TW201836599A - Aqueous formulation - Google Patents

Abstract

To provide a pharmaceutical technology that can suppress the deposition of ethyl aminobenzoate in spite of containing 5% by weight or less of ethanol, in an aqueous formulation containing ethyl aminobenzoate. In an aqueous formulation comprising ethyl aminobenzoate, by incorporating azulene derivative, the deposition of ethyl aminobenzoate can be suppressed even if content of ethanol is 5% by weight or less, and can have excellent formulation stability.

Description

Aqueous preparation

The present invention relates to an aqueous preparation which is an aqueous preparation containing ethyl benzoate and which has excellent formulation stability which inhibits precipitation of ethyl benzoate even though the ethanol content is 5% by weight or less.

Ethyl benzoate is known as a local anesthetic and is widely used to alleviate local itching and pain in mucous membranes or skin. In the past, various prescriptions for pharmaceutical compositions containing ethyl benzoate were also investigated. For example, Patent Document 1 reports that a local anesthetic containing an alkaline anaesthetic such as ethyl benzoate and a hydrochloride of a local anesthetic composition can have both a quick effect and a sustained effect of local anesthesia.

On the other hand, ethyl urethane has a property of being insoluble in water, and when it is blended into an aqueous preparation, there is a disadvantage that it cannot be dissolved without using a relatively large amount of ethanol as a solvent. An aqueous preparation containing a large amount of ethanol is strongly stimulated at the time of administration or causes a cause of allergy to ethanol. Therefore, it is necessary to reduce the content of ethanol from the viewpoint of feeling of use, safety, and the like.

However, once the amount of ethanol contained in the aqueous preparation containing ethyl benzoate is lowered, that is, ethyl benzoate cannot be stably dissolved, and the problem of so-called formulation stability of precipitation of ethyl benzoate occurs. In the past, there has been no research on a formulation technique for suppressing the precipitation of ethyl benzoate in an aqueous preparation containing ethyl benzoate while reducing the ethanol content. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. Hei 8-259464

[Problems to be solved by the invention]

An object of the present invention is to provide a formulation technique capable of suppressing the precipitation of ethyl benzoate in an aqueous preparation containing ethyl benzoate, although the ethanol content is 5% by weight or less. [Means to solve the problem]

In order to solve the above problems, the present inventors have found that by containing an anthracene derivative in an aqueous preparation containing ethyl urethane, it is possible to suppress the aminobenzoic acid B even though the ethanol content is 5% by weight or less. Excellent formulation stability of ester precipitation. The present invention has been completed based on these findings and after further research.

That is, the present invention provides the following aspects of the invention. Item 1. An aqueous preparation comprising (A) ethyl benzoate, (B) ethanol, and (C) an anthracene derivative, and the content of the component (B) is 5% by weight or less. Item 2. The aqueous preparation according to Item 1, which further comprises at least one selected from the group consisting of (D) a quaternary ammonium salt, a monoterpene, and a diol. Item 3. The aqueous preparation according to Item 1 or 2, wherein the component (C) is sulfonic acid and/or a salt thereof. The aqueous preparation according to any one of item 2 or 3, which comprises at least one selected from the group consisting of cetylpyridinium chloride, menthol and propylene glycol as the component (D). The aqueous preparation according to any one of the items 2 to 4, comprising at least cetylpyridinium chloride and propylene glycol as the component (D). Item 6. The aqueous preparation according to any one of items 1 to 5, which is a pharmaceutical for external use or a pharmaceutical for mucosa. Item 7. A method for suppressing precipitation of ethyl benzoate in an aqueous preparation, which is an ethyl benzoate inhibited in an aqueous preparation containing ethyl benzoate and ethanol and having an ethanol content of 5% by weight or less In the method of precipitation, the (C) anthracene derivative is blended while blending (A) ethyl benzoate and 5% by weight of (B) ethanol in an aqueous preparation. [Effects of the Invention]

According to the aqueous preparation of the present invention, although the ethanol content is 5% by weight or less, the precipitation of the ethyl benzoate can be suppressed in the aqueous preparation containing the ethyl benzoate, and thus the formulation stability can be excellent. Further, since the aqueous preparation of the present invention has the content of ethanol of 5 wt% or less, the adverse effects of ethanol on the human body can be reduced, and high safety can be achieved.

1. Aqueous Formulations The aqueous formulations of the present invention are characterized by comprising ethyl benzoate (sometimes also labeled as component (A)), ethanol (sometimes also labeled as component (B)), and anthraquinone derivatives (sometimes also It is indicated as (C) component), and the content of the component (B) is 5% by weight or less. The aqueous preparation of the present invention is described in detail below.

(A) Ethyl benzoate Ethyl benzoate is a public anesthetic known to the public as also known as ethyl 4-aminobenzoate or benzocaine.

In the aqueous preparation of the present invention, the content of the component (A) is not particularly limited, and may be appropriately set depending on the degree of local anesthetic action to be imparted to the aqueous preparation, the formulation type and use of the aqueous preparation, and the like, but for example, 0.1 to 5% by weight, preferably 0.3 to 2% by weight, more preferably 0.3 to 1% by weight.

(B) Ethanol Ethanol functions to dissolve the auxiliary amine benzoate in the aqueous preparation of the present invention. However, although the conventional technique is to dissolve a relatively large amount of ethanol in an aqueous preparation containing ethyl benzoate to dissolve the ethyl benzoate, the present invention sets the ethanol content to a small amount of 5% by weight or less. Although the amount of the ethanol is such a small amount, the precipitation of the ethyl benzoate can be suppressed by the hydrazine derivative described later and the dissolved state can be stably maintained.

In the aqueous preparation of the present invention, the content of the component (B) is 5% by weight or less, and specifically, it is 0.1 to 5% by weight, preferably 1 to 5% by weight, more preferably 3% to 5% by weight. .

(C) Anthracene derivative An anthracene derivative is a compound in which one or a plurality of substituents are bonded to an anthracene skeleton and a salt thereof. In the aqueous preparation of the present invention, the hydrazine derivative exhibits a function of suppressing the precipitation of ethyl benzoate and stably maintaining the dissolved state by a small amount of ethanol content of 5% by weight or less.

The anthracene derivative used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but from the viewpoint of more effectively inhibiting the precipitation of ethyl benzoate, it is exemplified An anthracene derivative in which the anthracene skeleton is bonded to at least an acidic functional group. Specific examples of the acidic functional group include a sulfonic acid group and a carboxyl group, and a sulfonic acid group is preferred.

Specific examples of the anthracene derivative used in the present invention include hydrazine sulfonic acid (guaiac sulfonic acid), dimethylisopropyl hydrazine (guaiac hydrazine), and dimethylethyl hydrazine ( Jerusalem artichoke). ), 1,4-dimethyl-7-ethylindole-3-sulfonic acid ( Jerusalem artichoke sulfonic acid), and the like.

When the anthracene derivative is in the form of a salt, the type of the salt is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include an alkali metal salt such as a sodium salt or a potassium salt; Alkaline earth metal salts such as calcium salts and magnesium salts; other metal salts such as aluminum salts; ammonium salts; acetate, trifluoroacetate, butyrate, palmitate, stearate, fumarate, Malay a carboxylate such as a salt, a succinate, a malonate, a lactate, a tartrate or a citrate; an organic sulfonate such as a methanesulfonate, a tosylate or a p-toluenesulfonate; An organic amine salt such as an amine salt, a triethylamine salt, a triethanolamine salt, a morpholine salt, a piperazine salt, a pyrrazine salt, a tripyridine salt or a pyridinium salt; a hydrochloride, a sulfate, a nitrate, a hydrobromic acid An inorganic acid salt such as a salt or a phosphate.

These anthracene derivatives may be used alone or in combination of two or more.

From the viewpoint of more effectively inhibiting the precipitation of ethyl benzoate, the hydrazine derivative is preferably hydrazine sulfonic acid and/or a salt thereof, and sulfonic acid and/or an alkali metal salt. For better, sodium sulfonate is especially good.

In the aqueous preparation of the present invention, the content of the component (C) is not particularly limited, and may be appropriately set depending on the type of the anthracene derivative to be used, the formulation type of the aqueous preparation, the use, and the like. ~0.2% by weight. From the viewpoint of more effectively suppressing the precipitation of ethyl benzoate, the content of the component (C) is preferably 0.02 to 0.1% by weight.

In the aqueous preparation of the present invention, the ratio of the component (C) to the component (A) is determined by the content of each of the components (A) and (C), and examples thereof include, for example, 100 parts by weight ( A) component, (C) component is 1 to 35 parts by weight, preferably 1 to 15 parts by weight, more preferably 1 to 10 parts by weight.

(D) quaternary ammonium salt, monoterpene and/or diol The aqueous preparation of the present invention may further comprise at least one selected from the group consisting of a quaternary ammonium salt, a monodecene and a diol (sometimes These are also collectively indicated as component (D)). By including the component (D), precipitation of ethyl benzoate can be more effectively suppressed.

The type of the quaternary ammonium salt to be used as the component (D) may be pharmaceutically or cosmetically acceptable as long as it has a bactericidal action, and examples thereof include cetylpyridinium chloride. , Bensonin chloride, benzalkonium chloride, decaquinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbensin chloride, lapirinate, and the like. These quaternary ammonium salts may be used alone or in combination of two or more.

From the viewpoint of more effectively inhibiting the precipitation of ethyl benzoate, among the above-mentioned quaternary ammonium salts, cetylpyridinium chloride, benzalkonium chloride and bensinin chloride are exemplified. Preferably, cetylpyridinium chloride is more preferred.

The so-called monoterpene which is used as the component (D) is a component having a structure of two isoprene units in a molecule and having a cooling effect and the like. The type of the monoterpene to be used as the component (C) is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but examples thereof include menthol, thymol, geraniol, and agarwood. An alcohol monoterpene such as alcohol, borneol, eucalyptol or terpineol; an aldehyde monoterpene such as citral, citronellal, perillaldehyde or crocetin; camphor, menthone, carminone A ketone monoterpene such as ionone or the like. If such monoterpenes have optical isomers, they may be any of d, l, and dl. These monoterpenes may be used alone or in combination of two or more.

Further, in the present invention, it may be used as a monoterpene in a state containing an essential oil of monoterpene. The essential oil containing a monoterpene can be suitably selected from the publicly known essential oils, and examples thereof include peppermint oil, peppermint oil, and spearmint oil as essential oils containing menthol. When the essential oil containing monoterpene is used, the content and ratio of the monoterpene in the present specification are described as values converted into the amount of monoterpene contained in the essential oil.

From the viewpoint of more effectively suppressing the precipitation of ethyl benzoate, one of these monoterpenes is preferably an alcohol-based monoterpene, preferably menthol, and 1-menthol. Very good.

The type of the diol to be used as the component (D) is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include 1,3-butanediol and ethylene glycol. Propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, polyethylene glycol, and the like. These diols may be used alone or in combination of two or more.

From the viewpoint of more effectively suppressing the precipitation of ethyl benzoate, propylene glycol is preferably included among these diols.

When the aqueous preparation of the present invention contains the component (D), one of the quaternary ammonium salt, the monoterpene and the diol may be used singly or in combination of two or more.

From the viewpoint of more effectively suppressing the precipitation of ethyl benzoate, it is preferred to use a combination of a quaternary ammonium salt and a diol as the component (D), and to combine cetylpyridinium chloride and propylene glycol. The component (D) is more preferred.

In the case where the quaternary ammonium salt and the diol are combined and used as the component (D), the ratio of these is not particularly limited, but from the viewpoint of more effectively inhibiting the precipitation of ethyl benzoate, The quaternary ammonium salt is usually from 300 to 20,000 parts by weight per 100 parts by weight of the quaternary ammonium salt, preferably from 2,000 to 15,000 parts by weight, and more preferably from 3,000 to 15,000 parts by weight.

In the case where the aqueous preparation of the present invention contains the component (D), the content thereof may be appropriately set depending on the type of the component (D) to be used, the formulation form of the aqueous preparation, the use, and the like. The amount of the component (D) is preferably 0.01 to 60% by weight, preferably 0.05 to 50% by weight, more preferably 0.1 to 40% by weight.

More specifically, the following ranges are mentioned as the content of each type of the component (D); in the case of using the quaternary ammonium salt: 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight, and 0.3. ~0.5% by weight is more preferred. In the case of using monoterpene: 0.01 to 3% by weight, preferably 0.05 to 1% by weight, more preferably 0.1 to 1% by weight. In the case of using a glycol: 1 to 60% by weight, preferably 1 to 50% by weight, more preferably 5 to 40% by weight.

In the case where the aqueous preparation of the present invention contains the component (D), the ratio of the component (D) relative to the component (A) is determined by the content of each of the components (A) and (D). For example, the component (A) per 100 parts by weight is preferably 5 to 25,000 parts by weight, and preferably 15 to 15,000 parts by weight.

More specifically, the following range is used as a ratio of each type of component (D) with respect to 100 parts by weight of component (A); in the case of using a quaternary ammonium salt: 10 to 300 by total amount The weight is preferably 50 to 200 parts by weight. In the case of using monoterpene: from 5 to 350 parts by weight, preferably from 15 to 250 parts by weight, more preferably from 30 to 200 parts by weight. In the case of using a glycol: from 300 to 20,000 parts by weight, preferably from 2,000 to 15,000 parts by weight, more preferably from 3,000 to 15,000 parts by weight.

Glycerin The aqueous formulation of the present invention preferably further comprises glycerin. By containing glycerin, the inhibition of precipitation of ethyl benzoate can be effectively exhibited.

In the case where the aqueous preparation of the present invention contains glycerin, the content thereof is not particularly limited, and is, for example, 10 to 60% by weight, preferably 30 to 60% by weight. Further, from the viewpoint of more effectively suppressing the precipitation of ethyl benzoate, the content of glycerin is particularly preferably 50% by weight or less, and particularly preferably 40 to 50% by weight.

Water In the present specification, the "aqueous preparation" is a preparation containing water, and the aqueous preparation of the present invention contains water. In the aqueous preparation of the present invention, the water content is appropriately set depending on the preparation form, and the like, for example, is 1 to 80% by weight, preferably 5 to 60% by weight, and 10 to 50% by weight. good.

A monohydric lower alcohol having a carbon number of 3-6 is conventionally a monohydric lower alcohol having a carbon number of 3-6. It is used in an aqueous preparation containing ethyl benzoate to assist ethanol to dissolve ethyl benzoate or as a substitute for ethanol, but Regardless of whether the aqueous preparation of the present invention contains a small amount or a monohydric lower alcohol having a carbon number of 3 to 6, the precipitation of ethyl benzoate can be suppressed and the dissolved state can be stably maintained. Therefore, as one of the suitable aspects of the aqueous preparation of the present invention, the content of the monohydric lower alcohol having 3 to 6 carbon atoms is 5% by weight or less, preferably 4% by weight or less, more preferably 3% by weight or less, It is preferably 2% by weight or less, more preferably 1% by weight or less, and most preferably 0% by weight.

The monohydric lower alcohol having a carbon number of 3 to 6 may specifically be propanol, butanol, pentanol, hexanol or isopropanol.

Other Ingredients In addition to the aforementioned ingredients, the aqueous preparation of the present invention may optionally contain other pharmacological ingredients. As such a pharmacological component, for example, an antihistamine (diphenhydramine, diphenhydramine hydrochloride, etc.) or a local anesthetic other than ethyl benzoate (procaine, tetracaine, bubi) may be mentioned. Bupivacaine, mepivacaine, chloroprocaine, c-cain, mepivain or these salts, orthocaine, hydroxycaine, oxidized polyethoxylate Bactericides other than quaternary ammonium salts (iodine, iodine, potassium iodide, chlorhexidine gluconate), based on decane, sulphate, dibucaine, polyethylene oxide lauryl ether, lidocaine, etc. , yellow syrup, etc., anti-inflammatory agents (dipotassium glycyrrhizinate, glycyrrhetinic acid, indomethacin, biphenylacetic acid, diclofenac sodium, epoxan sodium, etc.), skin protectants (fire cotton, castor oil, etc.) ), blood circulation promoting ingredients (vanillin citrate, benzyl nicotinic acid, capsaicin, capsicum extract, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) )Wait.

Further, the aqueous preparation of the present invention may optionally contain a substrate and an additive other than the aforementioned ingredients to prepare a desired formulation. Regarding such a substrate and an additive, it is pharmaceutically or cosmetically acceptable and is not particularly limited, but examples thereof include oils (olive oil, safflower oil, soybean oil, eucalyptus oil, corn oil, rapeseed) Oil, sunflower oil, cotton oil, peanut oil, lard, squalane, fish oil, etc.), mineral oil (mobile paraffin, paraffin, gelled hydrocarbon, petrolatum, etc.), wax (wax), wax ( Beeswax, carnauba wax, candelilla wax, ceresin, rice bran wax, microcrystalline wax, etc.), ester oil (isopropyl myristate, isopropyl adipate, diethyl sebacate, sebacic acid) Isopropyl ester, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, eucaly, linoleic acid, lanolin) Et,) fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, etc.), higher alcohols (stearyl alcohol, cetyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, lanolin alcohol, etc.), cholesterol, triethyl 2-ethylhexanoate, 2-ethylhexanoic acid whale Wax ester , oily bases such as eucalyptus oil (dimethyl polyoxane, cyclic oxirane, etc.); POE (10-50 moles) phytol ether, POE (10-50 moles) dihydrocholesterol ether, POE (10~50 mol) 2-octyl lauryl ether, POE (10~50 mol) decyltetradecyl ether, POE (10-50 mol) ether, POE (2~50 Molar) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl Polyoxyethylene alkyl ethers such as ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, and such phosphate phosphates (POE cetyl ether phosphate sodium) Etc.), POE (20~60 mol) to sorbitan monooleate, POE (10~60 mol) to sorbitan isostearate, POE (10~80 mol) glycerol mono-hard Fatty acid ester, POE (10~30 mol) glycerin monostearate, POE (20~100 mol), polyoxypropylene decyl fluorenone, POE•alkyl denatured fluorenone, polyethylene glycol monolaurate Ester, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, poly Ethylene glycol dioleate Diric oleic acid ester, polyoxyethylene hardened castor oil (5~100), polysorbate (20~85), glycerin fatty acid ester (glycerol monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanolin Surfactant such as alcohol; cooling agent (menthol, camphor, borneol, mint water, peppermint oil, etc.), preservative (methyl paraben, propyl paraben, benzoic acid, sodium benzoate, Sorbic acid, etc., flavoring agent (citral, 1,8-anthracene, citronellal, phycoerythrin, etc.), coloring agent (tar pigment (brown 201, blue 201, yellow 4, yellow) No. 403, etc., cocoa pigment, chlorophyll, alumina, etc.), viscosity agent (sodium alginate, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, xanthogen Glue, carrageenan, carboxyvinyl polymer, sodium polyacrylate, polyvinylpyrrolidone, etc., pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide) , triethanolamine, triisopropanolamine, etc.), wetting agent (d-pyrrolidone carboxylate, D-sorbitol solution, polyethylene glycol, etc.), Conditioner (dibutylhydroxytoluene, butylhydroxymethoxybenzene, sodium edetate, sodium metaphosphate, L-arginine, L-aspartate, DL-alanine, glycine, sodium erythorbate , propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizing agents Additives such as preservatives.

Formulation Form The dosage form of the aqueous preparation of the present invention is not particularly limited, and examples thereof include a liquid form or a semi-solid form (gel form, ointment form, paste form, etc.), and a liquid form is preferred.

The product classification of the aqueous preparation of the present invention is not particularly limited, and may be, for example, any of pharmaceuticals (external, mucosal, and internal), cosmetics, skin cleansers, oral care products, and the like, but External skin medicine; suitable for mucous membranes of oral cavity, pharyngeal head, nasal cavity, eye, etc.; pharmaceuticals; skin cleansers; oral care products are better, skin external medicines, mucous membranes for pharmaceuticals, cosmetics are better It is especially suitable for external skin medicines and mucous membranes.

When the aqueous preparation of the present invention is formulated into a pharmaceutical product, the form of the preparation is not particularly limited, and examples thereof include a gel, a cream, a lotion, an emulsion, a liquid, a patch, and an aerosol. , external preparations for skin such as ointments and masking agents; pharmaceuticals for mucous membranes such as gels, creams, lotions, lotions, liquids, ointments, etc.; pharmaceuticals for liquid medicines, jelly agents, etc. . Among these, it is preferable to use a skin external preparation such as a gel, a cream, a lotion, an emulsion, or a liquid, and a mucosa-suitable pharmaceutical.

When the aqueous preparation of the present invention is used as a cosmetic, the form of the preparation is not particularly limited, and examples thereof include a jelly, a cream, an emulsion, a lotion, a lotion, a mask, an ointment and the like. Among these, a cosmetic such as a jelly, a cream, an emulsion, or a lotion is preferred.

When the aqueous preparation of the present invention is used as a skin cleansing agent, the form of the preparation is not particularly limited, and examples thereof include body shampoo, shampoo, and moisturizing essence.

When the aqueous preparation of the present invention is formulated into an oral care preparation, the form of the preparation is not particularly limited, and examples thereof include a liquid dentifrice, a liquid dentifrice, a toothpaste, and a mouthwash (liquid dentifrice, Mouthwash is generally referred to as a mouth rinse, a mouth wash, a dental rinse, a mouth freshener (oral spray, etc.), an oral ointment. Oral hygiene agent. Among these, a liquid dentifrice, a liquid dentifrice, a toothpaste, and a mouthwash are preferred, and a liquid dentifrice, a toothpaste, and a mouthwash are more preferred.

2. Method for suppressing precipitation of ethyl benzoate. Further, the present invention is an aqueous solution containing (A) ethyl benzoate and (B) ethanol, and the content of the component (B) is 5% by weight or less. In the preparation, a method of suppressing precipitation of the component (A) is characterized in that the aqueous preparation is blended with a (C) anthracene derivative.

In the precipitation suppression method, the type and content of (A) to (C) used, the type and content of other components to be blended, the formulation type of the aqueous preparation, and the like, and the above "1. The same is true for the preparation. [Examples]

The invention will be more specifically described by the following examples, but the invention is not limited thereto.

Test Example 1. Preparation of aqueous preparation The aqueous preparation (external skin medicine, liquid preparation) shown in Table 1 was prepared. Specifically, a predetermined amount of ethyl benzoate and 1-menthol are separately dissolved in ethanol, and then added to water together with other components and mixed to obtain an aqueous preparation (medical preparation for skin external use, liquid preparation).

2. Evaluation of precipitation inhibitory effect Each aqueous preparation was placed in a spiral tube (a transparent container made of glass having a diameter of 24 mm and a height of 50 mm), and allowed to stand under light-shielding conditions at 20 ° C and 4 ° C for 24 hours. Thereafter, the mixing spiral tube was inverted 2 to 3 times, and the appearance of the aqueous preparation was visually observed, and the precipitation suppression effect was evaluated according to the following criteria. <Evaluation Criteria for Precipitation Inhibition Effect> ◎: No precipitate was observed at all, and it was in a transparent state. ○: Although a very small amount of precipitate was observed, it was in a transparent state. △: Precipitates were generated, and the transparency was slightly impaired. ́: A lot of precipitates are produced, which are white turbid and appear translucent to opaque. ́ ́: Produces distinct precipitates, showing a white, opaque opaque state.

3. Results The results obtained are shown in Table 1. Since ethyl urethane was not dissolved in water and dissolved in ethanol, ethyl benzoate did not precipitate in an aqueous preparation in which high concentration of ethanol was blended (Reference Example 1). On the other hand, when the ethanol content was reduced to 5% by weight or less, significant precipitates were observed regardless of the conditions at 20 ° C or 4 ° C (Comparative Examples 1 to 4). In contrast, when sodium sulfonate was blended with ethyl benzoate and 5% by weight or less of ethanol, the effect of suppressing the formation of precipitates was observed under conditions of 4° C. at 20° C. The effect of suppressing the formation of precipitates was remarkably improved (Examples 1 and 2). Further, by coexisting one or more of cetylpyridinium chloride, menthol, and propylene glycol with ethyl benzoate, 5% by weight or less of ethanol, and sodium sulfonate, not only at 20 ° C The effect of suppressing the formation of precipitates was remarkably improved, and the effect of suppressing the formation of precipitates at 4 ° C was also remarkably improved (Examples 3 to 11). In particular, in the aqueous preparations in which the precipitation inhibitory effect at 20 ° C and 40 ° C was evaluated as ◎, the effect of suppressing the formation of precipitates was particularly complicated when the combination of ethyl benzoate, cetylpyridinium chloride and propylene glycol was contained in combination. Significant (Examples 10 and 11).

Formulation Example The aqueous preparation shown in Table 2 (applicable medicine for oral mucosa) was prepared. When the appearance of the obtained aqueous preparation was observed in the same manner as in the above test example, it was found that the occurrence of precipitates can be sufficiently suppressed by any of them.

Claims (7)

An aqueous preparation comprising (A) ethyl benzoate, (B) ethanol, and (C) an anthracene derivative, and the content of the component (B) is 5% by weight or less. The aqueous preparation of claim 1, further comprising at least one selected from the group consisting of (D) a quaternary ammonium salt, a monoterpene, and a diol. An aqueous preparation according to claim 1 or 2, wherein the component (C) is sulfonic acid and/or a salt thereof. An aqueous preparation according to claim 2 or 3, which comprises at least one selected from the group consisting of cetylpyridinium chloride, menthol and propylene glycol as the component (D). The aqueous preparation according to any one of claims 2 to 4, which comprises at least cetylpyridinium chloride and propylene glycol as the component (D). The aqueous preparation according to any one of the items 1 to 5, which is a pharmaceutical preparation for external use or a mucosa. A method for suppressing precipitation of ethyl benzoate in an aqueous preparation, which is a method for inhibiting precipitation of ethyl benzoate in an aqueous preparation containing ethyl benzoate and ethanol and having an ethanol content of 5% by weight or less And (C) an anthracene derivative is blended while blending (A) ethyl benzoate and 5% by weight of (B) ethanol in an aqueous preparation.