WO2010113801A1 - Tooth calcification agent and method for producing same - Google Patents

Tooth calcification agent and method for producing same Download PDF

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Publication number
WO2010113801A1
WO2010113801A1 PCT/JP2010/055380 JP2010055380W WO2010113801A1 WO 2010113801 A1 WO2010113801 A1 WO 2010113801A1 JP 2010055380 W JP2010055380 W JP 2010055380W WO 2010113801 A1 WO2010113801 A1 WO 2010113801A1
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WO
WIPO (PCT)
Prior art keywords
tooth
particles
alkali metal
phosphate particles
phosphoric acid
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PCT/JP2010/055380
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French (fr)
Japanese (ja)
Inventor
正 橋本
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クラレメディカル株式会社
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Priority to JP2011507154A priority Critical patent/JP5501346B2/en
Publication of WO2010113801A1 publication Critical patent/WO2010113801A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the present invention relates to a tooth mineralizing agent that mineralizes the tooth surface.
  • fluorine is said to have a function of improving the acid resistance of teeth and strengthening the mineral content of the tooth, there is a problem of side effects caused by ingestion in large quantities.
  • a material containing a calcium solubilizer can supply a high concentration of minerals in the vicinity of the tooth, but has a problem of low ability to deposit minerals due to its high solubility.
  • TTCP tetracalcium phosphate
  • DCPA anhydrous calcium monohydrogen phosphate
  • CPC Calcium phosphate cement
  • Hp bioabsorbable hydroxyapatite
  • Patent Document 1 Japanese Patent No. 3017536
  • Patent Document 1 describes that a calcium phosphate composition containing tetracalcium phosphate and calcium hydrogen phosphate anhydride reacts in the presence of water to produce hydroxyapatite. Yes.
  • the hydroxyapatite thus obtained can be gradually replaced into bone by contact with the living hard tissue, and the calcium phosphate composition has a calcification ability, and therefore can be used as a mineralizing agent. It is said that.
  • an alkali metal salt of phosphoric acid such as disodium monohydrogen phosphate (Na 2 HPO 4 ) is added for the purpose of rapidly curing the calcium phosphate composition.
  • Na 2 HPO 4 disodium monohydrogen phosphate
  • Patent Document 2 JP-A-1-163127 (Patent Document 2) describes a composition for healing hypersensitivity comprising tetracalcium phosphate, calcium phosphate having a Ca / P molar ratio of less than 1.67, and a thickener.
  • hypersensitivity can be remarkably reduced by applying to a hypersensitive part of a tooth and holding it for a predetermined time.
  • the reason why the hypersensitivity is remarkably reduced is that calcium ions and phosphate ions eluted from the mixture of water and the like of the composition diffuse and penetrate into the dentinal tubule, and hydroxyapatite precipitates and deposits in the dentinal tubule This is to block mechanical stimulation, thermal stimulation, and chemical stimulation from the outside.
  • hydroxyapatite, calcium fluoride, titanium oxide, calcium hydroxide, sodium phosphate, ammonium phosphate, alumina for the above-mentioned composition for healing hypersensitivity to adjust kneadability with water and paste viscosity. It is described that other components such as silica may be added. However, there has been no description or suggestion of adding an alkali metal salt of phosphoric acid for the purpose of improving the effect of calcification.
  • the present invention has been made to solve the above-described problems, and an object of the present invention is to provide a tooth mineralizing agent having a high calcification effect.
  • An object of the present invention is to provide a dental calcification agent containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and the total amount of the dental calcification agent is 100 parts by weight. It contains 1 to 80 parts by weight of calcium particles (A), and the blending amount of the alkali metal salt of phosphoric acid (B) with respect to 100 parts by weight of tetracalcium phosphate particles (A) is 0.5 to 50 parts by weight. It is solved by providing the tooth mineralizing agent characterized.
  • the alkali metal salt (B) of phosphoric acid is disodium monohydrogen phosphate and / or monosodium dihydrogen phosphate, and it is further preferable to contain acidic calcium phosphate particles (C). is there.
  • Acidic calcium phosphate particles (C) are anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, tricalcium phosphate [Ca 3 (PO 4 ) 2.
  • the mixing ratio (A / C) of the calcium particles (A) and the acidic calcium phosphate particles (C) is preferably 40/60 to 60/40 in terms of molar ratio.
  • the average particle diameter of the tetracalcium phosphate particles (A) is preferably 0.5 to 40 ⁇ m, and the average particle diameter of the alkali metal salt of phosphoric acid (B) is preferably 0.5 to 20 ⁇ m. It is.
  • the acidic calcium phosphate particles (C) preferably have an average particle size of 0.1 to 7 ⁇ m, and further particles (E) selected from silica or metal oxide having an average particle size of 0.002 to 2 ⁇ m. It is preferable to contain.
  • the free alkali metal ion concentration of the suspension after 10 minutes from the addition was The standard deviation ⁇ when the average value of the free alkali metal ion concentration is d is preferably ⁇ ⁇ 0.3d, and the alkali metal ion is preferably 0.2 to 100 mg / L. Sodium ion is preferred.
  • a tooth surface treating material containing a tooth mineralizing agent is a preferred embodiment of the present invention
  • a dentifrice containing a tooth mineralizing agent is a preferred embodiment of the present invention
  • a chewing gum containing a tooth mineralizer is a preferred embodiment of the present invention
  • an enamel mineralizer comprising a tooth mineralizer is a preferred embodiment of the present invention.
  • the above-mentioned problem is a method for producing a tooth mineralizer that mixes tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component, 0.5 to 50 parts by weight of alkali metal salt (B) of phosphoric acid is added to 100 parts by weight of tetracalcium phosphate particles (A), and tetracalcium phosphate particles (100 parts by weight of the total amount of tooth mineralizing agent)
  • This can be solved by providing a method for producing a tooth mineralizing agent characterized in that the blending amount of A) is 1 to 80 parts by weight.
  • powder containing tetracalcium phosphate particles (A) and alkali metal salt of phosphoric acid (B), or tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles It is preferable to preliminarily mix the powder containing C), and at the time of the mixing, selected from a jet mill, a likai machine, a ball mill, a high-speed rotary mill, a planetary mill, a hybridizer, a mechano-fusion, or a mixing extruder It is preferable to use at least one kind.
  • a liquid or aqueous paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B) may be added to and mixed with the powder or non-aqueous paste containing the tetracalcium phosphate particles (A). Is preferred.
  • a tooth mineralizing agent comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component. Solved by providing a kit.
  • the above-mentioned problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C), and a liquid or aqueous paste containing water as a main component.
  • A tetracalcium phosphate particles
  • B alkali metal salt of phosphoric acid
  • C acidic calcium phosphate particles
  • the subject is a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and a liquid or aqueous paste containing water as a main component and an alkali metal salt of phosphoric acid (B). Solved by providing.
  • the above-mentioned problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and a liquid or water system containing water as a main component.
  • A tetracalcium phosphate particles
  • B an alkali metal salt of phosphoric acid
  • B a liquid or water system containing water as a main component.
  • the above-described problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or aqueous paste containing water as a main component and acidic calcium phosphate particles (C).
  • A tetracalcium phosphate particles
  • B alkali metal salt of phosphoric acid
  • C acidic calcium phosphate particles
  • the said subject is a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and acidic calcium phosphate particles (C). It can also be solved by providing a tooth mineralizer kit comprising a powder or non-aqueous paste containing water and a liquid or water-based paste containing water as a main component.
  • a tooth mineralizing agent having a high calcification effect is provided, and in particular, a tooth mineralizing agent having a high mineralization effect on the enamel surface is provided.
  • Example 1 it is a contact microradiogram image of the demineralized enamel (demineralized part) produced in the enamel surface layer. In Example 1, it is a contact microradiogram image of the enamel (calcification part) which calcified the decalcification enamel produced in the enamel surface layer with the tooth mineralization agent.
  • the tooth mineralizing agent of the present invention contains tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B).
  • the term “dental” used in the present invention includes both “enamel” and “dentin”.
  • a composition containing tetracalcium phosphate particles (A) is mixed in the presence of water, it is gradually converted into hydroxyapatite.
  • the present inventor has a high calcification effect, especially lime on the enamel surface. It became clear that the effect of crystallization is high. Although the reason for this is not necessarily clear, the following mechanism is presumed.
  • the present invention contains 1 to 80 parts by weight of tetracalcium phosphate particles (A) with respect to 100 parts by weight of the total amount of the tooth mineralizing agent.
  • the amount is preferably 5 parts by weight or more. More preferably, it is more preferably 20 parts by weight or more.
  • the content of the tetracalcium phosphate particles (A) exceeds 80 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and the amount is preferably 75 parts by weight or less.
  • the amount is more preferably no more than parts by weight and even more preferably no more than 60 parts by weight.
  • the manufacturing method of the tetracalcium phosphate [Ca 4 (PO 4 ) 2 O] particles (A) used in the present invention is not particularly limited. Commercially available tetracalcium phosphate particles may be used as they are, or may be used by appropriately pulverizing and adjusting the particle diameter. As the pulverization method, a method similar to the pulverization method of the acidic calcium phosphate particles (C) described later can be employed.
  • the average particle diameter of the tetracalcium phosphate particles (A) used in the present invention is preferably 0.5 to 40 ⁇ m.
  • the average particle diameter of the tetracalcium phosphate particles (A) is more preferably 5 ⁇ m or more, and even more preferably 10 ⁇ m or more.
  • the average particle size of the tetracalcium phosphate particles (A) is more preferably 35 ⁇ m or less, and further preferably 30 ⁇ m or less.
  • the average particle diameter of the tetracalcium phosphate particles (A) used in the present invention is measured and calculated using a laser diffraction particle size distribution measuring device.
  • the tooth mineralizing agent of the present invention contains 0.5 to 50 parts by weight of an alkali metal salt (B) of phosphoric acid with respect to 100 parts by weight of tetracalcium phosphate particles (A).
  • an alkali metal salt (B) of phosphoric acid in addition to the tetracalcium phosphate particles (A), tooth lime having a high calcification effect, particularly a high calcification effect on the enamel surface.
  • An agent can be provided.
  • the content of the alkali metal salt of phosphoric acid (B) is less than 0.5 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and it is preferably 1 part by weight or more.
  • the content of the alkali metal salt of phosphoric acid (B) exceeds 50 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and is preferably 40 parts by weight or less.
  • the amount is more preferably 30 parts by weight or less, and further preferably 25 parts by weight or less.
  • the alkali metal salt of phosphoric acid (B) used in the present invention is not particularly limited, and is disodium monohydrogen phosphate, dipotassium monohydrogen phosphate, dilithium monohydrogen phosphate, monosodium dihydrogen phosphate, phosphorus Examples include monopotassium dihydrogen acid, trisodium phosphate, tripotassium phosphate, and one or more of these are used.
  • the alkali metal salt (B) of phosphoric acid is disodium monohydrogen phosphate and / or monosodium dihydrogen phosphate from a viewpoint that a raw material with high safety and high purity can be easily obtained.
  • the alkali metal ion in the alkali metal salt (B) of phosphoric acid used in the present invention is preferably a sodium ion.
  • the average particle size of the alkali metal salt (B) of phosphoric acid used in the present invention is preferably 0.5 to 20 ⁇ m.
  • the average particle size of the alkali metal salt of phosphoric acid (B) is less than 0.5 ⁇ m, it becomes difficult to uniformly disperse in the liquid or powder due to significant aggregation.
  • the supply of phosphate ions derived from the alkali metal salt (B) of phosphoric acid released from the prepared tooth mineralizing agent of the present invention is insufficient for the teeth, and the supply balance with calcium ions is disrupted, resulting in a decrease in calcification rate.
  • the effect of improving the enamel hardness may be reduced, and the thickness is more preferably 1 ⁇ m or more.
  • the average particle size of the alkali metal salt of phosphoric acid (B) exceeds 20 ⁇ m, it is derived from the alkali metal salt of phosphoric acid (B) released from the tooth mineralizer of the present invention prepared in the presence of water.
  • the supply of phosphate ions to the teeth is insufficient, and the supply balance with calcium ions is lost, so that the calcification rate is lowered and the effect of improving enamel hardness may be reduced.
  • the average particle size of the alkali metal salt of phosphoric acid (B) is more preferably 15 ⁇ m or less, and further preferably 10 ⁇ m or less.
  • the tooth mineralizing agent of the present invention preferably further contains acidic calcium phosphate particles (C) in addition to tetracalcium phosphate particles (A) and alkali metal salt of phosphoric acid (B).
  • C acidic calcium phosphate particles
  • the inventor of the present invention contains calcium calcium phosphate particles (C) having low solubility in addition to tetracalcium phosphate particles (A) and alkali metal salts (B) of phosphoric acid, so that calcium ions are applied after applying the paste. It is assumed that not only phosphate ions can be supplied for a longer time, but also the supply balance becomes more appropriate.
  • the acidic calcium phosphate particles (C) used in the present invention are not particularly limited, and anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, phosphoric acid Tricalcium [Ca 3 (PO 4 ) 2 ] particles, amorphous calcium phosphate [Ca 3 (PO 4 ) 2 xH 2 O] particles, acidic calcium pyrophosphate [CaH 2 P 2 O 7 ] particles, calcium monohydrogen phosphate At least one selected from the group consisting of dihydrate [CaHPO 4 .2H 2 O] particles and calcium dihydrogen phosphate monohydrate [Ca (H 2 PO 4 ) 2 .H 2 O] particles.
  • the average particle diameter of the acidic calcium phosphate particles (C) used in the present invention is preferably 0.1 to 7 ⁇ m.
  • the average particle size is less than 0.1 ⁇ m, the solution is excessively dissolved in the liquid agent, so that not only the supply balance of calcium ions and phosphate ions is lost, but also the viscosity of the paste obtained by mixing with the liquid agent may be too high. More preferably, it is 0.3 ⁇ m or more.
  • the average particle diameter exceeds 7 ⁇ m, the acidic calcium phosphate particles (C) are difficult to dissolve in the liquid agent, so that the tetracalcium phosphate particles (A) may be excessively dissolved.
  • the average particle diameter of the acidic calcium phosphate particles (C) is more preferably 3 ⁇ m or less.
  • the average particle diameter of the acidic calcium phosphate particles (C) is calculated in the same manner as the average particle diameter of the tetracalcium phosphate particles (A).
  • the production method of acidic calcium phosphate particles (C) having such an average particle diameter is not particularly limited, and if a commercially available product can be obtained, it may be used, but it is preferable to further grind the commercially available product.
  • a pulverizing apparatus such as a ball mill, a likai machine, or a jet mill can be used.
  • acidic calcium phosphate raw material powder is pulverized with a liquid medium such as alcohol using a lykai machine, a ball mill or the like to prepare a slurry, and the resulting slurry is dried to obtain acidic calcium phosphate particles (C). it can.
  • a ball mill is preferably used as the pulverizer at this time, and alumina or zirconia is preferably used as the material of the pot and ball.
  • the average particle size of (A) is more preferably 2 times or more than the average particle size of (C), more preferably 4 times or more, and particularly preferably 7 times or more.
  • the average particle size of (A) is more preferably 35 times or less of the average particle size of (C), still more preferably 30 times or less, and particularly preferably 25 times or less.
  • the blending ratio (A / C) of the tetracalcium phosphate particles (A) and the acidic calcium phosphate particles (C) is not particularly limited, and is used in a blending ratio such that the molar ratio is in the range of 40/60 to 60/40. It is preferable. By this, the tooth mineralizer of this invention with a high calcification effect can be obtained.
  • the blending ratio (A / C) is more preferably 45/55 to 55/45, and most preferably substantially 50/50.
  • the tooth mineralizing agent of the present invention preferably further contains a fluorine compound (D).
  • a fluorine compound (D) used in the present invention is not particularly limited, and is sodium fluoride, potassium fluoride, ammonium fluoride, lithium fluoride, cesium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, fluorine.
  • Strontium fluoride barium fluoride, copper fluoride, zirconium fluoride, aluminum fluoride, tin fluoride, sodium monofluorophosphate, potassium monofluorophosphate, hydrofluoric acid, sodium titanium fluoride, potassium titanium fluoride,
  • Examples include hexylamine hydrofluoride, laurylamine hydrofluoride, glycine hydrofluoride, alanine hydrofluoride, fluorosilanes, and silver fluorinated diamine.
  • sodium fluoride, sodium monofluorophosphate, and tin fluoride are preferably used from the viewpoint of the calcification promoting effect.
  • the amount of the fluorine compound (D) used is not particularly limited, and it is preferable to contain 0.01 to 3 parts by weight of the converted fluoride ion of the fluorine compound (D) with respect to 100 parts by weight of the total amount of the tooth mineralizing agent.
  • the usage-amount of the fluoride ion of a fluorine compound (D) is less than 0.01 weight part, there exists a possibility that the effect which accelerates
  • the usage-amount of the fluoride ion of a fluorine compound (D) exceeds 3 weight part, safety
  • the tooth mineralizing agent of the present invention is other than tetracalcium phosphate particles (A), alkali metal salts of phosphoric acid (B), acidic calcium phosphate particles (C), and fluorine compounds (D) as long as the effects of the present invention are not impaired. These components may be contained. For example, a thickener can be mix
  • the thickener include carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, polystyrene sulfonic acid, polystyrene sulfonate, polyglutamic acid, polyglutamate, Polyaspartic acid, polyaspartate, poly L lysine, poly L lysine salt, starch other than cellulose, alginic acid, alginate, carrageenan, guar gum, chitansan gum, cellulose gum, hyaluronic acid, hyaluronate, pectin, pectin salt, chitin , Polysaccharides such as chitosan, acidic polysaccharide esters such as propylene glycol alginate, collagen, gelatin and these One or two or more selected from polymers such as proteins such as conductors may be mentioned.
  • the thickener may be blended into the powder, the liquid, or the paste being mixed.
  • inorganic fillers such as silica and metal oxides, polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol and diglycerin, sugar alcohols such as xylitol, sorbitol and erythritol, polyethylene glycol and polypropylene glycol Polyethers such as aspartame, acesulfame potassium, licorice extract, artificial sweeteners such as saccharin and sodium saccharin may be added.
  • the tooth mineralizing agent of the present invention preferably contains an inorganic filler, and contains particles (E) selected from silica or metal oxide having an average particle diameter of 0.002 to 2 ⁇ m. It is more preferable to contain silica particles (E) having an average particle diameter of 0.002 to 2 ⁇ m.
  • any pharmacologically acceptable drug or the like can be blended.
  • Antibacterial agents typified by cetylpyridinium chloride, antiseptics, anticancer agents, antibiotics, blood circulation improving agents such as actins and PEG1, growth factors such as bFGF, PDGF and BMP, osteoblasts, odontoblasts, and undifferentiated Bone marrow-derived stem cells, embryonic stem (ES) cells, induced pluripotent stem (iPS) cells obtained by dedifferentiation and production of differentiated cells such as fibroblasts by gene transfer, and cells such as these differentiated cells Cells or the like that promote tissue formation can be added.
  • ES embryonic stem
  • iPS induced pluripotent stem
  • the tooth mineralizer of the present invention was prepared by adding 0.05 g of the tooth mineralizer to 200 g of pure water at 25 ° C. to prepare a suspension, and the free alkali of the suspension 10 minutes after the addition.
  • the metal ion concentration is preferably 0.2 to 100 mg / L.
  • the free alkali metal ion concentration is in such a range, there is an advantage that a tooth mineralizing agent having an excellent effect of improving the calcification rate and enamel hardness can be obtained.
  • the free alkali metal ion concentration is less than 0.2 mg / L, phosphate ions supplied together with the alkali metal ions are insufficient, so the supply balance of ions to the teeth is disrupted, and conversion to hydroxyapatite is not smooth.
  • a tooth mineralizing agent having an excellent effect of improving the calcification rate and enamel hardness may not be obtained, and it is more preferably 0.5 mg / L or more, and further preferably 1 mg / L or more.
  • concentration of the free alkali metal ion exceeds 100 mg / L, the phosphate ion supplied together with the alkali metal ion becomes excessive, so the supply balance of ions to the teeth is disrupted, and the conversion to hydroxyapatite is smooth.
  • a tooth mineralizing agent having a good effect of improving the calcification rate and enamel hardness not obtained, but excessive sodium ions may inhibit the conversion to hydroxyapatite, and is 50 mg / L or less.
  • Any method can be selected as a method for measuring free alkali metal ions. It is possible to collect the supernatant of the suspension and measure with an ICP emission spectrophotometer or ion chromatography. A measurement method that directly immerses the electrode in response to the alkali metal ion concentration in the suspension. It may be used.
  • the dentin mineralizing agent of the present invention has a standard deviation ⁇ satisfying ⁇ ⁇ 0.3d when the average value of the free alkali metal ion concentration is d, that is, the standard deviation ⁇ is the free alkali metal.
  • the value ( ⁇ / d) divided by the average value d of ion concentrations is preferably 0.3 or less.
  • the alkali metal salt (B) of phosphoric acid when the uniformity of the alkali metal salt (B) of phosphoric acid is not good, the alkali metal salt (B) of phosphoric acid is agglomerated and is hardly dissolved in water.
  • a paste-like tooth is prepared by mixing a powder containing tetracalcium phosphate particles (A) and an alkali metal salt (B) of phosphoric acid with a liquid mainly composed of water or an aqueous paste.
  • a mineralizing agent can be obtained. Since this paste-like tooth mineralizer containing water immediately begins to undergo a reaction for conversion into HAp, it is preferably prepared by mixing immediately before use in a medical field.
  • the mixing operation is not particularly limited, and hand mixing, mixing using a static mixer, and the like are preferably employed.
  • the inventor has confirmed that the calcification effect is high when the content of the alkali metal salt (B) of phosphoric acid is in an appropriate range.
  • the above mixing method in which the alkali metal salt of phosphoric acid (B) is added in powder form is preferably employed.
  • the tooth mineralizing agent thus obtained is suitably used by applying it to the enamel surface.
  • the liquid containing water as a main component may be pure water, or a liquid containing water as a main component and containing other components, and the water-based paste containing water as a main component.
  • the paste-like liquid which has water as a main component and contains another component is shown.
  • Other components are not particularly limited, and the above-mentioned acidic calcium phosphate particles (C), polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, diglycerin, sugar alcohols such as xylitol, sorbitol, erythritol, polyethylene glycol, polypropylene glycol And the like.
  • acidic calcium phosphate particles (C) are contained as other components
  • acidic calcium phosphate particles containing water as a main component in a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B) A method of adding and mixing the liquid or aqueous paste containing (C) is also preferably employed.
  • a liquid or water-based paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B) is added to and mixed with powder or non-aqueous paste containing tetracalcium phosphate particles (A).
  • the paste-like tooth mineralizing agent can also be obtained.
  • a reaction occurs in which the tetracalcium phosphate particles (A) are dissolved and gradually converted to HAp. Therefore, a liquid or aqueous paste containing water as a main component and the tetracalcium phosphate particles (A) Cannot be premixed and stored.
  • a method of mixing with the paste is preferably employed, and there is also an advantage that the operation at the time of mixing and preparing immediately before use is simple.
  • the solvent other than water used in the non-aqueous paste is not particularly limited, and examples thereof include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, and diglycerin, and polyethers such as polyethylene glycol and polypropylene glycol. Is done.
  • a powder containing tetracalcium phosphate particles (A) and an alkali metal salt (B) of phosphoric acid, or tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B) and an acid It is preferable to previously mix powder containing calcium phosphate particles (C).
  • This has the advantage that the calcification rate is good.
  • the tooth mineralizing agent of the present invention when used on the enamel surface, it has the advantage that the enamel hardness after calcification is improved.
  • a jet mill it is preferable to use at least one selected from a jet mill, a likai machine, a ball mill, a high-speed rotary mill, a planetary mill, a hybridizer, a mechanofusion, or a mixing extruder.
  • a ball mill it is preferable to use at least one selected from a ball mill, a reiki machine, a high-speed rotary mill, and a jet mill.
  • the tooth mineralizing agent of the present invention is preferably used for various uses of tooth surface treatment materials, dentifrices, or chewing gums.
  • a reaction occurs in which the tetracalcium phosphate particles (A) are dissolved and gradually converted to HAp, so that moisture is appropriately supplied at the time of use such as a dentifrice or chewing gum.
  • it may be a mode in which it is appropriately mixed with a liquid just before use, such as a tooth surface treatment material.
  • a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component.
  • a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C), and a liquid or water-based paste containing water as a main component.
  • a tooth mineralizer kit is a tooth mineralizer kit.
  • a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and a liquid or aqueous paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B). This is one of the embodiments of the present invention.
  • a tooth mineralizer kit comprising: Further, it comprises a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or aqueous paste containing water as a main component and containing acidic calcium phosphate particles (C).
  • a tooth mineralizer kit is a tooth mineralizer kit.
  • A tetracalcium phosphate particles
  • B powder or non-aqueous paste containing an alkali metal salt of phosphoric acid
  • C powder containing acidic calcium phosphate particles
  • One embodiment of the present invention is a tooth mineralizer kit comprising a non-aqueous paste and a liquid or water-based paste containing water as a main component.
  • the tooth mineralizing agent of the present invention used in this way has a high calcification effect on the enamel surface, and an enamel mineralizing agent comprising a tooth mineralizing agent is a preferred embodiment of the present invention.
  • the average particle size of tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) particles, acidic calcium phosphate particles (C) and sodium fluoride (D) particles is measured by laser diffraction particle size distribution. Measurement was performed using a device (“SALD-2100 type” manufactured by Shimadzu Corporation), and the median diameter calculated from the measurement result was defined as the average particle diameter.
  • the bovine teeth were artificially decalcified (0.1 mol / L lactic acid, 0.5 g / L) according to the method of Reynolds et al. (EC Reynolds, J. Dent. Res., 76 (9), 1587-1595.). Decalcification was carried out by dipping in hydroxyapatite, 20 g / L polyacrylic acid (Mw: 250 kDa), appropriate amount of NaOH, pH 4.8) for 5 days. The artificial decalcification liquid was changed every day. Half of the decalcified enamel window was masked with nail polish and air dried for 1 hour to prepare bovine teeth for calcification.
  • Tetracalcium Phosphate Particles (A1) (average particle size 23.1 ⁇ m) used in this example grind crude tetracalcium phosphate prepared as follows. Was obtained.
  • Commercially available anhydrous calcium monohydrogen phosphate particles (Product No. 1430, JTBaker Chemical Co., NJ) and calcium carbonate (Product No. 1288, JTBaker Chemical Co., NJ) are added to water to make an equimolar amount.
  • the cake-like equimolar mixture obtained by filtration and drying was heated in an electric furnace (FUS732PB, Advantech Toyo Co., Ltd.) at 1500 ° C. for 24 hours, and then cooled to room temperature in a desiccator.
  • the tetracalcium phosphate lump was prepared. Further, the mixture was roughly crushed in a mortar and then sieved to remove fine powder and tetracalcium phosphate lump, and the particle size was adjusted to a range of 0.5 to 3 mm to obtain crude tetracalcium phosphate.
  • anhydrous calcium monohydrogen phosphate particles (C1) (average particle size 1.1 ⁇ m) used in this example are commercially available anhydrous phosphorus Calcium monohydrogen particles (Product No.
  • SM-1 high-speed rotating mill
  • the powder for tooth mineralization agent was obtained by mixing for 3 minutes at a rotational speed of 1000 rpm.
  • the method for preparing the powder obtained by mixing in this way was designated as “Method 1”.
  • the average value (d) of the sodium ion concentration of the powder in Example 1 is 10.4 mg / L, and the numerical value ( ⁇ / d) obtained by dividing the standard deviation ( ⁇ ) of the sodium ion concentration by (d) is 0.06. Met.
  • the obtained results are summarized in Table 1.
  • Epoxy resin was prepared according to the Lucas method, and an epoxy resin and a curing agent were uniformly mixed and then an accelerator was added. Disposyringe with 100 ml disposable cup, 41 ml of Rubeak 812 (epoxy resin, manufactured by Nacalai Tesque), 31 ml of Rubeac MNA (curing agent, manufactured by Nacalai Tesque), and 10 ml of Rubeak DDSA (curing agent, manufactured by Nacalai Tesque) was added to a disposable cup and stirred for 10 minutes.
  • Rubeak 812 epoxy resin, manufactured by Nacalai Tesque
  • Rubeac MNA curing agent, manufactured by Nacalai Tesque
  • Rubeak DDSA curing agent, manufactured by Nacalai Tesque
  • Lebeac DMP-30 (accelerator, manufactured by Nacalai Tesque Co., Ltd.) weighed with a disposable syringe was gradually dropped while stirring, and the mixture was further stirred for 10 minutes after the addition.
  • a bovine sample was placed in a plastic container containing an epoxy resin, and a curing reaction was performed at 45 ° C. for 1 day and at 60 ° C. for 2 days.
  • the polyethylene container and the precision low-speed cutting machine (BUEHLER, ISOMET 1000) were cut in a direction perpendicular to the demineralized surface to obtain a section having a thickness of about 1 mm including the cross section of the test portion.
  • This section is polished with a wrapping film (# 1200, # 3000, # 8000, manufactured by Sumitomo 3M), and the section thickness is set to 80 to 100 ⁇ m, so that CMR (Contact Micro Radiography; soft X-ray microscope image) is taken.
  • Sample (n 5).
  • CMR imaging CMR imaging and film development were all performed in a dark room.
  • CMR-2 manufactured by Softex Corporation
  • the CMR imaging samples obtained above were placed in close contact on a dedicated film (Kodac special Holographic, Kodac), and each sample was subjected to a tube voltage of 15 kV, a tube current of 2.6 mA, and an X-ray irradiation time of 30 minutes. A soft X-ray transmission image of was taken.
  • a developer (D-19, manufactured by Kodac) and a fixer (GBX, manufactured by Kodac) were used, soaked in the developer for 5 minutes, then washed with water for 30 seconds, immersed in the fixer for 5 minutes, and then washed with water for 1 minute. And dried to obtain a soft X-ray photographic film.
  • a transmission image of the obtained soft X-ray photograph was observed with an optical microscope (BX51, manufactured by Olympus) at an objective lens 40 times, and the transmission image was photographed using a CCD camera (Pro600ES, manufactured by Pixela) connected to the optical microscope. Obtained as data.
  • the obtained image was analyzed using image analysis computer software Scion Image ⁇ 4.03 (manufactured by Scion).
  • the film density (gray value) of the demineralized part and the calcified part is measured at a certain depth position (about 30 ⁇ m) from the enamel surface layer, the film density of the demineralized part is 0%, and the non-demineralized part further from the enamel surface
  • the calcification rate was calculated from the converted value (%) when the film density of the portion was 100%.
  • the calcification rate of the decalcified enamel calcified with the tooth mineralizing agent of Example 1 was 71.6%.
  • Vickers hardness measurement For measurement of Vickers hardness, a Mitsutoyo micro Vickers hardness tester (MicroWiZhard) was used, a test force of 0.01 kgf, a test time of 4 seconds for loading, 10 seconds for holding, 4 seconds for unloading, 100 Vickers hardness measurement was carried out under each condition for observing scratches at double magnification.
  • the Vickers hardness of the healthy bovine enamel was 377 HV
  • the Vickers hardness at a depth of 30 ⁇ m from the surface of the decalcified enamel masked with nail polish and kept decalcified was 122 HV.
  • the Vickers hardness at a depth of 30 ⁇ m from the surface of the demineralized enamel calcified with the tooth mineralizing agent of Example 1 was 314 HV.
  • Example 2 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that anhydrous calcium hydrogen phosphate particles (C1) were not used and the remainder was prepared with purified water, and the alkali metal ion concentration was measured. Morphological evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 3 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that disodium monohydrogen phosphate (B) particles were added to the powder and prepared instead of the powder. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 4 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 0.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 5 In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 0.2 part by weight of disodium monohydrogen phosphate (B) particles was added to the liquid paste, and the balance A tooth mineralizing agent was prepared in the same manner as in Example 1 except that was prepared with purified water, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 6 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 12 parts by weight and the remaining part was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 7 In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 12 parts by weight of disodium monohydrogen phosphate (B) particles were added to the liquid paste, and the remainder was purified.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 8 In Example 1, a tooth mineralization agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 1.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 9 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles used was 2.4 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 10 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1, except that the amount of disodium monohydrogen phosphate (B) particles was 7.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 11 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 73.5 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 14 parts by weight, and anhydrous calcium hydrogen phosphate particles ( C1), except that glycerin, propylene glycol, xylitol, polyethylene glycol, and silica particles (E) were not used, and the remainder was prepared with purified water. Concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 12 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 49 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 9.3 parts by weight, and anhydrous calcium hydrogen phosphate particles ( C1), except that glycerin, propylene glycol, xylitol, polyethylene glycol, and silica particles (E) were not used, and the remainder was prepared with purified water. Concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 13 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 2.62 parts by weight, the amount of anhydrous calcium monohydrogen phosphate particles (C1) used was 0.98 parts by weight, and disodium monohydrogen phosphate. (B) Instead of preparing by adding 5 parts by weight of particles to the powder, Example, except that 0.5 parts by weight of disodium monohydrogen phosphate (B) particles were added to the liquid paste and the remainder was prepared with purified water. A tooth mineralizing agent was prepared in the same manner as in No. 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 14 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 2.62 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 0.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of the particles (C1) used was 0.98 parts by weight, and the remainder was prepared with purified water, and the alkali metal ion concentration was measured. Evaluation and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 15 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 5.24 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 1 part by weight, and anhydrous calcium hydrogen phosphate particles (A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of C1) used was 1.96 parts by weight, and the balance was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, And Vickers hardness measurement. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
  • Example 16 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 13.1 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 2.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of the particles (C1) used was 4.9 parts by weight and the remainder was prepared with purified water. Evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 17 In Example 1, instead of using 5 parts by weight of disodium monohydrogen phosphate (B) particles, 5 teeth by weight of sodium dihydrogen phosphate (B) particles were used in the same manner as in Example 1, except that A mineralizer was prepared, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 18 In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 5 parts by weight of sodium dihydrogen phosphate (B) particles were added to the liquid paste, and the remainder was purified.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 19 In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that sodium fluoride (D) particles were not used and the balance was prepared with purified water, and measurement of alkali metal ion concentration and morphology Evaluation and Vickers hardness measurement.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 20 In Example 1, instead of using 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1), 12.3 parts of calcium monohydrogen phosphate dihydrate particles (C) (average particle size 1.2 ⁇ m) were used.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that parts by weight were used and the remainder was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • the calcium monohydrogen phosphate dihydrate particles (C) (average particle size 1.2 ⁇ m) are commercially available calcium monohydrogen phosphate dihydrate particles (Wako Pure Chemical Industries, Ltd., average particles). It was obtained by preparing in the same manner as the method for preparing anhydrous calcium hydrogen phosphate phosphate particles (C1) in Example 1.
  • Example 21 In Example 1, 16.7 parts by weight of anhydrous calcium dihydrogen phosphate particles (C) (average particle size 1.1 ⁇ m) was used instead of 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1).
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the remainder was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • anhydrous calcium dihydrogen phosphate particles (C) (average particle size 1.1 ⁇ m)
  • commercially available anhydrous calcium dihydrogen phosphate particles (manufactured by Wako Pure Chemical Industries, Ltd., average particle size 18 ⁇ m) are used. It was obtained by preparing in the same manner as the method for preparing anhydrous calcium monohydrogen phosphate particles (C1) in Example 1.
  • Example 22 In Example 1, instead of using 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1), 15.4 parts by weight of acidic calcium pyrophosphate particles (C) (average particle size: 1.0 ⁇ m) was used, and the remainder was used.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 1 As the acidic calcium pyrophosphate particles (C) (average particle size 1.0 ⁇ m), commercially available acidic calcium pyrophosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size 13 ⁇ m) were used, and anhydrous phosphoric acid in Example 1 was used. It was obtained by preparing in the same manner as the method for preparing calcium monohydrogen particles (C1).
  • Example 23 In Example 1, the amount of tetracalcium phosphate particles (A1) used was 18.4 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 3.5 parts by weight, and the remainder was prepared with purified water. Except for the above, a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 24 In Example 1, instead of preparing the powder and liquid paste, 26.2 parts by weight of tetracalcium phosphate particles (A1), 0.21 parts by weight of sodium fluoride (D) particles, 0.5 parts of silica particles (E) Non-aqueous paste prepared using parts by weight, 18.09 parts by weight of glycerin and 5 parts by weight of propylene glycol, 5 parts by weight of disodium monohydrogen phosphate (B) particles, anhydrous calcium monohydrogen phosphate particles (C1) 9 8 parts by weight, 5 parts by weight of xylitol, 3 parts by weight of polyethylene glycol, 0.05 parts by weight of cetylpyridinium chloride monohydrate, 3.5 parts by weight of silica particles (E) and the rest of the aqueous paste prepared with purified water
  • the tooth mineralization agent was prepared by mixing and morphological evaluation and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 3, and the obtained evaluation results are summarized in Table
  • Example 25 In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles are added together with 200 g of 10 mm zirconia balls into a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.) and 30 rpm at a rotation speed of 200 rpm. Powder was obtained by mixing for minutes. The method for preparing the powder obtained by mixing in this manner was designated as “Method 2”.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 26 In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles are added to a reiki machine (automatic mortar, “ANM-200” manufactured by ASONE Co., Ltd.), and the mortar is mixed at 6 rpm and the pestle at 100 rpm for 5 hours. A powder was obtained. The method for preparing the powder obtained by mixing in this manner was designated as “Method 3”.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 27 In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles were added to a 400 ml alumina grinding pot (“Type A-3 HD pot mill” manufactured by Nikkato Co., Ltd.) without adding zirconia balls, and 30 rpm at a rotation speed of 1500 rpm. Powder was obtained by mixing for minutes. The method for preparing the powder obtained by mixing in this way was designated as “Method 4”.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 1 a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 0.1 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 2 instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 0.1 part by weight of disodium monohydrogen phosphate (B) particles was added to the liquid paste, and the balance A tooth mineralizing agent was prepared in the same manner as in Example 1 except that was prepared with purified water, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 3 a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 14 parts by weight and the remaining part was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 4 the amount of tetracalcium phosphate particles (A1) used was 81.3 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 15.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate was used.
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that particles (C1), glycerin, propylene glycol, xylitol, polyethylene glycol and silica particles (E) were not used, and the remainder was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
  • Example 1 the amount of tetracalcium phosphate particles (A1) used is 0.87 parts by weight, the amount of disodium monohydrogen phosphate (B) particles is 0.17 parts by weight, and anhydrous calcium hydrogen phosphate particles
  • a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of (C1) used was 0.33 parts by weight, and the remainder was prepared with purified water, and the alkali metal ion concentration was measured and morphologically evaluated. And Vickers hardness measurement.
  • the composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.

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Abstract

A tooth calcification agent which comprises tetracalcium phosphate particles (A) and an alkali metal phosphate (B), characterized in that the content of the tetracalcium phosphate particles (A) is 1 to 80 parts by weight per 100 parts by weight of the total tooth calcification agent, and the content of the alkali metal phosphate (B) is 0.5 to 50 parts by weight per 100 parts by weight of the tetracalcium phosphate particles (A). Thus, a tooth calcification agent having an excellent calcification effect, in particular an excellent calcification effect on the surface of the enamel, is provided.

Description

歯牙石灰化剤及びその製造方法Tooth mineralizing agent and method for producing the same
　本発明は、歯牙表面を石灰化させる歯牙石灰化剤に関する。 The present invention relates to a tooth mineralizing agent that mineralizes the tooth surface.
　８０歳になっても２０本以上自分の歯を保とうとする、いわゆる８０２０運動（口腔衛生の向上、歯質の保存（ＭＩ：Ｍｉｎｉｍａｌ　Ｉｎｔｅｒｖｅｎｔｉｏｎ））に伴い、う蝕に罹患する前の初期う蝕の段階で石灰化を行い健全な歯質に戻す石灰化治療が近年脚光を浴びている。この観点から、有効成分としてフッ素やカルシウム可溶化剤（ＣＰＰ－ＡＣＰ；Casein Phosphopeptide-Amorphous Calcium Phosphate、ＰＯｓ－Ｃａ（登録商標）；リン酸化オリゴ糖カルシウム）が配合された機能性ガム、歯磨材、歯面処理材が各社より発売されている。しかしながら、フッ素は歯の耐酸性を向上させて、歯質のミネラル分を強化する機能があるとされているが、大量に摂取することによる副作用の問題があった。また、カルシウム可溶化剤を配合した材料は歯質付近に高濃度のミネラル分を供給できる反面、可溶性が高いためミネラル分の沈着能力は低いという問題もあった。 Early caries before suffering from caries due to so-called 8020 exercise (improving oral hygiene, preservation of tooth quality (MI: Minimal Intervention)), trying to keep 20 or more teeth even after 80 years old In recent years, calcification treatment that returns calcification to a healthy tooth has attracted attention in recent years. From this point of view, functional gums and dentifrices containing fluorine and calcium solubilizers as active ingredients (CPP-ACP; CaseinphoPhosphopeptide-Amorphous Calcium Phosphate, POs-Ca (registered trademark); phosphorylated oligosaccharide calcium), Tooth surface treatment materials are available from various companies. However, although fluorine is said to have a function of improving the acid resistance of teeth and strengthening the mineral content of the tooth, there is a problem of side effects caused by ingestion in large quantities. In addition, a material containing a calcium solubilizer can supply a high concentration of minerals in the vicinity of the tooth, but has a problem of low ability to deposit minerals due to its high solubility.
　一方、硬化性を有するリン酸カルシウム組成物として、リン酸四カルシウム（以下「ＴＴＣＰ」と略記することがある）と無水リン酸一水素カルシウム（以下「ＤＣＰＡ」と略記することがある）とを組み合わせたリン酸カルシウムセメント（以下「ＣＰＣ」と略記することがある）が知られており、生体内や口腔内において生体吸収性のヒドロキシアパタイト（以下「ＨＡｐ」と略記することがある；Ｃａ１０（ＰＯ４）６（ＯＨ）２）へ徐々に転化し、さらに形態を保ったままで生体硬組織と一体化し得るとされている。 On the other hand, as a calcium phosphate composition having curability, a combination of tetracalcium phosphate (hereinafter sometimes abbreviated as “TTCP”) and anhydrous calcium monohydrogen phosphate (hereinafter sometimes abbreviated as “DCPA”) is combined. Calcium phosphate cement (hereinafter may be abbreviated as “CPC”) is known, and is bioabsorbable hydroxyapatite (hereinafter abbreviated as “HAp” in vivo and oral cavity; Ca 10 (PO 4 ). 6 (OH) 2 ) is gradually converted to be integrated with living hard tissue while maintaining its form.
　例えば、特許第３０１７５３６号公報（特許文献１）には、リン酸四カルシウムとリン酸水素カルシウム無水物を含むリン酸カルシウム組成物が水の存在下で反応してヒドロキシアパタイトを生成することが記載されている。こうして得られたヒドロキシアパタイトは、生体硬組織と接触することによって骨へと徐々に置換することが可能であり、また、上記リン酸カルシウム組成物は石灰化能を有するため、石灰化剤としても使用できるとされている。一方、上記リン酸カルシウム組成物を迅速に硬化させる目的で、リン酸一水素二ナトリウム（Ｎａ２ＨＰＯ４）等のリン酸のアルカリ金属塩を加えることが記載されている。しかしながら、石灰化の効果を向上させる目的でリン酸のアルカリ金属塩を添加することについては記載も示唆もされていなかった。 For example, Japanese Patent No. 3017536 (Patent Document 1) describes that a calcium phosphate composition containing tetracalcium phosphate and calcium hydrogen phosphate anhydride reacts in the presence of water to produce hydroxyapatite. Yes. The hydroxyapatite thus obtained can be gradually replaced into bone by contact with the living hard tissue, and the calcium phosphate composition has a calcification ability, and therefore can be used as a mineralizing agent. It is said that. On the other hand, it is described that an alkali metal salt of phosphoric acid such as disodium monohydrogen phosphate (Na 2 HPO 4 ) is added for the purpose of rapidly curing the calcium phosphate composition. However, there has been no description or suggestion of adding an alkali metal salt of phosphoric acid for the purpose of improving the effect of calcification.
　また、特開平１－１６３１２７号公報（特許文献２）には、リン酸四カルシウム、Ｃａ／Ｐモル比が１．６７未満のリン酸カルシウム、及び増粘剤よりなる知覚過敏症治癒用組成物について記載されている。これによれば、歯牙の知覚過敏部位へ塗布して所定時間保持することにより、知覚過敏を著しく軽減させることができるとされている。知覚過敏が著しく低減する理由として、該組成物の水等との練和物中から溶出したカルシウムイオンやリン酸イオンが象牙細管へ拡散浸透して、この象牙細管中でヒドロキシアパタイトが析出沈積することにより外界からの機械的刺激、熱刺激、及び化学的刺激を遮断するためとされている。一方、上記知覚過敏症治癒用組成物に、水との練和性やペースト粘度の調節のために、ヒドロキシアパタイト、フッ化カルシウム、酸化チタン、水酸化カルシウム、リン酸ナトリウム、リン酸アンモニウム、アルミナ、シリカ等の他の成分を添加してもよいことが記載されている。しかしながら、石灰化の効果を向上させる目的でリン酸のアルカリ金属塩を添加することについては記載も示唆もされていなかった。 JP-A-1-163127 (Patent Document 2) describes a composition for healing hypersensitivity comprising tetracalcium phosphate, calcium phosphate having a Ca / P molar ratio of less than 1.67, and a thickener. Has been. According to this, it is said that hypersensitivity can be remarkably reduced by applying to a hypersensitive part of a tooth and holding it for a predetermined time. The reason why the hypersensitivity is remarkably reduced is that calcium ions and phosphate ions eluted from the mixture of water and the like of the composition diffuse and penetrate into the dentinal tubule, and hydroxyapatite precipitates and deposits in the dentinal tubule This is to block mechanical stimulation, thermal stimulation, and chemical stimulation from the outside. On the other hand, hydroxyapatite, calcium fluoride, titanium oxide, calcium hydroxide, sodium phosphate, ammonium phosphate, alumina for the above-mentioned composition for healing hypersensitivity to adjust kneadability with water and paste viscosity. It is described that other components such as silica may be added. However, there has been no description or suggestion of adding an alkali metal salt of phosphoric acid for the purpose of improving the effect of calcification.
特許第３０１７５３６号公報Japanese Patent No. 3017536 特開平１－１６３１２７号公報JP-A-1-163127
　本発明は上記課題を解決するためになされたものであり、石灰化効果の高い歯牙石灰化剤を提供することを目的とするものである。 The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a tooth mineralizing agent having a high calcification effect.
　上記課題は、リン酸四カルシウム粒子（Ａ）、及びリン酸のアルカリ金属塩（Ｂ）を含有する歯牙石灰化剤であって、該歯牙石灰化剤の全量１００重量部に対してリン酸四カルシウム粒子（Ａ）を１～８０重量部含み、かつリン酸四カルシウム粒子（Ａ）１００重量部に対するリン酸のアルカリ金属塩（Ｂ）の配合量が０．５～５０重量部であることを特徴とする歯牙石灰化剤を提供することによって解決される。 An object of the present invention is to provide a dental calcification agent containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and the total amount of the dental calcification agent is 100 parts by weight. It contains 1 to 80 parts by weight of calcium particles (A), and the blending amount of the alkali metal salt of phosphoric acid (B) with respect to 100 parts by weight of tetracalcium phosphate particles (A) is 0.5 to 50 parts by weight. It is solved by providing the tooth mineralizing agent characterized.
　このとき、リン酸のアルカリ金属塩（Ｂ）がリン酸一水素二ナトリウム及び／又はリン酸二水素一ナトリウムであることが好適であり、更に酸性リン酸カルシウム粒子（Ｃ）を含有することが好適である。酸性リン酸カルシウム粒子（Ｃ）が、無水リン酸一水素カルシウム［ＣａＨＰＯ４］粒子、無水リン酸二水素カルシウム［Ｃａ（Ｈ２ＰＯ４）２］粒子、リン酸三カルシウム［Ｃａ３（ＰＯ４）２］粒子、非晶性リン酸カルシウム［Ｃａ３（ＰＯ４）２・ｘＨ２Ｏ］粒子、酸性ピロリン酸カルシウム[ＣａＨ２Ｐ２Ｏ７]粒子、リン酸一水素カルシウム２水和物［ＣａＨＰＯ４・２Ｈ２Ｏ］粒子、及びリン酸二水素カルシウム１水和物［Ｃａ（Ｈ２ＰＯ４）２・Ｈ２Ｏ］粒子からなる群から選択される少なくとも１種であることが好適であり、リン酸四カルシウム粒子（Ａ）と酸性リン酸カルシウム粒子（Ｃ）の配合割合（Ａ／Ｃ）がモル比で４０／６０～６０／４０であることが好適である。更にフッ素化合物（Ｄ）を含有することが好適であり、フッ素化合物（Ｄ）がフッ化ナトリウムであることが好適である。リン酸四カルシウム粒子（Ａ）の平均粒径が０．５～４０μｍであることが好適であり、リン酸のアルカリ金属塩（Ｂ）の平均粒径が０．５～２０μｍであることが好適である。酸性リン酸カルシウム粒子（Ｃ）の平均粒径が０．１～７μｍであることが好適であり、更に平均粒径が０．００２～２μｍであるシリカ又は金属酸化物から選択される粒子（Ｅ）を含有することが好適である。 At this time, it is preferable that the alkali metal salt (B) of phosphoric acid is disodium monohydrogen phosphate and / or monosodium dihydrogen phosphate, and it is further preferable to contain acidic calcium phosphate particles (C). is there. Acidic calcium phosphate particles (C) are anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, tricalcium phosphate [Ca 3 (PO 4 ) 2. ] Particles, amorphous calcium phosphate [Ca 3 (PO 4 ) 2 · xH 2 O] particles, acidic calcium pyrophosphate [CaH 2 P 2 O 7 ] particles, calcium monohydrogen phosphate dihydrate [CaHPO 4 · 2H 2 O] particles, and at least one selected from the group consisting of calcium dihydrogen phosphate monohydrate [Ca (H 2 PO 4 ) 2 .H 2 O] particles. The mixing ratio (A / C) of the calcium particles (A) and the acidic calcium phosphate particles (C) is preferably 40/60 to 60/40 in terms of molar ratio. Furthermore, it is preferable to contain a fluorine compound (D), and it is preferable that the fluorine compound (D) is sodium fluoride. The average particle diameter of the tetracalcium phosphate particles (A) is preferably 0.5 to 40 μm, and the average particle diameter of the alkali metal salt of phosphoric acid (B) is preferably 0.5 to 20 μm. It is. The acidic calcium phosphate particles (C) preferably have an average particle size of 0.1 to 7 μm, and further particles (E) selected from silica or metal oxide having an average particle size of 0.002 to 2 μm. It is preferable to contain.
　また、このとき、該歯牙石灰化剤０．０５ｇを２５℃の純水２００ｇに投入して懸濁液を調製した際に、投入から１０分後における該懸濁液の遊離アルカリ金属イオン濃度が０．２～１００ｍｇ／Ｌであることが好適であり、遊離アルカリ金属イオン濃度の平均値をｄとしたときの標準偏差σがσ≦０．３ｄを満たすことが好適であり、アルカリ金属イオンがナトリウムイオンであることが好適である。 At this time, when a suspension was prepared by adding 0.05 g of the tooth mineralizing agent to 200 g of pure water at 25 ° C., the free alkali metal ion concentration of the suspension after 10 minutes from the addition was The standard deviation σ when the average value of the free alkali metal ion concentration is d is preferably σ ≦ 0.3d, and the alkali metal ion is preferably 0.2 to 100 mg / L. Sodium ion is preferred.
　また、歯牙石灰化剤を含有する歯面処理材が本発明の好適な実施態様であり、歯牙石灰化剤を含有する歯磨材が本発明の好適な実施態様である。歯牙石灰化剤を含有するチューイングガムが本発明の好適な実施態様であり、歯牙石灰化剤からなるエナメル質石灰化剤が本発明の好適な実施態様である。 Further, a tooth surface treating material containing a tooth mineralizing agent is a preferred embodiment of the present invention, and a dentifrice containing a tooth mineralizing agent is a preferred embodiment of the present invention. A chewing gum containing a tooth mineralizer is a preferred embodiment of the present invention, and an enamel mineralizer comprising a tooth mineralizer is a preferred embodiment of the present invention.
　また、上記課題は、リン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）、及び水を主成分とする液体又は水系ペーストを混合する歯牙石灰化剤の製造方法であって、リン酸四カルシウム粒子（Ａ）１００重量部に対してリン酸のアルカリ金属塩（Ｂ）を０．５～５０重量部配合し、歯牙石灰化剤の全量１００重量部に対するリン酸四カルシウム粒子（Ａ）の配合量を１～８０重量部とすることを特徴とする歯牙石灰化剤の製造方法を提供することによって解決される。 In addition, the above-mentioned problem is a method for producing a tooth mineralizer that mixes tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component, 0.5 to 50 parts by weight of alkali metal salt (B) of phosphoric acid is added to 100 parts by weight of tetracalcium phosphate particles (A), and tetracalcium phosphate particles (100 parts by weight of the total amount of tooth mineralizing agent) This can be solved by providing a method for producing a tooth mineralizing agent characterized in that the blending amount of A) is 1 to 80 parts by weight.
　このとき、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体、又はリン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体を予め混合することが好適であり、前記混合の際に、ジェットミル、ライカイ機、ボールミル、高速回転ミル、遊星ミル、ハイブリダイザー、メカノフュージョン又は混合押出し機から選択される少なくとも１種を用いることが好適である。 At this time, powder containing tetracalcium phosphate particles (A) and alkali metal salt of phosphoric acid (B), or tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles ( It is preferable to preliminarily mix the powder containing C), and at the time of the mixing, selected from a jet mill, a likai machine, a ball mill, a high-speed rotary mill, a planetary mill, a hybridizer, a mechano-fusion, or a mixing extruder It is preferable to use at least one kind.
　また、このとき、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストに、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストを加えて混合することが好適である。 At this time, a liquid or aqueous paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B) may be added to and mixed with the powder or non-aqueous paste containing the tetracalcium phosphate particles (A). Is preferred.
　更に上記課題は、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによって解決される。 Further, the above-mentioned problem is a tooth mineralizing agent comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component. Solved by providing a kit.
　上記課題は、リン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによって解決される。 The above-mentioned problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C), and a liquid or aqueous paste containing water as a main component. This is solved by providing a tooth mineralizer kit comprising:
　上記課題は、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによって解決される。 The subject is a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and a liquid or aqueous paste containing water as a main component and an alkali metal salt of phosphoric acid (B). Solved by providing.
　上記課題は、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによって解決される。 The above-mentioned problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and a liquid or water system containing water as a main component. This is solved by providing a tooth mineralizer kit comprising a paste.
　上記課題は、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とし酸性リン酸カルシウム粒子（Ｃ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによって解決される。 The above-described problems include a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or aqueous paste containing water as a main component and acidic calcium phosphate particles (C). This is solved by providing a tooth mineralizer kit comprising:
　また、上記課題は、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットを提供することによっても解決される。 Moreover, the said subject is a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and acidic calcium phosphate particles (C). It can also be solved by providing a tooth mineralizer kit comprising a powder or non-aqueous paste containing water and a liquid or water-based paste containing water as a main component.
　本発明により、石灰化効果の高い歯牙石灰化剤が提供され、特にエナメル質表面に対する石灰化効果の高い歯牙石灰化剤が提供される。このことにより、初期う蝕の段階での治療が可能となるばかりでなく、健全歯質、特に健全エナメル質を更に強化することが可能となり、う蝕を予防する材料を提供することが可能となる。 According to the present invention, a tooth mineralizing agent having a high calcification effect is provided, and in particular, a tooth mineralizing agent having a high mineralization effect on the enamel surface is provided. This makes it possible not only to treat at the stage of initial caries, but also to further strengthen healthy teeth, particularly healthy enamel, and to provide materials that prevent dental caries. Become.
実施例１において、エナメル質表層に作製した脱灰エナメル質（脱灰部分）のコンタクトマイクロラジオグラム像である。In Example 1, it is a contact microradiogram image of the demineralized enamel (demineralized part) produced in the enamel surface layer. 実施例１において、エナメル質表層に作製した脱灰エナメル質を歯牙石灰化剤により石灰化したエナメル質（石灰化部分）のコンタクトマイクロラジオグラム像である。In Example 1, it is a contact microradiogram image of the enamel (calcification part) which calcified the decalcification enamel produced in the enamel surface layer with the tooth mineralization agent.
　本発明の歯牙石灰化剤は、リン酸四カルシウム粒子（Ａ）、及びリン酸のアルカリ金属塩（Ｂ）を含有するものである。ここで、本発明で用いられる用語の「歯牙」には、「エナメル質」及び「象牙質」の両方が含まれる。リン酸四カルシウム粒子（Ａ）を含む組成物を水の存在下で混合するとヒドロキシアパタイトへ徐々に転化する。本発明者により、リン酸四カルシウム粒子（Ａ）、及びリン酸のアルカリ金属塩（Ｂ）を一定量含有する歯牙石灰化剤を用いることにより、石灰化効果が高く、特にエナメル質表面に対する石灰化効果が高いことが明らかとなった。この理由については必ずしも明らかではないが、以下のようなメカニズムが推定される。 The tooth mineralizing agent of the present invention contains tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B). Here, the term “dental” used in the present invention includes both “enamel” and “dentin”. When a composition containing tetracalcium phosphate particles (A) is mixed in the presence of water, it is gradually converted into hydroxyapatite. By using a tooth mineralizing agent containing a certain amount of tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), the present inventor has a high calcification effect, especially lime on the enamel surface. It became clear that the effect of crystallization is high. Although the reason for this is not necessarily clear, the following mechanism is presumed.
　すなわち、リン酸四カルシウム粒子（Ａ）、及びリン酸のアルカリ金属塩（Ｂ）を一定量含有する歯牙石灰化剤を水の存在下で調製して用いた際に、リン酸四カルシウム粒子（Ａ）が溶解して得られるカルシウムイオンと、リン酸のアルカリ金属塩（Ｂ）が溶解して得られるリン酸イオンとが反応してエネルギー的に安定なＨＡｐが析出するようである。その結果、エナメル質表面が石灰化されて該エナメル質表面のミネラル成分が回復されるようである。このことにより、初期う蝕の段階での治療が可能となる。ここで本発明者は、上記効果を奏するにはカルシウムイオンとリン酸イオンとが供給される速度のバランスが重要であると推察しており、また、カルシウムイオンを供給する化合物及びリン酸イオンを供給する化合物の溶解度が低い場合や極端に高い場合には、ＨＡｐの析出が良好ではないことを確認している。したがって、リン酸四カルシウム粒子（Ａ）とリン酸のアルカリ金属塩（Ｂ）を一定量含有することで、カルシウムイオンとリン酸イオンとの供給バランスが適切となる本発明の構成を採用する意義が大きい。 That is, when a tooth mineralization agent containing a certain amount of tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B) was prepared and used in the presence of water, tetracalcium phosphate particles ( It appears that calcium ions obtained by dissolving A) react with phosphate ions obtained by dissolving alkali metal salt (B) of phosphoric acid to precipitate energetically stable HAp. As a result, the enamel surface appears to be calcified and the mineral components on the enamel surface appear to be recovered. This allows treatment at the initial caries stage. Here, the present inventor presumes that the balance of the rate at which calcium ions and phosphate ions are supplied is important in order to achieve the above-described effects. When the solubility of the supplied compound is low or extremely high, it has been confirmed that the precipitation of HAp is not good. Therefore, the significance of adopting the configuration of the present invention in which the supply balance between calcium ions and phosphate ions is appropriate by containing a certain amount of tetracalcium phosphate particles (A) and alkali metal salt (B) of phosphate. Is big.
　本発明は、歯牙石灰化剤の全量１００重量部に対してリン酸四カルシウム粒子（Ａ）を１～８０重量部含む。リン酸四カルシウム粒子（Ａ）の含有量が１重量部未満の場合、ＨＡｐの析出が阻害されて石灰化効果が得られないおそれがあり、５重量部以上であることが好ましく、１０重量部以上であることがより好ましく、２０重量部以上であることが更に好ましい。一方、リン酸四カルシウム粒子（Ａ）の含有量が８０重量部を超える場合、ＨＡｐの析出が阻害されて石灰化効果が得られないおそれがあり、７５重量部以下であることが好ましく、７０重量部以下であることがより好ましく、６０重量部以下であることが更に好ましい。 The present invention contains 1 to 80 parts by weight of tetracalcium phosphate particles (A) with respect to 100 parts by weight of the total amount of the tooth mineralizing agent. When the content of the tetracalcium phosphate particles (A) is less than 1 part by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and the amount is preferably 5 parts by weight or more. More preferably, it is more preferably 20 parts by weight or more. On the other hand, when the content of the tetracalcium phosphate particles (A) exceeds 80 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and the amount is preferably 75 parts by weight or less. The amount is more preferably no more than parts by weight and even more preferably no more than 60 parts by weight.
　本発明で使用されるリン酸四カルシウム［Ｃａ４（ＰＯ４）２Ｏ］粒子（Ａ）の製造方法は特に限定されない。市販されているリン酸四カルシウム粒子をそのまま用いてもよいし、適宜粉砕して粒径を整えて使用してもよい。粉砕方法としては、後に説明する酸性リン酸カルシウム粒子（Ｃ）の粉砕方法と同様の方法を採用できる。 The manufacturing method of the tetracalcium phosphate [Ca 4 (PO 4 ) 2 O] particles (A) used in the present invention is not particularly limited. Commercially available tetracalcium phosphate particles may be used as they are, or may be used by appropriately pulverizing and adjusting the particle diameter. As the pulverization method, a method similar to the pulverization method of the acidic calcium phosphate particles (C) described later can be employed.
　本発明で用いられるリン酸四カルシウム粒子（Ａ）の平均粒径は、０．５～４０μｍであることが好ましい。平均粒径が０．５μｍ未満の場合、リン酸四カルシウム粒子（Ａ）の溶解が過度になることにより水溶液中のｐＨが高くなりヒドロキシアパタイトの析出が円滑でなくなることで、石灰化効果が得られないおそれがある。リン酸四カルシウム粒子（Ａ）の平均粒径は、より好適には５μｍ以上であり、更に好適には１０μｍ以上である。一方、平均粒径が４０μｍを超える場合、液剤との混合により得られるペーストが十分な粘性を示さないなどペースト性状が好ましくないおそれがある。また、ペースト練和時のざらつき感が大きくなり操作性が損なわれる、あるいは練和に用いられるスタティックミキサーからのペーストの取り出しが困難となるおそれもある。リン酸四カルシウム粒子（Ａ）の平均粒径は、３５μｍ以下であることがより好ましく、３０μｍ以下であることが更に好ましい。ここで、本発明で使用するリン酸四カルシウム粒子（Ａ）の平均粒径とは、レーザー回折式粒度分布測定装置を用いて測定し、算出したものである。 The average particle diameter of the tetracalcium phosphate particles (A) used in the present invention is preferably 0.5 to 40 μm. When the average particle size is less than 0.5 μm, the dissolution of the tetracalcium phosphate particles (A) becomes excessive, resulting in an increase in pH in the aqueous solution and the smooth precipitation of hydroxyapatite, thereby obtaining a calcification effect. There is a risk of not being able to. The average particle diameter of the tetracalcium phosphate particles (A) is more preferably 5 μm or more, and even more preferably 10 μm or more. On the other hand, when the average particle size exceeds 40 μm, the paste properties obtained by mixing with the liquid agent may not exhibit sufficient viscosity, such as insufficient viscosity. Further, the feeling of roughness during paste kneading may be increased and the operability may be impaired, or it may be difficult to take out the paste from a static mixer used for kneading. The average particle diameter of the tetracalcium phosphate particles (A) is more preferably 35 μm or less, and further preferably 30 μm or less. Here, the average particle diameter of the tetracalcium phosphate particles (A) used in the present invention is measured and calculated using a laser diffraction particle size distribution measuring device.
　本発明の歯牙石灰化剤は、リン酸四カルシウム粒子（Ａ）１００重量部に対してリン酸のアルカリ金属塩（Ｂ）を０．５～５０重量部含むものである。このように、リン酸四カルシウム粒子（Ａ）に加えてリン酸のアルカリ金属塩（Ｂ）を一定量含有することにより、石灰化効果が高く、特にエナメル質表面に対する石灰化効果が高い歯牙石灰化剤を提供することができる。リン酸のアルカリ金属塩（Ｂ）の含有量が０．５重量部未満の場合、ＨＡｐの析出が阻害されて石灰化効果が得られないおそれがあり、１重量部以上であることが好ましく、２重量部以上であることがより好ましい。一方、リン酸のアルカリ金属塩（Ｂ）の含有量が５０重量部を超える場合、ＨＡｐの析出が阻害されて石灰化効果が得られないおそれがあり、４０重量部以下であることが好ましく、３０重量部以下であることがより好ましく、２５重量部以下であることが更に好ましい。 The tooth mineralizing agent of the present invention contains 0.5 to 50 parts by weight of an alkali metal salt (B) of phosphoric acid with respect to 100 parts by weight of tetracalcium phosphate particles (A). Thus, by containing a certain amount of the alkali metal salt (B) of phosphoric acid in addition to the tetracalcium phosphate particles (A), tooth lime having a high calcification effect, particularly a high calcification effect on the enamel surface. An agent can be provided. When the content of the alkali metal salt of phosphoric acid (B) is less than 0.5 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and it is preferably 1 part by weight or more. More preferably, it is 2 parts by weight or more. On the other hand, when the content of the alkali metal salt of phosphoric acid (B) exceeds 50 parts by weight, precipitation of HAp may be inhibited and a calcification effect may not be obtained, and is preferably 40 parts by weight or less. The amount is more preferably 30 parts by weight or less, and further preferably 25 parts by weight or less.
　本発明で用いられるリン酸のアルカリ金属塩（Ｂ）としては特に限定されず、リン酸一水素二ナトリウム、リン酸一水素二カリウム、リン酸二水素一リチウム、リン酸二水素一ナトリウム、リン酸二水素一カリウム、リン酸三ナトリウム、リン酸三カリウム等が挙げられ、これらのうちの１種又は２種以上が用いられる。中でも、安全性や純度の高い原料が容易に入手できる観点から、リン酸のアルカリ金属塩（Ｂ）がリン酸一水素二ナトリウム及び／又はリン酸二水素一ナトリウムであることが好ましい。また、安全性の観点から、本発明で用いられるリン酸のアルカリ金属塩（Ｂ）におけるアルカリ金属イオンがナトリウムイオンであることが好ましい。 The alkali metal salt of phosphoric acid (B) used in the present invention is not particularly limited, and is disodium monohydrogen phosphate, dipotassium monohydrogen phosphate, dilithium monohydrogen phosphate, monosodium dihydrogen phosphate, phosphorus Examples include monopotassium dihydrogen acid, trisodium phosphate, tripotassium phosphate, and one or more of these are used. Especially, it is preferable that the alkali metal salt (B) of phosphoric acid is disodium monohydrogen phosphate and / or monosodium dihydrogen phosphate from a viewpoint that a raw material with high safety and high purity can be easily obtained. From the viewpoint of safety, the alkali metal ion in the alkali metal salt (B) of phosphoric acid used in the present invention is preferably a sodium ion.
　本発明で用いられるリン酸のアルカリ金属塩（Ｂ）の平均粒径が０．５～２０μｍであることが好ましい。リン酸のアルカリ金属塩（Ｂ）の平均粒径が０．５μｍ未満の場合、凝集が顕著となることで液剤又は粉剤中に均一に分散させることが困難となることから、水の存在下で調製した本発明の歯牙石灰化剤から放出されるリン酸のアルカリ金属塩（Ｂ）由来のリン酸イオンの歯牙に対する供給が不足し、カルシウムイオンとの供給バランスが崩れることで石灰化率が低下するとともにエナメル質硬度の向上効果が低下するおそれがあり、１μｍ以上であることがより好ましい。一方、リン酸のアルカリ金属塩（Ｂ）の平均粒径が２０μｍを超える場合、水の存在下で調製した本発明の歯牙石灰化剤から放出されるリン酸のアルカリ金属塩（Ｂ）由来のリン酸イオンの歯牙に対する供給が不足し、カルシウムイオンとの供給バランスが崩れることで石灰化率が低下するとともにエナメル質硬度の向上効果が低下してしまうおそれがある。リン酸のアルカリ金属塩（Ｂ）の平均粒径は１５μｍ以下であることがより好ましく、１０μｍ以下であることが更に好ましい。 The average particle size of the alkali metal salt (B) of phosphoric acid used in the present invention is preferably 0.5 to 20 μm. When the average particle size of the alkali metal salt of phosphoric acid (B) is less than 0.5 μm, it becomes difficult to uniformly disperse in the liquid or powder due to significant aggregation. The supply of phosphate ions derived from the alkali metal salt (B) of phosphoric acid released from the prepared tooth mineralizing agent of the present invention is insufficient for the teeth, and the supply balance with calcium ions is disrupted, resulting in a decrease in calcification rate. In addition, the effect of improving the enamel hardness may be reduced, and the thickness is more preferably 1 μm or more. On the other hand, when the average particle size of the alkali metal salt of phosphoric acid (B) exceeds 20 μm, it is derived from the alkali metal salt of phosphoric acid (B) released from the tooth mineralizer of the present invention prepared in the presence of water. The supply of phosphate ions to the teeth is insufficient, and the supply balance with calcium ions is lost, so that the calcification rate is lowered and the effect of improving enamel hardness may be reduced. The average particle size of the alkali metal salt of phosphoric acid (B) is more preferably 15 μm or less, and further preferably 10 μm or less.
　本発明の歯牙石灰化剤は、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）に加えて、更に酸性リン酸カルシウム粒子（Ｃ）を含有することが好ましい。このことにより、石灰化効果をより高めることが可能となる。本発明者は、この理由について、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）に加えて溶解度の低い酸性リン酸カルシウム粒子（Ｃ）を含有することにより、ペースト塗布後にカルシウムイオンとリン酸イオンをより長時間供給できるだけでなく、供給バランスがより適切となるためと推察している。 The tooth mineralizing agent of the present invention preferably further contains acidic calcium phosphate particles (C) in addition to tetracalcium phosphate particles (A) and alkali metal salt of phosphoric acid (B). This makes it possible to further enhance the calcification effect. For this reason, the inventor of the present invention contains calcium calcium phosphate particles (C) having low solubility in addition to tetracalcium phosphate particles (A) and alkali metal salts (B) of phosphoric acid, so that calcium ions are applied after applying the paste. It is assumed that not only phosphate ions can be supplied for a longer time, but also the supply balance becomes more appropriate.
　本発明で用いられる酸性リン酸カルシウム粒子（Ｃ）としては特に限定されず、無水リン酸一水素カルシウム［ＣａＨＰＯ４］粒子、無水リン酸二水素カルシウム［Ｃａ（Ｈ２ＰＯ４）２］粒子、リン酸三カルシウム［Ｃａ３（ＰＯ４）２］粒子、非晶性リン酸カルシウム［Ｃａ３（ＰＯ４）２・ｘＨ２Ｏ］粒子、酸性ピロリン酸カルシウム[ＣａＨ２Ｐ２Ｏ７]粒子、リン酸一水素カルシウム２水和物［ＣａＨＰＯ４・２Ｈ２Ｏ］粒子、及びリン酸二水素カルシウム１水和物［Ｃａ（Ｈ２ＰＯ４）２・Ｈ２Ｏ］粒子からなる群から選択される少なくとも１種であることが好ましい。これらの中でも、無水リン酸一水素カルシウム［ＣａＨＰＯ４］粒子、無水リン酸二水素カルシウム［Ｃａ（Ｈ２ＰＯ４）２］粒子、リン酸一水素カルシウム２水和物［ＣａＨＰＯ４・２Ｈ２Ｏ］粒子、及びリン酸二水素カルシウム１水和物［Ｃａ（Ｈ２ＰＯ４）２・Ｈ２Ｏ］粒子からなる群から選択される少なくとも１種がより好適に使用され、特に無水リン酸一水素カルシウム［ＣａＨＰＯ４］粒子、及び無水リン酸二水素カルシウム［Ｃａ（Ｈ２ＰＯ４）２］粒子からなる群から選択される少なくとも１種が更に好適に使用される。 The acidic calcium phosphate particles (C) used in the present invention are not particularly limited, and anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, phosphoric acid Tricalcium [Ca 3 (PO 4 ) 2 ] particles, amorphous calcium phosphate [Ca 3 (PO 4 ) 2 xH 2 O] particles, acidic calcium pyrophosphate [CaH 2 P 2 O 7 ] particles, calcium monohydrogen phosphate At least one selected from the group consisting of dihydrate [CaHPO 4 .2H 2 O] particles and calcium dihydrogen phosphate monohydrate [Ca (H 2 PO 4 ) 2 .H 2 O] particles. Preferably there is. Among these, anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, calcium monohydrogen phosphate dihydrate [CaHPO 4 .2H 2 O ], And at least one selected from the group consisting of calcium dihydrogen phosphate monohydrate [Ca (H 2 PO 4 ) 2 .H 2 O] particles is more preferably used. At least one selected from the group consisting of calcium hydrogen [CaHPO 4 ] particles and anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles is more preferably used.
　本発明で用いられる酸性リン酸カルシウム粒子（Ｃ）の平均粒径は、０．１～７μｍであることが好ましい。平均粒径が０．１μｍ未満の場合、液剤への溶解が過多となるためカルシウムイオンとリン酸イオンの供給バランスが崩れるだけでなく、液剤との混合により得られるペーストの粘度が高くなり過ぎるおそれがあり、より好適には０．３μｍ以上である。一方、平均粒径が７μｍを超える場合、酸性リン酸カルシウム粒子（Ｃ）が液剤へ溶解しにくくなるためリン酸四カルシウム粒子（Ａ）の溶解が過度となるおそれがある。その結果、カルシウムイオンとリン酸イオンの供給バランスが崩れることに加え、水溶液のｐＨが高くなることでヒドロキシアパタイトの析出が円滑でなくなり、石灰化効果が低下するおそれがある。酸性リン酸カルシウム粒子（Ｃ）の平均粒径は、より好適には３μｍ以下である。酸性リン酸カルシウム粒子（Ｃ）の平均粒径は、上記リン酸四カルシウム粒子（Ａ）の平均粒径と同様にして算出される。 The average particle diameter of the acidic calcium phosphate particles (C) used in the present invention is preferably 0.1 to 7 μm. When the average particle size is less than 0.1 μm, the solution is excessively dissolved in the liquid agent, so that not only the supply balance of calcium ions and phosphate ions is lost, but also the viscosity of the paste obtained by mixing with the liquid agent may be too high. More preferably, it is 0.3 μm or more. On the other hand, when the average particle diameter exceeds 7 μm, the acidic calcium phosphate particles (C) are difficult to dissolve in the liquid agent, so that the tetracalcium phosphate particles (A) may be excessively dissolved. As a result, the supply balance of calcium ions and phosphate ions is lost, and the pH of the aqueous solution is increased, so that the precipitation of hydroxyapatite is not smooth and the calcification effect may be reduced. The average particle diameter of the acidic calcium phosphate particles (C) is more preferably 3 μm or less. The average particle diameter of the acidic calcium phosphate particles (C) is calculated in the same manner as the average particle diameter of the tetracalcium phosphate particles (A).
　このような平均粒径を有する酸性リン酸カルシウム粒子（Ｃ）の製造方法は特に限定されず、市販品を入手できるのであればそれを使用してもよいが、市販品を更に粉砕することが好ましい場合が多い。その場合、ボールミル、ライカイ機、ジェットミルなどの粉砕装置を使用することができる。また、酸性リン酸カルシウム原料粉体をアルコールなどの液体の媒体と共にライカイ機、ボールミル等を用いて粉砕してスラリーを調製し、得られたスラリーを乾燥させることにより酸性リン酸カルシウム粒子（Ｃ）を得ることもできる。このときの粉砕装置としては、ボールミルを用いることが好ましく、そのポット及びボールの材質としては、好適にはアルミナやジルコニアが採用される。 The production method of acidic calcium phosphate particles (C) having such an average particle diameter is not particularly limited, and if a commercially available product can be obtained, it may be used, but it is preferable to further grind the commercially available product. There are many. In that case, a pulverizing apparatus such as a ball mill, a likai machine, or a jet mill can be used. Moreover, acidic calcium phosphate raw material powder is pulverized with a liquid medium such as alcohol using a lykai machine, a ball mill or the like to prepare a slurry, and the resulting slurry is dried to obtain acidic calcium phosphate particles (C). it can. A ball mill is preferably used as the pulverizer at this time, and alumina or zirconia is preferably used as the material of the pot and ball.
　ここで、酸性リン酸カルシウム粒子（Ｃ）の平均粒径に比べてリン酸四カルシウム粒子（Ａ）の平均粒径を大きくすることによって、両者の溶解度のバランスが適切となり、水溶液のｐＨを中性付近に維持することが可能となる。その結果、ヒドロキシアパタイトの析出が円滑となり、石灰化効果を向上させることができる。具体的には（Ａ）の平均粒径を（Ｃ）の平均粒径の２倍以上とすることがより好ましく、４倍以上とすることがさらに好ましく、７倍以上とすることが特に好ましい。一方、（Ａ）の平均粒径を（Ｃ）の平均粒径の３５倍以下とすることがより好ましく、３０倍以下とすることが更に好ましく、２５倍以下とすることが特に好ましい。 Here, by increasing the average particle size of the tetracalcium phosphate particles (A) compared to the average particle size of the acidic calcium phosphate particles (C), the solubility balance between the two becomes appropriate, and the pH of the aqueous solution is near neutral. Can be maintained. As a result, the precipitation of hydroxyapatite becomes smooth and the calcification effect can be improved. Specifically, the average particle size of (A) is more preferably 2 times or more than the average particle size of (C), more preferably 4 times or more, and particularly preferably 7 times or more. On the other hand, the average particle size of (A) is more preferably 35 times or less of the average particle size of (C), still more preferably 30 times or less, and particularly preferably 25 times or less.
　リン酸四カルシウム粒子（Ａ）と酸性リン酸カルシウム粒子（Ｃ）の配合割合（Ａ／Ｃ）は特に限定されず、モル比で４０／６０～６０／４０の範囲となるような配合割合で使用されることが好ましい。このことにより、石灰化効果の高い本発明の歯牙石灰化剤を得ることができる。上記配合割合（Ａ／Ｃ）は、より好適には４５／５５～５５／４５であり、実質的に５０／５０であることが最適である。 The blending ratio (A / C) of the tetracalcium phosphate particles (A) and the acidic calcium phosphate particles (C) is not particularly limited, and is used in a blending ratio such that the molar ratio is in the range of 40/60 to 60/40. It is preferable. By this, the tooth mineralizer of this invention with a high calcification effect can be obtained. The blending ratio (A / C) is more preferably 45/55 to 55/45, and most preferably substantially 50/50.
　本発明の歯牙石灰化剤は、更にフッ素化合物（Ｄ）を含有することが好ましい。このことにより、歯質に耐酸性を付与させるとともに石灰化を促進させることが可能となる。本発明で用いられるフッ素化合物（Ｄ）としては特に限定されず、フッ化ナトリウム、フッ化カリウム、フッ化アンモニウム、フッ化リチウム、フッ化セシウム、フッ化マグネシウム、フッ化カルシウム、フッ化ストロンチウム、フッ化ストロンチウム、フッ化バリウム、フッ化銅、フッ化ジルコニウム、フッ化アルミニウム、フッ化スズ、モノフルオロリン酸ナトリウム、モノフルオロリン酸カリウム、フッ化水素酸、フッ化チタンナトリウム、フッ化チタンカリウム、ヘキシルアミンハイドロフルオライド、ラウリルアミンハイドロフルオライド、グリシンハイドロフルオライド、アラニンハイドロフルオライド、フルオロシラン類、フッ化ジアミン銀等が挙げられる。中でも石灰化促進効果の観点からフッ化ナトリウム、モノフルオロリン酸ナトリウム、フッ化スズが好適に用いられる。フッ素化合物（Ｄ）の使用量は特に限定されず、歯牙石灰化剤の全量１００重量部に対してフッ素化合物（Ｄ）の換算フッ化物イオンを０．０１～３重量部含むことが好ましい。フッ素化合物（Ｄ）の換算フッ化物イオンの使用量が０．０１重量部未満の場合、石灰化を促進する効果が低下するおそれがあり、０．０５重量部以上であることがより好ましい。一方、フッ素化合物（Ｄ）の換算フッ化物イオンの使用量が３重量部を超える場合、安全性が損なわれるおそれがあり、１重量部以下であることがより好ましい。 The tooth mineralizing agent of the present invention preferably further contains a fluorine compound (D). This makes it possible to impart acid resistance to the tooth and promote calcification. The fluorine compound (D) used in the present invention is not particularly limited, and is sodium fluoride, potassium fluoride, ammonium fluoride, lithium fluoride, cesium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, fluorine. Strontium fluoride, barium fluoride, copper fluoride, zirconium fluoride, aluminum fluoride, tin fluoride, sodium monofluorophosphate, potassium monofluorophosphate, hydrofluoric acid, sodium titanium fluoride, potassium titanium fluoride, Examples include hexylamine hydrofluoride, laurylamine hydrofluoride, glycine hydrofluoride, alanine hydrofluoride, fluorosilanes, and silver fluorinated diamine. Of these, sodium fluoride, sodium monofluorophosphate, and tin fluoride are preferably used from the viewpoint of the calcification promoting effect. The amount of the fluorine compound (D) used is not particularly limited, and it is preferable to contain 0.01 to 3 parts by weight of the converted fluoride ion of the fluorine compound (D) with respect to 100 parts by weight of the total amount of the tooth mineralizing agent. When the usage-amount of the fluoride ion of a fluorine compound (D) is less than 0.01 weight part, there exists a possibility that the effect which accelerates | stimulates calcification may fall, and it is more preferable that it is 0.05 weight part or more. On the other hand, when the usage-amount of the fluoride ion of a fluorine compound (D) exceeds 3 weight part, safety | security may be impaired and it is more preferable that it is 1 weight part or less.
　本発明の歯牙石灰化剤は、本発明の効果を阻害しない範囲でリン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）、酸性リン酸カルシウム粒子（Ｃ）及びフッ素化合物（Ｄ）以外の成分を含有しても構わない。例えば、必要に応じて増粘剤を配合することができる。増粘剤の具体例としては、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ポリエチレングリコール、ポリアクリル酸、ポリスチレンスルホン酸、ポリスチレンスルホン酸塩、ポリグルタミン酸、ポリグルタミン酸塩、ポリアスパラギン酸、ポリアスパラギン酸塩、ポリＬリジン、ポリＬリジン塩、セルロース以外のデンプン、アルギン酸、アルギン酸塩、カラジーナン、グアーガム、キタンサンガム、セルロースガム、ヒアルロン酸、ヒアルロン酸塩、ペクチン、ペクチン塩、キチン、キトサン等の多糖類、アルギン酸プロピレングリコールエステル等の酸性多糖類エステル、またコラーゲン、ゼラチン及びこれらの誘導体などのタンパク質類等の高分子などから選択される１つ又は２つ以上が挙げられるが、水への溶解性及び粘性の面からはカルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、アルギン酸、アルギン酸塩、キトサン、ポリグルタミン酸、ポリグルタミン酸塩から選択される少なくとも１つが好ましい。増粘剤は、粉体に配合してもよいし液剤に配合してもよく、また混合中のペーストに配合してもよい。 The tooth mineralizing agent of the present invention is other than tetracalcium phosphate particles (A), alkali metal salts of phosphoric acid (B), acidic calcium phosphate particles (C), and fluorine compounds (D) as long as the effects of the present invention are not impaired. These components may be contained. For example, a thickener can be mix | blended as needed. Specific examples of the thickener include carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, polystyrene sulfonic acid, polystyrene sulfonate, polyglutamic acid, polyglutamate, Polyaspartic acid, polyaspartate, poly L lysine, poly L lysine salt, starch other than cellulose, alginic acid, alginate, carrageenan, guar gum, chitansan gum, cellulose gum, hyaluronic acid, hyaluronate, pectin, pectin salt, chitin , Polysaccharides such as chitosan, acidic polysaccharide esters such as propylene glycol alginate, collagen, gelatin and these One or two or more selected from polymers such as proteins such as conductors may be mentioned. From the viewpoint of solubility in water and viscosity, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginic acid, At least one selected from alginate, chitosan, polyglutamic acid, polyglutamate is preferred. The thickener may be blended into the powder, the liquid, or the paste being mixed.
　また、必要に応じてシリカ、金属酸化物等に代表される無機フィラー、グリセリン、エチレングリコール、プロピレングリコール、ジグリセリン等の多価アルコール、キシリトール、ソルビトール、エリスリトール等の糖アルコール、ポリエチレングリコール、ポリプロピレングリコール等のポリエーテル、アスパルテーム、アセスルファムカリウム、カンゾウ抽出液、サッカリン、サッカリンナトリウム等の人工甘味料などを加えてもよい。これらの中でも、本発明の歯牙石灰化剤は、無機フィラーを含有することが好ましく、平均粒径が０．００２～２μｍであるシリカ又は金属酸化物から選択される粒子（Ｅ）を含有することがより好ましく、平均粒径が０．００２～２μｍであるシリカ粒子（Ｅ）を含有することが更に好ましい。 If necessary, inorganic fillers such as silica and metal oxides, polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol and diglycerin, sugar alcohols such as xylitol, sorbitol and erythritol, polyethylene glycol and polypropylene glycol Polyethers such as aspartame, acesulfame potassium, licorice extract, artificial sweeteners such as saccharin and sodium saccharin may be added. Among these, the tooth mineralizing agent of the present invention preferably contains an inorganic filler, and contains particles (E) selected from silica or metal oxide having an average particle diameter of 0.002 to 2 μm. It is more preferable to contain silica particles (E) having an average particle diameter of 0.002 to 2 μm.
　更に、薬理学的に許容できるあらゆる薬剤等を配合することができる。セチルピリジニウムクロリド等に代表される抗菌剤、消毒剤、抗癌剤、抗生物質、アクトシン、ＰＥＧ１などの血行改善薬、ｂＦＧＦ、ＰＤＧＦ、ＢＭＰなどの増殖因子、骨芽細胞、象牙芽細胞、さらに未分化な骨髄由来幹細胞、胚性幹（ＥＳ）細胞、線維芽細胞等の分化細胞を遺伝子導入により脱分化・作製した人工多能性幹（ｉＰＳ：ｉｎｄｕｃｅｄ　Ｐｌｕｒｉｐｏｔｅｎｔ　Ｓｔｅｍ）細胞ならびにこれらを分化させた細胞など硬組織形成を促進させる細胞などを配合させることができる。 Furthermore, any pharmacologically acceptable drug or the like can be blended. Antibacterial agents typified by cetylpyridinium chloride, antiseptics, anticancer agents, antibiotics, blood circulation improving agents such as actins and PEG1, growth factors such as bFGF, PDGF and BMP, osteoblasts, odontoblasts, and undifferentiated Bone marrow-derived stem cells, embryonic stem (ES) cells, induced pluripotent stem (iPS) cells obtained by dedifferentiation and production of differentiated cells such as fibroblasts by gene transfer, and cells such as these differentiated cells Cells or the like that promote tissue formation can be added.
　本発明の歯牙石灰化剤は、該歯牙石灰化剤０．０５ｇを２５℃の純水２００ｇに投入して懸濁液を調製した際に、投入から１０分後における該懸濁液の遊離アルカリ金属イオン濃度が０．２～１００ｍｇ／Ｌであることが好ましい。前記遊離アルカリ金属イオン濃度がこのような範囲にあることで、石灰化率並びにエナメル質硬度の向上効果が良好な歯牙石灰化剤が得られる利点を有する。前記遊離アルカリ金属イオン濃度が０．２ｍｇ／Ｌ未満の場合、アルカリ金属イオンと共に供給されるリン酸イオンが不足することから歯牙へのイオンの供給バランスが崩れ、ヒドロキシアパタイトへの転化が円滑でなくなり、石灰化率並びにエナメル質硬度の向上効果が良好な歯牙石灰化剤が得られないおそれがあり、０．５ｍｇ／Ｌ以上であることがより好ましく、１ｍｇ／Ｌ以上であることが一層好ましい。一方、前記遊離アルカリ金属イオン濃度が１００ｍｇ／Ｌを超える場合、アルカリ金属イオンと共に供給されるリン酸イオンが過多となることから歯牙へのイオンの供給バランスが崩れ、ヒドロキシアパタイトへの転化が円滑でなくなり、石灰化率並びにエナメル質硬度の向上効果が良好な歯牙石灰化剤が得られないだけでなく、過剰のナトリウムイオンがヒドロキシアパタイトへの転化を阻害するおそれがあり、５０ｍｇ／Ｌ以下であることがより好ましく、３０ｍｇ／Ｌ以下であることが一層好ましい。遊離アルカリ金属イオンの測定方法は任意の方法を選択できる。懸濁液の上清を採取し、ＩＣＰ発光分光分析装置あるいはイオンクロマトグラフィーにより測定を行うことも可能であるし、懸濁液中にアルカリ金属イオン濃度に応答する電極を直接浸漬する測定方法を用いても良い。 The tooth mineralizer of the present invention was prepared by adding 0.05 g of the tooth mineralizer to 200 g of pure water at 25 ° C. to prepare a suspension, and the free alkali of the suspension 10 minutes after the addition. The metal ion concentration is preferably 0.2 to 100 mg / L. When the free alkali metal ion concentration is in such a range, there is an advantage that a tooth mineralizing agent having an excellent effect of improving the calcification rate and enamel hardness can be obtained. When the free alkali metal ion concentration is less than 0.2 mg / L, phosphate ions supplied together with the alkali metal ions are insufficient, so the supply balance of ions to the teeth is disrupted, and conversion to hydroxyapatite is not smooth. Further, there is a possibility that a tooth mineralizing agent having an excellent effect of improving the calcification rate and enamel hardness may not be obtained, and it is more preferably 0.5 mg / L or more, and further preferably 1 mg / L or more. On the other hand, when the concentration of the free alkali metal ion exceeds 100 mg / L, the phosphate ion supplied together with the alkali metal ion becomes excessive, so the supply balance of ions to the teeth is disrupted, and the conversion to hydroxyapatite is smooth. Not only is a tooth mineralizing agent having a good effect of improving the calcification rate and enamel hardness not obtained, but excessive sodium ions may inhibit the conversion to hydroxyapatite, and is 50 mg / L or less. More preferably, it is more preferably 30 mg / L or less. Any method can be selected as a method for measuring free alkali metal ions. It is possible to collect the supernatant of the suspension and measure with an ICP emission spectrophotometer or ion chromatography. A measurement method that directly immerses the electrode in response to the alkali metal ion concentration in the suspension. It may be used.
　また、本発明の象牙質石灰化剤は、前記遊離アルカリ金属イオン濃度の平均値をｄとしたときの標準偏差σがσ≦０．３ｄを満たすこと、すなわち、標準偏差σを前記遊離アルカリ金属イオン濃度の平均値ｄで割った値（σ／ｄ）が０．３以下であることが好ましい。このことにより、リン酸のアルカリ金属塩（Ｂ）の均一性が良好となり、更に石灰化率が良好でエナメル質硬度の向上効果が良好な歯牙石灰化剤が得られる利点を有する。この理由については必ずしも明らかではないが、以下のようなメカニズムが推定される。すなわち、リン酸のアルカリ金属塩（Ｂ）の均一性が良好でない場合、リン酸のアルカリ金属塩（Ｂ）が凝集しており、水に溶解しにくい状態になっていることから水の存在下で調製した本発明の歯牙石灰化剤から放出されるリン酸のアルカリ金属塩（Ｂ）由来のリン酸イオンの歯牙に対する供給が不足し、カルシウムイオンとの供給バランスが崩れることで石灰化率が低下するとともにエナメル質硬度の向上効果が低下してしまうと考えられる。 Further, the dentin mineralizing agent of the present invention has a standard deviation σ satisfying σ ≦ 0.3d when the average value of the free alkali metal ion concentration is d, that is, the standard deviation σ is the free alkali metal. The value (σ / d) divided by the average value d of ion concentrations is preferably 0.3 or less. As a result, the homogeneity of the alkali metal salt (B) of phosphoric acid is improved, and there is an advantage that a tooth mineralizing agent having a good calcification rate and a good effect of improving the enamel hardness can be obtained. Although the reason for this is not necessarily clear, the following mechanism is presumed. That is, when the uniformity of the alkali metal salt (B) of phosphoric acid is not good, the alkali metal salt (B) of phosphoric acid is agglomerated and is hardly dissolved in water. The lack of supply to the teeth of phosphate ions derived from alkali metal salt (B) of phosphoric acid released from the tooth mineralizing agent of the present invention prepared in the above, and the supply balance with calcium ions is disrupted, resulting in a calcification rate. It is thought that the improvement effect of enamel hardness will fall with decreasing.
　本発明では、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含有する粉体と、水を主成分とする液体又は水系ペーストとを混合することにより、ペースト状の歯牙石灰化剤を得ることができる。水を含むこのペースト状の歯牙石灰化剤は、直ちにＨＡｐに転化する反応が起こり始めるため、医療現場で使用する直前に混合して調製することが好ましい。混合操作としては特に限定されず、手混合、スタティックミキサーを用いた混合等が好ましく採用される。ここで、本発明者はリン酸のアルカリ金属塩（Ｂ）の含有量が適切な範囲にあると石灰化効果が高いことを確認している。しかしながら、リン酸のアルカリ金属塩（Ｂ）の水に対する溶解度がそれ程高くないため、リン酸のアルカリ金属塩（Ｂ）を粉体で加える上記混合方法が好ましく採用される。 In the present invention, a paste-like tooth is prepared by mixing a powder containing tetracalcium phosphate particles (A) and an alkali metal salt (B) of phosphoric acid with a liquid mainly composed of water or an aqueous paste. A mineralizing agent can be obtained. Since this paste-like tooth mineralizer containing water immediately begins to undergo a reaction for conversion into HAp, it is preferably prepared by mixing immediately before use in a medical field. The mixing operation is not particularly limited, and hand mixing, mixing using a static mixer, and the like are preferably employed. Here, the inventor has confirmed that the calcification effect is high when the content of the alkali metal salt (B) of phosphoric acid is in an appropriate range. However, since the solubility of the alkali metal salt of phosphoric acid (B) in water is not so high, the above mixing method in which the alkali metal salt of phosphoric acid (B) is added in powder form is preferably employed.
　こうして得られた歯牙石灰化剤は、エナメル質表面に塗布等することにより好適に使用される。ここで、水を主成分とする液体とは、純水であっても、水を主成分とし他の成分を含有する液体であってもよく、また、水を主成分とする水系ペーストとは、水を主成分とし他の成分を含有するペースト状の液体を示す。他の成分としては特に限定されず、上述の酸性リン酸カルシウム粒子（Ｃ）、グリセリン、エチレングリコール、プロピレングリコール、ジグリセリン等の多価アルコール、キシリトール、ソルビトール、エリスリトール等の糖アルコール、ポリエチレングリコール、ポリプロピレングリコール等のポリエーテルなどが例示される。他の成分として酸性リン酸カルシウム粒子（Ｃ）を含む場合、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストに、水を主成分とし酸性リン酸カルシウム粒子（Ｃ）を含む液体又は水系ペーストを加えて混合する方法も好ましく採用される。 The tooth mineralizing agent thus obtained is suitably used by applying it to the enamel surface. Here, the liquid containing water as a main component may be pure water, or a liquid containing water as a main component and containing other components, and the water-based paste containing water as a main component. The paste-like liquid which has water as a main component and contains another component is shown. Other components are not particularly limited, and the above-mentioned acidic calcium phosphate particles (C), polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, diglycerin, sugar alcohols such as xylitol, sorbitol, erythritol, polyethylene glycol, polypropylene glycol And the like. In the case where acidic calcium phosphate particles (C) are contained as other components, acidic calcium phosphate particles containing water as a main component in a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B) A method of adding and mixing the liquid or aqueous paste containing (C) is also preferably employed.
　また、本発明では、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストに、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストを加えて混合することによってもペースト状の歯牙石灰化剤を得ることができる。ここで、水の存在下ではリン酸四カルシウム粒子（Ａ）が溶解して徐々にＨＡｐに転化する反応が起こるため、水を主成分とする液体又は水系ペーストとリン酸四カルシウム粒子（Ａ）とを予め混合して保存しておくことができない。したがって、リン酸四カルシウム粒子（Ａ）を含む粉体又は水以外の他の溶媒を主成分とする非水系ペーストと、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストとを混合する方法が好適に採用され、使用直前に混合して調製する際の操作が簡便である利点も有する。また、非水系ペーストに使用される水以外の溶媒としては特に限定されず、例えば、グリセリン、エチレングリコール、プロピレングリコール、ジグリセリン等の多価アルコール、ポリエチレングリコール、ポリプロピレングリコール等のポリエーテルなどが例示される。 In the present invention, a liquid or water-based paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B) is added to and mixed with powder or non-aqueous paste containing tetracalcium phosphate particles (A). The paste-like tooth mineralizing agent can also be obtained. Here, in the presence of water, a reaction occurs in which the tetracalcium phosphate particles (A) are dissolved and gradually converted to HAp. Therefore, a liquid or aqueous paste containing water as a main component and the tetracalcium phosphate particles (A) Cannot be premixed and stored. Therefore, a liquid or aqueous system containing a non-aqueous paste containing a powder containing tetracalcium phosphate particles (A) or a solvent other than water as a main component and an alkali metal salt of phosphoric acid (B) containing water as a main component. A method of mixing with the paste is preferably employed, and there is also an advantage that the operation at the time of mixing and preparing immediately before use is simple. In addition, the solvent other than water used in the non-aqueous paste is not particularly limited, and examples thereof include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, and diglycerin, and polyethers such as polyethylene glycol and polypropylene glycol. Is done.
　また、本発明において、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体、又はリン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体を予め混合することが好ましい。このことにより、石灰化率が良好となる利点を有する。特に、本発明の歯牙石灰化剤をエナメル質表面に対して用いた場合、石灰化された後のエナメル質硬度が向上する利点を有する。ここで、前記混合の際には、ジェットミル、ライカイ機、ボールミル、高速回転ミル、遊星ミル、ハイブリダイザー、メカノフュージョン又は混合押出し機から選択される少なくとも１種を用いることが好ましい。石灰化率をより高める観点から、ボールミル、ライカイ機、高速回転ミル、ジェットミルから選択される少なくとも１種を用いることが好ましい。 In the present invention, a powder containing tetracalcium phosphate particles (A) and an alkali metal salt (B) of phosphoric acid, or tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B) and an acid It is preferable to previously mix powder containing calcium phosphate particles (C). This has the advantage that the calcification rate is good. In particular, when the tooth mineralizing agent of the present invention is used on the enamel surface, it has the advantage that the enamel hardness after calcification is improved. Here, at the time of the mixing, it is preferable to use at least one selected from a jet mill, a likai machine, a ball mill, a high-speed rotary mill, a planetary mill, a hybridizer, a mechanofusion, or a mixing extruder. From the viewpoint of further increasing the calcification rate, it is preferable to use at least one selected from a ball mill, a reiki machine, a high-speed rotary mill, and a jet mill.
　本発明の歯牙石灰化剤は、歯面処理材、歯磨材、又はチューイングガムの各種用途に好ましく用いられる。水の存在下ではリン酸四カルシウム粒子（Ａ）が溶解して徐々にＨＡｐに転化する反応が起こるため、歯磨材やチューイングガムなどのように使用時に適宜水分が供給されるような態様であってもよいし、歯面処理材などのように使用直前に液剤と適宜混合するような態様であってもよい。したがって、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットであることが本発明の実施態様の一つである。また、リン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットであることが本発明の実施態様の一つである。また、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キットであることが本発明の実施態様の一つである。また、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットであることが本発明の実施態様の一つである。また、リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とし酸性リン酸カルシウム粒子（Ｃ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キットであることが本発明の実施態様の一つである。また、リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キットであることも本発明の実施態様の一つである。また、こうして用いられる本発明の歯牙石灰化剤は、エナメル質表面に対する石灰化効果が高く、歯牙石灰化剤からなるエナメル質石灰化剤が本発明の好適な実施態様である。 The tooth mineralizing agent of the present invention is preferably used for various uses of tooth surface treatment materials, dentifrices, or chewing gums. In the presence of water, a reaction occurs in which the tetracalcium phosphate particles (A) are dissolved and gradually converted to HAp, so that moisture is appropriately supplied at the time of use such as a dentifrice or chewing gum. Alternatively, it may be a mode in which it is appropriately mixed with a liquid just before use, such as a tooth surface treatment material. Accordingly, a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component. This is one of the embodiments of the present invention. Further, it comprises a powder or non-aqueous paste containing tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C), and a liquid or water-based paste containing water as a main component. One embodiment of the present invention is a tooth mineralizer kit. Also, a tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and a liquid or aqueous paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B). This is one of the embodiments of the present invention. Further, a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and a liquid or aqueous paste mainly containing water One embodiment of the present invention is a tooth mineralizer kit comprising: Further, it comprises a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or aqueous paste containing water as a main component and containing acidic calcium phosphate particles (C). One embodiment of the present invention is a tooth mineralizer kit. Further, a powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and a powder containing acidic calcium phosphate particles (C) or One embodiment of the present invention is a tooth mineralizer kit comprising a non-aqueous paste and a liquid or water-based paste containing water as a main component. The tooth mineralizing agent of the present invention used in this way has a high calcification effect on the enamel surface, and an enamel mineralizing agent comprising a tooth mineralizing agent is a preferred embodiment of the present invention.
　以下、実施例を用いて本発明を更に具体的に説明する。本実施例においてリン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）粒子、酸性リン酸カルシウム粒子（Ｃ）及びフッ化ナトリウム（Ｄ）粒子の平均粒径は、レーザー回折式粒度分布測定装置（株式会社島津製作所製「ＳＡＬＤ－２１００型」）を用いて測定し、測定の結果から算出されるメディアン径を平均粒径とした。 Hereinafter, the present invention will be described more specifically using examples. In this example, the average particle size of tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) particles, acidic calcium phosphate particles (C) and sodium fluoride (D) particles is measured by laser diffraction particle size distribution. Measurement was performed using a device (“SALD-2100 type” manufactured by Shimadzu Corporation), and the median diameter calculated from the measurement result was defined as the average particle diameter.
［石灰化用牛歯の調製］
　健全牛歯切歯の頬側中央を＃８０，＃１０００研磨紙を用いて回転研磨機により研磨し、エナメル質を露出させた。この牛歯研磨面をさらにラッピングフィルム（＃１２００，＃３０００，＃８０００，住友スリーエム社製）を用いて研磨し、平滑とした。この研磨エナメル質部分に歯に対して縦軸方向及び横軸方向に各７ｍｍ試験部分の窓を残し（以下、「エナメル質窓」と称する）、周りをマニキュアでマスキングし、１時間風乾した。この牛歯を、Ｒｅｙｎｏｌｄｓら（E. C. Reynolds, J. Dent. Res., 76(9), 1587-1595.）の手法に準じて人工脱灰液（０．１ｍｏｌ／Ｌ乳酸、０．５ｇ／Ｌヒドロキシアパタイト、２０ｇ／Ｌポリアクリル酸（Ｍｗ：２５０ｋＤａ）、ＮａＯＨ適量、ｐＨ４．８）中に５日間浸漬して脱灰を行った。人工脱灰液は毎日交換した。脱灰エナメル質窓の半分をマニキュアでマスキングし、１時間風乾することで石灰化に用いる牛歯を調製した。 [Preparation of bovine teeth for calcification]
The center of the buccal side of a healthy bovine incisor was polished with a rotary polishing machine using # 80, # 1000 polishing paper to expose the enamel. The polished surface of the bovine teeth was further polished and smoothed using a wrapping film (# 1200, # 3000, # 8000, manufactured by Sumitomo 3M). The polished enamel portion was left with 7 mm test portion windows (hereinafter referred to as “enamel windows”) in the longitudinal and transverse directions with respect to the teeth, masked with nail polish, and air-dried for 1 hour. The bovine teeth were artificially decalcified (0.1 mol / L lactic acid, 0.5 g / L) according to the method of Reynolds et al. (EC Reynolds, J. Dent. Res., 76 (9), 1587-1595.). Decalcification was carried out by dipping in hydroxyapatite, 20 g / L polyacrylic acid (Mw: 250 kDa), appropriate amount of NaOH, pH 4.8) for 5 days. The artificial decalcification liquid was changed every day. Half of the decalcified enamel window was masked with nail polish and air dried for 1 hour to prepare bovine teeth for calcification.
［擬似唾液の調製］
　塩化ナトリウム（８．７７ｇ，１５０ｍｍｏｌ）、リン酸二水素カリウム（１２２ｍｇ，０．９ｍｍｏｌ）、塩化カルシウム（１６６ｍｇ，１．５ｍｍｏｌ）、Ｈｅｐｅｓ（４．７７ｇ，２０ｍｍｏｌ）をそれぞれ秤量皿に量り取り、約８００ｍｌの蒸留水を入れた２０００ｍｌビーカーに攪拌下に順次加えた。溶質が完全に溶解したことを確認した後、この溶液の酸性度をｐＨメータ（Ｆ５５、堀場製作所）で測定しながら、１０％水酸化ナトリウム水溶液を滴下し、ｐＨ７．０とした。次にこの溶液を１０００ｍｌメスフラスコに加えてメスアップし、擬似唾液１０００ｍｌを得た。 [Preparation of simulated saliva]
Sodium chloride (8.77 g, 150 mmol), potassium dihydrogen phosphate (122 mg, 0.9 mmol), calcium chloride (166 mg, 1.5 mmol), and Hepes (4.77 g, 20 mmol) were weighed into weighing pans, respectively. The mixture was sequentially added to a 2000 ml beaker containing 800 ml of distilled water with stirring. After confirming that the solute was completely dissolved, a 10% aqueous sodium hydroxide solution was added dropwise to measure pH 7.0 while measuring the acidity of the solution with a pH meter (F55, Horiba Seisakusho). Next, this solution was added to a 1000 ml volumetric flask and the volume was increased to obtain 1000 ml of simulated saliva.
実施例１
［歯牙石灰化剤の調製］
（１）リン酸四カルシウム粒子（Ａ）の調製
　本実施例で使用するリン酸四カルシウム粒子（Ａ１）（平均粒径２３．１μｍ）は、以下の通り調製した粗リン酸四カルシウムを粉砕することにより得た。市販の無水リン酸一水素カルシウム粒子（Product No. 1430, J.T.Baker Chemical Co., NJ）及び炭酸カルシウム（Product No. 1288, J.T.Baker Chemical Co., NJ）を等モルとなる様に水中に加え、１時間撹拌した後、ろ過・乾燥することで得られたケーキ状の等モル混合物を電気炉（ＦＵＳ７３２ＰＢ，アドバンテック東洋(株)製）中で１５００℃、２４時間加熱し、その後デシケータ中で室温まで冷却することでリン酸四カルシウム塊を調製した。さらに、乳鉢中で荒く砕き、その後篩がけを行うことで微粉ならびにリン酸四カルシウム塊を除き、０．５～３ｍｍの範囲に粒度を整え、粗リン酸四カルシウムを得た。この粗リン酸四カルシウム１００ｇ、及び直径が２０ｍｍのジルコニアボール２００ｇを４００ｍｌのアルミナ製粉砕ポット（株式会社ニッカトー製「Ｔｙｐｅ　Ａ－３　ＨＤポットミル」）中に加え、１５０ｒｐｍの回転速度で１５時間粉砕することでリン酸四カルシウム粒子（Ａ１）を得た。 Example 1
[Preparation of tooth mineralizer]
(1) Preparation of Tetracalcium Phosphate Particles (A) Tetracalcium phosphate particles (A1) (average particle size 23.1 μm) used in this example grind crude tetracalcium phosphate prepared as follows. Was obtained. Commercially available anhydrous calcium monohydrogen phosphate particles (Product No. 1430, JTBaker Chemical Co., NJ) and calcium carbonate (Product No. 1288, JTBaker Chemical Co., NJ) are added to water to make an equimolar amount. After stirring for a period of time, the cake-like equimolar mixture obtained by filtration and drying was heated in an electric furnace (FUS732PB, Advantech Toyo Co., Ltd.) at 1500 ° C. for 24 hours, and then cooled to room temperature in a desiccator. The tetracalcium phosphate lump was prepared. Further, the mixture was roughly crushed in a mortar and then sieved to remove fine powder and tetracalcium phosphate lump, and the particle size was adjusted to a range of 0.5 to 3 mm to obtain crude tetracalcium phosphate. 100 g of this crude tetracalcium phosphate and 200 g of zirconia balls having a diameter of 20 mm are added to a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.) and ground at a rotational speed of 150 rpm for 15 hours. Thus, tetracalcium phosphate particles (A1) were obtained.
（２）リン酸のアルカリ金属塩（Ｂ）粒子の調製
　リン酸のアルカリ金属塩（Ｂ）粒子の一例として本実施例で使用するリン酸一水素二ナトリウム（Ｂ）粒子（平均粒径１．７μｍ）は、市販のリン酸一水素二ナトリウム粒子（和光純薬工業株式会社製）５０ｇ、９５％エタノール（和光純薬工業株式会社製「Ｅｔｈａｎｏｌ（９５）」）２４０ｇ、及び直径が１０ｍｍのジルコニアボール４８０ｇを１０００ｍｌのアルミナ製粉砕ポット（株式会社ニッカトー製「ＨＤ－Ｂ－１０４　ポットミル」）中に加え、１５００ｒｐｍの回転速度で５時間湿式振動粉砕を行うことで得られたスラリーを、ロータリーエバポレータでエタノールを留去した後、６０℃で６時間真空乾燥することで得た。 (2) Preparation of Alkali Metal Salt (B) Particles of Phosphoric Acid Disodium monohydrogen phosphate (B) particles (average particle size of 1.B) used in this example as an example of alkali metal salt (B) particles of phosphoric acid 7 μm) is 50 g of commercially available disodium monohydrogen phosphate particles (manufactured by Wako Pure Chemical Industries, Ltd.), 240 g of 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.), and zirconia having a diameter of 10 mm. A slurry obtained by adding 480 g of the ball into a 1000 ml alumina grinding pot (“HD-B-104 pot mill” manufactured by Nikkato Co., Ltd.) and performing wet vibration grinding for 5 hours at a rotational speed of 1500 rpm is obtained with a rotary evaporator. After the ethanol was distilled off, it was obtained by vacuum drying at 60 ° C. for 6 hours.
（３）酸性リン酸カルシウム粒子（Ｃ）の調製
　酸性リン酸カルシウム粒子（Ｃ）の一例として本実施例で使用する無水リン酸一水素カルシウム粒子（Ｃ１）（平均粒径１．１μｍ）は、市販の無水リン酸一水素カルシウム粒子（Product No. 1430, J.T.Baker Chemical Co., NJ、平均粒径１０．２μｍ）５０ｇ、９５％エタノール（和光純薬工業株式会社製「Ｅｔｈａｎｏｌ（９５）」）２４０ｇ、及び直径が１０ｍｍのジルコニアボール４８０ｇを１０００ｍｌのアルミナ製粉砕ポット（株式会社ニッカトー製「ＨＤ－Ｂ－１０４　ポットミル」）中に加え、１５００ｒｐｍの回転速度で１５時間湿式振動粉砕を行うことで得られたスラリーを、ロータリーエバポレータでエタノールを留去した後、６０℃で６時間真空乾燥することで得た。 (3) Preparation of acidic calcium phosphate particles (C) As an example of acidic calcium phosphate particles (C), anhydrous calcium monohydrogen phosphate particles (C1) (average particle size 1.1 μm) used in this example are commercially available anhydrous phosphorus Calcium monohydrogen particles (Product No. 1430, JTBaker Chemical Co., NJ, average particle size 10.2 μm) 50 g, 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.) 240 g, and the diameter A slurry obtained by adding 480 g of 10 mm zirconia balls into a 1000 ml alumina grinding pot (“HD-B-104 pot mill” manufactured by Nikkato Co., Ltd.) and performing wet vibration grinding for 15 hours at a rotational speed of 1500 rpm, Ethanol was distilled off using a rotary evaporator, and then vacuum drying was performed at 60 ° C. for 6 hours.
（４）歯牙石灰化剤用の粉剤の調製
　上記で得たリン酸四カルシウム粒子（Ａ１）２６．２ｇ、リン酸一水素二ナトリウム（Ｂ）粒子５ｇ、無水リン酸一水素カルシウム粒子（Ｃ１）９．８ｇ及び特開平２－２５８６０２号公報に開示の方法で微粒子化したフッ化ナトリウム（Ｄ）粒子（平均粒径０．７μｍ）０．２１ｇを高速回転ミル（アズワン株式会社製「ＳＭ－１」）中に加え、１０００ｒｐｍの回転速度で３分間混合することで歯牙石灰化剤用の粉剤を得た。このように混合されて得られる粉剤の調製方法を「方法１」とした。 (4) Preparation of powder for tooth mineralization agent Tetracalcium phosphate particles (A1) 26.2 g obtained above, disodium monohydrogen phosphate (B) particles 5 g, anhydrous calcium hydrogen phosphate particles (C1) 9.8 g and 0.21 g of sodium fluoride (D) particles (average particle size 0.7 μm) finely divided by the method disclosed in Japanese Patent Application Laid-Open No. 2-258602 are mixed with a high-speed rotating mill (“SM-1” manufactured by ASONE CORPORATION). In addition, the powder for tooth mineralization agent was obtained by mixing for 3 minutes at a rotational speed of 1000 rpm. The method for preparing the powder obtained by mixing in this way was designated as “Method 1”.
（５）歯牙石灰化剤用の液状ペーストの調製
　グリセリン（和光純薬工業株式会社製）１０００ｇ、プロピレングリコール（和光純薬工業株式会社製）５００ｇ、キシリトール（和光純薬工業株式会社製）５００ｇ、ポリエチレングリコール（マクロゴール４００、三洋化成工業株式会社製）３００ｇ、セチルピリジニウムクロリド１水和物（和光純薬工業株式会社製）５ｇ、シリカ粒子（Ｅ）（デグサ社製「ＡＥＲＯＳＩＬ　１３０」、平均粒径：０．０１６μｍ）４００ｇ及び蒸留水１１７４ｇをユニバーサルミキサー（株式会社パウレックス製）中で乳化分散させることで歯牙石灰化剤用の液状ペーストを得た。 (5) Preparation of liquid paste for tooth calcification agent 1000 g of glycerin (manufactured by Wako Pure Chemical Industries, Ltd.), 500 g of propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.), 500 g of xylitol (manufactured by Wako Pure Chemical Industries, Ltd.), Polyethylene glycol (Macrogol 400, manufactured by Sanyo Chemical Industries, Ltd.) 300 g, cetylpyridinium chloride monohydrate (manufactured by Wako Pure Chemical Industries, Ltd.) 5 g, silica particles (E) (Degussa “AEROSIL 130”, average particle (Diameter: 0.016 μm) 400 g of distilled water and 1174 g of distilled water were emulsified and dispersed in a universal mixer (manufactured by Paulex Corporation) to obtain a liquid paste for a tooth mineralizing agent.
（６）歯牙石灰化剤の調製
　上記（４）で得た粉剤０．４１ｇを精秤し、これに上記（５）で得た液状ペースト０．５９ｇを加え混合することで歯牙石灰化剤を調製した。歯牙石灰化剤の組成を表１にまとめて示す。 (6) Preparation of tooth mineralizing agent 0.41 g of the powder obtained in (4) above is precisely weighed, and then 0.59 g of the liquid paste obtained in (5) above is added to and mixed with the tooth mineralizing agent. Prepared. The composition of the tooth mineralizer is summarized in Table 1.
［アルカリ金属イオン濃度の測定］
　マグネティックスターラー上で２５℃の純水２００ｇを攪拌させている中に、上記象牙質石灰化剤用の粉剤０．０５ｇを投入した。粉剤投入後１０分時点で撹拌を停止し、上清を採取し、メンブレンフィルターでろ過した後にＩＣＰ発光分光分析装置（ＩＲＩＳ　ＡＰ、日本ジャーレルアッシュ株式会社製）を用いて粉剤スラリーの遊離ナトリウムイオン濃度を測定した（ｎ＝５０）。実施例１における粉剤のナトリウムイオン濃度の平均値（ｄ）は１０．４ｍｇ／Ｌであり、ナトリウムイオン濃度の標準偏差（σ）を（ｄ）で除した数値（σ／ｄ）は０．０６であった。得られた結果を表１にまとめて示す。 [Measurement of alkali metal ion concentration]
While stirring 200 g of pure water at 25 ° C. on a magnetic stirrer, 0.05 g of the powder for dentin calcification agent was added. Stirring was stopped at 10 minutes after the powder was added, the supernatant was collected, filtered through a membrane filter, and then free sodium ions in the powder slurry using an ICP emission spectrophotometer (IRIS AP, manufactured by Nippon Jarrell Ash Co., Ltd.). The concentration was measured (n = 50). The average value (d) of the sodium ion concentration of the powder in Example 1 is 10.4 mg / L, and the numerical value (σ / d) obtained by dividing the standard deviation (σ) of the sodium ion concentration by (d) is 0.06. Met. The obtained results are summarized in Table 1.
［石灰化試験］
　上記で調製した石灰化用牛歯を蒸留水に浸漬し、３０分間静置した後、エナメル質窓に対してペースト状の歯牙石灰化剤を塗布し、３７℃、１００%RH条件下で３０分間インキュベートし、石灰化を行った。その後、歯牙石灰化剤を蒸留水で洗い流した後、擬似唾液中３７℃で保存した。歯牙石灰化剤塗布は１日毎に実施し、連続して７回実施した。歯牙石灰化剤の塗布・除去作業時間以外は常時擬似唾液中に浸漬した。また、擬似唾液は毎日交換した（ｎ＝５）。 [Calcification test]
The calcifying bovine teeth prepared above are immersed in distilled water and allowed to stand for 30 minutes, and then a paste-like dental calcification agent is applied to the enamel window, and the conditions are set at 37 ° C. and 100% RH. Incubation for min and calcification was performed. Thereafter, the tooth mineralizing agent was washed away with distilled water and then stored in simulated saliva at 37 ° C. Tooth mineralizing agent application was carried out every day and seven times in succession. Except for the application / removal time of the tooth mineralizing agent, it was always immersed in simulated saliva. The simulated saliva was changed every day (n = 5).
［形態学的評価］
（１）エポキシ樹脂の調製
　エポキシ樹脂の調製はＬｕｆｔ法に準じて行い、エポキシ樹脂、硬化剤を均一に混合した後、加速剤を添加する方法を用いた。１００ｍｌディスポカップに、ルベアック８１２（エポキシ樹脂、ナカライテスク株式会社製）４１ｍｌ、ルベアックＭＮＡ（硬化剤、ナカライテスク株式会社製）３１ｍｌ、ルベアックＤＤＳＡ（硬化剤、ナカライテスク株式会社製）１０ｍｌをそれぞれディスポシリンジを用いて量り取りディスポカップに加え、１０分間攪拌した。これにディスポシリンジで量り取ったルベアックＤＭＰ－３０（加速剤、ナカライテスク株式会社製）１．２ｍｌを攪拌しながら徐々に滴下し、添加後さらに１０分間攪拌することで調製した。 [Morphological evaluation]
(1) Preparation of Epoxy Resin Epoxy resin was prepared according to the Luft method, and an epoxy resin and a curing agent were uniformly mixed and then an accelerator was added. Disposyringe with 100 ml disposable cup, 41 ml of Rubeak 812 (epoxy resin, manufactured by Nacalai Tesque), 31 ml of Rubeac MNA (curing agent, manufactured by Nacalai Tesque), and 10 ml of Rubeak DDSA (curing agent, manufactured by Nacalai Tesque) Was added to a disposable cup and stirred for 10 minutes. To this, 1.2 ml of Lebeac DMP-30 (accelerator, manufactured by Nacalai Tesque Co., Ltd.) weighed with a disposable syringe was gradually dropped while stirring, and the mixture was further stirred for 10 minutes after the addition.
（２）ＣＭＲ撮影用サンプルの作製
　擬似唾液から石灰化牛歯を取り出し、水洗した後、バイアル中の７０％エタノール水溶液中に浸漬した。浸漬後、直ちにバイアルをデシケータ内に移し、１０分間減圧条件下に置いた。この後、バイアルをデシケータから取り出し、低速攪拌機（ＴＲ－１１８，ＡＳ－ＯＮＥ社製）に取り付け、約４ｒｐｍの回転速度で１時間攪拌した。同様の操作を、８０％エタノール水溶液、９０％エタノール水溶液、９９％エタノール水溶液、１００％エタノール（２回）を用いて行い、２回目の１００％エタノールにはそのまま１晩浸漬した。翌日、プロピレンオキサイドとエタノールの１：１混合溶媒、プロピレンオキサイド１００％（２回）についても順次同様の作業を行い、２回目のプロピレンオキサイドにそのまま１晩浸漬した。さらに、エポキシ樹脂：プロピレンオキサイド＝１：１混合溶液、エポキシ樹脂：プロピレンオキサイド＝４：１混合溶液、エポキシ樹脂１００％（２回）についても同様の作業を行った。これらについては浸漬時間を２時間とした。最後にエポキシ樹脂を入れたポリ容器に牛歯サンプルを入れ、４５℃にて１日間、６０℃にて２日間硬化反応を行った。硬化終了後、ポリエチレン製容器とともに精密低速切断機（ＢＵＥＨＬＥＲ、ＩＳＯＭＥＴ１０００）により脱灰面に対して垂直方向に切断し、試験部分の断面を含む厚さ約１ｍｍの切片を得た。この切片をラッピングフィルム（＃１２００，＃３０００，＃８０００，住友スリーエム社製）を用いて研磨し、切片厚さを８０～１００μｍとすることでＣＭＲ（Ｃｏｎｔａｃｔ　Ｍｉｃｒｏ　Ｒａｄｉｏｇｒａｐｈｙ；軟Ｘ線顕微鏡像）撮影用サンプルとした（ｎ＝５）。 (2) Preparation of sample for CMR imaging Calcified bovine teeth were taken out from simulated saliva, washed with water, and then immersed in a 70% ethanol aqueous solution in a vial. Immediately after immersion, the vial was transferred into a desiccator and placed under reduced pressure for 10 minutes. Thereafter, the vial was taken out from the desiccator, attached to a low speed stirrer (TR-118, manufactured by AS-ONE), and stirred at a rotational speed of about 4 rpm for 1 hour. The same operation was performed using an 80% aqueous ethanol solution, a 90% aqueous ethanol solution, a 99% aqueous ethanol solution, and 100% ethanol (twice), and was immersed in the second 100% ethanol as it was overnight. On the next day, a 1: 1 mixed solvent of propylene oxide and ethanol and 100% propylene oxide (twice) were sequentially subjected to the same operation and immersed in the second propylene oxide as it was overnight. Furthermore, the same operation was performed for epoxy resin: propylene oxide = 1: 1 mixed solution, epoxy resin: propylene oxide = 4: 1 mixed solution, and epoxy resin 100% (twice). For these, the immersion time was 2 hours. Finally, a bovine sample was placed in a plastic container containing an epoxy resin, and a curing reaction was performed at 45 ° C. for 1 day and at 60 ° C. for 2 days. After the curing, the polyethylene container and the precision low-speed cutting machine (BUEHLER, ISOMET 1000) were cut in a direction perpendicular to the demineralized surface to obtain a section having a thickness of about 1 mm including the cross section of the test portion. This section is polished with a wrapping film (# 1200, # 3000, # 8000, manufactured by Sumitomo 3M), and the section thickness is set to 80 to 100 μm, so that CMR (Contact Micro Radiography; soft X-ray microscope image) is taken. Sample (n = 5).
（３）ＣＭＲ撮影
　ＣＭＲ撮影およびフィルム現像はすべて暗室中において行った。ＣＭＲ撮影には、ＣＭＲ－２(ソフテックス株式会社製)を使用した。上記で得たＣＭＲ撮影用サンプルを専用フィルム（Ｋｏｄａｃ　ｓｐｅｃｉａｌ　Ｈｏｌｏｇｒａｐｈｉｃ，Ｋｏｄａｃ社製）上に密着させた状態で置き、管電圧１５ｋＶ、管電流２．６ｍＡ、Ｘ線照射時間３０分の条件で各サンプルの軟Ｘ線透過像を撮影した。現像は現像液（Ｄ－１９，Ｋｏｄａｃ社製）、定着液（ＧＢＸ，Ｋｏｄａｃ社製）を用い、現像液に５分間浸漬した後３０秒間水洗し、定着液に５分間浸漬した後１分間水洗、乾燥させ、軟Ｘ線写真フィルムを得た。得られた軟Ｘ線写真の透過像を光学顕微鏡（ＢＸ５１，オリンパス製）で対物レンズ４０倍にて観察し、透過像を光学顕微鏡に接続したＣＣＤカメラ（Ｐｒｏ６００ＥＳ，Ｐｉｘｅｒａ製）を用いて写真画像データとして得た。得られた画像を画像解析コンピュータソフトＳｃｉｏｎ　Ｉｍａｇｅβ４．０３（Ｓｃｉｏｎ社製）を用いて解析した。脱灰部分と石灰化部分のフィルム濃度（グレイ値）をエナメル表層から一定深さ位置（約３０μｍ）で測定し、脱灰部分のフィルム濃度を０％、エナメル質表面から更に深部の未脱灰部分のフィルム濃度を１００％としたときの換算値（％）により石灰化率を算出した。実施例１の歯牙石灰化剤により石灰化した脱灰エナメル質の石灰化率は７１．６％であった。 (3) CMR imaging CMR imaging and film development were all performed in a dark room. CMR-2 (manufactured by Softex Corporation) was used for CMR imaging. The CMR imaging samples obtained above were placed in close contact on a dedicated film (Kodac special Holographic, Kodac), and each sample was subjected to a tube voltage of 15 kV, a tube current of 2.6 mA, and an X-ray irradiation time of 30 minutes. A soft X-ray transmission image of was taken. For development, a developer (D-19, manufactured by Kodac) and a fixer (GBX, manufactured by Kodac) were used, soaked in the developer for 5 minutes, then washed with water for 30 seconds, immersed in the fixer for 5 minutes, and then washed with water for 1 minute. And dried to obtain a soft X-ray photographic film. A transmission image of the obtained soft X-ray photograph was observed with an optical microscope (BX51, manufactured by Olympus) at an objective lens 40 times, and the transmission image was photographed using a CCD camera (Pro600ES, manufactured by Pixela) connected to the optical microscope. Obtained as data. The obtained image was analyzed using image analysis computer software Scion Imageβ4.03 (manufactured by Scion). The film density (gray value) of the demineralized part and the calcified part is measured at a certain depth position (about 30 μm) from the enamel surface layer, the film density of the demineralized part is 0%, and the non-demineralized part further from the enamel surface The calcification rate was calculated from the converted value (%) when the film density of the portion was 100%. The calcification rate of the decalcified enamel calcified with the tooth mineralizing agent of Example 1 was 71.6%.
［石灰化部のビッカース硬度測定］
（１）ビッカース硬度測定用サンプルの作製
　上記ＣＭＲ用サンプル調製の際に得られた精密低速切断機により横断的に切断した切片（厚さ１ｍｍ）の両面をラッピングフィルム（＃３０００，＃８０００，住友スリーエム社製）を用いて研磨することで厚さが９００μｍの硬度測定用サンプルを調製した（ｎ＝５）。 [Measurement of Vickers hardness of calcified part]
(1) Preparation of Vickers Hardness Measurement Sample Wrapping film (# 3000, # 8000, Sumitomo) on both sides of a section (thickness 1 mm) cut transversely by a precision low-speed cutting machine obtained during the preparation of the above CMR sample A sample for hardness measurement having a thickness of 900 μm was prepared by polishing using 3M (n = 5).
（２）ビッカース硬度測定
　ビッカース硬度測定には、ミツトヨ製のマイクロビッカース硬度試験機（ＭｉｃｒｏＷｉＺｈａｒｄ）を用い、０．０１ｋｇｆの試験力、負荷４秒・保持１０秒・除荷４秒の試験時間、１００倍での傷観察の各条件でビッカース硬度測定を実施した。健全な牛歯エナメル質のビッカース硬度は３７７ＨＶ、マニキュアでマスキングし脱灰を保持した脱灰エナメル質の表面から３０μｍ深さのビッカース硬度は１２２ＨＶであった。実施例１の歯牙石灰化剤により石灰化した脱灰エナメル質の表面から３０μｍ深さ部分のビッカース硬度は３１４ＨＶであった。 (2) Vickers hardness measurement For measurement of Vickers hardness, a Mitsutoyo micro Vickers hardness tester (MicroWiZhard) was used, a test force of 0.01 kgf, a test time of 4 seconds for loading, 10 seconds for holding, 4 seconds for unloading, 100 Vickers hardness measurement was carried out under each condition for observing scratches at double magnification. The Vickers hardness of the healthy bovine enamel was 377 HV, and the Vickers hardness at a depth of 30 μm from the surface of the decalcified enamel masked with nail polish and kept decalcified was 122 HV. The Vickers hardness at a depth of 30 μm from the surface of the demineralized enamel calcified with the tooth mineralizing agent of Example 1 was 314 HV.
実施例２
　実施例１において、無水リン酸一水素カルシウム粒子（Ｃ１）を用いず、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 2
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that anhydrous calcium hydrogen phosphate particles (C1) were not used and the remainder was prepared with purified water, and the alkali metal ion concentration was measured. Morphological evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例３
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子を粉剤に加えて調製する代わりに液状ペーストに加えて調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 3
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that disodium monohydrogen phosphate (B) particles were added to the powder and prepared instead of the powder. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例４
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を０．２重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 4
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 0.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例５
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子５重量部を粉剤に加えて調製する代わりに、リン酸一水素二ナトリウム（Ｂ）粒子０．２重量部を液状ペーストに加え、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 5
In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 0.2 part by weight of disodium monohydrogen phosphate (B) particles was added to the liquid paste, and the balance A tooth mineralizing agent was prepared in the same manner as in Example 1 except that was prepared with purified water, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例６
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１２重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 6
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 12 parts by weight and the remaining part was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例７
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子５重量部を粉剤に加えて調製する代わりに、リン酸一水素二ナトリウム（Ｂ）粒子１２重量部を液状ペーストに加え、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 7
In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 12 parts by weight of disodium monohydrogen phosphate (B) particles were added to the liquid paste, and the remainder was purified. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例８
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１．２重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 8
In Example 1, a tooth mineralization agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 1.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例９
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を２．４重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 9
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles used was 2.4 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１０
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を７．２重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 10
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1, except that the amount of disodium monohydrogen phosphate (B) particles was 7.2 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１１
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を７３．５重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１４重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）、グリセリン、プロピレングリコール、キシリトール、ポリエチレングリコール及びシリカ粒子（Ｅ）を用いず、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 11
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 73.5 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 14 parts by weight, and anhydrous calcium hydrogen phosphate particles ( C1), except that glycerin, propylene glycol, xylitol, polyethylene glycol, and silica particles (E) were not used, and the remainder was prepared with purified water. Concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１２
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を４９重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を９．３重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）、グリセリン、プロピレングリコール、キシリトール、ポリエチレングリコール及びシリカ粒子（Ｅ）を用いず、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 12
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 49 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 9.3 parts by weight, and anhydrous calcium hydrogen phosphate particles ( C1), except that glycerin, propylene glycol, xylitol, polyethylene glycol, and silica particles (E) were not used, and the remainder was prepared with purified water. Concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１３
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を２．６２重量部、無水リン酸一水素カルシウム粒子（Ｃ１）の使用量を０．９８重量部とし、リン酸一水素二ナトリウム（Ｂ）粒子５重量部を粉剤に加えて調製する代わりに、リン酸一水素二ナトリウム（Ｂ）粒子０．５重量部を液状ペーストに加え、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 13
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 2.62 parts by weight, the amount of anhydrous calcium monohydrogen phosphate particles (C1) used was 0.98 parts by weight, and disodium monohydrogen phosphate. (B) Instead of preparing by adding 5 parts by weight of particles to the powder, Example, except that 0.5 parts by weight of disodium monohydrogen phosphate (B) particles were added to the liquid paste and the remainder was prepared with purified water. A tooth mineralizing agent was prepared in the same manner as in No. 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１４
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を２．６２重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を０．５重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）の使用量を０．９８重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 14
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 2.62 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 0.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of the particles (C1) used was 0.98 parts by weight, and the remainder was prepared with purified water, and the alkali metal ion concentration was measured. Evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１５
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を５．２４重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）の使用量を１．９６重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表１に、得られた評価結果を表４にまとめて示す。 Example 15
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 5.24 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 1 part by weight, and anhydrous calcium hydrogen phosphate particles ( A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of C1) used was 1.96 parts by weight, and the balance was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, And Vickers hardness measurement. The composition of the used tooth mineralizer is summarized in Table 1, and the obtained evaluation results are summarized in Table 4.
実施例１６
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を１３．１重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を２．５重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）の使用量を４．９重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 16
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 13.1 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 2.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of the particles (C1) used was 4.9 parts by weight and the remainder was prepared with purified water. Evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例１７
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子を５重量部用いる代わりに、リン酸二水素一ナトリウム（Ｂ）粒子を５重量部用いた以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 17
In Example 1, instead of using 5 parts by weight of disodium monohydrogen phosphate (B) particles, 5 teeth by weight of sodium dihydrogen phosphate (B) particles were used in the same manner as in Example 1, except that A mineralizer was prepared, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例１８
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子５重量部を粉剤に加えて調製する代わりに、リン酸二水素一ナトリウム（Ｂ）粒子５重量部を液状ペーストに加え、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 18
In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 5 parts by weight of sodium dihydrogen phosphate (B) particles were added to the liquid paste, and the remainder was purified. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例１９
　実施例１において、フッ化ナトリウム（Ｄ）粒子を用いず、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 19
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that sodium fluoride (D) particles were not used and the balance was prepared with purified water, and measurement of alkali metal ion concentration and morphology Evaluation and Vickers hardness measurement. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例２０
　実施例１において、無水リン酸一水素カルシウム粒子（Ｃ１）を９．８重量部用いる代わりに、リン酸一水素カルシウム２水和物粒子（Ｃ）（平均粒径１．２μｍ）を１２．３重量部用い、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。ここで、上記リン酸一水素カルシウム２水和物粒子（Ｃ）（平均粒径１．２μｍ）は、市販のリン酸一水素カルシウム２水和物粒子（和光純薬工業株式会社製、平均粒径１９μｍ）を用い、実施例１における無水リン酸一水素カルシウム粒子（Ｃ１）を調製する方法と同様に調製することにより得た。 Example 20
In Example 1, instead of using 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1), 12.3 parts of calcium monohydrogen phosphate dihydrate particles (C) (average particle size 1.2 μm) were used. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that parts by weight were used and the remainder was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4. Here, the calcium monohydrogen phosphate dihydrate particles (C) (average particle size 1.2 μm) are commercially available calcium monohydrogen phosphate dihydrate particles (Wako Pure Chemical Industries, Ltd., average particles). It was obtained by preparing in the same manner as the method for preparing anhydrous calcium hydrogen phosphate phosphate particles (C1) in Example 1.
実施例２１
　実施例１において、無水リン酸一水素カルシウム粒子（Ｃ１）を９．８重量部用いる代わりに、無水リン酸二水素カルシウム粒子（Ｃ）（平均粒径１．１μｍ）を１６．７重量部用い、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。ここで、上記無水リン酸二水素カルシウム粒子（Ｃ）（平均粒径１．１μｍ）は、市販の無水リン酸二水素カルシウム粒子（和光純薬工業株式会社製、平均粒径１８μｍ）を用い、実施例１における無水リン酸一水素カルシウム粒子（Ｃ１）を調製する方法と同様に調製することにより得た。 Example 21
In Example 1, 16.7 parts by weight of anhydrous calcium dihydrogen phosphate particles (C) (average particle size 1.1 μm) was used instead of 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1). A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the remainder was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4. Here, as the anhydrous calcium dihydrogen phosphate particles (C) (average particle size 1.1 μm), commercially available anhydrous calcium dihydrogen phosphate particles (manufactured by Wako Pure Chemical Industries, Ltd., average particle size 18 μm) are used. It was obtained by preparing in the same manner as the method for preparing anhydrous calcium monohydrogen phosphate particles (C1) in Example 1.
実施例２２
　実施例１において、無水リン酸一水素カルシウム粒子（Ｃ１）を９．８重量部用いる代わりに、酸性ピロリン酸カルシウム粒子（Ｃ）（平均粒径１．０μｍ）を１５．４重量部用い、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。ここで、上記酸性ピロリン酸カルシウム粒子（Ｃ）（平均粒径１．０μｍ）は、市販の酸性ピロリン酸カルシウム粒子（太平化学産業株式会社製、平均粒径１３μｍ）を用い、実施例１における無水リン酸一水素カルシウム粒子（Ｃ１）を調製する方法と同様に調製することにより得た。 Example 22
In Example 1, instead of using 9.8 parts by weight of anhydrous calcium monohydrogen phosphate particles (C1), 15.4 parts by weight of acidic calcium pyrophosphate particles (C) (average particle size: 1.0 μm) was used, and the remainder was used. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that it was prepared with purified water, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4. Here, as the acidic calcium pyrophosphate particles (C) (average particle size 1.0 μm), commercially available acidic calcium pyrophosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size 13 μm) were used, and anhydrous phosphoric acid in Example 1 was used. It was obtained by preparing in the same manner as the method for preparing calcium monohydrogen particles (C1).
実施例２３
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を１８．４重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を３．５重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 23
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 18.4 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 3.5 parts by weight, and the remainder was prepared with purified water. Except for the above, a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例２４
　実施例１において、粉剤及び液状ペーストを調製する代わりに、リン酸四カルシウム粒子（Ａ１）２６．２重量部、フッ化ナトリウム（Ｄ）粒子０．２１重量部、シリカ粒子（Ｅ）０．５重量部、グリセリン１８．０９重量部及びプロピレングリコール５重量部を用いて調製した非水系ペーストと、リン酸一水素二ナトリウム（Ｂ）粒子５重量部、無水リン酸一水素カルシウム粒子（Ｃ１）９．８重量部、キシリトール５重量部、ポリエチレングリコール３重量部、セチルピリジニウムクロリド１水和物０．０５重量部、シリカ粒子（Ｅ）３．５重量部及び残部を精製水で調製した水系ペーストとを混合することで歯牙石灰化剤を調製し、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表３に、得られた評価結果を表４にまとめて示す。 Example 24
In Example 1, instead of preparing the powder and liquid paste, 26.2 parts by weight of tetracalcium phosphate particles (A1), 0.21 parts by weight of sodium fluoride (D) particles, 0.5 parts of silica particles (E) Non-aqueous paste prepared using parts by weight, 18.09 parts by weight of glycerin and 5 parts by weight of propylene glycol, 5 parts by weight of disodium monohydrogen phosphate (B) particles, anhydrous calcium monohydrogen phosphate particles (C1) 9 8 parts by weight, 5 parts by weight of xylitol, 3 parts by weight of polyethylene glycol, 0.05 parts by weight of cetylpyridinium chloride monohydrate, 3.5 parts by weight of silica particles (E) and the rest of the aqueous paste prepared with purified water The tooth mineralization agent was prepared by mixing and morphological evaluation and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 3, and the obtained evaluation results are summarized in Table 4.
実施例２５
　実施例１において、高速回転ミルを用いて粉剤を調製した方法１の代わりに、それぞれ同量のリン酸四カルシウム粒子（Ａ１）、リン酸一水素二ナトリウム（Ｂ）粒子、無水リン酸一水素カルシウム粒子（Ｃ１）及びフッ化ナトリウム（Ｄ）粒子を１０ｍｍのジルコニアボール２００ｇとともに４００ｍｌのアルミナ製粉砕ポット（株式会社ニッカトー製「Ｔｙｐｅ　Ａ－３　ＨＤポットミル」）中に加え、２００ｒｐｍの回転速度で３０分間混合することで粉剤を得た。このように混合されて得られる粉剤の調製方法を「方法２」とした。次いで、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 25
In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles are added together with 200 g of 10 mm zirconia balls into a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.) and 30 rpm at a rotation speed of 200 rpm. Powder was obtained by mixing for minutes. The method for preparing the powder obtained by mixing in this manner was designated as “Method 2”. Next, a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例２６
　実施例１において、高速回転ミルを用いて粉剤を調製した方法１の代わりに、それぞれ同量のリン酸四カルシウム粒子（Ａ１）、リン酸一水素二ナトリウム（Ｂ）粒子、無水リン酸一水素カルシウム粒子（Ｃ１）及びフッ化ナトリウム（Ｄ）粒子をライカイ機（自動乳鉢、アズワン株式会社製「ＡＮＭ－２００」）中に加え、乳鉢を６ｒｐｍ、乳棒を１００ｒｐｍの回転速度で５時間混合することで粉剤を得た。このように混合されて得られる粉剤の調製方法を「方法３」とした。次いで、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 26
In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles are added to a reiki machine (automatic mortar, “ANM-200” manufactured by ASONE Co., Ltd.), and the mortar is mixed at 6 rpm and the pestle at 100 rpm for 5 hours. A powder was obtained. The method for preparing the powder obtained by mixing in this manner was designated as “Method 3”. Next, a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
実施例２７
　実施例１において、高速回転ミルを用いて粉剤を調製した方法１の代わりに、それぞれ同量のリン酸四カルシウム粒子（Ａ１）、リン酸一水素二ナトリウム（Ｂ）粒子、無水リン酸一水素カルシウム粒子（Ｃ１）及びフッ化ナトリウム（Ｄ）粒子をジルコニアボールを加えずに４００ｍｌのアルミナ製粉砕ポット（株式会社ニッカトー製「Ｔｙｐｅ　Ａ－３　ＨＤポットミル」）中に加え、１５００ｒｐｍの回転速度で３０分間混合することで粉剤を得た。このように混合されて得られる粉剤の調製方法を「方法４」とした。次いで、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Example 27
In Example 1, instead of Method 1 in which the powder was prepared using a high-speed rotating mill, the same amount of tetracalcium phosphate particles (A1), disodium monohydrogen phosphate (B) particles, and anhydrous monohydrogen phosphate Calcium particles (C1) and sodium fluoride (D) particles were added to a 400 ml alumina grinding pot (“Type A-3 HD pot mill” manufactured by Nikkato Co., Ltd.) without adding zirconia balls, and 30 rpm at a rotation speed of 1500 rpm. Powder was obtained by mixing for minutes. The method for preparing the powder obtained by mixing in this way was designated as “Method 4”. Next, a tooth mineralizing agent was prepared in the same manner as in Example 1, and measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
比較例１
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を０．１重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Comparative Example 1
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 0.1 parts by weight and the remainder was prepared with purified water. Measurement of alkali metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
比較例２
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子５重量部を粉剤に加えて調製する代わりに、リン酸一水素二ナトリウム（Ｂ）粒子０．１重量部を液状ペーストに加え、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Comparative Example 2
In Example 1, instead of preparing 5 parts by weight of disodium monohydrogen phosphate (B) particles in the powder, 0.1 part by weight of disodium monohydrogen phosphate (B) particles was added to the liquid paste, and the balance A tooth mineralizing agent was prepared in the same manner as in Example 1 except that was prepared with purified water, and alkali metal ion concentration measurement, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
比較例３
　実施例１において、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１４重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Comparative Example 3
In Example 1, a tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of disodium monohydrogen phosphate (B) particles was 14 parts by weight and the remaining part was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
比較例４
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量を８１．３重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を１５．５重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）、グリセリン、プロピレングリコール、キシリトール、ポリエチレングリコール及びシリカ粒子（Ｅ）を用いず、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Comparative Example 4
In Example 1, the amount of tetracalcium phosphate particles (A1) used was 81.3 parts by weight, the amount of disodium monohydrogen phosphate (B) particles was 15.5 parts by weight, and anhydrous calcium hydrogen phosphate phosphate was used. A tooth mineralizing agent was prepared in the same manner as in Example 1 except that particles (C1), glycerin, propylene glycol, xylitol, polyethylene glycol and silica particles (E) were not used, and the remainder was prepared with purified water. Measurement of metal ion concentration, morphological evaluation, and Vickers hardness measurement were performed. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
比較例５
　実施例１において、リン酸四カルシウム粒子（Ａ１）の使用量０．８７重量部、リン酸一水素二ナトリウム（Ｂ）粒子の使用量を０．１７重量部とし、無水リン酸一水素カルシウム粒子（Ｃ１）の使用量を０．３３重量部とし、残部を精製水で調製した以外は、実施例１と同様にして歯牙石灰化剤を調製し、アルカリ金属イオン濃度の測定、形態学的評価、及びビッカース硬度測定を行った。用いた歯牙石灰化剤の組成を表２に、得られた評価結果を表４にまとめて示す。 Comparative Example 5
In Example 1, the amount of tetracalcium phosphate particles (A1) used is 0.87 parts by weight, the amount of disodium monohydrogen phosphate (B) particles is 0.17 parts by weight, and anhydrous calcium hydrogen phosphate particles A tooth mineralizing agent was prepared in the same manner as in Example 1 except that the amount of (C1) used was 0.33 parts by weight, and the remainder was prepared with purified water, and the alkali metal ion concentration was measured and morphologically evaluated. And Vickers hardness measurement. The composition of the used tooth mineralizer is summarized in Table 2, and the obtained evaluation results are summarized in Table 4.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　　１　エナメル質脱灰部分
　　２　エナメル質深部未脱灰部分
　　３　エナメル質石灰化部分 1 Enamel demineralized part 2 Enamel deep undecalcified part 3 Enamel calcified part

Claims (28)

  1. 　リン酸四カルシウム粒子（Ａ）、及びリン酸のアルカリ金属塩（Ｂ）を含有する歯牙石灰化剤であって、該歯牙石灰化剤の全量１００重量部に対してリン酸四カルシウム粒子（Ａ）を１～８０重量部含み、かつリン酸四カルシウム粒子（Ａ）１００重量部に対するリン酸のアルカリ金属塩（Ｂ）の配合量が０．５～５０重量部であることを特徴とする歯牙石灰化剤。 Teeth calcification agent containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and tetracalcium phosphate particles (A 1) to 80 parts by weight, and the amount of the alkali metal salt (B) of phosphoric acid based on 100 parts by weight of the tetracalcium phosphate particles (A) is 0.5 to 50 parts by weight Calcifying agent.
  2. 　リン酸のアルカリ金属塩（Ｂ）がリン酸一水素二ナトリウム及び／又はリン酸二水素一ナトリウムである請求項１記載の歯牙石灰化剤。 The tooth mineralizing agent according to claim 1, wherein the alkali metal salt (B) of phosphoric acid is disodium monohydrogen phosphate and / or monosodium dihydrogen phosphate.
  3. 　更に酸性リン酸カルシウム粒子（Ｃ）を含有する請求項１又は２記載の歯牙石灰化剤。 The tooth calcification agent according to claim 1 or 2, further comprising acidic calcium phosphate particles (C).
  4. 　酸性リン酸カルシウム粒子（Ｃ）が、無水リン酸一水素カルシウム［ＣａＨＰＯ４］粒子、無水リン酸二水素カルシウム［Ｃａ（Ｈ２ＰＯ４）２］粒子、リン酸三カルシウム［Ｃａ３（ＰＯ４）２］粒子、非晶性リン酸カルシウム［Ｃａ３（ＰＯ４）２・ｘＨ２Ｏ］粒子、酸性ピロリン酸カルシウム[ＣａＨ２Ｐ２Ｏ７]粒子、リン酸一水素カルシウム２水和物［ＣａＨＰＯ４・２Ｈ２Ｏ］粒子、及びリン酸二水素カルシウム１水和物［Ｃａ（Ｈ２ＰＯ４）２・Ｈ２Ｏ］粒子からなる群から選択される少なくとも１種である請求項３記載の歯牙石灰化剤。 Acidic calcium phosphate particles (C) are anhydrous calcium monohydrogen phosphate [CaHPO 4 ] particles, anhydrous calcium dihydrogen phosphate [Ca (H 2 PO 4 ) 2 ] particles, tricalcium phosphate [Ca 3 (PO 4 ) 2. ] Particles, amorphous calcium phosphate [Ca 3 (PO 4 ) 2 · xH 2 O] particles, acidic calcium pyrophosphate [CaH 2 P 2 O 7 ] particles, calcium monohydrogen phosphate dihydrate [CaHPO 4 · 2H 2 The tooth mineralization agent according to claim 3, which is at least one selected from the group consisting of O] particles and calcium dihydrogen phosphate monohydrate [Ca (H 2 PO 4 ) 2 · H 2 O] particles. .
  5. 　リン酸四カルシウム粒子（Ａ）と酸性リン酸カルシウム粒子（Ｃ）の配合割合（Ａ／Ｃ）がモル比で４０／６０～６０／４０である請求項３又は４記載の歯牙石灰化剤。 The tooth mineralizing agent according to claim 3 or 4, wherein the blending ratio (A / C) of the tetracalcium phosphate particles (A) and the acidic calcium phosphate particles (C) is 40/60 to 60/40 in molar ratio.
  6. 　更にフッ素化合物（Ｄ）を含有する請求項１～５のいずれか記載の歯牙石灰化剤。 The tooth mineralizer according to any one of claims 1 to 5, further comprising a fluorine compound (D).
  7. 　フッ素化合物（Ｄ）がフッ化ナトリウムである請求項６記載の歯牙石灰化剤。 The tooth mineralizing agent according to claim 6, wherein the fluorine compound (D) is sodium fluoride.
  8. 　リン酸四カルシウム粒子（Ａ）の平均粒径が０．５～４０μｍである請求項１～７のいずれか記載の歯牙石灰化剤。 The tooth mineralizing agent according to any one of claims 1 to 7, wherein the average particle diameter of the tetracalcium phosphate particles (A) is 0.5 to 40 µm.
  9. 　リン酸のアルカリ金属塩（Ｂ）の平均粒径が０．５～２０μｍである請求項１～８のいずれか記載の歯牙石灰化剤。 The tooth mineralizer according to any one of claims 1 to 8, wherein the alkali metal salt (B) of phosphoric acid has an average particle size of 0.5 to 20 µm.
  10. 　酸性リン酸カルシウム粒子（Ｃ）の平均粒径が０．１～７μｍである請求項１～９のいずれか記載の歯牙石灰化剤。 The tooth mineralizer according to any one of claims 1 to 9, wherein the average particle diameter of the acidic calcium phosphate particles (C) is 0.1 to 7 µm.
  11. 　更に平均粒径が０．００２～２μｍであるシリカ又は金属酸化物から選択される粒子（Ｅ）を含有する請求項１～１０のいずれか記載の歯牙石灰化剤。 The tooth mineralizing agent according to any one of claims 1 to 10, further comprising particles (E) selected from silica or metal oxide having an average particle diameter of 0.002 to 2 µm.
  12. 　該歯牙石灰化剤０．０５ｇを２５℃の純水２００ｇに投入して懸濁液を調製した際に、投入から１０分後における該懸濁液の遊離アルカリ金属イオン濃度が０．２～１００ｍｇ／Ｌであることを特徴とする請求項１～１１のいずれか記載の歯牙石灰化剤。 When a suspension was prepared by adding 0.05 g of the tooth mineralizing agent to 200 g of pure water at 25 ° C., the free alkali metal ion concentration of the suspension after 10 minutes from the addition was 0.2 to 100 mg. The tooth mineralizer according to any one of claims 1 to 11, which is / L.
  13. 　遊離アルカリ金属イオン濃度の平均値をｄとしたときの標準偏差σがσ≦０．３ｄを満たす請求項１２記載の歯牙石灰化剤。 The tooth mineralization agent according to claim 12, wherein the standard deviation σ satisfies σ ≦ 0.3d when the average value of the free alkali metal ion concentration is d.
  14. 　アルカリ金属イオンがナトリウムイオンである請求項１２又は１３記載の歯牙石灰化剤。 The tooth mineralization agent according to claim 12 or 13, wherein the alkali metal ion is sodium ion.
  15. 　請求項１～１４のいずれか記載の歯牙石灰化剤を含有する歯面処理材。 A tooth surface treatment material containing the tooth mineralizer according to any one of claims 1 to 14.
  16. 　請求項１～１４のいずれか記載の歯牙石灰化剤を含有する歯磨材。 A dentifrice containing the tooth mineralizer according to any one of claims 1 to 14.
  17. 　請求項１～１４のいずれか記載の歯牙石灰化剤を含有するチューイングガム。 A chewing gum containing the tooth mineralizer according to any one of claims 1 to 14.
  18. 　請求項１～１４のいずれか記載の歯牙石灰化剤からなるエナメル質石灰化剤。 An enamel mineralizing agent comprising the tooth mineralizing agent according to any one of claims 1 to 14.
  19. 　リン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）、及び水を主成分とする液体又は水系ペーストを混合する歯牙石灰化剤の製造方法であって、
    リン酸四カルシウム粒子（Ａ）１００重量部に対してリン酸のアルカリ金属塩（Ｂ）を０．５～５０重量部配合し、歯牙石灰化剤の全量１００重量部に対するリン酸四カルシウム粒子（Ａ）の配合量を１～８０重量部とすることを特徴とする歯牙石灰化剤の製造方法。     Tetracalcium phosphate particles (A), an alkali metal salt of phosphoric acid (B), and a method for producing a tooth mineralizer comprising mixing a water-based liquid or water-based paste,
    0.5 to 50 parts by weight of alkali metal salt (B) of phosphoric acid is added to 100 parts by weight of tetracalcium phosphate particles (A), and tetracalcium phosphate particles (100 parts by weight of the total amount of tooth mineralizing agent) A method for producing a tooth mineralizing agent, wherein the blending amount of A) is 1 to 80 parts by weight.
  20. 　リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体、又はリン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体を予め混合する請求項１９記載の歯牙石灰化剤の製造方法。 Powder containing tetracalcium phosphate particles (A) and alkali metal salt (B) of phosphoric acid, or tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C) The method for producing a tooth mineralizing agent according to claim 19, wherein the powder containing the mixture is mixed in advance.
  21. 　前記混合の際に、ジェットミル、ライカイ機、ボールミル、高速回転ミル、遊星ミル、ハイブリダイザー、メカノフュージョン又は混合押出し機から選択される少なくとも１種を用いる請求項２０記載の歯牙石灰化剤の製造方法。 21. The production of a tooth mineralizing agent according to claim 20, wherein at the time of the mixing, at least one selected from a jet mill, a likai machine, a ball mill, a high-speed rotary mill, a planetary mill, a hybridizer, a mechanofusion, or a mixing extruder is used. Method.
  22. 　リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストに、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストを加えて混合する請求項１９記載の歯牙石灰化剤の製造方法。 The tooth lime according to claim 19, wherein a liquid or aqueous paste containing water as a main component and containing an alkali metal salt of phosphoric acid (B) is added to and mixed with powder or non-aqueous paste containing tetracalcium phosphate particles (A). A method for producing an agent.
  23. 　リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キット。 A tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component.
  24. 　リン酸四カルシウム粒子（Ａ）、リン酸のアルカリ金属塩（Ｂ）及び酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キット。 Tooth lime comprising powder or non-aqueous paste containing tetracalcium phosphate particles (A), alkali metal salt of phosphoric acid (B) and acidic calcium phosphate particles (C), and a liquid or water-based paste mainly containing water Agent kit.
  25. 　リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、水を主成分としリン酸のアルカリ金属塩（Ｂ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キット。 A tooth mineralizer kit comprising a powder or non-aqueous paste containing tetracalcium phosphate particles (A) and a liquid or aqueous paste containing water as a main component and an alkali metal salt of phosphoric acid (B).
  26. 　リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キット。 A powder or non-aqueous paste containing tetracalcium phosphate particles (A), a powder or non-aqueous paste containing an alkali metal salt of phosphoric acid (B), and a liquid or water-based paste containing water as a main component. Tooth mineralizer kit.
  27. 　リン酸四カルシウム粒子（Ａ）及びリン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、水を主成分とし酸性リン酸カルシウム粒子（Ｃ）を含む液体又は水系ペーストとからなる歯牙石灰化剤キット。 Dental lime comprising powder or non-aqueous paste containing tetracalcium phosphate particles (A) and alkali metal salt (B) of phosphoric acid, and liquid or aqueous paste containing water as a main component and acidic calcium phosphate particles (C) Agent kit.
  28. 　リン酸四カルシウム粒子（Ａ）を含む粉体又は非水系ペーストと、リン酸のアルカリ金属塩（Ｂ）を含む粉体又は非水系ペーストと、酸性リン酸カルシウム粒子（Ｃ）を含む粉体又は非水系ペーストと、水を主成分とする液体又は水系ペーストとからなる歯牙石灰化剤キット。 Powder or non-aqueous paste containing tetracalcium phosphate particles (A), powder or non-aqueous paste containing alkali metal salt of phosphoric acid (B), and powder or non-aqueous containing acidic calcium phosphate particles (C) A tooth mineralizer kit comprising a paste and a liquid or water-based paste containing water as a main component.
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