How mouthwash is manufactured

Abstract

To provide a method for manufacturing a mouthwash with uniform composition, which suppresses foaming and the precipitation of compounds at the time of manufacturing the mouthwash while improving the content stability of azulene sulfonic acid and / or a salt thereof, and the confirmability of the dissolution of powder raw materials during the manufacturing process.SOLUTION: Provided is a method for manufacturing a mouthwash, comprising the following steps (1) and (2): (1) a step of mixing a menthol phase, a cetylpyridinium phase, and a pH regulator phase in random order to prepare a mixed solution, the menthol phase being a phase obtained by dissolving l-menthol in a polyhydric alcohol or alcohol (excluding glycerin, D-sorbitol solution and D-maltitol solution as polyhydric alcohols), the cetylpyridinium phase being a phase obtained by dissolving cetylpyridinium and / or a salt thereof in alcohol, the pH regulator phase being a phase obtained by dissolving a pH regulator in water; and (2) a step of preparing an azulene sulfonic acid-containing mixed liquid by mixing the mixed liquid with azulene sulfonic acid and / or a salt thereof or an aqueous solution thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a mouthwash (gargle) containing azulene sulfonic acid and / or a salt thereof. [Background technology]

[0002] Azulene sulfonic acid and its salts have been widely used as anti-inflammatory agents, and it is known that gargling with a diluted aqueous solution of this agent has the effect of soothing tonsillitis, pharyngitis, stomatitis, and gingivitis. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2018-24609 A Summary of the Invention [Problem to be solved by the invention]

[0004] Mouthwashes often contain anti-inflammatory agents such as the above-mentioned azulene sulfonic acid and / or its salts to reduce throat swelling, antiseptics such as cetylpyridinium and / or its salts to suppress bacterial growth in the mucous membranes of the mouth and throat, and terpenes such as l-menthol, which give a refreshing feeling in the mouth and remove bad breath. Among these, when azulene sulfonic acid and / or its salt are added at the beginning of the manufacturing process, the content stability is poor in an environment of pH 6 or less, and the liquid color becomes dark blue, so that the solubility of the powder raw material cannot be confirmed after adding the powder raw material. In addition, when cetylpyridinium and / or its salt are dissolved in water in the manufacturing process of mouthwash, it foams a lot, and it takes time to leave it until the foaming disappears, or it is necessary to add an antifoaming agent. Furthermore, l-menthol has a low solubility in solutions containing highly polar polyhydric alcohols such as glycerin, D-sorbitol solution, and D-maltitol solution, and water, and crystals are precipitated.

[0005] The present invention provides a method for producing a mouthwash of uniform composition by improving the content stability of azulene sulfonic acid and / or its salt and the ease of confirming the dissolution of the powder raw material during the manufacturing process, while suppressing foaming and precipitation of the compound during the production of the mouthwash. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above problems, and have discovered a method for producing a mouthwash that has excellent stability of the content of azulene sulfonic acid and / or its salts, suppresses foaming caused by cetylpyridinium and / or its salts, and improves the solubility of l-menthol to suppress crystal precipitation, by examining the solvent and compounding order of the components, thereby completing the present invention.

[0007] That is, the present invention covers the following [1] to [7]. [1] A method for producing a mouthwash, comprising the following steps (1) and (2). (1) A step of mixing a menthol phase, a cetylpyridinium phase, and a pH adjuster phase in any order to prepare a mixed solution, The menthol phase is a phase obtained by dissolving 1-menthol in a polyhydric alcohol or alcohol (however, the polyhydric alcohol does not include glycerin, D-sorbitol liquid, and D-maltitol liquid), The cetylpyridinium phase is a phase obtained by dissolving cetylpyridinium and / or a salt thereof in alcohol, The pH adjuster phase is a phase obtained by dissolving a pH adjuster in water, (2) A step of preparing an azulene sulfonic acid-containing mixed liquid by mixing the mixed liquid with azulene sulfonic acid and / or a salt thereof or an aqueous solution thereof. [2] moreover, (3) adding water to the azulene sulfonic acid mixed solution; A method for producing the mouthwash described in [1], comprising: [3] The menthol phase is a phase in which l-menthol is dissolved in propylene glycol, macrogol 200, macrogol 300, macrogol 400 or ethanol, The cetylpyridinium phase is a phase in which cetylpyridinium hydrochloride is dissolved in ethanol, The pH adjuster phase is a phase in which at least one pH adjuster selected from the group consisting of citric acid, lactic acid, phosphoric acid, carbonic acid and salts thereof, sodium citrate hydrate, sodium lactate, sodium hydrogen phosphate, and sodium hydrogen carbonate is dissolved in water. The manufacturing method described in [1] or [2]. [4] The mouthwash, l-Menthol 0.01-10w / v%, Cetylpyridinium and / or its salts, 1.0 to 10 w / v%, Contains 0.4 to 0.6 w / v% azulene sulfonic acid and / or its salt; The manufacturing method according to any one of [1] to [3]. [5] A mouthwash manufactured according to the manufacturing method described in any one of [1] to [4]. [6] A mouthwash comprising l-menthol, cetylpyridinium and / or a salt thereof, ethanol, a pH adjuster, azulene sulfonic acid and / or a salt thereof, and water. [7] l-Menthol 0.01-10w / v%, Cetylpyridinium and / or its salts, 1.0 to 10 w / v%, Contains 0.4 to 0.6 w / v% azulene sulfonic acid and / or its salt; Mouthwash. Effect of the Invention

[0008] According to the present invention, it is possible to produce and provide a mouthwash having a uniform composition, in which the content stability of azulene sulfonic acid and / or a salt thereof is excellent and foaming and precipitation of l-menthol during the production of the mouthwash are suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] [Manufacturing method of mouthwash] The method for producing the mouthwash of the present invention includes: (1) a step of mixing a menthol phase, a cetylpyridinium phase, and a pH adjuster phase in any order to prepare a mixed liquid; and (2) a step of mixing the mixed liquid with azulene sulfonic acid and / or a salt thereof or an aqueous solution thereof to prepare an azulene sulfonic acid-containing mixed liquid, and optionally further includes a step of (3) adding water to the azulene sulfonic acid mixed liquid. Each step will be described in detail below.

[0010] (1) A step of preparing a mixed liquid This step is a step of preparing a mixed liquid by mixing a menthol phase, a cetylpyridinium phase, and a pH adjuster phase in any order. In this step, the mixing order of the above three phases is not particularly limited, and the mixing method is also not particularly limited.

[0011] [Menthol Phase] The menthol phase is a phase obtained by dissolving l-menthol in a polyhydric alcohol or alcohol, except that glycerin, D-sorbitol liquid, and D-maltitol liquid are excluded from the polyhydric alcohols used in the menthol phase. Examples of polyhydric alcohols used in the menthol phase include propylene glycol, polyethylene glycol (also called macrogol, e.g., Macrogol 200, Macrogol 300, Macrogol 400, etc.), 1,3-butylene glycol, sugar alcohols (mannitol, etc.), etc., of which propylene glycol or polyethylene glycol (Macrogol 200, Macrogol 300, Macrogol 400, etc.) are preferred, and of these, propylene glycol is preferred. The alcohol may be a monohydric alcohol, such as ethanol or propyl alcohol, and among these, ethanol is preferred. These polyhydric alcohols or alcohols may be used alone or in combination. The concentration of l-menthol in the menthol phase is not particularly limited as long as l-menthol is dissolved, and is appropriately adjusted so as to be a concentration necessary to obtain the effect of l-menthol in the final product, the mouthwash.

[0012] [Cetylpyridinium phase] The cetylpyridinium phase is a phase obtained by dissolving cetylpyridinium and / or a salt thereof in alcohol. Cetylpyridinium and / or its salts include, for example, cetylpyridinium hydrochloride, i.e., 1-hexadecylpyridinium chloride and its hydrates. This component has a bactericidal effect, and is known to suppress the proliferation of bacteria in mucous membranes, relieve throat inflammation, and prevent periodontal disease and bad breath. Examples of the alcohol used in the cetylpyridinium phase include ethanol and propyl alcohol, and among these, ethanol is preferred. The alcohol may be used alone or in combination. The concentration of cetylpyridinium and / or its salt in the cetylpyridinium phase is not particularly limited as long as the cetylpyridinium and / or its salt is dissolved, and is appropriately adjusted so that the concentration is necessary to obtain the above-mentioned effect in the final product, the mouthwash.

[0013] [pH Adjuster Phase] The pH adjuster phase is a phase in which a pH adjuster is dissolved in water. The pH adjuster used in the present invention refers to a substance that can maintain the pH of the target solution at 6.5 to 8.5 when added as a pH adjuster phase. The substance itself is often a substance that exhibits weak acidity (weakly acidic substance). Examples of the pH adjuster include citric acid, lactic acid, phosphoric acid, carbonic acid, and salts thereof, hydrates of the salts thereof, etc. Examples of the salts thereof and hydrates of the salts thereof include sodium citrate hydrate, citric acid hydrate, sodium lactate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium hydrogen carbonate, etc. These pH adjusters may be used alone or in combination of two or more. Among these, at least one selected from the group consisting of sodium citrate hydrate, sodium lactate, sodium hydrogen phosphate, and sodium hydrogen carbonate can be suitably used. The concentration of the pH regulator in the pH regulator phase is not particularly limited as long as the pH regulator is dissolved, and is appropriately adjusted to a concentration necessary to maintain the pH at 6.5 to 8.5. will be done.

[0014] (2) A step of adding an azulene sulfonic acid-containing mixed liquid This step is a step of preparing an azulene sulfonic acid-containing mixed liquid by mixing the mixed liquid prepared in the step (1) with azulene sulfonic acid and / or a salt thereof or an aqueous solution thereof. The above-mentioned salt of azulene sulfonic acid refers to the pharmacologically acceptable salt of 1,4-dimethyl-7-isopropylazulene-3-sulfonic acid and its hydrate, which is known to have anti-inflammatory action, anti-allergic action, granulation and epithelial formation promoting action.The pharmacologically acceptable salt can be sodium salt, potassium salt, ammonium salt, etc., and among them, sodium salt (usually called sodium azulene sulfonate) can be mentioned.

[0015] (3) A step of adding water to the azulene sulfonic acid mixed solution. This step is a step of adding water to the azulene sulfonic acid mixed solution after the step (2) to correct the volume. This step is an optional step, and if the desired mouthwash has already been prepared in the step (2), this step is not necessary.

[0016] (Other) pH adjustment process After the step (2), if necessary, a pH adjustment step can be carried out. This step is a step of adjusting the pH of the azulene sulfonic acid-containing mixed liquid. For example, the above-mentioned pH adjuster can be dissolved in water and added to the azulene sulfonic acid-containing mixed liquid.

[0017] [Other additives] The mouthwash according to the present invention may contain other additives as optional components other than those described above, provided that the effects of the present invention and the effects (pharmaceutical efficacy) of the mouthwash are not impaired. These other additives can be added directly, or as necessary, as a solution in which the other additives are dissolved in a solvent such as various alcohols, various polyhydric alcohols, or water, in which the other additives are soluble, or as a dispersion in which the other additives are uniformly dispersed without forming lumps. The order of addition is not particularly limited as long as it does not impair the effects of the present invention, and the other additives can be added at any stage (before, during, or after) of the above-mentioned steps (1), (2), and, if desired, the step (3). Adding the other additives before the above-mentioned step (2) has the advantage that undissolved or precipitated additives can be easily confirmed.

[0018] Representative examples of other additives are given below, but the present invention is not limited to these examples, and various additives commonly used in mouthwashes can be blended. The addition of these additives is also not limited to the following.

[0019] As an anti-inflammatory agent, for example, dipotassium glycyrrhizinate and the like can be used. As the disinfectant, for example, benzalkonium chloride, benzethonium chloride, etc. can be used. As flavoring agents, for example, menthol, camphor, lemon oil, fennel oil, eucalyptus oil, cinnamon oil, clove oil, vanillin, flavors, etc. can be used. As the stabilizer, for example, ascorbic acid, polyvinyl alcohol, macrogol, etc. can be used. Examples of sugar alcohols that can be used include xylitol, sorbitol, and glycerin. As the chelating agent, for example, sodium edetate, calcium disodium edetate, and hydrates thereof can be used. As the surfactant, for example, sodium lauryl sulfate, lauromacrogol, polysorbate, sucrose fatty acid ester, etc. can be used. As the isotonicity agent, for example, inorganic salts such as sodium chloride and magnesium chloride, polyhydric alcohols such as propylene glycol and D-mannitol, and the like can be used. Preservatives that can be used include, for example, parabens, thymol, sorbic acid, and the like. As the solubilizing agent, for example, triacetin, sucrose, benzyl alcohol, polyvinylpyrrolidone, etc. can be used. Examples of thickening agents that can be used include carboxyvinyl polymers, sodium carmellose, gelatin, hydroxypropyl cellulose, and hypromellose.

[0020] The prepared mouthwash preferably contains l-menthol at a concentration of 0.01 to 10 w / v%, cetylpyridinium and / or its salts at a concentration of 1.0 to 10 w / v%, and azulene sulfonic acid and / or its salts at a concentration of 0.4 to 0.6 w / v%. The mouthwash can be stored in a container made of a conventional resin such as polyethylene (PE), polypropylene (PP), or polyethylene terephthalate (PET), or in a glass container. The shape of the container is not particularly limited.

[0021] [Mouthwash] The present invention is also directed to mouthwashes containing azulene sulfonic acid and / or salts thereof. The mouthwash of the present invention contains 1-menthol, cetylpyridinium and / or a salt thereof, ethanol, a pH adjuster, azulene sulfonic acid and / or a salt thereof, and water. The mouthwash of the present invention also contains 0.01 to 10 w / v % l-menthol, 1.0 to 10 w / v % cetylpyridinium and / or a salt thereof, and 0.4 to 0.6 w / v % azulene sulfonic acid and / or a salt thereof. The mouthwash according to the present invention can be produced, for example, by the above-mentioned production method. EXAMPLES

[0022] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples.

[0023] [Prescription Examples 1-5] The formulations of the mouthwashes prepared in this example are as shown in the following Formulation Examples 1 to 5.

[0024] [Table 1]

[0025] For each of Formulation Examples 1 to 5 shown in Table 1, a total of 25 types of mouthwash were manufactured according to the following procedure.

[0026] [Manufacturing Example 1: Formulation Example 1] A menthol phase was prepared by dissolving l-menthol in propylene glycol, and this was placed in a stainless steel container. Cetylpyridinium chloride hydrate was dissolved in ethanol to prepare a cetylpyridinium phase, which was then poured into the menthol phase in the stainless steel vessel and mixed. Citric acid hydrate and sodium citrate hydrate were dissolved in an appropriate amount of purified water to prepare a pH adjuster phase, which was then poured into the mixture of the cetylpyridinium phase and the menthol phase in the stainless steel container to prepare a mixed liquid. Sodium azulene sulfonate was dissolved in an appropriate amount of purified water, and this was added to the above-mentioned mixed liquid to prepare an azulene sulfonic acid-containing mixed liquid. An appropriate amount of purified water was added to the azulene sulfonic acid-containing mixed liquid to make the total volume 100 mL, and a mouthwash was produced.

[0027] [Manufacturing Example 1: Formulation Examples 2-4] Mouthwashes were produced in the same manner as in [Production Example 1: Formulation Example 1], except that the menthol phase was prepared by dissolving l-menthol in macrogol 400 (Formulation Example 2), glycerin (Formulation Example 3), or D-sorbitol solution (Formulation Example 4) instead of propylene glycol. Since Formulation Example 5 does not contain polyhydric alcohol, it is a mouthwash according to Preparation Example 1. The company does not manufacture any of the following products:

[0028] [Production Examples 2 to 6] For each of Formulation Examples 1 to 5 shown in Table 1, mouthwashes were produced in the same manner as in Production Example 1, following the procedures of Production Examples 2 to 6 shown in Table 2. In Production Examples 2 to 6, the solvent for the menthol phase or the cetylpyridinium phase and the order of mixing were changed compared to Production Example 1, but the rest of the procedure was the same as in Production Example 1. <1> ~ <5> indicates the order of mixing (addition) into the system. As shown in Table 2, sodium azulene sulfonate was dissolved in purified water and added as necessary. In addition, in Production Example 2, a phase in which l-menthol was dissolved in an appropriate amount of ethanol was used as the menthol phase, and in this Production Example, the polyhydric alcohols propylene glycol (Formulation Example 1), macrogol 400 (Formulation Example 2), glycerin (Formulation Example 3), and D-sorbitol solution (Formulation Example 4) were used together with purified water when preparing the pH adjuster phase, and then added. In addition, in Production Example 3, a phase in which cetylpyridinium chloride hydrate was dissolved in an appropriate amount of purified water was used as the cetylpyridinium phase, and in this production example, ethanol was added together with azulene sulfonic acid when it was dissolved in an appropriate amount of purified water. Since Formulation Example 5 does not contain polyhydric alcohol, the mouthwashes were not produced according to Production Examples 3 to 6.

[0029] [Table 2]

[0030] [Evaluation 1] Sodium azulene sulfonate content (AZ content) The sodium azulene sulfonate content in the 25 types of mouthwashes prepared was measured by HPLC. 〇: The content hardly decreases △: The content is slightly decreased ×: The content is clearly decreased.

[0031] [Evaluation 2] Foaming of cetylpyridinium chloride hydrate (CPC foaming) In the process of manufacturing a total of 25 kinds of mouthwash, the foaming of the cetylpyridinium phase (a solution of cetylpyridinium chloride hydrate) was visually evaluated when preparing the cetylpyridinium phase. If there is a lot of foaming, it takes time to proceed to the next step, so low foaming is important in actual manufacturing. 〇: Low foaming, can be added directly to the system △: Foams, but can be added to the system as is ×: Excessive foaming prevented addition (required to stand until foaming subsided)

[0032] [Evaluation 3] Crystallization of l-menthol (LM precipitation) In the process of manufacturing a total of 25 types of mouthwash, the presence or absence of crystal precipitation in the menthol phase (dissolved l-menthol) when preparing the menthol phase, and the presence or absence of crystal precipitation in the compounds such as l-menthol in the manufactured mouthwash (for convenience, this is included in "LM precipitation") were visually evaluated. 〇: Dissolved (no crystal precipitation was observed) ×: Not soluble (crystal precipitation was observed (when crystal precipitation was observed in the menthol phase, it was used for blending as it was)) The crystal precipitation is mainly the precipitation of l-menthol, but even if no precipitation is observed during the preparation of the menthol phase, precipitation of the compound may be observed when it is made into a mouthwash (preparation). In the case of mouthwash (preparation), since it is divided into small containers for evaluation, it can be confirmed even if sodium azulene sulfonate is included.

[0033] [Evaluation Results] The evaluation results of the manufacture of a total of 25 types of mouthwashes, including the sodium azulene sulfonate content (AZ content), the presence or absence of foaming in the cetylpyridinium phase during the manufacturing process (CPC foaming), and the presence or absence of crystal precipitation of ingredients such as l-menthol (LM precipitation), are shown in Table 3.

[0034] [Table 3]

[0035] As shown in Tables 1 to 3, in Formulation Example 1 (containing propylene glycol as the polyhydric alcohol) and Formulation Example 2 (containing macrogol 400 as the polyhydric alcohol), it was possible to produce formulations in which the sodium azulene sulfonate content was stable and foaming of the cetylpyridinium phase and crystal precipitation of the ingredients including l-menthol were suppressed in Production Examples 1, 2, 4, and 5, except for Production Example 3 (dissolving cetylpyridinium chloride hydrate in purified water as the cetylpyridinium phase) and Production Example 6 (sodium azulene sulfonate was first added to purified water and dissolved, and then poured into a stainless steel container). Formulation Example 3 (containing glycerin as a polyhydric alcohol) and Formulation Example 4 (containing D-sorbitol liquid as a polyhydric alcohol) were able to produce a formulation with good stability of sodium azulene sulfonate content and suppressed foaming of the cetylpyridinium phase and crystal precipitation of l-menthol, etc., only in Preparation Example 2 (dissolving l-menthol in ethanol as the menthol phase). Ta. Formulation Example 5 (containing no polyhydric alcohol) had good stability of the sodium azulene sulfonate content in the carried out Manufacturing Example 2, and it was possible to produce a preparation in which foaming of the cetylpyridinium phase and crystal precipitation of l-menthol, etc. were suppressed.

[0036] On the other hand, in Production Examples 1 and 3 to 6 in which the menthol phase is prepared by dissolving it in a polyhydric alcohol, in the formulations in which glycerin (Formulation Example 3) or D-sorbitol solution (Formulation Example 4) was used as the polyhydric alcohol, precipitation of crystals was observed in the menthol phase. In addition, in Production Example 3, in which the cetylpyridinium phase was prepared by dissolving cetylpyridinium chloride hydrate in purified water, the cetylpyridinium phase foamed significantly in all formulations, and a standing time was required until the foaming subsided before it could be added. In addition, in Production Example 6, in which sodium azulene sulfonate was added to the system first, and then the menthol phase, cetylpyridinium phase, and pH adjuster phase were added, the content of azulene sulfonic acid decreased in all formulations.

[0037] From the above results, it was confirmed that the manufacturing method of the present invention can produce a mouthwash containing azulene sulfonic acid and / or its salts, cetylpyridinium and / or its salts, and l-menthol, which has excellent stability in the content of azulene sulfonic acid and / or its salts, and which suppresses foaming caused by cetylpyridinium and / or its salts and crystal precipitation of ingredients such as l-menthol.

[0038] Next, mouthwashes of Formulation Examples 6 to 10, each of which had a different ethanol content, were prepared. Formulation examples 6 to 10 are shown in Table 4 below.

[0039] [Table 4]

[0040] For each of the formulation examples 6 to 10 shown in Table 4, a total of 25 kinds of mouthwashes were manufactured by the procedures shown in the above-mentioned manufacturing examples 1 to 5 (see Table 2). Note that, since formulation example 10 does not contain polyhydric alcohol, the manufacture of mouthwashes according to manufacturing examples 1 and 3 to 6 was not performed.

[0041] [Evaluation 4] Clarity of the formulation The clarity of the prepared 25 kinds of mouthwashes (preparations) was evaluated visually. The clarity evaluation was performed before the addition of sodium azulene sulfonate in Production Examples 1 to 5, and after the addition of sodium azulene sulfonate in Production Example 6. ○: Transparent, and the appearance of the formulation can be evaluated △: Clarity is slightly reduced, but the appearance of the formulation can be evaluated. ×: The appearance of the preparation cannot be evaluated because it is not clear. Clarity is an index for confirming dissolution at each step during production (especially when adding powdered raw materials). As the production scale increases, the dissolution of the ingredients is visually confirmed from above the production system (production kettle), so high liquid clarity is essential in actual production.

[0042] In addition, in the process of manufacturing a total of 25 types of mouthwash, the foaming of the cetylpyridinium phase (solubilized cetylpyridinium chloride hydrate) was evaluated according to [Evaluation 2] above, and the presence or absence of crystal precipitation of the menthol phase (solubilized l-menthol) was evaluated according to [Evaluation 3] above, as well as the presence or absence of crystal precipitation of the compounds such as l-menthol in the manufactured mouthwashes.

[0043] [Evaluation Results] The evaluation results of the manufacture of a total of 25 types of mouthwashes, with regard to the clarity of the mouthwashes (preparations), the presence or absence of foaming in the cetylpyridinium phase during the manufacturing process (CPC foaming), and the presence or absence of crystal precipitation of ingredients such as l-menthol (LM precipitation), are shown in Table 5.

[0044] [Table 5]

[0045] As shown in Tables 4 and 5 (and Table 2), Formulation Example 6 (containing propylene glycol as the polyhydric alcohol) and Formulation Example 7 (containing macrogol 400 as the polyhydric alcohol) had good clarity and did not cause foaming of the cetylpyridinium (CPC) phase or l-menthol (LM) in Production Examples 1, 2, 4, and 5, except for Production Example 3 (dissolving cetylpyridinium chloride hydrate in purified water as the cetylpyridinium phase) and Production Example 6 (adding sodium azulene sulfonate to purified water first, dissolving the solution, and pouring it into a stainless steel container). It was possible to manufacture preparations in which crystal precipitation of the blends, including those mentioned above, was suppressed. In addition, in Formulation Example 8 (containing glycerin as a polyhydric alcohol), Formulation Example 9 (containing D-sorbitol liquid as a polyhydric alcohol), and Case 10 (containing no polyhydric alcohol), in Preparation Example 2 in which l-menthol is dissolved in ethanol, it was possible to manufacture preparations that were clear, had suppressed foaming of the CPC phase, and had suppressed crystal precipitation of LM, etc.

[0046] On the other hand, in the case of Production Example 6, in which sodium azulene sulfonate was first added to purified water and dissolved, and then poured into a stainless steel container, the clarity of the preparations in all of Formulation Examples 6 to 9 was poor, and the solubility of l-menthol and cetylpyridinium chloride hydrate in the system could not be confirmed. In the case of Production Example 3, in which cetylpyridinium chloride hydrate was dissolved in water as the cetylpyridinium phase, the preparations of Formulation Examples 6 to 9 all foamed a lot of cetylpyridinium, and could not be added to the system as is, and it took time for the foaming to subside before it could be added. When glycerin (Formulation Example 8) and D-sorbitol solution (Formulation Example 9) were used as the polyhydric alcohol, l-menthol did not dissolve in any of Production Examples 1 and 3 to 5, and crystals were precipitated.

[0047] From the above results, it was confirmed that the manufacturing method of the present invention can produce a mouthwash that has excellent dissolution confirmation (evaluated as clarity) when cetylpyridinium and / or its salts and l-menthol are added before the addition of azulene sulfonic acid and / or its salts, and that suppresses foaming caused by cetylpyridinium and / or its salts and crystal precipitation of ingredients such as l-menthol.

[0048] [Reference example] When preparing the menthol phase shown in the above formulation and manufacturing examples, the solubility of l-menthol in polyhydric alcohol was examined. As polyhydric alcohols, propylene glycol, macrogol 400, 1,3-butylene glycol, D-sorbitol solution (70%), glycerin, and D-maltitol solution (75%) were selected, and the solubility of l-menthol (per 1 g of l-menthol) at room temperature (25°C) was confirmed. The results are shown in Table 6.

[0049] [Table 6]

[0050] As shown in Table 6, in the above Production Examples 1 to 4, propylene glycol, Macrogol 400, and 1,3-butylene glycol used in Formulation Examples 1 and 2, in which no crystal precipitation was observed in the menthol phase (dissolved l-menthol), had a solubility of l-menthol of 40 m. On the other hand, in the glycerin and D-sorbitol solutions and the D-maltitol solution used in Formulation Examples 3 and 4, in which crystal precipitation of the menthol phase was observed, the solubility of l-menthol was less than 0.1 mg / g. These results indicate that polyhydric alcohols with a solubility in l-menthol of less than 0.1 mg / g may cause crystallization of the menthol phase, whereas solubility in the range of 40 mg / g or more may inhibit crystallization of the menthol phase, and thus it was confirmed that such polyhydric alcohols are suitable for use in the method for producing the mouthwash according to the present invention.

Claims

1. A method for producing a mouthwash, comprising the following steps (1) and (2). (1) A step of mixing a menthol phase, a cetylpyridinium phase, and a pH adjuster phase in any order to prepare a mixed liquid, The menthol phase is a phase obtained by dissolving 1-menthol in a polyhydric alcohol or alcohol (however, glycerin, D-sorbitol liquid, and D-maltitol liquid are excluded as the polyhydric alcohol), The cetylpyridinium phase is a phase obtained by dissolving cetylpyridinium and / or a salt thereof in alcohol, The pH adjuster phase is a phase obtained by dissolving a pH adjuster in water, (2) A step of preparing an azulene sulfonic acid-containing mixed liquid by mixing the mixed liquid with azulene sulfonic acid and / or a salt thereof or an aqueous solution thereof.

2. moreover, (3) adding water to the azulene sulfonic acid-containing mixed liquid; A method for producing the mouthwash of claim 1, comprising:

3. The menthol phase is a phase in which 1-menthol is dissolved in propylene glycol, macrogol 200, macrogol 300, macrogol 400 or ethanol, The cetylpyridinium phase is a phase in which cetylpyridinium hydrochloride is dissolved in ethanol, The pH adjuster phase is a phase in which at least one pH adjuster selected from the group consisting of citric acid, lactic acid, phosphoric acid, carbonic acid and salts thereof, sodium citrate hydrate, sodium lactate, sodium hydrogen phosphate, and sodium hydrogen carbonate is dissolved in water. The method according to claim 1 or 2.

4. The mouthwash, 0.01 to 10 w / v% l-menthol, 1.0 to 10 w / v % cetylpyridinium and / or a salt thereof, Contains 0.4 to 0.6 w / v% azulene sulfonic acid and / or a salt thereof; A method for producing the mouthwash according to claim 1 or 2.

5. A mouthwash produced by the method according to claim 1 or 2.

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