JP6967369B2 - Emulsifying composition - Google Patents

Description

The present invention relates to an emulsified composition containing allantoin and / or a derivative thereof, and a heparinoid, which can stably retain allantoin.

Allantoin and its derivatives are known to have a tissue repair activating effect, an anti-inflammatory effect, an antipruritic effect and the like, and are widely used as an active ingredient of an external composition. Further, heparinoids are known to have moisturizing action, anti-inflammatory action, blood circulation promoting action and the like, and have few side effects, so that they are used as an active ingredient of an external composition.

In recent years, there has been a strong demand for improved functionality for external compositions, and attention has been paid to the functionality of allantoin and its derivatives, as well as heparinoids, and the functionality has been improved by using these components in combination. External compositions have also been proposed. For example, Patent Document 1 discloses that an external pharmaceutical composition comprising a heparinoid, allantoin or a derivative thereof, and pantothenic acid or a derivative thereof can promote normal differentiation of epidermal keratinized cells into individual layer cells. ing.

On the other hand, allantoin has a drawback that it is decomposed when the pH is about 6.0 or higher. Conventionally, it has been known that it is effective to set the external composition to a lower pH, for example, pH 5.5 or lower in order to stabilize allantoin, but such a low pH external composition has been known. Then, there is a concern that problems such as skin irritation may occur.

In addition, emulsified compositions such as creams and lotions have a good usability and are widely accepted by consumers. However, in an emulsified composition containing allantoin and / or a derivative thereof, and a heparinoid, a pharmaceutical technique for stably maintaining allantoin and / or a derivative thereof has not been sufficiently studied.

Japanese Unexamined Patent Publication No. 2011-231128

The present inventor has studied to put into practical use an emulsified composition containing allantoin and / or a derivative thereof, and a heparinoid. We faced a new problem that the decomposition of allantoin and / or its derivatives cannot be suppressed even if the pH is adjusted to a low pH range where the decomposition can be suppressed. That is, in an emulsified composition containing allantoin and / or a derivative thereof, and a heparinoid, the allantoin and / or a derivative thereof cannot be stabilized unless a method different from that of a normal non-emulsifying solution is adopted. Faced with a problem.

Therefore, an object of the present invention is a preparation that suppresses the decomposition of allantoin and / or its derivative and stably retains allantoin and / or its derivative in an emulsified composition containing allantoin and / or a derivative thereof and a heparinoid. To provide technology.

As a result of diligent studies to solve the above problems, the present inventor has found that an emulsified composition containing an anionic surfactant and an amine-based alkaline agent together with allantoin and / or a derivative thereof, and a heparinoid. It has been found that the decomposition of allantoin and / or its derivative can be suppressed, and the stabilization of allantoin and / or its derivative can be achieved. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. An emulsified composition containing (A) allantoin and / or its derivative, (B) heparinoid, (C) anionic surfactant, and (D) amine-based alkaline agent.
Item 2. Item 2. The emulsified composition according to Item 1, wherein the (D) amine-based alkaline agent is an alkanolamine and / or arginine.
Item 3. Item 2. The emulsified composition according to Item 1 or 2, wherein the (C) anionic surfactant is an alkyl sulfate ester having 8 to 18 carbon atoms and / or a salt thereof.
Item 4. Item 2. The emulsified composition according to any one of Items 1 to 3, further comprising (E) a phosphocholine group-containing polymer.
Item 5. Item 6. The emulsified composition according to any one of Items 1 to 4, wherein the (E) phosphocholine group-containing polymer is a 2-methacryloxyethyl phosphocholine choline / butyl methacrylate copolymer.
Item 6. Item 6. The emulsified composition according to any one of Items 1 to 5, which has a pH of 5 to 7.
Item 7. Item 2. The emulsified composition according to any one of Items 1 to 6, which is an oil-in-water emulsified form.
Item 8. A method for stabilizing allantoin and / or its derivative in an emulsified composition containing allantoin and / or its derivative, and a heparinoid.
The stabilization method comprising (A) an anionic surfactant and (D) an amine-based alkaline agent, together with (A) allantoin and / or a derivative thereof, and (B) a heparinoid, in the emulsified composition. ..

According to the emulsified composition of the present invention, decomposition of allantoin and / or its derivative can be suppressed and stably maintained, even though allantoin and / or its derivative and a heparin-like substance are contained. Further, according to the emulsified composition of the present invention, it is possible to stabilize allantoin and / or its derivative without lowering the pH, which is generally required for stabilizing allantoin and / or its derivative. It is also possible to suppress skin irritation caused by pH.

1. 1. Emulsifying Composition The emulsified composition of the present invention contains allantin and / or a derivative thereof (sometimes referred to as component (A)), heparinoid (sometimes referred to as component (B)), and anionic surfactant. It is characterized by containing an agent (sometimes referred to as a component (C)) and an amine-based alkaline agent (sometimes referred to as a component (D)). The emulsified composition of the present invention contains an anionic surfactant and an amine-based alkaline agent together with an allantin and / or a derivative thereof, and a heparinoid, so that the emulsified composition is similar to the allantin and / or a derivative thereof and heparinoid. It is possible to suppress the decomposition of allantin and / or its derivative caused by the coexistence with a substance, and to provide excellent formulation stability. Hereinafter, the emulsified composition of the present invention will be described in detail.

(A) Allantoin and / or its derivative Allantoin is a compound also called 5-ureidohydantoin, and is a known drug known to have a tissue repair activating effect, an anti-inflammatory effect, an antipruritic effect and the like.

The derivative of allantoin is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include allantoin chlorohydroxyaluminum and allantoinhydroxyaluminum. These allantoin derivatives may be used alone or in combination of two or more.

In the emulsified composition of the present invention, only one of allantoin or a derivative thereof may be used as the component (A), or these may be used in combination. Among the components (A), allantoin is preferably mentioned from the viewpoint of further improving its stabilizing effect.

The content of the component (A) in the emulsified composition of the present invention is not particularly limited, but is, for example, 0.05 to 5% by weight, preferably 0.1 to 3% by weight, and more preferably 0.1 to 1% by weight. Weight% is mentioned.

(B) Heparin-like substance The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing effect, an anti-inflammatory effect, a blood circulation promoting effect, and the like.

The origin of the heparinoid used in the present invention is not particularly limited, but for example, those obtained by polysulfating mucopolysaccharides, tracheal cartilage of edible animal tissues (eg, tracheal cartilage of cattle, pigs, etc.). Examples include those extracted from (lungs including). In the emulsified composition of the present invention, a heparin-like substance contained in the Japanese Pharmacopoeia non-Japanese Pharmacopoeia pharmaceutical standard is preferably used as the heparin-like substance.

The content of the component (B) in the emulsified composition of the present invention is not particularly limited, but is, for example, 0.01 to 5% by weight, preferably 0.05 to 3% by weight, and more preferably 0.1 to 1. %% by weight, particularly preferably 0.1 to 0.5% by weight, most preferably 0.1 to 0.3% by weight.

In the emulsified composition of the present invention, the ratio of the component (B) to the component (A) is determined according to the contents of the component (A) and the component (B). For example, 100 parts by weight of the component (A). The component (B) is 0.1 to 10000 parts by weight, preferably 1 to 1000 parts by weight, and more preferably 10 to 300 parts by weight.

(C) Anionic surfactant The type of anionic surfactant used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but for example, lauryl sulfate, laureth sulfate, myristyl sulfate, etc. Alkyl sulfate esters with 8 to 18 carbon atoms such as cetyl sulfate and oleyl sulfate and their salts; fatty acid ester sulfate esters such as hydride palm oil fatty acid monoglyceride monosulfate and their salts; dodecylbenzenesulfonic acid, dodecylbenzenesulfonic acid triethanolamine Alkylarylsulfonic acid and salts thereof; Polyoxyethylene alkyl ether sulphate such as polyoxyethylene lauryl ether sulphate and salts thereof; Polyoxyethylene-alkyl ether sulfates such as lauryl sulphate and salts thereof; polyoxyethylene alkyl ether carboxylic acids such as polyoxyethylene lauryl ether acetic acid and salts thereof; N-acylsulfonic acids such as lauroyl sulcocin and salts thereof; myristylmethyl taurine , Palm oil fatty acid Methyl taurine, lauryl methyl taurine and other higher fatty acids amide sulfonic acid sulfosuccinic acid di-2-ethylhexyl sulfosuccinic acid, monolauroyl monoethanolamide polyoxyethylene sulfosuccinic acid, lauryl polypropylene glycol sulfosuccinic acid and other sulfosuccinic acids and salts thereof. N-acylglutamic acid such as N-palm oil fatty acid acylglutamic acid, N-lauroylglutamic acid, N-stearoylglutamic acid, N-myristoylglutamic acid and salts thereof; polyoxyethylene-alkyl ether carboxylic acid, polyoxyethylene-alkylallyl ether carboxylic acid. Examples thereof include acid, α-olefin sulfonic acid, higher fatty acid ester sulfonic acid, secondary alcohol sulfate ester, higher fatty acid alkylolamide sulfate ester, lauroyl monoethanolamide succinic acid, N-palmitoyl aspartic acid, and salts thereof.

Among the compounds exemplified as the anionic surfactant, examples of the salt form include alkali metal salts such as sodium salt and potassium salt; triethanolamine salt; ammonium salt and the like.

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

Among these anionic surfactants, an alkyl sulfate ester having 8 to 18 carbon atoms and a salt thereof are preferable, and sodium lauryl sulfate is more preferable, from the viewpoint of further improving the stabilizing effect of allantin and / or a derivative thereof. , Sodium laureth sulfate, sodium myristyl sulfate, sodium cetyl sulfate, sodium oleyl sulfate; particularly preferably sodium lauryl sulfate, sodium laureth sulfate, sodium cetyl sulfate.

The content of the component (C) in the emulsified composition of the present invention is not particularly limited, and examples thereof include 0.1 to 10% by weight. The content of the component (C) is preferably 0.2 to 5% by weight, more preferably 0.5 to 1% by weight, from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivative. Be done.

Further, in the emulsified composition of the present invention, the ratio of the component (C) to the component (A) is determined according to the contents of the component (A) and the component (C). The component (C) is 1 to 20000 parts by weight per part by weight. As the ratio of the component (C) to the component (A), the component (C) is preferably 5 per 100 parts by weight of the component (A) from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivative. 5,000 parts by weight, more preferably 10 to 1000 parts by weight.

(D) Amine-based alkaline agent The amine-based alkaline agent is a component having a monovalent functional group obtained by removing a hydrogen atom from ammonia, a primary amine, or a secondary amine, and exhibiting alkalinity in water. In the emulsified composition of the present invention, the amine-based alkaline agent contributes to the suppression of decomposition of allantoin and / or its derivative, and also plays a role of adjusting the pH of the emulsified composition within the range described later.

The type of amine-based alkaline agent used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkanolamine and arginine.

In the alkanolamine used as an amine-based alkaline agent, the number of hydroxyalkyl groups bonded to the nitrogen atom is not particularly limited, and examples thereof include 1 to 3, preferably 2 or 3. Further, the hydroxyalkyl group bonded to the nitrogen atom in the alkanolamine may be either linear or branched. The number of carbon atoms of the hydroxyalkyl group bonded to the nitrogen atom in the alkanolamine is not particularly limited, and examples thereof include 1 to 20, preferably 2 to 5, and more preferably 2 to 3.

As an amine-based alkaline agent, as an alkanolamine, specifically, monoethanolamine, monoisopropanolamine, monoalkanolamines such as 2-amino-2-methyl-1,3-propanediol; diethanolamine, diethanolamine, di. Dialkanolamines such as isopropanolamine; examples thereof include trialkanolamines such as triethanolamine and triisopropanolamine.

These amine-based alkaline agents may be used alone or in combination of two or more.

Among these amine-based alkaline agents, from the viewpoint of further improving the stabilizing effect of allantin and / or its derivatives, alycarmine is preferable, and hydroxyalkyl groups having 2 to 3 carbon atoms are more preferable. Examples thereof include alkanolamines having alkanolamines, more preferably dialkanolamines and trialkanolamines, and particularly preferably diisopropanolamines and triethanolamines.

The content of (D) in the emulsified composition of the present invention may be set to an amount such that the pH of the emulsified composition is 5 to 7, preferably 5 to 6.8. The emulsified composition containing allantoin and / or its derivative and a heparinoid has a problem that the decomposition of allantoin and / or its derivative cannot be suppressed at a pH of 5.5 or higher which can reduce irritation to the skin by the prior art. However, according to the present invention, by adjusting the pH using an amine-based alkaline agent, the decomposition of allantoin and / or its derivative is effectively suppressed even at a pH of 5.5 or higher, which can reduce irritation to the skin. , It is possible to stabilize it. In view of such effects of the present invention, the pH of the emulsified composition is more preferably 5.5 to 6.8, particularly preferably 5 as the content of (D) in the emulsified composition of the present invention. An amount of 5.5 to 6.5 can be mentioned.

(E) Phosphocholine group-containing polymer The emulsified composition of the present invention may be referred to as a phosphocholine group-containing polymer (sometimes referred to as a component (E)), if necessary, in addition to the components (A) to (D). May include. When a phosphocholine group-containing polymer is contained, the stabilizing effect of allantoin and / or its derivative can be further improved.

The phosphocholine group-containing polymer is a polymer obtained by polymerizing a monomer containing a phosphocholine group (hereinafter, may be referred to as “phosphocholine group-containing monomer”), and is a known component having a moisturizing effect and the like. ..

In the phosphocholine group-containing polymer used in the present invention, the type of the phosphocholine group-containing monomer is not particularly limited, and examples thereof include a monomer having a phosphocholine group and a vinyl group. More specific examples of the phosphocholine group-containing monomer include 2-methacryloyloxyethyl phosphorylcholine and 2-methacryloyloxyethylphosphorylethanolamine. In the phosphocholine group-containing polymer, the phosphocholine group-containing monomer may be contained alone or in combination of two or more. Among these phosphocholine group-containing monomers, 2-methacryloyloxyethyl phosphorylcholine is preferably mentioned from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivative.

The phosphocholine group-containing polymer used in the present invention may be a homopolymer composed of one kind of phosphocholine group-containing monomer, or may be a copolymer composed of two or more kinds of monomers. good.

When the phosphocholine group-containing polymer is a copolymer, it may be a copolymer composed of two or more kinds of phosphocholine group-containing monomers, and at least one kind of phosphocholine group-containing monomer and at least one kind. It may be a copolymer composed of a monomer other than the phosphocholine group-containing monomer.

The types of monomers other than the phosphocholine group-containing monomer contained in the phosphocholine group-containing polymer are pharmaceutically acceptable and are particularly capable of radical polymerization with a phosphocholine group-containing single amount. Examples include, but are not limited to, monomers having a vinyl group. Specific examples of the monomer other than the phosphocholine group-containing monomer include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, and 2-. Alkyl (meth) acrylates such as ethylhexyl (meth) acrylates; benzyl (meth) acrylates, phenoxyethyl (meth) acrylates, cyclohexyl (meth) acrylates, polypropylene glycol mono (meth) acrylates, polytetramethylene glycol mono (meth) acrylates, Examples thereof include polypropylene glycol di (meth) acrylate, polytetramethylene glycol mono (meth) acrylate, polypropylene glycol polyethylene glycol mono (meth) acrylate, sodium methacrylate, 2-hydroxy-3-methacryloyloxypropyltrimethylammonium and the like. In the phosphocholine group-containing polymer, a monomer other than the phosphocholine group-containing monomer may be contained alone or in combination of two or more. Among the monomers other than these phosphocholine group-containing monomers, alkyl (meth) acrylate and 2-hydroxy-3-methacryloyl are preferable from the viewpoint of further improving the stabilizing effect of allantin and / or its derivative. Oxypropyltrimethylammonium, more preferably an alkyl (meth) acrylate having an alkyl group having 1 to 18 carbon atoms, more preferably an alkyl (meth) acrylate having an alkyl group having 3 to 5 carbon atoms, particularly preferably butyl (meth). Acrylate can be mentioned. In addition, in this specification, "(meth) acrylate" means a methacrylate and / or an acrylate.

Specific examples of the phosphocholine group-containing polymer used in the present invention include polymethacryloxyethyl phosphorylcholine homopolymer, 2-methacryloyloxyethylphosphorylcholine-butyl methacrylate copolymer (polyquaternium-51), and 2-methacryloyloxy. Ethylenephosphorylcholine / butylmethacrylate / sodium methacrylate copolymer (polyquaternium-65), 2-methacryloyloxyethyl phosphorylcholine / 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer (polyquaternium-64), 2-methacryloyloxy Examples thereof include an ethylphosphorylcholine / stearyl methacrylate copolymer (polyquaternium-61). In the above notation regarding the phosphocholine group-containing polymer, the names in parentheses indicate the cosmetic ingredient display names.

These phosphocholine group-containing polymers may be used alone or in combination of two or more.

Among these phosphocholine group-containing polymers, 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer and polymethacryloyloxyethyl are preferable from the viewpoint of further improving the stabilizing effect of allantin and / or its derivatives. Phosphorylcholine homopolymer, 2-methacryloyloxyethyl phosphorylcholine 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer; more preferably 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl Phosphorylcholine 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer; particularly preferred include 2-methacryloxyethyl phosphorylcholine-butyl methacrylate copolymer.

When the emulsified composition of the present invention contains the component (E), the content thereof is not particularly limited, and examples thereof include 0.025 to 1% by weight. From the viewpoint of further improving the stabilizing effect of allantoin and / or its derivative, the content of the component (E) is preferably 0.05 to 0.5% by weight, more preferably 0.1 to 0.3. Weight% is mentioned.

When the emulsified composition of the present invention contains the component (E), the ratio of the component (E) to the component (A) is determined according to the contents of the component (A) and the component (E). For example, 1 to 2000 parts by weight of the component (E) may be mentioned per 100 parts by weight of the component (A). As the ratio of the component (E) to the component (A), the component (E) is preferably 10 per 100 parts by weight of the component (A) from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivative. It is about 500 parts by weight, more preferably 50 to 150 parts by weight.

Other ingredients [water]
The emulsified composition of the present invention contains water in order to form an aqueous phase in an emulsified state.

The water content in the emulsified composition of the present invention may be appropriately set according to the emulsified form. For example, in the case of an oil-in-water type, 20 to 90% by weight, preferably 30 to 80% by weight. More preferably, it is 40 to 80% by weight, and in the case of a water-in-oil type, it is 20 to 90% by weight, preferably 30 to 80% by weight, and further preferably 40 to 80% by weight.

[Oil]
The emulsified composition of the present invention contains an oil component in order to form an oil phase in an emulsified state.

The oil content used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and for example, vegetable oil, animal oil, mineral oil, cholesterol, fatty acid alkyl ester, fatty acid, etc. Examples include higher alcohol and silicone oil.

Specific examples of vegetable oils include olive oil, wheat germ oil, rice oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, sunflower oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, and hardened oil. , Avocado oil, uikyo oil, butterfly oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran, wood wax, rice wax, and the like. These vegetable oils may be used alone or in combination of two or more.

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

Specific examples of the mineral oil include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbon (plastibase and the like), selecin, microcrystalline wax, petrolatum and the like. These hydrocarbons may be used alone or in combination of two or more.

Examples of the fatty acid alkyl ester include esters of fatty acids having 4 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms, and specific examples thereof include diisopropyl adipate, isopropyl mytylate, isopropyl palmitate, and cetyl palmitate. Examples thereof include diethyl sebacate and ethyl oleate. These fatty acid alkyl esters may be used alone or in combination of two or more.

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

Examples of the higher alcohol include monohydric alcohols having 6 to 34 carbon atoms, and specifically, myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, lanolin alcohol and the like. Can be mentioned. These higher alcohols may be used alone or in combination of two or more.

Specific examples of the silicone oil include methylpolysiloxane, crosslinked methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, and phenyl-modified silicone. Be done. These silicone oils may be used alone or in combination of two or more.

Among these oily bases, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, and higher alcohols are preferably mentioned from the viewpoint of more effectively improving the anti-inflammatory effect.

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

The oil content in the emulsified composition of the present invention may be appropriately set according to the emulsified form. For example, in the case of an oil-in-water type, 1 to 80% by weight, preferably 3 to 50% by weight. , More preferably 5 to 20% by weight, and in the case of the water-in-oil type, 1 to 80% by weight, preferably 3 to 50% by weight, still more preferably 5 to 20% by weight.

[Surfactants other than anionic surfactants]
The emulsified composition of the present invention may contain a surfactant other than the anionic surfactant, if necessary. Such surfactants are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, and examples thereof include nonionic surfactants, cationic surfactants, and amphoteric surfactants. Will be. Among these surfactants, a nonionic surfactant is preferable from the viewpoint of imparting emulsion stability.

Specific examples of the nonionic surfactant include polyoxyethylene hydrogenated castor oil; sorbitan fatty acid esters (eg, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan mono). Stearate, sorbitan sesquioleate, sorbitan trioleate, penta-2-ethylhexylate diglycerol sorbitan, tetra-2-ethylhexylate diglycerol sorbitan, etc.); , Glycerin sesquioleate, Glycerin monostearate, α, α'-Glycerin pyroglutamate oleate, Glycerin monostearate, apple acid, etc.); Propropylene glycol fatty acid esters (eg, propylene glycol monostearate, etc.); Glycerin alkyl ethers Steares-2; Polyoxyethylene sorbitan fatty acid esters (eg, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tetraoleate, etc.); Polyoxyethylene sorbitan fatty acid esters (eg, polyoxyethylene sorbitan tetraoleate, etc.) , Polyoxyethylene sorbit monolaurate, P polyoxyethylene sorbit monooleate, polyoxyethylene sorbit pentaoleate, polyoxyethylene sorbit monostearate, etc.); Polyoxyethylene glycerin fatty acid esters (eg, polyoxyethylene glycerin) Monostearate, polyoxyethylene glycerin monoisostearate, polyoxyethylene glycerin triisostearate, etc.); Polyoxyethylene fatty acid esters (eg, polyoxyethylene monooleate, polyoxyethylene distearate, polyoxyethylene, etc.) Monodiolate, ethylene glycol distearate, etc.); Polyoxyethylene alkyl ethers (eg, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, polyoxyethylene 2- Octyldodecyl ether, polyoxyethylene cholestanol ether, etc.); Pluronic types (eg, pluronic, etc.); Polyoxyethylene / polyoxypropylene alkyl ethers (, etc.) For example, polyoxyethylene / POP-cetyl ether, polyoxyethylene / polyoxypropylene-2-decyltetradecyl ether, polyoxyethylene / polyoxypropylene monobutyl ether, polyoxyethylene / polyoxypropylene hydrogenated lanolin, polyoxyethylene. -Polyoxypropylene glycerin ether, etc.); Staires-21, etc. can be mentioned. Among these nonionic surfactants, polyoxyethylene hydrogenated castor oil is preferable.

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

When the emulsified composition of the present invention contains a surfactant other than the anionic surfactant, the content thereof may be appropriately set according to the type of the surfactant to be used, for example, 1 to 1. 10% by weight, preferably 2 to 9% by weight, more preferably 3 to 8% by weight.

[Multivalent alcohol]
The emulsified composition of the present invention may contain a polyhydric alcohol, if necessary, for the purpose of enhancing the moisturizing effect and the like.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 1,3-butylene glycol, ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and glycerin. .. These polyhydric alcohols may be used alone or in combination of two or more.

When the emulsified composition of the present invention contains a polyhydric alcohol, the content thereof may be appropriately set according to the type of the polyhydric alcohol used and the like, but is preferably 0.5 to 30% by weight, for example. Is 1 to 20% by weight, more preferably 2 to 15% by weight.

[Thickener]
In addition to the above-mentioned components, the emulsified composition of the present invention may contain a thickener, if necessary, for adjusting the viscosity and the like.

The thickener is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and for example, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, etc. Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, sodium polyacrylate, dextrin fatty acid Examples thereof include esters and pectins. Among these thickeners, a carboxyvinyl polymer is preferably mentioned. These thickeners can be used alone or in combination of two or more.

When the thickener is contained in the emulsified composition of the present invention, the content thereof may be appropriately set according to the type of the thickener to be used, and is preferably 0.1 to 3% by weight, for example. Is 0.2 to 1% by weight, more preferably 0.3 to 0.7% by weight.

[Other medicinal ingredients]
The emulsified composition of the present invention may contain, if necessary, a medicinal ingredient capable of exerting a pharmaceutical or cosmetic physiological function in addition to the above-mentioned ingredients. Examples of such medicinal ingredients include steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorhexidine maleate, etc.), and local anesthesia. Agents (Lidokine, Dibucaine, Procaine, Tetracaine, Bupipacine, Mepipacine, Chlorhexamine, Proparacaine, Meprilkine or salts thereof, Alkyl benzoate (eg, ethyl aminobenzoate, Diethylaminoethyl hydrochloride parabutylaminobenzoate), orthokine, oxamethasone , Oxypolyentoxydecane, funnel extract, percaminpase, tesitdecitin, etc.), anti-inflammatory agents (alantin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, fervinac, diclofenac sodium, sodium loxoprofen, etc.), bactericides (benzalkonium chloride, chloride Dexamethasone, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfaziazine, lactic acid, phenol, etc.), antipruritic agent (crotamiton, thiantoll, etc.), skin protectant (corodione, castor oil, etc.) , Blood circulation promoting components (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, peppermint extract, etc.), vitamins (vitamins A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.), etc. Can be mentioned. These medicinal ingredients may be used alone or in combination of two or more. Further, when these medicinal ingredients are contained in the emulsified composition of the present invention, the content thereof may be appropriately set according to the type of the medicinal ingredient to be used, the expected effect and the like.

[Other additives]
In addition to the above-mentioned components, the emulsified composition of the present invention may contain other additives usually used for external preparations, if necessary. Examples of such additives include buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, chelating agents, fragrances, coloring agents and the like. When these additives are contained in the emulsified composition of the present invention, the content thereof may be appropriately set according to the type of the additive to be used and the like.

pH
The pH of the emulsified composition of the present invention may be set within the range shown in the column of "(D) Amine-based alkaline agent".

Form of Formulation / Use The emulsified composition of the present invention may be in either an oil-in-water type or a water-in-oil emulsified form, and an oil-in-water type is preferable. In addition, the emulsified composition of the present invention may be in a state in which each contained component is solubilized.

The pharmaceutical form of the emulsified composition of the present invention is not particularly limited, and examples thereof include solubilized forms (solubilized lotions and the like), emulsions (emulsified lotions and the like), creams and the like.

The emulsified composition of the present invention is suitably used as an external preparation to be applied transdermally. Specific examples of the emulsified composition of the present invention include external medicines, quasi-drugs for external use, cosmetics, skin cleansers and the like. Among these pharmaceutical forms, preferably, an external drug and a quasi-drug for external use are mentioned.

The emulsified composition of the present invention can exert a tissue repair activating effect, an anti-inflammatory effect, an antipruritic effect, etc. based on the contained (A) component, and further has a moisturizing effect and an anti-inflammatory effect based on the contained (B) component. Since it can exert an action, a blood circulation promoting action, etc., it is suitably used for the purpose of prevention or treatment of moisturizing, rough skin improvement, dry skin disease, inflammatory skin disease, hypertrophic scar, keroid and the like.

Production Method The emulsified composition of the present invention can be produced according to a known method for producing an emulsified composition. Examples of the method for producing the emulsified composition of the present invention include the methods shown below. First, a composition for an aqueous phase is prepared by mixing the component (A), the component (B), water, and other water-soluble components added as needed. Separately, an oil component and other water-soluble components added as necessary are mixed to prepare a composition for an oil phase. The component (C) and the surfactant other than the component (C) may be added to or both of the aqueous phase composition and the oil phase composition and mixed, but the oil phase composition. It is preferable to add it to the product. Next, the obtained composition for an aqueous phase and the composition for an oil phase are mixed and emulsified by an emulsification method such as a homogenizer. At that time, the composition for the aqueous phase may be prepared in two or more portions, and may be mixed with the composition for the oil phase in stages and emulsified. Then, the emulsified composition of the present invention is produced by adding a predetermined amount of the component (D) to adjust the pH to a desired value.

2. 2. Method for Stabilizing Allantoin and / or Derivatives The present invention is a method for stabilizing allantoin and / or a derivative thereof in an emulsified composition containing allantoin and / or a derivative thereof, and a heparinoid. Stabilization comprising (C) an anionic surfactant and (D) an amine-based alkaline agent, together with (A) allantoin and / or a derivative thereof, and (B) a heparinoid. Provide a method.

Regarding the types and contents of (A) to (D) used in the stabilizing method of the present invention, the types and contents of other components to be blended, the formulation form of the emulsified composition produced by emulsification, etc. This is the same as in the case of the above-mentioned "1. Emulsification composition".

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Test Example 1
An oil-in-water emulsified composition having the composition shown in Table 1 (cream preparation, Examples 1 to 11 and Comparative Examples 1 to 8) and a liquid preparation (Reference Example 1) were produced and evaluated for the effect of suppressing decomposition of allantoin. The specific test method is as follows.

<Production of oil-in-water emulsified composition (Examples 1 to 11 and Comparative Examples 1 to 8)>
First, the components shown in (I) in Table 1 were mixed and dissolved to prepare an aqueous phase composition. Separately, the components shown in (II) and (III) in Table 1 were mixed and dissolved while heating to prepare an oil phase composition. Then, the composition for the aqueous phase and the composition for the oil phase were mixed in a state of being heated to 80 ° C., respectively, and emulsified using a homogenizer. After emulsification, the components shown in (IV) in Table 1 were added, the pH was adjusted to 5.5, and then the mixture was cooled to room temperature to obtain an oil-in-water emulsified composition.

<Manufacturing of liquid agent (Reference Example 1)>
A predetermined amount of each component shown in Table 1 was mixed to produce a liquid preparation.

<Evaluation of allantoin decomposition inhibitory effect>
The obtained emulsified composition and liquid preparation were stored in a light-shielded condition at 50 ° C. for 30 days immediately after production, and then the content of allant-in was measured by high performance liquid chromatography (column: PC HILIC S5 4.6 mm × 250 mm (stock). (Manufactured by Shiseido Co., Ltd.), mobile phase: acetonitrile / water = 80/20, flow velocity: 1.0 mL / min, column temperature: 40 ° C., measurement wavelength: 210 nm). From the measured allantoin content, the decomposition rate (%) of allantoin was calculated according to the following formula, and the effect of suppressing the decomposition of allantoin was evaluated according to the following criteria.

(Criteria for suppressing the decomposition of allantoin)
⊚: Allantoin decomposition rate is 0-3.9%
◯: Decomposition rate of allantoin is 4.0 to 5.9%
Δ: Allantoin decomposition rate is 6.0-7.9%
×: Allantoin decomposition rate is 8% or more

<Result>
The results obtained are shown in Table 1. In the composition containing allantoin and a heparinoid, allantoin was stable in a liquid preparation having a pH of 5.5 (Reference Example 1: the decomposition rate was 3.0%), but in the emulsified form, allantoin was decomposed. (Comparative Examples 1 to 8: The decomposition rate was 8.0 to 11.4%). Further, in the emulsified composition containing allantoin and a heparinoid, even when an anionic surfactant was contained, decomposition of allantoin was observed when potassium hydroxide was contained as an alkaline agent (Comparative Example 8). .. On the other hand, in an emulsified composition containing allantoin and a heparinoid, if an amine-based alkaline agent is contained as an alkaline agent together with an anionic surfactant, the decomposition of allantoin can be suppressed and the allantoin is stabilized. (Examples 1 to 11: The decomposition rate of Examples 1 to 4 was 5.2 to 5.5%). Further, when the 2-methacryloyloxyethyl phosphocholine / butyl methacrylate copolymer was further contained, the effect of suppressing the decomposition of allantoin was further improved (Examples 5 to 11: decomposition rate was 1.8 to 3.). It was 4%).

Formulation Examples An oil-in-water emulsified composition (cream preparation) (formulation examples 1 to 18) and a lotion liquid (formulation examples 19 and 20) having the compositions shown in Table 2 were prepared. When the obtained aqueous preparations were evaluated for the effect of suppressing the decomposition of allantoin by the same method as in the above test example, the decomposition rate of allantoin was low and the stability of allantoin was improved.

Claims (8)

(A) Arantoi emissions, (B) heparinoids, (C) an anionic surfactant other than dipotassium glycyrrhizinate, and (D) containing an amine based alkaline agent, emulsified composition. The emulsified composition according to claim 1, wherein the (D) amine-based alkaline agent is an alkanolamine and / or arginine. The emulsified composition according to claim 1 or 2, wherein the anionic surfactant other than the dipotassium glycyrrhizinate (C) is an alkyl sulfate ester having 8 to 18 carbon atoms and / or a salt thereof. The emulsified composition according to any one of claims 1 to 3, further comprising (E) a phosphocholine group-containing polymer. The emulsified composition according to any one of claims 1 to 4, wherein the (E) phosphocholine group-containing polymer is a 2-methacryloxyethyl phosphocholine choline / butyl methacrylate copolymer. The emulsified composition according to any one of claims 1 to 5, which has a pH of 5 to 7. The emulsified composition according to any one of claims 1 to 6, which is an oil-in-water emulsified form. A allantoin and / or stabilization method of a derivative in the emulsion composition containing allantoin及beauty heparin analogs,
During the emulsion composition, (A) allantoin及beauty (B) with heparinoid, blending (C) an anionic surfactant other than dipotassium glycyrrhizinate, and (D) an amine based alkaline agent, wherein the stabilizing method ..