JP2019006710A - Aqueous preparation - Google Patents

Abstract

To provide an aqueous preparation which is suppressed in white turbidity and has excellent preparation stability while containing glycyrrhizinic acids and a quaternary ammonium salt.SOLUTION: There is provided an aqueous preparation which is suppressed in white turbidity and has excellent preparation stability by blending dibucaine and/or a salt thereof in an aqueous preparation containing glycyrrhizinic acids a quaternary ammonium salt.SELECTED DRAWING: None

Description

  The present invention relates to an aqueous preparation having excellent preparation stability in which white turbidity is suppressed while containing glycyrrhizic acids and quaternary ammonium salts.

  Glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as “glycyrrhizic acids”) are known to have anti-inflammatory action and tissue repair action. Various pharmaceutical formulations using acids have been proposed (see, for example, Patent Document 1).

  On the other hand, quaternary ammonium salts such as cetylpyridinium chloride and benzalkonium chloride are known to have a bactericidal action and are widely used in preparations such as external preparations. However, when a quaternary ammonium salt is formulated into an aqueous preparation containing water and stored in a low temperature range, there is a disadvantage that precipitation occurs and the preparation stability is lowered.

  In recent years, improvement in functionality has been demanded in preparations such as external preparations, and if a preparation containing a combination of glycyrrhizic acids and a quaternary ammonium salt can be provided, it is expected that a medicinal effect based on both of these components will be exhibited. It is expected to follow consumer needs for further improvement of sex.

  However, at present, the formulation technology for glycyrrhizic acids and quaternary ammonium salts has not been sufficiently studied from the viewpoints of appearance and formulation stability.

Japanese Unexamined Patent Publication No. 2016-29025

  The present inventor has studied to commercialize an aqueous preparation containing glycyrrhizic acids and a quaternary ammonium salt, and the aqueous preparation containing glycyrrhizic acids alone shows a transparent and good appearance. In the aqueous preparation using a quaternary ammonium salt in combination, white turbidity occurred, and a new problem was faced in that it could not be stably maintained in a state in which the contained components were dissolved.

  Accordingly, an object of the present invention is to solve the above-mentioned new problem, that is, to provide an aqueous preparation having excellent preparation stability in which white turbidity is suppressed while containing glycyrrhizic acids and a quaternary ammonium salt. That is.

  The present inventor has conducted intensive studies to solve the above problems, and by adding dibucaine and / or a salt thereof to an aqueous preparation containing glycyrrhizic acids and a quaternary ammonium salt, the present invention can suppress white turbidity and is excellent. It was found that the preparation stability can be provided. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the invention of the aspect hung up below.
Item 1. (A) glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and at least one glycyrrhizic acid selected from the group consisting of these salts, (B) quaternary ammonium salts, (C) dibucaine and / or salts thereof An aqueous formulation containing.
Item 2. Item 2. The aqueous preparation according to Item 1, wherein the component (A) is glycyrrhizic acid and / or a salt thereof.
Item 3. Item 3. The aqueous preparation according to Item 1 or 2, wherein the component (B) is benzethonium chloride and / or benzalkonium chloride.
Item 4. Item 4. The aqueous preparation according to any one of Items 1 to 3, which is an external preparation.
Item 5. (A) A method for suppressing white turbidity of an aqueous preparation containing at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and (B) quaternary ammonium salt. And
A method for suppressing cloudiness, comprising, in an aqueous preparation, (C) dibucaine and / or a salt thereof together with the components (A) and (B).

  Although the aqueous preparation of the present invention contains glycyrrhizic acids and a quaternary ammonium salt, it can suppress white turbidity and can maintain good appearance properties, and thus can have excellent preparation stability.

1. Aqueous preparation The aqueous preparation of the present invention comprises at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as component (A)). A quaternary ammonium salt (hereinafter sometimes referred to as component (B)), and dibucaine and / or a salt thereof (hereinafter sometimes referred to as component (C)). . Hereinafter, the aqueous preparation of the present invention will be described in detail.

(A) Glycyrrhizic acids The aqueous preparation of the present invention contains at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.

  Glycyrrhizic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, and the like.

  The derivative of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and specific examples include methyl glycyrrhizinate and stearyl glycyrrhizinate. These glycyrrhizic acid derivatives may be used alone or in combination of two or more.

  Glycyrrhetinic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, and the like.

  The derivative of glycyrrhetinic acid is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate, and the like. Can be mentioned. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.

  The salt of glycyrrhizic acid, glycyrrhetinic acid and / or a derivative thereof is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but specifically, alkali metal salts such as sodium salt and potassium salt An ammonium salt and the like. These salts may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the aqueous preparation of the present invention, glycyrrhizic acid, glycyrrhizic acid salt, glycyrrhizic acid derivative, glycyrrhizic acid derivative salt, glycyrrhetinic acid, glycyrrhetinic acid salt, glycyrrhetinic acid derivative, and glycyrrhetinic acid derivative One type may be selected and used from the salts, or two or more types may be used in combination.

  Among these glycyrrhizic acids, preferably glycyrrhizic acid, glycyrrhizic acid salt, glycyrrhizic acid derivative, glycyrrhizic acid derivative salt; more preferably glycyrrhizic acid, glycyrrhizic acid salt; particularly preferably glycyrrhizic acid salt; Preferably, dipotassium glycyrrhizinate is used.

  The content of the component (A) in the aqueous preparation of the present invention may be appropriately set according to the type of the component (A) used, the preparation form of the aqueous preparation, etc., for example, 0.01 to 1% by weight Is mentioned. From the viewpoint of more effectively suppressing the white turbidity of the aqueous preparation, the content of the component (A) is preferably 0.03 to 0.5% by weight, more preferably 0.05 to 0.2% by weight. Can be mentioned.

(B) Quaternary ammonium salt The aqueous preparation of the present invention contains a quaternary ammonium salt. In the prior art, when glycyrrhizic acids and a quaternary ammonium salt are allowed to coexist in an aqueous preparation, white turbidity occurs and the preparation stability is impaired. However, the aqueous preparation of the present invention contains dibucaine and / or a salt thereof described later. By doing so, it is possible to suppress white turbidity caused by the coexistence of glycyrrhizic acids and a quaternary ammonium salt in an aqueous preparation.

  The type of quaternary ammonium salt used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. For example, a quaternary ammonium salt having a bactericidal action is preferably used. Can be used. Specific examples of such quaternary ammonium salts include cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, decalinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbenzethonium chloride, lauroyl colaminoformyl chloride. And methylpyridinium. These quaternary ammonium salts may be used individually by 1 type, and may be used in combination of 2 or more type.

  Among these quaternary ammonium salts, benzethonium chloride, benzalkonium chloride, and cetylpyridinium chloride are preferable, and benzethonium chloride and benzalkonium chloride are more preferable.

  The content of the component (B) in the aqueous preparation of the present invention may be appropriately set according to the type of the quaternary ammonium salt to be used, the preparation form of the aqueous preparation, and the like, for example, 0.01 to 1 weight %. From the viewpoint of more effectively suppressing the white turbidity of the aqueous preparation, the content of the component (B) is preferably 0.1 to 1% by weight, more preferably 0.1 to 0.5% by weight. .

  In the aqueous preparation of the present invention, the ratio of the component (A) and the component (B) is determined according to the contents of both of the above-mentioned components. For example, per 100 parts by weight of the component (A), the component (B) A component is 1-10000 weight part, Preferably it is 10-500 weight part, More preferably, 50-400 weight part is mentioned.

(C) Dibucaine and / or salt thereof The aqueous preparation of the present invention contains dibucaine and / or salt thereof. By including dibucaine and / or a salt thereof, it becomes possible to suppress cloudiness caused by the coexistence of glycyrrhizic acids and a quaternary ammonium salt in an aqueous preparation.

  Dibucaine is a known drug known to have a local anesthetic action and the like.

  The salt of dibucaine is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and specific examples thereof include acid addition salts such as hydrochloride, carbonate, sulfate and the like. These salts may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the aqueous preparation of the present invention, one kind of dibucaine and a salt thereof may be selected and used, or two or more kinds may be used in combination. Among dibucaine and its salt, the salt of dibucaine is preferable, and dibucaine hydrochloride is more preferable from the viewpoint of more effectively suppressing the cloudiness of the aqueous preparation.

  The content of the component (C) in the aqueous preparation of the present invention may be appropriately set according to the preparation form of the aqueous preparation, for example, 0.05 to 2% by weight. From the viewpoint of more effectively suppressing the cloudiness of the aqueous preparation, the content of the component (C) is preferably 0.05 to 1% by weight, more preferably 0.1 to 1% by weight.

  In the aqueous preparation of the present invention, the ratio of the component (A) and the component (C) is determined according to the content of each of the two components described above. For example, per 100 parts by weight of the component (A), (C) The component is 5 to 20000 parts by weight. From the viewpoint of more effectively suppressing the white turbidity of the aqueous preparation, the component (C) is preferably 50 to 1500 parts by weight, more preferably 200 to 1000 parts by weight per 100 parts by weight of the component (A). .

(D) Diphenhydramine and / or salt thereof In addition to the components (A) to (C), the aqueous preparation of the present invention contains diphenhydramine and / or a salt thereof (hereinafter sometimes referred to as component (D)). May be included. By containing diphenhydramine and / or a salt thereof, the white turbidity suppressing effect of the aqueous preparation can be further improved.

  Diphenhydramine is a known drug known to have an antihistamine action.

  The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable. Specifically, hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate And acid addition salts such as diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. These salts may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the aqueous preparation of the present invention, one type may be selected from diphenhydramine and a salt thereof, or two or more types may be used in combination. Among diphenhydramines and salts thereof, diphenhydramine salts are preferable, and diphenhydramine hydrochloride is more preferable from the viewpoint of further improving the white turbidity suppressing effect of the aqueous preparation.

  In the case where the component (D) is contained in the aqueous preparation of the present invention, the content thereof may be appropriately set according to the preparation form of the aqueous preparation, for example, 0.2 to 3% by weight. From the viewpoint of further improving the white turbidity suppressing effect of the aqueous preparation, the content of the component (D) is preferably 0.5 to 3% by weight, more preferably 1 to 3% by weight.

  When the component (D) is contained in the aqueous preparation of the present invention, the ratio of the component (A) and the component (D) is determined according to the content of each of these two components, for example, the component (A) Examples of the component (D) include 20 to 30000 parts by weight per 100 parts by weight. From the viewpoint of further improving the white turbidity suppressing effect of the aqueous preparation, the component (D) is preferably 100 to 6000 parts by weight, more preferably 500 to 4000 parts by weight per 100 parts by weight of the component (A).

(E) Polyhydric alcohol The aqueous preparation of the present invention may further contain a polyhydric alcohol (hereinafter sometimes referred to as component (E)). Polyhydric alcohols have a tendency to make white turbidity caused by the coexistence of glycyrrhizic acids and quaternary ammonium salts in aqueous preparations, but the aqueous preparations of the present invention contain polyhydric alcohols. Even with a composition that exhibits a tendency to become cloudy, white turbidity can be effectively suppressed.

  The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. For example, propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, etc. A trihydric alcohol such as glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

  Among these polyhydric alcohols, dihydric alcohols are preferable, and propylene glycol is more preferable.

  When the component (E) is contained in the aqueous preparation of the present invention, the content thereof may be appropriately set according to the preparation form of the aqueous preparation, for example, 1% by weight or more, preferably 3% by weight or more More preferably, it is 5% by weight or more. Further, the upper limit of the content of the component (E) is not particularly limited, and examples thereof include 80% by weight or less, preferably 75% by weight or less, and more preferably 70% by weight or less. In the prior art, when a polyhydric alcohol is contained in such a content, the tendency to notice white turbidity caused by the coexistence of glycyrrhizic acids and a quaternary ammonium salt becomes strong, but in the aqueous preparation of the present invention, Even if polyhydric alcohol is contained in such a content, cloudiness can be effectively suppressed.

In water this specification, the term "aqueous formulation" is a formulation comprising water. For this reason, the aqueous preparation of the present invention contains water. In the aqueous preparation of the present invention, the content of water is appropriately set according to the form of the preparation, and is, for example, 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 50 to 90% by weight. %, Particularly preferably 65 to 85% by weight.

Other Components The aqueous preparation of the present invention may contain other pharmacological components as necessary in addition to the components described above. Examples of such pharmacological components include antihistamines (eg, chlorpheniramine maleate), local anesthetics (eg, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or salts thereof, oxesasein, and roto extract). Anti-inflammatory agents (allantoin, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (colodion, castor oil, etc.), blood circulation promoting ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, red pepper extract, etc.), Examples include refreshing agents (menthol, camphor, borneol, mint water, mint oil, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) It is.

  Moreover, in order to make the aqueous formulation of this invention into a desired formulation form, base materials and additives other than the component mentioned above may be contained as needed. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, etc.), animal and vegetable oils, waxes, Waxes, ester oils, fatty acid alkyl esters, fatty acids, fatty acid esters, higher alcohols, surfactants, preservatives, flavoring agents, colorants, thickeners, pH adjusters, wetting agents, stabilizers, antioxidants UV absorbers, chelating agents, buffers, solubilizers, solubilizers, preservatives and the like.

Properties, Dosage Forms and Formulation Forms The properties of the aqueous preparation of the present invention are not particularly limited, but are preferably translucent, particularly transparent (including both colored and colorless and transparent). In an aqueous preparation having translucency (especially transparency), a white turbid state is easily visually recognized, and it is easy to feel the appearance deterioration. However, in the aqueous preparation of the present invention, white turbidity can be suppressed. Even if the property has transparency, a good appearance can be maintained.

  The dosage form of the aqueous preparation of the present invention is not particularly limited as long as it can contain water. For example, it is liquid or semi-solid (gel, ointment, paste, cream, etc.), preferably May be liquid.

  The aqueous preparation of the present invention may be either an external preparation or an internal preparation, and preferably an external preparation.

  When the aqueous preparation of the present invention is used as an external preparation, it may be any of external preparations, cosmetics, skin cleansing agents, oral care products, etc., preferably external pharmaceuticals, cosmetics, skin cleansing agents, more preferably A topical medicine is mentioned.

  When the aqueous preparation of the present invention is used as an external medicine, the form of the preparation is not particularly limited as long as it can be applied to the skin or mucous membrane. For example, gels, creams, lotions, emulsions, liquids , Patches, aerosols, ointments, packs and the like. Of these, gels, creams, lotions, emulsions, liquids and the like are preferable.

  When the aqueous preparation of the present invention is used as a cosmetic, the preparation form is not particularly limited, and examples thereof include gels, creams, emulsions, lotions, lotions, packs, ointments and the like. Among these, preferably, cosmetics such as gels, creams, milky lotions, and lotions are used.

  When the aqueous preparation of the present invention is used as a skin cleanser, the preparation form is not particularly limited, and examples thereof include body shampoo, hair shampoo, rinse and the like.

  When the aqueous preparation of the present invention is used as an oral care product, the preparation form is not particularly limited. For example, liquid dentifrice, liquid dentifrice, toothpaste, mouthwash (liquid dentifrice, mouthwash is Oral hygiene agents such as mouth rinses, mouthwashes, dental rinses, etc.), mouth fresheners (mouse sprays, etc.), oral ointments and the like. Among these, Preferably a liquid dentifrice, a liquid dentifrice, a toothpaste, and a mouthwash, More preferably, a liquid dentifrice, a toothpaste, and a mouthwash are mentioned.

2. Cloudy suppression method further, the present invention provides a method for inhibiting clouding aqueous formulation comprising glycyrrhizin acids and quaternary ammonium salts. Specifically, the white turbidity suppressing method of the present invention comprises, in an aqueous preparation, (A) at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and ( B) It is characterized by blending (C) dibucaine and / or a salt thereof with a quaternary ammonium salt. In the white turbidity suppression method of the present invention, the types and amounts of components used, the properties of the aqueous preparation, the dosage form, the preparation form, and the like are as described in the section of “1. Aqueous preparation”.

  EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Test example 1
Aqueous preparations (solutions, external medicines) having the compositions shown in Tables 2 and 3 were prepared. The obtained aqueous preparation 45 ml was filled into a glass screw tube (capacity 50 ml) and stored at 4 ° C. for 12 hours under light-shielding conditions. After storage for 12 hours, the appearance of each aqueous preparation was visually observed, and the white turbidity suppressing effect was evaluated according to the criteria shown in Table 1.

  The obtained results are shown in Tables 2 and 3. When dibucaine hydrochloride was not included and dipotassium glycyrrhizinate and benzethonium chloride or benzalkonium chloride were included, significant cloudiness was observed (Comparative Examples 1 to 4). On the other hand, when dibucaine hydrochloride was included together with dipotassium glycyrrhizinate and benzethonium chloride or benzalkonium chloride, white turbidity could be suppressed (Examples 1 to 19). Moreover, although propylene glycol was included with these three components, although it had a white turbidity suppression effect, the tendency to reduce a little was recognized (Examples 13-15), but also by containing diphenhydramine hydrochloride Moreover, the cloudiness suppression effect was fully improved (Examples 16-19).

Test example 2
About the aqueous formulation (Examples 1-19) prepared by the said test example 1, the cloudiness suppression effect in 30 degreeC was evaluated. The specific test conditions are the same as in Test Example 1 except that the storage temperature is changed to 30 ° C.

  Table 4 shows the obtained results. As a result, even when stored at 30 ° C., white turbidity could be suppressed when dibucaine hydrochloride was contained together with dipotassium glycyrrhizinate and benzethonium chloride or benzalkonium chloride (Examples 1 to 19). In addition, in the case where the content of dibucaine hydrochloride is 0.3% by weight or less, the effect of suppressing white turbidity was limited (Examples 1, 7 and 8), but by further containing diphenhydramine hydrochloride The improvement of the cloudiness suppression effect was recognized (Examples 4, 5 and 10). Moreover, although propylene glycol was included, although it had white turbidity suppression effect, the tendency to fall was recognized (Examples 13-15), but also by containing diphenhydramine hydrochloride, white turbidity suppression effect is enough. (Examples 16 to 19).

Formulation Examples Liquids and gels having the compositions shown in Tables 5 to 25 were prepared. These are preparations in which white turbidity is suppressed and excellent preparation stability is expected as in the above Examples.

Claims (5)

  (A) glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and at least one glycyrrhizic acid selected from the group consisting of these salts, (B) quaternary ammonium salts, (C) dibucaine and / or salts thereof An aqueous formulation containing.   The aqueous preparation according to claim 1, wherein the component (A) is glycyrrhizic acid and / or a salt thereof.   The aqueous preparation according to claim 1 or 2, wherein the component (B) is benzethonium chloride and / or benzalkonium chloride.   The aqueous preparation according to any one of claims 1 to 3, which is an external preparation. (A) A method for suppressing white turbidity of an aqueous preparation containing at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and (B) quaternary ammonium salt. And
A method for suppressing cloudiness, comprising, in an aqueous preparation, (C) dibucaine and / or a salt thereof together with the components (A) and (B).