Oral composition containing citric acid

Abstract

[Problem] To provide an oral composition that contains high concentrations of fluorine and hinokitiol while achieving stabilization of hinokitiol. [Solution] An oral composition containing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content is 1000 ppm or more.

Description

Oral composition containing citric acid

[0001] The present disclosure relates to an oral composition that contains hinokitiol and a high concentration of fluorine, while the hinokitiol is stably present in the composition.

[0002] Conventionally, bactericides have been blended into oral compositions such as dentifrices and mouthwashes to reduce the number of pathogenic bacteria causing dental caries or periodontal disease. Various bactericides for blending into oral compositions are known, and hinokitiol is widely used in oral compositions due to its low toxicity and broad antibacterial spectrum (Patent Document 1).

[0003] In addition, for the prevention of dental caries, the use of dentifrices containing fluorine compounds is recommended as a daily self-care practice. Fluorine compounds impart to teeth resistance to acids produced by cariogenic bacteria, repair initial caries through remineralization, and restore teeth to their original healthy state, and thus are widely used in oral compositions. Furthermore, fluorine compounds also have an effect of suppressing the growth of cariogenic bacteria (Patent Document 2).

[0004] Japanese Patent Application Laid-Open No. 2017-007991 Japanese Patent Application Laid-Open No. 2021-107362

[0005] The present inventors studied the storage stability of hinokitiol in the formulation of an oral composition containing a fluorine compound and hinokitiol. The present inventors found that when fluorine is contained in the oral composition at a general concentration, hinokitiol is stably stored in the oral composition; however, the inventors faced the problem that when fluorine is contained at a high concentration, hinokitiol becomes destabilized in the oral composition. Destabilization of hinokitiol reduces the bactericidal effect of the oral composition, and thus is an important problem that must be solved.

[0006] Accordingly, an object of the present disclosure is to provide an oral composition that contains a high concentration of fluorine and hinokitiol, while achieving stabilization of hinokitiol.

[0007] To achieve the above object, there is provided an oral composition comprising a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content is 1000 ppm or more.

[0008] According to this disclosure, it is possible to provide an oral composition that contains a high concentration of fluorine and hinokitiol while achieving hinokitiol stabilization. The oral composition can exhibit a bactericidal effect due to hinokitiol and a caries-preventive effect due to the high concentration of fluorine, and the problem of hinokitiol destabilization caused by the high concentration of fluorine is solved by citric acid or its salt.

[0009] 1. Oral Composition of the Disclosure The Disclosure provides an oral composition comprising a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content is 1000 ppm or more (the oral composition of the Disclosure).

[0010] (Fluorine compounds) The oral compositions of this disclosure contain fluorine compounds.

[0011] In the oral compositions of this disclosure, the fluorine compound is a known component that imparts resistance to acids produced by cariogenic bacteria to teeth, has the effect of remineralizing early caries, and also has the effect of suppressing the growth of cariogenic bacteria. The fluorine compound used in the oral compositions of this disclosure is not particularly limited as long as it is applicable in the oral cavity, but examples include alkali metal fluorides, fluorophosphates, fluorophosphates, stannous fluoride, and silver diamine fluoride. The fluorine compound may be used alone or in combination of two or more. From the viewpoint of obtaining the above effects on caries significantly, the fluorine compound is preferably at least one selected from the group consisting of alkali metal fluorides, fluorophosphates, and fluorophosphates, and more preferably fluorophosphates.

[0012] The alkali metal fluoride is not particularly limited as long as it is applicable in the oral cavity, but examples include sodium fluoride and potassium fluoride. The alkali metal fluoride may be used alone or in combination of two or more types. Among the alkali metal fluorides exemplified above, sodium fluoride is preferred from the viewpoint of obtaining the above-mentioned effect on dental caries significantly.

[0013] The fluorophosphate is not particularly limited as long as it can be applied in the oral cavity, but examples include monofluorophosphate and difluorophosphate. The fluorophosphate may be used alone or in combination of two or more types. Among the fluorophosphates exemplified above, monofluorophosphate is preferred from the viewpoint of obtaining the above-mentioned effects on dental caries.

[0014] The fluorophosphate is not particularly limited as long as it is applicable in the oral cavity, but examples include alkali metal salts of fluorophosphate, specifically sodium salts and potassium salts of fluorophosphate. The fluorophosphate may be used alone or in combination of two or more types. Among the fluorophosphates exemplified above, sodium salts are preferred, and sodium monofluorophosphate is more preferred, from the viewpoint of obtaining the above-mentioned effects on dental caries.

[0015] In the oral composition of this disclosure, the fluorine content in the oral composition is 1000 ppm or more in order to impart the above-mentioned effect against dental caries. Although the oral composition of this disclosure contains a high concentration of fluorine of 1000 ppm or more, the destabilization of hinokitiol caused by the high concentration of fluorine is suppressed because citric acid and / or its salts, as described later, are included.

[0016] In the oral composition of this disclosure, the lower limit of the fluorine content in the oral composition is 1000 ppm or more, preferably 1100 ppm or more, more preferably 1200 ppm or more, even more preferably 1300 ppm or more, and even more preferably 1400 ppm or more, from the viewpoint of imparting the above-mentioned effects against dental caries. Since the oral composition of this disclosure contains citric acid and / or its salts, as described later, the destabilization of hinokitiol can be suppressed even when the oral composition of this disclosure contains 1000 ppm or more of fluorine. Furthermore, in the oral composition of this disclosure, there is no particular upper limit to the fluorine content in the oral composition, but for example, it is 1500 ppm or less.

[0017] In one embodiment of the oral composition of the present disclosure, when the fluorine compound is sodium monofluorophosphate, the content of sodium monofluorophosphate is, for example, 0.76 to 1.14% by weight, preferably 0.83 to 1.14% by weight, more preferably 0.91 to 1.14% by weight, even more preferably 0.99 to 1.14% by weight, and most preferably 1.06 to 1.14% by weight, from the viewpoint of imparting the above-mentioned effect against dental caries to the oral composition.

[0018] (Hinokitiol) The oral compositions of this disclosure contain hinokitiol.

[0019] In the oral compositions of this disclosure, hinokitiol is a known component incorporated into oral compositions as a disinfectant, etc. Hinokitiol may be derived from natural products or may be chemically synthesized. Furthermore, the hinokitiol used in this disclosure may be a refined product or a crude product. When using a refined product, for example, a hinokitiol-containing essential oil obtained from a tree may be used.

[0020] In the oral composition of this disclosure, the hinokitiol content is appropriately set according to the formulation form and use of the oral composition, but is, for example, 0.1 to 1 part by weight per 1 part by weight of fluorine. Furthermore, from the viewpoint of exhibiting excellent bactericidal activity and stabilizing the hinokitiol contained in the oral composition, the hinokitiol content is, for example, 0.27 to 0.4 parts by weight, preferably 0.27 to 0.36 parts by weight, more preferably 0.27 to 0.33 parts by weight, even more preferably 0.27 to 0.31 parts by weight, and most preferably 0.27 to 0.29 parts by weight per 1 part by weight of fluorine.

[0021] In one embodiment of the oral composition of the present disclosure, when the fluorine compound is sodium monofluorophosphate, the hinokitiol content is, for example, 0.01 to 0.5 parts by weight per 1 part by weight of sodium monofluorophosphate. Furthermore, from the viewpoint of exhibiting excellent bactericidal activity and stabilizing the hinokitiol contained in the oral composition, the hinokitiol content is, for example, 0.035 to 0.053 parts by weight, preferably 0.035 to 0.048 parts by weight, more preferably 0.035 to 0.044 parts by weight, even more preferably 0.035 to 0.041 parts by weight, and most preferably 0.035 to 0.038 parts by weight per 1 part by weight of sodium monofluorophosphate.

[0022] In the oral composition of this disclosure, the hinokitiol content is appropriately set according to the formulation form and use of the oral composition, but for example, it is 0.005 to 1% by weight. Furthermore, from the viewpoint of exhibiting excellent bactericidal activity and stabilizing the hinokitiol contained in the oral composition, the hinokitiol content is, for example, 0.01 to 0.5% by weight, preferably 0.02 to 0.3% by weight, more preferably 0.03 to 0.2% by weight, and even more preferably 0.04 to 0.1% by weight.

[0023] (Citric Acid) The oral compositions of this disclosure comprise citric acid and / or salts thereof.

[0024] In the oral composition of this disclosure, citric acid (or a salt thereof) is incorporated into the oral composition to suppress the destabilization of hinokitiol caused by high concentrations of fluorine. Therefore, it is inferred that citric acid (or a salt thereof) has the function of inhibiting the reaction between fluorine compounds and hinokitiol.

[0025] In the oral compositions of this disclosure, examples of citric acid salts include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts of citric acid include monosodium citrate, disodium citrate, trisodium citrate, monopotassium citrate, dipotassium citrate, and tripotassium citrate, with trisodium citrate being preferred. Examples of alkaline earth metal salts of citric acid include magnesium citrate, calcium citrate, and strontium citrate. Citric acid or its salts may be solvates (e.g., hydrates) or solvates, and both are included.

[0026] In the oral compositions of this disclosure, citric acid or a salt thereof may be used alone or in combination of two or more types. When two or more types of citric acid or a salt thereof are included simultaneously, the mixing ratio is not particularly limited as long as it suppresses the destabilization of hinokitiol. For example, a mixing ratio (molar ratio) of two types of citric acid or a salt thereof may be 1:10 to 10:1.

[0027] In the oral composition of this disclosure, the citric acid content needs to be appropriately adjusted according to the fluorine content in the oral composition, but is, for example, 1.0 to 5.0 parts by weight per part by weight of fluorine. Furthermore, from the viewpoint of stabilizing the hinokitiol contained in the oral composition, the citric acid content is, for example, 2.62 to 3.93 parts by weight, preferably 2.62 to 3.57 parts by weight, more preferably 2.62 to 3.28 parts by weight, even more preferably 2.62 to 3.02 parts by weight, and most preferably 2.62 to 2.81 parts by weight per part by weight of fluorine.

[0028] In one embodiment of the oral composition of the present disclosure, when the fluorine compound is sodium monofluorophosphate, the citric acid content is, for example, 0.01 to 0.1 parts by weight per 1 part by weight of sodium monofluorophosphate. Furthermore, from the viewpoint of stabilizing the hinokitiol contained in the oral composition, the citric acid content is, for example, 0.35 to 0.52 parts by weight, preferably 0.35 to 0.47 parts by weight, more preferably 0.35 to 0.43 parts by weight, even more preferably 0.35 to 0.40 parts by weight, and most preferably 0.35 to 0.37 parts by weight per 1 part by weight of sodium monofluorophosphate.

[0029] In the oral composition of this disclosure, the citric acid content needs to be appropriately adjusted according to the content of fluorine compounds and hinokitiol in the oral composition, but for example, it is 0.1 to 10% by weight. Furthermore, from the viewpoint of suppressing the destabilization of hinokitiol contained in the oral composition, the citric acid content is preferably 0.1 to 4% by weight, more preferably 0.1 to 2% by weight, and even more preferably 0.1 to 1% by weight.

[0030] (Dosage Form, Form of Use) In the oral compositions of this disclosure, the dosage form or form of use is not particularly limited as long as it can be applied to the oral cavity, but examples include liquid or semi-solid forms (e.g., gel, paste, etc.).

[0031] The dosage form or form of use of the oral composition of this disclosure is not particularly limited as long as it can be applied to the oral cavity and remain there for a certain period of time. Examples include oral hygiene agents such as liquid toothpaste, tooth paste, mouthwash (mouthwash is sometimes referred to as mouth rinse, mouthwash, dental rinse, etc.), oral fresheners (such as mouth spray), and oral ointment. Preferably, liquid toothpaste, tooth paste, and mouthwash are included.

[0032] The method for preserving the oral composition of this disclosure is not particularly limited as long as citric acid or its salt suppresses the destabilization of hinokitiol by high concentrations of fluorine, but for example, the storage temperature can be 0 to 15°C, preferably 0 to 10°C, and more preferably 0 to 5°C.

[0033] In addition to the components described above, the oral composition of the present disclosure may contain components commonly used in the art depending on the form of the oral composition, as long as the effects of the pharmaceutical composition of the present disclosure, the bactericidal effect of hinokitiol, the caries-preventing effect of a fluorine compound, and the destabilization-inhibiting effect of citric acid or a salt thereof on hinokitiol are not impaired. Examples of components commonly used in the art include anti-inflammatory agents, antibacterial agents, hemostatic agents, hypersensitivity inhibitors, stabilizers, humectants, solubilizers, thickeners, abrasives, whitening agents, astringents, flavoring agents, detergents, pH adjusters, foaming agents, colorants, preservatives, bases, and cleaning agents.

[0034] Examples of the anti-inflammatory agent include dipotassium glycyrrhizinate and β-glycyrrhetinic acid.

[0035] Examples of the antibacterial agent include cetylpyridinium chloride.

[0036] Examples of the hemostatic agent include ε-aminocaproic acid.

[0037] Examples of the hypersensitivity inhibitor include aluminum lactate.

[0038] Examples of the stabilizer include DL-alanine, disodium edetate, titanium oxide, and metaphosphate.

[0039] Examples of the humectant include concentrated glycerin, PG, and sorbitol solution.

[0040] Examples of the solubilizer include ethanol and polyoxyethylene hydrogenated castor oil.

[0041] Examples of the thickener include carrageenan, silicic anhydride, and sodium carboxymethyl cellulose.

[0042] Examples of the abrasive include hydrated silicic acid and calcium pyrophosphate.

[0043] Examples of the whitening agent include titanium oxide.

[0044] Examples of the astringent include Angelica acutiloba extract (1) and peony root extract.

[0045] Examples of corrigents include sodium chloride, sodium saccharin, and the like.

[0046] Examples of cleaning agents include sapindus extract and the like.

[0047] Examples of pH adjusters include sodium hydroxide and the like.

[0048] Examples of foaming agents include sodium N-lauroyl-L-glutamate, sodium lauryl sulfate, alkyl glycosides and the like.

[0049] Examples of coloring agents include Yellow No. 203, Blue No. 1 and the like.

[0050] Examples of preservatives include ethyl parahydroxybenzoate, propyl parahydroxybenzoate, parabens and the like.

[0051] Examples of bases include purified water, sorbit solution and the like.

[0052] Examples of cleaning agents include propyldimethyl octadecyl ammonium chloride-bonded silicic anhydride (Bionium) and the like.

[0053] 2. Method for Producing the Oral Composition of the Present Disclosure (or Method for Stabilizing Hinokitiol According to the Present Disclosure) The present disclosure provides a method for producing an oral composition comprising the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more (the method for producing the oral composition of the present disclosure). The present disclosure also provides a method for stabilizing hinokitiol in an oral composition comprising mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more (the method for stabilizing hinokitiol of the present disclosure).

[0054] In the method for producing an oral composition of the present disclosure (or the method for stabilizing hinokitiol of the present disclosure), the fluorine compound, hinokitiol, and citric acid and / or a salt thereof may be the same as those described in the oral composition of the present disclosure.

[0055] A method for producing the oral composition of the present disclosure (or a method for stabilizing hinokitiol of the present disclosure) comprises the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof. The fluorine compound, hinokitiol, and citric acid (or a salt thereof) may be mixed simultaneously, or (i) the fluorine compound and hinokitiol, (ii) the fluorine compound and citric acid (or a salt thereof), or (iii) hinokitiol and citric acid (or a salt thereof) may be mixed beforehand, and the remaining components may be mixed afterward.

[0056] Next, examples of the present disclosure will be described. However, the present disclosure is not limited to the following examples. Commercial reagents were used according to their respective protocols unless otherwise specified.

[0057] 1. Hinokitiol Stability Evaluation Test Samples of the compositions shown in Tables 1 and 2 were prepared. Specifically, liquid or paste-type toothpaste was prepared by mixing the components shown in Tables 1 and 2. 40 g of the liquid from Table 1, or approximately 40 g of the paste-type toothpaste from Table 2, was taken and filled into 40 g capacity tubes (tubes with laminated aluminum layers and light-shielding interiors), and stored at 4°C for two weeks. The amount of hinokitiol remaining in each liquid or paste-type toothpaste was measured by high-performance liquid chromatography under the following conditions.

[0058]

[0059]

[0060] <Test Conditions> Equipment used: High-performance liquid chromatograph LC-20AD (Shimadzu Corporation) Detector: Ultraviolet spectrophotometer - measurement wavelength 350 nm Column: ODS column, length 15 cm Column temperature: 40°C Mobile phase: EDTA + phosphate buffer / acetonitrile mixture Flow rate: 1.0 mL / min

[0061] Test Example 1 The stability of hinokitiol after storage of Reference Example 1, Comparative Example 1, and Example 1, prepared above, was tested under the above conditions. When stored for two weeks at 4°C, Reference Example 1, which contained a low concentration of fluorine, had a residual amount of hinokitiol of 95% or more, and there were no problems. However, Comparative Example 1, which contained a high concentration of fluorine, had a residual amount of hinokitiol of less than 95%, indicating instability. On the other hand, in Example 1, to which citric acid was added, the residual amount of hinokitiol recovered to 95% or more, and stability was maintained. The results are shown in Table 3.

[0062]

[0063] Test Example 2 The stability of hinokitiol after storage of Reference Example 2, Comparative Example 2, and Example 2, prepared above, was tested under the above conditions. When stored for two weeks at 4°C, Reference Example 2, which contained a low concentration of fluorine, had a residual amount of hinokitiol of 95% or more (100%), and there were no problems. However, Comparative Example 2, which contained a high concentration of fluorine, had a residual amount of hinokitiol of less than 95% (92.4%), indicating instability. On the other hand, in Example 2, to which citric acid was added, the residual amount of hinokitiol recovered to 95% or more (100%), and stability was maintained. The results are shown in Table 4.

[0064]

[0065] Furthermore, in oral compositions with the compositions shown in Table 2, when sodium monofluorophosphate was replaced with sodium fluoride, stannous fluoride, and silver diamine fluoride to achieve equal fluorine content, the stability of hinokitiol was tested in the same manner as described above, and the same trend as when sodium monofluorophosphate was used was observed.

[0066] 2. Toothpastes with the compositions shown in Tables 5-1, 5-2, and 6 were prepared. The stability of hinokitiol in these oral compositions was tested using the same method as in "1. Hinokitiol Stability Evaluation Test," and a similar trend was observed.

[0067]

[0068]

[0069]

[0070] While the present disclosure has been described above with reference to embodiments, the present disclosure is not limited to the embodiments described above. Various modifications to the structure and details of the present disclosure may be made that will be understood by those skilled in the art within the scope of the present disclosure.

[0071] The patents, patent applications, and documents cited herein are incorporated herein by reference in the same manner as their contents are specifically described herein.

[0072] <Notes> Some or all of the above embodiments and examples may be described as follows, but are not limited to the following. <Oral Compositions of the Disclosure> (Note 1) An oral composition comprising a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content is 1000 ppm or more. (Note 2) The oral composition according to Note 1, wherein the fluorine compound is at least one selected from the group consisting of alkali metal fluorides, fluorophosphates, and salts of fluorophosphates. (Note 3) The oral composition according to Note 1 or 2, wherein the fluorine compound is at least one selected from the group consisting of sodium fluoride, stannous fluoride, silver diamine fluoride, monofluorophosphate, and sodium monofluorophosphate. (Note 4) The oral composition according to any one of Notes 1 to 3, wherein the fluorine compound is sodium monofluorophosphate. (Note 5) The oral composition according to any one of Notes 1 to 4, wherein the fluorine content is 1500 ppm or less. (Note 6) The oral composition according to any one of Notes 1 to 5, wherein the salt of citric acid is trisodium citrate. (Note 7) The oral composition according to any one of Notes 1 to 6, which is a liquid toothpaste, a tooth paste, or a mouthwash. <Method for producing the oral composition of the present disclosure> (Note 8) A method for producing an oral composition, comprising the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more. <Method for stabilizing hinokitiol of the present disclosure> (Note 9) A method for stabilizing hinokitiol in an oral composition, comprising the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more.

[0073] According to this disclosure, it is possible to provide an oral composition that contains a high concentration of fluorine and hinokitiol while achieving hinokitiol stabilization. The oral composition can exhibit a bactericidal effect due to hinokitiol and a caries prevention effect due to a higher concentration of fluorine than conventional compositions, and the problem of hinokitiol destabilization is solved by citric acid or a salt thereof.

Claims

1. An oral composition comprising a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content is 1000 ppm or more.

2. The oral composition according to claim 1, wherein the fluorine compound is at least one selected from the group consisting of alkali metal fluorides, fluorophosphates, and salts of fluorophosphates.

3. The oral composition according to claim 1 or 2, wherein the fluorine compound is at least one selected from the group consisting of sodium fluoride, stannous fluoride, silver diamine fluoride, monofluorophosphate, and sodium monofluorophosphate.

4. The oral composition according to any one of claims 1 to 3, wherein the fluorine compound is sodium monofluorophosphate.

5. The oral composition according to any one of claims 1 to 4, wherein the fluorine content is 1500 ppm or less.

6. The oral composition according to any one of claims 1 to 5, wherein the salt of citric acid is trisodium citrate.

7. An oral composition according to any one of claims 1 to 6, which is a liquid toothpaste, a paste toothpaste, or a mouthwash.

8. A method for producing an oral composition, comprising the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more.

9. A method for stabilizing hinokitiol in an oral composition, comprising the step of mixing a fluorine compound, hinokitiol, and citric acid and / or a salt thereof, wherein the fluorine content in the oral composition is 1000 ppm or more.

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