Dental hardening calcium phosphate cement

Abstract

To provide a dental curable calcium phosphate cement that excels in sealing dentinal tubules and exhibits superior capability in restoring mineral density even in dentin that has been demineralized and has low mineral density.SOLUTION: A dental curable calcium phosphate cement comprises a first material that is powder, and a second material that is liquid. The first material comprises a calcium phosphate compound (A), a fluoride salt of a divalent or higher cation (B), and a polyvalent organic acid that forms a divalent or higher cation (C). The second material comprises water (D). In the total amount of the fluoride salt (B), the volumetric cumulative particle size distribution indicates that the proportion of particles ranging in size from 0 μm to 3 μm constitutes at least 3% of the total.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a dental hardening calcium phosphate cement. [Background technology]

[0002] The so-called 8020 movement (improving oral hygiene and preserving tooth structure (MI: Minimal Intervention)), which aims to retain 20 or more of one's own teeth even at the age of 80, has led to a dramatic increase in the tooth retention rate among the elderly. However, this has also led to new problems such as dentin exposure due to new dental diseases (tooth wear, alveolar bone loss due to periodontal disease, etc.). Unlike enamel, exposed dentin has a low mineral concentration in the tissues that make up dentin, resulting in poor caries resistance. Furthermore, dentinal tubules, which are approximately 1 μm to 3 μm in diameter, can become perforated by the action of acids in the oral cavity, causing hypersensitivity.

[0003] To improve this, methods such as coating with polymer-based materials or alternately applying two types of materials to precipitate inorganic salts and form a physical barrier to seal the dentinal tubules are known. However, these methods only cover the shallow areas and surfaces near the openings of the dentinal tubules, and the coatings are easily destroyed by abrasion from toothbrushes, etc. Furthermore, even though the materials are highly biocompatible, the application of the materials can cause plaque to adhere, leading to inflammation or root caries.

[0004] On the other hand, calcium phosphate cement, which combines tetracalcium phosphate and anhydrous monohydrogen phosphate, is known as a hardening calcium phosphate composition, and bioabsorbable hydroxyapatite (Ca) is available in the body and oral cavity. 10It is said that it gradually converts to (PO4)6(OH)2) and can integrate with living hard tissue while maintaining its shape. As one example of using such calcium phosphate cement to seal dentinal tubules, Patent Document 1 discloses a dentin remineralizing agent containing a specific amount of alkali metal salt of phosphoric acid relative to tetracalcium phosphate particles, and it is stated that a dense hydroxyapatite layer is formed on the dentin surface, and hydroxyapatite precipitates deep into the dentinal tubules, sealing them.

[0005] Furthermore, Patent Document 1 discloses a calcium phosphate cement containing a fluorine compound, stating that the inclusion of the fluorine compound imparts acid resistance to the tooth structure and also promotes calcification. Specifically, sodium fluoride is used as the fluorine compound, and it is suggested that the formation of fluoroapatite imparts acid resistance to the tooth structure.

[0006] Furthermore, Patent Document 1 specifically describes the effect of improving dentinal tubule sealing even in the deep parts of the dentinal tubules by adding disodium monohydrogen phosphate (Na2HPO4) as an alkali metal salt of phosphoric acid.

[0007] Furthermore, Patent Document 2 also proposes calcium phosphate cement. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2010 / 113800 [Patent Document 2] Japanese Patent Application Publication No. 06-321515 [Overview of the project] [Problems that the invention aims to solve]

[0009] However, as explained below, the inventors found that when conventional calcium phosphate cement is used on demineralized dentin with low mineral density, such as in the early stages of root caries (hereinafter also referred to as "demineralized dentin"), the recovery rate of mineral density is low. Therefore, there is room for improvement in its effectiveness when used as an early-stage root caries inhibitor.

[0010] Due to aging, periodontal disease, and other factors, the gums recede, exposing the tooth roots that were previously covered by the gums. Unlike the crown, which has a thick layer of enamel, the tooth root consists of dentin that is not covered by enamel. Dentin has countless tubular structures and contains a large amount of organic matter, mainly collagen, resulting in a low mineral density of about 50%. Compared to enamel, which has a mineral density of about 97%, dentin is physically and chemically fragile. Therefore, tooth caries is more likely to occur in tooth roots exposed in the oral cavity. Here, "dental caries" refers to the loss of tooth substance caused by demineralization (dissolution of mineral components) of enamel and dentin by acids produced by bacteria in the oral cavity metabolizing carbohydrates. Among the various types of caries, dentin caries that occur in the tooth root are called "root caries."

[0011] In root caries, the dentin exposed by receding gums is demineralized, with a lower mineral density due to the dissolution of minerals by acids produced by microorganisms in the oral cavity. Even with conventional calcium phosphate cement, sufficient mineral density cannot be restored to this demineralized dentin, making it difficult to suppress or treat early-stage root caries.

[0012] As described above, when conventional calcium phosphate cement was applied to areas of early root caries, it was difficult to suppress or treat the early caries due to the nature of the root surface.

[0013] Furthermore, Patent Documents 1 and 2 do not disclose the ability to restore mineral density in demineralized dentin, nor do they disclose any problems that may arise when used on demineralized dentin in root caries.

[0014] The present invention has been made to solve the above problems, and an object of the present invention is to provide a dental curable calcium phosphate cement which is excellent in dentinal tubule sealing property and is also excellent in mineral density recovery ability for demineralized dentin having low mineral density. [Means for Solving the Problems]

[0015] As a result of intensive studies, the present inventors have found that a dental composition having a specific composition can solve the above problems, and have completed the present invention through further studies.

[0016] That is, the present invention includes the following inventions. [1] A dental curable calcium phosphate cement composed of a first material that is a powder and a second material that is a liquid, wherein the first material comprises a calcium phosphate compound (A), a fluoride salt of a divalent or higher valent cation (B), and a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher valent cation, wherein the second material comprises water (D), wherein, in the total amount of the fluoride salt of a divalent or higher valent cation (B), the cumulative frequency of particle diameters of 0 μm or more and 3 μm or less in the volume-based cumulative particle size distribution is 3% or more. [2] The dental curable calcium phosphate cement according to [1], wherein the fluoride salt (B) is zinc fluoride and strontium fluoride. [3] The dental curable calcium phosphate cement according to [1] or [2], wherein the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher valent cation is at least one selected from the group consisting of tannic acid, catechol, tyron monohydrate, protocatechuic acid, protocatechuic acid ester, pyrocatechol, pyrogallol, shikimic acid, gallic acid, gallic acid ester, and catechin. [4] The dental curable calcium phosphate cement according to any one of [1] to [3], wherein the average particle diameter of the fluoride salt of a divalent or higher valent cation (B) is less than 34 μm. [5] The dental curable calcium phosphate cement according to any one of [1] to [4], wherein the calcium phosphate compound (A) comprises at least one selected from the group consisting of tetracalcium phosphate, anhydrous calcium hydrogen phosphate (CaHPO₄), anhydrous calcium dihydrogen phosphate (Ca(H₂PO₄)₂), α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate (Ca₃(PO₄)₂·nH₂O), calcium pyrophosphate (CaH₂P₂O₇), octacalcium phosphate (Ca₈H₂(PO₄)₆·5H₂O), calcium hydrogen phosphate dihydrate (CaHPO₄·2H₂O), and calcium dihydrogen phosphate monohydrate (Ca(H₂PO₄)₂·H₂O). [6] The dental curable calcium phosphate cement according to any one of [1] to [5], wherein the first material or the second material further comprises a pH adjuster. [7] The dental curable calcium phosphate cement according to [6], wherein the pH adjuster is an alkali metal salt of phosphoric acid. [8] The dental curable calcium phosphate cement according to any one of [1] to [7], wherein the first material or the second material further comprises an inorganic filler. [9] The dental curable calcium phosphate cement according to [8], wherein the inorganic filler comprises at least one selected from the group consisting of light anhydrous silicic acid and metal oxides.

[10] The dental curable calcium phosphate cement according to any one of [1] to [9], wherein the second material further comprises an antibacterial agent.

[11] The dental curable calcium phosphate cement according to any one of [1] to

[10] , wherein the calcium phosphate compound (A) is in the form of particles having an average particle diameter of 0.1 to 40 µm.

[12] The dental curable calcium phosphate cement according to any one of [1] to

[11] , wherein the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher valent cation is in the form of particles having an average particle diameter of 5.0 to 100 µm.

[13] A tooth surface treatment material comprising the dental curable calcium phosphate cement according to any one of [1] to

[12] . A dentin desensitizing agent comprising a dental hardening calcium phosphate cement as described in any of

[14] [1] to

[12] . Toothpaste containing dental hardening calcium phosphate cement as described in any of

[15] [1] to

[12] . A root caries treatment material containing dental hardening calcium phosphate cement as described in any of

[16] [1] to

[12] . [Effects of the Invention]

[0017] According to the present invention, it is possible to provide a dental hardening calcium phosphate cement that exhibits excellent sealing properties for dentinal tubules and also has excellent mineral density restoration capabilities even in demineralized dentin with low mineral density. [Modes for carrying out the invention]

[0018] The present invention will now be described in detail. The dental hardening calcium phosphate cement of the present invention is composed of a first material which is a powder and a second material which is a liquid, wherein the first material contains a calcium phosphate compound (A), a fluoride salt of divalent or higher cations (B) (hereinafter also referred to as "fluoride salt (B)"), and a polyvalent organic acid (C) which forms an insoluble salt with divalent or higher cations (hereinafter also referred to as "polyvalent organic acid (C)"), and the second material contains water (D), wherein the cumulative frequency of particles with a diameter of 0 μm or more and 3 μm or less in the volume-based cumulative particle size distribution of the total amount of the fluoride salt of divalent or higher cations (B) is 3% or more.

[0019] By adopting the above configuration, a dental hardening calcium phosphate cement is produced that exhibits excellent sealing properties for dentinal tubules and also has excellent mineral density restoration capabilities even in demineralized dentin with low mineral density.

[0020] In this specification, the upper and lower limits of numerical ranges (content of each component, average particle size, etc.) can be combined as appropriate.

[0021] The present invention is not limited in any way, but the reasons for the excellent effects described above are thought to be as follows. First, by introducing calcium phosphate compounds (A) and fluoride salts of divalent or greater cations (B), with a particle size distribution of approximately 3 μm or less, into the "dentinal tubules" present in the dentin, which have a diameter of approximately 1 to 3 μm, and by introducing polyhydric organic acids (C) as dissolved substances in water, the dentinal tubules are sealed and the recovery of mineral density is promoted. Furthermore, even when polyhydric organic acids (C) are in particulate form, introducing them into the dentinal tubules yields even better results.

[0022] More specifically, by first mixing a first material (hereinafter also referred to as "powder") containing a calcium phosphate compound (A), a fluoride salt (B), and a polyhydric organic acid (C) with a second material (hereinafter also referred to as "liquid") containing water (D), and applying the resulting paste to the affected area (for example, demineralized dentin), the calcium phosphate compound (A) and fluoride salt (B) with a particle size distribution of approximately 3 μm or less penetrate the dentinal tubules in particle form. At the same time, some of the polyhydric organic acid (C) dissolved by mixing with water (D) also penetrates the dentinal tubules. In this case, since the surface portion of the polyhydric organic acid (C) is dissolved in water (D), the polyhydric organic acid (C) in particle form with a smaller particle size may also penetrate the dentinal tubules. In this case, both the dissolved polyhydric organic acid (C) and the polyhydric organic acid (C) in particle form act, resulting in a superior effect.

[0023] From the particles remaining within the dentinal tubules, calcium ions, phosphate ions, fluoride ions, divalent or higher cations (metal ions with a valency of 2 or higher, such as zinc), and polyvalent organic acids (C) (such as tannic acid), which are essential components for restoring mineral density, dissolve into the dentinal tubules and become present within them. As a result, these components work together to restore the mineral density of the dentin surrounding the dentinal tubules (especially dentin softened by demineralization such as early caries). Here, it is considered important that the presence of polyhydric organic acids (C) in particular causes the collagen fibers of the dentin to be recrosslinked, thereby reconstructing a "scaffold" for the precipitation of inorganic salts that make up tooth structure, such as hydroxyapatite.

[0024] • Calcium phosphate compound (A) The dental hardening calcium phosphate cement of the present invention contains a calcium phosphate compound (A) in the first component, which is a powder. The dental hardening calcium phosphate cement of the present invention exhibits excellent dentinal tubule sealing properties by using the calcium phosphate compound (A). Furthermore, by combining the calcium phosphate compound (A) with other components, the dental hardening calcium phosphate cement of the present invention exhibits excellent mineral density restoration ability even in demineralized dentin with low mineral density.

[0025] The calcium phosphate compound (A) used in the present invention is not particularly limited and includes tetracalcium phosphate (Ca4(PO4)2O; TTCP), anhydrous monocalcium phosphate (CaHPO4; DCPA), anhydrous dicalcium phosphate (Ca(H2PO4)2), α-tricalcium phosphate (Ca3(PO4)2; α-TCP), β-tricalcium phosphate (Ca3(PO4)2; β-TCP), amorphous calcium phosphate (Ca3(PO4)2·nH2O, ACP), calcium pyrophosphate (CaH2P2O7), octacalcium phosphate (Ca8H2(PO4)6·5H2O), and the like. The calcium phosphate compound (A) may be used alone or in combination of two or more types. One preferred embodiment is a dental hardening calcium phosphate cement in which the calcium phosphate compound (A) comprises tetracalcium phosphate and at least one selected from the group consisting of anhydrous monohydrogen phosphate (DCPA), anhydrous dihydrogen phosphate (Ca(H2PO4)2), α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate (ACP), calcium pyrophosphate (CaH2P2O7), and octacalcium phosphate (Ca8H2(PO4)6·5H2O).

[0026] The calcium phosphate compound (A) is preferably in the form of particles. The average particle size of calcium phosphate compound (A) is not particularly limited, but when the average particle size is 0.1 μm or more, agglomeration of calcium phosphate does not occur rapidly, thus preventing agglomeration during manufacturing and facilitating composition adjustment. Therefore, the average particle size of calcium phosphate compound (A) is preferably 0.1 μm or more, more preferably 0.5 μm or more, and even more preferably 1 μm or more. On the other hand, when the average particle size of calcium phosphate compound (A) is 40 μm or less, the paste obtained by mixing with the second material, which is a liquid, as described later, exhibits sufficient viscosity, resulting in desirable paste properties. Furthermore, the grittiness during paste mixing is reduced, allowing for good handling. Therefore, the average particle size of calcium phosphate compound (A) is preferably 40 μm or less, more preferably 20 μm or less, and even more preferably 10 μm or less.

[0027] Here, the average particle size of each component used in the present invention, such as the calcium phosphate compound (A), the fluoride salt of a divalent or higher cation (B), and the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation, was measured and calculated using a laser diffraction particle size distribution analyzer (SALD-2300 model, manufactured by Shimadzu Corporation). For example, it can be calculated by the method described in the examples below.

[0028] The method for producing the calcium phosphate compound (A) used in the present invention is not particularly limited. Commercially available products may be used as is, or they may be appropriately pulverized to adjust the particle size before use. When pulverizing commercially available products, pulverizing equipment such as ball mills, pulverizers, and jet mills can be used. Alternatively, the raw material powder for calcium phosphate compound (A) can be pulverized together with a liquid medium such as alcohol using a pulverizer, ball mill, etc. to prepare a slurry, and the resulting slurry can be dried to obtain calcium phosphate compound (A). In this case, a ball mill is preferably used as the pulverizing equipment, and alumina, zirconia, etc., are preferably used as the material for the pot and balls.

[0029] The content of calcium phosphate compound (A) in the dental hardening calcium phosphate cement of the present invention is not particularly limited, but is preferably 40 to 95 parts by mass, more preferably 45 to 90 parts by mass, and even more preferably 50 to 85 parts by mass, per 100 parts by mass of the total amount of the first material of the dental hardening calcium phosphate cement. When the content of calcium phosphate compound (A) is 40 parts by mass or more, the dentinal tubule sealing ability of the dental hardening calcium phosphate cement is improved. On the other hand, when the content of calcium phosphate compound (A) is 80 parts by mass or less, the viscosity of the dental hardening calcium phosphate cement is within an appropriate range, and a paste with good workability can be obtained.

[0030] • Fluoride salts of cations with a valence of 2 or more (B) The dental hardening calcium phosphate cement of the present invention contains a fluoride salt (B) with divalent or higher cations in the first component, which is a powder. Because the cations constituting the fluoride salt (B) are divalent or higher, when the cations dissolve into the dentinal tubules, they react with a polyvalent organic acid (C) that forms an insoluble salt with the divalent or higher cations inside the dentinal tubules, thereby forming an insoluble salt. By existing as an insoluble salt inside the dentinal tubules, the dentinal tubule sealing ability is improved. Furthermore, the dental hardening calcium phosphate cement of the present invention contains a fluoride salt (B) with divalent or higher cations. By using it in a predetermined particle size distribution described later, the fluoride salt (B) penetrates into the dentinal tubules in particle form. From the particles remaining in the dentinal tubules, fluoride ions and divalent metal ions, which are essential components for restoring mineral density, dissolve into the dentinal tubules while remaining sufficiently present. This results in excellent mineral density restoration even in demineralized dentin with low mineral density.

[0031] The fluoride salt (B) of a divalent or higher cation is not particularly limited and includes zinc fluoride, strontium fluoride, magnesium fluoride, titanium(IV) fluoride, etc. The fluoride salt (B) of a divalent or higher cation may be used alone or in combination of two or more. In particular, from the viewpoint of further improving the mineral density recovery ability, it is preferable to include zinc fluoride and / or strontium fluoride, and more preferably to include zinc fluoride and strontium fluoride. The cation constituting the fluoride salt (B) may be divalent or trivalent or higher.

[0032] The fluoride salt (B) of a cation with a valence of 2 or higher is preferably in the form of particles. In order to further enhance the ability to restore mineral density even in demineralized dentin, the cumulative frequency (ratio of cumulative particle diameter volume) of particles with a diameter of 0 μm or more and 3 μm or less in the volume-based cumulative particle diameter distribution of the total amount of divalent or higher cation fluoride salt (B) used in the present invention is 3% or more. If the cumulative frequency of particles with a diameter of 0 μm to 3 μm relative to the total particle diameter volume of fluoride salt (B) is less than 3%, then the fluoride salt (B) with divalent or higher cations cannot sufficiently remain in the dentinal tubules, and the mineral density recovery ability is insufficient. The cumulative frequency of particles with a diameter of 0 μm to 3 μm relative to the total particle diameter of fluoride salt (B) with divalent or higher cations is 3% or more, and from the viewpoint of having a superior mineral density recovery ability for demineralized dentin, 5% or more is preferable, 7% or more is more preferable, 10% or more is even preferable, 20% or more is particularly preferable, and 30% or more is most preferable.

[0033] When a fluoride salt (B) of a divalent or greater cation is present in a given form, each of the divalent or greater cation fluoride salts (B) is (B) (1)、 (B) (2) ...(B) (i) With this in mind, the cumulative particle size distribution based on volume was calculated as follows: The cumulative frequency (%) of fluoride salt (B) with particle sizes between 0 μm and 3 μm relative to the total particle size volume was determined.

[0034]

number

[0035] For example, if the fluoride salt (B) of a cation with two or more valents is zinc fluoride and strontium fluoride, the density of zinc fluoride (anhydrous) used in the above formula is 4.95 g / cm³. 3 The density of strontium fluoride used in the above formula is 4.24 g / cm³. 3 That is the case. Furthermore, the density of magnesium fluoride (MgF2) used in the above formula is 3.15 g / cm³. 3 The density of titanium(IV) fluoride used in the above formula is 2.8 g / cm³. 3 Therefore, the true density of the compound (B) of a fluoride salt with a cation of 2 or more valents can be used in the above formula.

[0036] The average particle size of the fluoride salt (B) containing divalent or higher cations is not particularly limited, but when the average particle size is 0.1 μm or more, aggregation of the fluoride salt (B) containing divalent or higher cations does not occur rapidly, thus preventing aggregation during manufacturing and facilitating composition adjustment. Therefore, the average particle size of the fluoride salt (B) containing divalent or higher cations is preferably 0.1 μm or more, more preferably 0.5 μm or more, and even more preferably 1 μm or more. On the other hand, when the average particle size of the fluoride salt (B) containing divalent or higher cations is less than 34 μm, the paste obtained by mixing with the second liquid material exhibits sufficient viscosity, resulting in desirable paste properties. Furthermore, the grittiness during paste mixing is reduced, allowing for good handling. Therefore, the average particle size of the fluoride salt (B) of divalent or greater cations is preferably less than 34 μm, more preferably 20 μm or less, and even more preferably 10 μm or less, as this makes it easier to adjust the cumulative frequency of particles with a particle size of 0 μm or more and 3 μm or less.

[0037] The method for producing the fluoride salt (B) of a divalent or higher cation is not particularly limited. Commercially available products may be used as is, or they may be appropriately pulverized to adjust the particle size before use. When pulverizing a commercially available product, the same pulverization method as in the production method of the calcium phosphate compound (A) can be used.

[0038] The content of divalent or higher cation fluoride salt (B) in the dental hardening calcium phosphate cement of the present invention is preferably 0.6 to 40 parts by mass per 100 parts by mass of the total amount of the first material. When the content of divalent cation fluoride salt (B) is 0.6 parts by mass or more, sufficient organic strengthening occurs, the ability to restore mineral density to demineralized dentin is obtained, and minerals are deposited in the demineralized dentin. The content of the fluoride salt (B) of divalent or higher cations is preferably 0.6 parts by mass or more, more preferably 1.0 part by mass or more, and even more preferably 2.0 parts by mass or more, per 100 parts by mass of the total amount of the first material. On the other hand, when the content of the fluoride salt (B) of divalent or higher cations is 40 parts by mass or less, good dentinal tubule sealing properties can be obtained. The content of the fluoride salt (B) of divalent cations is preferably 40 parts by mass or less, more preferably 25 parts by mass or less, and even more preferably 20 parts by mass or less, per 100 parts by mass of the total amount of the first material.

[0039] In the dental hardening calcium phosphate cement of the present invention, when the first material and the second material are mixed in a mass ratio of 1.6:1.0, the content of divalent or higher cation fluoride salt (B) in the paste (powder-liquid mixture) after mixing is preferably 20% by mass or less, more preferably 15% by mass or less, even more preferably 10% by mass or less, and particularly preferably 5% by mass or less, in order to easily obtain the ability to restore mineral density when the paste is applied to the affected area (for example, demineralized dentin). Furthermore, the content of divalent or higher cation fluoride salts (B) in the paste after kneading is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, even more preferably 0.5% by mass or more, and particularly preferably 1.0% by mass or more.

[0040] • Polyhydric organic acids (C) that form insoluble salts with cations of two or more valencies. The dental hardening calcium phosphate cement of the present invention contains a polyvalent organic acid (C) in the first component that forms an insoluble salt with divalent or higher cations. By including the polyvalent organic acid (C), the collagen fibers of dentin are recrosslinked, which can further enhance the effect of inhibiting collagen degradation, and when combined with other components, it can improve the ability to restore mineral density even in demineralized dentin.

[0041] Examples of polyhydric organic acids (C) used in the present invention include polyphenol compounds. Polyhydric organic acids (C) may be used alone or in combination of two or more. Examples of polyphenol compounds include tannic acid, catechol, tyron monohydrate, protocatechuic acid, protocatechuic acid esters (methyl protocatechuic acid, ethyl protocatechuic acid), pyrocatechol, pyrogallol, shikimic acid, gallic acid, gallic acid esters (methyl gallic acid, ethyl gallic acid, propyl gallic acid), epigallocatechin gallate (EGCG), catechin, and other polyphenol compounds containing aromatic rings having two or more hydroxyl groups. It is preferable that the substance is at least one selected from the group consisting of tannic acid, catechol, tyron monohydrate, protocatechuic acid, protocatechuic acid esters (methyl protocatechuic acid, ethyl protocatechuic acid), pyrocatechol, pyrogallol, shikimic acid, gallic acid, gallic acid esters (methyl gallic acid, ethyl gallic acid, propyl gallic acid), and catechin, with tannic acid being particularly preferred due to its superior ability to restore mineral density to demineralized dentin.

[0042] The polyhydric organic acid (C) is preferably in the form of particles. The average particle size of the polyhydric organic acid (C) is not particularly limited, but when the average particle size is 5.0 μm or more, it exhibits superior mineral density restoration ability for demineralized dentin. Therefore, the average particle size of the polyhydric organic acid (C) is preferably 5.0 μm or more, more preferably 7.5 μm or more, and even more preferably 10 μm or more. On the other hand, when the average particle size of the polyhydric organic acid (C) is 100 μm or less, the roughness of the paste obtained by mixing with the second liquid material is reduced, and good handling properties can be maintained. Therefore, the average particle size of the polyhydric organic acid (C) is preferably 100 μm or less, more preferably 75 μm or less, and even more preferably 40 μm or less, from the viewpoint of superior mineral density restoration ability for demineralized dentin. The polyvalent organic acid (C) may be water-soluble, and after dissolving it in water during paste preparation, an insoluble salt may be formed with a fluoride salt (B) of a divalent or higher cation. Furthermore, since polyhydric organic acids (C) dissolve to a degree that they can enter dentinal tubules, the effects of the present invention can be achieved even with particles that have an average particle size large relative to the size of the dentinal tubules.

[0043] The method for producing the polyhydric organic acid (C) is not particularly limited. Commercially available products may be used as is, or they may be appropriately pulverized to adjust the particle size before use. When pulverizing a commercially available product, the same pulverization method as in the production method of calcium phosphate compound (A) can be used.

[0044] The polyhydric organic acid (C) content is preferably 0.1 to 25 parts by mass per 100 parts by mass of the total amount of the first material. When the polyhydric organic acid (C) content is 0.1 parts by mass or more, sufficient organic strengthening occurs, the ability to restore mineral density to demineralized dentin is obtained, and minerals are deposited in the demineralized dentin. The polyhydric organic acid (C) content is preferably 0.1 parts by mass or more, more preferably 0.2 parts by mass or more, and even more preferably 0.5 parts by mass or more, per 100 parts by mass of the total amount of the first material. On the other hand, when the polyhydric organic acid (C) content is 40 parts by mass or less, good dentinal tubule sealing properties can be obtained. The polyhydric organic acid (C) content is preferably 25 parts by mass, more preferably 20 parts by mass or less, and even more preferably 15 parts by mass or less, per 100 parts by mass of the total amount of the first material.

[0045] ·Water (D) The dental hardening calcium phosphate cement of the present invention has a second material which is a liquid containing water (D). In one embodiment, the second material is a liquid mainly composed of water (D). The main component is the component that is present in the largest quantity. The water (D) content in the second material may be, for example, 50% by mass or more, 60% by mass or more, 70% by mass or more, or 100% by mass. The liquid mainly composed of water (D) may be a liquid mainly composed of water (D) and containing other solvents. Other solvents are not particularly limited and include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, and diglycerin; sugar alcohols such as xylitol, sorbitol, and erythritol; and polyethers such as polyethylene glycol and polypropylene glycol. The other solvents may be used alone or in combination of two or more.

[0046] ·pH adjustment material The dental hardening calcium phosphate cement of the present invention may contain a pH adjusting agent in at least one of the first or second material. The pH adjusting agent is not particularly limited and includes alkali metal salts of phosphoric acid such as disodium monohydrogen phosphate (Na2HPO4), dipotassium monohydrogen phosphate (K2HPO4), monolithium dihydrogen phosphate (LiH2PO4), monosodium dihydrogen phosphate (NaH2PO4; MSP), monopotassium dihydrogen phosphate (KH2PO4; KDP), trisodium phosphate (Na3PO4; TSP), and tripotassium phosphate (K3PO4); hydroxides such as calcium hydroxide and sodium hydroxide. Alkali metal salts of phosphoric acid are preferred, sodium salts of phosphoric acid are more preferred, and disodium monohydrogen phosphate is even more preferred.

[0047] The pH of the paste 30 seconds after mixing the first or second material is preferably 5.5 or higher, more preferably 6.0 or higher, and even more preferably 6.5 or higher, in order to prevent tooth dissolution. Furthermore, the pH of the paste is preferably 14 or lower, more preferably 12 or lower, and even more preferably 10 or lower. pH adjusters can be used to speed up the curing time and make the solution suitable for use in the oral cavity by adjusting the pH to the range of 6.5 to 10, where the solubility of hydroxyapatite (HAp) is lowest. Surprisingly, in systems containing polyvalent organic acids (C) that form insoluble salts with divalent or greater cations, adjusting the amount of pH adjuster added within a range that does not change the pH alters the rate of HAp formation.

[0048] The pH adjusting agent is preferably in the form of particles. While the average particle size of the pH adjusting agent is not particularly limited, when the average particle size of the pH adjusting agent is 0.5 μm or more, significant aggregation does not occur, and it can be uniformly dispersed in the paste or powder. When the dental hardening calcium phosphate cement of the present invention is converted to hydroxyapatite, it does not create pores in the hydroxyapatite, and a high dentinal tubule sealing rate can be maintained. Therefore, the average particle size of the pH adjusting agent in particle form is preferably 0.5 μm or more, more preferably 4 μm or more, and even more preferably 8 μm or more. On the other hand, when the average particle size of the pH adjusting agent in particle form is 20 μm or less, when the dental hardening calcium phosphate cement of the present invention is converted to hydroxyapatite, it does not create pores in the hydroxyapatite, a high dentinal tubule sealing rate can be maintained, and dentin hypersensitivity can be suppressed. Furthermore, when rubbing it onto the dentin surface to suppress dentin hypersensitivity, it is possible to prevent increased grittiness and decreased workability due to undissolved pH adjusting agent remaining in the paste. Therefore, the average particle size of the pH adjusting agent is preferably 20 μm or less, more preferably 16 μm or less, and even more preferably 12 μm or less. The average particle size of the pH adjusting agent can be calculated by the same method as described for measuring the average particle size of the calcium phosphate compound (A).

[0049] The method for producing the pH adjusting agent used in the present invention is not particularly limited. Commercially available products may be used as is, or they may be appropriately pulverized to adjust the particle size before use. As for the pulverization method, the same method as the pulverization method for calcium phosphate compound (A) can be employed.

[0050] • Antibacterial agents The dental hardening calcium phosphate cement of the present invention may contain an antibacterial agent in at least one of the first or second material to kill caries-causing bacteria that infect the inside of the tooth structure. When the dental hardening calcium phosphate cement of the present invention contains an antibacterial agent in its paste, and the antibacterial agent is a highly water-soluble antibacterial agent such as a cationic antibacterial agent or an anionic antibacterial agent, the antibacterial agent is more easily dissolved from the paste and exerts its antibacterial properties, thereby enabling the killing of caries-causing bacteria inside the tooth structure. One preferred embodiment is a dental hardening calcium phosphate cement in which the second material contains an antibacterial agent.

[0051] Various anionic, nonionic, cationic, and amphoteric antibacterial agents can be used as antibacterial agents. Anionic, nonionic, and cationic antibacterial agents are preferred because they have an inhibitory effect on collagen degradation. Furthermore, anionic and cationic antibacterial agents are preferred because they have high water solubility and allow for easy control of their sustained release. As antibacterial agents, cationic antibacterial agents containing quaternary ammonium salt compounds are more preferred, and quaternary ammonium salt compounds are even more preferred. Examples of quaternary ammonium salt compounds include benzalkonium chloride, cetylpyridinium chloride, and benzethonium chloride. The antibacterial agent may be used alone or in combination of two or more types.

[0052] When an antibacterial agent is incorporated into the second material, the amount of the antibacterial agent is preferably 0.0005 parts by mass or more, more preferably 0.005 parts by mass or more, even more preferably 0.05 parts by mass or more, and particularly preferably 0.1 parts by mass, per 100 parts by mass of the total amount of the second material. Sufficient antibacterial properties can be obtained when the antibacterial agent content is 0.0005 parts by mass or more. The antibacterial agent content in the second material is preferably 10 parts by mass or less, more preferably 5 parts by mass, and even more preferably 2.5 parts by mass. When the antibacterial agent content is 10 parts by mass or less, problems such as cytotoxicity and genotoxicity do not occur, and safety is excellent.

[0053] The dental hardening calcium phosphate cement of the present invention is not particularly limited, but it is preferable to pre-mix a powder containing a calcium phosphate compound (A), a fluoride salt of a divalent or higher cation (B), and a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation. This has the advantage of improving convenience by eliminating the need to weigh each powder during clinical use. For the mixing process, it is preferable to use a high-speed mixer, V-type mixer, lab mill, touch mixer, Wonder Crusher, jet mill, Raikai machine, ball mill, high-speed rotary mill, planetary mill, hybridizer, mechanofusion, or mixing extruder. To avoid excessive grinding during mixing, it is preferable to use a high-speed mixer, V-type mixer, lab mill, touch mixer, or Wonder Crusher, with high-speed mixers and V-type mixers being more preferable.

[0054] In the present invention, the dental hardening calcium phosphate cement undergoes a reaction in which the calcium phosphate compound (A) dissolves and gradually converts to hydroxyapatite in the presence of water; therefore, the first and second materials are mixed immediately before use. Furthermore, the dental hardening calcium phosphate cement of the present invention allows hydroxyapatite to precipitate deep into the dentinal tubules, thereby sealing them.

[0055] The dental hardening calcium phosphate cement of the present invention is used in paste form. The dental hardening calcium phosphate cement of the present invention may be available in packaged form. For example, the dental hardening calcium phosphate cement of the present invention may be available in the form of a kit packaged as a combination of a first material and a second material.

[0056] The method for producing the dental hardening calcium phosphate cement of the present invention is not particularly limited, and the components constituting the first material, which is in powder form (calcium phosphate compound (A), fluoride salt of a divalent or higher cation (B), polyhydric organic acid (C) that forms an insoluble salt with a divalent or higher cation, and optionally a pH adjuster, an antibacterial agent, etc.) can be mixed and packaged. Furthermore, the components that make up the liquid second material (water (D), and other solvents, pH adjusters, antibacterial agents, etc., as needed) can be mixed and packaged. The method of mixing the first and second materials is not particularly limited, and known methods and apparatus can be used depending on the form of the powder and liquid.

[0057] The dental hardening calcium phosphate cement of the present invention can be used as a filling and restorative material, lining material, luting material, temporary filling material, root canal filling material, temporary bonding material, coating material, sealant material, tooth surface treatment material, tooth polishing material, root caries treatment material, dentin hypersensitivity suppressing material, etc., and is particularly suitable as a tooth polishing material, tooth surface treatment material, root caries treatment material, and dentin hypersensitivity suppressing material.

[0058] In the present invention, the mixing ratio of the first material (powder) and the second material (liquid) directly affects the operability during mixing, and can therefore be set based on the ratio of the first material to the second material. The mixing ratio of the first material and the second material is not particularly limited, but a mass ratio of 1.1 or higher for the first material / second material is preferable because the consistency of the paste after mixing does not become too loose, more preferably 1.2 or higher, and even more preferably 1.3 or higher. On the other hand, a mass ratio of 2.1 or lower for the first material / second material is preferable because the consistency of the paste after mixing does not become too hard, more preferably 2.0 or lower, and even more preferably 1.9 or lower.

[0059] The dental hardening calcium phosphate cement of the present invention may contain other components besides calcium phosphate compounds (A), fluoride salts of divalent or higher cations (B), polyhydric organic acids (C) that form insoluble salts with divalent or higher cations, and water (D), pH adjusters, and antibacterial agents, as long as they do not impair the effects of the present invention. Examples of the other components include various additives such as thickeners, sweeteners (artificial sweeteners, etc.), preservatives, foaming agents, humectants, and fragrances; lactam compounds having a lactam skeleton of any of γ-lactam, δ-lactam, or ε-lactam skeletons and having an acidic group; carbodiimide compounds; and fluorine compounds other than fluoride salts of divalent or higher cations (B).

[0060] Specific examples of thickeners include polysaccharides such as carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, poly-L-lysine, poly-L-lysine salts, starches other than cellulose, carrageenan, guar gum, xanthan gum, cellulose gum, pectin, pectin salts, chitin, and chitosan; polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, and diglycerin; sugar alcohols such as xylitol, sorbitol, and erythritol; polyethers such as polyethylene glycol and polypropylene glycol; acidic polysaccharide esters such as propylene glycol alginate; proteins such as hyaluronic acid and its salts, collagen, gelatin, and their derivatives; polymers of polyglutamic acid and its salts, polyaspartic acid and its salts, polystyrene sulfonic acid and its salts, polyacrylic acid, or inorganic fillers such as light anhydrous silicic acid and metal oxides. A single thickener may be used alone, or two or more may be used in combination. When a thickening agent is incorporated into a paste, at least one selected from carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, and chitosan is preferred in terms of solubility in water and viscosity. The thickening agent may be incorporated into the first material or the second material. When a thickening agent is incorporated into a powder, it is preferable to include an inorganic filler, more preferably at least one particle selected from the group consisting of light anhydrous silicic acid and metal oxides with an average particle size of 0.002 to 20 μm, and even more preferably light anhydrous silicic acid particles with an average particle size of 0.002 to 20 μm.

[0061] Examples of sweeteners include artificial sweeteners such as aspartame, acesulfame potassium, licorice extract, saccharin, and sodium saccharin.

[0062] Preservatives, foaming agents, humectants, fragrances, etc., can be used from known materials without any particular limitations.

[0063] Examples of lactam compounds having a lactam skeleton of any of the following forms: γ-lactam, δ-lactam, or ε-lactam, and having an acidic group, include those described in International Publication No. 2013 / 047826. Examples of the aforementioned lactam compounds include pyrrolidone carboxylic acid (γ-lactam compound), 6-oxo-2-piperidine carboxylic acid (δ-lactam compound), and 3-(2-oxo-1-azepanyl)propanoic acid (ε-lactam compound), from the standpoint of inhibiting collagen degradation.

[0064] Examples of carbodiimide compounds include carbodiimide compounds having a cyclic structure and carbodiimide compounds without a cyclic structure. Carbodiimide compounds with 5 to 30 carbon atoms are preferred, carbodiimide compounds with 6 to 28 carbon atoms are more preferred, and carbodiimide compounds with 7 to 25 carbon atoms are even more preferred. Using the aforementioned carbodiimide compounds provides superior inhibition of collagen degradation in dentin and promotion of remineralization of demineralized dentin. Examples of carbodiimide compounds include 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-ethyl-3-tert-butylcarbodiimide, and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate.

[0065] Other fluorine compounds besides fluoride salts (B) with divalent or greater cations include alkali metal fluorides such as sodium fluoride, potassium fluoride, ammonium fluoride, and lithium fluoride; and monofluorophosphates such as sodium monofluorophosphate (Na2FPO3), sodium monofluorophosphate, and potassium monofluorophosphate, as these can promote the remineralization of dentin demineralized by the aforementioned components.

[0066] Furthermore, the dental hardening calcium phosphate cement of the present invention can be formulated with any pharmacologically acceptable drugs. In addition to the antibacterial agents mentioned above, other drugs that can be formulated include, for example, disinfectants, anticancer agents, antibiotics, blood circulation improving agents such as Actosin and PEG1, growth factors such as bFGF, PDGF, and BMP, osteoblasts, odontoblasts, and induced pluripotent stem (iPS) cells produced by dedifferentiating differentiated cells such as undifferentiated bone marrow-derived stem cells, embryonic stem (ES) cells, and fibroblasts through gene transfer, as well as cells differentiated from these, which promote hard tissue formation.

[0067] In this invention, a paste-like hardening dental calcium phosphate cement can be obtained by mixing a powder containing a calcium phosphate compound (A), a fluoride salt of a divalent or higher cation (B), and a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation, with a liquid containing water (D). This paste-like dental calcium phosphate cement containing water is preferably prepared by mixing immediately before use in a medical setting. The mixing operation is not particularly limited, and mixing by hand or using a static mixer is preferably employed. Furthermore, the solvent other than water used in the second material is not particularly limited, and examples include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, and diglycerin; and polyethers such as polyethylene glycol and polypropylene glycol.

[0068] Furthermore, the dental hardening calcium phosphate cement of the present invention allows hydroxyapatite to precipitate deep into the dentinal tubules, thereby sealing them. Therefore, the dentin hypersensitivity inhibitor containing the dental hardening calcium phosphate cement of the present invention self-hardens after a predetermined time, sealing the dentinal tubules. The dentin hypersensitivity inhibitor containing the dental hardening calcium phosphate cement of the present invention has excellent biocompatibility, low skin irritation, and superior safety. Moreover, it is easy to use because, after rubbing the dentin hypersensitivity inhibitor into the dentinal tubules, excess paste can be easily removed by rinsing with water, and no special application method is required. The dentin hypersensitivity inhibitor of the present invention is not particularly limited and may contain known additives. Examples of known additives include those similar to those exemplified in toothpaste.

[0069] The dental hardening calcium phosphate cement of the present invention preferably has a dentinal tubule sealing rate (%) of 70% or more, more preferably 75% or more, even more preferably 80% or more, particularly preferably 85% or more, and most preferably 90% or more. The method for measuring the dentinal tubule sealing rate (%) is as described in the examples below.

[0070] Furthermore, the dental hardening calcium phosphate cement of the present invention preferably has a mineral density restoration ability (%) of 22% or more for demineralized dentin, more preferably 23% or more, even more preferably 24% or more, particularly preferably 26% or more, and most preferably 27% or more. The method for measuring the mineral density recovery ability (%) is as described in the examples below.

[0071] Furthermore, in another embodiment, the material is composed of a first material which is a powder and a second material which is a liquid, wherein the first material contains a calcium phosphate compound (A) and a fluoride salt of a divalent or higher cation (B). The second material comprises a polyvalent organic acid (C) that forms an insoluble salt with divalent or greater cations, and water (D). In the total amount of the fluoride salt (B) of a divalent or higher cation, the integrated frequency of particle diameters of 0 μm or more and 3 μm or less in the volume-based cumulative particle size distribution is 3% or more. Examples include the dental curable calcium phosphate cement. As described above, in a preferred embodiment of the present invention, the first material contains a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation. On the other hand, if the product quality can be maintained, for example, without causing coloration of the second material, in addition to blending the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation into the first material, or instead of blending it into the first material, the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation can also be blended into the second material.

[0072] In another embodiment, the dental curable calcium phosphate cement is composed of a first material that is a powder and a second material that is a liquid, wherein the dentinal tubule occlusion rate (%) is 70% or more, and the mineral density recovery ability (%) for demineralized dentin is 22% or more. In the above embodiment, the first material contains a calcium phosphate compound (A), and the second material contains water (D). In the embodiment, the first material and / or the second material contains a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation. In the embodiment, the first material contains a fluoride salt (B) of a divalent or higher cation.

Examples

[0073] Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The average particle diameter of each particle of the calcium phosphate compound (A), the fluoride salt (B) of a divalent or higher cation, the polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation, and the pH adjuster was measured on a volume basis using a laser diffraction particle size distribution analyzer ("SALD-2300" manufactured by Shimadzu Corporation), and the median diameter calculated from the measurement results (d 50 ) was taken as the average particle diameter.

[0074] [Preparation of Calcium Phosphate Compound (A)] Preparation of tetracalcium phosphate The tetracalcium phosphate particles used in this example (average particle size d 50 Tetracalcium phosphate lumps were obtained by grinding crude tetracalcium phosphate (1.5 μm) prepared as follows: Commercially available anhydrous monohydrogen phosphate particles (Product No. 1430, JTBaker Chemical Co., NJ) and calcium carbonate (Product No. 1288, JTBaker Chemical Co., NJ) were added to water in equimolar amounts, stirred for 1 hour, filtered, and dried to obtain a cake-like equimolar mixture. This mixture was heated in an electric furnace (FUS732PB, manufactured by Advantec Toyo Co., Ltd.) at 1500°C for 24 hours, and then cooled to room temperature in a desiccator to prepare tetracalcium phosphate lumps. Furthermore, the mixture was roughly crushed in a mortar and then sieved to remove fine powder and tetracalcium phosphate lumps, and the particle size was adjusted to a range of 0.5 to 1.0 mm to obtain crude tetracalcium phosphate. 50g of crude tetracalcium phosphate, 200g of zirconia balls with a diameter of 10mm, and 100g of 99.5% dehydrated ethanol (Ethanol, Dehydrated (99.5) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a 1000ml alumina grinding pot (HD-B-104 pot mill manufactured by Nikkatoh Co., Ltd.), and wet vibratory grinding was performed at a rotation speed of 1500rpm for 20 hours to obtain a slurry. After removing the ethanol using a rotary evaporator, the slurry was vacuum dried at 60°C for 6 hours to obtain tetracalcium phosphate particles (average particle size d 50 A particle size of 1.5 μm was obtained.

[0075] Preparation of anhydrous calcium monohydrogen phosphate Particles of anhydrous calcium monohydrogen phosphate used in this example (average particle size d 50To obtain the slurry (average particle size d 4.4μm), 50g of commercially available anhydrous calcium monohydrogen phosphate particles (Product No. 1430, JTBaker Chemical Co., NJ, average particle size 10.2μm), 240g of 95% ethanol (Ethanol(95) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and 480g of zirconia balls with a diameter of 10mm were added to a 1000ml alumina grinding pot (HD-B-104 pot mill manufactured by Nikkatoh Co., Ltd.), and wet vibratory grinding was performed at a rotation speed of 1500rpm for 15 hours. After removing the ethanol using a rotary evaporator, the slurry was vacuum dried at 60°C for 6 hours to obtain anhydrous calcium monohydrogen phosphate particles (average particle size d 4.4μm). 50 A particle size of 4.4 μm was obtained.

[0076] Preparation of α-tricalcium phosphate The α-tricalcium phosphate particles used in this embodiment (average particle size d 50 The slurry (average particle size d) is obtained by adding 50g of commercially available α-tricalcium phosphate particles (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), 240g of 95% ethanol ("Ethanol (95)" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and 480g of zirconia balls with a diameter of 10mm to a 1000ml alumina grinding pot ("HD-B-104 Pot Mill" manufactured by Nikkatoh Co., Ltd.), and performing wet vibratory grinding at a rotation speed of 1500rpm for 1 hour. After removing the ethanol using a rotary evaporator, the slurry is vacuum dried at 60°C for 6 hours to obtain α-tricalcium phosphate particles (average particle size d 50 A particle size of 3.2 μm was obtained.

[0077] [Preparation of fluoride salts (B) of divalent or greater cations] • Zinc fluoride Either zinc fluoride (manufactured by Fluorochem, average particle size: 34 μm) was used as is, or zinc fluoride (manufactured by Hakushin Chemical Research Institute Co., Ltd., average particle size: 24 μm) was used as is. Zinc fluoride (manufactured by Hakushin Chemical Research Institute Co., Ltd., average particle size: 24 μm) was ground in a Lab Mill (manufactured by Osaka Chemical Co., Ltd.) for 1 minute x 9 times to obtain zinc fluoride with an average particle size of 3 μm.

[0078] Strontium fluoride Strontium fluoride (manufactured by Hakushin Chemical Research Institute Co., Ltd., average particle size: 20 μm) was used as is. Strontium fluoride (manufactured by Hakushin Chemical Research Institute Co., Ltd., average particle size: 20 μm) was ground in a Lab Mill (manufactured by Osaka Chemical Co., Ltd.) for 1 minute x 9 times to obtain zinc fluoride with an average particle size of 3 μm.

[0079] [Evaluation of the cumulative frequency (%) of particle sizes between 0 μm and 3 μm in the volume-based cumulative particle size distribution of the total amount of fluoride salt (B) containing divalent or greater cations] When the fluoride salts (B) of divalent or greater cations used in the examples and comparative examples contain i types (where i is a positive integer of 1 or more), each of the divalent or greater cation fluoride salts (B) is (B) (1)、 (B) (2) ...(B) (i) With this in mind, in the volume-based cumulative particle size distribution, the ratio of the cumulative particle size volume of particles with a diameter of 0 μm or more and 3 μm or less to the total particle size of (B) was determined as follows: i=2 in Examples 1-10 and 13 and Comparative Example 2, and i=1 in Examples 11-12 and Comparative Examples 1 and 4. The particle size distribution measurement conditions are shown below. Refractive index: Zinc fluoride 1.70-0.20i, Strontium fluoride 1.70-0.20i Cell type: batch cell Dispersion medium: Ethanol Pre-treatment: Touch mixer for 10 seconds, ultrasound for 5 minutes.

[0080]

number

[0081] [Preparation of polyhydric organic acids (C) that form insoluble salts with divalent or greater cations] Commercially available tannic acid (manufactured by Fuji Chemical Industry Co., Ltd., average particle size: 40 μm) was used as is. Commercially available tannic acid (manufactured by Fuji Chemical Industry Co., Ltd., average particle size: 40 μm) was ground for 15 seconds using a Lab Mill (manufactured by Osaka Chemical Co., Ltd.) to obtain tannic acid with an average particle size of 40 μm. Tannic acid with an average particle size of 5 μm was obtained by grinding it for 1 minute x 9 times using a Lab Mill (manufactured by Osaka Chemical Co., Ltd.).

[0082] [pH adjustment material] Commercially available disodium monohydrogen phosphate (manufactured by Taihei Chemical Industry Co., Ltd., average particle size: 1.5 μm) was used as is.

[0083] [Inorganic filler] Commercially available light anhydrous silicic acid (manufactured by Nippon Aerosil Co., Ltd., Aerosil® 130, average particle size: 16 μm) was used as is.

[0084] [Water(D)] Purified water was used as is.

[0085] [Antibacterial agent] Cetylpyridinium chloride anhydrous (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as is.

[0086] [Preparation of dental hardening calcium phosphate cement] <Examples 1-13, Comparative Examples 1-4> (1) Preparation of the first material (powder) The first material, a powder, was obtained by weighing the components shown in Tables 1 and 2, including a calcium phosphate compound (A), a fluoride salt of a divalent or greater cation (B), and a polyvalent organic acid (C) that forms an insoluble salt with a divalent or greater cation (C), and mixing them at 3500 rpm for 10 minutes using a Wonder Crusher (manufactured by Osaka Chemical Co., Ltd.).

[0087] (2) Preparation of the second material (liquid) The antibacterial agent, weighed according to the compositions shown in Tables 1 and 2, was added to water (D) and stirred until dissolved to obtain the liquid, which was the second material.

[0088] (3) Preparation of dental hardening calcium phosphate cement paste Dental hardening calcium phosphate cement was prepared by mixing the first and second components in a mass ratio of 1.6:1.0 for 30 seconds immediately before use. The composition of the obtained dental hardening calcium phosphate cement is shown in Tables 1 and 2.

[0089] [Evaluation of dentinal tubular sealing] (1) Preparation of bovine teeth for evaluation of dentinal tubule sealing ability A 2mm thick dentin plate was prepared by polishing the buccal center of a healthy bovine incisor using #80 and #1000 grit sandpaper on a rotary polishing machine and trimming it to expose the buccal dentin. The surface of this buccal dentin was further polished smooth using lapping film (#1200, #3000, #8000, manufactured by Sumitomo 3M Co., Ltd.). A 2mm window was left in the buccal dentin area in both the longitudinal and transverse directions relative to the tooth. This bovine tooth was immersed in a 3% EDTA solution and subjected to ultrasound for 10 minutes to demineralize the dentin window, and then rinsed with water to prepare a bovine tooth for evaluation of dentinal tubule sealing. A sufficient amount of the dental hardening calcium phosphate cement paste of the present invention, prepared as described above, was applied to the buccal dentin surface of the bovine teeth mentioned above, and the entire dentin window was rubbed in for 30 seconds using a microbrush (MICROBRUSH INTERNATIONAL "REGULAR SIZE (2.0 mm), MRB400"). After that, the paste on the dentin surface was removed with distilled water (n=3).

[0090] (2) Preparation of samples for SEM observation After the above processing, the bovine teeth were air-blown and dried to prepare samples for observation of dentinal tubules.

[0091] (3) SEM observation A Hitachi High-Technologies Corporation SU-3500 SEM was used for the SEM observation. Under an acceleration voltage of 5kV, the morphology of the dentin surface before application of dental hardening calcium phosphate cement paste and the bovine tooth surface after paste application were observed (n=3). Three arbitrary points were observed for each SEM observation sample, and the dentinal tubule sealing ability is expressed by the following formula. The average value of the dentinal tubule sealing rate of the three points was calculated. The obtained results are shown in Tables 1 and 2. Dentinal tubule sealing rate (%) = Number of sealed dentinal tubules / Number of observed dentinal tubules × 100

[0092] [Evaluation of mineral density recovery ability] The ability to promote remineralization of demineralized areas of dentin was evaluated as mineral density restoration capacity using the following method. (1) Preparation of decalcification solution A 50 mM aqueous solution of acetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) and a 50 mM aqueous solution of sodium acetate trihydrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were mixed and the pH was adjusted to 4.5.

[0093] (2) Preparation of artificial saliva 87.6 mg of sodium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), 122 mg of potassium dihydrogen phosphate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), 166 mg of calcium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and 477 mg of 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) (manufactured by Dojin Chemical Laboratories Co., Ltd.) were dissolved in approximately 800 mL of water, and the pH was adjusted to 7.0 with a saturated aqueous solution of NaOH (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and the volume was made up to 1.0 L.

[0094] (3) Reagents used in the preparation of test specimens The following compounds were used as reagents to prepare the test specimens. Ethanol: Manufactured by Kanto Chemical Co., Ltd. Propylene oxide: Manufactured by Fujifilm Wako Pure Chemical Corporation Epoxy resin main component: (EpoCure 2 main component, manufactured by BUEHLER) Hardener (EpoCure 2 hardener, manufactured by BUEHLER)

[0095] (4) Preparation of test specimens Test specimens were prepared using the cervical portion of bovine teeth. The cervical region of a bovine tooth was polished with #80 grit sandpaper to expose the dentin, then polished further with #1000 grit sandpaper, and ultrasonic treatment was performed for 5 minutes. A test window of approximately 5 mm x 2 mm was created on a portion of the surface of the bovine tooth cervical specimen, and the bovine tooth cervical specimen was divided into two symmetrically using a diamond cutter (Isomet 1000 manufactured by BUEHLER) with the dividing surface as the center. Nail polish was applied to the areas other than the test window of both divided test specimens, and two test specimens were prepared, each with a 5mm x 1mm test window. Both test specimens were immersed in a decalcifying solution and decalcified at 37°C for two weeks. The decalcifying solution was changed every three days from the start of immersion.

[0096] One of the test windows (test window A) was coated with nail polish and allowed to dry. The other test specimen's test window (test window B) was coated with the sample (dental hardening calcium phosphate cement for each example and comparative example) by rubbing it for 30 seconds. Then, both test specimens were stored in a constant temperature and humidity chamber at 37°C and 95% RH for 30 minutes. After storage, the test specimens were immersed in artificial saliva, and the artificial saliva was changed five times within seven days from the start of immersion. The specimens were then stored at 37°C for two weeks.

[0097] After removing the nail polish from the obtained test pieces, they were immersed for 10 minutes each in 70% ethanol, 80% ethanol, 90% ethanol, 99% ethanol, and 100% ethanol, and then immersed in 100% ethanol for 1 day. After immersing for 10 minutes each in a propylene oxide / ethanol = 1 / 1 mixture and propylene oxide, they were immersed in propylene oxide for 1 day. After immersing for 2 hours each in an epoxy resin main / propylene oxide = 1 / 1 mixture, epoxy resin main / propylene oxide = 4 / 1, and epoxy resin main, they were immersed in epoxy resin main / hardener = 4 / 1, and stored at 60°C for 1 day to cure. The hardened test specimen was cut perpendicular to the long side of the test window with a diamond cutter (Isomet 1000, manufactured by BUEHLER) to a thickness of approximately 1.2 mm, and then the thickness of the test specimen was reduced to 0.060 mm to 0.110 mm using lapping film (#1200, #3000, #8000, manufactured by 3M Japan Ltd.).

[0098] (5)CMR(Contact Micro Radiography) Both types of test specimens were photographed using a soft X-ray inspection device (product name "CMR-2", manufactured by Softex Co., Ltd.) and a glass plate (HIGH PRECISION PHOTO PLATE HPP-SN2 2×2, manufactured by Konica Minolta, Inc.) with a tube voltage of 10kV, a tube current of 2.0mA, and an irradiation time of 10 minutes. The photographed test specimens (plates) were immersed in a developer (medical X-ray liquid developer "Hylendol", Fujifilm Corporation) for 5 minutes, washed with distilled water for 1 minute, immersed in a fixer (fixer "Hylenfix", Fujifilm Corporation) for 5 minutes, and washed with distilled water for 30 seconds.

[0099] (6) Analysis The obtained CMR images were photographed with a microscope (Nikon DS-Ri1, manufactured by Nikon Solutions Inc.), and the brightness value at 100 μm directly beneath the nail polish protection of the undecalcified area was used as the reference. The brightness value was measured from the surface of the test window to the depth of the test window using image analysis software (ImageJ, open source, public domain) (n=3), and the mineral density recovery ability (%) was calculated using the following formula. In each of the following formulas, "control" means the case where the sample (dental hardening calcium phosphate cement of each example and comparative example) has not been treated.

[0100] Controlled mineral density at any depth = Control brightness value at any depth / Brightness value at 100 μm directly beneath the nail polish protection on the undecalcified area

[0101] Mineral density of the treated surface at any depth = Brightness value of the treated surface at any depth / Brightness value of the undecalcified area 100 μm directly beneath the nail polish protection layer

[0102] For the range from 7 μm to 497 μm, the measurement interval was set to 7 μm, and the calculation was performed using the following method.

number

[0103] [Table 1]

[0104] [Table 2]

[0105] As is clear from the results above, the dental hardening calcium phosphate cement according to the present invention (Examples 1-13) was found to have excellent dentinal tubule sealing properties and to have a high ability to restore mineral density in demineralized dentin.

[0106] In contrast, Comparative Example 1, which used a fluoride salt of divalent or greater cations (B) in which the cumulative frequency (%) of particles with a diameter of 0 μm or more and 3 μm or less in the volume-based cumulative particle size distribution was less than 3%, showed insufficient mineral density recovery ability.

[0107] Comparative Example 2, which did not contain calcium phosphate powder, did not form a paste, lacked dentinal tubule sealing properties, and did not remain in the tooth structure, so its mineral density restoration ability could not be confirmed. Comparative Examples 3 and 4, which did not contain sufficient amounts of a fluoride salt of a divalent or higher cation (B) and a polyvalent organic acid (C) that forms an insoluble salt with a divalent or higher cation, exhibited insufficient mineral density recovery ability. [Industrial applicability]

[0108] The dental hardening calcium phosphate cement according to the present invention is suitably used in the field of dental care as a tooth surface treatment material (for example, a dentin hypersensitivity suppressant, a root caries treatment material, etc.) and a tooth polishing material.

Claims

1. It consists of a first material which is a powder and a second material which is a liquid. The first material comprises a calcium phosphate compound (A), a fluoride salt of a divalent or higher cation (B), and a polyphenol compound (C) that forms a water-insoluble salt with a divalent or higher metal ion. The second material contains water (D), In the total amount of the fluoride salt (B) of the aforementioned divalent or higher cation, the cumulative frequency of particle sizes between 0 μm and 3 μm in the volume-based cumulative particle size distribution is 3% or more. The polyphenol compound (C) that forms a water-insoluble salt with the aforementioned divalent or higher metal ions is at least one selected from the group consisting of tannic acid, catechol, tyron monohydrate, protocatechuic acid, protocatechuic acid ester, pyrocatechol, pyrogallol, gallic acid, gallic acid ester, and catechin. Dental hardening calcium phosphate cement.

2. The dental hardening calcium phosphate cement according to claim 1, wherein the fluoride salt (B) of a divalent or greater cation is zinc fluoride and strontium fluoride.

3. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the average particle size of the fluoride salt (B) of divalent or greater cations is less than 34 μm.

4. The calcium phosphate compound (A) is selected from tetracalcium phosphate, anhydrous calcium monohydrogen phosphate (CaHPO 4 ), anhydrous calcium dihydrogen phosphate (Ca(H 2 PO 4 ) 2 ), α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate (Ca 3 (PO 4 ) 2 ・nH 2 O), calcium pyrophosphate (CaH 2 P 2 O 7 ), Calcium octaphosphate (Ca 8 H 2 (PO 4 ) 6 ・5H 2 O), Calcium monohydrogen phosphate dihydrate (CaHPO) 4 ・2H 2 O), and calcium dihydrogen phosphate monohydrate (Ca(H) 2 PO 4 ) 2 ・H 2 The tooth according to claim 1 or 2, comprising at least one selected from the group consisting of O). Industrial hardening calcium phosphate cement.

5. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the first or second material further comprises a pH adjusting agent.

6. The dental hardening calcium phosphate cement according to claim 5, wherein the pH adjusting agent is an alkali metal salt of phosphoric acid.

7. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the first or second material further comprises an inorganic filler.

8. The dental hardening calcium phosphate cement according to claim 7, wherein the inorganic filler comprises at least one selected from the group consisting of light anhydrous silicic acid and metal oxides.

9. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the second material further comprises an antibacterial agent.

10. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the calcium phosphate compound (A) is in the form of particles and has an average particle diameter of 0.1 to 40 μm.

11. The dental hardening calcium phosphate cement according to claim 1 or 2, wherein the polyphenol compound (C) that forms a water-insoluble salt with the aforementioned divalent or higher metal ions is in the form of particles, and has an average particle diameter of 5.0 to 100 μm.

12. A tooth surface treatment material comprising dental hardening calcium phosphate cement according to claim 1 or 2.

13. A dentin hypersensitivity inhibitor comprising dental hardening calcium phosphate cement according to claim 1 or 2.

14. A toothpaste comprising dental hardening calcium phosphate cement according to claim 1 or 2.

15. A root caries treatment material comprising dental hardening calcium phosphate cement according to claim 1 or 2.

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