Dental care products containing stannous fluoride

Abstract

The present invention provides a novel dental care product comprising stannous fluoride and at least 0.01% by weight of a self-assembling peptide, wherein the self-assembling peptide is present in the dental care product in an essentially aggregated form. The assembled peptide forms a three-dimensional matrix that can stabilize stannous fluoride by protecting it from oxidation. The dental care product may further contain polyphosphates such as sodium tripolyphosphate and stannous chelating substances such as sodium gluconate. They may be provided in the form of a dental gel, toothpaste, tooth foam, dental rinse, or preventive paste. Methods for stabilizing stannous fluoride in a dental care product are also disclosed. Finally, the present invention relates to therapeutic methods for protecting teeth from demineralization, therapeutic methods for remineralizing non-cavitary tooth lesions of tooth enamel, therapeutic methods for disrupting biofilms formed on teeth, and therapeutic methods for treating dentin hypersensitivity.

Description

[Technical Field]

[0001] The present invention provides a novel dental care product comprising stannous fluoride and at least 0.01% by weight of self-assembling peptides, wherein the self-assembling peptides are present in the dental care product in an essentially assembled form. The assembled peptides form a three-dimensional matrix that can stabilize stannous fluoride by protecting it from oxidation. The dental care product may further contain polyphosphates such as sodium tripolyphosphate and stannous chelating substances such as sodium gluconate. They may be provided in the form of a dental gel, toothpaste, prophylactic paste, tooth foam, or dental rinse. Methods for stabilizing stannous fluoride in the dental care product are also disclosed. Finally, the present invention relates to therapeutic methods for protecting teeth from demineralization, therapeutic methods for remineralizing tooth enamel, therapeutic methods for destroying biofilms formed on teeth, and therapeutic methods for treating dentin hypersensitivity. [Background technology]

[0002] The anti-cariogenic effect of fluoride is scientifically proven and therefore well-established. Fluoride reacts with calcium present in plaque and saliva to form calcium fluoride on the tooth surface, thereby inhibiting demineralization and promoting remineralization. Calcium fluoride eventually dissolves, and calcium and fluoride ions interact with the tooth to form fluoride-containing apatite within the tooth structure. By converting the calcium mineral apatite in teeth to fluoroapatite, fluoride also provides resistance to bacterial acid attack in tooth enamel. Furthermore, fluoride can directly inhibit plaque bacteria by interfering with their metabolism through various different mechanisms (https: / / en.wikipedia.org / wiki / Tin(II)_fluoride; Marquis, 1995; Nasser et al., 2023).

[0003] Given these known beneficial effects of fluoride, dental care products such as fluoride-containing toothpaste (dentrifices) are now widely used.

[0004] Historically, the first fluoride-containing toothpastes provided fluoride in the form of stannous fluoride (SnF2), also commonly known as stannous fluoride (SnF2). These stannous fluoride-containing toothpastes showed remarkable effectiveness in reducing dental caries. However, the use of stannous fluoride in oral care compositions was limited by its instability in the presence of water. 2+ ) is highly reactive and rapidly oxidizes to inert tin(IV) ions (Sn 4+ ) becomes Sn 2+The oxidation of stannous fluoride manifests in the oral cavity as a yellowish-brown stain on the tooth surface. Furthermore, the tin present in stannous fluoride readily hydrolyzes above pH 4, causing a precipitate to form in the solution, ultimately leading to a loss of its therapeutic properties. Importantly, the chemical reactions contributing to the deactivation of stannous fluoride occur not only during storage but also directly during processing (White, 1995).

[0005] As a result, manufacturers of fluoride-containing toothpaste products have switched to using alternative fluoride sources, such as monofluorophosphates or sodium fluoride, which exhibit anticariogenic activity comparable to that of fluoride ions in stannous fluoride. However, unlike monofluorophosphates or sodium fluoride, stannous fluoride is also known for its inherent antibacterial effects and clinically demonstrated efficacy in controlling gingivitis. It has also shown remarkable reactivity to the root surface and has been demonstrated to reduce dentin hypersensitivity. Therefore, in recent years, stannous fluoride has been considered an effective "all-in-one" active ingredient for treatment, and there is renewed interest in the manufacture of dental products containing stannous fluoride (White, 1995).

[0006] Therefore, scientists face the challenge of discovering ways to stabilize stannous fluoride in dental care products and during administration, as stabilized stannous fluoride formulations achieve higher bioavailability of tin and fluoride ions, thereby increasing oral health benefits. To stabilize stannous fluoride, Sn 2+ Sn 4+ Protection from oxidation and hydrolysis of SnF2 are necessary. As a result, conventional stannous fluoride toothpastes were often stable enough to provide some degree of anticariogenic efficacy, but did not provide bioavailable stannous fluoride sufficient to exert the antibacterial activity required to control gingivitis. In other words, the stability requirements for stannous fluoride as an active ingredient against gingivitis appeared to be more stringent than those for anticariogenic activity (White et al., 1995).

[0007] Over time, numerous strategies have been developed to obtain more stable stannous fluoride-containing formulations.

[0008] For example, Sn 2+ The oxidation of tin(IV) ions may be prevented, for example, by drastically reducing or completely eliminating the addition of water to SnF2-containing toothpaste formulations. However, low water content of less than 10% may affect the taste and texture of the resulting toothpaste.

[0009] Stannous fluoride may be dissolved in an anhydrous substance such as glycerin to obtain a non-aqueous gel formulation. For example, US4418057A and US3433544A describe a method for formulating stannous fluoride as a non-aqueous gel mixture containing anhydrous glycerin and hydroxyethylcellulose as a gelling substance.

[0010] Further attempts to stabilize stannous fluoride in dental care products include adding tin(II) salts that can react with oxygen to protect stannous fluoride from oxidation. Tin(II) salts such as tin(II) phosphate and tin(II) chloride can react with Sn(II) from the active SnF2. 2+ A storage source to replenish losses may also be provided. US5004597A is unstable Sn 2+ Exemplary stannous fluoride-containing compositions are disclosed, relying on stannous(II) chloride and stannous(II) gluconate as tin(II) reservoirs for ion substitution. However, the use of some of these tin(II) salts has been shown to negatively affect the taste of toothpaste and, more importantly, is rather ineffective in preventing the formation of large amounts of tin(IV) ions.

[0011] The use of chelating agents has also been contemplated to protect stannous fluoride complexes from hydrolysis and oxidation, thereby reducing or even eliminating precipitation of insoluble tin compounds. Suitable tin(II) chelating agents include sodium gluconate, tin(II) gluconate, citrates such as zinc citrate, as well as hydroxyl-substituted aliphatic dicarboxylic acids and tricarboxylic acids such as citric acid or malic acid. Preparations containing these chelating agents are disclosed, for example, in US5716600A, US5004597A, US9968803B2 or US3282792A. Alternatively, copolymers of maleic anhydride or maleic acid and a polymerizable ethylenically unsaturated monomer, preferably a lower alkyl vinyl ether such as methoxyethylene, are Sn 2+ capable of forming chelates with, thereby Sn 2+ ions are known to be protected from oxidation. The use of such polymeric chelating agents in stannous fluoride-containing preparations is disclosed, for example, in US5017363A, US4960586A or US4961924A. However, the inclusion of some of the aforementioned chelating agents can result in a dentifrice paste exhibiting a gritty texture and a bitter, metallic, astringent and salty taste profile (Li et al., 2019).

[0012] Finally, Colgate Total SF, manufactured by Colgate-Palmolive Company, relies on a formulation in which SnF2 is stabilized using zinc phosphate, which complexes with SnF2 to prevent oxidation.

[0013] Although different approaches and strategies have been contemplated for stabilizing stannous fluoride in dental care formulations, there remains a need for improved stannous fluoride-containing dental care products characterized by both stable formulations and increased efficacy. SUMMARY OF THE INVENTION

[0014] The problem is solved by the present invention, particularly by the subject matter defined in the claims.

[0015] The present invention i. Tin(II) fluoride, and ii. A self-assembling peptide comprising at least 0.01% by weight of the sequence X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid, aspartic acid, glutamine, and ornithine, and X2 is independently selected from the group consisting of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and glutamine, wherein the self-assembling peptide is present in the dental care product in an essentially aggregated form. We offer dental care products, including [specific product / service].

[0016] The dental care product of the present invention contains stannous fluoride, also known in the context of the present invention as stannous fluoride or SnF2. Stannous fluoride may be present in the dental care product at a concentration of 0.1 to 1.0% by weight.

[0017] Preferably, stannous fluoride is present in the dental care product at a concentration of 0.2–0.7% by weight. Previous studies have shown that stannous fluoride provides the best therapeutic protection against caries, gingivitis, plaque, and dentin sensitivity at concentrations of 0.4–0.7% by weight (equivalent to about 1000–1500 ppm of fluoride), particularly 0.454% by weight (West et al., 2018; Parkinson et al., 2020). For children, the recommended concentration is 0.227% by weight (about 500 ppm of fluoride). Therefore, in preferred embodiments, the dental care product of the present invention contains stannous fluoride at a concentration of 0.1–0.7% by weight, most preferably 0.454% by weight.

[0018] The inventors were surprised to find that the dispersion of stannous fluoride in a three-dimensional matrix formed by self-assembling peptides was due to the tin(II) ion (Sn 2+ ) into tin(IV) ions (Sn 4+We found that it efficiently protects against oxidation, thereby preventing the formation of extrinsic stains on the tooth surface caused by the aforementioned oxidation.

[0019] In the context of the present invention, self-assembling peptides (SAPs), as the name suggests, are peptides that can self-assemble in a pH-dependent manner to form a three-dimensional scaffold or matrix, thereby promoting tissue regeneration. As used herein, "self-assembly" of a peptide refers to a spontaneous and reversible assembly in which a peptide and other peptides of its own kind (or peptides having a similar structure) become a multimeric assembly through non-covalent interactions. Non-covalent interactions responsible for the formation of the multimeric assembly include van der Waals interactions, pistacking interactions, hydrogen bonding interactions, polar interactions, and ionic interactions between the amino acid backbone and / or amino acid side chains of the peptide.

[0020] Suitable self-assembling peptides are taught, for example, in WO 2004 / 007532 A1, US10 / 521,628, US12 / 729,046, US13 / 551,878, US 14 / 062,768, WO 2010 / 041636 A1 or WO2014 / 027012 A1, all of which are fully incorporated herein by reference. Self-assembling peptides can assemble in one dimension to form beta sheets and can form higher-order assemblies such as fiber or tape-like assemblies. Three-dimensional supramolecular structures of self-assembling proteins may be formed, which have affinity for calcium phosphate.

[0021] The size of self-assembling peptides used in the dental care product of the present invention is not particularly limited. They may be of any length that enables self-assembly in a pH-dependent manner. The peptides may have a size of about 5 to 200 amino acids, for example 9 to 100 amino acids, 10 to 50 amino acids, 10 to 30 amino acids or 11 to 20 amino acids. Preferably, the self-assembling peptides have a length of about 27 amino acids, 24 amino acids, 21 amino acids, 15 amino acids, or 11 amino acids. In a particularly preferred embodiment, the self-assembling peptides have a length of 11 amino acids, that is, they consist of 11 amino acids.

[0022] To enable adhesion to tooth surfaces, the matrix formed by the self-assembling peptides present in the dental care product of the present invention must be able to bind to mineral particles present in tooth surfaces. Accordingly, the matrix comprises binding sites for mineral particles, which enables binding to the particles, wherein the particles preferably comprise calcium and are present on tooth surfaces. For example, charged amino acid residues such as Glu on the surface of self-assembling peptides bind to hydroxyapatite particles and tooth surfaces, and tooth surfaces are also substantially formed of hydroxyapatite. The ability of three-dimensional self-organization is important for binding. In general, a highly charged surface will promote adhesion of mineral particles. The protein matrix works particularly well when the surface of the protein matrix presents glutamic acid residues that can attach to calcium phosphate or other mineral particles. Preferably, the protein comprises 5% or more, 10% or more, 20% or more, or 30% or more of charged amino acid residues such as glutamic acid residues.

[0023] In the context of the present invention, self-assembling peptides may be capable of self-assembling on their own, such as, for example, peptides P11-4, P11-8, P11-2 and P11-5 mentioned below, but may alternatively be capable of self-assembling as a combination of two self-assembling peptides, such as, for example, peptides P11-13 / P11-14, P11-28 / P11-29 and P11-30 / P11-31 mentioned below.

[0024] The self-assembling peptide in the dental care product of the present invention comprises a consensus sequence X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid, aspartic acid, glutamine and ornithine, and X2 is independently selected from the group consisting of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan and glutamine. The expression "independently selected" means that, for example, X1 at positions 1, 3 or 5 of the above sequence may be different from each other. Of course, they may also be identical.

[0025] In one embodiment, the self-assembling peptide comprises the sequence X1-X2-X1-X2-X1, wherein X1 is an amino acid having an acidic side chain, and X2 is an amino acid having a hydrophobic side chain or a polar side chain.

[0026] Preferably, the self-assembling peptide also comprises X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid and ornithine, and X2 is independently selected from the group consisting of tryptophan and phenylalanine.

[0027] The self-assembling peptide may further comprise X3-F-X1-W-X1-F-X1, wherein X1 is independently selected from the group consisting of glutamic acid and ornithine, X3 is selected from the group consisting of arginine, glutamic acid and ornithine, and X3 is preferably arginine.

[0028] The self-assembling peptide used in the dental care product of the present invention may contain, or preferably consists of, X4-X4-X3-F-X1-W-X1-F-X1-X4-X4, where X1 is independently selected from the group consisting of glutamic acid and ornithine, X3 is independently selected from the group consisting of arginine, glutamic acid and ornithine, and X4 is independently selected from the group consisting of glutamine, glutamic acid, serine, threonine and ornithine. X3 is preferably arginine. Independently, X4 is preferably glutamine.

[0029] The self-assembling peptide comprises, or preferably comprises, SEQ ID NO: 5: QQRF-X1-W-X1-F-X1-QQ, where X1 is independently selected from the group consisting of glutamic acid and ornithine.

[0030] In the context of the present invention, self-assembling peptides are taught in WO 2004 / 007532 A1, US10 / 521,628, US12 / 729,046, US13 / 551,878, US 14 / 062,768, or WO2014 / 027012 A1, all of which are fully incorporated herein by reference and are preferred. Most preferably, the peptides include or consist of the specific peptides listed in Table 2. Of course, self-assembling peptides assembled in combination with other self-assembling peptides, such as those disclosed above, may be formulated in the composition.

[0031] Preferably, the self-assembling peptide contains or consists of the sequence of SEQ ID NO: 6. The peptide consisting of the sequence of SEQ ID NO: 6 is also called P11-4 and is preferred throughout the invention. In another preferred embodiment, the self-assembling peptide contains or consists of the sequence of SEQ ID NO: 9 (P11-8). In another preferred embodiment, the self-assembling peptide contains or consists of the sequence of SEQ ID NO: 15 (P11-20).

[0032] Peptides of SEQ ID NOs. 6, 9, or 15 are particularly advantageous. For example, they are highly cellularly compatible and have a beneficial charge distribution because they can be used at relatively low concentrations.

[0033] Table 1: Consensus sequences of preferred self-assembling peptides [Table 1]

[0034] Table 2: Preferred self-assembling peptides. The position of X1 is underlined. "O" indicates the amino acid ornithine. [Table 2]

[0035] The composition of the present invention may include at least one self-assembling peptide having at least 45% sequence identity with the peptide comprising SEQ ID NO: 6. Preferably, the peptide has at least 54%, at least 63%, at least 72%, at least 81%, or at least 90% sequence identity with the peptide comprising SEQ ID NO: 6, or is the aforementioned peptide.

[0036] The self-assembling peptides used in the dental care products of the present invention may be further structurally modified at one or more amino acid positions, for example, by introducing one or more modified amino acids. According to the present invention, these modified amino acids may be amino acids altered by, for example, biotinylation, phosphorylation, glycosylation, acetylation, branching, and / or cyclization. Furthermore, the self-assembling peptides present in the dental care products of the present invention may additionally or alternatively contain other modifications such as terminal blocking groups, formyl groups, gammacarboxyglutamate hydroxyl groups, methyl groups, phosphoryl groups, pyrrolidone carboxylic acid groups, and / or sulfate groups.

[0037] In preferred embodiments, all self-assembling peptides present in the dental care products of the present invention are acetylated at the N-terminus and / or amidated (e.g., at the C-terminal terminus, by an NH2 group), most preferably both. Because the unblocked form tends to initiate a deamination reaction, the ends of the self-assembling peptides described herein are preferably blocked to enhance stability. Thus, in preferred embodiments, the self-assembling peptides present in the dental care products of the present invention, e.g., peptides of SEQ ID NOs: 6, 9 and / or 15, include both an Ac-N-terminus and an NH2-C-terminus. A particularly preferred embodiment is peptide P11-4 (SEQ ID NO: 6), which is acetylated at the N-terminus and amidated at the C-terminus with an NH2 group.

[0038] Dental care products may contain one type of self-assembling peptide or two or more different types of self-assembling peptides, such as three, four, or five types. For example, they may contain a mixture of the self-assembling peptide according to Sequence ID No. 6 and the self-assembling peptide according to Sequence ID No. 15.

[0039] In the dental care products of the present invention, the self-assembling peptides exist in an essentially associated form. As used herein, this means that at least about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or even about 100% of the peptides found in the dental care products are organized, i.e., in a polymeric or macromolecular form.

[0040] Most of the self-assembling peptides in the dental care products described in the present invention, such as P11-4 (SEQ ID NO: 6) and / or P11-20 (SEQ ID NO: 15) and their terminally modified variants, self-assemble immediately after the pH of their environment drops below pH 7.5. This means that when the pH drops below 7.5, the self-assembling peptides present in the dental care products of the present invention begin to self-assemble to a significant extent.

[0041] Organization is primarily controlled by pH. The pH at which self-assembling peptides organize depends on their sequence. For example, P11-4 organizes at a pH below 7.5. The pH of the present invention's dental care products containing P11-4 and similar peptides is preferably below 7.5, especially when the self-assembling peptide is P11-4. The pH is preferably between 4 and 7.5, for example, 5 to 7.5 or 6 to 7.

[0042] Other self-assembling peptides, such as P11-8, self-assemble at a pH above 7.5. When such self-assembling peptides are used, the pH of the dental care product is appropriately adjusted; that is, the pH is higher than the pH at which the self-assembling peptides assemble, for example, above pH 7.5.

[0043] The organized state of peptides is also influenced by ionic strength. The ionic strength of a solution is a function of the concentrations of all ions present in the solution. Therefore, even at pH levels higher than the pH at which peptides begin self-assembly, i.e., when peptides are essentially monomers in solution, particularly high ionic strengths can trigger peptide organization.

[0044] Those skilled in the art will know how to determine and measure the ionic strength of a solution. Ionic strength I is generally calculated by the formula I = 1 / 2Σzi2bi, where z is the valence factor and bi is the gravimetric molar concentration of the ion [mol / kg{H2O}]. The summation, Σ, is taken over all ions in the solution. For example, the ionic strength of a 150 mM NaCl solution is approximately 0.15 mol / L. This is also approximately the ionic strength of blood. The ionic strength of saliva present in the oral cavity is generally lower, for example, approximately 0.04 mol / L. In the context of this invention, the physiological range of ionic strength is considered to correspond to an ionic strength of 0.15 mol / L.

[0045] Those skilled in the art know that peptide concentration can affect peptide organization, meaning that certain high peptide concentrations may trigger organization. Correspondingly, exceptionally low peptide concentrations may prevent the organization of the peptides of the present invention, meaning that it may also be prevented under dental lesions and low pH conditions in the oral cavity.

[0046] Those skilled in the art will be able to determine by conventional experiments whether essentially all self-assembling peptides exist in an associated form. For example, the organized state of peptides in solution can be determined by nuclear magnetic resonance (NMR) such as 1H-NMR, circular dichroism analysis, dynamic light scattering (DLS) analysis, diffuse wave spectroscopy, native electrophoresis, viscosity measurement (rheology), and dissipative measurement quartz crystal microbalance (QCMD), preferably by native electrophoresis. The presence of self-assembling peptide fibers may be detected by TEM.

[0047] Suitable buffers and pH modifiers for obtaining the desired pH are known in this field.

[0048] As described herein, the stabilization of stannous fluoride is due to the tin(II) ion (Sn 2+ ) from tin(IV) ions (Sn 4+ This involves preventing premature oxidation of stannous fluoride. The inventors have surprisingly found that the dispersion of stannous fluoride in a three-dimensional matrix formed by the self-assembling peptides described herein protects the tin(II) ion from oxidation when the dental care product is applied to the tooth surface. Although not bound by theory, the fibers formed by the self-assembling peptides having a net charge of -2 may also function as stabilizing factors, thereby preventing oxidation of the tin(II) ion. The three-dimensional matrix of self-assembling peptides further helps stannous fluoride to remain on the enamel surface for a long time through its affinity for hydroxyapatite. The additional stabilization of the tin(II) ion by the presence of self-assembling peptides prevents the formation of tooth discoloration, which is typically observed as a result of SnF2 oxidation.

[0049] Notably, the inventors found that the remarkable ability of the self-assembling peptides described herein to stabilize stannous fluoride and protect it from oxidative changes is highly dependent on the concentration of the self-assembling peptides in the dental care product: the advantageous effect was observed only in formulations containing 100 PPM (i.e., 0.01 wt%) or more of the self-assembling peptides, and this effect was not significant in formulations with concentrations of less than 100 PPM of the self-assembling peptides.

[0050] Therefore, the self-assembling peptide is present in the dental care product of the present invention at a concentration of at least 100 PPM or at least 0.01% by weight, for example, 0.01-0.1% by weight, 0.1-1% by weight, 1-2% by weight, 2-3% by weight, 3-4% by weight, or 4-5% by weight, or a concentration of 0.01-5% by weight. Preferably, the self-assembling peptide is present in the dental care product at a concentration of 0.01-0.1% by weight, for example, about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1% by weight. Most preferably, the self-assembling peptide is present in the dental care product at a concentration of about 0.03-0.07% by weight, for example, about 0.05%.

[0051] In a preferred, though not essential, embodiment of the present invention, the dental care product further comprises polyphosphate. Polyphosphate is an inorganic polymer consisting mainly of two or more linearly arranged phosphate molecules, although in some cases cyclic derivatives may also be used. Polyphosphate acts as a chelating agent, and by binding to the tooth surface, it can prevent the formation of dental pellicle. Polyphosphate thereby reduces the adhesion of adsorbed salivary glycoproteins, helping salivary proteins desorb from enamel (Mason et al., 2019). As a result, polyphosphate contributes to stain removal and control of stain accumulation during brushing. Therefore, polyphosphate compounds are often used in whitening toothpastes. Furthermore, due to its ability to act as a chelating agent, polyphosphate can bind to calcium ions in saliva and plaque, thereby inhibiting the formation of calcified deposits (known as tartar) on the tooth surface.

[0052] Surprisingly, the inventors found that polyphosphate does not hinder the adhesion of self-assembling peptides to enamel, thereby allowing them to be incorporated into dental care products without compromising the dental effects of the self-assembling peptides.

[0053] The U.S. Food and Drug Administration (FDA) lists sodium pyrophosphate, sodium triphosphate, and sodium hexametaphosphate as generally recognized safe (GRAS) food additives (Moon et al., 2019). Any one of these, or any combination thereof, can be used in the dental care products of the present invention.

[0054] For the reduction of stains caused by the oxidation of stannous fluoride, dental care formulations containing polyphosphates such as sodium hexametaphosphate are disclosed, for example, in US6667027B2, US6350436B1, US6821507B2, US5578293A, US5145666A, US5281411A or US5281410A.

[0055] In some embodiments, the polyphosphate present in the dental care product of the present invention may be a pyrophosphate, i.e., a diphosphate characterized by two phosphorus atoms being linked to one oxygen atom. The pyrophosphate may be provided in the dental care product as a disodium salt or a tetrasodium salt.

[0056] However, in preferred embodiments, the polyphosphate present in the dental care product of the present invention is sodium tripolyphosphate (STP). STP may be present in the dental care product at a concentration of 1 to 10% by weight, for example, 2 to 5% by weight. Preferably, the dental care product of the present invention contains about 3% by weight of STP.

[0057] Dental care products may optionally further contain additional ingredients known to have the ability to stabilize stannous fluoride.

[0058] For example, in some embodiments, the oral care product may further contain one or more substances capable of chelating tin(II) ions. Chelating refers to a chemical reaction in which an ion or molecule binds to a metal ion. Suitable tin(II) chelating substances that can form a stable chelate with stannous fluoride, thereby protecting it from hydrolysis and oxidation, are known in the art and include, for example, sodium gluconate, tin(II) gluconate, or zinc citrate.

[0059] A substance capable of chelating tin(II) ions may be present in the dental care product at a concentration of 0-5% by weight, for example, 0.5-1% by weight, 1-2% by weight, 2-3% by weight, 3-4% by weight, or 4-5% by weight. More preferably, the substance capable of chelating tin(II) ions may be present in the dental care product at a concentration of 2-4% by weight, for example, 2% by weight, 3% by weight, or 4% by weight.

[0060] Preferably, the substance capable of chelating tin(II) ions is sodium gluconate. Sodium gluconate is non-corrosive, non-toxic, and readily biodegradable. It forms stable chelates with calcium, iron, copper, aluminum, and other heavy metals, including tin. Therefore, sodium gluconate is preferably used in the dental care products of the present invention to further stabilize stannous fluoride.

[0061] Therefore, in a preferred embodiment, the present invention is i. 0.1 to 1.0% by weight of tin(II) fluoride; ii. At least 0.01% by weight of a self-assembling peptide consisting of Sequence ID No. 6 (P11-4); iii. 1-10% by weight sodium tripolyphosphate; and iv. Optionally, 0.5 to 5% by weight of sodium gluconate. The present invention provides a dental care product that contains [a specific ingredient], wherein the pH of the dental care product is less than 7.5.

[0062] The dental care product described in the present invention may be a dental gel, toothpaste, preventive paste, tooth foam, or dental rinse, preferably a dental gel. The dental care product may be used by a professional in a dental clinic, preferably applied using a suitable dental instrument such as a rubber polisher. It may also be applied with a syringe. However, the dental care product may also be used at home, preferably applied to the tooth surface using a finger or a toothbrush, such as an interdental brush.

[0063] Dental care products may also contain one or more typical ingredients of each dental care product. Such typical ingredients are: - Abrasive substances such as carbonates, phosphates, silicates, acrylates, and alumina. - Suspended substances such as glycerin, polyethylene glycol (PEG), sorbitol, xylitol, and / or erythritol. -Cellulose and its derivatives such as carboxymethylcellulose (cellulose gum), binding substances such as carrageenan, paraffin, and xylose, - Hydrogenated castor oil, surfactants such as sodium lauryl sulfate, -Flavorings such as caramel, vanillin, and menthol, - Preservatives such as ethanol and sodium benzoate, -Coloring substances such as Solvent Red and Acid Blue 3, - An additional fluoride source, preferably a fluoride source in the form of a tertiary amine such as a fluoramine, or a fluoride source that is an organic fluoride such as sodium monofluorophosphate. That's fine.

[0064] Dental care products typically contain water, optionally more than 10% water.

[0065] For example, a particular preferred dental care product of the present invention comprising stannous fluoride and the self-assembling peptide described herein is a dental gel. a. Sodium tripolyphosphate, b. Sodium gluconate, c. Sorbitol, d. Cellulose gum, e. xylitol, f. Erythritol, g. Hydrated silica (hydrated silica), h. Phosphate, i. Optionally, NaOH, and j.Water It also includes.

[0066] The present invention provides a dental care product in which stannous fluoride is stabilized using a matrix formed by self-assembling peptides described herein. Thus, the present invention provides a novel method for stabilizing stannous fluoride in a dental care product, i. Tin(II) fluoride, and ii. A self-assembling peptide comprising at least 0.01% by weight of the sequence X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid, aspartic acid, glutamine, and ornithine, and X2 is independently selected from the group consisting of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and glutamine, wherein the self-assembling peptide is present in the dental care product in an essentially aggregated form. The present invention also relates to a method comprising mixing, preferably, a dental care product, which is the dental care product of the present invention.

[0067] The dental care product of the present invention may be stable at room temperature (20°C) for at least 6 months, at room temperature for at least 12 months, at room temperature for at least 18 months, at room temperature for at least 24 months, or at room temperature for at least 36 months. In this context, stability means that no visible discoloration occurs due to oxidation of stannous fluoride.

[0068] The use of the dental care products described herein is associated with a range of beneficial effects.

[0069] For example, the dental care product of the present invention may be used to prevent tooth demineralization or to remineralize tooth enamel, such as in non-cavitary tooth lesions.

[0070] Dental caries is one of the most widespread bacterial infections in the world. It is the decomposition of tooth material, primarily by acids, through bacterial metabolites produced by bacteria as they break down food residue or sugars on the tooth surface or within the tooth biofilm. This results in an imbalance between the demineralization and remineralization processes. The hard tooth structures, namely enamel, dentin, and cementum, are damaged by progressive demineralization, leading to carious lesions and eventually the appearance of carious cavities. The earliest sign of a new carious lesion is the appearance of a chalky white spot on the tooth surface, a so-called white spot lesion (also called a primary carious lesion), or subcutaneous lesion. As demineralization progresses, the calcified surface of the lesion (partially) breaks down and fractures, revealing microcavities or cavities, or holes in the tooth. This is called a (partially) cavitating carious lesion or cavitating carious lesion.

[0071] Stannous fluoride is known for its remarkable effectiveness in reducing crown caries by both preventing enamel demineralization and promoting enamel remineralization (Fiorillo et al., 2020). On the other hand, as disclosed, for example, in international patent application WO 2021 / 110923 A1, a matrix formed by the self-assembling peptides described herein may constitute a protective layer or film on the tooth to which it is administered. This protective layer formed by the assembled self-assembling peptides may effectively prevent further demineralization and protect tooth enamel from acid attack.

[0072] Furthermore, matrices formed by self-assembling peptides disclosed herein, such as P11-4, can lead to increased calcification (Soares et al., 2017). Self-assembling peptide matrices have also been found to prevent artificial caries lesions and promote remineralization of enamel around orthodontic brackets (Jablonsky-Momeni et al., 2019).

[0073] Both stannous fluoride and self-assembling peptides exert protective effects against enamel demineralization and remineralization activity, but they may act synergistically. Furthermore, by being suspended in a three-dimensional matrix formed by the self-assembling peptides disclosed herein, stannous fluoride is maintained and stabilized on the enamel surface for extended periods, resulting in sustained protection against tooth demineralization and prolonged enamel remineralization.

[0074] Therefore, the present invention provides a method for preventing tooth demineralization and a method for remineralizing tooth enamel in a subject that requires it, for example, in a non-cavitary tooth lesion, both methods comprising applying an effective amount of the dental care product of the present invention to the tooth. Of course, the tooth treatment may be the treatment of some, preferably all, teeth of the subject.

[0075] In another embodiment, the dental care product of the present invention may be for destroying bacterial biofilms formed on teeth.

[0076] Stannous fluoride is also known to exhibit intrinsic antibacterial activity through both a bactericidal mechanism and inhibition of bacterial metabolic enzymes. Accordingly, the effectiveness of stannous fluoride in controlling gingivitis has been clinically demonstrated (Paraskevas et al., 2006; Parkinson et al., 2020; Acherkouk et al., 2021). The inventors have found that the antibacterial activity of stannous fluoride can be further enhanced by the presence of self-assembling peptides, which form a negatively charged three-dimensional matrix that repels bacteria with a negative net charge during self-assembly. As a result, the biofilm formed on the tooth surface is less dense and can be more easily broken down with stannous fluoride. Therefore, the dental care product described in the present invention enables more efficient removal of tooth biofilm.

[0077] Therefore, the invention disclosed herein further provides a method for reducing or destroying a biofilm formed on a tooth, which includes applying an effective amount of the dental care product of the present invention to the tooth.

[0078] Enhanced disruption of the biofilm on the tooth surface may contribute to the prevention of gingivitis, periodontitis, and / or peri-implantitis.

[0079] Gingivitis is a non-destructive periodontal disease that most commonly develops as plaque-induced gingivitis, which occurs in response to a bacterial biofilm (also called plaque) that adheres to the tooth surface. Gingivitis can be reversed with good oral hygiene.

[0080] However, if left untreated or uncontrolled, gingivitis can progress to periodontitis. Periodontitis (or periodontal disease) is a set of inflammatory diseases that affect the periodontal tissues, i.e., the tissues that surround and support the teeth. Periodontitis is caused by microorganisms that adhere to and proliferate on the surface of the teeth and an overly aggressive immune response to these microorganisms. With the destruction of gingival fibers, the gum tissue separates from the teeth, creating deep grooves called periodontal pockets. Subgingival microorganisms, i.e., those located apically to the root of the gum line, colonize in the periodontal pockets, causing further inflammation and progressive bone loss in the gum tissue. If left undisturbed, microbial plaque calcifies to form calculus, commonly known as tartar. Tissue destruction, such as destruction of the periodontal ligament, and resorption of alveolar bone can ultimately lead to tooth looseness and subsequent tooth loss.

[0081] Peri-implantitis is a destructive inflammatory process that affects the soft and hard tissues surrounding dental implants, and it is caused by plaque formation in the tissues surrounding the dental implant.

[0082] Therefore, in another embodiment, the present invention provides a method for preventing gingivitis, periodontitis, and / or peri-implantitis in a person requiring it, comprising applying an effective amount of the dental care product of the present invention to the surface of a tooth enamel.

[0083] It has also been clinically demonstrated that stannous fluoride significantly reduces dentin hypersensitivity (Schiff et al., 2005; Hines et al., 2019). Although not bound by theory, tin(II) ions from stannous fluoride, in the presence of saliva, precipitate and block open dentin tubules, forming insoluble tin compounds, i.e., low-solubility hydroxyapatite containing tin impurities.

[0084] On the other hand, when the self-assembling peptides described herein self-assemble and assume a three-dimensional matrix configuration, the matrix forms a stable adhesive barrier to the exposed dentin tubules, physically blocking the pathway of external stimuli.

[0085] Therefore, the stannous fluoride and self-assembling peptides present in the dental care product of the present invention promote a parallel desensitization effect. They may also work synergistically to reduce dentin hypersensitivity. Furthermore, since the self-assembling peptides in the dental care product also contribute to the maintenance of tin(II) ions on the dentin surface, they ensure that the desensitization effect of stannous fluoride can be extended.

[0086] Therefore, by combining the desensitizing effects of self-assembling peptides and stannous fluoride, the dental care product of the present invention provides more sustained and faster relief of hypersensitivity through a self-assembling peptide matrix that forms an immediate barrier on exposed dentin. The relief is prolonged by the continued presence of tin(II) ions on the root surface via the self-assembling peptide matrix.

[0087] Therefore, in another aspect, the present invention also provides an improved method for treating dentin hypersensitivity in a person in need, comprising applying an effective amount of the dental care product of the present invention to a tooth.

[0088] In all the methods described herein, the subject is preferably a human. However, it may be a non-human mammal, such as a domestic pet like a cat or a dog, or another livestock such as a cow, a pig, a horse, a sheep, a goat, or a camel. The subject may also be a non-human primate, or another animal kept in captivity, such as a lion, a tiger, or a leopard.

[0089] In the context of this invention, “treating” any of the above conditions should be understood to include therapeutic medical treatment of the subject with the intention of curing, restoring, or stabilizing the condition. On the other hand, “preventing” a condition means precluding, averting, obviating, forestalling, stopping, or hindering the condition from occurring in its initial location. Thus, preventing a condition also explicitly includes preventive treatment of the subject.

[0090] Dental care products may be applied by using an applicator such as a rubber polisher or syringe, a finger, or a toothbrush, as described elsewhere in this specification.

[0091] In the various methods disclosed herein, the dental care product is preferably administered once, twice, or three times a day for one, two, three, four, five, six, or seven days or more, and in one embodiment, daily. It may also be administered less frequently, for example, once a week or once a month.

[0092] In summary, the inventors have unexpectedly discovered a novel method for stabilizing stannous fluoride in dental care products. By dispersing stannous fluoride in a three-dimensional matrix formed by self-assembling peptides, the bioavailability of biologically active tin(II) ions and fluoride ions can be increased. Thus, the resulting dental care products can be advantageously used in improved methods for treating and / or preventing various dental conditions, including caries, gingivitis, periodontitis, peri-implantitis, and dentin hypersensitivity.

[0093] Throughout this invention, the term “about” is intended to be understood as “+ / -10%”. When “about” refers to a range, it refers to both the lower and upper limits of the range. Unless otherwise specified, “a” is intended to mean “one or more”. As used herein, the term “comprising” also encompasses the meaning of “consisting of”.

[0094] The following examples are intended to illustrate the present invention and not to limit it. All references cited herein are incorporated herein by reference in their entirety. [Examples]

[0095] Self-assembling peptides have been shown to enable enamel remineralization, inhibit demineralization, and treat dentin hypersensitivity. Stannous fluoride has also been clinically shown to be effective in treating dentin hypersensitivity and preventing caries at concentrations between 0.4 and 0.5%.

[0096] The inventors have surprisingly observed that the combination with self-assembling peptides significantly increases the stability and therefore bioavailability of the incorporated stannous fluoride, which is likely due to its interaction with the self-assembling peptide fibers.

[0097] Historically, the use of stannous fluoride in oral care compositions has been due to the use of tin(II) ions (Sn 2+ Due to the instability issues of ), the tin(II) ion is limited to the inert tin(IV) ion (Sn 4+ It rapidly oxidizes to ) . In the oral cavity, this manifests as a yellowish-brown stain on the tooth surface.

[0098] Unexpectedly, this oxidation change was not observed with tin(II) ions dispersed in a self-assembling peptide matrix. Oxidation was inhibited both when exposed to atmospheric oxygen and when tested in laboratory redox experiments.

[0099] Prepare a gel formulation with a pH of less than 7.5 containing the following and evaluate its effect: 1.0.45% stannous fluoride 2.0.45% stannous fluoride + 50 PPM P11-4 self-assembling peptide matrix 3.0.45% stannous fluoride + 100 PPM P11-4 self-assembling peptide matrix 4.0.45% stannous fluoride + 250 PPM self-assembling peptide matrix 5.0.45% Stannous Fluoride + 500 PPM Self-Assembling Peptide Matrix

[0100] No oxidative changes were observed in any formulation containing a self-assembling peptide matrix of 100 PPM or more.

[0101] References White, 1995, A "Return" to stannous fluoride dentifrices. The Journal of Clinical Dentristry. Marquis RE. Antimicrobial actions of fluoride for oral bacteria. Can J Microbiol. 1995 Nov;41(11):955-64. doi: 10.1139 / m95-133. PMID: 7497353. Nassar Y, Brizuela M. The Role of Fluoride on Caries Prevention. [Updated 2023 Mar 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK587342 / . https: / / en.wikipedia.org / wiki / Tin(II)_fluoride Levine RS. Pyrophosphates in toothpaste: a retrospective and reappraisal. Br Dent J. 2020 Nov;229(10):687-689. doi: 10.1038 / s41415-020-2346-4. Epub 2020 Nov 27. PMID: 33247264. Stephen Mason, Sarah Young, Jimmy Qaqish, Guillaume Frappin, Chhaju Goyal, Stain control with two modified stannous fluoride / sodium tripolyphosphate toothpastes: A randomised controlled proof of concept study, Journal of Dentistry, Volume 91, Supplement, 2019. West N, et al. Erosion protection efficacy of a 0.454% stannous fluoride dentifrice versus an arginine-containing dentifrice. American Journal of Dentistry. 2018 Apr;31(2):63-66. PMID: 29630787. Fiorillo L, et al. Stannous Fluoride Effects on Enamel: A Systematic Review. Biomimetics (Basel). 2020 Aug 31;5(3):41. doi: 10.3390 / biomimetics5030041. PMID: 32878006; PMCID: PMC7559150. Parkinson CR, et al. Gingivitis efficacy of a 0.454% w / w stannous fluoride dentifrice: a 24-week randomized controlled trial. BMC Oral Health. 2020 Mar 26;20(1):89. doi: 10.1186 / s12903-020-01079-6. PMID: 32216778; PMCID: PMC7098169. Moon JH, et al. Effects of Sodium Tripolyphosphate on Oral Commensal and Pathogenic Bacteria. Pol J Microbiol. 2019;68(2):263-268. doi: 10.33073 / pjm-2019-029. PMID: 31257792; PMCID: PMC7256694. Soares R, De Ataide IN, Fernandes M, Lambor R. Assessment of Enamel Remineralisation After Treatment with Four Different Remineralising Agents: A Scanning Electron Microscopy (SEM) Study. J Clin Diagn Res. 2017 Apr;11(4):ZC136-ZC141. doi: 10.7860 / JCDR / 2017 / 23594.9758. Epub 2017 Apr 1. PMID: 28571281; PMCID: PMC5449906. Jablonsky-Momeni et al., 2019. Randomised in situ clinical trial investigating self-assembling peptide matrix P11-4 in the prevention of artificial caries lesions. Scientific Reports 9:269. Acherkouk Aet al. A randomised clinical study investigating efficacy of a stannous fluoride toothpaste in improving gingival health after 3 weeks' use. BMC Oral Health. 2021 Sep 12;21(1):441. doi: 10.1186 / s12903-021-01727-5. PMID: 34511098; PMCID: PMC8436562. Paraskevas S, van der Weijden GA. A review of the effects of stannous fluoride on gingivitis. J Clin Periodontol. 2006 Jan;33(1):1-13. doi: 10.1111 / j.1600-051X.2005.00860.x. PMID: 16367849. Schiff T, et al. Desensitizing effect of a stabilized stannous fluoride / Sodium hexametaphosphate dentifrice. Compend Contin Educ Dent. 2005 Sep;26(9 Suppl 1):35-40. PMID: 16999008. Hines D, et al. Effect of a stannous fluoride toothpaste on dentinal hypersensitivity: In vitro and clinical evaluation. J Am Dent Assoc. 2019 Apr;150(4S):S47-S59. doi: 10.1016 / j.adaj.2019.01.006. PMID: 30797259. US4418057A US3433544A US5004597A US5716600A US5004597A US9968803B2 US3282792A US5017363A US4960586A US4961924A WO 2004 / 007532 A1 US10 / 521,628 US12 / 729,046 US13 / 551,878 US14 / 062,768 WO 2010 / 041636 A1 WO2014 / 027012 A1 US6667027B2 US6350436B1 US6821507B2 US5578293A US5145666A US5281411A US5281410A WO 2021 / 110923 A1

Claims

1. i. Tin(II) fluoride, and ii. A self-assembling peptide comprising at least 0.01% by weight of the sequence X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid, aspartic acid, glutamine, and ornithine, and X2 is independently selected from the group consisting of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and glutamine, wherein the self-assembling peptide is present in the dental care product in an essentially aggregated form. Dental care products, including [specific product / feature].

2. The dental care product according to claim 1, wherein tin(II) fluoride is present in the dental care product at a concentration of 0.1 to 1.0% by weight.

3. The dental care product according to claim 1, wherein the self-assembling peptide contains or comprises the amino acid sequence of SEQ ID NO: 6 (P11-4), SEQ ID NO: 9 (P11-8), or SEQ ID NO: 15 (P11-20).

4. The dental care product according to claim 1, wherein the self-assembling peptide comprises Sequence ID No. 6 (P11-4).

5. The dental care product according to claim 1, further comprising polyphosphate.

6. The dental care product according to claim 5, wherein the polyphosphate is sodium tripolyphosphate.

7. The dental care product according to claim 6, wherein sodium tripolyphosphate is present in the dental care product at a concentration of 1 to 10% by weight.

8. The dental care product according to claim 1, further comprising sodium gluconate.

9. The dental care product according to claim 8, wherein sodium gluconate is present in the dental care product at a concentration of 0.5 to 5% by weight.

10. The dental care product according to claim 1, wherein the dental care product is a dental gel, toothpaste, preventive paste, tooth foam, or dental rinse.

11. a. Sodium tripolyphosphate, b. Sodium gluconate, c. Sorbitol, d. Cellulose gum, e. Xylitol, f. Erythritol, g. Hydrated silica, h. Phosphate, i. Optionally, NaOH, and j. water The dental care product according to claim 1, further comprising:

12. The dental care product according to claim 1, wherein the pH of the dental care product is less than 7.

5.

13. i. 0.1 to 1.0% by weight of tin(II) fluoride; ii. At least 0.01% by weight of a self-assembling peptide consisting of Sequence ID No. 6 (P11-4); iii. 1-10% by weight of sodium tripolyphosphate; and iv. 0.5–5% by weight sodium gluconate A dental care product containing [a specific ingredient], wherein the pH of the dental care product is less than 7.

5.

14. A method for preventing tooth demineralization, comprising applying an effective amount of the dental care product described in claim 1 to a tooth.

15. A method for remineralizing tooth enamel in a person requiring it, comprising applying an effective amount of the dental care product described in claim 1 to a tooth.

16. A method for destroying a biofilm formed on a tooth, comprising applying an effective amount of the dental care product described in claim 1 to the tooth.

17. A method for treating dentin hypersensitivity in a person requiring it, comprising applying an effective amount of the dental care product described in claim 1 to a tooth.

18. A method for stabilizing stannous fluoride in dental care products, i. Tin(II) fluoride, and ii. A self-assembling peptide comprising at least 0.01% by weight of the sequence X1-X2-X1-X2-X1, wherein X1 is independently selected from the group consisting of glutamic acid, aspartic acid, glutamine, and ornithine, and X2 is independently selected from the group consisting of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and glutamine, wherein the self-assembling peptide is present in the dental care product in an essentially aggregated form. A method that includes mixing.

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