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    • 专利摘要:
    DENTAL CARE PRODUCT FOR TEETH WHITENING The present invention relates to the field of dental care, in particular, a dental care product, such as toothpaste (toothpaste), prophylactic paste, tooth powder, tooth shine, tooth gel , chewing gum, candy, lozenge, mouthwash, whitening strips, coated dental floss, coated toothbrush, gel paint, varnish, veneer, and tube, syringe or dental tray comprising a gel or paste, mouthwash, whitening strips and teeth whitening trays, in which the product comprises mineral particles such as crystals and a compound, preferably a protein capable of forming a matrix, which is a hydrogel, in which the product comprises a fluorophore. The mineral particles can comprise, for example, calcium phosphate, preferably hydroxyapatite, preferably in crystalline form. The protein matrix can comprise, for example, a self-assembling peptide. The product also comprises a fluorophore, which can be a fluorescent amino acid residue from the protein matrix. The invention also relates to the use of the product for dental care for teeth whitening or for use in the treatment of a sensitive tooth or sensitive teeth and / or in the prevention or treatment of cavities, as well (...).
    公开号:BR112016000077B1
    申请号:R112016000077-3
    申请日:2014-09-25
    公开日:2020-12-22
    发明作者:Michael Hug；Dominikus Amadeus Lysek；Karl-Heinz KUNZELMANN
    申请人:Credentis Ag；
    IPC主号:
    专利说明:

    [001] The present invention relates to the field of dental care, in particular, a dental care product, such as toothpaste (toothpaste), prophylactic paste, tooth powder, tooth shine, tooth gel, chewing gum , candy, lozenge, mouthwash, whitening strips, coated dental floss, coated toothbrush, gel paint, varnish, veneer, and tube, syringe or dental tray comprising a gel or paste, mouthwash, whitening strips and whitening trays of the teeth, in which the product comprises mineral particles such as crystals and a compound, preferably a protein capable of forming a matrix which is a hydrogel, in which the product comprises a fluorophore. The mineral particles can comprise, for example, calcium phosphate, preferably hydroxyapatite, preferably in crystalline form. The protein matrix can comprise, for example, a self-assembling peptide. The product also comprises a fluorophore, which can be a fluorescent amino acid residue from the protein matrix. The invention also relates to the use of the dental care product for teeth whitening or for use in the treatment of sensitive teeth or sensitive teeth and / or in the prevention or treatment of cavities, as well as a related method for tooth whitening.
    [002] Tooth enamel is the hardest substance in the human body. It consists of about 98% hydroxyapatite, a crystalline form of calcium phosphate, and some organic components. A thin layer of enamel forms on the surface of the teeth with dentin as a base. The enamel is more resistant and suitable to absorb the stress of chewing without fracture. Dentin also comprises hydroxyapatite, with a higher porosity, and a higher content of organic structure.
    [003] Both extrinsic and intrinsic reasons contribute to tooth discoloration. For example, coffee, tea, wine, carrots, oranges or tobacco can stain the enamel surface. Certain antibiotics, excessive fluoride absorption or inherited diseases can cause intrinsic discoloration. Tooth discoloration can be an important aesthetic problem for dental patients. For example, in the UK, about 20% of people are dissatisfied with the color of their teeth. In the USA, 34% seem to be dissatisfied.
    [004] Often, superficial stains can be removed by thorough cleaning of the teeth by the patient or by a health professional. Gloss with abrasive material is sometimes used for this purpose, for example, using pastes comprising particles of calcium phosphate, chalk, pumice or silica. If the patient wants an even more intrinsic reduction in tooth discoloration, chemical whitening is the classic option. Various bleaching techniques are known, which are based on an oxidizing agent such as peroxide. Whitening can be performed by a health professional in a dental clinic or by the patient at home. For that, prescription products for overnight whitening or whitening toothpastes can be used.
    [005] However, in recent years, the awareness of side effects associated with whitening, such as demineralization, erosion and tooth sensitivity caused by peroxides, has increased (for example, Dahl et al., 2003). The use of hydroxyapatite nanocrystals has been suggested to remineralize the damaged tooth surfaces, for example, by whitening (Mohd et al., 2007, Jiang et al., 2008, Lim et al., 2009, Roveri et al., 2009) . Crystalline particles of hydroxyapatite, which closely mimic the natural material of the tooth, can be deposited on the tooth enamel. In addition to filling in scratched or eroded parts of a tooth, and preventing or treating cavities, the deposited hydroxyapatite can neutralize the hypersensitivity of the teeth caused by exposure of the dentin tubules over gum recession (WO 2007/137606 Al).
    [006] Amorphous Calcium Phosphate stabilized with phosphoproteins such as caseinfosphopeptide (CPP-ACP) has been used in oral care products for the prevention and treatment of caries lesions (zB US 20050037948 Al, US 20080075675 Al, US 20100297203 Al) .
    [007] Calcium phosphate, such as hydroxyapatite in the form of particles, has also been found to have whitening properties independent of lightening or brightness (Niwa et al., 2001, Dabanoglu et al., 2009). Dabanoglu et al. compared different materials, for example, nanohydroxyapatite or tricalcium nano-phosphate or a soluble polymer film (methacrylic acid copolymers - ethyl acrylate) comprising nanohydroxyapatite with respect to their bleaching properties. They obtained a color change, measured spectrometrically as ΔE (scale L * a * b), with all the materials tested. The measurement can be carried out according to the ISO 28399 standard. The effect increased with three applications at an ΔE of about 3, which decreased with some materials after subjecting the treated teeth to shear force. It is observed that the average casual observer can notice the difference between the two colors that are separated by 3-4 ΔE. A trained eye can differentiate between two colors that are separated by 2-3 ΔE. Thus, although a noticeable change can be generated, there is still room for improvement.
    [008] WO 2013/068020 discloses a dental care product comprising hydroxyapatite having a surface functionalized with lactoferrin. This is suggested to form a thin film on the enamel surface, which improves the remineralization of the teeth and has an antibacterial effect.
    [009] JPH115722 refers to an aqueous composition for cleaning the oral cavity, for example, a mouthwash, which comprises hydroxyapatite particles. JP2008 / 081424 describes teeth whitening by a composition comprising lactoferrin and lactoferrin decomposition product and cyclic or annular polyphosphates. JP2007 / 0176862 describes the use of a composition comprising hydrolyzed silk and precipitates calcium carbonate for suppressing dentin elution and preventing caries. JP 2001/131041 describes an oral composition, such as a toothpaste comprising hydroxyapatite with improved storage stability, comprising a magnesium salt. CN101385856 relates to a nanometric hydroxyapatite material used for the absorption and sustained release of muraminidase (lysozyme) for the treatment / prevention of dental caries.
    [010] US 20100247589 A1 describes an oral care system with different components, such as a monomeric peptide with one part attaching to oral surfaces and a second binding element and a composition that can comprise particles that can attach to the second linker and which comprise a beneficial agent such as a bleaching agent, for example, TiO2 or hydroxyapatite particles or an anti-stain agent or enzyme. It is suggested that the peptide facilitates the binding of the beneficial agent to the oral surface. US 2010/0247457 A1 also teaches peptide-based reagents comprising at least one binding peptide to the tooth surface to release at least one white polymer-coated dye to the teeth surface. Raoufi et al., 2010, compared an over-the-counter commercial toothpaste and hydroxyapatite toothpaste (designed to whiten or whiten teeth, respectively) with a fluoride placebo toothpaste, and found no objective whitening effect for any of the toothpastes in a 12 week clinical trial.
    [011] There is a need in the art for a dental care product effective in tooth whitening that preferably minimizes the disadvantages of whitening, such as demineralization and tooth sensitivity, which is safe, preferably, for commercial use. free, and that can be administered by the patient or consumer.
    [012] This problem was addressed by the present inventors. The invention provides a dental care product and its uses, as described in the claims. In particular, the 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, the particles having a size of 10 nm - 50 μm, and 0.001-5% by weight, preferably 0.02-2% by weight, 0.04-1% by weight, 0.05-0.5% by weight, 0.05-0.2% by weight of an organic compound capable of forming a organic matrix, preferably a protein capable of forming a protein matrix, for example, a self-assembling peptide. The protein matrix is a hydrogel. The dental care product comprises a fluorophore.
    [013] The inventors have surprisingly found that, by mixing mineral particles with a suitable organic matrix, such as a suitable protein matrix in a dental care product according to the invention, the previously described whitening effect of hydroxyapatite particles in the teeth can be significantly increased. The protein alone also does not achieve comparable effects, and the combination works in a synergistic way. In particular, the invention provides a dental care product capable of producing a difference in the whiteness of a tooth, measured on a CIELAB scale (= L * a * b *), of ΔE of more than 5 after 3 applications, preferably ΔE more than 5 after 1 application.
    [014] In the context of the present invention, the protein is capable of forming a protein or hydrogel matrix, in particular, through self-assembly. Preferably, the protein matrix is present in the dental care product in the form of a hydrogel, that is, proteins (e.g., self-assembling peptides), are not present as monomers. The term protein in the context of the present invention refers to a protein comprising more than 100 amino acids and / or a peptide having 7-100 amino acids. The protein may comprise natural and / or unnatural amino acid residues such as ornithine. Preferably, the protein of the invention is selected from the group comprising amelogenin, serum albumin (preferably, bovine serum albumin or human serum albumin), lysozyme, a self-assembly peptide, a supramolecular assembly, and family members of collagen proteins (preferably type I collagen, in particular human or bovine collagen), for example, in the form of gelatin, or other proteins rich in aromatic residues (for example, comprising more than 10% or more of 20% of aromatic residues). All of these proteins are known to be capable of forming a hydrogel.
    [015] The inventors have shown that the matrix of said protein and mineral particles on the tooth surface can be formed, which has a whitening-enhancing effect compared to the layer of mineral particles deposited on the tooth surface with the previous methods (for example, Dabanoglu et al., 2009). The structures that incorporate the mineral particles of the present invention are believed to be preformed in the dental care product and stable under oral conditions. They are also, at least in part, resistant to brushing with an ultrasound toothbrush.
    [016] Self-assembling peptides are the preferred proteins of the invention. Self-assembling peptides are provided, for example, in WO 2004/007532 A1, which is incorporated herein by reference. WO 2004/007532 A1 describes peptides that are capable of forming three-dimensional supports, thereby promoting de-novo calcium phosphate nucleation. These artificial peptides assemble in one dimension to form beta-leaf, and of a higher order they assemble, such as ribbon-like assemblies. Three-dimensional supramolecular structures of self-assembling proteins can be formed, which have an affinity for / with calcium phosphate.
    [017] Several other self-assembling peptides (SAP) that can be employed have been described in the prior art. For example, WO 2010/041636 A1 describes a bioadsorptive peptide tissue occlusion agent containing a peptide having artificial 8-200 amino acid residues with the hydrophilic and hydrophobic amino acids alternately linked, which self-assemble to a beta structure in one physiological pH. Self-assembling peptides with alternating residues or hydrophobic and hydrophilic stretches that interact with the extracellular matrix are also disclosed in WO 2008/113030 A2. WO 2010/103887 A1 discloses self-assembling peptides that comprise the basic, hydrophobic and acid amino acids of a specific primary sequence and peptide gels thereof which have high resistance. W02010 / 019651 A1 refers to other self-assembling peptides.
    [018] Another application, WO 2007/000979 A1, describes self-assembling peptides with polar and non-polar amino acids. The peptides are capable of forming a beta-leaf structure in which the non-polar amino acid residues are arranged on one side of the structure in the assembled form. Amphiphilic self-assembling peptides for use as stable macroscopic membranes, which are used in biomaterial applications, such as the release of drugs by slow diffusion, are described in US 6,548,630.
    [019] EP 2 327 428 A2 refers to a pharmaceutical composition comprising self-assembled peptide nanofibers, which are complementary to each other, and at least one cell for repairing damaged tissues, such as tissue after a myocardial infarction .
    [020] In the context of the present invention, the self-assembly peptides taught in WO 2004/007532 A1 are specifically preferred. Most preferably, said protein is the self-assembly peptide designated oligopeptide 104 (SEQ ID NO: 1, QQRFEWEFEQQ) or the self-assembly peptide having SEQ ID NO: 2, QQOFOWOFQQQ, or which comprises said peptide. This can also be a self-assembling peptide with 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 the SEQ IDs, of 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 with a peptide consisting of in SEQ ID NO: 1 or it is said peptide. Alternatively, the peptide can have at least 60%, at least 70%, at least 80%, or at least 90% sequence identity with a peptide consisting of SEQ ID NO: 2 or is said peptide. Examples of self-assembling peptides that can be used in the present invention are provided in Table 1 below. The self-assembling peptides can be modified peptides, which comprise an N-terminal and / or NH2-C-terminal, or unmodified peptides. Table 1:

    [021] To be able to bind mineral particles on a tooth surface, the matrix has to be able to bind mineral particles and adhere to the tooth surface. The matrix thus comprises the binding sites for the mineral particles that allow them to bind to the particles, which preferably comprise calcium, on the tooth surface. For example, the loaded amino acid residues, such as Glu or Orn on the surface of the self-assembling peptides bind to the hydroxyapatite particles and to the tooth surface, which is also substantially formed by hydroxyapatite. Without intending to stick to the theory, it is believed that both reactions increase the stability of the complex formed to generate a more efficient bleaching effect. A three-dimensional self-organizing ability, which is, for example, found in collagen, supramolecular assemblies or self-assembling peptides, is important for binding. In general, highly charged surfaces will promote the adhesion of mineral particles. Protein matrices work particularly well when their surface shows glutamate or ornithine residues that can stick to calcium phosphate or other mineral particles. Preferably, the protein comprises 5% or more, 10% or more, 20% or more or 30% or more charged amino acid residues, such as glutamate and / or ornithine residues.
    [022] The dental care product comprises a fluorophore. Trp is a preferred fluorophore. Preferably, said fluorophore is an amino acid residue of the matrix protein, preferably Trp, Tyr and / or Phe. Preferably, at 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.
    [023] 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 glutamate 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.
    [024] In an alternative embodiment, the dental care product comprises a fluorophore which is no amino acid residue from the protein, and which in one embodiment, is not covalently linked to the matrix. The covalent attachment of a fluorophore to the protein is also envisaged. For example, the fluorophore can be a phthalocyanine derivative, for example, copper phthalocyanine (blue covarin). The incorporation of such a fluorophore in the combination of matrix and particles and minerals as described above surprisingly leads to a more permanent and more intense whitening effect compared to the incorporation of such fluorophores in a conventional toothpaste. Of course, the dental care product may also comprise both a fluorophore which is an amino acid residue of the protein and an additional fluorophore which is not an amino acid residue of the protein. However, surprisingly, the addition of a fluorophore to a dental care product of the present invention is not necessary to achieve the whitening effect, if the protein comprises a fluorescent amino acid residue as described above.
    [025] Mineral particles preferably comprise or consist of calcium phosphate. Calcium phosphate may, in the context of the present invention, be monocalciophosphate monohydrate (MCPM) Ca (H2PO4) * H2O, monocalcicophosphate anhydrate (MCPA) Ca (H2PO4), dicalcium phosphate dihydrate (DCPD, Brushit), CaHPO4 * 2H2O, dicalciophosphate anhydrate (DCPA, Monetit) CaHPO4], Octacalcophosphate (OCP) Ca8 (HPO4) (PO4) 4 * 5H2O, α-tricalcium phosphate («-TCP) α-Ca3 (P04), β-tricalcium phosphate (β- TCP) β-Ca3 (P04), amorphous calcium phosphate (ACP) Cax (PO4) y * nH2O, calcium-deficient hydroxyapatite (CDHA) Ca10-x (HPO4) x (PO4) 6-x (OH) 2- x (0 <x <1), hydroxyapatite (HA) Ca10 (PO4) 6 (OH) 2, or tetracalcium phosphate (TTCP) Ca4 (PO4) 2O), or a mixture of different calcium phosphates. In one embodiment, the particles either have a degree of crystallinity of 40% or more, for example, 40-60%, 60% or more, 80% or more or 90% or more, or they are crystals. A higher degree of crystallinity is expected to make the teeth whitening effect more lasting. Throughout the invention, calcium phosphate is preferably hydroxyapatite. The hydroxyapatite can be substituted hydroxyapatite for example, carbonate hydroxyapatite and zinc carbonate hydroxyapatite, or pure calcium phosphate, preferably in crystalline form. In the context of the invention, reference to hydroxyapatite or calcium phosphate includes reference to derivatized calcium phosphates or hydroxyapatites of this type unless otherwise indicated. Of course, calcium phosphate or hydroxyapatite may also consist of CaPO4 (and, of course, crystal water as appropriate for the respective crystal form) only. The mineral can also be a bioglass (comprising acid-soluble calcium silicates), kaolin (Al2Si5hO5 (OH) 4) or TiO2 in its different crystalline forms.
    [026] Hydroxyapatite particles can be obtained according to methods described, for example, in Roveri, Battistelli et al., 2009, EP 1 762 215 Al, US 20050037948 Al, US 20080075675 Al, US 20100247589 Al, US 20100297203 Al , WO 2007/137606 Al, or WO 2013/068020 Al. Preferably, hydroxyapatite is obtainable according to WO 2007/137606 Al and can be obtained commercially from Budenheim, Budenheim, Germany.
    [027] Mineral particle size is preferably measured by granulometry, for example, with a light scattered particle size distribution analyzer (such as LA-950, Horiba, Kyoto, Japan). The shape of the crystals is preferably shaped like a needle, but it can also be shaped like a stem or an acicular.
    [028] The particle size is 10 nm - 50 μm, preferably 0.1 μm- 25 μm, more preferably 1-25 μm, 4-20 μm or 5-15 μm, 8.12 μm or about 10 μm. In one embodiment, the size is 10-1200 nm. In the context of the present invention, this means that at least 80%, preferably at least 90% of the particles, at least 95% or 100% of the particles are of the respective size.
    [029] In one embodiment, 30-100% or 50-90% of the particles are 200-600 nm in size. This size was selected for the experiments, as it corresponds to the wavelength of UV light or visible light, which plays an important role in the white appearance of the teeth. In the context of the invention, "about" means +/- 10%, preferably +/- 5%.
    [030] In one embodiment, the particles have a mixture of different sizes, which can provide an even more intense bleaching effect. In particular, for example, 30-70% of the particles can have a size of 200-400 nm, 30-70% of the particles have a size of 400-600 nm, and optionally, 30-70% of the particles have a size 10-200 nm. Alternatively, for example, 30-70% of the particles can have a size of about 10 -15 μm, about 30-70% of the particles have a size of about 4-10 μm and, optionally, about 10-40 % of the particles have a size of 4 μM (all referring to% by weight).
    [031] In a preferred embodiment, the protein is a self-assembly peptide, and the fluorophore is an amino acid residue from the self-assembly peptide, preferably Trp, and the particles, which are preferably hydroxyapatite particles, have a size of 1-25 μm, preferably 4-20 μm.
    [032] The dental care product is selected from the group comprising toothpaste (toothpaste), prophylactic paste, tooth powder, tooth shine, tooth gel, chewing gum, candy, lozenge, mouthwash, whitening strip, paint on gel, varnish, veneer and tube, syringe or dental tray comprising a gel or paste, or a gel or paste coated on an application support such as dental floss or a toothbrush (a manual, electric, sound, a combination thereof or toothbrush with ultrasound). 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, more preferably, is a toothpaste or a dental gel that comprises 0.5-40% by weight of said mineral particles and 0.02 -1% by weight, preferably 0.05-0.5% by weight of said matrix, preferably of the organic matrix protein. A gel is a polymeric network or non-fluid colloidal network that expands over its entire volume by a fluid. In the case of a hydrogel, the fluid is water. In contrast to a liquid, a gel has a finite elasticity limit, normally the elasticity limit is quite small.
    [033] The dental care product may additionally comprise one or more ingredients typical of the respective dental care product. Such typical ingredients can be: - abrasive agents, such as carbonates, phosphates, silicates, acrylates, alumina, - suspending agents, such as glycerin, polyethylene glycols (PEG), sorbitol, xylitol, - binding agents, such as cellulose and derivatives carrageenan, paraffin, xylose, - detergents such as hydrogenated castor oil and sodium lauryl sulfate, - flavorings such as caramel, vanilla, menthol, - preservative such as ethanol, sodium benzoate, - coloring agents such as red solvent, blue acid 3, - active agents, such as fluorides, preferably in the form of tertiary amines, such as amine fluoride or organic fluoride, such as sodium monofluorophosphate, potassium nitrate, and / or oxalate .
    [034] In one embodiment of the invention, the product is a toothpaste comprising all or the main ingredients of Curodont ™ repair (i.e., Oligopeptide 104 (SEQ ID NO: 1) and a bulking agent) or, preferably, of Curodont ™ Protect, (both available from credentis ag, Switzerland) and mineral particles added, in particular, calcium phosphate, preferably particles of hydroxyapatite and / or another crystalline form, more preferably, hydroxyapatite. Thus, the ingredients can be, for example, particles of hydroxyapatite and / or calcium phosphate in another crystalline form, preferably hydroxyapatite, and Curodont ™ protect, that is, hydrogenated starch hydrolyzate, aqua, hydrated silica, PEG- 8; cellulose gum, sodium monofluorophosphate, flavor, sodium saccharin, citric acid, sodium hydroxide, dicalcium phosphate, oligopeptide-104, calcium glycerophosphate, sodium chloride, sodium sulfate, limonene, cinnamal, and CI 42090.
    [035] In one embodiment, the product is a toothpaste that comprises about 50% of Curodont ™ Protect, about 25% of hydroxyapatite particles and about 25% of water.
    [036] The present invention also relates to the use of the dental care product of the present invention for whitening teeth. A method of whitening teeth for cosmetic reasons is also described, comprising administering the dental care product of the present invention to a tooth. In the context of the invention, unless explicitly mentioned or clear from the context, "one, one" is not limited to the singular, but can also mean "one or more". For example, the reference to "one tooth" includes the option of more than one tooth, in particular, all of a person's teeth are designated. The dental care product of the present invention can also be used for bleaching crowns, implants, fillers and other oral utensils.
    [037] In the method of the invention, the composition is preferably administered once, twice or three times a day on days 1, 2, 3, 4, 5, 6, 7 or more days, in one embodiment, daily. It can also be administered less frequently, for example, once a week or once a month. The frequency of administration is strongly dependent on the whitening effect desired by the user, as well as the amount of mechanical abrasion to which the teeth are subjected. This includes administration throughout life, preferably starting after the permanent teeth have appeared, in particular, after discoloration of a tooth has been noticed. Administration means that one tooth, or, preferably, all of a person's teeth is brought into contact with the dental care product so that the respective type of product is typically used. For example, a toothpaste is usually used to brush your teeth for a period of 1-5 minutes, in particular, about 2-3 minutes.
    [038] As the dental care product of the invention does not lead to undesirable side effects of whitening products comprising peroxide, it can be used daily for all cycles of dental care, without damage to teeth or gums. As the dental care product can further increase the remineralization of the teeth, reduce tooth sensitivity and prevent cavities, and can even be used to treat caries lesions at the beginning, no additional dental care products are needed. In addition, the product can be used to inhibit tooth demineralization. In particular, the toothpaste or toothpaste of the invention can be used for each toothbrushing.
    [039] Alternatively, it can be used in addition to, or alternatively with, a different toothpaste, for example, a toothpaste containing alternative fluoride. For example, a toothpaste containing alternative fluoride can be used every morning, and the toothpaste of the invention can be used the night after the last meal of the day. The dental care product can also be used after normal dental care, for example, in the evening after tooth brushing.
    [040] The present invention also provides the dental care product of the present invention for use in treating a sensitive tooth and / or for preventing or treating cavities. Also disclosed is a method of treating a sensitive tooth and / or preventing and / or treating cavities and / or tooth whitening which comprises administering an effective amount of the dental care product of the present invention to a tooth or teeth.
    [041] The following examples are intended to illustrate, but not to limit the invention. All of the literature cited in the present patent application is thus incorporated herein in its entirety. Subtitles:
    [042] Fig. 1 (A) Electron microscopy image of the tooth surface treated with a mixture of Pl1-4 matrix and suspension of hydroxyapatite particles. The tooth surface shows particles that are firmly attached. (B) Electron microscopy image of the tooth treated only with suspension of hydroxyapatite particles in water. The surface shows irregular positioning of the particles on the surface.
    [043] Fig. 2 Photographic evaluation of the bleaching effect of different hydroxyapatite particles in clay plates in the absence (1-4) and in the presence (1 + -4 +) of self-assembling peptide (Curodont ™ Protect), according with the protocol of example 2. The images show the clay plates after brushing with a toothbrush. Examples Example 1: Materials and methods
    [044] Oligopeptide suspensions 104 (5 mg / ml) with or without hydroxyapatite particles (average size d50 <300nm (Horiba); 40-60% crystallinity, 25% by weight) were generated.
    [045] The suspensions were applied directly to a tooth enamel surface, and the residues washed (10 seconds). The sample was stored in distilled water for 24 hours at 37 ° C. The procedure was repeated 3 times.
    [046] The tooth color was measured with a dental spectrophotometer (VITA EasyShade). The lighting conditions were standardized with a black box as the bottom for the teeth during the measurement. The tip was applied perpendicularly to the tooth surface and the mean L * a * b values of three repetitions were used for evaluations. Color measurements were performed at baseline (t1 = without treatment), 24 hours after the first application (t2), 24 hours after the second application (t3), 24 hours after the third application (t4).
    [047] The average variations of the L * a * b * values between different measurements in each group were expressed, as ΔE (according to ISO 28399). Results
    [048] The results are provided in Table 2 below: Table 2

    [049] The experiment shows that, surprisingly, the combination of a protein matrix according to the invention with HA significantly increases the bleaching effect seen when applying HA only. Example 2: Test Protocol
    [050] 1. A ceramic plate made of clay is divided into four compartments using colorless nail polish. All chemicals are weighed and combined in a tube. The tube is filled with nanopure water ad 100% by weight. If gelatin is used, the suspension is heated in an 80 ° C water bath for 5 minutes. Then, the suspension is mixed by a vortex mixer. The suspension is ready to be applied to the ceramic plate; this is done in two pipetting steps with a volume of 50 μl. Between the two pipetting steps, a 10-minute break is taken. The ceramic plate is dried for about 3 hours.
    [051] 2. The ceramic plate is incubated in nanopure water for 24 hours. After incubation, the ceramic plate is removed and allowed to dry.
    [052] 3. The whiteness of the ceramic plate is measured by the spectrophotometer Vita Easyshade (Advance 4.0, SN: H26818, Vita Zahnfabrik GmbH, Bad Sackingen). Each field is measured three times and the average value is used.
    [053] 4. The described process (1-3) is repeated three times. The average variations of the L * a * b * values between different measurements in each group were expressed as ΔE, which was calculated using the method according to ISO 28399: 2011 (Products for external teeth whitening).
    [054] 5. After three applications, the ceramic plate is brushed by an ultrasonic toothbrush at a distance of 0.5 cm, for 2 minutes. The laboratory values of the plate are measured again, as described above. Tested materials
    [055] Different compositions according to the invention and the state of the art have been tested according to the test protocol described above. % refers to% by weight / weight. Water is added ad 100%. Curodont Pro tect ™ comprises 1 mg / g of Oligopeptide 104.



    [056] The experiment demonstrates that different amounts of HA, along with self-assembling peptide, have a bleaching effect that is improved with a greater amount of HA. Table 5A: Comparative compositions of the state of the art;


    [057] Comparison with the prior art compositions shows that the compositions of the present invention are surprisingly much more suitable for tooth whitening. In particular, it should be noted that after application, the 3lJP composition formed a thick crust, which, by itself, floated during the 24-hour incubation in water. The composition 10JP has turned yellow. Example 3:
    [058] A mono-centric uncontrolled cosmetic study with 40 volunteers who want whiter / lighter teeth was carried out. The primary objective of the study was to evaluate the whitening effect of the product evaluated in vivo, using a dental spectrometer (VITA Easyshade). The secondary objectives were a) evaluation of product safety and tolerability, b) identification and verification of the frequency of application of the product, c) evaluation of the durability of the bleaching effect, d) evaluation of an additional effect of repeated application.
    [059] All subjects were between 18 and 75 years old. At least one tooth had achieved a gloss level> = 15 with VITA Easyshade. The subjects had healthy upper jaw incisors and canines, that is, free of dental caries, no erosion, no partial restorations (referred to criteria applied to at least one tooth that had to reach the level of brightness> = 15 with VITA Easyshade). The subjects still had to understand all the procedures and be able and willing to follow the instructions, they had to agree with all the measurements and controls, and they had to sign a statement of correspondent before the study started. Subjects with general sensitivity to sugar, poor oral hygiene, fluorosis in the studied teeth, or subjects who participated in another clinical study or performed whitening during the study were excluded.
    [060] The tested product consisted of 50% Curodont Protect ™ (comprising 1 mg of Oligopeptide 104 / g of Curodont Protect ™, accordingly, the product contained 0.5 mg / g of Oligopeptide 104, ie 0.05 % of self-assembly peptide), 25% of hydroxyl apatits (d50 <300 nm (Horiba)) and 25% of water).
    [061] On day 0, in a dental surgery, the dentist or a member of the study team applied the product to the teeth with a dental tray for upper and lower jaw, respectively. After 5-10 min, the subject spat the product and washed his teeth with water. On days 1-7, once a day, at night after regular dental care, the subject brushed the front teeth for 1-2 minutes with the product. During the study period, subjects were instructed to clean their teeth 2-3 times a day, as usual, using a fluoride toothpaste, Candida Fresh®, and an electric toothbrush (Sonicare®).
    [062] The brightness of at least one evaluated tooth was recorded with the dental spectrometer before and after the first treatment (D0T), on the 1st day (before contact with the product on that day) on the 7th (D7) (before the contact with the product on that day) and on the 30th (D30). The average changes in L * a * b values between different measurements in each group were expressed as ΔE (according to ISO 28399). The results are shown in Table 6 below. Table 6:
    Average 2.61 3.32 4.03 3.88 ** extrapolated, therefore, no data are available
    [063] The study clearly demonstrates that significant whitening in tooth color was achieved by the product of the invention. After the first application, visual tooth whitening (AE> 3) occurred for a large number of patients. On average, a visual whitening effect was seen after D 1. In addition, the improvement occurred after one week of daily treatment at home. Notably, the whitening effect of the treatment occurred for all patients, with varying degrees. Even after 30 days, the bleaching effect was still detectable for most subjects.
    [064] Notably, most patients do not have homogeneous discolorations or yellowing of the teeth. The effects of the composition of the invention on individual teeth with a darker anterior color were more pronounced than the effects observed on average values.
    [065] The average degree of tooth whitening is comparable to the state of the art chemical bleaching methods (for example, leading to AE of - AE of less than 4 for home whitening, - AE of about 2.4-5 , 7 after 7 days, or 2.9-5.5 after 14 days for bleaching strips, - and up to ΔE 12 for powder whitening (for exercise use only) (Gerlach et al., 2002 .; De Marco et al., 2009; Delfino et al., 2009.)
    [066] However, the dental care product and method of the present invention have significant advantages over whitening chemicals over undesirable effects, such as tooth erosion, increased tooth sensitivity, etc. Literature
    [067] Dabanoglu et al., 2009, Am J Dent 22: 23-29.
    [068] Dahl et al., 2003, Crit Rev Oral Biol Med 14 (4): 292-304. Delfino et al., 2009, J Appl. Oral Sci 17 (4): 284-8.
    [069] Demarco et al., 2009. Braz Oral Res. 23 Suppl 1: 64-70.
    [070] Gerlach et al., 2002. Am J Dent. 15 Spec No: 7A-12A.
    [071] Jiang et al, 2008, J Dent 36 (11): 907-914.
    [072] Jin et al., 2013, Eur I Oral Sci 121: 382-388.
    [073] Lim et al., 2009, Biomed Mater 4 (2): 025017.
    [074] Mohd et al., 2007, Biomed Mater Eng 17 (2): 69-75.
    [075] Niwa et al. J Mater Sci Mater Med 2001; 12: 277-281.
    [076] Raoufi, S. and D. Birkhed (2010). Int Dent J60 (6): 419-423.
    [077] Roveri, Battistelli et al., 2009, J Nanomaterial, special issue, Article ID 746383 EP 1762 215 Al, EP 2 327 428 A2,
    [078] US 20050037948 Al, US 20080075675 Al, US 2008199431 Al, US 20100247589 Al, US 20100297203 Al, US 2010/0247457 Al,
    [079] US 6,548,630,
    [080] WO 2004/007532 Al, WO 2006/073889 A2, WO 2007/000979 Al, WO 2006/047315 A2, WO 2007/137606 Al, WO 2008/113030 A2, WO 2009/026729 Al, WO 2010/041636 Al , WO 2010/103887 Al, WO 2013/068020 Al, W02010 / 019651 Al
    [081] JP2008 / 081424, JPHl 15722 JPH115722,
    [082] JP2008 / 081424, JP 2007/0176862, JP 2001/131041, CN101385856.
    权利要求:
    Claims (12)
    [0001]
    1. Dental care product, characterized by the fact that it comprises (i) 0.4-40%, by weight, of calcium phosphate particles, the particles having a size of 0.01-50 μm; and (ii) 0.001-5%, by weight, of a protein capable of forming a protein matrix which is a hydrogel, in which the dental care product comprises a fluorophore, and in which the protein is a self-assembly peptide comprising SEQ ID NO: 1.
    [0002]
    2. Dental care product according to claim 1, characterized in that said particles are preferably 1-25 μm in size, more preferably 4-20 μm in size.
    [0003]
    3. Dental care product according to claim 1 or 2, characterized in that said fluorophore is an amino acid residue of the protein, preferably Trp, in which, preferably, 5% or more of the protein residues are Trp.
    [0004]
    4. Dental care product according to any one of claims 1 to 3, characterized in that the protein forms a hydrogel.
    [0005]
    Dental care product according to any one of claims 1 to 4, characterized in that said calcium phosphate particles comprise hydroxyapatite.
    [0006]
    6. Dental care product according to any one of claims 1 to 5, characterized in that it is selected from the group comprising toothpaste, prophylactic paste, tooth powders, tooth shine, tooth gel, chewing gums , candy, lozenge, mouthwash, whitening strips, coated dental floss, coated toothbrush, gel paint, varnish, veneer, and tube, syringe or dental tray comprising a gel or paste.
    [0007]
    Dental care product according to any one of claims 1 to 6, characterized in that it comprises (i) 0.5-40%, by weight, of said calcium phosphate particles; and (ii) 0.02-1% by weight, preferably 0.05% by weight, of said matrix protein, wherein the dental care product is a toothpaste or gel, which is optionally coated in dental floss or a toothbrush.
    [0008]
    Dental care product according to any one of claims 1 to 7, characterized in that 30-70% of said calcium phosphate particles have a size of 200-600 nm.
    [0009]
    Dental care product according to any one of claims 1 to 8, characterized in that the product comprises hydrogenated starch hydrolyzate, aqua, hydrated silica, PEG-8, cellulose gum, sodium monofluorophosphate, aroma, saccharin sodium, citric acid, sodium hydroxide, dicalcium phosphate, self-assembling peptide comprising SEQ ID NO: 1, calcium glycerophosphate, sodium chloride, sodium sulfate, limonene, cinnamal, CI 42090 and added hydroxyapatite particles.
    [0010]
    10. Cosmetic use of the dental care product defined in any one of claims 1 to 9, characterized by the fact that it is for whitening teeth.
    [0011]
    11. Use of calcium phosphate particles and a protein, characterized by the fact that it is used to prepare a dental care product, defined in any one of claims 1 to 9, for the treatment of a sensitive tooth and / or for the prevention or treatment of cavities.
    [0012]
    12. Cosmetic tooth whitening method, characterized by the fact that it comprises the use of the dental care product, defined in any one of claims 1 to 9, for a tooth, in which the composition is preferably used one, two or three times a day for 1, 2, 3, 4, 5, 6, 7 or more days, preferably daily.
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    同族专利:
    公开号 | 公开日
    RU2016115635A|2017-10-30|
    CA2915962A1|2015-04-02|
    ES2669548T3|2018-05-28|
    CN105555255A|2016-05-04|
    EP3049054A1|2016-08-03|
    HK1218870A1|2017-03-17|
    RU2016115635A3|2018-05-21|
    JP6649251B2|2020-02-19|
    CN105555255B|2019-07-12|
    US20160199283A1|2016-07-14|
    SG11201600874YA|2016-04-28|
    CA2915962C|2021-09-21|
    US10314776B2|2019-06-11|
    WO2015044268A1|2015-04-02|
    BR112016000077B8|2022-01-18|
    PL3049054T3|2018-08-31|
    AU2014327234B2|2019-02-21|
    RU2673820C2|2018-11-30|
    EP3049054B1|2018-04-04|
    JP2016533325A|2016-10-27|
    AU2014327234A1|2016-02-25|
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    法律状态:
    2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-06-09| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2020-10-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-22| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/09/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-01-05| B09W| Correction of the decision to grant [chapter 9.1.4 patent gazette]|Free format text: RETIFICA-SE O DEFERIMENTO PUBLICADO NA RPI 2596 DE 06/10/2020 POR TER SIDO EFETUADO COM INCORRECAO. |
    2022-01-18| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2607 DE 22/12/2020 QUANTO AO TITULO E A LISTAGEM DE SEQUENCIA. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP13185928.2|2013-09-25|
    EP13185928.2A|EP2853256A1|2013-09-25|2013-09-25|Dental care product for tooth whitening|
    EP14180365.0|2014-08-08|
    EP14180365|2014-08-08|
    PCT/EP2014/070487|WO2015044268A1|2013-09-25|2014-09-25|Dental care product for tooth whitening|
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