JP2018193318A - Emulsion composition - Google Patents

Abstract

To provide a formulation technique whereby: in an emulsion composition containing allantoin and/or a derivative thereof, and a heparin analog, the decomposition of the allantoin and/or derivative thereof is inhibited, and the allantoin and/or derivative thereof is stably.SOLUTION: An emulsion composition contains allantoin and/or a derivative thereof, and a heparin analog, as well as a phosphocholine group-containing polymer and an amine alkali agent. The emulsion composition can inhibit the decomposition of the allantoin and/or derivative thereof, and stabilize the allantoin and/or derivative thereof.SELECTED DRAWING: None

Description

  The present invention relates to an emulsified composition containing allantoin and / or a derivative thereof and a heparin-like substance and capable of stably holding allantoin.

  Allantoin and its derivatives are known to have a tissue repair activating action, an anti-inflammatory action, an antipruritic action, and the like, and are widely used as active ingredients in compositions for external use. Heparin-like substances are known to have moisturizing action, anti-inflammatory action, blood circulation promoting action and the like, and have few side effects, and are therefore used as active ingredients in externally used compositions.

  In recent years, there has been a strong demand for improved functionality for externally applied compositions. Focusing on the functionality of allantoin and its derivatives, and heparin-like substances, the functionality has been improved by using these components in combination. A composition for external use has also been proposed. For example, Patent Document 1 discloses that an external pharmaceutical composition comprising a heparin-like substance, allantoin or a derivative thereof, and pantothenic acid or a derivative thereof can promote normal differentiation of epidermal keratinocytes into cells of each layer. ing.

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

  In addition, emulsified compositions such as creams and lotions have a good feeling of use and are widely accepted by consumers. However, in the emulsion composition containing allantoin and / or a derivative thereof and a heparin-like substance, sufficient investigation has not been made on a preparation technique for stably maintaining allantoin and / or a derivative thereof.

JP 2011-231128 A

  The present inventor studied to put an allantoin and / or derivative thereof and an emulsified composition containing a heparin-like substance into practical use, and in the emulsified composition, in a normal non-emulsified liquid agent, allantoin and / or a derivative thereof Even when the pH was adjusted to a low pH range that can suppress decomposition, a new problem was faced in that decomposition of allantoin and / or its derivatives could not be suppressed. That is, in an emulsion composition containing allantoin and / or a derivative thereof and a heparin-like substance, the allantoin and / or the derivative thereof cannot be stabilized unless a method different from that of a normal non-emulsified liquid is adopted. I faced a problem.

  Accordingly, an object of the present invention is to provide a preparation that stably retains allantoin and / or a derivative thereof in an emulsion composition containing allantoin and / or a derivative thereof and a heparin-like substance, by suppressing the decomposition of the allantoin and / or the derivative thereof. Is to provide technology.

  The present inventor has intensively studied to solve the above problems, and as a result, an emulsion composition containing a phosphocholine group-containing polymer and an amine alkaline agent together with allantoin and / or a derivative thereof, and a heparin-like substance, It has been found that the decomposition of allantoin and / or its derivatives can be suppressed, and that allantoin and / or its derivatives can be stabilized. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the invention of the aspect hung up below.
Item 1. An emulsified composition comprising (A) allantoin and / or a derivative thereof, (B) a heparin-like substance, (C) a phosphocholine group-containing polymer, and (D) an amine-based alkaline agent.
Item 2. Item 2. The emulsified composition according to Item 1, wherein the amine alkaline agent (D) is alkanolamine and / or arginine.
Item 3. Item 3. The emulsion composition according to Item 1 or 2, wherein the (C) phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer.
Item 4. Item 4. The emulsified composition according to any one of Items 1 to 3, wherein the pH is 5 to 7.
Item 5. Item 5. The emulsified composition according to any one of Items 1 to 4, which is an oil-in-water emulsified form.
Item 6. A method for stabilizing allantoin and / or a derivative thereof in an emulsion composition comprising allantoin and / or a derivative thereof and a heparin-like substance,
The stabilization method, wherein (A) an allantoin and / or derivative thereof, and (B) a heparin-like substance, (C) a phosphocholine group-containing polymer, and (D) an amine-based alkaline agent are blended in the emulsified composition. .

  According to the emulsion composition of the present invention, allantoin and / or a derivative thereof and a heparin-like substance can be contained, and decomposition of allantoin and / or a derivative thereof can be suppressed and stably maintained. Moreover, according to the emulsion composition of the present invention, it is possible to stabilize allantoin and / or its derivative without lowering the pH generally required for stabilizing allantoin and / or its derivative. Skin irritation caused by pH can also be suppressed.

1. Emulsified Composition The emulsified composition of the present invention comprises allantoin and / or a derivative thereof (sometimes referred to as (A) component), a heparin-like substance (sometimes referred to as (B) component), a phosphocholine group-containing weight. It is characterized by containing a coalescence (sometimes referred to as (C) component) and an amine alkaline agent (sometimes referred to as (D) component). In the emulsion composition of the present invention, allantoin and / or a derivative thereof, and a heparin-like substance, together with a phosphocholine group-containing polymer and an amine-based alkaline agent, are similar to allantoin and / or a derivative thereof and heparin in the emulsion composition. It is possible to suppress decomposition of allantoin and / or a derivative thereof caused by coexistence with a substance and to have 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 that is also referred to as 5-ureidohydantoin, and is a known drug known to have a tissue repair activating action, an anti-inflammatory action, an antipruritic action, and the like.

  The allantoin derivative is not particularly limited as long as it is pharmaceutically acceptable, and specific examples 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, either allantoin or a derivative thereof may be used as the component (A), or a combination thereof may be used. Among the components (A), allantoin is preferable from the viewpoint of further improving the stabilization effect.

  The content of the component (A) in the emulsion 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.

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

  The origin of the heparin-like substance used in the present invention is not particularly limited. For example, it is obtained by polysulfating mucopolysaccharides, tissues of edible animals (for example, tracheal cartilage such as cattle and pigs) And the like extracted from the lung including In the emulsified composition of the present invention, as the heparin-like substance, a heparin-like substance included in the Japanese Pharmacopoeia pharmaceutical standards is preferably used.

  The content of the component (B) in the emulsion 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 10,000 parts by weight, preferably 1 to 1000 parts by weight, and more preferably 10 to 300 parts by weight.

(C) Phosphocholine group-containing polymer A phosphocholine group-containing polymer is a polymer in which a monomer containing a phosphocholine group (hereinafter sometimes referred to as “phosphocholine group-containing monomer”) is polymerized, and has a moisturizing action. It is a well-known component which has etc.

  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-methacryloyloxyethyl phosphorylethanolamine. In the phosphocholine group-containing polymer, the phosphocholine group-containing monomer may be included singly or in combination of two or more. Among these phosphocholine group-containing monomers, 2-methacryloyloxyethyl phosphorylcholine is preferable from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivatives.

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

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

  The types of monomers other than the phosphocholine group-containing monomer contained in the phosphocholine group-containing polymer are pharmaceutically acceptable and are particularly limited to the extent that they can be radically polymerized with a phosphocholine group-containing monomer. Although it does not restrict | limit, For example, the monomer which has a vinyl group is mentioned. Specific examples of monomers other than phosphocholine group-containing monomers include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, 2- Alkyl (meth) acrylates such as ethylhexyl (meth) acrylate; benzyl (meth) acrylate, phenoxyethyl (meth) acrylate, cyclohexyl (meth) acrylate, polypropylene glycol mono (meth) acrylate, polytetramethylene glycol mono (meth) acrylate, Polypropylene glycol di (meth) acrylate, polytetramethylene glycol mono (meth) acrylate, polypropylene glycol polyethylene glycol mono (meth) acrylate, methacryl Sodium 2-hydroxy-3-methacryloyloxy propyl trimethyl ammonium, and the like. In the phosphocholine group-containing polymer, monomers other than the phosphocholine group-containing monomer may be included singly or in combination of two or more. Among these monomers other than phosphocholine group-containing monomers, alkyl (meth) acrylate and 2-hydroxy-3-methacryloyl are preferable from the viewpoint of further improving the stabilizing effect of allantoin and / or its derivatives. Oxypropyltrimethylammonium, more preferably an alkyl (meth) acrylate having 1 to 18 carbon atoms in the alkyl group, more preferably an alkyl (meth) acrylate having 3 to 5 carbon atoms in the alkyl group, particularly preferably butyl (meth) An acrylate is mentioned. In the present specification, “(meth) acrylate” refers to methacrylate and / or acrylate.

  Specific examples of the phosphocholine group-containing polymer used in the present invention include polymethacryloyloxyethyl phosphorylcholine homopolymer, 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer (polyquaternium-51), 2-methacryloyloxy. Ethylene phosphorylcholine / butyl methacrylate / sodium methacrylate copolymer (polyquaternium-65), 2-methacryloyloxyethyl phosphorylcholine / 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer (polyquaternium-64), 2-methacryloyloxy And ethyl phosphorylcholine / stearyl methacrylate copolymer (polyquaternium-61). In addition, in the said description regarding a phosphocholine group containing polymer, the name in a parenthesis shows a cosmetics component display name.

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

  Among these phosphocholine group-containing polymers, from the viewpoint of further improving the stabilizing effect of allantoin and / or derivatives thereof, 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer, polymethacryloyloxyethyl is preferable. 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 preferably 2-methacryloyloxyethylphospho Rukorin-butyl methacrylate copolymer.

  In the emulsified composition of the present invention, the content of the component (C) 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 derivatives thereof, the content of component (C) is preferably 0.05 to 0.5% by weight, more preferably 0.1 to 0.3%. % By weight.

  In the emulsion composition of the present invention, the ratio of the component (C) to the component (A) is determined according to the contents of the component (A) and the component (C), for example, 100 parts by weight of the component (A) The component (C) is 1 to 2000 parts by weight. From the viewpoint of further improving the stabilizing effect of allantoin and / or a derivative thereof as the ratio of the component (C) to the component (A), the component (C) is preferably 10 per 100 parts by weight of the component (A). -500 weight part, More preferably, 50-150 weight part is mentioned.

(D) Amine-based alkali agent An amine-based alkali 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 a derivative thereof, and also plays a role of adjusting the pH of the emulsified composition to a range described later.

  The type of amine 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 the amine-based alkali 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. Moreover, although it does not restrict | limit especially about carbon number of the hydroxyalkyl group couple | bonded with the nitrogen atom in alkanolamine, For example, 1-20, Preferably it is 2-5, More preferably, 2-3 is mentioned.

  As alkanolamines as amine-based alkali agents, specifically, monoalkanolamines such as monoethanolamine, monoisopropanolamine, 2-amino-2-methyl-1,3-propanediol; Examples include dialkanolamines such as isopropanolamine; trialkanolamines such as triethanolamine and triisopropanolamine.

  These amine alkali agents may be used alone or in combination of two or more.

  Among these amine-based alkali agents, from the viewpoint of further improving the stabilizing effect of allantoin and / or derivatives thereof, preferably alkanolamine, more preferably 1 to 3 hydroxyalkyl groups having 2 to 3 carbon atoms. Examples thereof include alkanolamines, more preferably dialkanolamines and trialkanolamines, particularly preferably diisopropanolamine and triethanolamine.

  What is necessary is just to set about content of (D) in the emulsion composition of this invention to the quantity from which the pH of the said emulsion composition will be 5-7, Preferably it will be 5-6.8. The emulsified composition containing allantoin and / or a derivative thereof and a heparin analog has a problem in the prior art that decomposition of allantoin and / or a derivative thereof cannot be suppressed at pH 5.5 or higher, which can reduce skin irritation. However, according to the present invention, by adjusting the pH using an amine-based alkaline agent, the decomposition of allantoin and / or its derivatives can be effectively suppressed even at pH 5.5 or higher, which can reduce irritation to the skin. It is possible to stabilize it. In view of the effects of the present invention, the content of (D) in the emulsified composition of the present invention is such that the pH of the emulsified composition is more preferably 5.5 to 6.8, particularly preferably 5. The amount which becomes 0.5-6.5 is mentioned.

(E) Anionic surfactant In addition to the components (A) to (D), the emulsified composition of the present invention may be an anionic surfactant (may be referred to as (E) component) as necessary. May be included. When an anionic surfactant is included, the stabilizing effect of allantoin and / or a derivative thereof can be further improved.

  The type of anionic surfactant used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, carbon such as lauryl sulfate, laureth sulfate, myristyl sulfate, cetyl sulfate, oleyl sulfate, etc. Alkyl sulfate esters and salts thereof of formula 8-18; Fatty acid ester sulfate esters and salts thereof such as hydrogenated coconut oil fatty acid monoglyceride monosulfate; Alkyl aryl sulfonates such as dodecylbenzenesulfonic acid and dodecylbenzenesulfonic acid triethanolamine Salts; polyoxyethylene alkyl ether sulfuric acid such as polyoxyethylene lauryl ether sulfuric acid and salts thereof; esters of 1,2-dihydroxypropanesulfonic acid and higher fatty acids and salts thereof; polyoxyethylene such as polyoxyethylene-lauryl sulfuric acid; Alkyl -Tersulfuric acid and salts thereof; polyoxyethylene alkyl ether carboxylic acids such as polyoxyethylene lauryl ether acetic acid and salts thereof; N-acyl sarcosine acids and salts thereof such as lauroyl sarcosine; myristoyl methyl taurine, palm oil fatty acid methyl taurine, lauryl methyl Higher fatty acid amide sulfonic acid sulfosuccinic acid di-2-ethylhexyl sulfosuccinic acid such as taurine, sulfosuccinic acid such as monolauroyl monoethanolamide polyoxyethylene sulfosuccinic acid, lauryl polypropylene glycol sulfosuccinic acid and salts thereof; N-coconut oil fatty acid acyl glutamic acid, N-acyl glutamic acid and salts thereof such as N-lauroyl glutamic acid, N-stearoyl glutamic acid, N-myristoyl glutamic acid; Kill ether carboxylic acid, polyoxyethylene-alkyl allyl ether carboxylic acid, α-olefin sulfonic acid, higher fatty acid ester sulfonic acid, secondary alcohol sulfate, higher fatty acid alkylolamide sulfate, lauroyl monoethanolamide succinic acid, N- Examples include palmitoyl aspartic acid and salts thereof.

  In addition, 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 individually by 1 type, and may be used in combination of 2 or more type.

  Among these anionic surfactants, from the viewpoint of further improving the stabilizing effect of allantoin and / or derivatives thereof, preferably alkyl sulfates having 8 to 18 carbon atoms and salts thereof; more preferably sodium lauryl sulfate. Sodium laureth sulfate, sodium myristyl sulfate, sodium cetyl sulfate, sodium oleyl sulfate; particularly preferably sodium lauryl sulfate, sodium laureth sulfate, sodium cetyl sulfate.

  When the component (E) is contained in the emulsified composition of the present invention, the content thereof is not particularly limited, and examples thereof include 0.1 to 10% by weight. The content of the component (E) 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 derivatives. It is done.

  Further, when the component (E) is contained in the emulsion composition of the present invention, the ratio of the component (E) to the component (A) is determined depending on the contents of the component (A) and the component (E), For example, the component (E) is 1 to 20000 parts by weight per 100 parts by weight of the component (A). From the viewpoint of further improving the stabilizing effect of allantoin and / or a derivative thereof as the ratio of the component (E) to the component (A), the component (E) is preferably 5 per 100 parts by weight of the component (A). -5000 weight part, More preferably, 10-1000 weight part is mentioned.

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, it is 20 to 90% by weight, preferably 30 to 80% by weight. 40 to 80% by weight is more preferable, and in the case of a water-in-oil type, 20 to 90% by weight, preferably 30 to 80% by weight, and more 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 used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. For example, vegetable oil, animal oil, mineral oil, cholesterol, fatty acid alkyl ester, fatty acid, Examples include higher alcohols and silicone oils.

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

  Specific examples of animal oils include lard, fish oil, 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 (plasty base, etc.), ceresin, microcrystalline wax, petrolatum and the like. These hydrocarbons may be used individually by 1 type, and may be used in combination of 2 or more type.

  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. Specifically, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, Examples 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 include lauric acid, myristic acid, palmitic acid, sebacic acid, oleic acid, linoleic acid, and the like. These fatty acids may be used alone or in combination of two or more.

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

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

  Among these oleaginous bases, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, and higher alcohols are preferable from the viewpoint of more effectively improving the anti-inflammatory action.

  These oil components 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, it is 5 to 20% by weight. In the case of a water-in-oil type, 1 to 80% by weight, preferably 3 to 50% by weight, and more preferably 5 to 20% by weight.

[Surfactants other than anionic surfactants]
The emulsion composition of the present invention may contain a surfactant other than the anionic surfactant as necessary. Such a surfactant is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include nonionic surfactants, cationic surfactants, and amphoteric surfactants. It is done. Among these surfactants, nonionic surfactants are preferable from the viewpoint of further improving the emulsion stability and the stabilizing effect of allantoin and / or derivatives thereof.

  Specific examples of the nonionic surfactant include polyoxyethylene hydrogenated castor oil; sorbitan fatty acid esters (for example, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monopalmitate). Stearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate); glycerin polyglycerin fatty acids (eg mono cottonseed oil fatty acid glycerin, glycerin monoerucate) Glyceryl sesquioleate, glyceryl monostearate, α, α'-oleic acid pyroglutamic acid glycerin, monostearic acid glycerin malic acid, etc.); propylene glycerin Cole fatty acid esters (eg, propylene glycol monostearate); Glycerin alkyl ether; Steareth-2; Polyoxyethylene sorbitan fatty acid esters (eg, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, poly Oxyethylene sorbitan tetraoleate, etc.); polyoxyethylene sorbite fatty acid esters (for example, polyoxyethylene sorbite monolaurate, P polyoxyethylene sorbite monooleate, polyoxyethylene sorbite pentaoleate, polyoxyethylene sorbite monostea) Polyoxyethylene glycerol fatty acid esters (for example, polyoxyethylene glycerol monostearate, polyoxyethylene) Polyglycerin monoisostearate, polyoxyethylene glycerin triisostearate, etc.); polyoxyethylene fatty acid esters (eg, polyoxyethylene monooleate, polyoxyethylene distearate, polyoxyethylene monodiolate, distearin) Polyoxyethylene alkyl ethers (for example, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, polyoxyethylene 2-octyldodecyl ether, polyoxy) Ethylene cholestanol ether, etc.); pluronic type (eg, pluronic, etc.); polyoxyethylene / polyoxypropylene alkyl ethers ( For example, polyoxyethylene / POP-cetyl ether, polyoxyethylene / polyoxypropylene-2-decyltetradecyl ether, polyoxyethylene / polyoxypropylene monobutyl ether, polyoxyethylene / polyoxypropylene hydrogenated lanolin, polyoxyethylene -Polyoxypropylene glycerol ether etc.); Steareth-21 etc. are mentioned. Among these nonionic surfactants, polyoxyethylene hydrogenated castor oil is preferable.

  These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the emulsified composition of the present invention, when a surfactant other than the anionic surfactant is contained, the content may be appropriately set according to the type of the surfactant to be used. 10 weight%, Preferably it is 2-9 weight%, More preferably, 3-8 weight% is mentioned.

[Polyhydric alcohol]
The emulsified composition of the present invention may contain a polyhydric alcohol as necessary for the purpose of enhancing the moisturizing action.

  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, glycerin and the like. . These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

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

[Thickener]
The emulsified composition of the present invention may contain a thickener, if necessary, in addition to the components described above, for viscosity adjustment and the like.

  The thickener is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but for example, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, Hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, sodium polyacrylate bentonite, dextrin fatty acid Examples include esters and pectin. Among these thickeners, carboxyvinyl polymer is preferable. These thickeners can be used alone or in combination of two or more.

  In the emulsified composition of the present invention, when a thickener is contained, the content may be appropriately set according to the type of the thickener used, etc., for example, 0.1 to 3% by weight, preferably 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 a medicinal component capable of exerting a pharmacological or cosmetic physiological function, if necessary, in addition to the components described above. Examples of such medicinal ingredients include steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthesia Agents (lidocaine, dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or salts thereof, alkyl benzoates (for example, ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate hydrochloride), orthocaine, oxesasein , Oxypolyentoxydecane, funnel extract, percamin ase, tesit decite, etc.), anti-inflammatory agents (allantoin, sacrificial) Tylic acid, glycol salicylate, methyl salicylate, indomethacin, ferbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, Ammonia water, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonyl acid vanillyl amide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.) Vitamins (vitamins A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.) That. These medicinal ingredients may be used alone or in combination of two or more. Moreover, what is necessary is just to set suitably about the content etc. of the medicinal component to be used, the effect to anticipate, etc., when these medicinal components are contained in the emulsion composition of this invention.

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

pH
The pH of the emulsified composition of the present invention may be set within the range shown in the column of “(D) amine alkaline agent”.

Formulation Form / Use The emulsified composition of the present invention may be either an oil-in-water type or a water-in-oil type, preferably an oil-in-water type. The emulsified composition of the present invention may be in a state where each component is solubilized.

  The formulation 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), and creams.

  The emulsified composition of the present invention is suitably used as an external preparation for transdermal application. Specific examples of the emulsified composition of the present invention include external medicines, external quasi drugs, cosmetics, skin cleansing agents and the like. Among these pharmaceutical forms, preferably, external medicines and quasi drugs are used.

  The emulsified composition of the present invention can exhibit a tissue repair activating action, an anti-inflammatory action, an antipruritic action, etc., based on the component (A) contained, and further, a moisturizing action, anti-inflammatory based on the ingredient (B) contained. It can be used suitably for the purpose of preventing or treating moisturizing, improving rough skin, dry skin diseases, inflammatory skin diseases, hypertrophic scars, keloids, and the like.

Production Method The emulsion composition of the present invention can be produced according to a known method for producing an emulsion composition. As a manufacturing method of the emulsion composition of this invention, the method shown below is mentioned, for example. First, the aqueous phase composition is prepared by mixing the component (A), the component (B), the component (C), water, and other water-soluble components added as necessary. Separately, an oil component and another water-soluble component added as necessary are mixed to prepare an oil phase composition. The component other than the component (E) and the component (E) may be added to and mixed with one or both of the aqueous phase composition and the oil phase composition. It is preferable to add to the product. Next, the obtained aqueous phase composition and oil phase composition are mixed and emulsified by an emulsification technique such as a homogenizer. At that time, the aqueous phase composition may be prepared by dividing into two or more, and may be mixed and emulsified stepwise with the oil phase composition. Then, the emulsion composition of this invention is manufactured by adding predetermined amount of (D) component and adjusting to desired pH.

2. The present invention further relates to a method for stabilizing allantoin and / or a derivative thereof in an emulsion composition comprising allantoin and / or a derivative thereof and a heparin-like substance, the emulsion composition comprising: (A) Allantoin and / or its derivative, and (B) a heparin-like substance, (C) a phosphocholine group-containing polymer, and (D) an amine-based alkaline agent. Provide a method.

  In the stabilization method of the present invention, the type and content of (A) to (D) to be used, the type and content of other components to be blended, the formulation form of the emulsion composition produced by emulsification, etc. The same as in the case of “1. Emulsion composition”.

  EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Test example 1
An oil-in-water emulsion composition (cream agent, Examples 1 to 9 and Comparative Examples 1 to 5) and a liquid agent (Reference Example 1) having the composition shown in Table 1 were produced and evaluated for the effect of inhibiting the decomposition of allantoin. The specific test method is as follows.

<Production of oil-in-water emulsion compositions (Examples 1 to 9 and Comparative Examples 1 to 5)>
First, the components shown in Table 1 (I) were mixed and dissolved to prepare an aqueous phase composition. Separately, the components shown in Table 1 (II) and (III) were mixed and dissolved while heating to prepare an oil phase composition. Subsequently, the composition for water phases and the composition for oil phases were mixed in the state heated at 80 degreeC, respectively, and it emulsified using the homogenizer. After emulsification, the component indicated by (IV) in Table 1 was added and adjusted to pH 5.5, and then cooled to room temperature to obtain an oil-in-water emulsion composition.

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

<Evaluation of allantoin decomposition inhibitory effect>
About the obtained emulsified composition and liquid, immediately after production and after storage at 50 ° C. for 30 days under shading conditions, the content of allantoin was determined 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 rate: 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 decomposition inhibiting effect of allantoin was evaluated according to the following criteria.

(Criteria for allantoin decomposition inhibition effect)
A: Decomposition rate of allantoin is 0 to 3.9%
A: Allantoin decomposition rate is 4.0 to 5.9%
Δ: Allantoin decomposition rate of 6.0 to 7.9%
×: Allantoin decomposition rate is 8% or more

<Result>
The obtained results are shown in Table 1. In a composition containing allantoin and a heparin-like substance, the allantoin was stable in the solution of pH 5.5 (Reference Example 1: Decomposition rate was 3.0%). (Comparative Examples 1 to 5: Decomposition rate was 8.0 to 11.4%). Further, in the emulsion composition containing allantoin and heparin-like substance, even when 2-methacryloyloxyethylphosphocholine / butyl methacrylate copolymer is contained, if potassium hydroxide is contained as an alkaline agent, the decomposition of allantoin Was observed (Comparative Example 5). In contrast, in an emulsion composition containing allantoin and a heparin-like substance, when an amine-based alkaline agent is contained as an alkaline agent together with a 2-methacryloyloxyethylphosphocholine / butyl methacrylate copolymer, the decomposition of allantoin is caused. The allantoin was stabilized (Examples 1 to 9: the decomposition rate of Example 1 was 4.0%, and the decomposition rate of Example 8 was 4.2%). Further, when an anionic surfactant was further contained, the effect of inhibiting the decomposition of allantoin was further improved (Examples 2 to 7 and 9: the decomposition rate was 1.8 to 3.4%).

Formulation Example Oil-in-water emulsion compositions (cream agents) (formulation examples 1 to 18) and lotion solutions (formulation examples 19 and 20) having the composition shown in Table 2 were prepared. When the obtained aqueous preparation was evaluated for the effect of inhibiting the decomposition of allantoin by the same method as in the above test example, the allantoin decomposition rate was low, and the stability of allantoin was improved.

Claims (6)

  An emulsified composition comprising (A) allantoin and / or a derivative thereof, (B) a heparin-like substance, (C) a phosphocholine group-containing polymer, and (D) an amine-based alkaline agent.   The emulsified composition according to claim 1, wherein the (D) amine alkaline agent is alkanolamine and / or arginine.   The emulsion composition according to claim 1 or 2, wherein the (C) phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer.   The emulsified composition according to any one of claims 1 to 3, wherein the pH is 5 to 7.   The emulsified composition according to any one of claims 1 to 4, which is an oil-in-water emulsified form. A method for stabilizing allantoin and / or a derivative thereof in an emulsion composition comprising allantoin and / or a derivative thereof and a heparin-like substance,
The stabilization method, wherein (A) an allantoin and / or derivative thereof, and (B) a heparin-like substance, (C) a phosphocholine group-containing polymer, and (D) an amine-based alkaline agent are blended in the emulsion composition. .