JP7170385B2 - emulsion composition - Google Patents

Description

The present invention comprises glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and/or salts thereof, and ufenamate, which can suppress the formation of precipitates and precipitates, and further suppress phase separation between the oil phase and the aqueous phase, It relates to an emulsified composition with excellent formulation stability.

Non-steroidal anti-inflammatory drugs have almost no concerns about serious side effects like those seen with steroidal anti-inflammatory drugs, and there are few restrictions on the amount and duration of use, so they can be used to treat rashes, redness, dry dermatitis, and atopic dermatitis. It is also widely used as an external preparation for alleviating inflammatory skin diseases such as dermatitis.

Among non-steroidal anti-inflammatory agents, glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as "glycyrrhetinic acids") have anti-inflammatory action and tissue repair action. and is widely used in topical preparations. In addition, among non-steroidal anti-inflammatory agents, ufenamate has an anti-inflammatory effect equivalent to that of flufenamic acid and less local irritation than flufenamic acid, so it is suitable for application to delicate skin and long-term use. and is widely used in topical preparations.

On the other hand, non-steroidal anti-inflammatory agents have the disadvantage that their anti-inflammatory action is slower than that of steroidal anti-inflammatory agents. Therefore, in recent years, attempts have been made to combine two or more types of non-steroidal anti-inflammatory agents with different mechanisms of action in order to effectively exert anti-inflammatory effects. is being developed.

In addition, since glycyrrhetinic acids and ufenamate are easily destabilized in formulations and may form deposits and precipitates, external preparations containing these require a formulation design that enhances formulation stability. Therefore, conventionally, formulation techniques for enhancing the formulation stability of external preparations containing glycyrrhetinic acids and ufenamate have been studied. For example, Patent Document 1 discloses that a gel ointment containing a sparingly water-soluble active ingredient such as ufenamate, a nonionic surfactant, an auxiliary agent such as glycyrrhetinic acid, and water can stably retain a sparingly water-soluble active ingredient. has been reported. However, the formulation technology disclosed in Patent Document 1 is applicable only to gel ointments, lacks versatility, and is not necessarily satisfactory in terms of formulation stability.

In addition, when glycyrrhetinic acids and ufenamate are blended and formulated into an emulsified composition, there is the problem of phase separation between the oil phase and the water phase, in addition to the formation of the above-mentioned deposits and precipitates. Therefore, in order to put an emulsified composition containing glycyrrhetinic acids and ufenamate into practical use, it is also necessary to design a formulation that suppresses phase separation between the oil phase and the aqueous phase.

Japanese Patent Application Laid-Open No. 2003-321347

An object of the present invention is to contain glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and/or salts thereof, and ufenamate, which can suppress the formation of precipitates and precipitates, and also suppress phase separation between the oil phase and the aqueous phase. To provide an emulsified composition having excellent formulation stability.

As a result of intensive studies to solve the above problems, the present inventor found that an emulsified composition containing glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof and/or salts thereof, and ufenamate, diphenhydramine and/or its It has been found that by blending a salt with wool wax alcohol, it is possible to suppress the formation of deposits and precipitates, and furthermore, it is possible to suppress phase separation between the oil phase and the aqueous phase. The present invention has been completed through further studies based on such findings.

That is, the present invention provides inventions in the following aspects.
Section 1. (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, (B) ufenamate, (C) diphenhydramine and/or salts thereof, and (D) wool An emulsified composition containing a wax alcohol.
Section 2. Item 1. The emulsified composition according to item 1, containing (E) a non-polar oil.
Item 3. Item 3. The emulsified composition according to Item 1 or 2, which is an oil-in-water emulsified composition.
Section 4. Item 4. The emulsified composition according to any one of items 1 to 3, which is an external preparation for skin.
Item 5. (A) At least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) ufenamate, in an emulsified composition containing deposits and precipitates, and an oil phase A method for suppressing phase separation between the aqueous phase and the aqueous phase,
(A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) ufenamate, (C) diphenhydramine and/or salts thereof, and (D) wool A method of compounding a wax alcohol.

The emulsified composition of the present invention contains glycyrrhetinic acids and ufenamate, but also contains diphenhydramine and/or a salt thereof and wool wax alcohol, thereby suppressing the formation of deposits and precipitates, while maintaining the oil phase and water. Since phase separation can also be suppressed, excellent formulation stability can be provided.

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)). , ufenamate (hereinafter sometimes referred to as component (B)), diphenhydramine and/or its salt (hereinafter sometimes referred to as component (C)), and wool wax alcohol (hereinafter referred to as component (D) It is characterized by containing The emulsified composition of the present invention is described in detail below.

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

Glycyrrhetinic acid is a known drug known to have anti-inflammatory effects, anti-allergic effects, and the like.

Glycyrrhizic acid is a known drug known to have anti-inflammatory effects, anti-allergic effects, and the like.

The derivatives of glycyrrhetinic acid are not particularly limited as long as they are pharmaceutically acceptable, and specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, and monoglucuronide glycyrrhetinate. These derivatives of glycyrrhetinic acid may be used singly 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 derivatives of glycyrrhizic acid may be used singly or in combination of two or more.

Salts of glycyrrhizic acid, glycyrrhetinic acid and/or derivatives thereof are not particularly limited as long as they are pharmaceutically acceptable. Specific examples include alkali metal salts such as sodium salts and potassium salts; ammonium salts and the like. mentioned. These salts may be used singly or in combination of two or more.

The emulsified composition of the present invention contains, as component (A), glycyrrhetinic acid, a salt of glycyrrhetinic acid, a derivative of glycyrrhetinic acid, a salt of a derivative of glycyrrhetinic acid, glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, and glycyrrhizic acid. may be used by selecting one of the salts of derivatives of, or may be used in combination of two or more.

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

In the emulsified composition of the present invention, the content of component (A) is not particularly limited and may be set appropriately according to the efficacy 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 component (B) is appropriately set according to the efficacy to be exhibited, and is, for example, 1 to 20% by weight, preferably 1 to 6% by weight, more preferably 1 to 6% by weight. 1 to 5% by weight can be mentioned.

In the emulsified composition of the present invention, the ratio of component (B) to component (A) is determined according to the respective contents of component (A) and component (B). The total amount of component (B) is 10 to 200,000 parts by weight, preferably 20 to 60,000 parts by weight, more preferably 50 to 10,000 parts by weight.

(C) Diphenhydramine and/or its salt The emulsified composition of the present invention contains diphenhydramine and/or its salt. Emulsified compositions containing the components (A) and (B) tend to be destabilized by forming deposits and precipitates, but the emulsified composition of the present invention contains diphenhydramine and / or a salt thereof. By containing it, it is possible to suppress the generation of precipitates and precipitates.

Diphenhydramine is a known drug known to have antihistamine properties.

The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrochloride, citrate, succinate, tartrate, fumarate, maleate, and salicylate. , diphenyldisulfonate, tannate, lauryl sulfate, and acid addition salts such as sulfate. These salts may be used singly or in combination of two or more.

In the emulsified composition of the present invention, one of diphenhydramine and salts thereof may be selected and used as the component (C), or two or more thereof may be used in combination.

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

In the emulsified composition of the present invention, the content of component (C) is not particularly limited, but for example, the total amount of 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 component (C) in the emulsified composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.1%. ~2% by weight.

In the emulsified composition of the present invention, the ratio of component (C) to component (A) is determined according to the respective contents of component (A) and component (C). The total amount of component (C) is 0.1 to 50,000 parts by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the total amount of component (C) is preferably from 2 to 30,000 parts by weight, more preferably from 5 to 5 parts by weight, per 100 parts by weight of the total amount of component (A). 4000 parts by weight.

(D) Wool Wax Alcohol The emulsified composition of the present invention contains wool wax alcohol. The emulsified composition containing the components (A) and (B) tends to destabilize the formulation due to phase separation between the oil phase and the aqueous phase. However, in the emulsion composition of the present invention, wool wax alcohol By containing, it is possible to suppress phase separation between the oil phase and the aqueous phase.

Wool wax alcohol is an alcohol component obtained by saponifying and decomposing sheep skin oil (wool grease) or lanolin, and is also called lanolin alcohol.

Wool wax alcohols are rich in compounds having a steroid skeleton such as cholesterol, lanosterol, and dihydrolanosterol, and include monohydric or dihydric alcohols (normal alcohols, isoalols, and anteisoalcohols) having about 14 to 36 carbon atoms. include.

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

In the emulsified composition of the present invention, the ratio of component (D) to component (A) is determined according to the respective contents of component (A) and component (D). The total amount of component (D) is 1 to 200,000 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 (D) is preferably 2 to 150,000 parts by weight, more preferably 2 to 150,000 parts by weight per 100 parts by weight of the total amount of component (A). 15 to 20,000 parts by weight can be mentioned.

Higher Alcohol Solid at 25°C The emulsified composition of the present invention may contain a higher alcohol that is solid at 25°C. By containing a higher alcohol that is solid at 25°C, it becomes possible to further improve the effect of suppressing phase separation between the oil phase and the water phase.

Higher alcohols that are solid at 25° C. are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include those having 12 to 34 carbon atoms. Specific examples of higher alcohols that are solid at 25°C include lauryl alcohol, mystyryl alcohol, cetanol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, linolyl alcohol, behenyl alcohol, arachidyl alcohol, behenyl alcohol, lignoceryl alcohol, and ceryl. alcohol, montanyl alcohol, myricyl alcohol, gedyl alcohol and the like. These higher alcohols may be used singly or in combination of two or more.

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

In the emulsified composition of the present invention, the content of higher alcohols that are solid at 25° C. is not particularly limited, but for example, the total amount of the higher alcohols is 0.3 to 20% by weight or more. From the viewpoint of more effectively suppressing phase separation between the oil phase and the aqueous phase, the content of the higher alcohol in the emulsified composition of the present invention is preferably 0.3 to 15% by weight, more preferably 0.3% by weight. 5 to 10% by weight can be mentioned.

In the emulsified composition of the present invention, the ratio of the higher alcohol that is solid at 25 ° C. to the component (A) is determined according to the content of the component (A) and the higher alcohol. The total amount of the higher alcohol is 3 to 200,000 parts by weight per 100 parts by weight of the total amount. From the viewpoint of more effectively suppressing phase separation between the oil phase and the aqueous phase, the total amount of the higher alcohol is preferably 3 to 150,000 parts by weight, more preferably 25 parts by weight, per 100 parts by weight of the total amount of component (A). ~20000 parts by weight.

Polyoxyethylene hydrogenated castor oil The emulsion composition of the present invention may contain polyoxyethylene hydrogenated castor oil. By containing polyoxyethylene hydrogenated castor oil, it becomes 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, but for example, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, 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 oil, polyoxyethylene (100) hydrogenated castor oil, and the like. These polyoxyethylene hydrogenated castor oils may be used singly or in combination of two or more.

Among these polyoxyethylene hydrogenated castor oils, polyoxyethylene (20) hydrogenated castor oil and polyoxyethylene (30) hydrogenated castor oil are preferred from the viewpoint of more effectively suppressing the formation of precipitates and precipitates. 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 Oil; more preferably polyoxyethylene (50) hydrogenated castor oil.

In the emulsified composition of the present invention, the content of polyoxyethylene hydrogenated castor oil is not particularly limited, but for example, the total amount of polyoxyethylene hydrogenated castor oil is 0.1 to 10% by weight. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the content of polyoxyethylene hydrogenated castor oil in the emulsified composition of the present invention is preferably 0.1 to 8% by weight, more preferably 0. .2 to 5% by weight.

In the emulsified composition of the present invention, the ratio of polyoxyethylene hydrogenated castor oil to component (A) is determined according to the contents of component (A) and polyoxyethylene hydrogenated castor oil. The total amount of polyoxyethylene hydrogenated castor oil is 1 to 100,000 parts by weight per 100 parts by weight of the total amount of ingredients. From the viewpoint of more effectively suppressing the formation of precipitates and precipitates, the total amount of polyoxyethylene hydrogenated castor oil is preferably 2 to 80000 parts by weight, more preferably 2 to 80000 parts by weight per 100 parts by weight of the total amount of component (A). 10 to 10,000 parts by weight can be mentioned.

(E) Non-polar oil The emulsified composition of the present invention may contain a non-polar oil (hereinafter sometimes referred to as component (E)) as a component that forms the oil phase. In the prior art, when a non-polar oil is contained in an emulsified composition containing components (A) and (B), there is a tendency for the formation of deposits and precipitates to become noticeable. However, in the emulsified composition of the present invention, Even if non-polar oil is included, the formation of deposits and precipitates can be effectively suppressed.

Apolar oil means an oil having an IOB (inorganic/organic balance) of 0 or more and less than 0.05, and specifically includes hydrocarbon oils extracted from mineral oils. Such hydrocarbon oil is not particularly limited as long as it is pharmaceutically acceptable, but examples include liquid paraffin (normal liquid paraffin, liquid isoparaffin), α-olefin oligomer, petrolatum, microcrystalline wax, gel Hydrocarbons (plastibase, etc.), hydrogenated polyisobutene, and the like. These non-polar oils may be used singly or in combination of two or more.

Among these non-polar oils, preferred are liquid paraffin, α-olefin oligomer, petrolatum, and microcrystalline wax.

In the emulsified composition of the present invention, the content of component (E) may be appropriately set based on the emulsified form of the emulsified composition, the feeling of use, etc. For example, the total amount of component (E) is 1 weight. % or more, preferably 1 to 30% by weight. In addition, in the prior art, when the emulsion composition containing the components (A) and (B) contains the component (E) in an amount of 5% by weight or more, particularly 8% by weight or more, precipitates and precipitates are formed. However, in the emulsified composition of the present invention, even if the component (E) is contained at such a high content, it is possible to suppress the formation of precipitates and precipitates. . In view of such effects of the present invention, the content of component (E) in the emulsified 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 forming the oil phase. When the emulsified composition of the present invention contains the non-polar oil, the polar oil may not be contained, or the non-polar oil and the polar oil may be used in combination.

By polar oil is meant an oil with an IOB (inorganic/organic balance) in the range of 0.05 to 1.1. Polar oils are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, animal oils, mineral oils, fatty acid alkyl esters, fatty acids and the like.

Specific examples of vegetable oils include olive oil, wheat germ oil, rice bran oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, and hydrogenated oil. , avocado oil, fennel oil, clove oil, mint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, wood wax and the like. These vegetable oils may be used singly or in combination of two or more.

Animal oils specifically include lard, fish oil, beeswax and the like. These animal oils may be used singly 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 Acid Isopropyl Adipate, Isobutyl Adipate, Diethyl Sebacate, Isopropyl Sebacate, Diisopropyl Sebacate, Cetyl Ethylhexanoate, Isopropyl Myristate, Myristyl Myristate, Isopropyl Palmitate, Cetyl Palmitate, Ethyl Oleate, Bacyl Stearate , hexyldecyl isostearate, isopropyl linoleate, caprylic-capric triglyceride, cetyl octanoate, butyl stearate, hexyl laurate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, Isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexanoate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, di-2-heptylundecanoic acid glycerin, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythrityl tetra-2-ethylhexanoate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, Diethylhexyl Naphthalenedicarboxylate, Alkyl Benzoate (C12-15), Cetearyl Isononanoate, Caprylic/Capric Triglycerin, Butylene Glycol (Dicaprylic/Capric), Glyceryl Trimyristate, Tri 2 - heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleyl oleate, cetostearyl alcohol, acetoglyceride, 2-heptylundecyl palmitate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, di-2-adipate 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 singly or in combination of two or more.

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

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

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

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

Water The emulsified composition of the present invention contains water as a base material that forms the aqueous phase.

In the emulsified composition of the present invention, the content of water may be appropriately set in consideration of 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. , and more preferably 30 to 85% by weight.

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

Specific examples of nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) include polyoxyethylene (10 to 50 mol) phytosterol ether, polyoxyethylene (10 to 50 mol) dihydrocholesterol ether, polyoxyethylene (10-50 mol) 2-octyldodecyl ether, polyoxyethylene (10-50 mol) decyltetradecyl 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 to 30 mol) polyoxyethylene alkyl ethers such as cetyl ether, their phosphoric acids and phosphates (polyoxyethylene cetyl ether sodium phosphate, etc.), polyoxyethylene (20 to 60 mol) sorbitan monooleate, polyoxy Ethylene (10-60 mol) sorbitan monoisostearate, polyoxyethylene (10-80 mol) glyceryl monoisostearate, polyoxyethylene (10-30 mol) glyceryl monostearate, polyoxyethylene (20-100 mol) )・polyoxypropylene-modified silicone, polyoxyethylene/alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, diolein Polyethylene glycol diricinoleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), glycerol fatty acid ester (glycerol monostearate, etc.) 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 anionic surfactants include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-mystryl sarcosinate, sodium dodecylbenzene sulfonate, sodium hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutarate, sodium N-methyl-N-acyl taurine; These anionic surfactants may be used singly or in combination of two or more.

Specific examples of cationic surfactants include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, benzalkonium chloride, and stearyldimethylbenzylammonium chloride. These cationic surfactants may be used singly or in combination of two or more.

Specific examples of amphoteric surfactants include coconut oil fatty acid amidopropyl betaine, lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryl diaminoethylglycine, N-myristyldiaminoethylglycine, N-alkyl-1-hydroxyethylimidazoline betaine sodium and the like. These amphoteric surfactants may be used singly or in combination of two or more.

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

These surfactants may be used singly 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, emulsification form, etc., for example, 0.5 to 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, if necessary, a polyhydric alcohol in addition to the components described above in order to provide moisturizing properties and the like.

Polyhydric alcohols are not particularly limited as long as they are pharmaceutically acceptable, and examples include ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol and the like. These polyhydric alcohols may be used singly or in combination of two or more.

In the emulsion composition of the present invention, the content of the polyhydric alcohol is not particularly limited, but is, for example, 0.5 to 30% by weight, preferably 0.5 to 25% by weight, more preferably 1 to 20% by weight. mentioned.

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

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

In the emulsified composition of the present invention, the content of the thickening agent may be appropriately set according to the viscosity to be imparted, and is, for example, 0.01 to 5% by weight, preferably 0.1 to 4% by weight. , and more preferably 0.1 to 3% by weight.

Other Ingredients The emulsified composition of the present invention may contain, if necessary, other additives commonly used in external preparations for skin, in addition to the above-mentioned ingredients. Examples of such additives include pH adjusters, buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, chelating agents, perfumes, colorants and the like.

Furthermore, the emulsified composition of the present invention may contain medicinal ingredients other than the ingredients described above, if necessary. Examples of such drugs include steroids (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, meprilcaine or salts thereof, benzoic acid alkyl esters (e.g. ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate hydrochloride), orthocaine, oxethazein, oxypolyentoxydecane, Rohto extract, percamimpase, tecit decitin, etc.), anti-inflammatory agents (allantoin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, dequalinium chloride, benzethonium chloride, chloride) cetylpyridinium, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation promoting ingredients (nonyl) acid vanillylamide, benzyl nicotinate, capsaicin, hot pepper extract, etc.), vitamins (vitamin A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, hyaluronic acid, etc.), and the like.

Emulsified state, formulation form, etc. The emulsified state of the emulsified composition of the present invention may be either oil-in-water type or water-in-oil type, but preferably oil-in-water type.

The formulation form of the emulsified composition of the present invention is not particularly limited, and examples thereof include milky lotions (emulsified lotions) and creams.

The emulsified composition of the present invention is suitably used as an external preparation for transdermal application. Specific examples of the emulsified composition of the present invention include pharmaceuticals for external use, cosmetics, skin cleansers and the like. Among these formulation forms, pharmaceuticals for external use are preferred.

Manufacturing Method The emulsified composition of the present invention can be manufactured according to a known emulsified composition manufacturing method. Examples of the method for producing the emulsified composition of the present invention include the method shown below. First, component (A), component (B), component (C), component (D), non-polar oil and/or polar oil, and optionally other lipophilic components are mixed to form an oil phase. Prepare a composition for Separately, water and other water-soluble components added as necessary are mixed to prepare a composition for an aqueous phase. When polyoxyethylene hydrogenated castor oil and/or surfactants (other than polyoxyethylene hydrogenated castor oil) are contained, they are added to either or both of the oil phase composition and the aqueous phase composition. It may be added to the oil phase composition and mixed, but it is preferable to add it to the oil phase composition. Next, the obtained oil phase composition and aqueous phase composition are mixed and emulsified by an emulsifying technique such as a homogenizer to produce the emulsified composition of the present invention.

2. Method for Suppressing Formation of Precipitates and Precipitates, and Phase Separation of Oil Phase and Water Phase 1 and (B) a method for suppressing the formation of precipitates and precipitates and the phase separation of an oil phase and an aqueous phase in an emulsified composition containing ufenamate, comprising (A) glycyrrhetinic acid, glycyrrhizic acid, and At least one selected from the group consisting of derivatives and salts thereof, and (B) ufenamate, (C) diphenhydramine and / or a salt thereof, and (D) wool wax alcohol are blended, A method for inhibiting the formation of precipitates and precipitates and phase separation of oil and water phases is provided.

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 prepared by emulsification, etc. are described in the above "1. Emulsion composition".

A creamy oil-in-water emulsified composition having the composition shown in Test Example Table 1 was produced, and the degree of precipitation, the degree of precipitate formation, and the degree of phase separation were evaluated. The production method and test method for 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) in Table 1, a predetermined amount of components other than component (A) (glycyrrhetinic acid or dipotassium glycyrrhizinate) was weighed, heated to 80° C. and mixed. Thereafter, a predetermined amount of component (A) was added and mixed to prepare an oil phase composition. Separately, predetermined amounts of the components shown in (II) in Table 1 were weighed and mixed to prepare a composition for an aqueous phase. After heating the composition for the aqueous phase to 80° C., the composition for the oil phase at 80° C. was added little by little and emulsified while being mixed. Thereafter, the mixture was cooled to 30°C to obtain a creamy oil-in-water emulsion composition.

[Test method]
(Extent of precipitation)
The appearance of the oil phase composition prepared in the manufacturing process of each emulsified composition was visually observed immediately after preparation, and the degree of precipitation was evaluated according to the following criteria.
<Criteria for determining the degree of precipitation>
◯: The liquid is clear and no precipitate is observed.
x: The liquid is clear, but a slight amount of precipitation occurs.
XX: The liquid is suspended, and some precipitates are observed.
XXX: The liquid is suspended, and significant precipitation is observed.

(Extent of formation of precipitates)
After each emulsified composition was stored at room temperature for 1 day, it was observed under a polarizing microscope, and the degree of deposit formation was evaluated according to the following criteria.
<Criteria for Determination of Degree of Precipitate Generation>
◯: No precipitate was observed.
x: Fine precipitates are observed.
XX: There are not many large precipitates, but many precipitates are observed.
XXX: A large number of large precipitates are observed.

(degree of phase separation)
After each emulsion composition was stored at 40° C. for 3 months, 50° C. for 1 month, and 60° C. for 2 weeks, 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 5, the degree of phase separation was not evaluated because precipitation and deposits were observed.
<Criteria for determination of degree of phase separation>
○: No phase separation between the oil phase and the water phase was observed at 40°C for 3 months and 50°C for 1 month, and almost no phase separation between the oil phase and the water phase was observed even at 60°C for 2 weeks. unacceptable.
x: Almost no phase separation between the oil phase and the water phase was observed under the conditions of 40°C for 3 months and 50°C for 1 month. However, phase separation between the oil phase and the water phase is clearly observed under the condition of 60° C. for 2 weeks.
XX: No phase separation between the oil phase and the water phase was observed under the conditions of 40°C for 3 months, but phase separation between the oil phase and the water phase was evident under the conditions of 50°C for 1 month and 60°C for 2 weeks. recognized by
XXX: Phase separation of the oil phase and the water phase is clearly observed under the conditions of 40°C for 3 months, 50°C for 1 month, and 60°C for 2 weeks.

[Test results]
Table 1 shows the results obtained. In the emulsified composition containing glycyrrhetinic acid and ufenamate but not containing diphenhydramine, formation of precipitates and deposits was significantly observed (Comparative Examples 1 to 4). In addition, in the emulsified composition containing glycyrrhetinic acid, ufenamate, and diphenhydramine but not wool wax alcohol, the formation of precipitates and deposits could be suppressed, but phase separation between the oil phase and the water phase could not be sufficiently suppressed. None (Comparative Examples 5 to 9).

On the other hand, in the emulsion composition containing glycyrrhizic acid or dipotassium glycyrrhizinate, ufenamate, diphenhydramine, and wool wax alcohol, the formation of precipitates and deposits can be suppressed, and phase separation of the oil phase and the water phase can be prevented. It was sufficiently suppressed (Examples 1 and 2).

Formulation Examples An oil-in-water emulsion composition having the composition shown in Table 2 was prepared. All of these formulations are emulsified compositions in which the formation of precipitates and deposits is suppressed, as in the case of the test examples.

Claims (4)

(A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, methyl glycyrrhizinate, stearyl glycyrrhizinate , and salts thereof; (B) ufenamate, (C) diphenhydramine and/or a salt thereof, and (D) wool wax alcohol, and is an oil-in-water emulsified composition (provided that it contains lidocaine and allantoin (unless it contains tocopherol acetate). 2. The emulsified composition of claim 1, comprising (E) a non-polar oil. 3. The emulsified composition according to claim 1, which is an external preparation for skin. (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, methyl glycyrrhizinate, stearyl glycyrrhizinate , and salts thereof, and (B) In an oil-in-water emulsion composition containing ufenamate (except when lidocaine is contained and when allantoin and tocopherol acetate are contained), formation of precipitates and precipitates, and phase separation of the oil phase and the aqueous phase A method for suppressing
(A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, methyl glycyrrhizinate, stearyl glycyrrhizinate , and salts thereof, and A method of blending (C) diphenhydramine and/or a salt thereof and (D) wool wax alcohol with (B) ufenamate.