JP7682602B2 - Oral composition - Google Patents

Description

The present disclosure relates to oral compositions and the like, and more specifically to oral compositions and the like containing hydroxyapatite particles. The contents of all documents described in this specification (particularly JP 2017-036176 A) are incorporated herein by reference.

Tooth hypersensitivity occurs when the dentin of the tooth becomes exposed due to physical wear such as brushing, or chemical wear caused by acid. When the dentin is exposed, external stimuli stimulate the nerves in the dentinal tubules in the dentin, making it more likely that pain will occur.

For treating dentin hypersensitivity, for example, particles of fluoride, aluminum salts, etc. (see Patent Document 1) are used to block the dentinal tubules, thereby preventing external stimuli from reaching the nerves. However, most of the conventional methods have insufficient adhesion after blocking, and there are problems with the durability of the effect.

JP 2010-222325 A JP 2017-036176 A

The objective is to provide particles that have the ability to seal dentinal tubules and have excellent adhesion within the dentinal tubules.

As a result of intensive research conducted by the inventors in consideration of the above problems, they discovered that specific hydroxyapatite particles (hydroxyapatite particles in which the ratio of the diffraction peak intensity around 2θ=32° to the diffraction peak intensity around 2θ=26° in an X-ray diffraction pattern is 0.8 to 1.5) can solve the above problems. Based on this finding, they then conducted further research.

The present disclosure includes, for example, the subject matter described in the following sections:
Item 1.
An oral composition containing hydroxyapatite particles,
The hydroxyapatite particles have a ratio of a diffraction peak intensity around 2θ=32° to a diffraction peak intensity around 2θ=26° in a powder X-ray diffraction pattern measured by CuKα characteristic X-rays of 0.8 to 1.5.
Oral composition.
Item 2.
Item 2. The oral composition according to item 1, wherein the hydroxyapatite particles have a Ca/P molar ratio of less than 1.67 (preferably 1.60 or less).
Item 3.
Item 3. The oral composition according to item 1 or 2, wherein the hydroxyapatite particles have a median diameter of 5 μm or less.
Item 4.
Item 4. The oral composition according to any one of Items 1 to 3, wherein the hydroxyapatite particles have a specific surface area of 55 to 200 m ² /g.
Item 5.
Item 5. The oral composition according to any one of Items 1 to 4, wherein the hydroxyapatite particles have a ratio of a diffraction peak intensity at about 2θ=34° to a diffraction peak intensity at about 2θ=32° in a powder X-ray diffraction pattern measured using CuKα characteristic X-rays of 1 or less.
Item 6.
The hydroxyapatite particles are aggregates of hydroxyapatite platelet crystals.
Item 6. The oral composition according to any one of Items 1 to 5.
Section 7.
Item 7. The oral composition according to any one of Items 1 to 6, further comprising potassium nitrate and/or aluminum lactate.
Section 8.
Item 8. The oral composition according to any one of Items 1 to 7, which is used for preventing or improving dentin hypersensitivity.
Item 9.
Item 9. The oral composition according to any one of Items 1 to 8, wherein the hydroxyapatite particles are produced by a method for producing hydroxyapatite particles, the method including a step of mixing an aqueous solution of an alkali phosphate having a pH of 4 or more and less than 7 with a calcium hydroxide slurry and reacting the mixture at 35 to 85° C.
Item 10.
Item 10. The oral composition according to item 9, wherein the calcium hydroxide slurry is a ground calcium hydroxide slurry.
Item 11.
Item 11. The oral composition according to item 9 or 10, wherein the oxalic acid reactivity of the calcium hydroxide slurry is 40 minutes or less (the time (minutes) required for the pH to reach 7.0 after the addition of 40 g of an aqueous oxalic acid solution having a concentration of 0.5 mol/L and kept at 25±1° C. to 50 g of calcium hydroxide slurry prepared to a concentration of 5% by mass and kept at 25±1° C.).
Item 12.
Item 12. The oral composition according to any one of Items 9 to 11, wherein the calcium hydroxide slurry has a BET specific surface area of 5 m ² /g or more.
Section 1a.
An oral composition comprising hydroxyapatite particles and potassium nitrate,
The hydroxyapatite particles have a ratio of a diffraction peak intensity around 2θ=32° to a diffraction peak intensity around 2θ=26° in a powder X-ray diffraction pattern measured by CuKα characteristic X-rays of 0.8 to 1.5.
Oral composition.
Section 2a.
Item 1. The oral composition according to item 1a, wherein the hydroxyapatite particles have a Ca/P molar ratio of less than 1.67 (preferably 1.60 or less).
Section 3a.
Item 1a or 2a. The oral composition according to item 1a or 2a, wherein the hydroxyapatite particles have a median diameter of 5 μm or less.
Section 4a.
The oral composition according to any one of Items 1a to 3a, wherein the specific surface area of the hydroxyapatite particles is 55 to 200 m ² /g.
Section 5a.
The hydroxyapatite particles have a ratio of a diffraction peak intensity at about 2θ=34° to a diffraction peak intensity at about 2θ=32° in a powder X-ray diffraction pattern measured using CuKα characteristic X-rays of 1 or less.
Section 6a.
The hydroxyapatite particles are aggregates of hydroxyapatite platelet crystals.
The oral composition according to any one of items 1a to 5a.
Section 7a.
The oral composition according to any one of Items 1a to 6a, further comprising aluminum lactate.
Section 8a.
The oral composition according to any one of Items 1a to 7a, which is for preventing or improving dentin hypersensitivity.
Section 9a.
The oral composition according to any one of Items 1a to 8a, wherein the hydroxyapatite particles are produced by a method for producing hydroxyapatite particles, the method including a step of mixing an aqueous solution of an alkali phosphate having a pH of 4 or more and less than 7 with a calcium hydroxide slurry and reacting the mixture at 35 to 85°C.
Section 10a.
Item 9. The oral composition according to item 9a, wherein the calcium hydroxide slurry is a ground calcium hydroxide slurry.
Section 11a.
Item 9. The oral composition according to item 9a or 10a, wherein the oxalic acid reactivity of the calcium hydroxide slurry is 40 minutes or less (the time (minutes) required for the pH to reach 7.0 after the addition of 40 g of an aqueous oxalic acid solution having a concentration of 0.5 mol/L and kept at 25±1° C. to 50 g of calcium hydroxide slurry prepared to a concentration of 5% by mass and kept at 25±1° C.).
Section 12a.
The oral composition according to any one of Items 9a to 11a, wherein the calcium hydroxide slurry has a BET specific surface area of 5 m ² /g or more.
Section 13a.
The oral composition according to any one of Items 1a to 12a, comprising 0.1 to 15 mass% potassium nitrate.
Section 13b.
The oral composition according to any one of Items 1a to 12a, which contains 0.1 to 15% by mass of potassium nitrate (excluding oral compositions containing 5% by mass of potassium nitrate).
Section 13c.
An oral composition comprising hydroxyapatite particles and potassium nitrate,
The oral composition according to any one of Items 1a to 12a, wherein the hydroxyapatite particles have a ratio of a diffraction peak intensity at about 2θ=32° to a diffraction peak intensity at about 2θ=26° in a powder X-ray diffraction pattern measured using CuKα characteristic X-rays of 0.8 to 1.5 (excluding oral compositions containing 5% by mass of potassium nitrate).
In addition, although not particularly limited, the subject matter of the present disclosure may exclude, for example, the oral compositions described in Tables 1 to 3 in the Examples below.

An oral composition is provided that has the ability to seal dentinal tubules and has excellent adhesion within the dentinal tubules.

1 shows the X-ray diffraction peaks of the hydroxyapatite particles of Example 1. 1 shows the X-ray diffraction peaks of commercially available reagent hydroxyapatite particles. 1 shows an SEM photograph of the hydroxyapatite particles of Example 1. 1 shows the X-ray diffraction peaks of the hydroxyapatite particles of Example 2. 1 shows an SEM photograph of the hydroxyapatite particles of Example 2. 1 shows X-ray diffraction peaks of the hydroxyapatite particles of Example 3. 1 shows an SEM photograph of the hydroxyapatite particles of Example 3. 1 shows X-ray diffraction peaks of the hydroxyapatite particles of Example 4. 1 shows an SEM photograph of the hydroxyapatite particles of Example 4. 1 shows X-ray diffraction peaks of the hydroxyapatite microparticles of Example 5. 1 shows an SEM photograph of the hydroxyapatite microparticles of Example 5. 1 shows X-ray diffraction peaks of hydroxyapatite particles of Comparative Example 1. 1 shows an SEM photograph of hydroxyapatite particles of Comparative Example 1. 1 shows the X-ray diffraction peaks of the sample of Comparative Example 2. The peaks indicated by black circles are the diffraction peaks of monetite. 1 shows an SEM photograph of a sample of Comparative Example 2. 4 shows the X-ray diffraction peaks of the sample of Comparative Example 3. 1 shows an SEM photograph of a sample of Comparative Example 3. 1 shows X-ray diffraction peaks of hydroxyapatite particles of Comparative Example 4. 1 shows an SEM photograph of hydroxyapatite particles of Comparative Example 4. 1 shows the X-ray diffraction peaks of the sample of Comparative Example 5. The peaks indicated by black circles are the diffraction peaks of monetite. 1 shows an SEM photograph of a sample of Comparative Example 5. 1 shows X-ray diffraction peaks (Test Example 1) of hydroxyapatite particles before and after immersion in artificial saliva. 1 shows SEM photographs of dentinal tubules before and after brushing (Test Example 2). 1 shows SEM photographs of dentinal tubules before and after water pressure treatment (Test Example 3). 1 shows SEM photographs (Test Example 4) of dentinal tubules before and after brushing with a dentifrice solution containing hydroxyapatite particles. 1 shows SEM photographs (Test Example 5) of dentinal tubules before and after a gel preparation containing hydroxyapatite particles was applied to dentin with a soft pick. 1 shows the flow of a clinical trial using a gel formulation containing hydroxyapatite particles. 1 shows the results of evaluating the degree of abrasion pain using a VAS scale in a clinical trial using a gel preparation containing hydroxyapatite particles. From the left, the b* values of each oral composition are shown: Reference Example 1, Reference Example 2, Reference Example 3, Comparative Example 1, Example 1, and Comparative Example 2.

Each embodiment included in the present disclosure will be described in more detail below. Note that the present disclosure preferably includes oral compositions, particularly oral compositions containing specific hydroxyapatite particles, but is not limited thereto, and the present disclosure includes all that is disclosed in the present specification and that can be recognized by a person skilled in the art.

The oral composition encompassed by the present disclosure contains specific hydroxyapatite particles. In this specification, the oral composition may be referred to as the "oral composition of the present disclosure."

The specific hydroxyapatite particles are hydroxyapatite particles having an X-ray diffraction pattern in which the ratio of the diffraction peak intensity around 2θ = 32° to the diffraction peak intensity around 2θ = 26° is 0.8 to 1.5. In this specification, the hydroxyapatite particles may be referred to as "particles of the present disclosure."

The diffraction peak near 2θ=26° is a hydroxyapatite peak, specifically a diffraction peak at 2θ=25.5-26.5°, preferably a diffraction peak at 2θ=25.8-26.2°. When there are multiple diffraction peaks near 2θ=26°, this refers to the diffraction peak with the highest intensity.

The diffraction peak near 2θ=32° is a hydroxyapatite peak, specifically a diffraction peak at 2θ=31.5 to 32.5°, preferably a diffraction peak at 2θ=31.8 to 32.2°. When there are multiple diffraction peaks near 2θ=32°, this refers to the diffraction peak with the highest intensity.

In this specification, the X-ray diffraction pattern is a powder X-ray diffraction pattern measured using CuKα characteristic X-rays. An example of the measurement conditions is as follows: target: Cu, tube voltage: 40 kV, tube current: 30 mA, sampling width: 0.02°, scan speed: 2.00°/min, divergence slit: 1.0°, scattering slit: 1.0°, receiving slit: 0.3 mm.

The particles of the present disclosure have a ratio (32°/26°) of the diffraction peak intensity around 2θ=32° to the diffraction peak intensity around 2θ=26° of 0.8 to 1.5. The peak intensity ratio is preferably 0.9 to 1.3, more preferably 1.0 to 1.25, even more preferably 1.05 to 1.2, and even more preferably 1.05 to 1.15.

The particles of the present disclosure are preferably aggregates of hydroxyapatite plate crystals. The shape of the plate crystals constituting the particles of the present disclosure is not particularly limited, and examples thereof include circular, polygonal (particularly hexagonal), rod-like, or a combination of these. The plate crystals may be in either a folded state or a flat state without folded faces. Generally, plate hydroxyapatite crystals have a structure called a hexagonal crystal, with the top surface of the plate being the c-plane and the side surface being the a-plane. When a particle is formed of multiple crystals, the crystals are called crystallites.

The particles of the present disclosure are particles containing hydroxyapatite as a main component, and preferably particles essentially consisting of hydroxyapatite. In the X-ray diffraction pattern of the particles of the present disclosure, even if other substances (e.g., monetite, etc.) are contained, the peaks are not observed separately or the peak intensities are relatively low. For this reason, the particles of the present disclosure are distinguished from particles in which the peak intensities of these peaks are high.

Although no limiting interpretation is desired, it is believed that the particles disclosed herein have a shape and structure that is expressed by a specific X-ray diffraction pattern and are composed of aggregated plate-like particles, which, in combination, provide excellent sealing of dentinal tubules and excellent adhesion within the dentinal tubules.

The particles of the present disclosure preferably have an X-ray diffraction pattern in which the ratio (34°/32°) of the diffraction peak intensity around 2θ=34° to the diffraction peak intensity around 2θ=32° is 1 or less. Specifically, the diffraction peak around 2θ=34° is a diffraction peak at 2θ=33.5 to 34.5°, preferably a diffraction peak at 2θ=33.8 to 34.2°. When there are multiple diffraction peaks around 2θ=34°, the diffraction peak with the highest intensity is the one with the highest intensity. The peak intensity ratio is preferably 0.1 to 1, more preferably 0.2 to 0.9, even more preferably 0.3 to 0.8, even more preferably 0.4 to 0.7, and particularly preferably 0.4 to 0.6.

The particles of the present disclosure preferably have a total sum of the areas of all diffraction peaks in the range of 25.5°≦2θ≦26.5° and the area of all diffraction peaks in the range of 31.5°≦2θ≦32.5° of 30 to 45% of the total sum of the areas of all diffraction peaks in the range of 25°≦2θ≦35°, which is 100%. This value is preferably 33 to 42%, more preferably 35 to 40%. In addition, the particles of the present disclosure preferably have a crystallite size calculated from the diffraction peak due to the (130) plane near 2θ=40° of 4 to 12 nm, more preferably 5 to 10 nm. Although no limiting interpretation is desired, it is believed that the relatively low crystallinity enhances the crystal growth in the dentinal tubules after sealing, which in turn enhances the adhesion in the tubules.

The Ca/P molar ratio of the particles of the present disclosure is not particularly limited as long as it is a value that hydroxyapatite can take. Although it is not desired to interpret it in a restrictive manner, it is considered that in the particles of the present disclosure, a part of the calcium is replaced with other elements (sodium, etc.), and therefore the Ca/P molar ratio may be a relatively low value. From this viewpoint, the Ca/P molar ratio of the particles of the present disclosure is preferably less than 1.67, more preferably 1.65 or 1.60 or less, even more preferably 1.55 or 1.50 or less, and even more preferably 1.45 or 1.40 or less. The lower limit of the Ca/P molar ratio of the particles of the present disclosure is not particularly limited, and may be, for example, 1.0, 1.1, or 1.2. The Ca/P molar ratio is a value calculated from the measured values of the Ca and P contents of the particles of the present disclosure measured by inductively coupled plasma atomic emission spectrometry.

The median diameter (d50) of the particles of the present disclosure is not particularly limited, but is preferably 5 μm or less, more preferably 4.5 μm or less, from the viewpoint of dentinal tubule sealing ability, adhesion, etc. The lower limit of the median diameter is not particularly limited, but examples include 1 μm or more, 2 μm or more, or 3 μm or more. More specifically, examples include 1 to 5 μm. The median diameter is a value measured by a laser diffraction/scattering method. More specifically, it is a value measured by dry particle size distribution measurement using a laser diffraction particle size distribution measurement device.

The specific surface area of the particles of the present disclosure is not particularly limited, but from the viewpoint of dentinal tubule sealing property, adhesion property, etc., it is, for example, 30 m ² /g or more, preferably 40 m ² /g or more, more preferably 50 m ² /g or more, and even more preferably 55 m ² /g or more. The upper limit of the specific surface area is not particularly limited, but is, for example, 150 m ² /g, 120 m ² /g, 100 m ² /g, or 90 m ² /g. The specific surface area is a value measured by a nitrogen gas adsorption method.

The particles of the present disclosure preferably react with saliva to improve their crystallinity. Here, the improvement in crystallinity means that in the powder X-ray diffraction pattern measured by CuKα characteristic X-rays, the sharpness of at least one (preferably 1, 2, 3, 4 or more) peaks is improved (more specifically, the diffraction intensity is improved) after the reaction with saliva compared to before the reaction. As the saliva, artificial saliva (CaCl ₂ : 1.5 mM, KH ₂ PO ₄ : 0.9 mM, KCl: 130 mM, HEPES: 20 mM, pH 7.0 (KOH)) is used. The reaction is performed by immersing the particles in saliva for 7 days.

The particles of the present disclosure can be prepared, for example, by a method for producing hydroxyapatite particles, which includes a step of mixing an aqueous solution of an alkali phosphate salt having a pH of 4 or more and less than 7 with a calcium hydroxide slurry and reacting the mixture at 35 to 85°C.

The alkali phosphate salt is not particularly limited and includes hydrates and anhydrides. Examples of the alkali phosphate salt include sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, tetrasodium pyrophosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, etc., and preferably sodium phosphate salts such as sodium dihydrogen phosphate, disodium hydrogen phosphate, and trisodium phosphate, and more preferably sodium dihydrogen phosphate.

The concentration of the alkali phosphate in the aqueous alkali phosphate solution is not particularly limited and is, for example, 3 to 50% by mass. The concentration is preferably 3 to 30% by mass, more preferably 5 to 20% by mass, and even more preferably 7 to 15% by mass.

The pH of the aqueous solution of alkali phosphate is preferably 4 or more and less than 7. The pH is more preferably 5 to 6.5. As described below, when the pH of the aqueous solution of alkali phosphate is relatively low (for example, when the pH is 4 or more and less than 5), it is desirable to use an anhydride as the alkali phosphate and set the reaction temperature to a relatively high temperature, for example, 65 to 85°C, preferably 70 to 85°C, more preferably 75 to 85°C.

The calcium hydroxide slurry has oxalic acid reactivity, and it is preferable that the calcium hydroxide slurry is a slurry of calcium hydroxide that has a specific reactivity with oxalic acid.

The reactivity towards oxalic acid can be expressed, for example, by the following definition:
Oxalic acid reactivity: 40 g of an aqueous oxalic acid solution having a concentration of 0.5 mol/L and kept at 25±1° C. is added all at once to 50 g of calcium hydroxide slurry prepared to a concentration of 5% by mass and kept at 25±1° C., and the time (min) until the pH reaches 7.0 after the addition.

The specific reactivity to oxalic acid, as defined above, is preferably 1 to 40 minutes, more preferably 5 to 30 minutes, and even more preferably 10 to 20 minutes.

The BET specific surface area of the calcium hydroxide slurry is preferably 5 m ² /g or more, more preferably 6 m ² /g or more. The upper limit of the BET specific surface area is not particularly limited, but is, for example, 20 m ² /g, 15 m ² /g, or 10 m ² /g.

Calcium hydroxide slurry having high oxalic acid reactivity (e.g., reactivity to the specific oxalic acid described above) can typically be obtained by grinding calcium hydroxide slurry. The grinding process can further increase the oxalic acid reactivity (shorten the time defined above). The grinding process is performed, for example, using a bead mill. There are no particular limitations on the conditions for the grinding process, and for example, the conditions according to the method described in JP 2017-036176 A can be adopted.

Calcium hydroxide slurry can be prepared, for example, by reacting water with quicklime (calcium oxide) obtained by calcining limestone. For example, limestone is calcined in a kiln at about 1000°C to produce quicklime, and calcium hydroxide slurry can be prepared by adding about 10 times the amount of hot water to this quicklime and stirring for 30 minutes.

The solids concentration of the calcium hydroxide slurry is not particularly limited, but is, for example, 1 to 30% by mass, preferably 3 to 20% by mass, more preferably 5 to 15% by mass, and even more preferably 6 to 12% by mass.

The ratio of the amount of the aqueous alkali phosphate solution to the calcium hydroxide slurry is not particularly limited as long as it is a ratio that allows the production of hydroxyapatite particles. It is desirable to adjust the ratio so that the Ca/P molar ratio is preferably 0.3 to 0.7, more preferably 0.4 to 0.6, and even more preferably 0.45 to 0.55.

The manner in which the aqueous alkali phosphate solution and the calcium hydroxide slurry are mixed is not particularly limited. For example, the aqueous alkali phosphate solution may be added to a reaction vessel containing the aqueous alkali phosphate solution (mode 1), the aqueous alkali phosphate solution may be added to a reaction vessel containing the calcium hydroxide slurry (mode 2), or the aqueous alkali phosphate solution and the calcium hydroxide slurry may be added to the reaction vessel simultaneously (mode 3). Among these, mode 1 is preferred. During the above-mentioned addition to the reaction vessel, the liquid in the reaction vessel is usually stirred.

It is desirable to carry out the above-mentioned addition to the reaction vessel over a certain period of time. The time from the start of addition to the end of addition is, for example, 10 to 90 minutes, preferably 20 to 60 minutes, and more preferably 20 to 40 minutes.

The reaction is usually carried out under stirring. The reaction temperature is 35 to 85°C. The reaction temperature is preferably 40 to 75°C, more preferably 45 to 70°C, even more preferably 50 to 70°C, and even more preferably 55 to 65°C. When the pH of the aqueous alkali phosphate solution is relatively low (for example, when the pH is 4 or more and less than 5), the reaction temperature is relatively high, for example, 65 to 85°C, preferably 70 to 85°C, and more preferably 75 to 85°C. The reaction time (the time starting from when the aqueous alkali phosphate solution and the calcium hydroxide slurry are completely mixed, and in the above embodiments 1 to 3, the time starting from the time when the addition of the aqueous alkali phosphate solution and the calcium hydroxide slurry is completed) is, for example, 10 to 180 minutes, preferably 20 to 120 minutes, more preferably 40 to 90 minutes, and even more preferably 50 to 70 minutes.

The particles of the present disclosure produced by the above process may be subjected to a purification process, if necessary. Examples of purification processes include filtration and water washing. If necessary, the particles may also be subjected to a drying process.

The particles of the present disclosure have the ability to seal dentinal tubules and have excellent adhesion within the dentinal tubules. Therefore, an oral composition containing the particles of the present disclosure (i.e., the oral composition of the present disclosure) can be preferably used, particularly for preventing or improving dentin hypersensitivity.

The particles of the present disclosure can be contained in the oral composition in an amount of, for example, about 1 to 10% by mass. The upper or lower limit of the content range may be, for example, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, or 9.5% by mass. For example, the range is more preferably 2 to 8% by mass or 3 to 7% by mass.

The oral composition of the present disclosure can be manufactured by a conventional method, and can be used as, for example, a pharmaceutical product, a quasi-drug product, or a cosmetic product. The form of the oral composition of the present disclosure is not particularly limited, but can be made into a form (dosage form) such as an ointment, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, or coating agent according to a conventional method. Among them, mouthwash, liquid dentifrice, toothpaste, paste, liquid, spray, gel, or coating agent is preferable, and toothpaste, paste, or gel is more preferable. In addition, it is preferable to brush the oral composition by placing it on a toothbrush or applying the oral composition to the oral cavity, and therefore, it is preferable that the composition is in a form suitable for brushing. By brushing, the particles of the present disclosure can be pushed into the cavities of the dentin of the tooth, and the effect can be obtained more preferably.

In addition to the particles of the present disclosure, the oral composition of the present disclosure may further contain any optional components that can be incorporated into the oral composition, either alone or in combination of two or more, as long as the effects are not impaired.

A preferred example of such a component is potassium nitrate. In other words, the oral composition of the present disclosure preferably includes a form that contains the particles of the present disclosure and potassium nitrate. This is because an oral composition that contains potassium nitrate in addition to the particles of the present disclosure can suppress yellowing that occurs over time.

To explain in more detail, the present inventors have found that, unlike conventional hydroxyapatite particles, when the particles of the present disclosure are contained in an oral composition, there is a problem that the oral composition yellows (over time) when the oral composition is stored at a relatively high temperature (e.g., about 40 to 60°C). This temperature is quite possible during the distribution of oral composition products (especially during summer distribution), and yellowing can be one of the reasons why consumers avoid oral compositions when selecting them, so it is preferable to suppress it. Here, as described above, oral compositions that further contain potassium nitrate in addition to the particles of the present disclosure are particularly preferable because the yellowing that can occur over time is suppressed.

Potassium nitrate may be contained in the oral composition in an amount of, for example, about 0.1 to 15% by mass. The upper or lower limit of this range may be, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, or 14% by mass. For example, the range may be about 0.5 to 10% by mass, or 1 to 8% by mass.

Other optional components include, for example, nonionic surfactants, anionic surfactants, or amphoteric surfactants. Specifically, examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers with a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group with 13 to 15 carbon atoms; polyoxyethylene alkylphenyl ethers with a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group with 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; fatty acid polyoxyethylene sorbitan; and the like. Examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and polyoxyethylene lauryl ether sodium sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and polyoxyethylene lauryl ether sodium sulfosuccinate; acyl amino acid salts such as sodium cocoyl sarcosine and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurine. Examples of amphoteric surfactants include acetate betaine type surfactants such as lauryl dimethylamino acetate betaine and coconut oil fatty acid amidopropyl dimethylamino acetate betaine; imidazoline type surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine sodium; and amino acid type surfactants such as N-lauryl diaminoethyl glycine. These surfactants can be blended alone or in combination of two or more. The blending amount is usually 0.1 to 5% by mass based on the total amount of the composition.

Sweetening agents such as saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, and p-methoxycinnamic aldehyde may also be added. These may be used alone or in combination of two or more. These may be added in an amount of 0.01 to 1% by mass based on the total amount of the composition.

As the binder, for example, one or more of the following may be used in combination: cellulose derivatives such as sodium carboxymethylcellulose, carboxymethylethylcellulose salts, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; microbial polymers such as xanthan gum and gellan gum; natural polymers or natural rubbers such as tragacanth gum, karaya gum, gum arabic, carrageenan, and dextrin; synthetic polymers such as polyvinyl alcohol and polyvinylpyrrolidone; inorganic binders such as veegum and thickening silica; and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride.

In addition, sorbitol, glycerin, polypropylene glycol, xylitol, maltitol, lactitol, polyoxyethylene glycol, etc. can be used alone or in combination of two or more types as humectants.

Preservatives that can be used include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride, either alone or in combination of two or more.

Coloring agents may include legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, and titanium oxide, either alone or in combination of two or more kinds.

As a pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, etc. may be blended. These may be blended alone or in combination of two or more kinds so that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The amount of pH adjuster blended is, for example, 0.01 to 2% by weight.

As a medicinal ingredient, a bactericide may be blended. Examples include cationic bactericides such as cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, and chlorhexidine gluconate, amphoteric bactericides such as dodecyldiaminoethylglycine, nonionic bactericides such as triclosan and isopropylmethylphenol, and hinokitiol. Furthermore, medicinal ingredients other than bactericides may be blended. For example, vitamin E such as aluminum lactate, dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate, sodium fluoride, etc. may be blended. The medicinal ingredients may be blended alone or in combination of two or more kinds. Among them, aluminum lactate is a medicinal ingredient for preventing dentin hypersensitivity, and is therefore particularly preferable for blending in the oral composition of the present disclosure.

As bases, for example, alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. can be added alone or in combination of two or more.

Note that the above optional ingredients are merely examples and do not limit the optional ingredients that may be used.

In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes any combination of the constituent elements described in this specification.

Furthermore, the various characteristics (properties, structures, functions, etc.) described for each embodiment of the present disclosure above may be combined in any way to identify the subject matter encompassed by the present disclosure. In other words, the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described in this specification.

The subject matter of the present disclosure will be described in more detail below with reference to examples, but the subject matter of the present disclosure is not limited to these examples.

Example 1
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a 8.6% by mass solids grinding-treated calcium hydroxide slurry (BET specific surface area: 6.7 m ² /g, oxalic acid reactivity: 15 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 60°C while stirring, and maintained until the stirring was stopped. A 10% aqueous solution of NaOH was added to adjust the pH to 5.5. The calcium hydroxide slurry was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction, specific surface area measurement, particle size distribution measurement, Ca/P molar ratio measurement, and shape observation.

Measurements were performed in the range of 2θ = 25 to 45° using an X-ray diffraction device MultiFlex (manufactured by Rigaku Corporation). The measurement conditions were as follows: target: Cu, tube voltage: 40 kV, tube current: 30 mA, sampling width: 0.02°, scan speed: 2.00°/min, divergence slit: 1.0°, scattering slit: 1.0°, receiving slit: 0.3 mm. The results are shown in Figure 1. Figure 2 also shows the X-ray diffraction pattern of hydroxyapatite (reagent HAp), a commercially available reagent product. The ratio of the diffraction peak intensity due to the (211) plane near 2θ = 32° to the diffraction peak intensity ratio due to the (002) plane near 2θ = 26° was 1.1, which was clearly lower than the peak intensity ratio of 2.7 for reagent HAp. This showed that the obtained hydroxyapatite particles were aggregates of plate-shaped crystals with relatively large amounts of the c-plane exposed. In addition, the sum of the areas of all diffraction peaks in the range of 25°≦2θ≦35° was 100%, while the sum of the areas of all diffraction peaks in the range of 25.5°≦2θ≦26.5° and the range of 31.5°≦2θ≦32.5° was 37.2%. This is clearly lower than the 52.1% shown by the reagent HAp, and the X-ray diffraction pattern is relatively broad, which indicates low crystallinity. In addition, the crystallite size calculated from the diffraction peak due to the (130) plane near 2θ=40° was 7 nm, which is clearly smaller than the 52 nm shown by the reagent HAp, and this also indicates low crystallinity.

The specific surface area of the hydroxyapatite particles was measured by a nitrogen gas adsorption method using a fully automatic specific surface area measuring device Macsorb HM model-1208 (manufactured by Mountec Co., Ltd.) The result was that the specific surface area was 61.9 m ² /g.

The particle size distribution of the hydroxyapatite particles was measured by dry particle size distribution measurement using a laser diffraction particle size distribution measuring device MASTER SIZER 3000. As a result, the median diameter (d50) was 3.76 μm.

The Ca/P molar ratio of the hydroxyapatite particles was calculated from the measured values of Ca and P content by inductively coupled plasma optical emission spectrometry using an iCAP 6000 ICP-OES (manufactured by ThermoFisher). As a result, the Ca/P molar ratio was 1.33.

The shape of the hydroxyapatite particles was observed using a scanning electron microscope (manufactured by JEOL Ltd.: hereafter referred to as SEM). The results are shown in Figure 3. These results indicate that the obtained hydroxyapatite particles are aggregates of plate-like crystals.

Example 2
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a 8.6% by mass solids grinding-treated calcium hydroxide slurry (BET specific surface area: 7.9 m ² /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 60°C while stirring, and maintained until the stirring was stopped. A 10% aqueous solution of NaOH was added to adjust the pH to 6.0. The calcium hydroxide slurry was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction, specific surface area measurement, and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in FIG. 4. The ratio of the diffraction peak intensity due to the (211) plane near 2θ=32° to the diffraction peak intensity due to the (002) plane near 2θ=26° was 1.1, which was the same value as in Example 1. In addition, the sum of the areas of all diffraction peaks in the range of 25°≦2θ≦35° was 100%, and the sum of the areas of all diffraction peaks in the range of 25.5°≦2θ≦26.5° and the range of 31.5°≦2θ≦32.5° was 38.6%. In addition, the crystallite size calculated from the diffraction peak due to the (130) plane near 2θ=40° was 7 nm.

The specific surface area was 75.4 m ² /g.

The shape observation results are shown in Figure 5. As in Example 1, it was confirmed that the particles were aggregates of plate-like crystals.

Example 3
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a 8.6% by mass ground calcium hydroxide slurry (BET specific surface area 7.9 m ² /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 40°C while stirring, and maintained until the stirring was stopped. A 10% aqueous solution of NaOH was added to adjust the pH to 5.5. The calcium hydroxide slurry was added thereto over 50 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction, specific surface area measurement, and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in FIG. 6. The ratio of the diffraction peak intensity due to the (211) plane near 2θ=32° to the diffraction peak intensity due to the (002) plane near 2θ=26° was 1.2, which was the same value as in Example 1. In addition, the sum of the areas of all diffraction peaks in the range of 25°≦2θ≦35° was 100%, and the sum of the areas of all diffraction peaks in the range of 25.5°≦2θ≦26.5° and the range of 31.5°≦2θ≦32.5° was 36.0%. In addition, the crystallite size calculated from the diffraction peak due to the (130) plane near 2θ=40° was 6 nm.

The specific surface area was 81.5 m ² /g.

The shape observation results are shown in Figure 7. As in Example 1, it was confirmed that the obtained hydroxyapatite particles were aggregates of plate-like crystals.

Example 4
A 10.7% by mass anhydrous aqueous solution of sodium dihydrogen phosphate and a ground calcium hydroxide slurry with a solid content of 8.6% by mass (BET specific surface area 7.9 ^{m 2} /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The anhydrous aqueous solution of sodium dihydrogen phosphate was placed in a stainless steel beaker and heated to 80°C while stirring. The pH was left at 4.2 without adjustment. The calcium hydroxide slurry was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction, specific surface area measurement, and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in FIG. 8. The ratio of the diffraction peak intensity due to the (211) plane near 2θ=32° to the diffraction peak intensity due to the (002) plane near 2θ=26° was 1.4, which was the same value as in Example 1. In addition, the sum of the areas of all diffraction peaks in the range of 25°≦2θ≦35° was 100%, and the sum of the areas of all diffraction peaks in the range of 25.5°≦2θ≦26.5° and the range of 31.5°≦2θ≦32.5° was 37.8%. In addition, the crystallite size calculated from the diffraction peak due to the (130) plane near 2θ=40° was 9 nm.

The specific surface area was 163.4 m ² /g.

The shape observation results are shown in Figure 9. As in Example 1, it was confirmed that the obtained hydroxyapatite particles were aggregates of plate-like crystals.

Example 5
A 10.7% by mass anhydrous aqueous solution of sodium dihydrogen phosphate and a ground calcium hydroxide slurry with a solid content of 8.6% by mass (BET specific surface area 7.9 ^{m 2} /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The anhydrous aqueous solution of sodium dihydrogen phosphate was placed in a stainless steel beaker and heated to 60°C while stirring. The pH was left at 4.2 without adjustment. The calcium hydroxide slurry was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite fine particles (powder).

The obtained hydroxyapatite microparticles were subjected to X-ray crystal diffraction, specific surface area measurement, and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 10. The ratio of the diffraction peak intensity due to the (211) plane near 2θ = 32° to the diffraction peak intensity due to the (002) plane near 2θ = 26° was 1.1, which was the same value as in Example 1. In addition, the sum of the areas of all diffraction peaks in the range of 25° ≦ 2θ ≦ 35° was 100%, while the sum of the areas of all diffraction peaks in the range of 25.5° ≦ 2θ ≦ 26.5° and the sum of the areas of all diffraction peaks in the range of 31.5° ≦ 2θ ≦ 32.5° was 31.6%. In addition, the crystallite size calculated from the diffraction peak due to the (130) plane near 2θ = 40° was 7 nm.

The specific surface area was 94.7 m ² /g.

The shape observation results are shown in Figure 11. As in Example 1, it was confirmed that the particles were aggregates of plate-like fine particles.

Comparative Example 1
A 10.7% by mass anhydrous aqueous solution of sodium dihydrogen phosphate and a ground calcium hydroxide slurry with a solid content of 8.6% by mass (BET specific surface area 7.9 ^{m 2} /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The calcium hydroxide slurry was placed in a stainless steel beaker and heated to 40°C while stirring. An aqueous solution of sodium dihydrogen phosphate anhydrous (pH: 4.2) was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction, specific surface area measurement, and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 12. The ratio of the diffraction peak intensity due to the (211) plane near 2θ = 32° to the diffraction peak intensity due to the (002) plane near 2θ = 26° was 1.7, which was clearly higher than that of Example 1. In addition, the diffraction peak due to the (300) plane near 2θ = 33° appeared separately.

The specific surface area was 50.9 m ² /g.

The results of the shape observation are shown in Figure 13. It was confirmed that the obtained hydroxyapatite particles were formed by agglomeration of spindle-shaped crystals.

Comparative Example 2
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a calcium hydroxide slurry with a solid content of 8.6% by mass (JP Patent Publication No. 2017-036176) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 60°C while stirring, and maintained until the stirring was stopped. The pH was not adjusted to 4.2. The calcium hydroxide slurry was added thereto over 45 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain a sample.

The obtained samples were subjected to X-ray crystal diffraction and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 14. In addition to the diffraction peaks of hydroxyapatite, diffraction peaks of other substances were confirmed. The peaks indicated by black circles in the figure are the diffraction peaks of monetite, a calcium phosphate that is easily formed in acidic conditions.

The results of the shape observation are shown in Figure 15. Large plate-like particles of monetite were confirmed.

Comparative Example 3
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a high-purity calcium hydroxide slurry with a solid content of 8.6% by mass (BET specific surface area: 2.4 m ² /g, oxalic acid reactivity: 25 seconds, JP 2011-126772 A) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 60°C while stirring, and maintained until the stirring was stopped. A 10% aqueous solution of NaOH was added to adjust the pH to 5.5. The calcium hydroxide slurry was added thereto over 30 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain a sample.

X-ray crystal diffraction was performed on the obtained sample in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 16. In addition to the diffraction peaks of hydroxyapatite, diffraction peaks of calcium hydroxide were confirmed near 2θ = 28° and 34°.

The shape observation results are shown in Figure 17. Large plate-like particles of calcium hydroxide were confirmed. The difference from Example 1 was thought to be due to the physical properties of the raw material calcium hydroxide.

Comparative Example 4
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a 8.6% by mass solids grinding treated calcium hydroxide slurry (BET specific surface area 7.9 m ² /g, oxalic acid reactivity: 12 minutes 30 seconds, JP 2017-036176 A) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, and a 10% aqueous solution of NaOH was added to adjust the pH to 5.5. The calcium hydroxide slurry was added thereto over 50 minutes. After the addition was completed, the mixture was stirred for another hour, and then the stirring was stopped. The mixture was left to stand at room temperature for 9 days, filtered, washed with water, and dried at 80°C to obtain hydroxyapatite particles (powder).

The obtained hydroxyapatite particles were subjected to X-ray crystal diffraction and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 18. The ratio of the diffraction peak intensity due to the (211) plane near 2θ = 32° to the diffraction peak intensity due to the (002) plane near 2θ = 26° was 1.3.

The shape observation results are shown in Figure 19. It was confirmed that the particle shape was an aggregate of tiny spindle-shaped particles.

Comparative Example 5
A 10.7% by mass aqueous solution of sodium dihydrogen phosphate dihydrate and a calcium hydroxide slurry with a solid content of 8.6% by mass (JP Patent Publication No. 2017-036176) were prepared so that the Ca/P molar ratio was 0.5. The aqueous solution of sodium dihydrogen phosphate dihydrate was placed in a stainless steel beaker, heated to 80°C while stirring, and maintained until the stirring was stopped. The pH was not adjusted to 4.2. The calcium hydroxide slurry was added thereto over a period of 50 minutes. After the addition was completed, the mixture was stirred for another hour, filtered, washed with water, and dried at 80°C to obtain a sample.

The obtained samples were subjected to X-ray crystal diffraction and shape observation in the same manner as in Example 1.

The results of X-ray crystal diffraction are shown in Figure 20. In addition to the diffraction peaks of hydroxyapatite, diffraction peaks of other substances were confirmed. The peaks indicated by black circles in the figure are the diffraction peaks of monetite, a calcium phosphate that is easily formed in acidic conditions.

The results of the shape observation are shown in Figure 21. Large plate-like particles of monetite were confirmed.

Test Example 1. Crystallinity change confirmation test [Test purpose]
In order to evaluate the reactivity of hydroxyapatite particles in the oral cavity, the change in crystallinity before and after immersion in artificial saliva was measured using a powder X-ray diffractometer.

[Test Method]
0.5 g of hydroxyapatite particles obtained in the same manner as in Example 1 was immersed in 200 mL of artificial saliva ( _CaCl2 : 1.5 _mM , _KH2PO4 : 0.9 mM, KCl: 130 mM, HEPES: 20 mM, pH 7.0 (KOH)) for 7 days. The powder separated by suction filtration was measured using a powder X-ray diffraction apparatus to observe the change in crystallinity before and after immersion in the artificial saliva.

[Measurement conditions]
・Model used: Miniflex II (Rigaku Corporation)
・Starting angle: 20°
End angle: 40°
・Sampling width: 0.02°
Scan speed: 4.0°/min
Target: Cu,
Tube voltage: 30 kV
・Tube current: 15mA
Divergence slit: 1.25°
Scattering slit: 8.0 mm
- Receiving slit: 0.3 mm.

The results are shown in Figure 22. It was confirmed that immersion in artificial saliva improved crystallinity (increased peak sharpness, and broad, hidden peaks appeared). This confirmed that the hydroxyapatite particles were particles that changed (had a reactive nature) in the oral cavity.

In addition, when a similar study was carried out using known hydroxyapatite particles instead of the hydroxyapatite particles obtained in the same manner as in Example 1, the peaks did not change at all before and after immersion in artificial saliva, and the crystallinity did not change.

Test Example 2. Dentinal tubule occlusion test of hydroxyapatite particles [Test purpose]
In order to evaluate the ability of hydroxyapatite particles to seal dentinal tubules, the surface of bovine dentin was brushed with a solution of hydroxyapatite particles, and the degree of sealing of the dentinal tubules was examined by scanning electron microscope (SEM).

[Test Method]
Preparation of dentin blocks (samples)
1. Dentin from the root surface of an extracted bovine tooth was cut into pieces measuring 5 x 5 mm.
2. The cut tooth pieces were embedded in resin (polymethyl methacrylate) to create blocks, which were then polished with waterproof abrasive paper to expose the surface.
3. The dentin block was immersed in a 5% w/w aqueous solution of EDTA (pH 7.0) for 2 minutes.
4. Sonicate in distilled water for 5 minutes.

5. Preparation of hydroxyapatite particle liquid 0.3 g of hydroxyapatite particles obtained in the same manner as in Example 1 was suspended in 39.7 g of a viscous diluent to obtain hydroxyapatite particles. The viscous diluent was an aqueous solution containing 0.5 w/w % sodium carboxymethylcellulose and 10 w/w % glycerin.

Brushing Treatment 6. The dentin block was brushed with a toothbrush (GUM #211) in the hydroxyapatite particle solution (40 g) for 30 seconds (stroke: 150 rpm, load: 160 g).
7. The dentin block was washed with water and then immersed in artificial saliva (CaCl ₂ : 1.5 mM, KH ₂ PO ₄ : 0.9 mM, KCl: 130 mM, HEPES: 20 mM, pH 7.0 (KOH)) for 5 minutes.
8. The above steps 1 and 2 were repeated six times.

SEM Observation 9. After the surface was subjected to deposition treatment, it was observed with an electron microscope.

[Observation and measurement conditions]
{Vapor deposition process}
・Model used: MCI1000 (Hitachi High-Technologies Corporation)
・Current: 20mA
Processing time: 120 seconds {SEM observation}
・Model used: S-3400N (Hitachi High-Technologies Corporation)
Detector: SE (secondary electron image)
Applied voltage: 5 kV
Probe current: 50mA
・Magnification: 25,000 times.

The results are shown in Figure 23. It was confirmed that the dentinal tubules were blocked by brushing in the hydroxyapatite particle solution. This confirmed that the hydroxyapatite particles are particles that block the dentinal tubules present on the dentin surface.

Test Example 3. Adhesion test [Test purpose]
To evaluate the ability of hydroxyapatite particles to adhere within dentinal tubules, the surface of bovine dentin was brushed with a hydroxyapatite particle solution, and then water pressure was applied from the back side of the dentin. Whether the sequestered hydroxyapatite particles could withstand the water pressure was examined by scanning electron microscope (SEM).

[Test Method]
Preparation of dentin discs (samples)
1. Dentin from the root surface of an extracted bovine tooth was cut into pieces measuring 5 x 5 mm.
2. The cut tooth pieces were polished with waterproof abrasive paper.
3. The resulting dentin disk was immersed in a 5% w/w aqueous solution of EDTA (pH 7.0) for 2 minutes.
4. Sonicate in distilled water for 5 minutes.

5. Preparation of hydroxyapatite particle liquid 1 g of hydroxyapatite particles obtained in the same manner as in Example 1 was suspended in 39 g of a viscous diluent to obtain a hydroxyapatite particle liquid. The viscous diluent was an aqueous solution containing 0.5 w/w % sodium carboxymethylcellulose and 10 w/w % glycerin.

Brushing treatment 6. The dentin disk was brushed with a toothbrush (GUM #211) in the hydroxyapatite particle solution (40 g) for 30 seconds (stroke: 150 rpm, load: 160 g).
7. The disk was washed with water and then immersed in artificial saliva (CaCl ₂ : 1.5 mM, KH ₂ PO ₄ : 0.9 mM, KCl: 130 mM, HEPES: 20 mM, pH 7.0 (KOH)) for 5 minutes.
8. The above steps 1 and 2 were repeated six times.
9. Immersed in artificial saliva for 7 days.

Water pressure treatment 10. The dentin disk after the brushing treatment was pressurized at 0.1 MPa for 30 minutes using a device based on the report by Pashley et al. (Pashley DH, Galloway SE. The effects of oxalate treatment on the smear layer of ground surfaces of human dentin. Arch Oral Biol 1983; 30: 731-737.).

SEM Observation 11. After the surface was subjected to deposition treatment, it was observed with an electron microscope.

[Observation and measurement conditions]
{Vapor deposition process}
・Model used: MCI1000 (Hitachi High-Technologies Corporation)
・Current: 20mA
Processing time: 120 seconds {SEM observation}
・Model used: S-3400N (Hitachi High-Technologies Corporation)
Detector: SE (secondary electron image)
Applied voltage: 5 kV
Probe current: 50mA
・Magnification: 25,000 times.

The results are shown in Figure 24. It was confirmed that the dentinal tubules remained sealed even after the water pressure treatment. This confirmed that the hydroxyapatite particles were fixed inside the dentinal tubules and maintained a sealed state.

Test Example 4. Dentinal tubule occlusion test of toothpaste [Test purpose]
In order to confirm the ability of toothpaste formulations containing the materials to seal dentinal tubules, the surface of bovine dentin was brushed with the material solution, and the degree of sealing of the dentinal tubules was examined using a scanning electron microscope (SEM).

[Test Method]
Preparation of dentin blocks (samples)
1. Dentin from the root surface of an extracted bovine tooth was cut into pieces measuring 5 x 5 mm.
2. The cut tooth pieces were embedded in resin (polymethyl methacrylate) to create blocks, which were then polished with waterproof abrasive paper to expose the surface.
3. The dentin block was immersed in a 5 w/w % EDTA aqueous solution (pH 7.0) for 2 minutes.
4. Sonicate in distilled water for 5 minutes.

5. Preparation of Dentifrice Solution 10 g of dentifrice containing 3 w/w% of the hydroxyapatite particles obtained in the same manner as in Example 1 was prepared by a conventional method. The composition of the dentifrice is shown in Table 1 below. In the following, the unit "%" for the amount of the mixture in the table indicates % by mass.

Brushing treatment 6. 10 g of the dentifrice was diluted 4 times with distilled water to obtain a dentifrice solution. In the dentifrice solution (40 g), the dentin block was brushed with a toothbrush (GUM #211) for 30 seconds (stroke: 150 rpm, load: 160 g).
7. The dentin block was washed with water and then immersed in artificial saliva (CaCl ₂ : 1.5 mM, KH ₂ PO ₄ : 0.9 mM, KCl: 130 mM, HEPES: 20 mM, pH 7.0 (KOH)) for 5 minutes.
8. The above steps 1 and 2 were repeated six times.

SEM Observation 9. After the surface was subjected to deposition treatment, it was observed with an electron microscope.

[Observation and measurement conditions]
{Vapor deposition process}
・Model used: MCI1000 (Hitachi High-Technologies Corporation)
・Current: 20mA
Processing time: 120 seconds {SEM observation}
・Model used: S-3400N (Hitachi High-Technologies Corporation)
Detector: SE (secondary electron image)
Applied voltage: 5 kV
・Probe current 50mA
・Magnification: 25000x

The results are shown in Figure 25. It was confirmed that the dentinal tubules were sealed by brushing in a dentifrice solution containing hydroxyapatite particles. This confirmed that dentifrice containing hydroxyapatite particles is highly effective at sealing dentinal tubules.

Test Example 5. Dentinal tubule occlusion test when gel preparation is applied with a soft pick [Test purpose]
In order to confirm the ability of the gel preparation containing hydroxyapatite particles to seal dentinal tubules, the gel preparation was applied to the surface of bovine dentin using a soft pick (a rubber interdental brush), and the degree of sealing of the dentinal tubules was examined using a scanning electron microscope (SEM).

[Test Method]
Preparation of dentin blocks (samples)
1. Dentin from the root surface of an extracted bovine tooth was cut into pieces measuring 5 x 5 mm.
2. The cut tooth pieces were embedded in resin (polymethyl methacrylate) to create blocks, which were then polished with waterproof abrasive paper to expose the surface.
3. The dentin block was immersed in a 5 w/w % EDTA aqueous solution (pH 7.0) for 2 minutes.
4. Sonicate in distilled water for 5 minutes.
5. The two dentin blocks were fixed with tape so that the dentin surfaces faced each other with a gap of 1.1 mm between them to form a simulated interdental space.

Application treatment 6. The gel preparation containing (or not containing) hydroxyapatite particles obtained in the same manner as in Example 1 was placed on the brush part of a soft pick (Gum Soft Pick Curved Type: Sunstar Corporation), and inserted into the gap and reciprocated five times. The composition of the gel preparation is shown in Table 2 below.
7. The dentin block was rinsed with water.

SEM Observation 8. After the surface was subjected to deposition treatment, it was observed with an electron microscope.

[Observation and measurement conditions]
{Vapor deposition process}
・Model used: MCI1000 (Hitachi High-Technologies Corporation)
・Current: 20mA
Processing time: 120 seconds {SEM observation}
・Model used: S-3400N (Hitachi High-Technologies Corporation)
Detector: SE (secondary electron image)
Applied voltage: 5 kV
・Probe current 50mA
・Magnification: 25000x

The results are shown in Figure 26. It was confirmed that the dentinal tubules were sealed by applying the gel preparation containing hydroxyapatite particles using a soft pick.

Test Example 6. Clinical trial of gel formulation [Test objective]
The clinical effect of a gel preparation containing hydroxyapatite particles on anti-hypersensitivity was examined. In this examination, hydroxyapatite particles obtained in the same manner as in Example 1 were used as the hydroxyapatite particles.

[Study design]
Three formulations were compared: (i) a gel formulation containing hydroxyapatite particles, aluminum lactate, and potassium nitrate (HAp+Al+K), (ii) a gel formulation containing aluminum lactate and potassium nitrate (Al+K), and (iii) a gel formulation containing potassium nitrate (K). The compositions of these gel formulations are shown in Table 3 below.

Twenty subjects were asked to use each gel formulation, and the degree of abrasion pain (a probe was placed on the exposed root surface and scraped horizontally) was recorded on a VAS scale 1, 2, or 4 weeks after use. The VAS scale is a visual scale in which the patient is shown a 10 cm long black line (the left end being "no pain at all" and the right end being "most painful/strong pain") to indicate the current level of pain. The flow of the study is shown in Figure 27. In Figure 27, "dentin hypersensitivity care set (gel formulation (test product))" refers to the gel formulations (i) to (iii) above, and "dentin hypersensitivity care set (gel formulation (placebo product))" refers to the gel formulation (iii) above without potassium nitrate.

[How to use the test sample]
The subjects were instructed to use the gel preparation (test product) twice a day (morning and evening) (no restrictions were placed on when to use the gel preparation after waking up, after meals, or before going to bed, but rather on the basis of their own oral hygiene habits). Specifically, the subjects first brushed their teeth with a designated toothbrush (Gum Pros Dental Brush #3C: Sunstar Co., Ltd.) and dentifrice (Coop Non-Foam Toothpaste N), then rinsed their mouths with about 10 ml of water for 20 seconds (no restrictions were placed on brushing time), and then used the gel preparation. Specifically, the gel preparation was applied to the test site with a tuft brush (Butler Single Tuft Brush #01F: Sunstar Co., Ltd.) with about 0.04 g (about the size of a grain of rice) of the gel preparation (test product) for each test tooth, and the test site and both adjacent teeth were brushed for at least 5 seconds per tooth. When a specified interdental cleaner (Gum Soft Pick Curved Type: Sunstar Corporation) could be inserted between the test site and both adjacent teeth, the interdental cleaner was inserted from the cheek side into the gap between the test site and both adjacent teeth and moved back and forth five times. After using the gel preparation (test product), the subjects were made to rinse their mouths with about 10 ml of water for 20 seconds.

The results of evaluating the degree of abrasion pain using a VAS scale are shown in Figure 28. The group that used the hydroxyapatite-containing preparation showed a significant improvement in abrasion pain one week after use compared to the group that did not use the preparation. This shows that the hydroxyapatite-containing preparation is effective in suppressing hypersensitivity symptoms early when used in combination with aluminum lactate and potassium nitrate, which are known medicinal ingredients for preventing hypersensitivity.

Test Example 7. Study of the effect of oral compositions containing hydroxyapatite particles and potassium nitrate Oral compositions were prepared using hydroxyapatite particles obtained in the same manner as in Example 1 (HAp produced by the procedure of Example 1) or commercially available hydroxyapatite particles (commercially available HAp (manufactured by Tomita Pharmaceutical Co., Ltd.); a commercially available hydroxyapatite different from the above-mentioned reagent HAp), and potassium nitrate. Specifically, each oral composition was prepared by mixing each component shown in Table 4. The numerical values of each component shown in Table 4 indicate mass %. In addition, when X-ray crystal diffraction was performed on the HAp produced by the procedure of Example 1 and the commercially available HAp in the same manner as in Example 1, the ratio of the diffraction peak intensity due to the (211) plane near 2θ=32° to the diffraction peak intensity ratio due to the (002) plane near 2θ=26° was 1.44 for the HAp produced by the procedure of Example 1, and 2.72 for the commercially available HAp.

25 g of each oral composition was filled into an 8 mm diameter laminated tube, stored at 55°C in a dark place for 6 months, and then returned to room temperature. The color difference was measured as follows. The stored oral compositions were filled into a polystyrene container to a height of 2 cm, and photographed on a white board using an FD-5 (Konica Minolta fluorescence spectrodensitometer). The photographing conditions were constant lighting, shutter speed, aperture, and focal length. The b* in the L*a*b* color system was measured at six measurement sites, and the average value was calculated to be used as an index for evaluating yellowing (yellowing). The results (b* value of each oral composition) are shown in Figure 29. The nine bar graphs in Figure 29 show the b* values of Reference Example 1a, Reference Example 2a, Reference Example 3a, Comparative Example 1a, Example 1a, and Comparative Example 2a, from the left.

These results confirm that, unlike conventional hydroxyapatite particles, the hydroxyapatite particles obtained in the Examples cause the oral composition to yellow (over time) when stored at relatively high temperatures (e.g., about 40 to 60°C) when contained in the oral composition (Reference Examples 2a and 3a), and that the oral composition containing potassium nitrate in addition to the hydroxyapatite particles obtained in the Examples significantly inhibits this yellowing (Example 1a).

Claims (3)

An oral composition comprising 1 to 10% by mass of hydroxyapatite particles and 0.1 to 15% by mass of potassium nitrate,
the hydroxyapatite particles have a ratio of a diffraction peak intensity at about 2θ=32° to a diffraction peak intensity at about 2θ=26° in a powder X-ray diffraction pattern measured with CuKα characteristic X-rays of 1.0 to 1.2 ;
The hydroxyapatite particles have a Ca/P molar ratio of 1.2 to 1.4 ;
The hydroxyapatite particles have a median diameter of 3 to 4.5 μm;
The specific surface area of the hydroxyapatite particles is 55 to 90 m ² /g;
The crystallite size of the hydroxyapatite particles calculated from the diffraction peak due to the (130) plane around 2θ = 40 ° is 4 to 12 nm.
Oral composition. The oral composition according to claim 1 , further comprising aluminum lactate. 3. The oral composition according to claim 1 or 2 , which is for preventing or improving hypersensitivity.

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