JPH06287137A - External agent for skin containing sulfonium compound - Google Patents

Abstract

PURPOSE:To provide an external agent containing an antiallergic sulfonium compound and having excellent percutaneous absorption. CONSTITUTION:The external skin agent containing antiallergic sulfonium compound contains (i) the sulfonium compound, (ii) a water-soluble organic solvent exhibiting liquid state at normal temperature, (iii) an oily substance, (iv) purified water of pH 3-5.5 and (v) a surfactant, wherein the content of the sulfonic compound is 0.1-10wt.%.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a skin external preparation containing an antiallergic sulfonium compound.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 3-70698 discloses a general formula.

[Chemical 1] (In the formula, R ₁ and R ₂ are lower alkyl groups, R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a carboxyethylcarbonyloxy group, a benzoyloxy group,
Alkoxycarbonyloxy group, R ₄ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cycloalkyloxy group, a phenoxy group, a lower acyloxy group or a benzoyloxy group, n is an integer of 1 to 3 and Y is an acid residue, respectively) It is described that the sulfonium compound represented by the formula (1) has an antiallergic effect. In this publication, there are oral dosage forms, injection preparations, rectal suppositories, and inhalation dosage forms as the administration form of the sulfonium compound, but there is no description about administration as a skin external preparation. Unlike the above-mentioned systemic administration method using oral agents, injection agents, rectal suppositories, and inhalants, the external preparation for skin is an administration method in which the drug is delivered through the topical epidermis with a lesion, so that the amount of the drug can be reduced. Further, there is an advantage that it is possible to enhance the drug efficacy and reduce systemic side effects associated with the local increase in the drug concentration. However, formulation into an external preparation with good skin absorbability is not accompanied by significant difficulties, and even if an sulfonium compound, which is a medicinal substance, is added as an aqueous solution to an oily substance such as petrolatum and emulsified, it has good skin absorbability. No external preparation can be obtained.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an external preparation containing the sulfonium compound and having excellent skin absorbability.

[0004]

The present inventors have completed the present invention as a result of intensive studies to solve the above problems. That is, according to the present invention, in a skin external preparation containing an antiallergic sulfonium compound,
(I) the sulfonium compound, (ii) a water-soluble organic solvent which is liquid at room temperature, (iii) an oily substance, (iv) a pH of 3 to 5.
There is provided a sulfonium compound-containing external preparation for skin, comprising the purified water of 5 and (v) a surfactant, and the content of the sulfonium compound is in the range of 0.1 to 10 wt%. Further, according to the present invention, the antiallergic sulfonium compound is mixed in a liquid mixture comprising a water-soluble organic solvent which is liquid at room temperature, purified water having a pH of 3.5 to 5, a substance which is liquid at room temperature, and a surfactant. And a sulfonium compound content of 0.05 to 10
There is provided a sulfonium compound-containing external preparation for skin, which is in the range of wt%. Furthermore, according to the present invention, agent A comprising a solution of an antiallergic sulfonium compound dissolved in a water-soluble and oil-soluble organic solvent is prepared from a hot-melt mixture of a solid oily substance and a solid surfactant. After being added and mixed with the agent B, the agent C, which is a solution of the sulfonium compound in water, a water-soluble organic solvent or a mixed solution of water and a water-soluble organic solvent, is added and mixed, and if necessary, water and A method for producing a sulfonium compound-containing external preparation for skin, comprising adding and mixing a sticky agent and cooling.

The external preparation of the present invention, as its medicinal substance,
It contains a sulfonium compound represented by the above general formula.
In the above general formula, the acid residue represented by Y is
As long as it can be used as a medicine, hydrogen chloride,
Acid residues such as hydrogen iodide, hydrogen bromide, tetrafluoroboric acid, perchloric acid and phosphoric acid, and organics such as methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and 1,5-naphthalenedisulfonic acid Sulfonic acid residue and lactic acid, maleic acid,
Examples thereof include carboxylic acid residues such as malonic acid. The content of the sulfonium compound is 0.05 to 20 wt% in the total external preparation.
%, Preferably 0.5 to 10 wt%.

The external preparation of the present invention contains a water-soluble organic solvent which is soluble in the sulfonium compound. The organic solvent can be water-soluble as well as oil-soluble.
Such organic solvents include alcohols, alkanolamines, polyhydric alcohol partial esters, polyhydric alcohol partial ester alkylene oxide adducts, alcohol alkylene oxide adducts, alkylene glycol monoalkyl ethers, N-alkylpyrrolidones, N,
N-dialkylacetamide, dialkylimidazolidine, dialkyl sulfoxide, alkylene carbonate and the like are included. As the alcohol, a monohydric alcohol and / or a polyhydric alcohol is used. Examples of the monohydric alcohol include ethanol and lower alcohols such as propyl alcohol and butyl alcohol. As polyhydric alcohol, other than glycerin, sorbit, mannite,
Examples thereof include alkylene glycols such as ethylene glycol, propylene glycol and butylene glycol, and polyalkylene glycols such as polyethylene glycol, polypropylene glycol and poly (ethylene / propylene) glycol. The polyhydric alcohol is preferably used in the form of a mixture of alkylene glycol and polyalkylene glycol. In this polyhydric alcohol mixture, the proportion of polyalkylxylene glycol is from 10 to 10.
It is preferable to set it in the range of 25 wt%, preferably 15 to 20 wt%. Examples of the alkanolamine include diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dibutanolamine, tributanolamine and the like.

As a partial ester of polyhydric alcohol,
Monoesters of higher aliphatic carboxylic acids of various polyhydric alcohols as described above, for example, monostearic acid ester of glycerin, monobehenic acid ester of glycerin, monostearic acid ester of polyethylene glycol, monostearic acid ester of propylene glycol, butylene glycol. And monostearic acid ester of sorbitan, monolauric acid ester of sorbitan, monopalmitic acid ester of sorbitan, monostearic acid ester of sorbitan, monoisostearic acid ester of sorbitan, and the like.

As the alkylene oxide adduct of the partial ester of polyhydric alcohol, the ethylene oxide adduct or propylene oxide adduct of glycerin monostearate or the ethylene oxide adduct or propylene oxide of polyethylene glycol monostearate. Addition product, ethylene oxide addition product or propylene oxide addition product of propylene glycol monostearate ester, ethylene oxide addition product or propylene oxide addition product of polypropylene glycol monostearate ester, ethylene oxide addition product of propylene glycol monostearate ester or propylene Oxide adduct, sorbitan monofatty acid ester (lauric acid ester, palmitic acid ester, stearic acid ester Tel, oleic acid ester, etc.) ethylene oxide adduct or propylene oxide adduct, and batyl alcohol ethylene oxide adduct or propylene oxide adduct. Examples of the alkylene oxide adducts of alcohols include the ethylene oxide adducts or propylene oxide adducts of the above-mentioned monohydric or polyhydric alcohols.

As the above-mentioned N-alkylpyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N
-Butylpyrrolidone and the like, N, N-dimethylacetamide, N, N-dibutylacetamide and the like as N, N-dialkylacetamide, and dimethylsulfoxide, as dialkylsulfoxide,
Examples thereof include dibutyl sulfoxide, and examples of the alkylene carbonate include propylene carbonate and butylene carbonate.

The above-mentioned water-soluble organic solvent has the action of improving the skin permeability of the sulfonium compound dissolved in water and the action of uniformly dispersing the sulfonium compound dissolved in water in the oily substance. The content of the water-soluble organic solvent is 1 to 40% by weight based on the total external preparation. Further, these water-soluble organic solvents may be used in a proportion of 0.1 to 30 parts by weight, preferably 0.5 to 20 parts by weight, relative to 1 part by weight of the sulfonium compound.

The external preparation of the present invention contains an oily substance which is solid (including semi-solid) at room temperature. Such oily substances include fatty acid esters, aromatic carboxylic acid esters, phosphoric acid esters, higher fatty acid triglycerides, higher aliphatic alcohols, higher fatty acids, petrolatum, lanolin, beeswax, anionic self-emulsifying wax, nonionic self-emulsifying wax. Examples thereof include emulsifying wax and reduced lanolin.

As the fatty acid ester, myristyl myristate, methyl stearate, stearyl stearate, cetyl palmitate, cholesteryl stearate,
Methyl behenate, behenyl behenate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan distearate, sorbitan monobehenate, polyoxyethylene sorbitan tristearate, polyethylene glycol distearate, pentaerythritol mono Examples thereof include stearate, stearic acid monoglyceride, palmitic acid monoglyceride, oleic acid monoglyceride, behenic acid monoglyceride, behenyl methacrylate and stearyl methacrylate.

Examples of the aromatic carboxylic acid ester include distearyl phthalate, dicyclohexyl phthalate, diphenyl phthalate and dibehenyl phthalate. Examples of the phosphoric acid ester include lauryl phosphoric acid and stearyl phosphoric acid. The higher fatty acid triglyceride includes vegetable oils and fats and animal oils and fats. Examples thereof include hydrogenated jojoba oil, beef tallow fatty acid triglyceride, hydrogenated beef tallow fatty acid triglyceride, hydrogenated palm oil and fat fatty acid triglyceride, and the like. Examples of higher aliphatic alcohols include cetanol, stearyl alcohol, behenyl alcohol, lauryl alcohol and the like. Examples of the higher fatty acid include capric acid, lauric acid, tridecyl acid, myristic acid, palmitic acid, stearic acid, behenic acid, montanic acid, and elaidic acid. The amount of the oily substance that is solid at room temperature is not particularly limited, and an appropriate amount is added according to the desired form of the external preparation.

The external preparation of the present invention optionally contains an oily substance which is liquid at room temperature. Examples of such oily substances include fatty acid esters, aromatic carboxylic acid esters, phosphoric acid esters, higher fatty acid triglycerides (fats and oils), polyhydric alcohol esters, higher fatty acids, higher aliphatic alcohols, terpene alcohols and the like. The fatty acid ester has a total carbon number of 8 or more, preferably 12
The above is used. In the fatty acid ester, the alcohol component can be a monohydric or polyhydric alcohol. The monohydric alcohol may be a linear or branched aliphatic alcohol having 1 to 22 carbon atoms, preferably 2 to 18 carbon atoms. Further, the fatty acid component may be a linear or branched monovalent or divalent fatty acid having 4 to 22 carbon atoms, preferably 6 to 18 carbon atoms. These aliphatic alcohols and fatty acids may have an unsaturated bond. Specific examples of the alcohol component in the fatty acid ester include ethanol, propanol, isopropanol, butanol, hexanol, octanol, isooctanol, myristyl alcohol, dodecanol,
Examples include isododecanol, cetyl alcohol, hexadecyl alcohol, 2-ethylhexyl alcohol, 2-octyldodecanol and the like. Fatty acid components in the fatty acid ester include butyric acid, octanoic acid, nonanoic acid,
Capric acid, capric acid, myristic acid, palmitic acid,
In addition to monovalent fatty acids such as stearic acid, linolenic acid, linoleic acid and erucic acid, succinic acid, adipic acid, pimelic acid,
Examples thereof include suberic acid, azelaic acid, sebacic acid and dodecanedioic acid. Suitable fatty acid esters include, for example, ethyl myristate, isopropyl myristate,
Isotridecyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmitate, isopropyl butyrate, amyl butyrate, other monovalent fatty acid esters such as octyl butyrate, diethyl succinate, diisopropyl succinate, diethyl adipate, Diisopropyl adipate, diisooctyl adipate, dioctyl adipate, didecyl adipate,
Examples include decylisooctyl adipate, diethyl azelate, diisopropyl azelate, diisooctyl azelate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, dioctyl sebacate and the like. In the present invention, it is particularly preferable to use a lower alcohol ester of a monovalent or divalent fatty acid having 8 or more carbon atoms.

Examples of the aromatic carboxylic acid ester include dioctyl phthalate, didecyl phthalate, triisodecyl trimellitate and the like. Examples of the phosphate ester include trioleyl phosphate and tridecyl phosphate. As triglyceride, jojoba oil, macadamia nut oil, safflower oil, sunflower oil, avocado oil,
Examples include olive oil. As the polyhydric alcohol ester, sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyethylene glycol monolaurate, polyethylene glycol monooleate, olein. Examples thereof include acid monoglyceride, capric acid triglyceride, and polyoxyethylene sorbit monolaurate. As higher fatty acids, capric acid,
Examples thereof include linoleic acid, linolenic acid and arachidonic acid. Examples of the higher aliphatic alcohol include 2-octyldodecanol, 2-hexyldecanol, octyl alcohol, nonyl alcohol and decyl alcohol. As terpene alcohol, farnesol,
Examples include borneol, menthol, patchouli alcohol, phytol, and hinokiol. Furthermore, the external preparation of the present invention may contain squalane, terpenes, liquid paraffin, etc., if necessary.

The above-mentioned oily substance which is liquid at room temperature has the effect of improving the skin permeability of the sulfonium compound dissolved in water, and is mixed with an organic solvent to dissolve the sulfonium compound dissolved in water in the solid oily substance. It has the effect of evenly dispersing in. The amount of the oily substance that is liquid at room temperature is 1 to 20% by weight, preferably 3 to 10% by weight, based on the total external preparation.

Hydrocarbon-based terpenes can be preferably added to the external preparation of the present invention. As for this,
For example, limonene, myrcene, pinene, sapinen, etc. are mentioned. These terpenes have the effect of significantly reducing the peculiar odor of the sulfonium compound, and also show the effect of improving the skin absorbability of the sulfonium compound.
The content of the hydrocarbon terpene is 0.1 to 5 in the external preparation.
%, Preferably 0.5-2% by weight.

In addition to the above-mentioned components, the external preparation of the present invention may further contain a filler, a thickener, a coloring agent, an aromatic agent, water, if necessary.
Liquid paraffin, squalane, emulsion stabilizers, bactericides, fungicides and the like can be contained. As the filler, organic and inorganic fine powders are used. The particle size of this filler is usually 0.1 to 20 μm, preferably 0.5 to 1
It is 0 μm. Preferable examples of the filler include silica, alumina, tinania, resin powder silicate powder, clay powder, sepiolite powder, montmorillonite powder, fluorine-containing mica powder, hydroxypropylcellulose powder and the like. Examples of the thickener include various water-soluble polymers such as polyvinyl alcohol, sodium alginate, carboxyvinyl polymer and carboxymethyl cellulose.

The external preparation of the present invention contains a surfactant.
As the surfactant, various anionic, cationic, nonionic and amphoteric surfactants can be used, but from the viewpoint of mildness to the skin, the nonionic surfactant is advantageously used. To be Examples of the nonionic surfactant include ethylene oxide-based surfactants, polyhydroxy-based surfactants, polymer-based surfactants and the like. Examples of the ethylene oxide-based surfactant include ethylene oxide adducts of higher alcohols, ethylene oxide adducts of higher fatty acids, ethylene oxide adducts of alkylphenols, ethylene oxide adducts of fatty acid amines, ethylene oxide adducts of fatty acid amides, ethylene oxide adducts of polyhydric alcohols. And ethylene oxide / propylene oxide block copolymers. As the polyhydroxy surfactant, for example, glycerin mono fatty acid ester, pentaerythritol fatty acid ester,
Examples thereof include sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid amide of ethanolamine, and alkylene oxide adducts thereof. In the present invention, particularly, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl monofatty acid ester, polyoxypropylene monofatty acid ester, sorbitan fatty acid ester, polyoxyethylene alcohol ether and the like are advantageously used. These surfactants are used alone or in the form of a mixture. The blending amount of the surfactant is not particularly limited, and an appropriate amount is blended depending on the desired properties of the external drug.

The external preparation of the present invention contains purified water. The purified water has a pH of 3 to 5.5, preferably 3.5 to 4.
Adjust to the range of. If the pH of the purified water deviates from this range, the stability of the sulfonium compound will be impaired and the efficacy of the external preparation will be reduced. The pH of the purified water can be adjusted with a pH buffer solution such as a phosphate buffer solution. The amount of purified water blended is determined according to the desired properties of the external preparation, and is not particularly limited.

The external preparation of the present invention is applied in various forms such as an ointment, a cream and a lotion, and its composition is adjusted appropriately according to the form of the product. When the external preparation of the present invention is applied in the form of a non-emulsion type ointment-like mixture, the following component composition is preferable. (1) Sulfonium compound 0.05-20 wt%, preferably 0.5-10 wt% (2) Organic solvent 1-40 wt%, preferably 2-20 wt% (3) Oily substance 20-80 wt%, preferably 20- 60 wt% (4) Surfactant 20-80 wt%, preferably 40-70 wt% (5) Filler 0-15 wt%, preferably 5-10 wt% (6) Purified water 1-10 wt%, preferably 1-5 wt %

In the external preparation consisting of the non-emulsion type ointment mixture, a solid oily substance or a mixture of a solid oily substance and a liquid oily substance is used as the oily substance. In the case of this external preparation, it is necessary to contain a surfactant and / or an oily substance in a solid state at room temperature in an amount of 20 to 80 wt%, preferably 40 to 70 wt%.
Examples of the solid oily substance in this case include the above-mentioned various substances. The solid surface active agents include POE (5) glyceryl monostearate, POE (15) glyceryl monostearate and PO monostearate.
E (40) Polyoxyethylene glycerin fatty acid ester such as glyceryl, tetraglyceryl monostearate, tetraglyceryl tristearate, polyglycerin fatty acid ester such as decaglyceryl trioleate, glyceryl monomyristate, glyceryl monostearate, distearate Glycerin fatty acid ester such as diglyceryl, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquistearate, sorbitan trisstearate and the like, polyoxyethylene sorbitan tristearate POE (20) sorbitan, hexastearic acid Polyoxyethylene sorbit fatty acid ester such as POE (6) sorbit, monostearic acid PEG
(4EO), polyethylene glycol fatty acid ester such as polyethylene glycol distearate, POE (6
0) Polyethylene hydrogenated castor oil such as hydrogenated castor oil, POE (100) hydrogenated castor oil, polyoxyethylene alkyl ether such as POE (2) cetyl ether, POE (5) behenyl ether, and polyoxy such as POE (30) phytosterol Ethylene phytosterol, POE
(25) Polyoxyethylene phytostanol such as phytostanol, POE (20) POP (8) cetyl ether, POE (20) POP (6) decyltetradecyl ether and other polyoxyethylene polyoxypropylene alkyl ether, POE (30 ) Polyoxyethylene alkyl phenyl ether such as octyl phenyl ether, POE (40) lanolin alcohol, POE (1
0) Polyoxyethylene lanolin alcohol such as lanolin alcohol, POE (6) sorbit beeswax, PO
Examples thereof include polyoxyethylene beeswax derivatives such as E (20) sorbit beeswax, and polyoxyethylene alkyl ether phosphates such as diPOE (10) alkyl ether phosphate. Any of these solid surfactants can also be used as an oily substance. The external preparation is a solution prepared by dissolving a sulfonium compound in a mixed solution of purified water and an organic solvent, and a mixed molten solution of an oily substance and a surfactant that has been heated and melted, and then, if necessary. It can be prepared by adding a filler, mixing uniformly, and cooling.

When the external preparation of the present invention is applied in the form of an emulsion type ointment-like mixture, the following component composition is preferable. (1) Sulfonium compound 0.05-20 wt%, preferably 0.5-10 wt% (2) Organic solvent 1-40 wt%, preferably 2-20 wt% (3) Oily substance 60-90 wt%, preferably 75- 85 wt% (4) Surfactant 1-20 wt%, preferably 2-10 wt% (5) Filler 0-15 wt%, preferably 5-10 wt% (6) Purified water 1-10 wt%, preferably 2-5 wt% %

In the above external preparation, the oily substance is
A solid at room temperature or a mixture of a solid at room temperature and a liquid at room temperature is used. As the surfactant, one having an HLB of 2 to 15, preferably 3 to 12 is used. The external preparation is a solution prepared by dissolving a sulfonium compound in a mixed solution of water and an organic solvent under heating,
It can be prepared by gradually adding to a molten mixed liquid of an oily substance and a surfactant under stirring, mixing a filler if necessary, and cooling the resulting mixture.

When the external preparation of the present invention is applied in the form of an emulsion-type creamy mixture, the following component composition is preferable. (1) Sulfonium compound 0.05-20 wt%, preferably 0.5-10 wt% (2) Organic solvent 1-40 wt%, preferably 2-20 wt% (3) Oily substance 10-40 wt%, preferably 2- 20 wt% (4) Surfactant 10 to 35 wt%, preferably 15 to 30 wt% (5) Thickener (water-soluble polymer) 0 to 5 wt%, preferably 0.05 to 2 wt% (6) Purified water 30 -75 wt%, preferably 40-60 wt% (7) Filler 0-10 wt%, preferably 0.1-5 wt%

In order to produce the above-mentioned external preparation, the above-mentioned components (1), (2) and (6) are mixed under heating to prepare a mixture A. On the other hand, the components (3) and (4) are mixed under heating to form a molten mixture B. Next, the mixture A is gradually added to the molten mixture B under heating and stirring, and then the components (5) and (7) as necessary are added and mixed, followed by cooling. In this case, the external preparation can be an oil / water type emulsion and a water / oil type emulsion. In the case of the oil / water type, a surfactant having HLB 9 to 18 is preferably used as the surfactant, and in the case of the water / oil type, the surfactant having HLB 2 to 8 is preferably used. As the oily substance, a solid substance at normal temperature or a mixture of a solid substance at normal temperature and a liquid substance at normal temperature is used. As the thickener, a water-soluble polymer, for example, carboxyvinyl polymer, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium alginate, propylene glycol alginate, chitosan, polyvinyl alcohol, sodium starch glycolate, polyvinyl. Examples thereof include pyrrolidone, polyacrylic acid, polyacrylic acid ester, polymethacrylic acid, polymethacrylic acid ester and the like.

In order to preferably produce the external preparation comprising the above creamy mixture, the agent A comprising a solution prepared by dissolving the sulfonium compound of the component (1) in the water-soluble and oil-soluble organic solvent of the component (2). Is added to the agent B which is a hot melt mixture of the solid oily substance of the component (3) or the solid oily substance, the liquid oily substance and the solid surfactant of the component (4), and then the sulfonium compound is added. The agent C, which is a solution of water, a water-soluble organic solvent or a mixed solution of water and a water-soluble organic solvent, is added and mixed. In these mixing steps, the temperature of the hot melt of the solid oily substance at room temperature and the solid surfactant at room temperature is kept above the melting point of those substances so that these substances do not precipitate as solids. warn. Next, if necessary, water of the component (6) and a thickener of the component (5) are added to and mixed with the mixed liquid obtained as described above, and if necessary, a filler of the component (7). Is mixed and cooled. In this case, the thickener of component (5) is preferably added after the addition of water of component (6), but it can be dissolved in water of component (6) in advance and added at the same time as water. In addition, in the water of the component (6), other water-soluble substances such as an ultraviolet absorber such as oxybenzone (2-hydroxy-4-methoxybenzophenone) as a product stabilizer, urea as a moisturizer, or a large amount of water. It is also possible to dissolve the polyhydric alcohol in advance. The amount of these substances added to water is 5 to 20 wt% in the total external preparation.
%, Preferably 5 to 10 wt%.
Further, it is preferable that the pH of the water of the component (6) is kept in the range of 3 to 5.5, and it is preferable to use a phosphate buffer as the pH-adjusted water.

The above-mentioned agent A preferably contains at least one oil-soluble liquid oily substance selected from higher aliphatic alcohols and terpene alcohols in order to improve its oil solubility. Further, the agent C preferably contains at least one selected from lower aliphatic alcohols and polyhydric alcohols in order to improve its water solubility. A
The total amount of the agent and the agent B is 2 to 40 wt%, preferably 10 to 30 wt% in the total external preparation. The ratio of the A agent to the total amount of the A agent and the B agent is 20 to 80 wt%, preferably 30 to 60 wt%. In the external preparation consisting of the creamy mixture obtained as described above, the sulfonium compound content is 3 wt% or more, particularly 5 wt%.
%, The sulfonium compound is uniformly and stably dispersed in the whole mixture in a state of being dissolved in an organic solvent, and is maintained in a state of being easily absorbed by the skin.

When the external preparation of the present invention is applied in the form of a solution type lotion, it is preferable that it has the following component composition. (1) Sulfonium compound 0.01 to 20 wt%, preferably 0.5 to 10 wt% (2) Organic solvent 2 to 40 wt%, preferably 10 to 30 wt% (3) Liquid oily substance 0 to 30 wt%, preferably 0 -20 wt% (4) Surfactant 0.1-20 wt%, preferably 0.5-7 wt% (5) Water 1-60 wt%, preferably 5-40 wt% (6) Thickener 0-5 wt%, Preferably 0.05-1 wt%

The external preparation is prepared by dissolving the sulfonium compound of component (1) in a mixed solution of the organic solvent of component (2) and water of component (5) to prepare a solution. ), Component (4) and component (6) are added and mixed. This lotion type can be applied as a liquid lotion as it is, or can be used as an aerosol type lotion by filling an aerosol can with a propellant such as liquefied natural gas.
As the thickener, a polymer soluble in an organic solvent and / or water is used.

[0031]

In the administration of the external preparation of the present invention, the external preparation is directly applied to the affected area several times a day, for example, 1 to 3 times, or processed into the form of a patch, plaster, pap, etc., This can likewise be applied several times a day to the affected area. The number of times of application can be appropriately increased or decreased depending on the severity of the disease. In the external preparation of the present invention, the sulfonium compound is uniformly dispersed in the oily substance in the form of a mixture with liquid water and an organic solvent. Therefore, the external preparation of the present invention has a high skin permeability, and exhibits excellent therapeutic effect on allergic skin diseases only by applying it to the skin of the lesion. Further, the external preparation of the present invention has no skin irritation or low skin irritation, and is very excellent in safety. The external preparation of the present invention is based on the pharmacological action of the sulfonium compound contained therein,
It shows various medicinal effects. This medicinal effect includes various medicinal effects such as an antiallergic effect, an effect that enhances the immune system of the living body, an immunomodulatory effect, an antiphlogistic and analgesic effect, an infection protective effect, and an anticancer effect.

[0032]

EXAMPLES Next, the present invention will be described in more detail by way of examples. All parts and% shown below are based on weight. Example 1 (1) IPD-1151T 0.5 part (2) Butylene glycol 5 parts (3) Methylparaben 0.1 part (4) Purified water (phosphate buffer solution, pH 3.5 to 4.5) 52 parts ( 5) Carboxyvinyl polymer 0.1 part (6) Isopropyl myristate 4.0 parts (7) Isotridecyl myristate 5.0 parts (8) Diethyl sebacate 3.0 parts (9) Behenyl alcohol 3.0 parts (10) Squalene 3.0 parts (11) Olive oil 7.0 parts (12) Whale wax 5.0 parts (13) POE monostearate (5) Glyceryl 2.0 parts (14) Sorbitan monostearate 2.0 parts (15) ) Polyoxyethylene (2) lauryl ether 0.2 part (16) PEG stearate (40) 2.0 parts (17) Farnesol 1.0 part (18) Steer 5.0 parts phosphate (19) Propylparaben 0.1 parts

The above components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. Meanwhile, the components (6) to (19) were heated at 60 ° C. and uniformly mixed to prepare a mixture B. Next, the mixture A is emulsified by adding the mixture A little by little thereto while vigorously stirring the mixture B under heating. When mixture A has been added, heating is stopped, the whole is left to cool and a creamy product is obtained.

Example 2 (1) IPD-1151T 5 parts (2) Butylene glycol 120 parts (3) Purified water (phosphate buffer solution, pH about 4.5) 374 parts (4) Methylparaben 1 part (5) Myristin Isopropyl isopropylate 40 parts (6) Isotridecyl myristate 30 parts (7) Squalene 30 parts (8) White petrolatum 300 parts (9) Stearyl alcohol 50 parts (10) POE (60) Hardened castor oil 40 parts (11) Monostearic acid Glyceryl 10 parts

The above components (1) to (4) were uniformly mixed under heating at 70 ° C. or lower to prepare a solution-like mixture A. On the other hand, the components (5) to (11) were heated at 60 ° C. and uniformly mixed to prepare a mixture B. Next, the mixture A is emulsified by adding the mixture A little by little thereto while vigorously stirring the mixture B under heating. When mixture A has been added, heating is stopped, the whole is left to cool and a creamy product is obtained.

Example 3 (1) IPD-1151T 0.5 part (2) Propylene carbonate 1.3 parts (3) 1,3-Butanediol (butylene glycol) 1.0 part (4) Purified water (phosphoric acid Buffer solution, pH about 4.5) 1.0 part (5) white petrolatum 91.5 parts (6) sorbitan monostearate 2.0 parts (7) polyethylene glycol monostearate (40EO) 0.5 parts (8) ) Stearyl alcohol 2.0 parts

The above components (1) to (4) were uniformly mixed under heating at 70 ° C. or lower to prepare a mixture A in the form of a solution. On the other hand, the components (5) to (8) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, the mixture B is added thereto little by little while being heated and vigorously stirred. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 4 (1) IPD-1151T 0.5 part (2) Polyethylene glycol (molecular weight 400) 3.0 parts (3) Purified water (phosphate buffer solution, pH about 4.5) 5.0 parts (4) Isoprene glycol 4.0 parts (5) Butylene glycol 3.0 parts (6) Carboxycellulose 0.7 part (7) Monostearate POE (5) Glyceryl 0.5 part (8) Monooleate POE ( 20) sorbitan 1.0 part (9) sorbitan sesquioleate 3.0 parts (10) stearyl alcohol 2.0 parts (11) white petrolatum 77.1 parts (12) methylparaben 0.1 part (13) propylparaben 0 1st copy

The components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. On the other hand, the components (6) to (12) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, the mixture B is added thereto little by little while being heated and vigorously stirred. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 5 (1) IPD-1151T 0.5 part (2) Polyethylene glycol (molecular weight 400) 3.0 parts (3) Purified water (phosphate buffer, pH about 4.5) 5.0 parts (4) Isoprene glycol 4.0 parts (5) Butylene glycol 3.0 parts (6) Carboxycellulose 0.7 part (7) Monostearate POE (5) Glyceryl 0.5 part (8) Monooleate POE ( 20) sorbitan 1.0 part (9) sorbitan sesquioleate 3.0 parts (10) stearyl alcohol 2.0 parts (11) diisopropyl adipate 2.0 parts (12) white petrolatum 74.6 parts (13) sebacine Diethyl acid 0.5 part (14) Methylparaben 0.1 part (15) Propylparaben 0.1 part

The components (1) to (5) were uniformly mixed under heating at 70 ° C. or lower to prepare a solution-like mixture A. On the other hand, the components (6) to (15) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, the mixture B is added thereto little by little while being heated and vigorously stirred. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 6 (1) IPD-1151T 0.5 part (2) Propylene carbonate 0.3 part (3) Ethylene carbonate 0.7 part (4) Butylene glycol 1.0 part (5) Purified water (phosphorus Acid buffer, pH about 3.0) 1.0 part (6) White petrolatum 90.5 parts (7) Sorbitan monostearate 2.0 parts (8) PEG monostearate (40EO) 0.5 parts (9) ) Stearyl alcohol 2.0 parts

The above components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. On the other hand, the components (6) to (9) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, the mixture B is added thereto little by little while being heated and vigorously stirred. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 7 (A agent) (1) IPO-1151T 0.2 part (2) Propylene carbonate 1.0 part (B agent) (3) Dibutyl adipate 3.0 parts (4) Diethyl sebacate 2 0.0 parts (5) Isopropyl myristate 2.0 parts (6) Cetanol 3.0 parts (7) Cetyl palmitate 4.0 parts (8) Stearic acid 5.0 parts (9) Macadamia nut oil 5.0 parts ( 10) Squalene 3.0 parts (11) POE (5) glyceryl monostearate 2.0 parts (12) PEG (40EO) stearate 2.0 parts (13) Sorbitan monostearate 2.0 parts (14) Propyl Paraben 0.1 part (C agent) (15) IPD-1151T 0.3 part (16) Propylene glycol 2.0 part (17) Purified water (phosphate buffer solution) (pH 3.5 to 4.5) 60.8 parts (18) Methylparaben 0.1 part (19) Urea 2.0 parts (D agent) (20) Carboxyvinyl polymer 0.5 parts

Components (3) to (14) are dissolved and mixed at 80 ° C. and then cooled to 65 ° C. to prepare agent B. Components (1) and (2) are dissolved in agent B at 60 ° C. A obtained by mixing
After adding and mixing the agents, the components (15) to (19) are added at 60 ° C.
The agent C obtained by dissolving and mixing in (1) is added and mixed, and finally the component (2
The agent D consisting of 0) was added and mixed, and the whole was cooled to obtain a creamy product.

The IPD-shown in the above embodiment is used.
1151T is a sulfonium compound represented by the following formula.

[Chemical 2]

Example 7 A reddish brown papule accompanied by marked pruritus was found on the trunk (anterior chest, abdomen), bleeding due to partial scratching was observed, and lichenification on the flexor side of the elbow joint node was observed. For a boy with an age of 8 years old,
The creamy product obtained in Example 1 was rubbed twice a day,
Continuing every day, the reddish brown papules disappeared from the 2nd to 3rd day, and pruritus decreased, and after 1 week, a slightly dry skin surface became visible, and a skin surface improvement effect was observed. It was

Example 8 The creamy product obtained in Example 1 was applied to the shoulder and back of a 5-year-old boy with atopic dermatitis by rubbing twice a day and continuing from the second day. The effect of improving dermatitis was recognized. The skin properties were improved and the dryness and desquamation were alleviated.

Example 9 A three-year-old boy with atopic dermatitis was continuously rubbed twice daily with the creamy product obtained in Example 1,
From the 2nd to 3rd days, an improving effect on dermatitis was observed. The skin properties were improved and the dryness and desquamation were alleviated. It should be noted that this patient had been using Kinderbate and Linderon VG for a long time, but it was confirmed that the product of the present invention exhibits the same or greater effect as those.

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[Procedure amendment]

[Submission date] July 23, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

[Title of Invention] External preparation for skin containing sulfonium compound

[Claims]

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a skin external preparation containing an antiallergic sulfonium compound.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 3-70698 discloses a general formula.

[Chemical 1] (In the formula, R ₁ and R ₂ are lower alkyl groups, R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a carboxyethylcarbonyloxy group, a benzoyloxy group,
Alkoxycarbonyloxy group, R ₄ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cycloalkyloxy group, a phenoxy group, a lower acyloxy group or a benzoyloxy group, n is an integer of 1 to 3 and Y is an acid residue, respectively) It is described that the sulfonium compound represented by the formula (1) has an antiallergic effect. In this publication, a dosage form of the sulfonium compounds, oral agents, injections, suppository rectal
Although there is a description about the agent and inhalant, there is no description about the administration as an external preparation for skin. Unlike the above-mentioned systemic administration method using oral agents, injection agents, rectal suppositories, and inhalants, the external preparation for skin is an administration method in which a drug is delivered through a localized epidermis with a lesion, so that the amount of the drug can be reduced. In addition, there is an advantage that the drug effect can be enhanced and systemic side effects can be reduced due to the local increase in drug concentration. However, formulation into an external preparation with good skin absorbability is not accompanied by significant difficulties, and even if an sulfonium compound, which is a medicinal substance, is added as an aqueous solution to an oily substance such as petrolatum and emulsified, it has good skin absorbability. No external preparation can be obtained.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an external preparation containing the sulfonium compound and having excellent skin absorbability.

[0004]

The present inventors have completed the present invention as a result of intensive studies to solve the above problems. That is, according to the present invention, in a skin external preparation containing an antiallergic sulfonium compound,
(I) the sulfonium compound, (ii) a water-soluble organic solvent which is liquid at room temperature, (iii) an oily substance, (iv) a pH of 3 to 5.
There is provided a sulfonium compound-containing external preparation for skin, comprising the purified water of (5) and (v) a surfactant, and the content of the sulfonium compound is in the range of 0.1 to 20 % by weight . Further, according to the present invention, the antiallergic sulfonium compound is mixed in a liquid mixture comprising a water-soluble organic solvent which is liquid at room temperature, purified water having a pH of 3.5 to 5, a substance which is liquid at room temperature, and a surfactant. And a sulfonium compound content of 0.05 to 20.
There is provided a skin external preparation containing a sulfonium compound, which is characterized by being in the range of wt %. Furthermore, according to the present invention, agent A comprising a solution of an antiallergic sulfonium compound dissolved in a water-soluble and oil-soluble organic solvent is prepared from a hot-melt mixture of a solid oily substance and a solid surfactant. After being added and mixed with the agent B, the agent C, which is a solution of the sulfonium compound in water, a water-soluble organic solvent or a mixed solution of water and a water-soluble organic solvent, is added and mixed, and if necessary, water and A method for producing a sulfonium compound-containing external preparation for skin, comprising adding and mixing a sticky agent and cooling.

The external preparation of the present invention, as its medicinal substance,
It contains a sulfonium compound represented by the above general formula.
In the above general formula, the acid residue represented by Y is
As long as it can be used as a medicine, hydrogen chloride,
Acid residues such as hydrogen iodide, hydrogen bromide, tetrafluoroboric acid, perchloric acid and phosphoric acid, and organics such as methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and 1,5-naphthalenedisulfonic acid Sulfonic acid residue and lactic acid, maleic acid,
Examples thereof include carboxylic acid residues such as malonic acid. The content of the sulfonium compound in the total external preparation is 0.05 to 20% by weight , preferably 0.5 to 10% by weight .

The external preparation of the present invention contains a water-soluble organic solvent which is soluble in the sulfonium compound. The organic solvent can be water-soluble as well as oil-soluble.
Such organic solvents include alcohols, alkanolamines, polyhydric alcohol partial esters, polyhydric alcohol partial ester alkylene oxide adducts, alcohol alkylene oxide adducts, alkylene glycol monoalkyl ethers, N-alkylpyrrolidones, N,
N-dialkylacetamide, dialkylimidazolidine, dialkyl sulfoxide, alkylene carbonate and the like are included. As the alcohol, a monohydric alcohol and / or a polyhydric alcohol is used. As monohydric alcohols, ethanol, propanol, isopropanol,
Lower alcohols such as butanol may be mentioned. Examples of the polyhydric alcohol include glycerin, sorbitol, mannitol, alkylene glycol such as ethylene glycol, propylene glycol, butylene glycol, and polyalkylene glycol such as polyethylene glycol, polypropylene glycol, poly (ethylene / propylene) glycol, and the like. To be The polyhydric alcohol is preferably used in the form of a mixture of alkylene glycol and polyalkylene glycol. In this polyhydric alcohol mixture, the proportion of polyalkylene glycol is 10
-25% by weight , preferably 15-20% by weight . Examples of the alkanolamine include diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dibutanolamine, tributanolamine and the like.

As a partial ester of polyhydric alcohol,
Monoesters of higher aliphatic carboxylic acids of various polyhydric alcohols as described above, for example, monostearic acid ester of glycerin, monobehenic acid ester of glycerin, monostearic acid ester of polyethylene glycol, monostearic acid ester of propylene glycol, butylene glycol. And monostearic acid ester of sorbitan, monolauric acid ester of sorbitan, monopalmitic acid ester of sorbitan, monostearic acid ester of sorbitan, monoisostearic acid ester of sorbitan, and the like.

As the alkylene oxide adduct of the partial ester of polyhydric alcohol, the ethylene oxide adduct or propylene oxide adduct of glycerin monostearate or the ethylene oxide adduct or propylene oxide of polyethylene glycol monostearate. Addition product, ethylene oxide addition product or propylene oxide addition product of propylene glycol monostearate ester, ethylene oxide addition product or propylene oxide addition product of polypropylene glycol monostearate ester, ethylene oxide addition product of propylene glycol monostearate ester or propylene Oxide adduct, sorbitan monofatty acid ester (lauric acid ester, palmitic acid ester, stearic acid ester And propylene oxide), ethylene oxide adducts or propylene oxide adducts, and monostearic acid ester ethylene oxide adducts or propylene oxide adducts of batyl alcohol. Examples of the alkylene oxide adducts of alcohols include the ethylene oxide adducts or propylene oxide adducts of the above-mentioned monohydric or polyhydric alcohols.

As the above-mentioned N-alkylpyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N
-Butylpyrrolidone and the like, N, N-dimethylacetamide, N, N-dibutylacetamide and the like as N, N-dialkylacetamide, and dimethylsulfoxide, as dialkylsulfoxide,
Examples thereof include dibutyl sulfoxide, and examples of the alkylene carbonate include propylene carbonate and butylene carbonate.

The above-mentioned water-soluble organic solvent has the action of improving the skin permeability of the sulfonium compound dissolved in water and the action of uniformly dispersing the sulfonium compound dissolved in water in the oily substance. The content of the water-soluble organic solvent is 1 to 40% by weight based on the total external preparation. Further, these water-soluble organic solvents may be used in a proportion of 0.1 to 30 parts by weight, preferably 0.5 to 20 parts by weight, relative to 1 part by weight of the sulfonium compound.

The external preparation of the present invention contains an oily substance which is solid (including semi-solid) at room temperature. Such oily substances include fatty acid esters, aromatic carboxylic acid esters, phosphoric acid esters, higher fatty acid triglycerides, higher aliphatic alcohols, higher fatty acids, petrolatum, lanolin, beeswax, anionic self-emulsifying wax, nonionic self-emulsifying wax. Emulsifying wax, reduced lanolin , polyglyceride
And the like.

As the fatty acid ester, myristyl myristate, methyl stearate, stearyl stearate, cetyl palmitate, cholesteryl stearate,
Methyl behenate, behenyl behenate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan distearate, sorbitan monobehenate, polyoxyethylene sorbitan tristearate, polyethylene glycol distearate, pentaerythritol mono Examples thereof include stearate, stearic acid monoglyceride, palmitic acid monoglyceride, oleic acid monoglyceride, behenic acid monoglyceride, behenyl methacrylate and stearyl methacrylate.

Examples of the aromatic carboxylic acid ester include distearyl phthalate, dicyclohexyl phthalate, diphenyl phthalate and dibehenyl phthalate. Examples of the phosphoric acid ester include lauryl phosphoric acid and stearyl phosphoric acid. The higher fatty acid triglyceride includes vegetable oils and fats and animal oils and fats. Examples thereof include hydrogenated jojoba oil, beef tallow fatty acid triglyceride, hydrogenated beef tallow fatty acid triglyceride, hydrogenated palm oil and fat fatty acid triglyceride, and the like. Examples of higher aliphatic alcohols include cetanol, stearyl alcohol, behenyl alcohol, lauryl alcohol , and cetos.
Tearyl alcohol, 2-octyldodecanol, 2-
Hexyldecanol or the like or a mixture thereof can be used. As the higher fatty acid, capric acid, lauric acid, tridecyl acid, millimeter cystine acid, palmitic acid, stearic acid, behenic acid, montanic acid, and elaidic acid. The amount of the oily substance that is solid at room temperature is not particularly limited, and an appropriate amount is added according to the desired form of the external preparation.

The external preparation of the present invention optionally contains an oily substance which is liquid at room temperature. Examples of such oily substances include fatty acid esters, aromatic carboxylic acid esters, phosphoric acid esters, higher fatty acid triglycerides (fats and oils), polyhydric alcohol esters, higher fatty acids, higher aliphatic alcohols, terpene alcohols and the like. The fatty acid ester has a total carbon number of 8 or more, preferably 12
The above is used. In the fatty acid ester, the alcohol component can be a monohydric or polyhydric alcohol. The monohydric alcohol may be a linear or branched aliphatic alcohol having 1 to 22 carbon atoms, preferably 2 to 18 carbon atoms. Further, the fatty acid component may be a linear or branched monovalent or divalent fatty acid having 4 to 22 carbon atoms, preferably 6 to 18 carbon atoms. These aliphatic alcohols and fatty acids may have an unsaturated bond. Specific examples of the alcohol component in the fatty acid ester include ethanol, propanol, isopropanol, butanol, hexanol, octanol, isooctanol, myristyl alcohol, dodecanol,
Examples include isododecanol, cetyl alcohol, hexadecyl alcohol, 2-ethylhexyl alcohol, 2-octyldodecanol and the like. Fatty acid components in the fatty acid ester include butyric acid, octanoic acid, nonanoic acid,
Capric acid, capric acid, myristic acid, palmitic acid,
In addition to monovalent fatty acids such as stearic acid, linolenic acid, linoleic acid and erucic acid, succinic acid, adipic acid, pimelic acid,
Examples thereof include suberic acid, azelaic acid, sebacic acid and dodecanedioic acid. Suitable fatty acid esters include, for example, ethyl myristate, isopropyl myristate,
Isotridecyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmitate, isopropyl butyrate, amyl butyrate, other monovalent fatty acid esters such as octyl butyrate, diethyl succinate, diisopropyl succinate, diethyl adipate, Diisopropyl adipate, diisooctyl adipate, dioctyl adipate, didecyl adipate,
Examples include decylisooctyl adipate, diethyl azelate, diisopropyl azelate, diisooctyl azelate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, dioctyl sebacate and the like. In the present invention, it is particularly preferable to use a lower alcohol ester of a monovalent or divalent fatty acid having 8 or more carbon atoms.

Examples of the aromatic carboxylic acid ester include dioctyl phthalate, didecyl phthalate, triisodecyl trimellitate and the like. Examples of the phosphate ester include trioleyl phosphate and tridecyl phosphate. As triglyceride, jojoba oil, macadamia nut oil, safflower oil, sunflower oil, avocado oil,
Examples include olive oil , soybean oil, rapeseed oil, cottonseed oil and the like.
As the polyhydric alcohol ester, sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate,
Examples thereof include polyethylene glycol monolaurate, polyethylene glycol monooleate, oleic acid monoglyceride, capric acid triglyceride, and polyoxyethylene sorbitol monolaurate. Examples of higher fatty acids include capric acid, linoleic acid, linolenic acid, arachidonic acid and the like. Examples of the higher aliphatic alcohol include 2-octyldodecanol, 2-hexyldecanol, octyl alcohol, nonyl alcohol and decyl alcohol. Examples of the terpene alcohol include farnesol, borneol, menthol, patchouli alcohol, phytol, hinokiol and the like. Furthermore, the external preparation of the present invention may contain squalane, terpenes, liquid paraffin, etc., if necessary.

The above-mentioned oily substance which is liquid at room temperature has the effect of improving the skin permeability of the sulfonium compound dissolved in water, and is mixed with an organic solvent to dissolve the sulfonium compound dissolved in water in the solid oily substance. It has the effect of evenly dispersing in. The amount of the oily substance that is liquid at room temperature is 1 to 20% by weight, preferably 3 to 10% by weight, based on the total external preparation.

Hydrocarbon-based terpenes can be preferably added to the external preparation of the present invention. As for this,
For example, limonene, myrcene, pinene, sapinen, etc. are mentioned. These terpenes have the effect of significantly reducing the peculiar odor of the sulfonium compound, and also show the effect of improving the skin absorbability of the sulfonium compound.
The content of the hydrocarbon terpene is 0.1 to 5 in the external preparation.
%, Preferably 0.5-2% by weight.

In addition to the above-mentioned components, the external preparation of the present invention may further contain a filler, a thickener, a coloring agent, an aromatic agent, water, if necessary.
Liquid paraffin, disk Wa orchid, emulsion stabilizers, fungicides, can contain fungicide. As the filler, organic and inorganic fine powders are used. The particle size of this filler is usually 0.1 to 20 μm, preferably 0.5 to 1
It is 0 μm. Preferable examples of the filler include silica, alumina, tinania, resin powder , silicate powder, clay powder, sepiolite powder, montmorillonite powder, fluorine-containing mica powder, hydroxypropylcellulose powder and the like. Examples of the thickener include various water-soluble polymers such as polyvinyl alcohol, sodium alginate, carboxyvinyl polymer and carboxymethyl cellulose. Antifungal agents include, for example, methylpara
Ben, propylparaben, etc. are mentioned.

The external preparation of the present invention contains a surfactant.
As the surfactant, various anionic, cationic, nonionic and amphoteric surfactants can be used, but from the viewpoint of mildness to the skin, the nonionic surfactant is advantageously used. To be Examples of the nonionic surfactant include ethylene oxide-based surfactants, polyhydroxy-based surfactants, polymer-based surfactants and the like. Examples of the ethylene oxide-based surfactant include ethylene oxide adducts of higher alcohols, ethylene oxide adducts of higher fatty acids, ethylene oxide adducts of alkylphenols, ethylene oxide adducts of fatty acid amines, ethylene oxide adducts of fatty acid amides, ethylene oxide adducts of polyhydric alcohols. And ethylene oxide / propylene oxide block copolymers. As the polyhydroxy surfactant, for example, glycerin mono fatty acid ester, pentaerythritol fatty acid ester,
Examples thereof include sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid amide of ethanolamine, and alkylene oxide adducts thereof. In the present invention, particularly, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl monofatty acid ester, polyoxypropylene monofatty acid ester, sorbitan fatty acid ester, polyoxyethylene alcohol ether and the like are advantageously used. These surfactants are used alone or in the form of a mixture. The blending amount of the surfactant is not particularly limited, and an appropriate amount is blended depending on the desired properties of the external drug.

The external preparation of the present invention contains purified water. This
The purified water of pH has a pH of 3 to 5.5, preferably 3.5 to
Adjust to the range of 4. If the pH of the purified water deviates from this range, the stability of the sulfonium compound will be impaired and the efficacy of the external preparation will be reduced. The pH of the purified water can be adjusted with a pH buffer solution such as a phosphate buffer solution. The amount of purified water blended is determined according to the desired properties of the external preparation, and is not particularly limited.

The external preparation of the present invention is applied in various forms such as an ointment, a cream and a lotion, and its composition is adjusted appropriately according to the form of the product. When the external preparation of the present invention is applied in the form of a non-emulsion type ointment-like mixture, the following component composition is preferable. (1) Sulfonium compound 0.05 to 20% by weight , preferably 0.5 to 10% by weight (2) Organic solvent 1 to 40% by weight , preferably 2 to 20% by weight (3) Oily substance 20 to 80% by weight , Preferably 20 to 60% by weight (4) surfactant 20 to 80% by weight , preferably 40 to 70% by weight (5) filler 0 to 15% by weight , preferably 5 to 10% by weight (6) purified water 1 to 10% by weight , preferably 1 to 5% by weight

[0022] In the external preparation consisting of an ointment-like mixture of the non-emulsion type, the oily substance, a mixture of solid oily substance or a solid oily substance and liquid oil substance is Ru is used. Examples of the solid oily substance in this case include the above-mentioned various substances. Examples of solid surfactants include polyoxyethylene glycerin fatty acid esters such as POE (5) glyceryl monostearate, POE (15) glyceryl monostearate and POE (40) glyceryl monostearate, and tetraglyceryl monostearate. Polyglycerin fatty acid ester such as triglyceryl tristearate and decaglyceryl trioleate, glyceryl monomyristate, glyceryl monostearate, glyceryl fatty acid ester such as diglyceryl distearate, sorbitan monopalmitate, sorbitan monostearate, sesquistearin Sorbitan acid, sorbitan fatty acid esters such as sorbitan trisstearate, POE tris stearate (2
0) Polyoxyethylene sorbitan such as sorbitan, polyoxyethylene sorbit fatty acid ester such as POE (6) sorbit hexastearate, PEG monostearate (4EO), polyethylene glycol fatty acid ester such as polyethylene glycol distearate, P
OE (60) hydrogenated castor oil, POE (100) hydrogenated castor oil and other polyethylene hydrogenated castor oil, POE (2) cetyl ether, POE (5) behenyl ether and other polyoxyethylene alkyl ethers, POE (30) phytosterol and the like Polyoxyethylene phytosterol,
Polyoxyethylene phytostanol such as POE (25) phytostanol, POE (20) POP (8) cetyl ether, POE (20) POP (6) decyl tetradecyl ether and other polyoxyethylene polyoxypropylene alkyl ether, POE ( 30) Polyoxyethylene alkyl phenyl ethers such as octyl phenyl ether, POE (40) lanolin alcohol, POE
(10) Polyoxyethylene lanolin alcohol such as lanolin alcohol, POE (6) sorbit beeswax,
Examples thereof include polyoxyethylene beeswax derivatives such as POE (20) sorbit beeswax, and polyoxyethylene alkyl ether phosphates such as diPOE (10) alkyl ether phosphate. Any of these solid surfactants can also be used as an oily substance. The external preparation is a solution prepared by dissolving a sulfonium compound in a mixed solution of purified water and an organic solvent, and a mixed molten solution of an oily substance and a surfactant that has been heated and melted, and then, if necessary. It can be prepared by adding a filler, mixing uniformly, and cooling.

When the external preparation of the present invention is applied in the form of an emulsion type ointment-like mixture, the following component composition is preferable. (1) Sulfonium compound 0.05 to 20% by weight , preferably 0.5 to 10% by weight (2) Organic solvent 1 to 40% by weight , preferably 2 to 20% by weight (3) Oily substance 60 to 97.5 % By weight , preferably 75-95 % by weight (4) Surfactant 1-20% by weight , preferably 2-10% by weight (5) Filler 0-15% by weight , preferably 5-10% by weight (6) Purified water 0.5 to 10 % by weight , preferably 1 to 5 % by weight

In the above external preparation, the oily substance is
A solid at room temperature or a mixture of a solid at room temperature and a liquid at room temperature is used. As the surfactant, one having an HLB of 2 to 15, preferably 3 to 12 is used. The external preparation is a solution prepared by dissolving a sulfonium compound in a mixed solution of water and an organic solvent under heating,
It can be prepared by gradually adding to a molten mixed liquid of an oily substance and a surfactant under stirring, mixing a filler if necessary, and cooling the resulting mixture.

When the external preparation of the present invention is applied in the form of an emulsion-type creamy mixture, the following component composition is preferable. (1) Sulfonium compound 0.05 to 20 wt %, preferably 0.5 to 10 wt % (2) Organic solvent 1 to 40 wt %, preferably 2 to 20 wt % (3) Oily substance 10 to 50 wt % , Preferably 15 to 45 % by weight (4) surfactant 1 to 35 % by weight , preferably 2 to 20 % by weight (5) thickener (water-soluble polymer) 0 to 5% by weight , preferably 0.05 ~ 2 wt % (6) Purified water 25-75 wt %, preferably 30-70 wt % (7) Filler 0-10 wt %, preferably 0.1-5 wt %

In order to produce the above-mentioned external preparation, the above-mentioned components (1), (2) and (6) are mixed under heating to prepare a mixture A. On the other hand, the components (3) and (4) are mixed under heating to form a molten mixture B. Then, the mixture A warming under stirring, was gradually added to the melt mixture B, necessary response
Then, the components (5) and (7) are added, mixed and cooled. In this case, the external preparation can be an oil / water type emulsion and a water / oil type emulsion. In the case of the oil / water type, a surfactant having HLB 9 to 18 is preferably used as the surfactant, and in the case of the water / oil type, the surfactant having HLB 2 to 8 is preferably used. As the oily substance, a solid substance at normal temperature or a mixture of a solid substance at normal temperature and a liquid substance at normal temperature is used. As the thickener, a water-soluble polymer, for example, carboxyvinyl polymer, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium alginate, propylene glycol alginate, chitosan, polyvinyl alcohol, sodium starch glycolate, polyvinyl. Examples thereof include pyrrolidone, polyacrylic acid, polyacrylic acid ester, polymethacrylic acid, polymethacrylic acid ester and the like.

In order to preferably produce the external preparation comprising the above creamy mixture, the agent A comprising a solution prepared by dissolving the sulfonium compound of the component (1) in the water-soluble and oil-soluble organic solvent of the component (2). Is added to the agent B which is a hot melt mixture of the solid oily substance of the component (3) or the solid oily substance, the liquid oily substance and the solid surfactant of the component (4), and then the sulfonium compound is added. The agent C, which is a solution of water, a water-soluble organic solvent or a mixed solution of water and a water-soluble organic solvent, is added and mixed. In these mixing step, the temperature of the heat melt the solid surfactant solid oily substance and normal temperature at normal temperature, and held at least those materials melting, so that their material does not precipitate as a solid warn. Next, if necessary, water of the component (6) and a thickener of the component (5) are added to and mixed with the mixed liquid obtained as described above, and if necessary, a filler of the component (7). Is mixed and cooled. In this case, the thickener of component (5) is preferably added after the addition of water of component (6), but it can be dissolved in water of component (6) in advance and added at the same time as water. In addition, in the water of the component (6), other water-soluble substances, for example, an ultraviolet absorber such as oxybenzone (2-hydroxy-4-methoxybenzophenone) as a product stabilizer, urea or lactic acid as a moisturizer. Natriu
, Sodium pyrrolidonecarboxylate, polyhydric alcohol
Etc. can be dissolved in advance. The addition amount of these substances added to water, the total external preparation, 5 to 20 wt%, and it is preferably in the range of 5 to 10 wt%.
Further, it is preferable that the pH of the water of the component (6) is kept in the range of 3 to 5.5, and it is preferable to use a phosphate buffer as the pH-adjusted water.

The above-mentioned agent A preferably contains at least one oil-soluble liquid oily substance selected from higher aliphatic alcohols and terpene alcohols in order to improve its oil solubility. Further, the agent C preferably contains at least one selected from lower aliphatic alcohols and polyhydric alcohols in order to improve its water solubility. A
The total amount of agent and the B agent, the total external preparation, 2 to 40 wt%, preferably from 10 to 30 wt%. The ratio of the agent A to the total amount of the agent A and the agent B is 20 to 80% by weight , preferably 30 to 60% by weight . In the external preparation comprising the creamy mixture obtained as described above, even if the sulfonium compound content is increased to 3% by weight or more, particularly 5% by weight or more, the sulfonium compound is still dissolved in an organic solvent. It is uniformly and stably dispersed in the whole mixture, and is kept in a state of being easily absorbed by the skin.

When the external preparation of the present invention is applied in the form of a solution type lotion, it is preferable that it has the following component composition. (1) Sulfonium compound 0.01 to 20% by weight , preferably 0.5 to 10% by weight (2) Organic solvent 2 to 40% by weight , preferably 10 to 30% by weight (3) Liquid oily substance 0 to 30% by weight %, Preferably 0 to 20% by weight (4) Surfactant 0.1 to 20% by weight , preferably 0.5 to 7% by weight (5) Water 1 to 60% by weight , preferably 5 to 40% by weight ( 6) Thickener 0-5% by weight , preferably 0.05-1% by weight

The external preparation is prepared by dissolving the sulfonium compound of component (1) in a mixed solution of the organic solvent of component (2) and water of component (5) to prepare a solution. ), Component (4) and component (6) are added and mixed. This lotion type can be applied as a liquid lotion as it is, or can be used as an aerosol type lotion by filling an aerosol can with a propellant such as liquefied natural gas.
As the thickener, a polymer soluble in an organic solvent and / or water is used.

[0031]

In the administration of the external preparation of the present invention, the external preparation is directly applied to the affected area several times a day, for example, 1 to 3 times, or processed into the form of a patch, plaster, pap, etc., This can likewise be applied several times a day to the affected area. The number of times of application can be appropriately increased or decreased depending on the severity of the disease. In the external preparation of the present invention, the sulfonium compound is uniformly dispersed in the oily substance in the form of a mixture with liquid water and an organic solvent. Therefore, the external preparation of the present invention has a high skin permeability, and exhibits excellent therapeutic effect on allergic skin diseases only by applying it to the skin of the lesion. Further, the external preparation of the present invention has no skin irritation or low skin irritation, and is very excellent in safety. The external preparation of the present invention is based on the pharmacological action of the sulfonium compound contained therein,
It shows various medicinal effects. This medicinal effect includes various medicinal effects such as an antiallergic effect, an effect that enhances the immune system of the living body, an immunomodulatory effect, an antiphlogistic and analgesic effect, an infection protective effect, and an anticancer effect.

[0032]

EXAMPLES Next, the present invention will be described in more detail by way of examples. All parts and% shown below are based on weight. Example 1 (1) IPD-1151T 0.5 part (2) Butylene glycol 5 parts (3) Methylparaben 0.1 part (4) Purified water (phosphate buffer solution, pH 3.5 to 4.5) 52 parts ( 5) Carboxyvinyl polymer 0.1 part (6) Isopropyl myristate 4.0 parts (7) Isotridecyl myristate 5.0 parts (8) Diethyl sebacate 3.0 parts (9) Behenyl alcohol 3.0 parts (10) Squalene 3.0 parts (11) Olive oil 7.0 parts (12) Whale wax 5.0 parts (13) POE monostearate (5) Glyceryl 2.0 parts (14) Sorbitan monostearate 2.0 parts (15) ) Polyoxyethylene (2) lauryl ether 0.2 part (16) PEG stearate (40) 2.0 parts (17) Farnesol 1.0 part (18) Steer 5.0 parts phosphate (19) Propylparaben 0.1 parts

The above components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. Meanwhile, the components (6) to (19) were heated at 60 ° C. and uniformly mixed to prepare a mixture B. Then, while vigorously stirring the mixture B under heating to emulsify the mixture A was added One not a little to this. When mixture A has been added, heating is stopped, the whole is left to cool and a creamy product is obtained.

Example 2 (1) IPD-1151T 5 parts (2) Butylene glycol 120 parts (3) Purified water (phosphate buffer solution, pH about 4.5) 374 parts (4) Methylparaben 1 part (5) Myristin Isopropyl isopropylate 40 parts (6) Isotridecyl myristate 30 parts (7) Squalene 30 parts (8) White petrolatum 300 parts (9) Stearyl alcohol 50 parts (10) POE (60) Hardened castor oil 40 parts (11) Monostearic acid Glyceryl 10 parts

The above components (1) to (4) were uniformly mixed under heating at 70 ° C. or lower to prepare a solution-like mixture A. On the other hand, the components (5) to (11) were heated at 60 ° C. and uniformly mixed to prepare a mixture B. Then, while vigorously stirring the mixture B under heating to emulsify the mixture A was added One not a little to this. When mixture A has been added, heating is stopped, the whole is left to cool and a creamy product is obtained.

Example 3 (1) IPD-1151T 0.5 part (2) Propylene carbonate 1.3 parts (3) 1,3-Butanediol (butylene glycol) 1.0 part (4) Purified water (phosphoric acid Buffer solution, pH about 4.5) 1.0 part (5) white petrolatum 91.5 parts (6) sorbitan monostearate 2.0 parts (7) polyethylene glycol monostearate (40EO) 0.5 parts (8) ) Stearyl alcohol 2.0 parts

The above components (1) to (4) were uniformly mixed under heating at 70 ° C. or lower to prepare a mixture A in the form of a solution. On the other hand, the components (5) to (8) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, while vigorously stirring the mixture B under heating, the mixture is added A One not a little to this. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 4 (1) IPD-1151T 0.5 part (2) Polyethylene glycol (molecular weight 400) 3.0 parts (3) Purified water (phosphate buffer solution, pH about 4.5) 5.0 parts (4) Isoprene glycol 4.0 parts (5) Butylene glycol 3.0 parts (6) Carboxycellulose 0.7 part (7) Monostearate POE (5) Glyceryl 0.5 part (8) Monooleate POE ( 20) sorbitan 1.0 part (9) sorbitan sesquioleate 3.0 parts (10) stearyl alcohol 2.0 parts (11) white petrolatum 77.1 parts (12) methylparaben 0.1 part (13) propylparaben 0 1st copy

The components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. On the other hand, the components (6) to ( 13 ) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, while vigorously stirring the mixture B under heating, the mixture is added A One not a little to this. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 5 (1) IPD-1151T 0.5 part (2) Polyethylene glycol (molecular weight 400) 3.0 parts (3) Purified water (phosphate buffer, pH about 4.5) 5.0 parts (4) Isoprene glycol 4.0 parts (5) Butylene glycol 3.0 parts (6) Carboxycellulose 0.7 part (7) Monostearate POE (5) Glyceryl 0.5 part (8) Monooleate POE ( 20) sorbitan 1.0 part (9) sorbitan sesquioleate 3.0 parts (10) stearyl alcohol 2.0 parts (11) diisopropyl adipate 2.0 parts (12) white petrolatum 74.6 parts (13) sebacine Diethyl acid 0.5 part (14) Methylparaben 0.1 part (15) Propylparaben 0.1 part

The components (1) to (5) were uniformly mixed under heating at 70 ° C. or lower to prepare a solution-like mixture A. On the other hand, the components (6) to (15) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, while vigorously stirring the mixture B under heating, the mixture is added A One not a little to this. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 6 (1) IPD-1151T 0.5 part (2) Propylene carbonate 0.3 part (3) Ethylene carbonate 0.7 part (4) Butylene glycol 1.0 part (5) Purified water (phosphorus Acid buffer, pH about 3.0) 1.0 part (6) White petrolatum 90.5 parts (7) Sorbitan monostearate 2.0 parts (8) PEG monostearate (40EO) 0.5 parts (9) ) Stearyl alcohol 2.0 parts

The above components (1) to (5) were uniformly mixed under heating at 70 ° C. or less to prepare a solution-like mixture A. On the other hand, the components (6) to (9) were uniformly mixed under heating at 60 ° C. to prepare a mixture B. Then, while vigorously stirring the mixture B under heating, the mixture is added A One not a little to this. When the mixture A is completely added, heating is stopped and the whole is allowed to cool to obtain an ointment-like product.

Example 7 (A agent) (1) IPO-1151T 0.2 part (2) Propylene carbonate 1.0 part (B agent) (3) Dibutyl adipate 3.0 parts (4) Diethyl sebacate 2 0.0 parts (5) Isopropyl myristate 2.0 parts (6) Cetanol 3.0 parts (7) Cetyl palmitate 4.0 parts (8) Stearic acid 5.0 parts (9) Macadamia nut oil 5.0 parts ( 10) Squalene 3.0 parts (11) POE (5) glyceryl monostearate 2.0 parts (12) PEG (40EO) stearate 2.0 parts (13) Sorbitan monostearate 2.0 parts (14) Propyl Paraben 0.1 part (C agent) (15) IPD-1151T 0.3 part (16) Propylene glycol 2.0 part (17) Purified water (phosphate buffer solution) (pH 3.5 to 4.5) 60.8 parts (18) Methylparaben 0.1 part (19) Urea 2.0 parts (D agent) (20) Carboxyvinyl polymer 0.5 parts

Components (3) to (14) are dissolved and mixed at 80 ° C. and then cooled to 65 ° C. to prepare agent B. Components (1) and (2) are dissolved in agent B at 60 ° C. A obtained by mixing
After adding and mixing the agents, the components (15) to (19) are added at 60 ° C.
The agent C obtained by dissolving and mixing in (1) is added and mixed, and finally the component (2
The agent D consisting of 0) was added and mixed, and the whole was cooled to obtain a creamy product.

The IPD-shown in the above embodiment is used.
1151T is a sulfonium compound represented by the following formula.

[Chemical 2]

[0047] Example 7 body stem (front chest, abdomen) to, there is accompanied red brown papules significant pruritus, observed bleeding from some scratching and elbows function
A cream product obtained in Example 1 was rubbed twice a day for a boy aged 8 years old who had a lichenified stage on the nodular side, and continued daily for 2 to 3 days. Along with the disappearance of brown papules, a decrease in pruritus was observed, and after one week, a slightly dry skin surface became visible, and an effect of improving the skin surface was recognized.

Example 8 The creamy product obtained in Example 1 was applied to the shoulder and back of a 5-year-old boy with atopic dermatitis by rubbing twice a day and continuing from the second day. The effect of improving dermatitis was recognized. The skin properties were improved and the dryness and desquamation were alleviated.

Example 9 A three-year-old boy with atopic dermatitis was continuously rubbed twice daily with the creamy product obtained in Example 1,
From the 2nd to 3rd days, an improving effect on dermatitis was observed. The skin properties were improved and the dryness and desquamation were alleviated. It should be noted that this patient had been using Kinderbate and Linderon VG for a long time, but it was confirmed that the product of the present invention exhibits the same or greater effect as those.

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Claims (7)

[Claims] 1. A skin external preparation containing an antiallergic sulfonium compound, comprising: (i) the sulfonium compound, (ii) a water-soluble organic solvent which is liquid at room temperature, and (ii)
i) oily substance, (iv) purified water of pH 3 to 5.5, and (v)
A sulfonium compound-containing external preparation for skin, which contains a surfactant and the content of the sulfonium compound is in the range of 0.05 to 10 wt%. 2. The organic solvent is alcohol, alkanolamine, partial ester of polyhydric alcohol, alkylene oxide adduct of partial ester of polyhydric alcohol, alkylene oxide adduct of alcohol, alkylene glycol monoalkyl ether, N-alkylpyrrolidone. ,
The external skin preparation according to claim 1, which contains at least one selected from N, N-dialkylacetamide, dialkylimidazolidine, dialkyl sulfoxide, and alkylene carbonate. 3. The external preparation for skin according to claim 1, which comprises an ointment-like mixture containing a solid oily substance. 4. The external preparation for skin according to claim 1, which comprises a creamy mixture containing a solid oily substance. 5. An antiallergic sulfonium compound, a water-soluble organic solvent which is liquid at room temperature, pH 3.5 to 5.
Sulfonium characterized by comprising a solution of a purified water, a substance which is liquid at room temperature and a surfactant, and the content of the sulfonium compound is in the range of 0.05 to 10 wt%. Compound-containing external preparation for skin. 6. The organic solvent is alcohol, alkanolamine, partial ester of polyhydric alcohol, alkylene oxide adduct of partial ester of polyhydric alcohol, alkylene oxide adduct of alcohol, alkylene glycol monoalkyl ether, N-alkylpyrrolidone. ,
The external preparation for skin according to claim 5, which contains at least one selected from N, N-dialkylacetamide, dialkylimidazolidine, dialkyl sulfoxide, and alkylene carbonate. 7. An agent A comprising a solution of an antiallergic sulfonium compound dissolved in a water-soluble and oil-soluble organic solvent, and an agent B comprising a hot-melt mixture of a solid oily substance and a solid surfactant. And then mixed with, and then added and mixed with a C agent comprising a solution of the sulfonium compound in water, a water-soluble organic solvent or a mixed solution of water and a water-soluble organic solvent,
A method for producing a sulfonium compound-containing external preparation for skin, which comprises adding water and a thickening agent as needed, and cooling.