JP7654206B2 - How mouthwash is manufactured - Google Patents

Description

The present invention relates to a method for producing a mouthwash (gargle) containing azulene sulfonic acid and/or its salt.

Azulene sulfonic acid and its salts have traditionally been widely used as anti-inflammatory agents, and gargling with a diluted aqueous solution of this is known to have the effect of soothing tonsillitis, pharyngitis, stomatitis, and gingivitis.

JP 2018-24609 A

Mouthwashes often contain anti-inflammatory agents such as the above-mentioned azulene sulfonic acid and/or its salts to suppress throat swelling, bactericides 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 salts 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 after the subsequent powder raw material is added, the solubility of the powder raw material cannot be confirmed. In addition, when cetylpyridinium and/or its salts are dissolved in water in the manufacturing process of mouthwash, foaming is large, and it is necessary to leave it for a while until the foaming disappears, or to add an antifoaming agent. Furthermore, 1-menthol has a problem of 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.

The present invention provides a method for producing a mouthwash with a uniform composition by improving the stability of the content of azulene sulfonic acid and/or its salts and the solubility confirmation of the powder raw material during the manufacturing process, while suppressing foaming and precipitation of the compound during the manufacture of the mouthwash.

The inventors of the present invention have conducted extensive research to solve the above problems, and by examining the solvent and compounding order of the formulation, 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 further improves the solubility of l-menthol to suppress crystal precipitation, thereby completing the present invention.

That is, the present invention relates to 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 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 mixed solution;
The method for producing the mouthwash according to [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 manufacturing method according to [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;
The manufacturing method according to any one of [1] to [3].
[5]
A mouthwash produced according to the method for producing the same according to any one of [1] to [4].
[6]
A mouthwash comprising 1-menthol, cetylpyridinium and/or a salt thereof, ethanol, a pH adjuster, azulene sulfonic acid and/or a salt thereof, and water.
[7]
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;
Mouthwash.

According to the present invention, it is possible to produce and provide a mouthwash with a uniform composition that has excellent stability of the content of azulene sulfonic acid and/or its salts and suppresses foaming and precipitation of l-menthol during the manufacture of the mouthwash.

[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.

(1) 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.

[Menthol Phase]
The menthol phase is a phase obtained by dissolving 1-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 the polyhydric alcohol 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 alcohol (mannitol, etc.), etc., and 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 1-menthol in the menthol phase is not particularly limited as long as 1-menthol is dissolved, and is appropriately adjusted so as to have a concentration necessary for obtaining the effect of 1-menthol in the final product, which is a mouthwash.

[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 have the effects of suppressing bacterial growth in mucous membranes, relieving throat inflammation, and preventing periodontal disease and bad breath.
The alcohol used in the cetylpyridinium phase may be, for example, ethanol or propyl alcohol, and among these, ethanol is preferred. The alcohol may be used alone or in combination.
The concentration of cetylpyridinium and/or a salt thereof in the cetylpyridinium phase is not particularly limited as long as the cetylpyridinium and/or a salt thereof is dissolved, and is appropriately adjusted so that the concentration is necessary to obtain the above-mentioned effect in the final product, which is the mouthwash.

[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, when added as a pH adjuster phase, can maintain the pH of the target solution at 6.5 to 8.5. 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 adjuster in the pH adjuster phase is not particularly limited as long as the pH adjuster is dissolved, and is appropriately adjusted to a concentration necessary to maintain the pH at 6.5 to 8.5.

(2) Step of adding 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 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 a pharmacologically acceptable salt of 1,4-dimethyl-7-isopropylazulene-3-sulfonic acid and its hydrate, which is known to have an anti-inflammatory effect, an anti-allergic effect, and an effect of promoting granulation and epithelial formation. Examples of the pharmacologically acceptable salt include sodium salt, potassium salt, ammonium salt, etc., and among them, sodium salt (usually referred to as sodium azulene sulfonate) can be mentioned.

(3) 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.

(Other) pH adjustment step 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.

[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, 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 additives can be added at any stage (before, during, or after) of the above-mentioned steps (1) and (2), and, if desired, the step (3). Adding the other additives before the step (2) has the advantage that undissolved or precipitated additives can be easily confirmed.

The following are examples of typical components that can be listed as other additives, but they are not limited to these examples, and various additives commonly used in mouthwashes can be blended. Furthermore, the types of additives that can be added are not limited to those listed below.

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, etc. 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.

In the prepared mouthwash, it is preferable that l-menthol is contained at a concentration of 0.01 to 10 w/v %, cetylpyridinium and/or a salt thereof is contained at a concentration of 1.0 to 10 w/v %, and azulene sulfonic acid and/or a salt thereof is contained 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.

[Mouthwash]
The present invention is also directed to mouthwashes containing azulene sulfonic acid and/or its salts.
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 production method described above.

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

[Formulation Examples 1 to 5]
The mouthwash formulations prepared in this example are as shown in Formulation Examples 1 to 5 below.

A total of 25 types of mouthwash were manufactured for each of the formulation examples 1 to 5 shown in Table 1 using the following procedure.

[Production Example 1: Formulation Example 1]
A menthol phase was prepared by dissolving 1-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, to prepare a mouthwash.

[Production Example 1: Formulation Examples 2 to 4]
Mouthwashes were produced in the same manner as in [Production Example 1: Formulation Example 1], except that a menthol phase was prepared by dissolving 1-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 a polyhydric alcohol, a mouthwash was not produced according to Preparation Example 1.

[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 blending were changed compared to Production Example 1, but the rest of the procedure was the same as that of Production Example 1. In Table 2, <1> to <5> indicate the order of blending (addition) into the system. As shown in Table 2, sodium azulene sulfonate was dissolved in purified water and added as necessary.
In Production Example 2, a phase in which 1-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 the pH adjuster phase was 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 a polyhydric alcohol, mouthwashes were not produced according to Preparation Examples 3 to 6.

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

[Evaluation 2] Foaming of cetylpyridinium chloride hydrate (CPC foaming)
In the process of manufacturing a total of 25 kinds of mouthwashes, when preparing the cetylpyridinium phase, the foaming of the cetylpyridinium phase (a solution of cetylpyridinium chloride hydrate) was visually evaluated. If there is a lot of foaming, it takes time to proceed to the next step, so it is important in actual production that there is little foaming.
◯: Little foaming, can be added to the system as is △: Foaming occurs, but can be added to the system as is ×: Too much foaming, cannot be added (had to stand until foaming subsided)

[Evaluation 3] Crystallization of l-menthol (LM precipitation)
In the process of producing a total of 25 kinds of mouthwashes, 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 of the blend such as l-menthol in the produced mouthwashes (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 that of l-menthol, but even if no precipitation is observed during preparation of the menthol phase, precipitation of the compound may be observed when it is made into a mouthwash (preparation). Note that in the case of mouthwash (preparation), since it is divided into small containers for evaluation, it is possible to confirm even if sodium azulene sulfonate is included.

[Evaluation Results]
In the manufacture of a total of 25 types of mouthwash, the evaluation results regarding the sodium azulene sulfonate content (AZ content) in the manufactured mouthwashes, 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 the compounds such as l-menthol (LM precipitation) are shown in Table 3.

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 preparations in which the content stability of sodium azulene sulfonate was good and foaming of the cetylpyridinium phase and crystal precipitation of the blended ingredients, including l-menthol, was 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 the polyhydric alcohol) and Formulation Example 4 (containing D-sorbitol liquid as the polyhydric alcohol) were able to produce a preparation 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).
Formulation Example 5 (containing no polyhydric alcohol) had good stability of the sodium azulene sulfonate content in the carried out Production 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.

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.

The above results confirm 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.

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

For each of the formulation examples 6 to 10 shown in Table 4, a total of 25 types of mouthwash were manufactured using the procedures shown in the above-mentioned manufacturing examples 1 to 5 (see Table 2). Note that, because formulation example 10 does not contain polyhydric alcohol, no mouthwash was manufactured using manufacturing examples 1 and 3 to 6.

[Evaluation 4] Preparation clarity The clarity of the 25 kinds of mouthwashes (preparations) prepared was visually evaluated. 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.
◯: Clear and the appearance of the formulation can be evaluated △: Clarity is slightly reduced, but the appearance of the formulation can be evaluated ×: Not clear and the appearance of the formulation cannot be evaluated Clarity is an index for confirming dissolution at each step during production (especially when adding powdered raw materials), and as the production scale increases, the dissolution of the blended ingredients is visually confirmed from above the production system (production kettle), so high liquid clarity is important in actual production.

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, the presence or absence of crystal precipitation of the menthol phase (solubilized l-menthol) was evaluated according to [Evaluation 3] above, and the presence or absence of crystal precipitation of the compounds such as l-menthol in the manufactured mouthwashes was evaluated.

[Evaluation Results]
In the manufacture of a total of 25 types of mouthwashes, the evaluation results regarding 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 the blend such as 1-menthol (LM precipitation) are shown in Table 5.

As shown in Tables 4 and 5 (as well as 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 were excellent in foaming of the cetylpyridinium (CPC) phase and in the foaming of the 1-menthol (LM) phase 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 the solution into a stainless steel container).
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 1-menthol is dissolved in ethanol, it was possible to produce a preparation that exhibited clarity, suppressed foaming of the CPC phase, and suppressed crystal precipitation of LM, etc.

On the other hand, in the case of Production Example 6, in which sodium azulene sulfonate was first added to purified water and dissolved, the solution was 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, all of the preparations in Formulation Examples 6 to 9 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, 1-menthol did not dissolve in any of Production Examples 1 and 3 to 5, and crystals were precipitated.

The above results confirm 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 the compound, including l-menthol.

[Reference Example]
When preparing the menthol phase shown in the above Formulation Examples and Production Examples, the solubility of 1-menthol in polyhydric alcohols 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.

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 product of l-menthol), had a solubility of l-menthol of 40 ml.
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.
The results show that polyhydric alcohols with a solubility in l-menthol of less than 0.1 mg/g can cause crystallization of the menthol phase, while those with a solubility in the range of 40 mg/g or more can inhibit crystallization of the menthol phase, and thus it was confirmed that these polyhydric alcohols are suitable for use in the method for producing a mouthwash according to the present invention.

Claims (5)

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