WO2018216659A1 - Emulsion composition - Google Patents

Abstract

[Problem] The purpose of the present invention is to provide an emulsion composition which contains glycyrrhetinic acid, glycyrrhizic acid and derivatives and/or salts thereof, and ufenamate, and is prevented from the formation of precipitates or settlings. [Solution] An emulsion composition containing glycyrrhetinic acid, glycyrrhizic acid and derivatives and/or salts thereof, and ufenamate, wherein diphenhydramine and/or a salt thereof is added to the emulsion composition to prevent the formation of precipitates or settlings in the emulsion compositon.

Description

Emulsified composition

The present invention relates to an emulsified composition containing glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and / or salts thereof, and ufenamate, and suppressing the formation of precipitates and precipitates.

Non-steroidal anti-inflammatory drugs have almost no serious side effects as seen with steroidal anti-inflammatory drugs, and there are few restrictions on the amount and period of use, so rash, redness, dry dermatitis, atopy It is also widely used in external preparations for the purpose of alleviating inflammatory skin diseases such as atopic dermatitis.

Among non-steroidal anti-inflammatory agents, glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as “glycyrrhetinic acids”) have a tissue repair action in addition to an anti-inflammatory action. And is widely used in external preparations. Of the non-steroidal anti-inflammatory agents, ufenamate has the same anti-inflammatory effect as flufenamic acid and has lower local irritation than flufenamic acid, making it suitable for delicate skin applications and long-term use. It is widely used for external preparations.

On the other hand, non-steroidal anti-inflammatory agents have a drawback that their anti-inflammatory action is slower than steroidal anti-inflammatory agents. Therefore, in recent years, in order to effectively exert an anti-inflammatory effect, an attempt has been made to combine two or more types of non-steroidal anti-inflammatory agents having different action mechanisms, and an external preparation using a combination of glycyrrhetinic acids and ufenamate. Has been developed.

In addition, glycyrrhetinic acids and ufenamate are easily destabilized in the preparation and may cause precipitates and precipitates. Therefore, for external preparations containing these, a formulation design with improved preparation stability is required. Therefore, conventionally, preparation techniques for improving the preparation stability have been studied for external preparations containing glycyrrhetinic acids and ufenamate. For example, Patent Document 1 discloses that a gel ointment containing a poorly water-soluble active ingredient such as ufenamate, a nonionic surfactant, an auxiliary agent such as glycyrrhetinic acid, and water can stably hold the poorly water-soluble active ingredient. Has been reported. However, since the formulation technique disclosed in Patent Document 1 can be applied only to gel ointment, it lacks versatility, and it is not always satisfactory in terms of formulation stability.

JP 2003-321347 A

An object of the present invention is to provide an emulsified composition containing glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and / or their salts, and ufenamate, and suppressing the formation of precipitates and precipitates.

The present inventor conducted intensive studies to solve the above-mentioned problems. As a result, in an emulsion composition containing glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and / or salts thereof, and ufenamate, diphenhydramine and / or its It discovered that the production | generation of a precipitate and precipitation can be suppressed by mix | blending salt. Furthermore, the present inventor suppresses the formation of precipitates and precipitates by mixing polyoxyethylene hydrogenated castor oil together with diphenhydramine and / or a salt thereof into the emulsified composition, and separates the oil phase from the water phase. It has also been found that the effect of stably maintaining the emulsified state can be improved. The present invention has been completed by further studies based on these findings.

That is, this invention provides the invention of the aspect hung up below.
Item 1. (A) Emulsifying composition containing at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, (B) ufenamate, and (C) diphenhydramine and / or a salt thereof. object.
Item 2. Item (D) The emulsified composition according to Item 1, containing a higher alcohol that is solid at 25 ° C.
Item 3. Item (E) The emulsified composition according to Item 2, comprising polyoxyethylene hydrogenated castor oil.
Item 4. (F) The emulsion composition of claim | item 2 or 3 containing wool wax alcohol.
Item 5. Item 5. The emulsified composition according to any one of Items 1 to 4, comprising a nonpolar oil.
Item 6. Item 6. The emulsion composition according to any one of Items 1 to 5, which is an oil-in-water emulsion composition.
Item 7. Item 7. The emulsified composition according to any one of Items 1 to 6, which is an external preparation for skin.
Item 8. (A) At least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) a method for suppressing the formation of precipitates and precipitates in an emulsified composition containing ufenamate And (A) glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and at least one selected from the group consisting of these salts, and (A) Ufenamate and (C) diphenhydramine and / or a salt thereof. how to.
Item 9. (A) At least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) formation of precipitates and precipitates, and an oil phase in an emulsion composition containing ufenamate A method of suppressing phase separation between the water phase and the water phase,
(A) glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and at least one selected from the group consisting of these salts, and (B) ufenamate, (C) diphenhydramine and / or a salt thereof, and (D) 25 A method of blending a higher alcohol that is solid at ℃.

The emulsified composition of the present invention can suppress the formation of precipitates and precipitates by containing diphenhydramine and / or a salt thereof while containing glycyrrhetinic acids and ufenamate. Moreover, the emulsion composition of this invention can also suppress isolation | separation of an oil phase and an aqueous phase by containing a solid higher alcohol at 25 degreeC, and can be equipped with the outstanding formulation stability.

1. Emulsified composition The emulsified composition of the present invention comprises at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as component (A)). And Ufenamate (hereinafter sometimes referred to as the component (B)) and diphenhydramine and / or a salt thereof (hereinafter sometimes referred to as the component (C)). Hereinafter, the emulsified composition of the present invention will be described in detail.

(A) Glycyrrhizic acids The emulsified composition of the present invention contains glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and / or salts thereof.

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

Glycyrrhizic 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 acceptable, and specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate and the like. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.

The derivative of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically 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.

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

The emulsified composition of the present invention comprises, as component (A), glycyrrhetic acid, a salt of glycyrrhetic acid, a derivative of glycyrrhetic acid, a salt of a derivative of glycyrrhetinic acid, a glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, and glycyrrhizic acid Of these derivative salts, one may be selected and used, or two or more may be used in combination.

Among these components (A), glycyrrhetinic acid, glycyrrhizic acid, and salts thereof are preferred; glycyrrhetinic acid and glycyrrhizic acid salts are more preferred; glycyrrhetinic acid and dipotassium glycyrrhizinate are particularly preferred.

In the emulsified composition of the present invention, the content of the component (A) is not particularly limited, and may be set as appropriate according to the medicinal effect to be imparted. 01 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.05 to 2% by weight.

(B) Ufenamate The emulsified composition of the present invention contains ufenamate. Ufenamate is a drug known as a fat-soluble non-steroidal anti-inflammatory drug.

In the emulsified composition of the present invention, the content of the component (B) is appropriately set according to the medicinal effect to be exhibited, for example, 1 to 20% by weight, preferably 1 to 6% by weight, more preferably 1 to 5% by weight.

In the emulsion composition of the present invention, the ratio of the component (B) to the component (A) is determined according to the contents of the component (A) and the component (B). For example, the total amount of the component (A) is 100. The total amount of component (B) per 10 parts by weight is 10 to 200,000 parts by weight, preferably 20 to 60000 parts by weight, more preferably 50 to 10,000 parts by weight.

(C) Diphenhydramine and / or salt thereof The emulsified composition of the present invention contains diphenhydramine and / or a salt thereof. The emulsified composition containing the component (A) and the component (B) tends to be destabilized by forming precipitates and precipitates. However, in the emulsified composition of the present invention, diphenhydramine and / or a salt thereof is added. By containing, it becomes possible to suppress the formation of precipitates and precipitates.

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.

The emulsion composition of the present invention may be used by selecting one type from among diphenhydramine and a salt thereof as the component (C), or may be used in combination of two or more types.

Among these components (C), diphenhydramine and diphenhydramine hydrochloride are preferable from the viewpoint of effectively suppressing the formation of precipitates and precipitates.

In the emulsified composition of the present invention, the content of the component (C) is not particularly limited. For example, the total amount of the component (C) is 0.01 to 5% by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the content of the component (C) in the emulsion composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.1%. Up to 2% by weight.

In the emulsion composition of the present invention, the ratio of the component (C) to the component (A) is determined according to the contents of the component (A) and the component (C). For example, the total amount of the component (A) is 100. The total amount of component (C) is 0.1 to 50000 parts by weight per part by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the total amount of component (C) is preferably 2 to 30000 parts by weight, more preferably 5 to 5 parts per 100 parts by weight of component (A). 4000 parts by weight can be mentioned.

(D) Higher alcohol solid at 25 ° C. The emulsified composition of the present invention may contain a higher alcohol solid at 25 ° C. (hereinafter also referred to as component (D)). By containing a solid higher alcohol at 25 ° C., it is possible to suppress the phase separation of the oil phase and the aqueous phase and to improve the formulation stability.

The higher alcohol solid at 25 ° C. is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 12 to 34 carbon atoms. Specific examples of the higher alcohol solid at 25 ° C. include lauryl alcohol, mystyryl alcohol, cetanol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, linoleyl alcohol, behenyl alcohol, arachidyl alcohol, behenyl alcohol, lignoceryl alcohol, ceryl. Examples include alcohol, montanyl alcohol, myricyl alcohol, gedyl alcohol and the like. These higher alcohols may be used alone or in combination of two or more.

Among these higher alcohols, from the viewpoint of further improving the effect of suppressing the phase separation between the oil phase and the aqueous phase, preferably a higher alcohol having 16 to 22 carbon atoms, more preferably lauryl alcohol, myristyl alcohol. , Cetanol, stearyl alcohol, cetostearyl alcohol, behenyl alcohol; more preferably cetanol, stearyl alcohol, stearyl alcohol, behenyl alcohol.

In the emulsified composition of the present invention, the content of the component (D) is not particularly limited. For example, the total amount of the component (D) is 0.3 to 20% by weight or more. From the viewpoint of more effectively suppressing the phase separation of the oil phase and the aqueous phase, the content of the component (D) in the emulsion composition of the present invention is preferably 0.3 to 15% by weight, more preferably 0. 5 to 10% by weight.

In the emulsion composition of the present invention, the ratio of the component (D) to the component (A) is determined according to the contents of the component (A) and the component (D). For example, the total amount of the component (A) is 100. The total amount of component (D) is 3 to 200000 parts by weight per part by weight. From the viewpoint of more effectively suppressing the phase separation between the oil phase and the aqueous phase, the total amount of component (D) is preferably 3 to 150,000 parts by weight, more preferably 100 parts by weight of component (A). 25 to 20000 parts by weight may be mentioned.

(E) Polyoxyethylene hydrogenated castor oil The emulsified composition of the present invention may contain polyoxyethylene hydrogenated castor oil (hereinafter sometimes referred to as component (E)). By including polyoxyethylene hydrogenated castor oil, it is possible to further improve the effect of suppressing the formation of precipitates and precipitates.

The polyoxyethylene hydrogenated castor oil used in the present invention is not particularly limited, and examples thereof include polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, and polyoxyethylene (20) hydrogenated castor oil. Oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor Oil, polyoxyethylene (100) hydrogenated castor oil, and the like. These polyoxyethylene hydrogenated castor oils may be used individually by 1 type, and may be used in combination of 2 or more type.

Among these polyoxyethylene hydrogenated castor oils, from the viewpoint of more effectively suppressing the formation of precipitates and precipitates, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil are preferable. Oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil More preferably, polyoxyethylene (50) hydrogenated castor oil is used.

In the emulsified composition of the present invention, the content of the component (E) is not particularly limited. For example, the total amount of the component (E) is 0.1 to 10% by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the content of the component (E) in the emulsion composition of the present invention is preferably 0.1 to 8% by weight, more preferably 0.2%. Up to 5% by weight.

In the emulsion composition of the present invention, the ratio of the component (E) to the component (A) is determined depending on the contents of the component (A) and the component (E). For example, the total amount of the component (A) is 100. The total amount of the component (E) is 1 to 100,000 parts by weight per part by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the total amount of component (E) is preferably 2 to 80000 parts by weight, more preferably 10 to 100 parts by weight per 100 parts by weight of component (A). 10,000 parts by weight are mentioned.

(F) Wool Wax Alcohol The emulsified composition of the present invention may contain wool wax alcohol (hereinafter sometimes referred to as (F) component). In particular, by including wool wax alcohol together with the component (D) described above, phase separation between the oil phase and the aqueous phase can be more effectively suppressed, and the formulation stability can be dramatically improved. .

Wool wax alcohol is an alcohol component obtained by saponifying and decomposing sheep sebum (wool grease) or lanolin, and is also referred to as lanolin alcohol.

Wool wax alcohol includes abundant compounds having a steroid skeleton such as cholesterol, lanosterol, dihydrolanosterol, and monohydric or dihydric alcohols having about 14 to 36 carbon atoms (normal alcohol, isoalol, and anteisoalcohol). include.

In the emulsified composition of the present invention, the content of the component (F) is not particularly limited. For example, the total amount of the component (F) is 0.1 to 20% by weight. From the viewpoint of more effectively suppressing the phase separation of the oil phase and the aqueous phase, the content of the component (F) in the emulsion composition of the present invention is preferably 0.1 to 15% by weight, more preferably 0. 3 to 10% by weight.

In the emulsion composition of the present invention, the ratio of the component (F) to the component (A) is determined according to the contents of the components (A) and (F). For example, the total amount of the component (A) is 100. The total amount of component (F) is 1 to 200000 parts by weight per part by weight. From the viewpoint of more effectively suppressing phase separation between the oil phase and the aqueous phase, the total amount of component (F) is preferably 2 to 150,000 parts by weight, more preferably 100 parts by weight of component (A). 15 to 20000 parts by weight may be mentioned.

(G) Nonpolar Oil The emulsion composition of the present invention may contain a nonpolar oil (hereinafter sometimes referred to as the (G) component) as a component that forms an oil phase. In the prior art, when a nonpolar oil is included in the emulsion composition containing the component (A) and the component (B), the formation of precipitates and precipitates tends to be noticeable, but in the emulsion composition of the present invention, Even when nonpolar oil is contained, the formation of precipitates and precipitates can be effectively suppressed.

Nonpolar oil means an oil component having an IOB (inorganic / organic balance) of 0 or more and less than 0.05, and specifically includes hydrocarbon oil extracted from mineral oil. Such hydrocarbon oil is not particularly limited as long as it is pharmaceutically acceptable. For example, liquid paraffin (liquid normal paraffin, liquid isoparaffin), α-olefin oligomer, petrolatum, microcrystalline wax, gelation Examples include hydrocarbons (such as plastibase) and hydrogenated polyisobutene. These nonpolar oils may be used alone or in combination of two or more.

Among these nonpolar oils, liquid paraffin, α-olefin oligomer, petrolatum, and microcrystalline wax are preferable.

In the emulsified composition of the present invention, the content of the component (G) may be appropriately set based on the emulsified form of the emulsion composition, the feeling of use, etc., for example, the total amount of the component (G) is 1 weight. % Or more, preferably 1 to 30% by weight. Further, in the prior art, when an emulsion composition containing the component (A) and the component (B) contains 5% by weight or more, particularly 8% by weight or more, a precipitate or a precipitate is formed. However, in the emulsion composition of the present invention, it is possible to suppress the formation of precipitates and precipitates even when the component (G) is contained in a high content. . In view of the effects of the present invention, the content of the component (G) in the emulsion composition of the present invention is more preferably 5 to 30% by weight, particularly preferably 8 to 30% by weight.

Polar oil The emulsified composition of the present invention may contain a polar oil as a component for forming an oil phase. In the emulsion composition of the present invention, when the nonpolar oil is contained, the polar oil may not be contained, and the nonpolar oil and the polar oil may be used in combination.

Polar oil means an oil component having an IOB (inorganic / organic balance) in the range of 0.05 to 1.1. The polar oil is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include animal oil, mineral oil, fatty acid alkyl ester, and fatty acid.

Examples of vegetable oils include olive oil, wheat germ oil, rice oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, hydrogenated oil Avocado oil, fennel oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, tree wax and the like. These vegetable oils may be used individually by 1 type, and may be used in combination of 2 or more type.

Specific examples of animal oils include lard, fish oil, beeswax and the like. These animal oils may be used alone or in combination of two or more.

Examples of fatty acid alkyl esters include esters of fatty acids having 4 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms. Specifically, glyceryl triisopalmitate, glyceryl tri-2-ethylhexanoate, glyceryl triisooctanoate, octyldodecyl myristate, diisostearyl malate, neopentyl glycol dioctanoate, dipentaerythritol fatty acid ester, hydroxystearin Cholesteryl adipate, isopropyl adipate, isobutyl adipate, diethyl sebacate, isopropyl sebacate, diisopropyl sebacate, cetyl ethylhexanoate, isopropyl myristate, myristyl myristate, isopropyl palmitate, cetyl palmitate, ethyl oleate, butyl stearate , Hexyldecyl isostearate, isopropyl linoleate, glyceryl tri (capryl / caprate), cetyl octoate, steer Butylate, hexyl laurate, decyl oleate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearylate, ethylene glycol di-2-ethylhexanoate , Dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, tetra-2-ethyl Hexanoic acid pentaerythritol, triisostearic acid trimethylolpropane, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, Diethylhexyl phthalin dicarboxylate, alkyl benzoate (C12-15), cetearyl isononanoate, tri (caprylic / capric) glycerin, (dicaprylic / capric) butylene glycol, glyceryl trimyristate, tri 2-heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleic oleate, cetostearyl alcohol, acetoglyceride, 2-heptylundecyl palmitate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, adipic acid di-2 -Heptylundecyl, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, di-2-ethylhexyl succinate And the like. These fatty acid alkyl esters may be used alone or in combination of two or more.

Examples of the fatty acid include fatty acids having 4 to 30 carbon atoms, and specific examples include lauric acid, myristic acid, palmitic acid, sebacic acid, oleic acid, linoleic acid, and the like. These fatty acids may be used alone or in combination of two or more.

Among these polar oils, fatty acid alkyl esters are preferable.

These polar oils may be used alone or in combination of two or more.

In the emulsified composition of the present invention, the polar oil content may be appropriately set in consideration of the emulsified form of the emulsified composition, the feeling of use, etc., for example, 0.5 to 20% by weight, preferably 1 to 20% by weight, more preferably 3 to 15% by weight.

Emulsion composition of the water present invention contains water as a substrate for forming an aqueous phase.

In the emulsified composition of the present invention, the water content may be appropriately set based on the emulsified form of the emulsified composition, the feeling of use, etc., for example, 10 to 90% by weight, preferably 20 to 85% by weight. More preferred is 30 to 85% by weight.

Surfactant (other than polyoxyethylene hydrogenated castor oil)
The emulsion composition of the present invention may contain a surfactant other than the polyoxyethylene hydrogenated castor oil in order to stably form an emulsified state. The surfactant (other than polyoxyethylene hydrogenated castor oil) is not particularly limited as long as it is pharmaceutically acceptable. Nonionic surfactant (other than polyoxyethylene hydrogenated castor oil), anionic surfactant Any of cationic surfactants and amphoteric surfactants may be used.

Specific examples of nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) include polyoxyethylene (10-50 mol) phytosterol ether, polyoxyethylene (10-50 mol) dihydrocholesterol ether, polyoxyethylene (10-50 mol) 2-octyldodecyl ether, polyoxyethylene (10-50 mol) decyl tetradecyl ether, polyoxyethylene (10-50 mol) oleyl ether, polyoxyethylene (2-50 mol) cetyl ether, Polyoxyethylene (5-50 mol) behenyl ether, polyoxyethylene (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, polyoxyethylene (10-50 mol) polyoxypropylene ( 2-30 E) Polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acid / phosphates thereof (such as sodium polyoxyethylene cetyl ether phosphate), polyoxyethylene (20 to 60 mol) sorbitan monooleate, polyoxyethylene (10 -60 mol) sorbitan monoisostearate, polyoxyethylene (10-80 mol) glyceryl monoisostearate, polyoxyethylene (10-30 mol) glyceryl monostearate, polyoxyethylene (20-100 mol) poly Oxypropylene-modified silicone, polyoxyethylene / alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate Coal, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5 to 100), polysorbate (20 to 85), glycerin fatty acid ester (monostearic acid Glycerin and the like). These nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) may be used singly or in combination of two or more.

Specific examples of the anionic surfactant include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristol sarcosinate, sodium dodecylbenzene sulfonate, Examples include hydrogenated coconut fatty acid monoglyceride sodium monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutarate, sodium N-methyl-N-acyl taurate, and the like. These anionic surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

Specific examples of the cationic surfactant include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, benzalkonium chloride, and stearyldimethylbenzylammonium chloride. These cationic surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

Specific examples of amphoteric surfactants include coconut oil fatty acid amidopropyl betaine, lauryl dimethylaminoacetic acid betaine, lauryl dimethylamine oxide, 2-alkyl-N-
Examples include carboxymethyl-N-hydroxyethyl imidazolium betaine, N-lauryl diaminoethyl glycine, N-myristyl diaminoethyl glycine, N-alkyl-1-hydroxyethyl imidazoline betaine sodium and the like. These amphoteric surfactants may be used alone or in combination of two or more.

Among these surfactants, nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) are preferable from the viewpoint of stably maintaining the emulsified state.

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

In the emulsified composition of the present invention, the content of the surfactant (other than polyoxyethylene hydrogenated castor oil) may be appropriately set according to the type of surfactant, the emulsified form, etc. 10% by weight, preferably 1 to 9% by weight, more preferably 2 to 8% by weight.

Polyhydric alcohol The emulsified composition of the present invention may contain a polyhydric alcohol, if necessary, in addition to the above-described components in order to have moisture retention and the like.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol and the like. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

In the emulsified composition of the present invention, the content of the polyhydric alcohol is not particularly limited. For example, it is 0.5 to 30% by weight, preferably 0.5 to 25% by weight, and more preferably 1 to 20% by weight. Can be mentioned.

Thickener The emulsified composition of the present invention may contain a thickener as necessary in order to have a desired viscosity and the like in addition to the components described above.

The thickener is not particularly limited as long as it is pharmaceutically acceptable.For example, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropyl Cellulose, hydroxypropyl methylcellulose, sodium alginate, propylene glycol ester alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin, etc. Can be mentioned. Among these thickeners, xanthan gum and carboxyvinyl polymer are preferable. These thickeners can be used alone or in combination of two or more.

In the emulsified composition of the present invention, the content of the thickener may be appropriately set according to the viscosity to be imparted, etc., for example, 0.01 to 5% by weight, preferably 0.1 to 4% by weight. More preferred is 0.1 to 3% by weight.

Other components In addition to the components described above, the emulsion composition of the present invention may contain other additives usually used for external preparations for skin, etc., if necessary. Examples of such additives include pH adjusters, buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, chelating agents, fragrances, and coloring agents.

Furthermore, the emulsified composition of the present invention may contain a medicinal component other than the components described above, if necessary. Examples of such drugs include steroid drugs (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, Procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or a salt thereof, alkyl benzoate (for example, ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate), orthocaine, oxesazein, oxypolyentoxydecane, Funnel extract, percamin ase, tesit decite, etc.), anti-inflammatory agents (allantoin, salicylic acid, glycol salicylate, methyl salicylate) Indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc. ), Antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), vitamins (vitamins A, B, C, D, etc.), mucopolysaccharide (sodium chondroitin sulfate, hyaluronic acid, etc.) and the like.

The emulsified state of the emulsified composition of the present invention such as emulsified state / form of preparation may be either oil-in-water type or water-in-oil type, preferably oil-in-water type.

The formulation form of the emulsified composition of the present invention is not particularly limited, and examples thereof include emulsion (emulsion lotion) and cream.

The emulsified composition of the present invention is suitably used as a skin external preparation applied transdermally. Specific examples of the emulsified composition of the present invention include external medicines, cosmetics, skin cleansing agents and the like. Among these preparation forms, an external medicine is preferable.

Production Method The emulsion composition of the present invention can be produced according to a known method for producing an emulsion composition. As a manufacturing method of the emulsion composition of this invention, the method shown below is mentioned, for example. First, (A) component, (B) component, (C) component, nonpolar oil and / or polar oil, and other lipophilic components added as necessary are prepared to prepare an oil phase composition. To do. Separately, water and other water-soluble components added as needed are mixed to prepare an aqueous phase composition. In addition, when (E) component and / or surfactant (other than (E) component) are included, these are added to either or both of the oil phase composition and the aqueous phase composition. What is necessary is just to mix, but adding to the composition for oil phases is preferable. Next, the obtained oil phase composition and aqueous phase composition are mixed and emulsified by an emulsification technique such as a homogenizer to produce the emulsified composition of the present invention.

2. The present invention further relates to an emulsion comprising (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) ufenamate. In the composition, a method for suppressing the formation of precipitates and precipitates, comprising: (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof; and (B) Provided is a method for suppressing the formation of precipitates and precipitates, which comprises blending (C) diphenhydramine and / or a salt thereof together with ufenamate.

In the method, the types and contents of (A) to (C) to be used, the types and contents of other components to be blended, the formulation form of an emulsified composition produced by emulsification, and the like are described in “1. The same as in the case of the “emulsified composition”.

3. The present invention further includes (A) glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof selected from the group consisting of a precipitate and a precipitate, and a method for suppressing phase separation between an oil phase and an aqueous phase. In the emulsion composition containing 1 type and (B) Ufenamate, it is a method for suppressing the formation of precipitates and precipitates, and the phase separation of the oil phase and the aqueous phase, comprising (A) glycyrrhetinic acid, glycyrrhizic acid, (C) diphenhydramine and / or a salt thereof, and (D) a higher alcohol that is solid at 25 ° C., together with at least one selected from the group consisting of derivatives, and salts thereof, and (B) ufenamate. The present invention provides a method for suppressing the formation of precipitates and precipitates, and the phase separation of an oil phase and an aqueous phase.

In the method, the types and contents of (A) to (D) to be used, the types and contents of other components to be blended, the formulation form of the emulsified composition produced by emulsification, etc. are described in “1. The same as in the case of the “emulsified composition”.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Test Example A creamy oil-in-water emulsion composition having the composition shown in Table 1 was produced and evaluated for the degree of precipitation, the degree of precipitation, and the degree of phase separation. The production method and test method of the creamy oil-in-water emulsion composition are as follows.

[Method for producing creamy oil-in-water emulsion composition]
First, among the components shown in (I) of Table 1, a predetermined amount of components other than the component (A) (glycyrrhetinic acid or dipotassium glycyrrhizinate) was weighed and heated to 80 ° C. and mixed. Thereafter, a predetermined amount of component (A) was added and mixed to prepare an oil phase composition. Separately, a predetermined amount of the component shown in (II) of Table 1 was weighed and mixed to prepare an aqueous phase composition. After the water phase composition was heated to 80 ° C., the 80 ° C. oil phase composition was added in small portions and emulsified while mixing. Then, it cooled to 30 degreeC and obtained the cream-like oil-in-water emulsion composition.

[Test method]
(Degree of precipitation)
About the oil phase composition prepared in the manufacturing process of each emulsified composition, the appearance immediately after the preparation was visually observed, and the degree of precipitation was evaluated according to the following criteria.
<Criteria for the degree of precipitation formation>
A: The liquid is clear and no precipitation is observed.
○: The liquid is clear, but slight precipitation occurs.
X: The liquid is suspended and some precipitation is observed.
XX: The liquid is suspended and precipitation is remarkably observed.

(Degree of precipitate formation)
Each emulsion composition was stored for 1 day at room temperature, then observed with a polarizing microscope, and the degree of precipitate formation was evaluated according to the following criteria.
<Criteria for the degree of precipitate formation>
A: No precipitate is observed at all.
○: Slight fine precipitates are observed, but no problematic precipitates are observed.
X: There are not many large precipitates, but many precipitates are observed.
XX: Many large precipitates are observed.

(Degree of phase separation)
After each emulsion composition was stored at 40 ° C. for 3 months and at 50 ° C. for 1 month, the appearance was observed, and the degree of phase separation was evaluated according to the following criteria. In the emulsified compositions of Comparative Examples 1 to 8, precipitation and formation of precipitates were observed, and thus the degree of phase separation was not evaluated.
<Criteria for the degree of phase separation>
(Double-circle): The phase separation of an oil phase and a water phase is not recognized at all on both conditions for 3 months at 40 degreeC and for 1 month at 50 degreeC.
○: Almost no phase separation between the oil phase and the aqueous phase is observed under both conditions of 40 ° C. for 3 months and 50 ° C. for 1 month.
(Triangle | delta): The phase separation of an oil phase and a water phase is hardly recognized on the conditions for 3 months at 40 degreeC. However, the phase separation of the oil phase and the water phase is clearly observed at 50 ° C. for one month.
X: Phase separation of the oil phase and the aqueous phase is clearly observed under conditions of 3 months at 40 ° C. or 1 month at 50 ° C.

[Test results]
The obtained results are shown in Table 1. In the emulsion composition containing glycyrrhetinic acid and ufenamate and not containing diphenhydramine, precipitation and formation of precipitates were observed (Comparative Examples 1 to 8). In addition, in the emulsion composition containing both non-polar oil and not containing diphenhydramine, both glycyrrhetinic acid and ufenamate tended to show significant precipitation and precipitate formation (Comparative Examples 2 to 8).

On the other hand, in the emulsion composition containing glycyrrhetinic acid or dipotassium glycyrrhizinate, ufenamate, and diphenhydramine, the formation of precipitates and precipitates could be suppressed (Examples 1 to 14). In addition to these components, an emulsion composition containing a higher alcohol that is solid at 25 ° C. has improved the effect of suppressing precipitation and precipitate formation (Examples 2 to 14).

Further, in the emulsion composition containing polyoxyethylene hydrogenated castor oil in addition to glycyrrhetinic acid or dipotassium glycyrrhizinate, ufenamate, and diphenhydramine, phase separation between the oil phase and the aqueous phase could be suppressed (Examples 7 to 14). ). Furthermore, in the emulsion composition containing wool wax alcohol in addition to these components, the effect of suppressing the phase separation between the oil phase and the aqueous phase was further improved (Examples 12 and 13).

Formulation Example An oil-in-water emulsion composition having the composition shown in Table 2 was prepared. Each of these preparations is an emulsified composition in which the formation of precipitates and precipitates is suppressed as in the case of the test example.

Claims (9)

(A) Emulsifying composition containing at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, (B) ufenamate, and (C) diphenhydramine and / or a salt thereof. object. (D) The emulsified composition according to claim 1, comprising a higher alcohol that is solid at 25 ° C. (E) The emulsion composition of Claim 2 containing polyoxyethylene hydrogenated castor oil. (F) The emulsion composition of Claim 2 or 3 containing wool wax alcohol. The emulsion composition according to any one of claims 1 to 4, comprising (G) a nonpolar oil. The emulsified composition according to any one of claims 1 to 5, which is an oil-in-water emulsified composition. The emulsified composition according to any one of claims 1 to 6, which is an external preparation for skin. (A) At least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) a method for suppressing the formation of precipitates and precipitates in an emulsified composition containing ufenamate Because
A method of blending (C) diphenhydramine and / or a salt thereof with (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (A) ufenamate. (A) At least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) formation of precipitates and precipitates, and an oil phase in an emulsion composition containing ufenamate A method of suppressing phase separation between the water phase and the water phase,
(A) glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and at least one selected from the group consisting of these salts, and (B) ufenamate, (C) diphenhydramine and / or a salt thereof, and (D) 25 A method of blending a higher alcohol that is solid at ℃.