixed composition was then applied onto the white spot lesion. A dental curing light at setting 2 was then used on the surface for 40 seconds. The result is impressive coverage of the enamel white spots (Figure 5).

[0185] Example 8 Formation of a protective layer on dentin Another application of the present invention is the sealing or obturation of exposed root (dentin) surfaces (elderly people have exposed root surfaces, which are more susceptible to caries / erosion). To simulate these exposed root surfaces, root dentin was treated with 15% EDTA for 2 minutes, thereby removing the smear layer and exposing the dentinal tubules (Figure 6, right block). The mixed composition described in Example 7 was applied to the dentin, forming a gel on the surface (Figure 6, left block).

[0186] Furthermore, when the mixed composition is applied to a dentin surface (either sound or before demineralization with an acid buffer), the solution not only forms a gel, but also starts to form a fluoroapatite (FA) layer on the surface to seal the dentin (as shown in Figures 7, 8, and 9). This will have a dramatic effect on reducing tooth sensitivity and reducing the risk of root caries. Interestingly, the fluoroapatite layer is white, so it not only provides a sealing and protective layer that hides the yellow dentin, thereby reducing the risk of sensitivity and caries / erosion, but also improves the aesthetics of the tooth.

[0187] The protective layer formed was intentionally dehydrated to demonstrate its uniformity over the surface (shown in Figure 9) which completely sealed the dentin tubules (shown exposed on the right side of Figure 8).

[0188] Elemental analysis showed that the protective layer formed had a composition similar to that of fluorohydroxyapaptite (FIG. 9B).

[0189] Example 9 Formation of a protective layer on dentin method: All dentin blocks were polished The dentin block was treated with 15% EDTA for 2 minutes. Etch for 15 seconds (37% phosphoric acid) Mix degassed 63% (w / v) CPP-ACP / 8,100 ppm F (pH 5.5) with an equal volume of 2 M NaOH. Premixed 63% (w / v) CPP-ACP / 8,100 ppm F (pH 5.5) and 2 M NaOH was applied topically onto the dentin surface using a microbrush. 40 seconds light cure Leave at 37℃ for 48 hours Sectioning, lapping and microradiography.

[0190] As shown in FIG. 10, an inorganic layer was formed on the dentin surface.

[0191] Example 10 Formation of a protective layer on the enamel method: All enamel blocks were polished Etch for 15 seconds (37% phosphoric acid) 63% (w / v) CPP-ACP / 8100 ppm F (pH 5.5) mixed with an equal volume of 2 M NaOH Premixed 63% (w / v) CPP-ACP / 8,100 ppm F( pH 5.5) and 2 M NaOH were applied topically onto the enamel surface using a microbrush. 40 seconds light cure Leave at 37℃ for 48 hours Sectioning, lapping and microradiography.

[0192] As shown in FIG. 11, an inorganic layer was formed on the enamel surface.

[0193] Example 11 Masking white spot lesions by forming a mixed composition prior to application to the tooth surface 30 g of CPP-ACP powder (commercially available Recaldent) was added to 19.5 g of a 20,000 ppm F(NaF) solution, to which was added 0.5 g of an 11 M HCl solution to give a final 50 g (so this final solution is 60% w / w CPP-ACP with 7,800 ppm F at pH 7.8, or 75% w / v CPP-ACP containing 10,000 mg / L F at pH 7.8).

[0194] Upon thorough stirring (approximately 30 min), a homogeneous, very viscous, but stable solution was prepared at a pH of 7.8. The solution was then degassed by placing it under vacuum for 24 h to remove trapped air bubbles.

[0195] The solution was applied to the white spot lesions using a microbrush and then light-cured for 40 seconds using a dental curing light (described above). Images before and after curing are shown (Figure 12(a) before, Figure 12(b) 40 seconds after curing, Figure 12(c) 15 minutes after curing, and Figure 12(d) 24 hours after curing). The cured stabilized high concentration solution concealed the white spots very effectively, and this effect was maintained for at least 24 hours at 37°C.

[0196] This viscous, stable, and safe (neutral pH) solution is easy to apply in oral surgery and the more concentrated it is the better the effect over a longer period of time.

[0197] It will be understood that the invention disclosed and defined herein extends to any alternative combination of two or more of the features described or apparent from the text or drawings, all of which constitute various alternative aspects of the invention.

Claims

1. 1. A method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: contacting the surface or subsurface of the hypomineralized tooth with a liquid composition comprising at least 40% w / w phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and having a pH of at least pH 5 but not more than pH 9; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The method includes:

2. 1. A method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: contacting the exposed dentinal tubules with a liquid composition comprising at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of greater than or equal to 5 but less than or equal to 9; thereby treating or preventing dentin hypersensitivity in said subject in need thereof; The method includes:

3. 3. The method of claim 1 or 2, wherein the pH of the liquid composition is 6 or more but 8 or less, preferably 7 or more but 8 or less.

4. The method of any one of claims 1 to 3, wherein the liquid composition further comprises free fluoride ions.

5. The method of claim 4, wherein the free fluoride ions are present in the liquid composition at a concentration in the range of about 200 ppm to 10,000 ppm.

6. The method of claim 4, wherein the free fluoride ions are present in the liquid composition at a concentration in the range of about 2,600 ppm to about 8,500 ppm.

7. 5. The method of claim 4, wherein said free fluoride ions are present in said liquid composition at a concentration of about 7,800 ppm.

8. The method of any one of claims 1 to 7, wherein the method further comprises applying heat to the surface or subsurface of the tooth or lesion.

9. 9. The method of claim 8, wherein the tooth surface or subsurface is heated to a temperature greater than 37°C.

10. 9. The method of claim 8, wherein the tooth surface or subsurface is heated to a temperature of 40°C or greater.

11. 9. The method of claim 8, wherein the tooth surface or subsurface is heated to a temperature of 45°C or greater.

12. 9. The method of claim 8, wherein the tooth surface or subsurface is heated to a temperature of 50°C or greater.

13. 9. The method of claim 8, wherein the tooth surface or subsurface is heated to a temperature of 55°C or greater.

14. 10. The method of claim 9, wherein the tooth surface or subsurface is heated to a temperature of 60°C or greater.

15. 10. The method of claim 9, wherein the tooth surface or subsurface is heated to a temperature of 65°C or greater.

16. The method according to any one of claims 1 to 15, wherein the liquid composition comprises more than 45% w / w of stabilized ACP and / or ACFP.

17. The method according to any one of claims 1 to 15, wherein the liquid composition comprises more than 50% w / w of stabilized ACP and / or ACFP.

18. The method according to any one of claims 1 to 15, wherein the liquid composition comprises more than 55% w / w of stabilized ACP and / or ACFP.

19. The method according to any one of claims 1 to 15, wherein the liquid composition comprises more than 60% w / w of stabilized ACP and / or ACFP.

20. The method of any one of claims 1 to 15, wherein the liquid composition comprises about 65% w / v stabilized ACP and / or ACFP.

21. The method of any one of claims 1 to 15, wherein the liquid composition comprises about 70% w / v stabilized ACP and / or ACFP.

22. The method of any one of claims 1 to 15, wherein the liquid composition comprises about 75% w / v stabilized ACP and / or ACFP.

23. 23. The method of any one of claims 1 to 22, wherein the phosphopeptide is a casein phosphopeptide.

24. 1. A method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (i) contacting the surface or subsurface of the hypomineralized tooth with a liquid composition comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The method includes:

25. 1. A method of forming a gel in and / or on a tooth surface or subsurface lesion, comprising: (i) contacting the tooth surface or subsurface lesion with a liquid composition comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the tooth surface or subsurface lesion to about 9 or greater, thereby forming a gel in and / or on the tooth surface or subsurface lesion; thereby forming a gel in and / or on said tooth surface or subsurface lesion; The method includes:

26. 1. A method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: (i) applying at least 40% w / v of phosphopeptide (PP)-stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) to exposed dentinal tubules; ) at a pH of 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel in and / or on the exposed dentinal tubules; thereby treating or preventing dentin hypersensitivity in said subject in need thereof; The method includes:

27. 1. A method for forming a protective layer on a tooth surface, comprising: (i) contacting said tooth surface with a liquid composition comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a pH of 6 or less; (ii) subsequent to (i), increasing the pH of the liquid composition applied to the tooth surface to about 9 or greater; thereby forming a protective layer on the tooth surface; The method includes:

28. 28. The method of any one of claims 24 to 27, wherein the pH of the liquid composition applied to the tooth surface or subsurface lesion is raised to about 10 or greater.

29. 28. A method according to any one of claims 24 to 27, wherein the step of increasing the pH of the liquid composition applied to the tooth surface or subsurface lesion is carried out by contacting the liquid composition applied to the tooth surface or subsurface with a further composition of alkaline pH.

30. A method according to any one of claims 24 to 29, wherein the tooth surface is tooth enamel.

31. A method according to any one of claims 24 to 30, wherein the tooth surface is a lesion in the enamel, caused by caries, dental erosion or fluorosis.

32. 32. The method of claim 31 , wherein the lesion is a vitiligo lesion.

33. 33. A method according to any one of claims 24 to 32, wherein the step of increasing the pH of the liquid composition applied to the tooth surface or subsurface lesion is carried out by contacting the liquid composition applied to the tooth surface or subsurface with a further composition of alkaline pH.

34. 1. A method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (i) mixing (a) a liquid composition having a pH of 6 or less, comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and (b) a further composition having an alkaline pH, thereby forming a mixed composition having a pH of about 9 or more; (ii) contacting the mixed composition with the surface or subsurface of the hypomineralized tooth, thereby forming a gel in and / or on the surface or subsurface of the hypomineralized tooth; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; The method includes:

35. 1. A method of treating or preventing dentin hypersensitivity in a subject in need thereof, comprising: (a) a phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) at a concentration of at least 40% w / v, (b) mixing the liquid composition at a pH of about 9 or greater with an additional composition at an alkaline pH, thereby forming a mixed composition having a pH of about 9 or greater; (ii) contacting the exposed dentinal tubules with the mixed composition, thereby forming a gel in and / or on the exposed dentinal tubules; thereby treating or preventing dentin hypersensitivity in said subject in need thereof; The method includes:

36. 1. A method for forming a protective layer on a tooth surface, comprising: (i) mixing (a) a liquid composition having a pH of 6 or less, comprising at least 40% w / v of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP), and (b) a further composition having an alkaline pH, thereby forming a mixed composition having a pH of about 9 or more; (ii) contacting the mixed composition with a tooth surface; thereby forming a protective layer on the tooth surface; The method includes:

37. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is a pH of about 8.

38. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is a pH of about 9.

39. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is at a pH of about 10.

40. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is at a pH of about 11.

41. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is at a pH of about 12.

42. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is a pH of about 13.

43. The method of any one of claims 34 to 36, wherein the alkaline pH of the further composition is a pH of about 14.

44. The method of any one of claims 24 to 43, wherein the liquid composition further comprises free fluoride ions.

45. 45. The method of claim 44, wherein the free fluoride ions are present in the liquid composition at a concentration in the range of about 200 ppm to about 10,000 ppm.

46. 45. The method of claim 44, wherein the free fluoride ions are present in the liquid composition at a concentration in the range of about 2,600 ppm to about 8,500 ppm.

47. 45. The method of claim 44, wherein the free fluoride ions are present in the liquid composition at a concentration of about 8,200 ppm.

48. A method according to any one of claims 24 to 33, wherein step (i) further comprises applying heat to the surface or subsurface of the tooth or lesion.

49. A method according to any one of claims 24 to 33, wherein step (i) is followed by a step of heating the surface or subsurface of the tooth or lesion.

50. 50. The method of any one of claims 24 to 49, wherein step (ii) further comprises applying heat to the surface or subsurface of the tooth or lesion.

51. 50. A method according to any one of claims 24 to 49, wherein step (ii) is followed by a step of heating the surface or subsurface of the tooth or lesion.

52. 52. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature above 37°C.

53. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of 40°C or greater.

54. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of 45°C or greater.

55. The tooth surface or subsurface or lesion is heated to a temperature of 50°C or greater.

52. The method according to any one of claims 48 to 51.

56. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of 55°C or greater.

57. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of 60°C or greater.

58. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of 65°C or greater.

59. A method according to any one of claims 48 to 51, wherein the tooth surface or subsurface or lesion is heated to a temperature of less than 65°C.

60. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises more than 45% w / v stabilized ACP and / or ACFP.

61. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises more than 50% w / v stabilized ACP and / or ACFP.

62. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises more than 55% w / v stabilized ACP and / or ACFP.

63. The liquid composition comprising more than 40% w / v of phosphopeptide (PP) stabilized ACP and / or ACFP comprises more than 60% w / v of stabilized ACP and / or ACFP. Item 24 to 59. The method according to any one of items 24 to 59.

64. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises about 65% w / v stabilized ACP and / or ACFP.

65. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises about 70% w / v stabilized ACP and / or ACFP.

66. 60. The method of any one of claims 24 to 59, wherein the liquid composition comprising more than 40% w / v phosphopeptide (PP) stabilized ACP and / or ACFP comprises about 75% w / v stabilized ACP and / or ACFP.

67. 34. A method according to any one of claims 24 to 33, wherein the liquid composition in (i) is contacted with the hypomineralised tooth surface or subsurface or lesion for up to 20 minutes prior to the step of increasing the pH of the liquid composition applied to the hypomineralised tooth surface or subsurface to above about 9.

68. 68. The method of claim 67, wherein the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for at least about several seconds to about 5 minutes.

69. 69. The method of claim 68, wherein the liquid composition in (i) is contacted with the hypomineralized tooth surface or subsurface or lesion for at least about 5 minutes to about 20 minutes.

70. 70. The method of any one of claims 24 to 69, wherein the method further comprises the step of acid etching the hypomineralized surface, subsurface, or lesion prior to contacting with the liquid composition in (i).

71. 71. The method of any one of claims 24 to 70, wherein the phosphopeptide is a casein phosphopeptide.

72. 72. The method of any one of claims 1 to 71, wherein the liquid, further composition and / or mixed composition is applied to the tooth surface, subsurface or lesion by a dental health care professional.

73. 73. The method of claim 72, wherein the liquid, further composition, and / or mixed composition is applied to the tooth surface, subsurface, or lesion using a microbrush.

74. The method further comprises identifying a subject having a white spot lesion, a fluorosis lesion, a caries lesion, or a lesion caused by dental erosion.

74. The method of any one of claims 1 to 73.

75. 1. A cosmetic method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (i) contacting the surface or subsurface of the hypomineralized tooth with a liquid composition comprising at least 40% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) and having a pH of 6 or less; (ii) following (i), increasing the pH of the liquid composition applied to the surface or subsurface of the hypomineralized tooth to about 9 or greater, thereby forming a gel therein and / or thereon; thereby reducing the visibility of the hypomineralized tooth surface or subsurface; Including beauty methods.

76. 1. A cosmetic method for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: contacting the surface or subsurface of the hypomineralized tooth with a liquid composition having a pH of at least 6 but not more than 8, the liquid composition comprising at least 40% w / w of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP); thereby reducing the visibility of the hypomineralized tooth surface or subsurface; Including beauty methods.

77. 1. A kit for reducing the surface or subsurface visibility of hypomineralized teeth, comprising or consisting of: (a) a liquid composition having a pH of 6 or less comprising at least 40% by weight of phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP); and (b) a further composition having an alkaline pH.

78. 78. The kit of claim 77, further comprising written instructions for use in the method of any one of claims 1 to 76.

79. 1. A kit for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (a) a first composition comprising a powder of phosphopeptide stabilized ACP and / or ACFP; (b) a second composition having a pH of 6 or less comprising a solution of fluoride; (c) a third composition at an alkaline pH; and A kit comprising or consisting of:

80. 80. The kit of any one of claims 77 to 79, wherein the alkaline pH of the third composition is at a pH of about 9, 10, 11, 12, 13, or 14.

81. 80. The kit of claim 77 or 78, wherein the first composition contains an amount of phosphopeptide stabilized ACP and / or ACFP that, when mixed with the second composition, forms a liquid composition containing at least 40% w / v phosphopeptide stabilized ACP and / or ACFP.

82. 1. A kit for reducing the surface or subsurface visibility of hypomineralized teeth, comprising: (a) 5 g of CPP-ACP and / or CPP-ACFP; (b) 5 ml of 0.73 M NaF in 1.146 M HCl; (c) 1.5 M NaOH; A kit comprising or consisting of:

83. 83. The kit of claim 82, further comprising two microbrushes.

84. 1. A method or process for preparing a liquid composition comprising at least 40% w / v PP-stabilized ACP and / or ACFP, comprising: mixing a solvent with a powder comprising or consisting of PP-stabilized ACP and / or ACFP; maintaining the pH below 7; A method or process comprising or consisting of:

85. 1. A method or process for preparing a liquid composition comprising at least 40% w / v PP-stabilized ACP and / or ACFP, comprising: mixing a solvent with a powder comprising or consisting of PP-stabilized ACP and / or ACFP; reducing the pH to less than 7, preferably reducing said pH to 6 or less, preferably 5.5 or less; A method or process comprising or consisting of:

86. 86. The method or process of claim 84 or 85, wherein the pH is maintained below 6, preferably the pH is maintained below 5.

5.

87. To prepare a powder comprising or consisting of PP stabilized ACP and / or ACFP: mixing one or more solutions comprising phosphopeptides, calcium ions, phosphate ions, hydroxide ions, and optionally fluoride ions while maintaining a pH of about 7.0 or greater, preferably about 9, to form a solution comprising stabilized ACP and / or ACFP; drying the solution containing PP-stabilized ACP and / or ACFP; thereby forming a powder comprising or consisting of PP stabilized ACP and / or ACFP; 87. The method or process of any one of claims 84 to 86, further comprising:

88. 88. The method or process of claim 87, wherein the drying is spray drying or freeze drying.

89. 89. The method or process of claim 87 or 88, further comprising filtering the solution comprising PP-stabilized ACP and / or ACFP prior to drying to form a retentate, and subsequently drying the retentate to form a powder comprising or consisting of PP-stabilized ACP and / or ACFP.

Images