HK1218870B - Dental care product for tooth whitening - Google Patents

Description

Dental care products for teeth whitening

The present invention relates to the field of dental care, and specifically to dental care products, such as toothpaste (dentifrices), preventive pastes, tooth powders, tooth polishes, tooth gels, chewing gums, candies, lozenges, mouthwashes, whitening strips, coated dental floss, coated toothbrushes, spreadable gels, tooth varnishes, veneers, and tubes, syringes, or trays containing gels or pastes, as well as mouthwashes, whitening strips, and trays for whitening teeth, wherein the product comprises mineral particles (such as crystals) and a compound (preferably a protein capable of forming a matrix as a hydrogel), wherein the product comprises a fluorophore. The mineral particles may comprise, for example, calcium phosphate, preferably hydroxyapatite, preferably in crystalline form. The protein matrix may comprise, for example, a self-assembling peptide. The product further comprises a fluorophore, which may be a fluorescent amino acid residue of the protein matrix. The present invention also relates to cosmetic uses of the dental care product for whitening teeth or for treating one or more sensitive teeth and/or preventing or treating dental caries, as well as related methods for whitening teeth.

Tooth enamel is the hardest substance in the human body. It is composed of approximately 98% hydroxyapatite (a crystalline form of calcium phosphate) and some organic components. A thin layer of enamel forms on the tooth surface, with dentin as a base. Enamel is tougher and better suited to absorbing the stresses of chewing without breaking. Dentin, which also contains hydroxyapatite, has a higher porosity and a higher organic structure.

Tooth discoloration can occur both externally and internally. For example, coffee, tea, alcohol, carrots, oranges, or tobacco can stain tooth enamel. Certain antibiotics, excessive fluoride intake, or genetic disorders can also cause endogenous discoloration. Tooth discoloration can be a significant aesthetic concern for dental patients. For example, in the UK, approximately 20% of people are dissatisfied with the color of their teeth. In the US, 34% of people are dissatisfied with their appearance.

Typically, surface stains can be removed by thorough cleaning of the teeth by the patient or a health professional. Polishing with abrasive materials is sometimes used for this purpose, for example using a paste containing particles of calcium phosphate, chalk, pumice or silica. If the patient wishes to further reduce the endogenous discoloration of the teeth, chemical bleaching is a classic option. Various bleaching techniques are known, which are based on oxidizing agents (such as peroxides). Bleaching can be performed in a dental clinic by a health professional or by the patient at home. For this purpose, prescription products for overnight bleaching or bleaching toothpastes can be used.

However, in recent years, awareness of the side effects associated with bleaching, such as peroxide-induced demineralization, erosion, and tooth sensitivity, has increased (e.g., Dahl et al., 2003). Hydroxyapatite nanocrystals have been proposed for remineralizing tooth surfaces damaged by bleaching (Mohd et al., 2007, Jiang et al., 2008, Lim et al., 2009, Roveri et al., 2009). Hydroxyapatite crystalline particles, which closely resemble the natural material of teeth, can be deposited on tooth enamel. In addition to filling scratched or eroded areas of teeth and preventing or treating caries, the deposited hydroxyapatite can also counteract tooth hypersensitivity caused by exposure of dentinal tubules during gingival recession (WO 2007/137606 Al).

Amorphous calcium phosphate stabilized with phosphoproteins such as casein phosphopeptides (CPP-ACP) has been used in oral care products for the prevention and treatment of caries lesions (eg, US 20050037948 A1, US 20080075675 A1, US20100297203 A1).

Certain forms of calcium phosphate, such as hydroxyapatite, have been found to possess whitening properties independent of bleaching or polishing (Niwa et al., 2001, Dabanoglu et al., 2009). Dabanoglu et al. compared the whitening properties of different materials, such as nano-hydroxyapatite, nano-tricalcium phosphate, or a soluble polymer film (methacrylic acid-ethyl acrylate copolymer) containing nano-hydroxyapatite. They achieved a color change, spectroscopically measured as ΔE (L*a*b scale), with all tested materials. This can be measured according to ISO 28399. This effect increased to approximately 3 ΔE after three applications and decreased with some materials after subjecting the treated teeth to shear forces. It is important to note that the average casual observer can notice a difference between two colors that are 3-4 ΔE apart. A trained eye can distinguish between two colors that are 2-3 ΔE apart. Therefore, while perceptible changes can be achieved, there is still room for improvement.

WO 2013/068020 discloses a dental care product comprising hydroxyapatite having a surface functionalized with lactoferrin. It is suggested that a film is formed on the enamel surface, which improves the remineralization of the teeth and has an antibacterial effect.

JPH115722 relates to an aqueous composition for oral hygiene, i.e., a mouthwash, containing hydroxyapatite particles. JP2008/081424 describes tooth whitening using a composition comprising lactoferrin and lactoferrin decomposition products and cyclic or annular polyphosphates. JP2007/0176862 describes the use of a composition comprising hydrolyzed silk and precipitated calcium carbonate for inhibiting dentin washout and preventing dental caries. JP2001/131041 describes an oral composition, such as a toothpaste, containing hydroxyapatite with improved storage stability, which also contains magnesium salts. CN101385856 relates to a nanohydroxyapatite material for absorbing and slowly releasing lysozyme (lysozyme) for treating/preventing dental caries.

US 20100247589 A1 describes an oral care system comprising various components, such as a monomeric peptide that partially binds to oral surfaces, a second binding element, and a composition that may include particles that can bind to the second binding element, and the composition comprises a beneficial agent, such as a whitening agent, for example, _TiO2 or hydroxyapatite particles, or an anti-staining agent or enzyme. The peptide is said to facilitate the binding of the beneficial agent to oral surfaces. US 2010/0247457 A1 also teaches a peptide-based agent comprising at least one tooth-surface-binding peptide for delivering at least one polymer-coated white colorant to the tooth surface. Raoufi et al. (2010) compared commercial over-the-counter calcium peroxide and hydroxyapatite toothpastes (intended to bleach or whiten teeth, respectively) with a fluoride placebo toothpaste and found no targeted whitening effect for any of the toothpastes in a 12-week clinical trial.

There is a need in the art for dental care products that effectively whiten teeth, preferably while minimizing the disadvantages of bleaching, such as demineralization and tooth sensitivity, that are safe, preferably for commercial over-the-counter sale, and that can be applied by the patient or consumer.

The present inventors have solved this problem. The present invention provides a dental care product and its use as described in the claims. Specifically, the present invention provides a dental care product comprising 0.4-60% by weight, preferably 0.5-50% by weight, 1-40% by weight, 5-30% by weight, or 10-25% or 15-20% by weight, for example 20-30% by weight or about 25% by weight of mineral particles having a size of 10 nanometers to 50 micrometers, and 0.001-5% by weight, preferably 0.02-2% by weight, 0.04-1% by weight, 0.05-0.5% by weight, or 0.05-0.2% by weight of an organic compound capable of forming an organic matrix, preferably a protein capable of forming a protein matrix, such as a self-assembling peptide. The protein matrix is a hydrogel. The dental care product contains a fluorophore.

The inventors surprisingly discovered that, in a dental care product according to the present invention, the aforementioned whitening effect of hydroxyapatite particles on teeth can be significantly enhanced by combining the mineral particles with a suitable organic matrix, such as a suitable protein matrix. The protein alone does not achieve a comparable effect, and the combination works synergistically. Specifically, the present invention provides a dental care product capable of producing a difference in tooth whiteness of more than 5 ΔE, measured on the CIELAB (=L*a*b*) scale, after three applications, preferably more than 5 ΔE after one application.

In the context of the present invention, the protein is capable of forming a protein matrix or hydrogel, in particular by self-assembly. Preferably, the protein matrix is present in the dental care product in the form of a hydrogel, i.e., the protein (e.g., a self-assembling peptide) is not present as a monomer. The term protein, in the context of the present invention, refers to proteins comprising more than 100 amino acids and/or peptides having 7-100 amino acids. The protein may contain natural and/or unnatural amino acid residues, such as ornithine. Preferably, the protein of the present invention is selected from amelogenin, serum albumin (preferably bovine serum albumin or human serum albumin), lysozyme, self-assembling peptides, supramolecular assemblies, and members of the collagen family (preferably type I collagen, in particular human or bovine collagen), for example in the form of gelatin, or other proteins rich in aromatic residues (e.g., containing more than 10% or more than 20% aromatic residues). All of these proteins are known to be capable of forming hydrogels.

The present inventors have shown that a matrix of the protein and the mineral particles can be formed on the tooth surface that has an enhanced whitening effect compared to a layer of mineral particles deposited on the tooth surface using previous methods (e.g., Dabanoglu et al., 2009). The structure of the mineral particles incorporated into the present invention is believed to be preformed in the dental care product and stable under oral conditions. They are also at least partially resistant to brushing using an ultrasonic toothbrush.

Self-assembling peptides are preferred proteins for use in the present invention. Self-assembling peptides are provided, for example, in WO 2004/007532A1, which is incorporated herein by reference in its entirety. WO 2004/007532A1 discloses peptides capable of forming three-dimensional scaffolds, thereby promoting the nucleation of de-novo calcium phosphate. These artificial peptides assemble in one dimension to form beta-sheets, as well as higher-order assemblies such as ribbons. Three-dimensional supramolecular structures of self-assembling proteins can be formed that have an affinity for calcium phosphate.

Several other self-assembling peptides (SAPs) that can be used have been described in the prior art. For example, WO 2010/041636 A1 describes biosorbable peptide tissue occlusive agents containing artificial peptides with 8-200 amino acid residues, which have alternating combinations of hydrophilic and hydrophobic amino acids and self-assemble into β-structures at physiological pH. Self-assembling peptides with alternating hydrophobic and hydrophilic residues or stretches that interact with the extracellular matrix are also disclosed in WO 2008/113030 A2. WO 2010/103887 A1 discloses self-assembling peptides comprising basic, hydrophobic, and acidic amino acids with a specific primary sequence and peptide gels with high strength. WO 2010/019651 A1 relates to other self-assembling peptides.

Another application, WO 2007/000979 A1, describes self-assembling peptides containing polar and nonpolar amino acids. These peptides are capable of forming a β-pleated sheet structure, in which the nonpolar amino acid residues are arranged in an assembled pattern on one side of the structure. Amphiphilic self-assembling peptides used as stable macroscopic membranes for biomaterial applications such as slow-diffusion drug delivery are described in US Pat. No. 6,548,630.

EP 2 327 428 A2 relates to a pharmaceutical composition comprising self-assembling peptide nanofibers, which are complementary to each other, and at least one cell for repairing damaged tissue, such as tissue after myocardial infarction.

In the context of the present invention, the self-assembling peptides taught in WO 2004/007532 A1 are particularly preferred. Most preferably, the protein is the self-assembling peptide designated as oligopeptide 104 (SEQ ID NO: 1, QQRFEWEFEQQ) or the self-assembling peptide having SEQ ID NO: 2, QQOFOWOFQQQ, or comprises said peptide. It may also be a self-assembling peptide having at least 60% sequence identity with a peptide consisting of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19. Preferably, the peptide has at least 70%, at least 80% or at least 90% sequence identity with a peptide consisting of SEQ ID, preferably SEQ ID NO: 1 or SEQ ID NO: 2. Most preferably, the peptide has at least 60%, at least 70%, at least 80% or at least 90% sequence identity to or is a peptide consisting of SEQ ID NO: 1. Alternatively, the peptide may have at least 60%, at least 70%, at least 80% or at least 90% sequence identity to or is a peptide consisting of SEQ ID NO: 2. Examples of self-assembling peptides useful in the present invention are provided in Table 1 below. The self-assembling peptides may be modified peptides comprising an Ac-N-terminus and/or an NH2-C-terminus, or unmodified peptides.

Table 1:

SEQ ID NO sequence SEQ ID NO: 1 QQRFEWEFEQQ SEQ ID NO: 2 QQOFOWOFQQQ SEQ ID NO: 3 QQRFOWOFEQQ SEQ ID NO: 4 QQRFQWQFEQQ SEQ ID NO: 5 QQEFEWEFEQQ SEQ ID NO: 6 QQOFOWOFOQ SEQ ID NO: 7 EQEFEWEFEQE SEQ ID NO: 8 QQEFEWEFEQQ SEQ ID NO: 9 ESEFEWEFESE SEQ ID NO: 10 QQOFOWOFOQQ SEQ ID NO: 11 OQOFOWOFOQO SEQ ID NO: 12 SSOFOWOFOSS SEQ ID NO: 13 SSRFEWEFESS SEQ ID NO: 14 SSRFOWOFESS SEQ ID NO: 15 QQOFOWOFOQQ SEQ ID NO: 16 NNRFEWEFENN SEQ ID NO: 17 NNRFOWOFENN SEQ ID NO: 18 TTRFEWEFETT SEQ ID NO: 19 TTRFOWOFETT

In order to bind mineral particles to the tooth surface, the matrix must be able to bind the mineral particles and adhere to the tooth surface. The matrix thus contains binding sites for the mineral particles, which enable the particles, preferably comprising calcium, to bind to the tooth surface. For example, charged amino acid residues such as Glu or Orn on the surface of the self-assembling peptide bind to hydroxyapatite particles and to the tooth surface, which is also primarily composed of hydroxyapatite. Without wishing to be bound by theory, it is believed that these two reactions enhance the stability of the formed complex, resulting in a more durable whitening effect. The ability to self-organize in three dimensions (such as found in collagen, supramolecular assemblies, or self-assembling peptides) is important for binding. Generally, highly charged surfaces promote the adhesion of mineral particles. Protein-matrices work particularly well when their surfaces exhibit glutamic acid or ornithine residues that can attach to calcium phosphate or other mineral particles. Preferably, the protein contains 5% or more, 10% or more, 20% or more, or 30% or more charged amino acid residues, such as glutamic acid and/or ornithine residues.

The dental care product comprises a fluorophore. Trp is a preferred fluorophore. Preferably, the fluorophore is an amino acid residue of the protein matrix, preferably Trp, Tyr, and/or Phe. Preferably, 5% or more, 10% or more, 20% or more, or 30% or more of the matrix protein residues are Trp, Tyr, and/or Phe. Most preferably, 5% or more, 10% or more, 20% or more, or 30% or more of the matrix protein residues are Trp.

In one embodiment, the protein comprises 5% or more, 10% or more, 20% or more, or 30% or more charged amino acid residues, such as glutamic acid and/or ornithine, and the protein comprises 5% or more, 10% or more, 20% or more, or 30% or more fluorescent amino acid residues, such as Trp.

In an alternative embodiment, the dental care product comprises a fluorophore that is not an amino acid residue of the protein, and in one embodiment, the fluorophore is not covalently bonded to the matrix. Covalent bonding of the fluorophore to the protein is also contemplated. For example, the fluorophore can be a derivative of phthalocyanine, such as copper phthalocyanine (covarin blue). Embedding such a fluorophore in a combination of the matrix and mineral particles described above surprisingly results in a longer-lasting and more intense whitening effect compared to incorporating such a fluorophore into conventional toothpaste. Of course, the dental care product can also comprise both a fluorophore that is an amino acid residue of the protein and an additional fluorophore that is not an amino acid residue of the protein. However, surprisingly, if the protein comprises a fluorescent amino acid residue as described above, it is not necessary to add a fluorophore to the dental care product of the present invention to achieve a whitening effect.

The mineral particles preferably comprise or consist of calcium phosphate. Calcium phosphate in the context of the present invention may be monocalcium phosphate monohydrate (MCPM) Ca(H ₂ PO ₄ ) ₂ •H ₂ O, monocalcium phosphate anhydrous (MCPA) Ca(H ₂ PO ₄ ) ₂ , dicalcium phosphate dihydrate (DCPD, Brushit) CaHPO ₄ •2H ₂ O, dicalcium phosphate anhydrous (DCPA, Monetit) CaHPO ₄ , octacalcium phosphate (OCP) Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ •5H ₂ O, α-tricalcium phosphate (α-TCP) α-Ca ₃ (PO ₄ ) ₂ , β-tricalcium phosphate (β –TCP) β-Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate (ACP) Ca _x (PO ₄ ) _y •nH ₂ O, calcium-deficient hydroxyapatite (CDHA) Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0<x<1), hydroxyapatite (HA) Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , or tetracalcium phosphate (TTCP) Ca ₄ (PO ₄ ) ₂ O, or a mixture of different calcium phosphates. In one embodiment, the particles have a crystallinity of 40% or more, such as 40-60%, 60% or more, 80% or more or 90% or more, or they are crystalline. A higher crystallinity is expected to result in a longer-lasting effect on tooth whiteness. Throughout the present invention, the calcium phosphate is preferably hydroxyapatite. The hydroxyapatite may be a substituted hydroxyapatite, such as carbonate hydroxyapatite and zinc carbonate hydroxyapatite, or pure calcium phosphate, preferably in crystalline form. In the context of the present invention, unless otherwise mentioned, reference to calcium phosphate or hydroxyapatite includes reference to such types of derivatized calcium phosphate or hydroxyapatite. Of course, the calcium phosphate or hydroxyapatite can also consist solely of CaPO ₄ (and, of course, water of crystallization appropriate for the respective crystal form). The mineral can also be bioglass (comprising acid-soluble calcium silicates), kaolin (Al ₂ Si ₂ O ₅ (OH) ₄ ) or TiO ₂ in its various crystal forms.

The hydroxyapatite particles can be obtained according to the methods disclosed in the following documents: for example, Roveri, Battistelli et al., 2009, EP 1 762 215 A1, US 20050037948 A1, US 20080075675 A1, US 20100247589 A1, US 20100297203 A1, WO 2007/137606 A1 or WO 2013/068020 A1. Preferably, the hydroxyapatite can be obtained according to WO 2007/137606 A1 and can be commercially obtained from Budenheim, Budenheim, Germany.

The size of the mineral particles is preferably measured by granulometry, for example using a light scattering particle size distribution analyzer (such as LA-950, Horiba, Kyoto, Japan). The crystal form is preferably needle-shaped, but it can also be rod-shaped or needle-shaped.

The particles have a size of 10 nanometers to 50 microns, preferably 0.1 micron to 25 microns, more preferably 1-25 microns, 4-20 microns, or 5-15 microns, 8.12 microns, or about 10 microns. In one embodiment, the size is 10-1200 nanometers. In the context of the present invention, this means that at least 80%, preferably at least 90%, at least 95%, or 100% of the particles have a respective size.

In one embodiment, 30-100% or 50-90% of the particles have a size of 200-600 nanometers. This size was chosen for the experiments because it corresponds to the wavelength of UV light or visible light, which plays an important role in the white appearance of teeth. In the context of the present invention, "about" means +/- 10%, preferably +/- 5%.

In one embodiment, the particles have a mixture of different sizes, which can provide an even more intense whitening effect. In particular, for example, 30-70% of the particles can have a size of 200-400 nanometers, 30-70% of the particles can have a size of 400-600 nanometers, and optionally, 30-70% of the particles can have a size of 10-200 nanometers. Alternatively, for example, 30-70% of the particles can have a size of approximately 10-15 microns, approximately 30-70% of the particles can have a size of approximately 4-10 microns, and optionally, approximately 10-40% of the particles can have a size of 0.1-4 microns (all percentages are weight percent).

In a preferred embodiment, the protein is a self-assembling peptide and the fluorophore is an amino acid residue of the self-assembling peptide, preferably Trp, and the particle, which is preferably a hydroxyapatite particle, has a size of 1-25 microns, preferably 4-20 microns.

The dental care product is selected from toothpaste (dentifrices), preventive pastes, tooth powders, tooth polishes, tooth gels, chewing gums, candies, lozenges, mouthwashes, whitening strips, spreadable gels, tooth varnishes, adhesive strips, and tubes, syringes, or trays containing gels or pastes, or gels or pastes applied to an application carrier such as dental floss or a toothbrush (manual toothbrush, electric toothbrush, sonic toothbrush, combinations thereof, or ultrasonic toothbrush). The toothpaste can be a toothpaste for a conventional toothbrush, but it can also be a toothpaste for an ultrasonic toothbrush. In one embodiment, the dental care product is not a liquid, but a paste or gel, most preferably a toothpaste or tooth gel comprising 0.5-40% by weight of the mineral particles and 0.02-1% by weight, preferably 0.05-0.5% by weight of the organic matrix, preferably a protein matrix. A gel is a non-fluid colloidal network or polymer network that is expanded throughout its entire volume by a fluid. In the case of a hydrogel, the fluid is water. Unlike liquids, gels have a finite, usually quite small, yield stress.

The dental care product may additionally contain one or more typical ingredients of the respective dental care product. Such typical ingredients may be:

- abrasives such as carbonates, phosphates, silicates, acrylates, aluminum oxide,

- suspending agents such as glycerol, polyethylene glycol (PEG), sorbitol, xylitol,

- binders such as cellulose and its derivatives, carrageenan, paraffin, xylose,

- Cleansing agents such as hydrogenated castor oil, sodium lauryl sulfate,

- flavors such as caramel, vanillin, menthol,

- Preservatives such as ethanol, sodium benzoate,

- Colorants, such as solvent red, acid blue 3,

- an active agent, such as a fluoride, preferably in the form of a tertiary amine, such as an amine fluoride or an organic fluoride, such as sodium monofluorophosphate, potassium nitrate and/or oxalate.

In one embodiment of the present invention, the product is a toothpaste comprising all or the major ingredients of Curodont™ Repair (i.e., oligopeptide 104 (SEQ ID NO: 1) and fillers) or preferably Curodont™ Protect (both available from Credentis ag, Switzerland) and added mineral particles, in particular calcium phosphate, preferably hydroxyapatite particles and/or another crystalline form, most preferably hydroxyapatite. Thus, the ingredients may be, for example, hydroxyapatite particles and/or another crystalline form of calcium phosphate, preferably hydroxyapatite, and Curodont™ Protect, i.e., hydrogenated starch hydrolysate, water (aqua), hydrated silica, PEG-8; cellulose gum, sodium monofluorophosphate, flavoring, sodium saccharin, citric acid, sodium hydroxide, dicalcium phosphate, oligopeptide-104, calcium glycerophosphate, sodium chloride, sodium sulfate, limonene, cinnamaldehyde, and CI 42090.

In one embodiment, the product is a toothpaste comprising about 50% Curodont™ Protect, about 25% hydroxyapatite particles, and about 25% water.

The present invention also relates to the cosmetic use of the dental care product of the present invention for tooth whitening. A method for whitening teeth for cosmetic reasons is also disclosed, comprising applying the dental care product of the present invention to teeth. In the context of the present invention, "one" is not limited to the singular, but may also refer to "one or more," unless expressly stated or apparent from the context. For example, reference to "a tooth" includes the option of specifically referring to more than one tooth, particularly all teeth of a person. The dental care product of the present invention may also be used to whiten crowns, implants, filling materials, and other oral appliances.

In the method of the present invention, the composition is preferably applied once, twice or three times a day on 1, 2, 3, 4, 5, 6, 7 days or more, in one embodiment, the composition is applied every day. It can also be applied less frequently, for example once a week or once a month. The frequency of application strongly depends on the whitening effect desired by the user, and on the amount of mechanical wear experienced by the teeth. This includes lifelong application, preferably starting after the permanent teeth have grown, particularly after tooth discoloration has been noticed. Application refers to a tooth, or preferably all teeth of a person being contacted with the dental care product in the manner of a product of the respective type that is usually used. For example, toothpaste is usually used for brushing teeth for 1-5 minutes, particularly for a period of about 2-3 minutes.

Because the dental care products of the present invention do not cause the undesirable side effects of peroxide-containing bleaching products, they can be used daily throughout all cycles of dental care without damaging teeth or gums. Since the dental care products can further enhance tooth remineralization, reduce tooth sensitivity, and prevent caries, they can even be used to treat incipient caries lesions without the need for additional dental care products. Furthermore, the products can be used to inhibit tooth demineralization. In particular, the dentifrice or toothpaste of the present invention can be used every time you brush your teeth.

Alternatively, it can be used with or in place of a different dentifrice, such as an alternative fluoride toothpaste. For example, the alternative fluoride toothpaste can be used in the morning, while the toothpaste of the present invention can be used in the evening after the last meal of the day. The dental care product can also be used after normal dental care, such as in the evening after brushing the teeth.

The present invention also provides use of the dental care product of the present invention for treating sensitive teeth and/or for preventing or treating dental caries. Also disclosed is a method for treating sensitive teeth and/or preventing and/or treating dental caries and/or whitening teeth, comprising applying an effective amount of the dental care product of the present invention to one or more teeth.

The following examples are intended to illustrate but not to limit the present invention.All documents cited in this application are hereby incorporated in their entirety.

Description of the drawings:

Figure 1. (A) Electron micrograph of a tooth surface treated with a mixture of P11-4 matrix and a suspension of hydroxyapatite particles. The tooth surface shows tightly bound particles. (B) Electron micrograph of a tooth surface treated with a suspension of hydroxyapatite particles in water alone. The surface shows irregular positioning of the particles.

Figure 2 Photographic evaluation of the whitening effect of different hydroxyapatite particles on a clay plate in the absence (1-4) and presence (1+-4+) of a self-assembling peptide (Curodont™ Protect) according to the protocol of Example 2. The photograph shows the clay plate after scrubbing with a toothbrush.

Example

Example 1:

Materials and Methods

Suspensions of oligopeptide 104 (5 mg/mL) with or without hydroxyapatite particles (average size d50 ≤ 300 nm (Horiba); 40-60% crystallinity, 25 wt %) were generated.

The suspension was applied directly to the enamel surface of the teeth and the residue was washed off (10 seconds). The specimens were stored in distilled water at 37°C for 24 hours. This procedure was repeated three times.

Tooth color was measured using a dental spectrophotometer (VITA EasyShade). A black box served as the tooth background to standardize lighting conditions during measurement. The tip was applied perpendicular to the tooth surface, and the average L*a*b value from three replicates was used for evaluation. Color measurements were completed at baseline (t1 = untreated), 24 hours after the first application (t1), 24 hours after the second application (t3), and 24 hours after the third application (t4).

The mean change in L*a*b values between the different measurements in each group is expressed as ΔE (according to ISO 28399).

result

The results are provided in Table 2 below:

Table 2

Control (HA only) Test (HA + oligopeptide 104) △E (t2-t1) - 1st application 2.3 4.6 △E (t3-t2) - 2nd application 1.1 1.9 △E (t4-t3) - 3rd application 1.5 0.6

This experiment shows that, surprisingly, the combination of a protein matrix according to the invention with HA significantly enhances the whitening effect seen when HA alone is applied.

Example 2:

Test plan

1. Divide a clay ceramic plate into four sections using colorless nail polish. Weigh all chemicals and combine them in a tube. Fill the tube to 100% by weight with ultrapure water. If using gelatin, heat the suspension in a water bath at 80°C for 5 minutes. Then, mix the suspension using a vortex mixer. Prepare the suspension for application to the ceramic plate using two 50 μl pipetting steps. Allow 10 minutes to rest between pipetting steps. Allow the ceramic plate to dry for approximately 3 hours.

2. Incubate the ceramic plate in ultrapure water for 24 hours. After incubation, remove the ceramic plate and dry it.

3. The whiteness of the ceramic panels was measured using a Vita Easyshade spectrophotometer (Advance 4.0, SN: H26818, VitaZahnfabrik GmbH, Bad Säckingen). Each area was measured three times and the average value was used.

4. The described procedures (1-3) were repeated three times. The average change in L*a*b* values between the different measurements in each group was expressed as ΔE, which was calculated using the method according to ISO standard 28399:2011 (products for external tooth bleaching).

5. After three applications, the ceramic plate was brushed with an ultrasonic toothbrush at a distance of 0.5 cm for 2 minutes. The Lab value of the plate was measured again as described above.

Test materials

Different compositions according to the invention and the prior art were tested according to the test protocol described above. % refers to weight/weight%. Water was added to 100%. Curodont Protect ^™ contains 1 mg/g of oligopeptide 104.

Table 3A: Compositions containing different HA particles with or without self-assembling peptides/Curodont Protect ^™

Table 3B: Whitening effect of different HA particles with or without self-assembling peptides/Curodont Protect ^™ . ΔE is the change from baseline.

*Baseline corrected.

Table 4A: Compositions containing different amounts of HA

Table 4B: Whitening effect of compositions containing different amounts of HA

*Baseline corrected.

This experiment demonstrated that different amounts of HA together with the self-assembling peptides had a whitening effect, which was improved with higher amounts of HA.

Table 5A: Comparative compositions from the prior art;

31JP Composition according to Example 31 of JP2008/081424

8% lactoferrin,

2% Lactoferrin Hydrolysate,

43% glycerin,

23.5% polyethylene glycol (PEG),

15% Silicic Anhydride

5% Hydroxyapatite, 10 microns

3% sodium methylcellulose

0.3% Sodium Lauryl Sulfate

10JP Composition according to Example 10 of JPH115722 (mouthwash)

1% Hydroxyapatite, 1 micron

2% ascorbic acid

1% sodium ascorbate

0.5% collagen

0.5% gelatin/collagen breakdown products

10% glycerol

1% ethanol

Table 5B: Whitening effect of compositions according to the prior art

*Baseline corrected.

Comparison with prior art compositions shows that the compositions of the present invention are surprisingly much more suitable for teeth whitening. In particular, it should be noted that after application, composition 31JP accumulated a thick crust, which itself floated off during the 24-hour incubation in water. Composition 10JP turned yellow.

Example 3:

A single-center, uncontrolled cosmetic study was conducted on 40 volunteers who desired brighter/whiter teeth. The primary objective of the study was to evaluate the whitening effect of the evaluated products in vivo using a dental spectrophotometer (VITA easyshade). Secondary objectives were to:

a) evaluate the safety and tolerability of the product,

b) determine and verify the frequency of application of the product,

c) evaluate the durability of the whitening effect,

d) To evaluate the additive effects of repeated administration.

All subjects were between 18 and 75 years of age. At least one tooth had to achieve a brightness level of ≥15 using VITA easyshade. Subjects had healthy incisors and maxillary canines, i.e., no caries, no decay, and no local restorations (these criteria applied to at least one tooth, which had to achieve a brightness level of ≥15 using VITA easyshade). Subjects also had to understand all procedures and be able and willing to follow instructions. They had to accept all measurements and controls, and they had to sign the corresponding declaration before the start of the study. Subjects with a general sensitivity to sugars, poor oral hygiene, fluorosis on the studied tooth, or those participating in another clinical study or undergoing bleaching during the study were excluded.

The test product consisted of 50% Curodont Protect™ (containing 1 mg oligopeptide 104/g Curodont Protect™, thus the product contained 0.5 mg/g oligopeptide 104, i.e. 0.05% self-assembling peptides), 25% hydroxyapatite (d50 ≤300 nm (Horiba)) and 25% water.

On Day 0, at the Oral Surgery Department, a dentist or research team member applied the product to the teeth using a tray for the upper and lower jaws, respectively. After 5-10 minutes, the subject spat out the product and rinsed their teeth with water. On Days 1-7, once daily, in the evening after their regular dental care, the subject brushed their front teeth with the product for 1-2 minutes. During the study, the subjects were instructed to clean their teeth as usual 2-3 times daily using the fluoride toothpaste Candida Fresh® and an electric toothbrush (Sonicare®).

The lightness of at least one tooth evaluated was recorded using a dental spectrophotometer before and after the first treatment (D0T), on day 1 (before product contact on that day), on day 7 (D7) (before product contact on that day), and on day 30 (D30). The average change in L*a*b values between the different measurements in each group was expressed as ΔE (according to ISO 28399). The results are shown in Table 3 below.

Table 6: In vivo effect of teeth whitening according to the present invention. The table provides ΔE values with reference to the measurements before treatment, ie all values are baseline corrected.

** Exited, therefore failed to obtain data.

This study clearly demonstrates that the product of the present invention achieves a significant whitening of tooth color. Visual tooth whitening (ΔE > 3) occurred in many patients after the first application. On average, a visual whitening effect was seen after Day 1. Further improvement occurred after a week of daily treatment at home. It is important to note that the whitening effect of the treatment occurred in all patients, to varying degrees. Even after 30 days, the whitening effect was still detectable in the majority of subjects.

It is to be noted that most patients do not have a uniform discoloration or yellowing of the teeth. The effect of the composition of the present invention on individual teeth that were previously darker in color is more pronounced than that seen in the average values.

The average degree of tooth whitening is comparable to that of state-of-the-art chemical bleaching methods (e.g. resulting in the following ΔE)

- For home bleaching, ΔE is less than 4,

- For whitening strips, the ΔE is approximately 2.4-5.7 after 7 days, or 2.9-5.5 after 14 days,

- and power bleaching (for clinical use only), with ΔE as high as 12 (Gerlach et al., 2002; Demarco et al., 2009; Delfino et al., 2009).

However, the dental care products and methods of the present invention have significant advantages over chemical bleaching with respect to undesirable effects such as tooth erosion, increased tooth sensitivity, and the like.

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Claims (18)

1. A dental care product comprising 0.4-40% by weight of mineral particles having a size of 0.01-50 micrometers, and 0.001-5% by weight of a protein capable of forming a protein matrix as a hydrogel, wherein the dental care product comprises a fluorophore, wherein the protein is a self-assembled peptide having at least 60% sequence identity with SEQ ID NO: 1 or SEQ ID NO: 2, and wherein the mineral particles are calcium phosphate particles. 2. The dental care product of claim 1, wherein the particles have a size of 1-25 micrometers. 3. The dental care product of claim 1, wherein the particles have a size of 4-20 micrometers. 4. The dental care product of claim 1, wherein the fluorophore is an amino acid residue of the protein. 5. The dental care product of claim 1, wherein the fluorophore is Trp. 6. The dental care product of claim 1, wherein the fluorophore is an amino acid residue of the protein, wherein 5% or more of the protein residues are Trp. 7. The dental care product of claim 1, wherein the protein forms a hydrogel. 8. The dental care product of claim 1, wherein the protein is a self-assembled peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2. 9. The dental care product of claim 1, wherein the mineral particles comprise hydroxyapatite. 10. The dental care product of claim 1, wherein the dental care product is selected from toothpaste, preventative paste, tooth powder, tooth polish, tooth gel, chewing gum, candy, lozenges, mouthwash, whitening strips, coated dental floss, coated toothbrush, spreadable gel, tooth paint, adhesive strips, and tubes, syringes, or dental trays containing gel or paste. 11. The dental care product of claim 1, comprising 0.5-40% by weight of the mineral particles and 0.02-1% by weight of the matrix protein, wherein the dental care product is toothpaste or gel, optionally applied to dental floss or a toothbrush. 12. The dental care product of claim 1, comprising 0.5-40% by weight of the mineral particles and 0.05% by weight of the matrix protein, wherein the dental care product is toothpaste or gel, optionally applied to dental floss or a toothbrush. 13. The dental care product of claim 1, wherein 30-70% of the mineral particles have a size of 200-600 nanometers. 14. The dental care product of claim 1, wherein the product comprises Curdont™ Protect and added hydroxyapatite particles. 15. The dental care product of any of the preceding claims is used for cosmetic purposes of teeth whitening. 16. Use of the dental care product of any one of claims 1-14 in the preparation of a medicament for treating sensitive teeth and/or for preventing or treating dental caries. 17. A cosmetic method for teeth whitening, comprising applying to teeth the dental care product of any one of claims 1-14, wherein the composition is applied once, twice, or three times a day for 1, 2, 3, 4, 5, 6, 7 days or more. 18. A cosmetic method for teeth whitening, comprising applying to teeth the dental care product of any one of claims 1-14, wherein the composition is applied daily.