WO2012165468A1 - Method for manufacturing liquid crystalline composition containing lipophilic compound in high concentration, and liquid crystalline composition manufactured by said method - Google Patents

Method for manufacturing liquid crystalline composition containing lipophilic compound in high concentration, and liquid crystalline composition manufactured by said method Download PDF

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WO2012165468A1
WO2012165468A1 PCT/JP2012/063903 JP2012063903W WO2012165468A1 WO 2012165468 A1 WO2012165468 A1 WO 2012165468A1 JP 2012063903 W JP2012063903 W JP 2012063903W WO 2012165468 A1 WO2012165468 A1 WO 2012165468A1
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lipophilic compound
liquid crystal
group
fatty acid
acid
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PCT/JP2012/063903
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French (fr)
Japanese (ja)
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葉子 山口
山下　裕司
芳樹 久保田
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学校法人 聖マリアンナ医科大学
株式会社ナノエッグ
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Priority to JP2013518120A priority Critical patent/JP6054291B2/en
Publication of WO2012165468A1 publication Critical patent/WO2012165468A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0295—Liquid crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to a method for producing a liquid crystal composition containing a lipophilic compound at a high concentration, and a liquid crystal composition produced by the method.
  • the lyotropic liquid crystal is in an intermediate state between a solid and a liquid that maintain fluidity and regularity of molecular arrangement with surfactants and water as main components.
  • Lyotropic liquid crystals are used as emulsion stabilizers, solubilizers, and the like in various industrial fields such as pharmaceuticals, cosmetics, cleaning agents, paints, inks, fat products, and synthetic rubbers (for example, Patent Document 1). .
  • the lyotropic liquid crystal can be formed, for example, by adjusting an appropriate amphiphilic molecule (for example, a surfactant), a water-soluble component, and an oil-soluble component at appropriate concentrations.
  • an appropriate amphiphilic molecule for example, a surfactant
  • a water-soluble component for example, a water-soluble component
  • an oil-soluble component at appropriate concentrations.
  • a compound such as a drug is included in the lyotropic liquid crystal, there is an upper limit of the compound concentration that does not impair the structure of the liquid crystal, and in particular, there is a problem that the lipophilic compound cannot be included at a high concentration.
  • an object of the present invention is to provide a liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
  • the inventors of the present invention have made extensive studies in order to solve the above-mentioned problems.
  • the lipophilic compound or the lipophilic compound and the interface are used as the amphiphilic molecule.
  • a liquid crystal composition containing a lipophilic compound at a high concentration by adding / mixing a combination of activators and then reacting the lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide was found to be prepared.
  • a method for producing a liquid crystal composition containing a lipophilic compound, which has an ionic dissociation group as an amphiphilic molecule in a liquid crystal preparation process including adding and mixing an amphiphilic molecule and water Adding and mixing a lipophilic compound or a combination of the lipophilic compound and a surfactant, wherein the lipophilic compound is added and mixed in the form of an alkali metal salt or an alkaline earth metal salt.
  • a process comprising reacting the lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide.
  • the ionic dissociation group is selected from the group consisting of a carboxylic acid group, a sulfonic acid group, a sulfenic acid group, and a hydroperoxide group.
  • the lipophilic compound having an ionic dissociation group is selected from the group consisting of ⁇ -lipoic acid, ferulic acid, glycyrrhetinic acid, naproxen, mefenamic acid, docosahexaenoic acid, eicosapentaenoic acid, tamibarotene, chlorogenic acid, and cholesteryl sulfate The method according to (1) above.
  • Nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sucrose fatty acid esters, The method according to (6) above, which is at least one selected from the group consisting of propylene glycol fatty acid ester, monoglycerin fatty acid ester, diglycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene fatty acid ester.
  • liquid crystal preparation step further includes mixing a polyhydric alcohol.
  • liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
  • FIG. 1 is a photographic diagram showing the appearance of the compositions of Example 1 (A), Example 3 (B), Example 4 (C), and Example 5 (D) prepared in Preparation Examples 1 to 4. is there.
  • FIG. 2 is a histogram showing the residual ratio of ⁇ -lipoic acid in the composition of Example 1 after storage at 50 ° C. for 30 days.
  • lipophilic compound used in the present invention refers to any organic compound that is more easily soluble in an oil solvent than an aqueous solvent. Therefore, the lipophilic compound used in the present invention has both a lipophilic group and a hydrophilic group (that is, strictly amphiphilic), but has solubility in an oil solvent in an aqueous solvent. Contains higher organic compounds.
  • composition of the present invention a method for producing a liquid crystal composition containing a lipophilic compound (hereinafter also referred to as “method of the present invention”), and a liquid crystal composition produced by the method (hereinafter also referred to as “composition of the present invention”).
  • method of the present invention a method for producing a liquid crystal composition containing a lipophilic compound
  • composition of the present invention a liquid crystal composition produced by the method
  • the method of the present invention comprises a lipophilic drug having an ionic dissociation group as an amphiphilic molecule or a lipophilic drug and a surfactant in a liquid crystal preparation process including adding and mixing an amphiphilic molecule and water. And adding and mixing the combinations.
  • liquid crystal preparation process appropriately refers to amphiphilic molecules and water necessary for forming a liquid crystal and other optional components (eg, polyhydric alcohol, oil, co-surfactant).
  • the terms “in the liquid crystal formation process” or “in the liquid crystal formation process” refer to any stage of the process of preparing the lyotropic liquid crystal.
  • the lipophilic compound that can be used in the present invention has an ionic dissociation group necessary for salt formation with an alkali metal or alkaline earth metal.
  • ionic dissociation groups include, but are not limited to, carboxylic acid groups, sulfonic acid groups, sulfenic acid groups, hydroperoxide groups, and the like, and lipophilic compounds having these dissociation groups. Any of them is suitable for the present invention.
  • the ionic dissociation group is a carboxylic acid group.
  • lipophilic compounds examples include, but are not limited to, ⁇ -lipoic acid, ferulic acid, retinoic acid, indomethacin, glycyrrhizic acid, glycyrrhetinic acid, naproxen, mefenamic acid, docosahexaenoic acid, Examples include icosapentaenoic acid, tamibarotene, chlorogenic acid, cholesteryl sulfate, and the like.
  • the present inventors formed an alkali metal or alkaline earth metal salt into the amphiphilic molecule constituting the lyotropic liquid crystal in the lipophilic compound. It has been found that a liquid crystal composition containing a highly lipophilic compound can be prepared, which can impart similar physical properties and has all or part of the amphiphilic molecules constituting the liquid crystal as a lipophilic compound.
  • the method of the present invention adds a lipophilic compound in the form of an alkali metal salt or an alkaline earth metal salt in a liquid crystal preparation process including adding and mixing an amphiphilic molecule containing a lipophilic compound and water. Or a treatment of reacting a lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide.
  • the alkali metal or alkaline earth metal that can be used in the present invention is not particularly limited as long as it belongs to these, but sodium is preferable.
  • alkali metal or alkaline earth metal hydroxide or phosphorus oxide examples include, but are not limited to, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, phosphorus Examples include potassium phosphate, sodium phosphate, calcium phosphate, and magnesium phosphate. Preferably, sodium hydroxide is used.
  • a combination of a lipophilic compound and a surfactant is used as an amphiphilic molecule. It is preferable to use it. This is because by using the surfactant, the contact probability between the lipophilic compounds can be reduced, and the stability of the lipophilic compound in the liquid crystal composition can be significantly increased.
  • a surfactant is desired.
  • concentration of the lipophilic compound can be adjusted to a low level.
  • the surfactant that can be used in the present invention is not particularly limited as long as it can form a liquid crystal in combination with water and, if necessary, an oil component, a polyhydric alcohol, and an auxiliary surfactant, a nonionic surfactant, Either a cationic surfactant or an anionic surfactant may be used.
  • a nonionic surfactant is used.
  • an ionic surfactant is used as the surfactant, for example, when an alkali metal or alkaline earth metal hydroxide or phosphorous oxide is added, there is an ionic interaction between the surfactant and the lipophilic compound. As a result, the formation of desired liquid crystals may be hindered.
  • the nonionic surfactant used in the present invention may be any of an ester type, an ether type, an ester / ether type, and an amino acid type nonionic surfactant.
  • an ester type an ether type, an ester / ether type, and an amino acid type nonionic surfactant.
  • polyoxyethylene hydrogenated castor oil polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester , Propylene glycol fatty acid ester, monoglycerin fatty acid ester, diglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester and the like.
  • the polyoxyethylene hydrogenated castor oil used in the present invention can have any average degree of polymerization of ethylene oxide.
  • the lower limit of the average degree of polymerization of ethylene oxide is about 5 or more
  • the upper limit of the average degree of polymerization of ethylene oxide is about 200 or less.
  • preferred polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 80.
  • this number represents the average degree of polymerization of ethylene oxide.
  • the polyoxyethylene hydrogenated castor oil 40 indicates that the average degree of polymerization of ethylene oxide is 40.
  • the polyoxyethylene alkyl ether used in the present invention can have any average degree of polymerization of ethylene oxide.
  • the lower limit of the average degree of polymerization of ethylene oxide is about 5 or more, and the upper limit of the average degree of polymerization of ethylene oxide is about 30 or less.
  • polyoxyethylene alkyl ethers examples include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether (also referred to as POE stearyl ether), polyoxyethylene oleyl ether (also referred to as POE oleyl ether), polyoxyethylene octyldodecyl ether ( And POE octyldodecyl ether) and polyoxyethylene isostearyl ether (also referred to as POE isostearyl ether).
  • polyoxyethylene cetyl ether examples include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether (also referred to as POE stearyl ether), polyoxyethylene oleyl ether (also referred to as POE oleyl ether), polyoxyethylene octyldodecyl ether ( And POE octyldodecyl ether) and polyoxyethylene isostearyl ether (also referred to as PO
  • the polyoxyethylene sorbitan fatty acid ester used in the present invention can have any average degree of polymerization of ethylene oxide.
  • the lower limit of the average degree of polymerization of ethylene oxide is about 5 or more, and the upper limit of the average degree of polymerization of ethylene oxide is about 30 or less.
  • polyoxyethylene sorbitan acid esters examples include polyoxyethylene sorbitan monooleate (also referred to as POE sorbitan monooleate), polyoxyethylene sorbitan monolaurate (also referred to as POE sorbitan monolaurate), polyoxyethylene sorbitan Examples include monostearate (also referred to as POE sorbitan monostearate), polyoxyethylene sorbitan monopalmitate (also referred to as POE sorbitan monopalmitate) and polyoxyethylene sorbitan trioleate (also referred to as POE sorbitan trioleate).
  • polyoxyethylene sorbitan monooleate also referred to as POE sorbitan monooleate
  • polyoxyethylene sorbitan monolaurate also referred to as POE sorbitan monolaurate
  • polyoxyethylene sorbitan examples include monostearate (also referred to as POE sorbitan monostearate), polyoxyethylene sorbitan monopalmitate (also
  • the polyoxyethylene polyoxypropylene alkyl ether used in the present invention can have any average degree of polymerization of ethylene oxide.
  • the lower limit of the average degree of polymerization of the polyoxyethylene portion is about 5 or more, and the upper limit of the average degree of polymerization of the polyoxyethylene portion is about 30 or less.
  • the lower limit of the average degree of polymerization of the polyoxypropylene part is about 4 or more, and the upper limit of the average degree of polymerization of the polyoxypropylene part is about 8 or less.
  • polyoxyethylene polyoxypropylene alkyl ethers examples include polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene decyl tetradecyl Examples include ether and polyoxyethylene isostearyl ether.
  • polyglycerol fatty acid ester used in the present invention examples include decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monooleate and decaglycerol monostearate.
  • sucrose fatty acid esters used in the present invention include sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristic ester, and sucrose laurate.
  • the amino acid surfactant used in the present invention is not limited to this, but for example, lauroylglutamate dioctyldecesses-2, lauroylglutamate dioctyldecesses-5, lauroylglutamate disteales-2, lauroylglutamic acid Select from the group consisting of Disteales-5, PCA isostearic acid PEG-30 hydrogenated castor oil, PCA isostearic acid PEG-40 hydrogenated castor oil, PCA isostearic acid PEG-60 hydrogenated castor oil, PCA isostearic acid glyceres-25. Can do.
  • the nonionic surfactant used in the present invention is preferably one having an HLB value of about 5 or more.
  • the HLB value is 0 when the amount of hydrophilic groups in the molecule is 0%, and 20 when the amount is 100%.
  • the HLB value represents the size and strength of hydrophilic and hydrophobic groups that form a surfactant molecule in a surfactant, and a surfactant having a high hydrophobicity has a small HLB value and a high hydrophilicity. Has a large HLB value.
  • Nonionic surfactants may be used alone or in combination of two or more.
  • preferred nonionic surfactants include, for example, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene octyldodecyl ether and the like.
  • the cationic surfactant that can be used in the present invention may be any cationic surfactant of amine salt type, alkyl quaternary ammonium salt type, or cyclic quaternary ammonium salt type. Specific examples include, but are not limited to, diethylaminoethylamide stearate, lauryltrimethylammonium chloride, lauryltrimethylammonium bromide, dialkyldimethylammonium chloride, and benzalkonium chloride.
  • Anionic surfactants that can be used in the present invention include fatty acid salt type, alkyl ether carboxylate type, acyl lactate type, N-acyl sarcosinate type, N-acyl glutamate type, N-acyl methyl type Alanine salt type, N-acylmethyl taurate salt type, alkane sulfonate salt type, ⁇ -olefin sulfonate salt type, alkyl sulfosuccinate salt type, acyl isethionate salt type, alkyl sulfate ester salt type, alkyl ether sulfate ester salt type, Any of fatty acid alkanolamide sulfate salt type, monoacylglycerol sulfate ester salt type, and polyoxyethylene alkyl ether phosphate ester salt type may be used.
  • the amount of the amphiphilic molecule (ie, lipophilic compound and optional surfactant) to be blended may vary depending on the type of amphiphilic molecule used and the combination thereof.
  • the total weight of the composition may be 15 to 70% by weight, preferably 20 to 60% by weight, for example 40% by weight.
  • the mixing ratio of the lipophilic compound and the surfactant is not particularly limited.
  • ⁇ -lipoic acid or the like is stable depending on the concentration.
  • the amount of the surfactant is preferably an amount that does not fall below the amount of the lipophilic compound.
  • the blending ratio of lipophilic compound and surfactant is in the range of 1: 1 to 1:10, for example 1: 3.
  • the amount of alkali metal or alkaline earth metal hydroxide or phosphorous oxide added is Depending on the concentration of the oleophilic compound added, the amount is such that all of the oleophilic compound added forms an alkali metal salt or alkaline earth metal salt. Specifically, it may be added in a range of 0.25 to 1.5 times the molar amount of the ionic dissociation group of the lipophilic compound to be added.
  • the water used for liquid crystal preparation can be any water known to those skilled in the art.
  • tap water distilled water
  • ion exchange water sterilizing water, etc.
  • sterilizing water etc.
  • the amount of water blended can be appropriately determined by those skilled in the art according to the type and presence of other components used, such as the type of amphiphilic molecules and combinations thereof.
  • An exemplary range of such amounts is 3 to 85% by weight of the total weight of the composition of the present invention.
  • the method of the present invention may further include adding a polyhydric alcohol during the liquid crystal preparation process.
  • a polyhydric alcohol By adding a polyhydric alcohol, it may be useful in terms of facilitating the formation of liquid crystal (e.g. expansion of phase region) and stabilization.
  • the polyhydric alcohol that can be used in the present invention include, but are not limited to, polyalkylene glycols such as polymethylene glycol and polyethylene glycol, glycerin, propylene glycol, 1,3-propanediol, 2- Butene-1,4-diol, pentane-1,5-diol, 2,2-dimethylpropane-1,3-diol, 3-methylpentane-1,5-diol, pentane-1,2-diol, 2, Examples include 2,4-trimethylpentane-1,3-diol, 2-methylpropane-1,3-diol, hexylene glycol, 1,3-butylene glyco
  • the amount of polyhydric alcohol added is 70% by weight or less, preferably 50% by weight or less.
  • the method of the present invention may further include adding an oil during the liquid crystal preparation process.
  • an oil such as wheat germ oil, corn oil, sunflower oil, and soybean oil
  • silicone oils eg, isopropylmyristate, cetyl ethylhexanoate, glyceryl trioctanoate, Diethylene glycol monopropylene pentaerythritol ether, pentaerythrityl tetraoctanoate, etc.
  • squalane squalene
  • liquid paraffin for example, vitamin D, vitamin E
  • vitamins for example, vitamin D, vitamin E
  • vitamins for example, vitamin D, vitamin E
  • One oil may be used alone, or a plurality of oils may be used in combination.
  • the blending amount may vary depending on the type of the amphiphilic molecule and the lipophilic compound, but is preferably 0. 0 of the total weight of the composition of the present invention. It is in the range of 01 to 30% by weight.
  • the method of the present invention may further include adding an auxiliary surfactant during the liquid crystal preparation process.
  • an auxiliary surfactant By adding an auxiliary surfactant, it may be useful in that the interface film curvature can be reduced to facilitate the formation of a stable lyotropic liquid crystal.
  • auxiliary surfactants that can be used in the present invention include, but are not limited to, cholesterol, phytosterols, higher alcohols, and the like.
  • the blending amount of the auxiliary surfactant is not particularly limited as long as the formation of the lyotropic liquid crystal is not hindered.
  • the co-surfactant can be added in the range of 0.1 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the composition of the present invention.
  • the method of the present invention includes adding an aqueous or oily additional component generally used in cosmetics, pharmaceuticals, and industrial products in the liquid crystal preparation process as long as the liquid crystal structure is not impaired.
  • additional ingredients include, but are not limited to, humectants, preservatives, antioxidants, UV absorbers, cosmetic ingredients, vitamins (eg, vitamin B 1 , vitamin C), flavors , Flavoring agents, thickeners, color pigments, glitter pigments, organic powders, metal oxides, tar dyes, and the like.
  • the addition / blending component may be appropriately heated in the liquid crystal preparation process.
  • the order of addition and mixing of the above components is not particularly limited.
  • the liquid crystal composition of the present invention may be prepared by preparing a mixture of all components except the lipophilic compound and adding and mixing the lipophilic compound to the mixture, or adding and mixing all the components simultaneously. May be.
  • a liquid crystal composition containing a lipophilic compound can be produced in the range of 0.01 to 70% by weight of the total weight.
  • composition of the present invention thus produced also has pharmacological effects based on lipophilic compounds in addition to the physical properties inherent in liquid crystals (for example, the ability to stabilize emulsions and the ability to solubilize components). Therefore, it can be used as an external preparation for skin, for example, cosmetics, pharmaceuticals, or raw materials thereof.
  • the above-mentioned additional components can be included, it can also be used as an industrial product, for example, paint, ink, oil / fat product, synthetic rubber, or a raw material thereof.
  • ⁇ -lipoic acid product name: ⁇ -lipoic acid: manufactured by Tateyama Kasei Co., Ltd.
  • polyoxyethylene alkyl ether product name: NIKKOL BS-20: manufactured by Nikko Chemicals Co., Ltd.
  • polyoxyethylene alkyl ether (2.98 g) was added to a mixed solution of pure water (1.39 g) and glycerin (3.09 g), and heated and mixed until uniform. Subsequently, ⁇ -lipoic acid (0.83 g) was added and dispersed and dissolved while heating to 50 to 55 ° C. Next, 2.5 mol / L sodium hydroxide (1.61 g) was gradually added and stirred to obtain a transparent solution. To this solution, gradually add cetyl ethylhexanoate (0.1 g) or vitamin E (0.1 g), and heat and mix at about 80 ° C. to prepare a transparent gel composition (Examples 1 and 2). did.
  • Example 1A A photograph of the composition of Example 1 prepared according to this Preparation Example is shown in FIG. 1A.
  • Preparation Example 2 In this preparation example, ferulic acid (product name: ferulic acid: manufactured by Tsukino Food Industry Co., Ltd.) as a lipophilic compound, polyoxyethylene alkyl ether (product name: NIKKOL BS-20: manufactured by Nikko Chemicals) as a nonionic surfactant, The example which prepared the liquid crystal of this invention using glycerin (product name concentrated glycerin: Kao company make) as a polyhydric alcohol is shown.
  • glycerin product name concentrated glycerin: Kao company make
  • polyoxyethylene alkyl ether (3.01 g) was added to a mixed solution of pure water (1.37 g) and glycerin (3.05 g), and heated and mixed until uniform.
  • ferulic acid (0.84 g) was added and dispersed and dissolved while heating to about 50 ° C. 2.5 mol / L sodium hydroxide (1.73 g) was gradually added, and the mixture was heated and mixed to prepare a transparent gel composition (Example 3).
  • Example 3 prepared according to this Preparation Example is shown in FIG. 1B.
  • polyoxyethylene alkyl ether (3.26 g) was added to a mixed solution of pure water (1.44 g) and glycerin (3.21 g), and heated and mixed until uniform.
  • glycyrrhetinic acid (0.72 g) was added and dispersed and dissolved while heating to about 50 ° C.
  • 2.5 mol / L sodium hydroxide (0.68 g) was gradually added and stirred to obtain a transparent solution.
  • Cetyl ethylhexanoate (0.69 g) was gradually added to this solution, and heated and mixed at about 80 ° C. to prepare a transparent gel composition (Example 4).
  • Example 4 prepared according to this Preparation Example is shown in FIG. 1C.
  • This preparation example shows an example in which the liquid crystal of the present invention was prepared using ⁇ -lipoic acid (product name ⁇ -lipoic acid: manufactured by Tateyama Kasei Co., Ltd.) as the lipophilic compound.
  • ⁇ -lipoic acid product name ⁇ -lipoic acid: manufactured by Tateyama Kasei Co., Ltd.
  • ⁇ -lipoic acid (10 g) was completely dissolved in 0.26 mol / L sodium hydroxide (193.9 g), and this solution was freeze-dried for 24 to 48 hours to produce powdered ⁇ -lipoic acid sodium salt. did.
  • the obtained sodium ⁇ -lipoate (0.5 g) and purified water (0.5 g) were accurately weighed and heated and mixed at about 80 ° C. to prepare a transparent gel composition (Example 5). .
  • Table 1 shows the composition (w / w%) of each component of Examples 1 to 5 prepared in Preparation Examples 1 to 4.
  • Test example In this test example, the stability of ⁇ -lipoic acid in the composition of Example 1 was evaluated.
  • Example 1 The composition of Example 1 was stored in a constant temperature bath at 50 ° C. for one month, and the lipoic acid-containing concentration on the 30th day after storage was quantified using HPLC, and the residual ratio relative to ⁇ -lipoic acid at the time of preparation was calculated. did.
  • an aqueous solution containing an equal concentration of ⁇ -lipoic acid was used as a control. The result is shown in FIG.
  • liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
  • the liquid crystal composition of the present invention has a pharmacological effect based on a lipophilic compound in addition to the physical properties inherent in the liquid crystal (for example, the ability to stabilize emulsification and the ability to solubilize components).
  • a lipophilic compound for example, the ability to stabilize emulsification and the ability to solubilize components.
  • it can be used as a cosmetic, a pharmaceutical product, or a raw material thereof.

Abstract

Provided are: a method for manufacturing a liquid crystalline composition which contains a lipophilic compound, said composition having an enhanced lipophilic compound content; and a liquid crystalline composition manufactured by the method. The method comprises a liquid crystal preparation step of adding and mixing amphiphilic molecules and water and is characterized in that: either a lipophilic compound having an ionically dissociable group or a combination of the lipophilic compound with a surfactant is added and mixed as the amphiphilic molecules; and the lipophilic compound is added and mixed in the form of an alkali metal salt or an alkaline earth metal salt or subjected to a subsequent reaction with a hydroxide of an alkali or alkaline earth metal or a phosphate thereof.

Description

親油性化合物を高濃度で含有する液晶組成物の製造方法及びその方法によって製造された液晶組成物Method for producing liquid crystal composition containing lipophilic compound at high concentration and liquid crystal composition produced by the method
　本発明は、親油性化合物を高濃度で含有する液晶組成物を製造する方法、及び該方法によって製造された液晶組成物に関する。 The present invention relates to a method for producing a liquid crystal composition containing a lipophilic compound at a high concentration, and a liquid crystal composition produced by the method.
　リオトロピック液晶は、界面活性剤と水とを主要構成要素とする流動性と分子配列の規則性とを保持する固体と液体の中間状態である。リオトロピック液晶は、医薬品、化粧料、洗浄料、塗料、インキ、油脂製品、合成ゴムなど各種産業分野で、エマルションの乳化安定化剤や、可溶化剤などとして使用されている（例えば特許文献１）。 The lyotropic liquid crystal is in an intermediate state between a solid and a liquid that maintain fluidity and regularity of molecular arrangement with surfactants and water as main components. Lyotropic liquid crystals are used as emulsion stabilizers, solubilizers, and the like in various industrial fields such as pharmaceuticals, cosmetics, cleaning agents, paints, inks, fat products, and synthetic rubbers (for example, Patent Document 1). .
　また近年、リオトロピック液晶自体の生体への効果の報告もなされており、リオトロピック液晶の薬剤の経皮吸収性亢進効果や皮膚再生亢進効果が示唆されている（例えば特許文献２、３）。 In recent years, the effect of lyotropic liquid crystal itself on the living body has been reported, suggesting an effect of enhancing transdermal absorbability and enhancing skin regeneration of drugs of lyotropic liquid crystal (for example, Patent Documents 2 and 3).
特開２００７－１８１７８９号公報JP 2007-181789 A ＷＯ　２００６／１１８２４６WO 2006/118246 ＷＯ　２００６／１１８２４５WO 2006/118245
　かかる背景の下、現在、リオトロピック液晶の構造的規則性を維持したままその構造内に各種化合物を包接する組成物が提案されている。 Under such background, currently, a composition in which various compounds are included in the structure while maintaining the structural regularity of the lyotropic liquid crystal has been proposed.
　リオトロピック液晶は、例えば、適切な両親媒性分子（例えば界面活性剤）、水溶性成分及び油溶性成分を適切な濃度で調整することにより形成することができる。しかし、リオトロピック液晶に薬剤等の化合物を包接する場合には、液晶の構造を損なわない化合物の配合濃度上限があり、特に親油性化合物は高濃度で包接させることができないという問題があった。 The lyotropic liquid crystal can be formed, for example, by adjusting an appropriate amphiphilic molecule (for example, a surfactant), a water-soluble component, and an oil-soluble component at appropriate concentrations. However, when a compound such as a drug is included in the lyotropic liquid crystal, there is an upper limit of the compound concentration that does not impair the structure of the liquid crystal, and in particular, there is a problem that the lipophilic compound cannot be included at a high concentration.
　そこで本発明は、親油性化合物の含有量が高められた、親油性化合物含有の液晶組成物を提供することを目的とする。 Accordingly, an object of the present invention is to provide a liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
　本発明者らは、上記課題を解決すべく鋭意検討を重ねたところ、両親媒性分子及び水を混合することを含む液晶調製過程で、両親媒性分子として親油性化合物又は親油性化合物と界面活性剤の組合せを添加・混合し、次いで、親油性化合物とアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物とを反応させることにより、親油性化合物を高濃度で含有する液晶組成物が調製できることを見出した。 The inventors of the present invention have made extensive studies in order to solve the above-mentioned problems. As a result of the liquid crystal preparation process including mixing the amphiphilic molecule and water, the lipophilic compound or the lipophilic compound and the interface are used as the amphiphilic molecule. A liquid crystal composition containing a lipophilic compound at a high concentration by adding / mixing a combination of activators and then reacting the lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide Was found to be prepared.
　本発明は上記知見に基づくものであり、以下の特徴を包含する。
（１）親油性化合物を含有する液晶組成物の製造方法であって、両親媒性分子及び水を添加及び混合することを含む液晶調製過程で、両親媒性分子としてイオン性の解離基を有する親油性化合物又は該親油性化合物と界面活性剤との組み合わせを添加及び混合する工程を含んでおり、その際、該親油性化合物をアルカリ金属塩又はアルカリ土類金属塩の形態で添加及び混合するか、又は該親油性化合物とアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物とを反応させる処理を含んでいることを特徴とする、前記方法。 The present invention is based on the above findings and includes the following features.
(1) A method for producing a liquid crystal composition containing a lipophilic compound, which has an ionic dissociation group as an amphiphilic molecule in a liquid crystal preparation process including adding and mixing an amphiphilic molecule and water Adding and mixing a lipophilic compound or a combination of the lipophilic compound and a surfactant, wherein the lipophilic compound is added and mixed in the form of an alkali metal salt or an alkaline earth metal salt. Or a process comprising reacting the lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide.
（２）イオン性の解離基は、カルボン酸基、スルホン酸基、スルフェン酸基、ヒドロぺルオキシド基よりなる群から選択される、上記（１）記載の方法。 (2) The method according to (1) above, wherein the ionic dissociation group is selected from the group consisting of a carboxylic acid group, a sulfonic acid group, a sulfenic acid group, and a hydroperoxide group.
（３）イオン性の解離基を有する親油性化合物は、α‐リポ酸、フェルラ酸、グリチルレチン酸、ナプロキセン、メフェナム酸、ドコサヘキサエン酸、エイコサペンタエン酸、タミバロテン、クロロゲン酸、コレステリル硫酸よりなる群から選択される、上記（１）記載の方法。 (3) The lipophilic compound having an ionic dissociation group is selected from the group consisting of α-lipoic acid, ferulic acid, glycyrrhetinic acid, naproxen, mefenamic acid, docosahexaenoic acid, eicosapentaenoic acid, tamibarotene, chlorogenic acid, and cholesteryl sulfate The method according to (1) above.
（４）前記親油性化合物のアルカリ金属塩はナトリウム塩である、上記（１）記載の方法。 (4) The method according to (1) above, wherein the alkali metal salt of the lipophilic compound is a sodium salt.
（５）アルカリ金属の水酸化物は水酸化ナトリウムである、上記（１）記載の方法。 (5) The method according to (1) above, wherein the alkali metal hydroxide is sodium hydroxide.
（６）界面活性剤は非イオン界面活性剤である、上記（１）記載の方法。 (6) The method according to (1) above, wherein the surfactant is a nonionic surfactant.
（７）非イオン界面活性剤は、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル類、プロピレングリコール脂肪酸エステル、モノグリセリン脂肪酸エステル、ジグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステルよりなる群から選択される少なくとも１種である、上記（６）記載の方法。 (7) Nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sucrose fatty acid esters, The method according to (6) above, which is at least one selected from the group consisting of propylene glycol fatty acid ester, monoglycerin fatty acid ester, diglycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene fatty acid ester.
（８）前記液晶調製過程は多価アルコールを混合することをさらに含んでいる、上記（１）記載の方法。 (8) The method according to (1), wherein the liquid crystal preparation step further includes mixing a polyhydric alcohol.
（９）前記液晶調製過程は油分を混合することをさらに含んでいる、上記（１）記載の方法。 (9) The method according to (1), wherein the liquid crystal preparation process further includes mixing an oil component.
（１０）上記（１）～（９）のいずれか記載の方法によって製造された液晶組成物。 (10) A liquid crystal composition produced by the method according to any one of (1) to (9) above.
（１１）上記（１０）記載の液晶組成物を含んでいる皮膚外用剤。 (11) A skin external preparation containing the liquid crystal composition according to the above (10).
（１２）化粧料である上記（１１）記載の皮膚外用剤。 (12) The external preparation for skin according to (11), which is a cosmetic.
（１３）医薬品である上記（１１）記載の皮膚外用剤。 (13) The external preparation for skin according to (11), which is a pharmaceutical product.
　本発明によれば、親油性化合物の含有量が高められた、親油性化合物含有の液晶組成物が提供される。 According to the present invention, there is provided a liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
図１は、調製例１～４で調製した実施例１（Ａ）、実施例３（Ｂ）、実施例４（Ｃ）、及び実施例５（Ｄ）の組成物の外観を示す写真図である。FIG. 1 is a photographic diagram showing the appearance of the compositions of Example 1 (A), Example 3 (B), Example 4 (C), and Example 5 (D) prepared in Preparation Examples 1 to 4. is there. 図２は、５０℃で３０日間保管後の、実施例１の組成物中のα‐リポ酸残存率を示すヒストグラムである。FIG. 2 is a histogram showing the residual ratio of α-lipoic acid in the composition of Example 1 after storage at 50 ° C. for 30 days.
　本発明で使用する用語「親油性化合物」とは、水溶媒に比較して油溶媒により溶け易い任意の有機化合物をいう。したがって、本発明で使用する親油性化合物は、親油性基と親水性基の両方を有している（すなわち厳密にいえば両親媒性である）が、油溶媒に対する溶解性が水溶媒に対するものより高い有機化合物を含んでいる。 The term “lipophilic compound” used in the present invention refers to any organic compound that is more easily soluble in an oil solvent than an aqueous solvent. Therefore, the lipophilic compound used in the present invention has both a lipophilic group and a hydrophilic group (that is, strictly amphiphilic), but has solubility in an oil solvent in an aqueous solvent. Contains higher organic compounds.
　以下、親油性化合物を含有する液晶組成物の製造方法（以下、「本発明の方法」とも称する）、及び該方法によって製造された液晶組成物（以下、「本発明の組成物」とも称する）について説明する。 Hereinafter, a method for producing a liquid crystal composition containing a lipophilic compound (hereinafter also referred to as “method of the present invention”), and a liquid crystal composition produced by the method (hereinafter also referred to as “composition of the present invention”). Will be described.
　本発明の方法は、両親媒性分子及び水を添加及び混合することを含む液晶調製過程で、両親媒性分子としてイオン性の解離基を有する親油性薬剤又は該親油性薬剤と界面活性剤との組み合わせを添加及び混合する工程を含んでいる。本明細書で使用する用語「液晶調製過程」とは、液晶を形成するために必要な両親媒性分子及び水、並びに他の任意成分（例えば多価アルコール、油分、補助界面活性剤）を適切な比率で添加・混合して液晶を調製するプロセスをいう。この関連で、「液晶形成過程において」又は「液晶形成過程で」という文言は、リオトロピック液晶を調製するプロセスのいずれかの段階をいう。 The method of the present invention comprises a lipophilic drug having an ionic dissociation group as an amphiphilic molecule or a lipophilic drug and a surfactant in a liquid crystal preparation process including adding and mixing an amphiphilic molecule and water. And adding and mixing the combinations. As used herein, the term “liquid crystal preparation process” appropriately refers to amphiphilic molecules and water necessary for forming a liquid crystal and other optional components (eg, polyhydric alcohol, oil, co-surfactant). A process for preparing liquid crystals by adding and mixing them at various ratios. In this context, the terms “in the liquid crystal formation process” or “in the liquid crystal formation process” refer to any stage of the process of preparing the lyotropic liquid crystal.
　本発明で使用できる親油性化合物は、アルカリ金属又はアルカリ土類金属との塩形成に必要なイオン性の解離基を有するものである。イオン性の解離基として、これに限定されるものではないが、例えばカルボン酸基、スルホン酸基、スルフェン酸基、ヒドロぺルオキシド基などを挙げることができ、これらの解離基を有する親油性化合物であればいずれも本発明に好適である。好ましくは、イオン性の解離基はカルボン酸基である。 The lipophilic compound that can be used in the present invention has an ionic dissociation group necessary for salt formation with an alkali metal or alkaline earth metal. Examples of ionic dissociation groups include, but are not limited to, carboxylic acid groups, sulfonic acid groups, sulfenic acid groups, hydroperoxide groups, and the like, and lipophilic compounds having these dissociation groups. Any of them is suitable for the present invention. Preferably, the ionic dissociation group is a carboxylic acid group.
　本発明で使用できる親油性化合物としては、これに限定されるものではないが、例えばα‐リポ酸、フェルラ酸、レチノイン酸、インドメタシン、グリチルリチン酸、グリチルレチン酸、ナプロキセン、メフェナム酸、ドコサヘキサエン酸、エイコサペンタエン酸、タミバロテン、クロロゲン酸、コレステリル硫酸などを挙げることができる。 Examples of the lipophilic compounds that can be used in the present invention include, but are not limited to, α-lipoic acid, ferulic acid, retinoic acid, indomethacin, glycyrrhizic acid, glycyrrhetinic acid, naproxen, mefenamic acid, docosahexaenoic acid, Examples include icosapentaenoic acid, tamibarotene, chlorogenic acid, cholesteryl sulfate, and the like.
　本発明者らは、液晶調製過程で添加及び混合される親油性化合物について、アルカリ金属又はアルカリ土類金属の塩を形成させることにより、当該親油性化合物にリオトロピック液晶を構成する両親媒性分子に類似した物性を付与することができ、液晶を構成する両親媒性分子の全部又は一部を親油性化合物とする、親油性化合物高配合の液晶組成物を調製できることを見出した。 For the lipophilic compound added and mixed in the liquid crystal preparation process, the present inventors formed an alkali metal or alkaline earth metal salt into the amphiphilic molecule constituting the lyotropic liquid crystal in the lipophilic compound. It has been found that a liquid crystal composition containing a highly lipophilic compound can be prepared, which can impart similar physical properties and has all or part of the amphiphilic molecules constituting the liquid crystal as a lipophilic compound.
　したがって、本発明の方法は、親油性化合物を含む両親媒性分子と水とを添加及び混合することを含む液晶調製過程で、親油性化合物をアルカリ金属塩又はアルカリ土類金属塩の形態で添加するか、又は親油性化合物とアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物とを反応させる処理を含んでいることを特徴とする。 Therefore, the method of the present invention adds a lipophilic compound in the form of an alkali metal salt or an alkaline earth metal salt in a liquid crystal preparation process including adding and mixing an amphiphilic molecule containing a lipophilic compound and water. Or a treatment of reacting a lipophilic compound with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide.
　本発明で使用できるアルカリ金属又はアルカリ土類金属は、これらに属するものであれば特に制限されないが、好ましくはナトリウムである。 The alkali metal or alkaline earth metal that can be used in the present invention is not particularly limited as long as it belongs to these, but sodium is preferable.
　本発明で使用できるアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物として、これに限定されるものではないが、例えば水酸化カリウム、水酸化ナトリウム、水酸化カルシウム、水酸化マグネシウム、リン酸カリウム、リン酸ナトリウム、リン酸カルシウム、リン酸マグネシウムなどを挙げることができる。好ましくは、水酸化ナトリウムを使用する。 Examples of the alkali metal or alkaline earth metal hydroxide or phosphorus oxide that can be used in the present invention include, but are not limited to, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, phosphorus Examples include potassium phosphate, sodium phosphate, calcium phosphate, and magnesium phosphate. Preferably, sodium hydroxide is used.
　本発明において、例えば分子間の相互作用に起因して、濃度依存的に安定性が低下する親油性化合物を使用する場合には、両親媒性分子として親油性化合物と界面活性剤との組み合わせを使用することが好ましい。界面活性剤を使用することにより、親油性化合物同士の接触確率を低減させることができ、液晶組成物中の親油性化合物の安定性を顕著に高めることができるからである。 In the present invention, for example, when using a lipophilic compound whose stability decreases depending on the concentration due to interaction between molecules, a combination of a lipophilic compound and a surfactant is used as an amphiphilic molecule. It is preferable to use it. This is because by using the surfactant, the contact probability between the lipophilic compounds can be reduced, and the stability of the lipophilic compound in the liquid crystal composition can be significantly increased.
　また、親油性化合物の種類に応じて、適度に低い濃度（例えば本発明の組成物の総重量の１５重量％以下）で親油性化合物を含む液晶組成物を所望する場合には、界面活性剤の使用により、親油性化合物の濃度を低めに調整することができる。 In addition, when a liquid crystal composition containing a lipophilic compound at an appropriately low concentration (for example, 15% by weight or less of the total weight of the composition of the present invention) is desired depending on the type of the lipophilic compound, a surfactant is desired. The concentration of the lipophilic compound can be adjusted to a low level.
　本発明で使用できる界面活性剤は、水、及び必要に応じて油分、多価アルコール、補助界面活性剤と組み合わせることで液晶を形成できるものであれば特に制限されず、非イオン界面活性剤、陽イオン界面活性剤、陰イオン界面活性剤のいずれを用いてもよい。好ましくは、非イオン界面活性剤を使用する。界面活性剤としてイオン性界面活性剤を使用する場合、例えばアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物を添加した際に、界面活性剤と親油性化合物の間にイオン相互作用が発生し、その結果所望の液晶形成を阻害するおそれがある。 The surfactant that can be used in the present invention is not particularly limited as long as it can form a liquid crystal in combination with water and, if necessary, an oil component, a polyhydric alcohol, and an auxiliary surfactant, a nonionic surfactant, Either a cationic surfactant or an anionic surfactant may be used. Preferably, a nonionic surfactant is used. When an ionic surfactant is used as the surfactant, for example, when an alkali metal or alkaline earth metal hydroxide or phosphorous oxide is added, there is an ionic interaction between the surfactant and the lipophilic compound. As a result, the formation of desired liquid crystals may be hindered.
　本発明で使用される非イオン界面活性剤は、エステル型、エーテル型、エステル・エーテル型、及びアミノ酸系の非イオン界面活性剤のいずれであってもよい。例えば、これに限定されるものではないが、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル類、プロピレングリコール脂肪酸エステル、モノグリセリン脂肪酸エステル、ジグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステルなどが挙げられる。 The nonionic surfactant used in the present invention may be any of an ester type, an ether type, an ester / ether type, and an amino acid type nonionic surfactant. For example, but not limited to, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester , Propylene glycol fatty acid ester, monoglycerin fatty acid ester, diglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester and the like.
　本発明で使用されるポリオキシエチレン硬化ヒマシ油は、酸化エチレンの平均重合度が任意のものであることができる。好ましくは、酸化エチレンの平均重合度の下限は約５以上であり、酸化エチレンの平均重合度の上限は約２００以下である。好ましいポリオキシエチレン硬化ヒマシ油の例としては、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油６０及びポリオキシエチレン硬化ヒマシ油８０が挙げられる。なお、この数字は、酸化エチレンの平均重合度を表し、例えば、ポリオキシエチレン硬化ヒマシ油４０は、酸化エチレンの平均重合度が４０であることを示す。 The polyoxyethylene hydrogenated castor oil used in the present invention can have any average degree of polymerization of ethylene oxide. Preferably, the lower limit of the average degree of polymerization of ethylene oxide is about 5 or more, and the upper limit of the average degree of polymerization of ethylene oxide is about 200 or less. Examples of preferred polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 80. In addition, this number represents the average degree of polymerization of ethylene oxide. For example, the polyoxyethylene hydrogenated castor oil 40 indicates that the average degree of polymerization of ethylene oxide is 40.
　本発明で使用されるポリオキシエチレンアルキルエーテルは、酸化エチレンの平均重合度が任意のものであることができる。好ましくは、酸化エチレンの平均重合度の下限は約５以上であり、酸化エチレンの平均重合度の上限は約３０以下である。好ましいポリオキシエチレンアルキルエーテルの例としては、ポリオキシエチレンセチルエーテル、ポリオキシエチレンステアリルエーテル（ＰＯＥステアリルエーテルとも称する）、ポリオキシエチレンオレイルエーテル（ＰＯＥオレイルエーテルとも称する）、ポリオキシエチレンオクチルドデシルエーテル（ＰＯＥオクチルドデシルエーテルとも称する）及びポリオキシエチレンイソステアリルエーテル（ＰＯＥイソステアリルエーテルとも称する）が挙げられる。 The polyoxyethylene alkyl ether used in the present invention can have any average degree of polymerization of ethylene oxide. Preferably, the lower limit of the average degree of polymerization of ethylene oxide is about 5 or more, and the upper limit of the average degree of polymerization of ethylene oxide is about 30 or less. Examples of preferred polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether (also referred to as POE stearyl ether), polyoxyethylene oleyl ether (also referred to as POE oleyl ether), polyoxyethylene octyldodecyl ether ( And POE octyldodecyl ether) and polyoxyethylene isostearyl ether (also referred to as POE isostearyl ether).
　本発明で使用されるポリオキシエチレンソルビタン脂肪酸エステルは、酸化エチレンの平均重合度が任意のものであることができる。酸化エチレンの平均重合度の下限は約５以上であり、酸化エチレンの平均重合度の上限は約３０以下である。好ましいポリオキシエチレンソルビタン酸エステルの例としては、ポリオキシエチレンソルビタンモノオレエート（ＰＯＥソルビタンモノオレエートとも称する）、ポリオキシエチレンソルビタンモノラウレート（ＰＯＥソルビタンモノラウレートとも称する）、ポリオキシエチレンソルビタンモノステアレート（ＰＯＥソルビタンモノステアレートとも称する）、ポリオキシエチレンソルビタンモノパルミテート（ＰＯＥソルビタンモノパルミテートとも称する）及びポリオキシエチレンソルビタントリオレート（ＰＯＥソルビタントリオレートとも称する）が挙げられる。 The polyoxyethylene sorbitan fatty acid ester used in the present invention can have any average degree of polymerization of ethylene oxide. The lower limit of the average degree of polymerization of ethylene oxide is about 5 or more, and the upper limit of the average degree of polymerization of ethylene oxide is about 30 or less. Examples of preferred polyoxyethylene sorbitan acid esters include polyoxyethylene sorbitan monooleate (also referred to as POE sorbitan monooleate), polyoxyethylene sorbitan monolaurate (also referred to as POE sorbitan monolaurate), polyoxyethylene sorbitan Examples include monostearate (also referred to as POE sorbitan monostearate), polyoxyethylene sorbitan monopalmitate (also referred to as POE sorbitan monopalmitate) and polyoxyethylene sorbitan trioleate (also referred to as POE sorbitan trioleate).
　本発明で使用されるポリオキシエチレンポリオキシプロピレンアルキルエーテルは、酸化エチレンの平均重合度が任意のものであることができる。好ましくは、ポリオキシエチレン部分の平均重合度の下限は約５以上であり、ポリオキシエチレン部分の平均重合度の上限は約３０以下である。好ましくは、ポリオキシプロピレン部分の平均重合度の下限は約４以上であり、ポリオキシプロピレン部分の平均重合度の上限は約８以下である。好ましいポリオキシエチレンポリオキシプロピレンアルキルエーテルの例としては、ポリオキシエチレンポリオキシプロピレンセチルエーテル、ポリオキシエチレンポリオキシプロピレンセチルエーテル、ポリオキシエチレンポリオキシプロピレンセチルエーテル、ポリオキシエチレンポリオキシプロピレンデシルテトラデシルエーテル及びポリオキシエチレンイソステアリルエーテルが挙げられる。 The polyoxyethylene polyoxypropylene alkyl ether used in the present invention can have any average degree of polymerization of ethylene oxide. Preferably, the lower limit of the average degree of polymerization of the polyoxyethylene portion is about 5 or more, and the upper limit of the average degree of polymerization of the polyoxyethylene portion is about 30 or less. Preferably, the lower limit of the average degree of polymerization of the polyoxypropylene part is about 4 or more, and the upper limit of the average degree of polymerization of the polyoxypropylene part is about 8 or less. Examples of preferred polyoxyethylene polyoxypropylene alkyl ethers include polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene decyl tetradecyl Examples include ether and polyoxyethylene isostearyl ether.
　本発明に使用されるポリグリセリン脂肪酸エステルとしては、例えば、デカグリセリンモノラウレート、デカグリセリンモノミリステート、デカグリセリンモノオレート及びデカグリセリンモノステアレートが挙げられる。 Examples of the polyglycerol fatty acid ester used in the present invention include decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monooleate and decaglycerol monostearate.
　本発明に使用されるショ糖脂肪酸エステル類としては、例えば、ショ糖ステアリン酸エステル、ショ糖オレイン酸エステル、ショ糖パルミチン酸エステル、ショ糖ミリスチン酸エステル及びショ糖ラウリン酸エステルが挙げられる。 Examples of sucrose fatty acid esters used in the present invention include sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristic ester, and sucrose laurate.
　本発明に使用されるアミノ酸系界面活性剤は、これに限定されるものではないが、例えばラウロイルグルタミン酸ジオクチルドデセス－２、ラウロイルグルタミン酸ジオクチルドデセス－５、ラウロイルグルタミン酸ジステアレス－２、ラウロイルグルタミン酸ジステアレス－５、ＰＣＡイソステアリン酸ＰＥＧ－３０水添ヒマシ油、ＰＣＡイソステアリン酸ＰＥＧ－４０水添ヒマシ油、ＰＣＡイソステアリン酸ＰＥＧ－６０水添ヒマシ油、ＰＣＡイソステアリン酸グリセレス－２５よりなる群から選択することができる。 The amino acid surfactant used in the present invention is not limited to this, but for example, lauroylglutamate dioctyldecesses-2, lauroylglutamate dioctyldecesses-5, lauroylglutamate disteales-2, lauroylglutamic acid Select from the group consisting of Disteales-5, PCA isostearic acid PEG-30 hydrogenated castor oil, PCA isostearic acid PEG-40 hydrogenated castor oil, PCA isostearic acid PEG-60 hydrogenated castor oil, PCA isostearic acid glyceres-25. Can do.
　本発明で使用される非イオン界面活性剤は、好ましくは、約５以上のＨＬＢ値を有するものである。非イオン界面活性剤のＨＬＢ値が約５を下回る場合には、適切にリオトロピック液晶を調製できない虞がある。なお、本明細書で用いられる用語「ＨＬＢ値」とは、親水性疎水性バランス（Ｈｙｄｒｏｐｈｉｌｅ　Ｌｉｐｏｐｈｉｌｅ　Ｂａｌａｎｃｅ）をいい、一般に、２０×ＭＨ／Ｍ（式中、ＭＨ＝親水基部分の分子量であり、Ｍ＝分子全体の分子量である）により算出される。ＨＬＢ値は、分子中の親水基の量が０％のとき０であり、１００％のとき２０である。ＨＬＢ値は、界面活性剤では界面活性剤分子を形成する親水性および疎水性の基の大きさと強さを表し、疎水性の高い界面活性剤はＨＬＢ値が小さく、親水性の高い界面活性剤はＨＬＢ値が大きい。 The nonionic surfactant used in the present invention is preferably one having an HLB value of about 5 or more. When the HLB value of the nonionic surfactant is less than about 5, there is a possibility that the lyotropic liquid crystal cannot be appropriately prepared. The term “HLB value” used in the present specification refers to a hydrophilic-hydrophobic balance, generally 20 × M H / M (where M H = molecular weight of the hydrophilic group part). Yes, M = the molecular weight of the whole molecule). The HLB value is 0 when the amount of hydrophilic groups in the molecule is 0%, and 20 when the amount is 100%. The HLB value represents the size and strength of hydrophilic and hydrophobic groups that form a surfactant molecule in a surfactant, and a surfactant having a high hydrophobicity has a small HLB value and a high hydrophilicity. Has a large HLB value.
　非イオン界面活性剤は上記の１種を単独で用いてもよいし、複数種を組み合わせて用いてもよい。本発明の組成物において、好ましい非イオン界面活性剤として、例えばポリオキシエチレンステアリルエーテル、ポリオキシエチレンセチルエーテル、ポリオキシエチレンオクチルドデシルエーテルなどが挙げられる。 Nonionic surfactants may be used alone or in combination of two or more. In the composition of the present invention, preferred nonionic surfactants include, for example, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene octyldodecyl ether and the like.
　本発明で使用することができる陽イオン界面活性剤は、アミン塩型、アルキル４級アンモニウム塩型、環式四級アンモニウム塩型のいずれの陽イオン界面活性剤を用いてもよい。具体的に、これに限定されるものではないが、ステアリン酸ジエチルアミノエチルアミド、塩化ラウリルトリメチルアンモニウム、臭化ラウリルトリメチルアンモニウム、塩化ジアルキルジメチルアンモニウム、塩化ベンザルコニウムなどを挙げることができる。 The cationic surfactant that can be used in the present invention may be any cationic surfactant of amine salt type, alkyl quaternary ammonium salt type, or cyclic quaternary ammonium salt type. Specific examples include, but are not limited to, diethylaminoethylamide stearate, lauryltrimethylammonium chloride, lauryltrimethylammonium bromide, dialkyldimethylammonium chloride, and benzalkonium chloride.
　本発明に使用することができる陰イオン界面活性剤は、脂肪酸塩型、アルキルエーテルカルボン酸塩型、アシル乳酸塩型、Ｎ－アシルサルコシン酸塩型、Ｎ－アシルグルタミン酸塩型、Ｎ－アシルメチルアラニン塩型、Ｎ－アシルメチルタウリン塩型、アルカンスルホン酸塩型、α－オレフィンスルホン酸塩型、アルキルスルホコハク酸塩型、アシルイセチオン酸塩型、アルキル硫酸エステル塩型、アルキルエーテル硫酸エステル塩型、脂肪酸アルカノールアミド硫酸エステル塩型、モノアシルグリセリン硫酸エステル塩型、ポリオキシエチレンアルキルエーテルリン酸エステル塩型のいずれを用いてもよい。具体的に、これに限定されるものではないが、ヤシ油脂肪酸カリウム、パルミチン酸ナトリウム、ポリオキシエチレンラウリルエーテル酢酸、ポリオキシエチレンラウリルエーテル酢酸カリウム、ステアロイル乳酸ナトリウム、ラウロイルサルコシントリエタノールアミン、ミリストイルグルタミン酸カリウム、ヤシ油脂肪酸メチルアラニン、ラウロイルメチルアラニントリエタノールアミン、ココイルメチルアミノエチルスルホン酸ナトリウム、テトラデセンスルホン酸ナトリウム、スルホコハク酸ラウリル二ナトリウム、ヤシ油脂肪酸エチルエステルスルホン酸ナトリウム、アルキル硫酸トリエタノールアミン、アルキルエーテル硫酸ナトリウム、ポリオキシエチレンアルキルエーテル硫酸トリエタノールアミン、硬化ヤシ油脂肪酸グリセリル硫酸ナトリウム、ポリオキシエチレンアルキルエーテルリン酸トリエタノールアミンから選択することができる。 Anionic surfactants that can be used in the present invention include fatty acid salt type, alkyl ether carboxylate type, acyl lactate type, N-acyl sarcosinate type, N-acyl glutamate type, N-acyl methyl type Alanine salt type, N-acylmethyl taurate salt type, alkane sulfonate salt type, α-olefin sulfonate salt type, alkyl sulfosuccinate salt type, acyl isethionate salt type, alkyl sulfate ester salt type, alkyl ether sulfate ester salt type, Any of fatty acid alkanolamide sulfate salt type, monoacylglycerol sulfate ester salt type, and polyoxyethylene alkyl ether phosphate ester salt type may be used. Specifically, but not limited to, palm oil fatty acid potassium, sodium palmitate, polyoxyethylene lauryl ether acetic acid, potassium polyoxyethylene lauryl ether acetate, sodium stearoyl lactate, lauroyl sarcosine triethanolamine, myristoyl glutamic acid Potassium, coconut oil fatty acid methylalanine, lauroylmethylalanine triethanolamine, sodium cocoylmethylaminoethyl sulfonate, sodium tetradecene sulfonate, disodium lauryl sulfosuccinate, coconut oil fatty acid ethyl ester sulfonate sodium, alkyl sulfate triethanolamine, Sodium alkyl ether sulfate, polyoxyethylene alkyl ether triethanolamine sulfate, hardened coconut oil fatty acid grease It can be selected sodium Lil sulfate, polyoxyethylene alkyl ether phosphoric acid triethanolamine.
　本発明において、配合する両親媒性分子（すなわち親油性化合物、及び任意の界面活性剤）の量は、使用する両親媒性分子の種類及びその組み合わせに応じて変化する場合があるが、本発明の組成物の総重量の１５～７０重量％、好ましくは２０～６０重量％、例えば４０重量％とすることができる。 In the present invention, the amount of the amphiphilic molecule (ie, lipophilic compound and optional surfactant) to be blended may vary depending on the type of amphiphilic molecule used and the combination thereof. The total weight of the composition may be 15 to 70% by weight, preferably 20 to 60% by weight, for example 40% by weight.
　また両親媒性分子として親油性化合物と界面活性剤との組み合わせを使用する場合、親油性化合物と界面活性剤の配合比は特に制限されないが、例えばα‐リポ酸など、濃度依存的に安定性が低下する親油性化合物を用いる場合には、界面活性剤の量が親油性化合物の量を下回らない量であることが好ましい。好ましくは、親油性化合物と界面活性剤の配合比は、１：１～１：１０の範囲、例えば１：３である。 In addition, when a combination of a lipophilic compound and a surfactant is used as an amphiphilic molecule, the mixing ratio of the lipophilic compound and the surfactant is not particularly limited. For example, α-lipoic acid or the like is stable depending on the concentration. In the case of using a lipophilic compound that decreases the amount of the surfactant, the amount of the surfactant is preferably an amount that does not fall below the amount of the lipophilic compound. Preferably, the blending ratio of lipophilic compound and surfactant is in the range of 1: 1 to 1:10, for example 1: 3.
　本発明の方法において、親油性化合物とアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物とを反応させる場合、アルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物の添加量は、添加する親油性化合物の濃度に応じて、添加する親油性化合物の全てがアルカリ金属塩又はアルカリ土類金属塩を形成するような量である。具体的に、添加する親油性化合物のイオン性解離基に対して、０．２５～１．５倍モル量の範囲で添加すればよい。 In the method of the present invention, when a lipophilic compound is reacted with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide, the amount of alkali metal or alkaline earth metal hydroxide or phosphorous oxide added is Depending on the concentration of the oleophilic compound added, the amount is such that all of the oleophilic compound added forms an alkali metal salt or alkaline earth metal salt. Specifically, it may be added in a range of 0.25 to 1.5 times the molar amount of the ionic dissociation group of the lipophilic compound to be added.
　本発明において、液晶調製に使用される水は、当業者に公知の任意の水であることができる。例えば、これに限定されるものではないが、水道水、蒸留水、イオン交換水、殺菌水などを使用することができる。 In the present invention, the water used for liquid crystal preparation can be any water known to those skilled in the art. For example, although not limited to this, tap water, distilled water, ion exchange water, sterilizing water, etc. can be used.
　本発明において、水の配合量は、両親媒性分子の種類及びその組み合わせ等、使用する他の構成成分の種類や存否に応じて、当業者は適宜適切な量を設定することができる。そのような量の例示的範囲は、本発明の組成物の総重量の３～８５重量％である。 In the present invention, the amount of water blended can be appropriately determined by those skilled in the art according to the type and presence of other components used, such as the type of amphiphilic molecules and combinations thereof. An exemplary range of such amounts is 3 to 85% by weight of the total weight of the composition of the present invention.
　本発明の方法は、液晶調製過程で多価アルコールを添加することをさらに含んでもよい。多価アルコールを添加することにより、液晶の形成容易化（相領域の拡大など）や安定化を図ることができる点で有用である場合がある。本発明で使用することができる多価アルコールとしては、これに限定されるものではないが、ポリメチレングリコール、ポリエチレングリコールなどのポリアルキレングリコール、グリセリン、プロピレングリコール、１，３－プロパンジオール、２－ブテン－１，４－ジオール、ペンタン－１，５－ジオール、２，２－ジメチルプロパン－１，３－ジオール、３－メチルペンタン－１，５－ジオール、ペンタン－１，２－ジオール、２，２，４－トリメチルペンタン－１，３－ジオール、２－メチルプロパン－１，３－ジオール、ヘキシレングリコール、１，３－ブチレングリコール、ジプロピレングリコール、ジエチレングリコール、トリエチレングリコールなどが挙げられる。多価アルコールは１種を単独で用いてもよいし、複数種を組み合わせて用いてもよい。 The method of the present invention may further include adding a polyhydric alcohol during the liquid crystal preparation process. By adding a polyhydric alcohol, it may be useful in terms of facilitating the formation of liquid crystal (e.g. expansion of phase region) and stabilization. Examples of the polyhydric alcohol that can be used in the present invention include, but are not limited to, polyalkylene glycols such as polymethylene glycol and polyethylene glycol, glycerin, propylene glycol, 1,3-propanediol, 2- Butene-1,4-diol, pentane-1,5-diol, 2,2-dimethylpropane-1,3-diol, 3-methylpentane-1,5-diol, pentane-1,2-diol, 2, Examples include 2,4-trimethylpentane-1,3-diol, 2-methylpropane-1,3-diol, hexylene glycol, 1,3-butylene glycol, dipropylene glycol, diethylene glycol, and triethylene glycol. A polyhydric alcohol may be used individually by 1 type, and may be used in combination of multiple types.
　多価アルコールの添加量は、７０重量％以下、好ましくは５０重量％以下である。多価アルコールを使用する場合、好ましくは、水及び多価アルコールの合計量が本発明の組成物の総重量の８５％を超えないことが好ましい。水及び多価アルコールの合計量が本発明の組成物の総重量の８５％を超えると、リオトロピック液晶が適切に形成されない虞があるからである。 The amount of polyhydric alcohol added is 70% by weight or less, preferably 50% by weight or less. When using a polyhydric alcohol, it is preferred that the total amount of water and polyhydric alcohol does not exceed 85% of the total weight of the composition of the present invention. This is because if the total amount of water and polyhydric alcohol exceeds 85% of the total weight of the composition of the present invention, the lyotropic liquid crystal may not be formed properly.
　本発明の方法は、液晶調製過程で油分を添加することをさらに含んでもよい。油分を添加することにより、リオトロピック液晶の形成容易化（相領域の拡大）及び安定に親油性化合物を界面に配向することができる。本発明で使用できる油分としては、小麦胚芽油やトウモロコシ油やヒマワリ油やダイズ油などの植物油、シリコーン油、エステル油（例えば、イソプリピルミリステート、エチルヘキサン酸セチル、グリセリルトリオクタノエート、ジエチレングリコールモノプロピレンペンタエリスリトールエーテル、ペンタエリスリチルテトラオクタノエートなど）、スクアラン、スクアレン、流動パラフィン、ポリブテン、ビタミン類（例えばビタミンＤ、ビタミンＥ）などが挙げられる。油分は、１種を単独で用いてもよいし、複数種を組み合わせて用いてもよい。 The method of the present invention may further include adding an oil during the liquid crystal preparation process. By adding the oil, it is possible to facilitate the formation of the lyotropic liquid crystal (expansion of the phase region) and to stably align the lipophilic compound at the interface. Examples of oils that can be used in the present invention include vegetable oils such as wheat germ oil, corn oil, sunflower oil, and soybean oil, silicone oils, ester oils (eg, isopropylmyristate, cetyl ethylhexanoate, glyceryl trioctanoate, Diethylene glycol monopropylene pentaerythritol ether, pentaerythrityl tetraoctanoate, etc.), squalane, squalene, liquid paraffin, polybutene, vitamins (for example, vitamin D, vitamin E) and the like. One oil may be used alone, or a plurality of oils may be used in combination.
　本発明の組成物に油分を配合する場合、その配合量は両親媒性分子及び親油性化合物の種類に応じて変化する場合があるが、好ましくは、本発明の組成物の総重量の０．０１～３０重量％の範囲である。 When the oil component is blended in the composition of the present invention, the blending amount may vary depending on the type of the amphiphilic molecule and the lipophilic compound, but is preferably 0. 0 of the total weight of the composition of the present invention. It is in the range of 01 to 30% by weight.
　本発明の方法は、液晶調製過程で補助界面活性剤を添加することをさらに含んでもよい。補助界面活性剤を添加することによって、界面膜曲率を低減させて、安定なリオトロピック液晶の形成の容易化を図ることができる点で有用である場合がある。本発明で使用することができる補助界面活性剤としては、これに限定されるものではないが、例えばコレステロール、フィトステロール、高級アルコールなどを挙げることができる。 The method of the present invention may further include adding an auxiliary surfactant during the liquid crystal preparation process. By adding an auxiliary surfactant, it may be useful in that the interface film curvature can be reduced to facilitate the formation of a stable lyotropic liquid crystal. Examples of auxiliary surfactants that can be used in the present invention include, but are not limited to, cholesterol, phytosterols, higher alcohols, and the like.
　補助界面活性剤の配合量は、リオトロピック液晶の形成を妨げない限り特に制限されない。例えば、補助界面活性剤は、本発明の組成物の総重量の０．１～１０重量％、好ましくは１～５重量％の範囲で配合することができる。 The blending amount of the auxiliary surfactant is not particularly limited as long as the formation of the lyotropic liquid crystal is not hindered. For example, the co-surfactant can be added in the range of 0.1 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the composition of the present invention.
　本発明の方法は、上記成分の他に、液晶調製過程で、化粧料、医薬品、工業製品で一般的に用いられる水性又は油性の付加成分を、液晶構造を損なわない範囲で添加することを含んでもよい。そのような付加成分の例には、これに限定されるものではないが、保湿剤や防腐剤、酸化防止剤、紫外線吸収剤、美容成分、ビタミン類（例えばビタミンＢ１、ビタミンＣ）、香料、保香剤、増粘剤、着色顔料、光輝性顔料、有機粉体、金属酸化物、タール色素などを挙げることができる。 In addition to the above components, the method of the present invention includes adding an aqueous or oily additional component generally used in cosmetics, pharmaceuticals, and industrial products in the liquid crystal preparation process as long as the liquid crystal structure is not impaired. But you can. Examples of such additional ingredients include, but are not limited to, humectants, preservatives, antioxidants, UV absorbers, cosmetic ingredients, vitamins (eg, vitamin B 1 , vitamin C), flavors , Flavoring agents, thickeners, color pigments, glitter pigments, organic powders, metal oxides, tar dyes, and the like.
　本発明の方法において、添加・配合成分の混合を容易化するために、液晶調製過程で適宜、添加・配合成分の加熱処理を含んでもよい。 In the method of the present invention, in order to facilitate mixing of the addition / blending component, the addition / blending component may be appropriately heated in the liquid crystal preparation process.
　本発明の方法において、上記各成分の添加・混合順序は特に制限されない。例えば、親油性化合物を除く全ての成分の混合物を調製し、該混合物に親油性化合物を添加・混合して本発明の液晶組成物を製造してもよいし、全ての成分を同時に添加・混合してもよい。 In the method of the present invention, the order of addition and mixing of the above components is not particularly limited. For example, the liquid crystal composition of the present invention may be prepared by preparing a mixture of all components except the lipophilic compound and adding and mixing the lipophilic compound to the mixture, or adding and mixing all the components simultaneously. May be.
　本発明の方法によれば、総重量の０．０１～７０重量％の範囲で親油性化合物を含有した液晶組成物を製造することができる。 According to the method of the present invention, a liquid crystal composition containing a lipophilic compound can be produced in the range of 0.01 to 70% by weight of the total weight.
　また、こうして製造される本発明の組成物は、また、液晶が本来的に有する物性（例えば乳化の安定化能、成分の可溶化能）の他、親油性化合物に基づく薬理効果も有しているため、皮膚外用剤、例えば、化粧料、医薬品、又はその原料として使用することができる。 Further, the composition of the present invention thus produced also has pharmacological effects based on lipophilic compounds in addition to the physical properties inherent in liquid crystals (for example, the ability to stabilize emulsions and the ability to solubilize components). Therefore, it can be used as an external preparation for skin, for example, cosmetics, pharmaceuticals, or raw materials thereof.
　更に、上述したような付加成分を含ませることもできるため、工業製品、例えば、塗料、インキ、油脂製品、合成ゴム、又は、その原料として使用することもできる。 Furthermore, since the above-mentioned additional components can be included, it can also be used as an industrial product, for example, paint, ink, oil / fat product, synthetic rubber, or a raw material thereof.
　以下、本発明を実施例により詳細に説明するが、本発明は下記実施例に制限されるものではない。 Hereinafter, the present invention will be described in detail by way of examples. However, the present invention is not limited to the following examples.
（調製例１）
　本調製例では、親油性化合物としてα‐リポ酸（製品名　α-リポ酸：立山化成社製）、非イオン界面活性剤としてポリオキシエチレンアルキルエーテル（製品名　ＮＩＫＫＯＬ　ＢＳ－２０：日光ケミカルズ社製）、多価アルコールとしてグリセリン（製品名　濃グリセリン：花王社製）、油分としてエチルヘキサン酸セチル（製品名　ＣＩＯ：日光ケミカルズ社製）又はビタミンＥ（製品名　ｄｌ-α-トコフェロール：ＤＳＭ社製）を用いて本発明の液晶を調製した例を示す。 (Preparation Example 1)
In this preparation example, α-lipoic acid (product name: α-lipoic acid: manufactured by Tateyama Kasei Co., Ltd.) as a lipophilic compound, and polyoxyethylene alkyl ether (product name: NIKKOL BS-20: manufactured by Nikko Chemicals Co., Ltd.) as a nonionic surfactant. ), Glycerin (product name: concentrated glycerin: manufactured by Kao Corporation) as polyhydric alcohol, and cetyl ethylhexanoate (product name: CIO: manufactured by Nikko Chemicals) or vitamin E (product name: dl-α-tocopherol: manufactured by DSM) as the oil component The example which prepared the liquid crystal of this invention using this is shown.
　まず、純水（１．３９ｇ）およびグリセリン（３．０９ｇ）の混合溶液にポリオキシエチレンアルキルエーテル（２．９８ｇ）を添加し、均一になるまで加熱・混合した。次いで、α‐リポ酸（０．８３ｇ）を添加し、５０～５５℃に加熱しながら分散・溶解した。次いで、２．５ｍｏｌ／Ｌ水酸化ナトリウム（１．６１ｇ）を徐々に添加・撹拌し、透明な溶液を得た。この溶液にエチルヘキサン酸セチル（０．１ｇ）又はビタミンＥ（０．１ｇ）を徐々に添加し、約８０℃で加熱・混合し、透明なゲル状組成物（実施例１、２）を調製した。 First, polyoxyethylene alkyl ether (2.98 g) was added to a mixed solution of pure water (1.39 g) and glycerin (3.09 g), and heated and mixed until uniform. Subsequently, α-lipoic acid (0.83 g) was added and dispersed and dissolved while heating to 50 to 55 ° C. Next, 2.5 mol / L sodium hydroxide (1.61 g) was gradually added and stirred to obtain a transparent solution. To this solution, gradually add cetyl ethylhexanoate (0.1 g) or vitamin E (0.1 g), and heat and mix at about 80 ° C. to prepare a transparent gel composition (Examples 1 and 2). did.
　これらゲル状組成物が液晶であることは、偏光顕微鏡及び小角Ｘ線散乱によって確認した。本調製例に従って調製した実施例１の組成物の写真図を図１Ａに示す。 It was confirmed by a polarizing microscope and small angle X-ray scattering that these gel compositions were liquid crystals. A photograph of the composition of Example 1 prepared according to this Preparation Example is shown in FIG. 1A.
（調製例２）
　本調製例では、親油性化合物としてフェルラ酸（製品名　フェルラ酸：築野食品工業社製）、非イオン界面活性剤としてポリオキシエチレンアルキルエーテル（製品名　ＮＩＫＫＯＬ　ＢＳ－２０：日光ケミカルズ社製）、多価アルコールとしてグリセリン（製品名　濃グリセリン：花王社製）を用いて本発明の液晶を調製した例を示す。 (Preparation Example 2)
In this preparation example, ferulic acid (product name: ferulic acid: manufactured by Tsukino Food Industry Co., Ltd.) as a lipophilic compound, polyoxyethylene alkyl ether (product name: NIKKOL BS-20: manufactured by Nikko Chemicals) as a nonionic surfactant, The example which prepared the liquid crystal of this invention using glycerin (product name concentrated glycerin: Kao company make) as a polyhydric alcohol is shown.
　まず、純水（１．３７ｇ）およびグリセリン（３．０５ｇ）の混合溶液にポリオキシエチレンアルキルエーテル（３．０１ｇ）を添加し、均一になるまで加熱・混合した。次いで、フェルラ酸（０．８４ｇ）を添加し、約５０℃に加熱しながら分散・溶解した。２．５ｍｏｌ／Ｌ水酸化ナトリウム（１．７３ｇ）を徐々に添加し、加熱・混合して透明なゲル状組成物（実施例３）を調製した。 First, polyoxyethylene alkyl ether (3.01 g) was added to a mixed solution of pure water (1.37 g) and glycerin (3.05 g), and heated and mixed until uniform. Next, ferulic acid (0.84 g) was added and dispersed and dissolved while heating to about 50 ° C. 2.5 mol / L sodium hydroxide (1.73 g) was gradually added, and the mixture was heated and mixed to prepare a transparent gel composition (Example 3).
　このゲル状組成物が液晶であることは、偏光顕微鏡及び小角Ｘ線散乱によって確認した。本調製例に従って調製した実施例３の組成物の写真図を図１Ｂに示す。 It was confirmed by a polarizing microscope and small angle X-ray scattering that the gel composition was a liquid crystal. A photograph of the composition of Example 3 prepared according to this Preparation Example is shown in FIG. 1B.
（調製例３）
　本調製例では、親油性化合物としてグリチルレチン酸（製品名　グリチルレチン酸：丸善製薬社製）、非イオン界面活性剤としてポリオキシエチレンアルキルエーテル（製品名　ＮＩＫＫＯＬ　ＢＳ－２０：日光ケミカルズ社製）、多価アルコールとしてグリセリン（製品名　濃グリセリン：花王社製）、油分としてエチルヘキサン酸セチル（製品名　ＣＩＯ：日光ケミカルズ社製）を用いて本発明の液晶を調製した例を示す。 (Preparation Example 3)
In this preparation example, glycyrrhetic acid (product name: glycyrrhetinic acid: manufactured by Maruzen Pharmaceutical Co., Ltd.) as the lipophilic compound, polyoxyethylene alkyl ether (product name: NIKKOL BS-20: manufactured by Nikko Chemicals) as the nonionic surfactant, polyvalent An example in which the liquid crystal of the present invention was prepared using glycerin (product name: concentrated glycerin: manufactured by Kao Corporation) as an alcohol and cetyl ethylhexanoate (product name: CIO: manufactured by Nikko Chemicals) as an oil component is shown.
　まず、純水（１．４４ｇ）およびグリセリン（３．２１ｇ）の混合溶液にポリオキシエチレンアルキルエーテル（３．２６ｇ）を添加し、均一になるまで加熱・混合した。次いで、グリチルレチン酸（０．７２ｇ）を添加し、約５０℃に加熱しながら分散・溶解した。２．５ｍｏｌ／Ｌ水酸化ナトリウム（０．６８ｇ）を徐々に添加・撹拌し、透明な溶液を得た。この溶液にエチルヘキサン酸セチル（０．６９ｇ）を徐々に添加し、約８０℃で加熱・混合し、透明なゲル状組成物（実施例４）を調製した。 First, polyoxyethylene alkyl ether (3.26 g) was added to a mixed solution of pure water (1.44 g) and glycerin (3.21 g), and heated and mixed until uniform. Next, glycyrrhetinic acid (0.72 g) was added and dispersed and dissolved while heating to about 50 ° C. 2.5 mol / L sodium hydroxide (0.68 g) was gradually added and stirred to obtain a transparent solution. Cetyl ethylhexanoate (0.69 g) was gradually added to this solution, and heated and mixed at about 80 ° C. to prepare a transparent gel composition (Example 4).
　このゲル状組成物が液晶であることは、偏光顕微鏡及び小角Ｘ線散乱によって確認した。本調製例に従って調製した実施例４の組成物の写真図を図１Ｃに示す。 It was confirmed by a polarizing microscope and small angle X-ray scattering that the gel composition was a liquid crystal. A photograph of the composition of Example 4 prepared according to this Preparation Example is shown in FIG. 1C.
（調製例４）
　本調製例では、親油性化合物としてα‐リポ酸（製品名　α-リポ酸：立山化成社製）を用いて本発明の液晶を調製した例を示す。 (Preparation Example 4)
This preparation example shows an example in which the liquid crystal of the present invention was prepared using α-lipoic acid (product name α-lipoic acid: manufactured by Tateyama Kasei Co., Ltd.) as the lipophilic compound.
　まず、α-リポ酸（１０ｇ）を０．２６ｍｏｌ／Ｌ水酸化ナトリウム（１９３．９ｇ）で完全に溶解し、この溶液を２４～４８時間凍結乾燥して粉末のα-リポ酸ナトリウム塩を作製した。得られたα-リポ酸ナトリウム（０．５ｇ）と精製水（０．５ｇ）を正確に秤量し、約８０℃で加熱・混合し、透明なゲル状組成物（実施例５）を調製した。 First, α-lipoic acid (10 g) was completely dissolved in 0.26 mol / L sodium hydroxide (193.9 g), and this solution was freeze-dried for 24 to 48 hours to produce powdered α-lipoic acid sodium salt. did. The obtained sodium α-lipoate (0.5 g) and purified water (0.5 g) were accurately weighed and heated and mixed at about 80 ° C. to prepare a transparent gel composition (Example 5). .
　これらゲル状組成物が液晶であることは、偏光顕微鏡によって確認した。本調製例に従って調製した実施例５の組成物の写真図を図１Ｄに示す。 It was confirmed with a polarizing microscope that these gel compositions were liquid crystals. A photograph of the composition of Example 5 prepared according to this Preparation Example is shown in FIG. 1D.
　調製例１～４で調製した実施例１～５の各成分組成（ｗ／ｗ％）を表1に示す。
Figure JPOXMLDOC01-appb-T000001
 Table 1 shows the composition (w / w%) of each component of Examples 1 to 5 prepared in Preparation Examples 1 to 4.
Figure JPOXMLDOC01-appb-T000001
（試験例）
　本試験例では、実施例１の組成物中のα‐リポ酸の安定性を評価した。 (Test example)
In this test example, the stability of α-lipoic acid in the composition of Example 1 was evaluated.
　実施例１の組成物を１ヶ月間５０℃の恒温漕に保管し、保管後３０日目のリポ酸含有濃度はＨＰＬＣを用いて定量し、調製時点でのα‐リポ酸に対する残存率を算出した。なお、本試験例では、対照として等濃度のα‐リポ酸を含有する水溶液を用いた。その結果を図２に示す。 The composition of Example 1 was stored in a constant temperature bath at 50 ° C. for one month, and the lipoic acid-containing concentration on the 30th day after storage was quantified using HPLC, and the residual ratio relative to α-lipoic acid at the time of preparation was calculated. did. In this test example, an aqueous solution containing an equal concentration of α-lipoic acid was used as a control. The result is shown in FIG.
　図２の結果から明らかな通り、液晶に包接されたα‐リポ酸は、３０日間の保管後、水溶液中のα‐リポ酸に比較して顕著に高安定で維持されていることが分かった。 As is apparent from the results of FIG. 2, it was found that the α-lipoic acid included in the liquid crystal was maintained with significantly higher stability than the α-lipoic acid in the aqueous solution after storage for 30 days. It was.
　本発明によれば、親油性化合物の含有量が高められた、親油性化合物含有の液晶組成物が提供される。 According to the present invention, there is provided a liquid crystal composition containing a lipophilic compound in which the content of the lipophilic compound is increased.
　本発明の液晶組成物は、液晶が本来的に有する物性（例えば乳化の安定化能、成分の可溶化能）の他、親油性化合物に基づく薬理効果も有しているため、皮膚外用剤、例えば、化粧料、医薬品、又はその原料として使用することができる。 The liquid crystal composition of the present invention has a pharmacological effect based on a lipophilic compound in addition to the physical properties inherent in the liquid crystal (for example, the ability to stabilize emulsification and the ability to solubilize components). For example, it can be used as a cosmetic, a pharmaceutical product, or a raw material thereof.
　また、増粘剤、着色顔料、光揮性顔料、有機粉体、金属酸化物、色素などの付加成分を含ませることもできるため、工業製品、例えば、塗料、インキ、油脂製品、合成ゴム、又は、その原料として使用することもできる。
  Moreover, since it can also contain additional components, such as a thickener, a coloring pigment, a volatile pigment, organic powder, a metal oxide, and a pigment | dye, industrial products, for example, a paint, ink, fat and oil products, synthetic rubber, Or it can also be used as the raw material.

Claims (13)

  1. 　親油性化合物を含有する液晶組成物の製造方法であって、
    　両親媒性分子及び水を添加及び混合することを含む液晶調製過程で、両親媒性分子としてイオン性の解離基を有する親油性化合物又は該親油性化合物と界面活性剤との組み合わせを添加及び混合する工程を含んでおり、
    　その際、該親油性化合物をアルカリ金属塩又はアルカリ土類金属塩の形態で添加及び混合するか、又は該親油性化合物とアルカリ金属又はアルカリ土類金属の水酸化物又はリン酸化物とを反応させる処理を含んでいることを特徴とする、前記方法。     A method for producing a liquid crystal composition containing a lipophilic compound,
    In the liquid crystal preparation process including adding and mixing an amphiphilic molecule and water, adding and mixing a lipophilic compound having an ionic dissociation group or a combination of the lipophilic compound and a surfactant as an amphiphilic molecule Including the step of
    At that time, the lipophilic compound is added and mixed in the form of an alkali metal salt or alkaline earth metal salt, or the lipophilic compound reacts with an alkali metal or alkaline earth metal hydroxide or phosphorous oxide. The method comprising the following steps:
  2. 　イオン性の解離基は、カルボン酸基、スルホン酸基、スルフェン酸基、ヒドロぺルオキシド基よりなる群から選択される、請求項１記載の方法。 The method according to claim 1, wherein the ionic dissociation group is selected from the group consisting of a carboxylic acid group, a sulfonic acid group, a sulfenic acid group, and a hydroperoxide group.
  3. 　イオン性の解離基を有する親油性化合物は、α‐リポ酸、フェルラ酸、グリチルレチン酸、ナプロキセン、メフェナム酸、ドコサヘキサエン酸、エイコサペンタエン酸、タミバロテン、クロロゲン酸、コレステリル硫酸よりなる群から選択される、請求項１記載の方法。 The lipophilic compound having an ionic dissociation group is selected from the group consisting of α-lipoic acid, ferulic acid, glycyrrhetinic acid, naproxen, mefenamic acid, docosahexaenoic acid, eicosapentaenoic acid, tamibarotene, chlorogenic acid, cholesteryl sulfate, The method of claim 1.
  4. 　前記親油性化合物のアルカリ金属塩はナトリウム塩である、請求項１記載の方法。 The method according to claim 1, wherein the alkali metal salt of the lipophilic compound is a sodium salt.
  5. 　アルカリ金属の水酸化物は水酸化ナトリウムである、請求項１記載の方法。 The method according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide.
  6. 　界面活性剤は非イオン界面活性剤である、請求項１記載の方法。 The method according to claim 1, wherein the surfactant is a nonionic surfactant.
  7. 　非イオン界面活性剤は、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル類、プロピレングリコール脂肪酸エステル、モノグリセリン脂肪酸エステル、ジグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステルよりなる群から選択される少なくとも１種である、請求項６記載の方法。 Nonionic surfactant is polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester, propylene glycol fatty acid The method of Claim 6 which is at least 1 sort (s) selected from the group which consists of ester, monoglycerol fatty acid ester, diglycerol fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene fatty acid ester.
  8. 　前記液晶調製過程は多価アルコールを混合することをさらに含んでいる、請求項１記載の方法。 The method of claim 1, wherein the liquid crystal preparation process further comprises mixing a polyhydric alcohol.
  9. 　前記液晶調製過程は油分を混合することをさらに含んでいる、請求項１記載の方法。 The method according to claim 1, wherein the liquid crystal preparation process further includes mixing oil.
  10. 　請求項１～９のいずれか１項記載の方法によって製造された液晶組成物。 A liquid crystal composition produced by the method according to any one of claims 1 to 9.
  11. 　請求項１０記載の液晶組成物を含んでいる皮膚外用剤。 A skin external preparation containing the liquid crystal composition according to claim 10.
  12. 　化粧料である請求項１１記載の皮膚外用剤。 The skin external preparation according to claim 11, which is a cosmetic.
  13. 　医薬品である請求項１１記載の皮膚外用剤。 The external preparation for skin according to claim 11, which is a pharmaceutical product.
PCT/JP2012/063903 2011-05-31 2012-05-30 Method for manufacturing liquid crystalline composition containing lipophilic compound in high concentration, and liquid crystalline composition manufactured by said method WO2012165468A1 (en)

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