WO2014003015A1 - 分散液及びヒドロゲル形成方法 - Google Patents
分散液及びヒドロゲル形成方法 Download PDFInfo
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- WO2014003015A1 WO2014003015A1 PCT/JP2013/067407 JP2013067407W WO2014003015A1 WO 2014003015 A1 WO2014003015 A1 WO 2014003015A1 JP 2013067407 W JP2013067407 W JP 2013067407W WO 2014003015 A1 WO2014003015 A1 WO 2014003015A1
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- 0 *C(C(NC(*)C(NC(*)C(O)=O)=O)=O)NC(*)=O Chemical compound *C(C(NC(*)C(NC(*)C(O)=O)=O)=O)NC(*)=O 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0052—Preparation of gels
- B01J13/0065—Preparation of gels containing an organic phase
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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
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
-
- 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
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- 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
-
- 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
- A61K8/34—Alcohols
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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
- A61K8/34—Alcohols
- A61K8/345—Alcohols containing more than one hydroxy group
-
- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K3/00—Materials not provided for elsewhere
-
- 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
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/48—Thickener, Thickening system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Definitions
- the present invention relates to a dispersion containing a low molecular weight lipid peptide compound useful as a thickener or a gelling agent, and a method for forming a hydrogel using the dispersion.
- Hydrogel is useful as a highly biocompatible gel because it uses water as a medium, and is used in a wide range of fields such as disposable diapers, cosmetics, and fragrances for daily necessities.
- the conventional hydrogel includes a polymer gel formed by crosslinking a polymer chain to form a three-dimensional network structure, which forms a non-covalent bond with a medium such as water and swells.
- the research on physical properties and development of applications of this polymer gel are based on natural polymer gels formed from polysaccharides such as agarose and proteins, and synthetic polymer gels such as acrylamide gels, in which polymer chains are crosslinked by chemical covalent bonds. Many have been made.
- not only gels composed of the above-mentioned polymer compounds but also hydrogels composed of self-assembly of relatively low molecular weight organic compounds have been found and variously studied.
- Gel formation by self-assembly of low molecular weight compounds is based on non-covalent interactions between substances in a group of substances (low molecular weight compounds) that are initially in a random state under appropriate external conditions (in the medium). It is explained that a group of substances spontaneously associate with each other while having a direction to form a macromolecular assembly, which forms a network and swells the surrounding solvent.
- the driving force for this molecular association (self-assembly) is the action of a hydrogen bond with a relatively weak binding force and the van der Waals interaction (non-hydrogen bond) with a weaker binding force than a hydrogen bond. The thing by is mentioned.
- the low-molecular gelling agents proposed so far are amphiphilic compounds in which a long-chain alkyl group, which is a hydrophobic part, and a hydrophilic part are combined.
- the hydrophilic part is an amino acid [non-patent document 1], peptides [Patent Documents 1 and 2], monopolysaccharides [Non-Patent Documents 2 and 3] or polyols [Non-Patent Document 4].
- a low molecular gelling agent [Non-patent Document 5] utilizing the fact that a peptide composed of valine easily takes a ⁇ -sheet structure has also been proposed.
- Such a low molecular hydrogelator is prepared by heating and stirring the hydrogelator and water as a medium under a temperature condition of about 100 ° C. to dissolve and disperse the gelator in water. By allowing to stand, a hydrogel can be formed.
- An object of the present invention is a dispersion containing a lipid peptide type compound useful as a low molecular weight gelling agent such as lipid dipeptide or lipid tripeptide, and a solvent capable of dissolving the lipid peptide type compound more easily at a lower temperature. Is to provide.
- the present invention can form a hydrogel by a simpler method and under milder conditions (low temperature), and a method for forming a dispersion and a gel in which the obtained gel becomes a gel having high thermal stability Is to provide.
- a lipid peptide type compound comprising a low molecular weight lipid peptide or a pharmaceutically usable salt thereof has a hydrophilic part and a hydrophobic part in the molecule.
- the specific solvent has high solubility and high dispersibility at a lower temperature than before, and is a suitable dispersion as a gel premix raw material and a thickener for antifreeze.
- the gel is prepared even when stirring and cooling are performed when the gel is prepared using the dispersion.
- the dispersion is useful as a gel premix that can be used in cosmetics or quasi-drugs. Furthermore, it has been found that adding a heat resistance improver to this dispersion gives high thermal stability to the gel obtained using the dispersion, and the present invention has been completed.
- the present invention provides, as a first aspect, a lipid peptide type compound in which a peptide part having a repeating structure of amino acids is bound to a lipid part composed of an aliphatic group having 9 to 23 carbon atoms, Dispersion containing at least one alcohol selected from the group consisting of 1,2-alkanediol, 1,3-alkanediol and ethylene glycol monoalkyl ether or a mixed solution of the at least one alcohol and water Regarding liquids.
- the lipid peptide type compound is composed of at least one of a compound represented by the following formulas (1) to (3) or a pharmaceutically usable salt thereof, The dispersion liquid according to the first aspect.
- R 1 represents an aliphatic group having 9 to 23 carbon atoms
- R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms
- R 3 represents a — (CH 2 ) n —X group, n represents a number of 1 to 4, and X has an amino group, a guanidino group, a —CONH 2 group, or 1 to 3 nitrogen atoms.
- R 4 represents an aliphatic group having 9 to 23 carbon atoms
- R 5 to R 7 each independently represents a hydrogen atom, or a carbon atom number that can have a branched chain having 1 or 2 carbon atoms.
- R 8 represents an aliphatic group having 9 to 23 carbon atoms
- R 9 to R 12 each independently represents a hydrogen atom, or the number of carbon atoms that may have a branched chain having 1 or 2 carbon atoms.
- the dispersion according to the third aspect which is a premix for the preparation of cosmetics or quasi drugs.
- the dispersion liquid as described in a 1st viewpoint or a 2nd viewpoint used as a thickener of an antifreeze.
- the polymer emulsifier is selected from the group consisting of a graft polymer compound obtained by grafting a hydrophobic site to a hydrophilic main chain and a block polymer compound comprising a hydrophobic constituent unit and a hydrophilic constituent unit. It is related with the dispersion liquid as described in a 3rd viewpoint or a 4th viewpoint which is at least 1 sort (s) of high molecular compound.
- the dispersion liquid as described in a 6th viewpoint which contains a heat resistance improver is at least one fatty acid selected from the group consisting of saturated and unsaturated fatty acids having 10 to 20 carbon atoms and salts of these fatty acids.
- the heat resistance improver is capric acid, lauric acid, myristic acid, palmitic acid or stearic acid.
- the present invention relates to the dispersion according to any one of the sixth aspect to the ninth aspect, in which the polymer compound is selected from the group consisting of carboxymethylcellulose and an alginate.
- An eleventh aspect relates to the dispersion according to the tenth aspect, in which the polymer compound is propylene glycol alginate.
- a thirteenth aspect relates to a hydrogel formed using the dispersion liquid according to any one of the third aspect, the fourth aspect, and the sixth to eleventh aspects.
- the dispersion of the present invention dissolves the lipid peptide type compound in a relatively short time by stirring the lipid peptide type compound and 1,2-alkanediol, etc. under a relatively mild temperature condition such as 80 ° C. It can be prepared by dispersing.
- the dispersion liquid of the present invention is a dispersion liquid suitable as a premix raw material for gel or a thickener for antifreeze liquid.
- the dispersion of the present invention is prepared by adding a polymer emulsifier, so that when the gel is prepared using the dispersion, for example, under a mild temperature condition of 80 ° C. A good hydrogel can be obtained without forming an object.
- the dispersion is also useful as a gel premix that can be used in cosmetics or quasi drugs.
- the dispersion of the present invention can impart high thermal stability to the gel formed using the dispersion by adding a heat resistance improver.
- the lipid peptide type compound contained in the dispersion of the present invention is a very safe artificial low molecular weight compound composed only of lipid and peptide, and 1,2-alkanediol, 1,3-alkanediol.
- Ethylene glycol monoalkyl ether is an additive that can be used in foods, cosmetics, and pharmaceuticals. That is, the dispersion of the present invention has high biological safety, and is particularly useful in the above applications from the viewpoint of high safety required for cell culture substrates, medical materials, cosmetic materials, and the like.
- the dispersion liquid of the present invention can form a gel by gelling water without using a crosslinking agent or the like required for forming a conventionally proposed synthetic polymer gel.
- the resulting hydrogel does not have the problem of remaining unreacted substances such as unreacted cross-linking agents.
- the lipid peptide type compound contained in the dispersion can form a hydrogel with an addition amount of only about 1% by mass, and has a low load when taken up in the environment or in vivo.
- the hydrogel production method of the present invention can form a gel even under stirring under relatively mild conditions of less than 100 ° C., and is intended for cosmetic additives and quasi-drugs that eliminate the influence of heat as much as possible. Even when additives are added, a hydrogel can be formed without modifying these additives.
- the gel of the present invention can be obtained by adding a small amount of a gelling agent as compared with the conventional gel as described above, it can be said that the gel is highly safe in both biological and environmental aspects. Furthermore, as described above, a gel obtained from a lipid peptide, which is a low molecular weight compound, is easily degraded by soil bacteria when used in an external environment, for example, in soil, and when used in vivo. Since it is easily decomposed by metabolic enzymes, the burden on the environment and living body is low. And the gel of this invention is a gel which can be formed on comparatively mild conditions, and is a gel which can mix
- lipid peptide lipid peptide
- Patent Documents 1 and 2 have low solubility in a solvent, and in order to gel the solvent, the solvent to be gelled first was heated to a high temperature of 100 ° C. to dissolve and disperse the gelling agent.
- the lipid peptide low-molecular gelling agent is considered to lead to gel formation by forming a macromolecular assembly by weak interaction (van der Waals interaction, etc.) between molecules. This will prevent gel formation. For this reason, in order to form a gel, it is necessary to let it stand at the time of cooling of the gelatinizer dispersion prepared by heating at a high temperature. If stirring is performed at the time of cooling, gel formation may not be achieved.
- the present inventors have made it an object to provide a material capable of forming a gel under milder temperature conditions, for example, a temperature of less than 100 ° C., and capable of forming a gel while stirring during cooling. It came.
- the present inventors once dissolved and dispersed the lipid peptide type compound in a solvent having high solubility of the compound to form a solution (dispersion), which is a so-called premix of gelled material.
- blending with a solvent (water etc.) was examined. First, a study was made on a highly safe solvent that can dissolve lipid peptide compounds at high concentrations, and among them, a highly safe solvent that is approved for use in quasi drugs and cosmetics.
- 1,3-alkanediol and ethylene glycol monoalkyl ether have been found to be suitable.
- the present inventors made various studies using the above premix to enable gel formation at low temperature and under stirring, and blended the premix with a solvent by blending a polymer emulsifier such as an alginate. It has been found that the solubility and dispersibility of the gel and the strength of the gel can be secured, and the heat resistance of the gel formed by blending a heat resistance improver such as fatty acid can be improved. With the above process, the present invention has been completed.
- the dispersion of the present invention comprises a lipid peptide type compound in which a peptide portion having a repeating structure of amino acids is bound to a lipid portion comprising an aliphatic group having 9 to 23 carbon atoms, 1,2-alkanediol, , 3-alkanediol and ethylene glycol monoalkyl ether, or at least one alcohol selected from the group consisting of ethylene glycol monoalkyl ethers or a mixed solution with the at least one alcohol.
- the lipid peptide type compound refers to a low molecular weight compound in which a peptide part having a repeating structure of amino acids is bound to a lipid part composed of an aliphatic group.
- the lipid peptide type compound used in the dispersion of the present invention preferably has a structure in which the lipid part is an aliphatic group having 9 to 23 carbon atoms.
- the lipid peptide type compound used in the dispersion of the present invention preferably has a plurality of amino acid repetitive bond structures, preferably 2 to 4, has a carboxylic acid or a salt thereof at the terminal, and the opposite.
- a structure containing an aliphatic group having 9 to 23 carbon atoms at the end on the side is preferable. More preferably, a compound (lipid peptide) represented by the following formulas (1) to (3) or a pharmaceutically usable salt thereof can be used as the lipid peptide type compound in the dispersion of the present invention.
- R 1 represents an aliphatic group having 9 to 23 carbon atoms, and preferably R 1 is a straight chain having 11 to 23 carbon atoms which may have 0 to 2 unsaturated bonds.
- An aliphatic group is desirable.
- Specific examples of the lipid moiety (acyl group) composed of R 1 and an adjacent carbonyl group include lauroyl group, dodecylcarbonyl group, myristoyl group, tetradecylcarbonyl group, palmitoyl group, margaroyl group, oleoyl group, and eridoyl.
- R 2 contained in the peptide part represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms.
- the alkyl group having 1 to 4 carbon atoms that may have a branched chain having 1 or 2 carbon atoms is a branched chain having 1 to 4 carbon atoms in the main chain and 1 or 2 carbon atoms.
- Means an alkyl group which may have, and specific examples thereof include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group or tert-butyl group Etc.
- R 2 is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which may have a branched chain having 1 carbon atom, and more preferably a hydrogen atom.
- the alkyl group having 1 to 3 carbon atoms which can have a branched chain having 1 carbon atom is an alkyl group having 1 to 3 carbon atoms in the main chain and having a branched chain having 1 carbon atom.
- a methyl group an ethyl group, an n-propyl group, an i-propyl group, an i-butyl group, or a sec-butyl group, preferably a methyl group, an i-propyl group, An i-butyl group or a sec-butyl group.
- R 3 represents a — (CH 2 ) n—X group.
- n represents a number of 1 to 4
- X is an amino group, a guanidino group, a —CONH 2 group, or a 5-membered cyclic group having 1 to 3 nitrogen atoms.
- X is preferably an amino group, guanidino group, carbamoyl group (—CONH 2 group), pyrrole group, imidazole group, pyrazole group or indole group, and more Preferably it is an imidazole group.
- n is preferably 1 or 2, and more preferably 1.
- the — (CH 2 ) n- group is preferably an aminomethyl group, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, carbamoylmethyl group, 2-carbamoylethyl group, 3-carbamoyl group.
- a lipid peptide particularly suitable as a lipid peptide type compound is a compound formed from the following lipid part and peptide part (amino acid assembly part).
- amino acids alanine (Ala), asparagine (Asn), glutamine (Gln), glycine (Gly), histidine (His), isorosine (Ile), leucine (Leu), lysine (Lys), tryptophan (Trp) ), Valine (Val).
- Lauroyl-Gly-His Lauroyl-Gly-Gln, Lauroyl-Gly-Asn, Lauroyl-Gly-Trp, Lauroyl-Gly-Lys, Lauroyl-Ala-His, Lauroyl-Ala-Gln, Lauroyl-Ala-Asn, Lauroyl -Ala-Trp, Lauroyl-Ala-Lys; Myristoyl-Gly-His, Myristoyl-Gly-Gln, Myristoyl-Gly-Asn, Myristoyl-Gly-Trp, Myristoyl-Gly-Lys, Myristoyl-Ala-His, Myristoyl-Ala -Gln, Myristoyl-Ala-Asn, Myristoyl-Ala-Trp, Myristoyl-Ala-Lys; Palmitoyl-Gly-His, Palmitoyl-Gly-Gln, Palmi
- lauroyl-Gly-His lauroyl-Ala-His-myristoyl-Gly-His, myristoyl-Ala-His; palmitoyl-Gly-His, palmitoyl-Ala-His; stearoyl-Gly-His, stearoyl-Ala -His.
- R 4 represents an aliphatic group having 9 to 23 carbon atoms, and preferred specific examples include the same groups as defined for R 1 above.
- R 5 to R 7 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms, or — ( CH 2 ) nX group, and at least one of R 5 to R 7 represents a — (CH 2 ) nX group.
- n a number of 1 to 4
- X represents an amino group, a guanidino group, a —CONH 2 group, or a 5-membered cyclic group or a 6-membered cyclic group which may have 1 to 3 nitrogen atoms, or a 5-membered ring And a condensed heterocyclic group composed of a 6-membered ring.
- R 5 to R 7 include the same groups as defined for R 2 and R 3 above.
- a preferable lipid peptide is a compound formed from the following lipid part and peptide part (amino acid assembly part).
- Myristoyl-Gly-Gly-His Myristoyl-Gly-Gly-Gln, Myristoyl-Gly-Gly-Asn, Myristoyl-Gly-Gly-Trp, Myristoyl-Gly-Gly-Lys, Myristoyl-Gly-Ala-His Gly-Ala-Gln, Myristoyl-Gly-Ala-Asn, Myristoyl-Gly-Ala-Trp, Myristoyl-Gly-Ala-Lys, Myristoyl-Ala-Gly-His, Myristoyl-Ala-Gly-Gln, Myristoyl-Ala- Gly-Asn, Myristoyl-Ala-Gly-Trp, Myristoyl-Ala-Gly-His, Myristoyl-
- lauroyl-Gly-Gly-His myristoyl-Gly-Gly-His, palmitoyl-Gly-Gly-His, palmitoyl-Gly-His-Gly, palmitoyl-His-Gly-Gly, stearoyl -Gly-Gly-His.
- R 8 represents an aliphatic group having 9 to 23 carbon atoms, and preferred specific examples include the same groups as defined for R 1 above.
- R 9 to R 12 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms, or — ( CH 2 ) nX group, and at least one of R 9 to R 12 represents a — (CH 2 ) nX group.
- n a number of 1 to 4
- X represents an amino group, a guanidino group, a —CONH 2 group, or a 5-membered cyclic group or a 6-membered cyclic group which may have 1 to 3 nitrogen atoms, or a 5-membered ring And a condensed heterocyclic group composed of a 6-membered ring.
- R 9 to R 12 include the same groups as defined for R 2 and R 3 above.
- particularly preferred lipid peptides include lauroyl-Gly-Gly-Gly-His, myristoyl-Gly-Gly-Gly-His, palmitoyl. -Gly-Gly-Gly-His, Palmitoyl-Gly-Gly-His-Gly, Palmitoyl-Gly-His-Gly-Gly, Palmitoyl-His-Gly-Gly-Gly, Stearoyl-Gly-Gly-Gly-His, etc. Can be mentioned.
- the amount of the lipid peptide type compound is, for example, 0.01 to 30% by mass, preferably 0.05 to 10% by mass, more preferably 0.1 to 0.1% by mass with respect to the total mass of the resulting hydrogel. 5% by mass.
- the compounding amount of the lipid peptide type compound is, for example, 0.1 to 40% by mass, preferably 0.1 to 30% by mass with respect to the total mass of the obtained dispersion.
- the lipid peptide type compound used in the present invention comprises at least one of the compounds represented by the above formulas (1) to (3) (lipid peptide) or a pharmaceutically usable salt thereof, and is a hydrogel. These compounds can be used alone or in combination of two or more as the agent.
- the alcohol used in the dispersion of the present invention is at least one selected from the group consisting of 1,2-alkanediol, 1,3-alkanediol, and ethylene glycol monoalkyl ether.
- 1,2-alkanediol include 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,2-decanediol, and the like.
- Preferred are 1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol. More preferred is 1,2-pentanediol or 1,2-hexanediol.
- the 1,3-alkanediol include 2-ethyl-1,3-hexanediol and 1,3-butanediol. 2-ethyl-1,3-hexanediol is preferred.
- the ethylene glycol monoalkyl ether is preferably an alkyl ether having an alkyl group of methyl group, ethyl group, propyl group or butyl group, that is, ethylene glycol monoethyl ether, monopropyl ether or monobutyl ether. It is done. More preferred is ethylene glycol monopropyl ether or ethylene glycol monobutyl ether.
- the compounding quantity of the said alcohol is 1-20 mass% with respect to the total mass of the hydrogel obtained, for example, More preferably, it is 2-5 mass%.
- the blending amount of the alcohol is, for example, 50% to 90%, preferably 70 to 90% with respect to the total mass of the obtained dispersion.
- the said alcohol used in this invention is at least 1 sort (s) of the above-mentioned alcohol group, These alcohol can be used individually or in combination of 2 or more types.
- the dispersion containing the lipid peptide type compound and the alcohol can be suitably used as a thickener for antifreeze.
- Polymer emulsifier By adding a polymer emulsifier to the dispersion of the present invention, a gel can be provided even when stirring is performed during gel preparation.
- the polymer emulsifier at least one selected from the group consisting of a graft polymer compound obtained by grafting a hydrophobic site to a hydrophilic main chain and a block polymer compound comprising a hydrophobic constituent unit and a hydrophilic constituent unit.
- a high molecular compound may be mix
- Examples of the graft polymer compound obtained by grafting a hydrophobic site to the hydrophilic main chain include xanthan gum, alginic acid ester, cellulose derivative and the like.
- Examples of the block polymer compound composed of the hydrophobic structural unit and the hydrophilic structural unit include acrylic acid / alkyl methacrylate copolymers.
- the polymer compound is preferably a compound selected from the group consisting of carboxymethyl cellulose and alginic acid ester, and particularly preferably propylene glycol alginate.
- the amount of the polymer emulsifier is, for example, 0.1 to 5% by mass, and more preferably 0.2 to 0.5% by mass, based on the total mass of the resulting hydrogel. In the present invention, the amount of the polymer emulsifier is, for example, 1.0 to 20.0%, preferably 1.0 to 10.0%, based on the total mass of the resulting dispersion.
- the polymer emulsifier used in the present invention is at least one selected from the group consisting of graft polymer compounds and block polymer compounds, and these polymer compounds are used alone or in combination of two or more. be able to.
- the dispersion containing the lipid peptide type compound as a gelling agent and containing a polymer emulsifier in addition to the alcohol is a premix for the preparation of cosmetics or quasi-drugs, It can be suitably used as a premix material for preparing gels used in cosmetics and quasi drugs.
- the dispersion (premix) can be blended with various additives known as heat resistance improvers described below and additives for cosmetics and / or quasi drugs.
- the premix is prepared by adding alcohol to a lipid peptide type compound and stirring at room temperature or higher and lower than 100 ° C, preferably 50 ° C to 90 ° C, more preferably 60 ° C to 90 ° C, for example, 80 ° C. It can be produced by adding a heat resistance improver, an additive for cosmetics and / or quasi-drugs and stirring.
- Heat resistance improver Fatty acids can be added as heat resistance improvers used in the dispersion of the present invention.
- the fatty acids include the following saturated fatty acids, unsaturated fatty acids and salts thereof: caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid.
- Linear saturated fatty acids such as margaric acid, stearic acid, nonadecanoic acid, arachidic acid and their salts; 2-butyl-5-methylpentanoic acid, 2-isobutyl-5-methylpentanoic acid, dimethyloctanoic acid, dimethylnonanoic acid 2-butyl-5-methylhexanoic acid, methylundecanoic acid, dimethyldecanoic acid, 2-ethyl-3-methylnonanoic acid, 2,2-dimethyl-4-ethyloctanoic acid, methyldocosanoic acid, 2-propyl-3-methylnonane Acid, methyltridecanoic acid, dimethyldodecanoic acid, 2-butyl-3 Methylnonanoic acid, methyltetradecanoic acid, ethyltridecanoic acid, propyldodecanoic acid, butylundecanoic acid, pentyldede
- fatty acids it is preferably at least one selected from the group consisting of saturated and unsaturated fatty acids having 10 to 20 carbon atoms and salts of these fatty acids, preferably capric acid, undecanoic acid, lauric acid, Examples include tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, and stearic acid. More preferred are capric acid, lauric acid, myristic acid, palmitic acid and stearic acid.
- the effect expression mechanism of the heat improver is as follows. It is expected to show.
- the lipid ester type compound is poured into water as a solvent and dissolved / dispersed, the lipid parts of the two lipid ester type compounds form a non-covalent bond between molecules in a hydrophobic manner to form a pair.
- Peptide moieties present on the outside of this pair of binding moieties can form intermolecular non-covalent bonds with other pairs of peptide moieties by hydrogen bonding.
- pairs formed from two lipid ester-type compounds form a large number of pairs through hydrogen bonds in the peptide part, that is, so-called lamellar aggregates.
- a network structure is formed by connecting a plurality of lamellar aggregates, and the solvent (water) existing between the networks is retained by the peptide portion (hydrophilicity) existing on the outer surface of the lamellar aggregates to form a gel. Is believed to be preserved.
- the temperature increases, the mobility of the alkyl chain of the lipid peptide-type compound increases, and the peptide parts present on the outer surface of multiple lamellar aggregates come together and form hydrogen bonds and aggregate to form lamellae.
- a peptide part existing on the outer surface of one lamellar assembly can form a non-covalent bond, and the peptide part existing on the outer surface of another lamellar assembly is It is considered effective to add a compound having a structure that does not form a bond (causes repulsion).
- the compounding quantity of the said heat resistance improver is 0.05 to 0.10 mass% with respect to the total mass of the hydrogel obtained.
- the blending amount of the heat resistance improver is, for example, 0.5 to 2.0%, preferably 0.5 to 1.0%, based on the total mass of the resulting dispersion.
- the said heat resistance improving agent used in this invention is at least 1 sort (s) selected from the said fatty acid group, These fatty acids can be used individually or in combination of 2 or more types.
- Additives that can be generally used as cosmetic additives and quasi-drug additives can be added to the composition as necessary.
- an additive component such as a physiologically active substance and a functional substance to be blended in an external preparation for skin such as cosmetics or quasi-drugs, for example, an oily base, a moisturizing agent, a feeling improver, a surfactant, a polymer, a thickening agent Gelling agent, solvent, propellant, antioxidant, reducing agent, oxidizing agent, preservative, antibacterial agent, bactericidal agent, chelating agent, pH adjuster, acid, alkali, powder, inorganic salt, UV absorber, Whitening agents, vitamins and derivatives thereof, hair growth agents, blood circulation promoters, stimulants, hormones, anti-wrinkle agents, anti-aging agents, squeeze agents, cooling sensation agents, warming sensation agents, wound healing promoters, stimulation relief Agent, analgesic agent, cell activator, plant / animal / microbe extract, antipruritic agent
- additive components include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, seraalkyl alcohol, batyl.
- Higher (polyhydric) alcohols such as alcohol, hexyldecanol, isostearyl alcohol, 2-octyldodecanol, dimer diol; aralkyl alcohols such as benzyl alcohol and their derivatives; lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid , Behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitooleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahe Higher fatty acids such as saenoic acid, eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long chain branched fatty acid, dimer acid, hydrogenated dimer acid, and aluminum salts, calcium salts, magnesium salts, zinc salts thereof, Metal soaps such as potassium salts and sodium salt
- humectants and feel improvers examples include glycerin, 1,3-butylene glycol, propylene glycol, 3-methyl-1,3-butanediol, 1,3-propanediol, 2-methyl-1,3-propanediol, Polyols such as trimethylolpropane, pentaerythritol, hexylene glycol, diglycerin, polyglycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol / propylene glycol copolymer and polymers thereof; diethylene glycol monoethyl ether (Ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dibutyl ether, etc.
- Ethoxydiglycol ethylene glycol monoethyl ether
- ethylene glycol monobutyl ether diethylene glycol dibutyl
- Water-soluble esters such as polyglyceryl-10 and tetradecandioic acid polyglyceryl-10; sugar alcohols such as sorbitol, xylitol, erythritol, mannitol, maltitol; glucose, fructose, galactose Mannose, threose, xylose, arabinose, fucose, ribose, deoxyribose, maltose, trehalose, lactose, raffinose, gluconic acid, glucuronic acid, cyclodextrins ( ⁇ -, ⁇ -, ⁇ -cyclodextrin, and maltosylation, Modified cyclodextrins such as hydroxyalkylation), ⁇ -glucan, chitin, chitosan, heparin and derivatives, pectin, arabinogalactan, dextrin, dextran, glycoge Sugars and
- the surfactant include an anionic surfactant, a nonionic surfactant, a cationic surfactant, an amphoteric surfactant, and a polymer surfactant.
- preferable surfactants include fatty acid salts such as potassium laurate and potassium myristate; alkyl sulfate esters such as sodium lauryl sulfate, triethanolamine lauryl sulfate, and ammonium lauryl sulfate; Polyoxyethylene alkyl sulfates such as sodium laureth sulfate and triethanolamine laureth sulfate; cocoyl methyl taurine sodium, cocoyl methyl taurine potassium, lauroyl methyl taurine sodium, myristoyl methyl taurine sodium, lauroyl methyl alanine sodium, lauroyl sarcosine sodium, lauroyl sarcosine tri Acyl N-methyl amino acid salts such as ethanolamine and sodium methylalanine sodium, la
- Alkyl glyceryl ethers polyhydric alcohol alkyl ethers; polyoxyethylene alkylamines; tetrapolyoxyethylene / tetrapolyoxypropylene-ethylenediamine condensates; natural surfactants such as saponins and sophorolipids; polyoxyethylene fatty acid amides; Oil fatty acid monoethanolamide (cocamide MEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acid monoethanolamide Lauramide MEA), lauric acid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acid monoethanolamide (partamid MEA), palmitic acid diethanolamide (partamide DEA), palm oil fatty acid methylethanolamide (cocamidomethyl) Fatty acid alkanolamides such as MEA); alkyldimethylamine oxides such as lauramine oxide, cocamamine oxide, stearamine oxide, and behenamine oxide; al
- cationic surfactant examples include alkyltrimethylammonium chlorides such as behentrimonium chloride, steartrimonium chloride, cetrimonium chloride, lauryltrimonium chloride; stearyltrimonium bromide, etc.
- Alkyltrimethylammonium bromides dialkyldimethylammonium chlorides such as distearyldimonium chloride and dicocodimonium chloride; fatty acid amidoamines and salts thereof such as stearamidepropyldimethylamine and stearamideethyldiethylamine; alkyl etheramines such as stearoxypropyldimethylamine And salts or quaternary salts thereof; ethyl sulfate long-chain branched fatty acid (12 to 31) aminopropylethyldimethylammonium, ethylsulfur Lanolin fatty acid fatty acid amide type quaternary ammonium salt such as aminopropylethyldimethylammonium; polyoxyethylene alkylamine and its salt or quaternary salt; alkylamine salt; fatty acid amidoguanidinium salt; alkyl etheraminemonium salt; Benzalkonium salt; Pyridinium salt such as
- Polymers, thickeners and gelling agents include guar gum, locust bean gum, queens seed, carrageenan, galactan, arabic gum, tara gum, tamarind, far selelain, karaya gum, troarooi, cara gum, tragacanth gum, pectin, pectic acid and sodium Salt such as salt, salt such as alginic acid and sodium salt, mannan; starch such as rice, corn, potato, wheat; xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid and its salt, xanthan gum, pullulan, gellan gum, chitin , Chitosan, agar, gypsophila extract, chondroitin sulfate, casein, collagen, gelatin, albumin; methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypro Cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof such as
- Acrylic acid / methyl acrylate / methacrylamidopropyltrimethylammonium chloride copolymer such as polyquaternium-47, methacrylic acid choline ester polymer; cationized oligosaccharide, cationized dextran, guar hydroxypropyltri Cationic polysaccharides such as monium chloride; polyethyleneimine; cationic polymers; copolymers of 2-methacryloyloxyethyl phosphorylcholine such as polyquaternium-51 and copolymers of butyl methacrylate; acrylic resin emulsion, polyacrylic acid Polymer emulsions such as ethyl emulsion, polyacrylic alkyl ester emulsion, polyvinyl acetate resin emulsion, natural rubber latex, synthetic latex; nitrocellulose; Tans and various copolymers; Various silicones; Various silicone-based copolymers such as acrylic-silicone graft
- Solvents and propellants include ethanol, 2-propanol (isopropyl alcohol), butanol, isobutyl alcohol and other lower alcohols; propylene glycol, 1,3-butylene glycol, diethylene glycol, dipropylene glycol, isopentyl diol and other glycols Diethylene glycol monoethyl ether (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, triethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, propylene glycol monoethyl ether, dipropylene glycol monoethyl ether Glycol ethers such as ethylene glycol monoethyl ether Glycol ether esters such as diacetate, diethylene glycol monoethyl ether acetate, propylene glycol monoethyl ether acetate; glycol esters such as dieth
- Antioxidants include tocopherol derivatives such as tocopherol (vitamin E) and tocopherol acetate; BHT, BHA; gallic acid derivatives such as propyl gallate; vitamin C (ascorbic acid) and / or derivatives thereof; erythorbic acid and derivatives thereof; Preferred are sulfites such as sodium sulfite; bisulfites such as sodium bisulfite; thiosulfates such as sodium thiosulfate; metabisulfites; thiotaurine, hypotaurine; thioglycerol, thiourea, thioglycolic acid, cysteine hydrochloride As mentioned.
- Preferred examples of the reducing agent include thioglycolic acid, cysteine, cysteamine and the like.
- Preferred examples of the oxidizing agent include hydrogen peroxide water, ammonium persulfate, sodium bromate, percarbonate, and the like.
- preservatives, antibacterial agents, and bactericides include hydroxybenzoic acid such as methylparaben, ethylparaben, propylparaben, and butylparaben, and salts or esters thereof; salicylic acid; sodium benzoate; phenoxyethanol; methylchloroisothiazolinone, methylisothiazo Isothiazolinone derivatives such as linone; imidazolinium urea; dehydroacetic acid and its salts; phenols; halogenated bisphenols such as triclosan, acid amides, quaternary ammonium salts; trichlorocarbanide, zinc pyrithione, benzalkonium chloride, chloride Benzethonium, sorbic acid, chlorhexidine, chlorhexidine gluconate, halocarban, hexachlorophene, hinokitiol; phenol, isopropylphenol, cresol, Mall
- chelating agents include edetate (ethylenediaminetetraacetate) such as EDTA, EDTA2Na, EDTA3Na, and EDTA4Na; hydroxyethylethylenediaminetriacetate such as HEDTA3Na; pentetate (diethylenetriaminepentaacetate); phytic acid; Phosphonic acid and its sodium salt; sodium oxalate; polyamino acids such as polyaspartic acid and polyglutamic acid; sodium polyphosphate, sodium metaphosphate, phosphoric acid; sodium citrate, citric acid, alanine, dihydroxyethylglycine Gluconic acid, ascorbic acid, succinic acid, and tartaric acid are preferable.
- edetate ethylenediaminetetraacetate
- HEDTA3Na EDTA3Na
- EDTA4Na hydroxyethylethylenediaminetriacetate
- pentetate diethylenetriaminepentaa
- pH adjusters / acids / alkalis include citric acid, sodium citrate, lactic acid, sodium lactate, potassium lactate, glycolic acid, succinic acid, acetic acid, sodium acetate, malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloric acid, sulfuric acid , Monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, arginine Sodium hydroxide, potassium hydroxide, aqueous ammonia, guanidine carbonate, and ammonium carbonate are preferable.
- powders include mica, talc, kaolin, sericite, montmorillonite, kaolinite, mica, muscovite, phlogopite, synthetic mica, saucite, biotite, permiculite, magnesium carbonate, calcium carbonate, aluminum silicate, and silicic acid.
- Inorganic salts include sodium chloride-containing salts such as salt, common salt, rock salt, sea salt, natural salt; potassium chloride, aluminum chloride, calcium chloride, magnesium chloride, bittern, zinc chloride, ammonium chloride; sodium sulfate, aluminum sulfate, Aluminum sulfate / potassium sulfate (alum), aluminum sulfate / ammonium sulfate, barium sulfate, calcium sulfate, potassium sulfate, magnesium sulfate, zinc sulfate, iron sulfate, copper sulfate; sodium phosphates such as 1Na, 2Na and 3Na phosphates, phosphoric acid Potassium, calcium phosphates and magnesium phosphates are preferred.
- sodium chloride-containing salts such as salt, common salt, rock salt, sea salt, natural salt
- potassium chloride aluminum chloride, calcium chloride, magnesium chloride, bittern, zinc chloride, ammonium chlor
- ultraviolet absorbers examples include paraaminobenzoic acid, paraaminobenzoic acid monoglycerin ester, N, N-dipropoxyparaaminobenzoic acid ethyl ester, N, N-diethoxyparaaminobenzoic acid ethyl ester, and N, N-dimethylparaaminobenzoic acid ethyl ester.
- Benzoic acid ultraviolet absorbers such as esters, N, N-dimethylparaaminobenzoic acid butyl ester, N, N-dimethylparaaminobenzoic acid ethyl ester; Anthranilic acid ultraviolet absorbers such as homomenthyl-N-acetylanthranilate; Salicylic acid And its sodium salt amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, etc.
- Benzophenone series External line absorber 3- (4′-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5- 2- (2′-hydroxy-5′-t-octylphenyl) benzotriazole; 2- (2′-hydroxy-5′-methylphenylbenzotriazole; dibenzalazine; dianisoylmethane; 5- (3 , 3-dimethyl-2-norbornylidene) -3-pentan-2-one; dibenzoylmethane derivatives such as 4-t-butylmethoxydibenzoylmethane; octyl triazone; urocanic acid derivatives such as urocanic acid and ethyl urocanate; 2- (2′-hydroxy-5′-methylphenyl) benzotriazole, 1- (3 , 4-Dimethoxyphenyl
- whitening agents include hydroquinone glycosides such as arbutin and ⁇ -arbutin and their esters; ascorbic acid phosphates such as ascorbic acid, sodium ascorbic acid phosphate and magnesium ascorbic acid phosphate, ascorbic acid Ascorbic acid fatty acid esters such as tetraisopalmitic acid ester, ascorbic acid alkyl ethers such as ascorbic acid ethyl ether, ascorbic acid glucosides such as ascorbic acid-2-glucoside and fatty acid esters thereof, ascorbic acid sulfate ester, tocopheryl ascorbyl phosphate Ascorbic acid derivatives such as kojic acid, ellagic acid, tranexamic acid and its derivatives, ferulic acid and its derivatives, placenta extract, glutathione, oryzanol, butylreso Shinoru, oil-soluble Kamomiraekisu, oil-soluble licorice extract,
- Vitamins and their derivatives include vitamin A such as retinol, retinol acetate, retinol palmitate; thiamine hydrochloride, thiamine sulfate, riboflavin, riboflavin acetate, pyridoxine hydrochloride, pyridoxine dioctanoate, pyridoxine dipalmitate, Flavin adenine dinucleotide, cyanocobalamin, folic acid, nicotinic acid such as nicotinic acid amide / benzyl nicotinate, vitamin B group such as choline; vitamin C such as ascorbic acid and its sodium salt; vitamin D; ⁇ , Vitamin E such as ⁇ , ⁇ , and ⁇ -tocopherol; other vitamins such as pantothenic acid and biotin; ascorbic acid phosphates such as ascorbic acid phosphate sodium salt and ascorbic acid phosphate magnesium salt, Ascorbic acid fatty acid esters
- Plant growth and tinctures such as assembly extract, red pepper tincture, ginger tincture, ginger extract, cantalis tincture; capsaicin, nonyl acid valenylamide, gingeron, ictamol, tannic acid Borneol, cyclandrate, cinnarizine, trazoline, acetylcholine, verapamil, cephalanthin, ⁇ -oryzanol, vitamin E and derivatives such as tocopherol / nicotinic acid tocopherol, ⁇ -oryzanol, nicotinic acid, nicotinic acid amide, nicotinic acid benzyl ester, Inositol hexanicotinate, derivatives such as nicotine alcohol, allantoin, photosensitive element 301, photosensitive element 401, capronium chloride, pentadecanoic acid monoglyceride, flavonol Derivatives, stigmasterol or stigmasterol and its glycoside
- hormones include estradiol, estrone, ethinyl estradiol, cortisone, hydrocortisone, prednisone and the like.
- Other remedies such as anti-wrinkle agents, anti-aging agents, squeeze agents, cooling sensations, warming sensation agents, wound healing promoters, irritation relievers, analgesics, cell activators include retinols, retinoic acids, retinoin Acid tocopheryl; derivatives such as lactic acid, glycolic acid, gluconic acid, fruit acid, salicylic acid and glycosides / esterified products thereof, ⁇ - or such as hydroxycapric acid, long chain ⁇ -hydroxy fatty acid, long chain ⁇ -hydroxy fatty acid cholesteryl ⁇ -hydroxy acids and derivatives thereof; ⁇ -aminobutyric acid, ⁇ -amino- ⁇ -hydroxybutyric acid; carnitine; carnosine; creatine; ceramides, sphingosines; caffeine, xant
- Antioxidant / active oxygen scavengers include catechins; flavones such as quercetin; isoflavones; gallic acid and ester sugar derivatives; polyphenols such as tannin, sesamin, protoanthocyanidin, chlorogenic acid, apple polyphenol; rutin and glycosides, etc.
- antipruritic agents examples include diphenhydramine hydrochloride, chlorpheniramine maleate, camphor, substance-P inhibitor, and the like.
- exfoliating / dissolving agent examples include salicylic acid, sulfur, resorcin, selenium sulfide, pyridoxine and the like.
- antiperspirants examples include chlorohydroxyaluminum, aluminum chloride, zinc oxide, zinc paraphenol sulfonate, and the like.
- Examples of the refreshing agent include menthol and methyl salicylate.
- astringents include citric acid, tartaric acid, lactic acid, aluminum sulfate / potassium, and tannic acid.
- Enzymes include superoxide dismutase, catalase, lysozyme chloride, lipase, papain, pancreatin, protease, and the like.
- Preferred nucleic acids include ribonucleic acid and its salts, deoxyribonucleic acid and its salts, and adenosine triphosphate disodium.
- Anti-inflammatory and anti-inflammatory agents include glycyrrhizic acid and its derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, guaiazulene, allantoin, indomethacin, ketoprofen, ibuprofen, diclofenac, loxoprofen, celecoxib, infliximab, etanercept, zinc oxide, hydroxanthone acetate Prednisone, difedramine hydrochloride, chlorpheniramine maleate; plant extracts such as peach leaf extract and persimmon leaf extract are preferable.
- Anti-asthma, anti-chronic obstructive pulmonary disease, anti-allergy, immunomodulators include aminophylline, theophylline, steroids (fluticasone, beclomethasone, etc.), leukotriene antagonists, thromboxane inhibitors, intal, ⁇ 2-stimulant (Formoterol, salmeterol, albuterol, tulobuterol, clenbuterol, epinephrine, etc.), tiotropium, ipratropium, dextromethorphan, dimemorphan, bromhexine, tranilast, ketotifen, azelastine, cetirizine, chlorpheniramine, polyquitolsine, Preferred examples include cytokine regulators, interferons, omalizumab, and protein / antibody preparations.
- Preferred examples of the anti-infective and antifungal agents include oseltamivir, zanamivir, and itraconazole.
- cosmetic raw material standards cosmetic ingredient-specific combination ingredient standards, Japan Cosmetic Industry Association ingredient display name list, INCI dictionary (The International Cosmetic Ingredients and Handbooks), quasi-drug ingredients standards, Japanese pharmacopoeia, pharmaceutical additive standards Ingredients listed in the Food Addendum, etc., and the international patent classification IPC described in Japan and other foreign patent gazettes and patent publications (including publications and republications) belonging to the A61K7 and A61K8 classifications It is possible to contain known cosmetic ingredients, pharmaceutical ingredients, food ingredients, etc., in known combinations, blending ratios and blending amounts.
- a hydrogel is formed by the following steps using the above-described dispersion, that is, a dispersion containing a lipid peptide type compound, a specific alcohol and a polymer emulsifier, and a dispersion containing a heat resistance improver.
- the cosmetic additive and the quasi-drug additive can be added simultaneously with the dispersant in the step a).
- the heating temperature is preferably 50 ° C. to 90 ° C., more preferably 60 ° C. to 90 ° C., for example 80 ° C.
- stirring is performed while heating.
- the heating and stirring time in the step a) is not particularly limited.
- the heating time can be appropriately selected from 6 hours immediately after adding the dispersant, preferably 30 minutes to 3 hours after adding the dispersant.
- the amount of the dispersion to be added is, for example, 5 to 40% by mass, preferably 5 to 20% by mass, more preferably 5 to 10% by mass, based on the total mass of the resulting hydrogel. .
- step b cooling is performed with stirring until the liquid temperature is lower than the temperature in step a) (step b).
- the cooling temperature is room temperature to 80 ° C., preferably room temperature to 40 ° C.
- Hydrogels formed using the above-described dispersions as well as gels obtained by the above-described manufacturing methods are also objects of the present invention.
- the solid obtained here was dissolved in a mixed solution of 600 g of water and 750 g of methanol, and 30.5 ml (183.2 mmol) of 6N hydrochloric acid was added thereto for neutralization to precipitate a solid, followed by filtration.
- the obtained solid was dissolved in a mixed solution of 120 g of tetrahydrofuran and 30 g of water at 60 ° C., 150 g of ethyl acetate was added, and the mixture was cooled from 60 ° C. to 30 ° C.
- Example 1 to Example 5 Comparative Example 1 to Comparative Example 3: Preparation of N-palmitoyl-Gly-His Dispersion and Evaluation of Dispersibility
- a sample tube No. 7, manufactured by Marum Co., Ltd.
- the Pal-GH obtained in the above synthesis example and various alcohols and / or water shown in Table 1 were combined with the composition (mass%) shown in Table 1.
- Weighed and charged so that the mixture was heated and stirred at 80 ° C. to obtain a Pal-GH dispersion.
- the dispersibility of Pal-GH after heating and stirring at 80 ° C. indicates that the Pal-GH powder is uniformly dispersed in the solvent, and Pal-GH is non-uniformly dispersed (powder And the like were evaluated visually as x.
- the obtained results are also shown in Table 1.
- Example 11 and Example 12 Preparation of premix
- a total of 0.3 g of alginic acid PG was added to the dispersion liquid of Example 3 or Example 5, and 14.7 g of pure water was further added to prepare a premix.
- Example 13 and Example 14 Gelation test using premix
- a 300 mL tall beaker was charged with 80 g of pure water, and heated and stirred at 80 ° C. Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE. Subsequently, 20 g of the premix of Example 11 or Example 12 heated to 80 ° C. was added, and further heated and stirred for 5 minutes (80 ° C., 200 rpm). After heating and stirring, the mixture was stirred and cooled until the liquid temperature reached about 40 ° C., and the presence or absence of gel formation was confirmed. The gel formation was confirmed by the test tube inversion method described above, and the presence or absence of gelation was determined. The obtained test results are shown in Table 4.
- Example 15 to 18 Gelation and thermal stability evaluation of fatty acid-containing gel using premix
- Pure water was put into a 300 mL tall beaker and heated and stirred at 80 ° C. Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE.
- fatty acid lauric acid, palmitic acid or stearic acid
- This fatty acid-containing premix was added to pure water previously heated and stirred at 80 ° C., and further heated and stirred for 5 minutes (80 ° C., 200 rpm).
- Example 19 Gelation test using premix
- a 300 mL tall beaker was charged with 90 g of pure water, and heated and stirred at 80 ° C. Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE.
- 10 g of a premix having the following composition heated to 80 ° C. was added, and further heated and stirred for 5 minutes (80 ° C., 200 rpm). After heating and stirring, the mixture was stirred and cooled until the liquid temperature reached about 40 ° C., and the presence or absence of gel formation was confirmed. The gel formation was confirmed by the test tube inversion method described above to confirm gelation.
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Abstract
Description
従来型のヒドロゲルとしては、高分子鎖が架橋されて3次元網目構造を形成し、これが水などの媒体間と非共有結合を形成して膨潤することにより形成される高分子ゲルが挙げられる。この高分子ゲルの物性研究並びに用途開発は、アガロースなどの多糖類やタンパク質から形成される天然高分子ゲルや、アクリルアミドゲルなどの高分子鎖間を化学共有結合にて架橋した合成高分子ゲルにおいて数多くなされている。
近年、上述の高分子化合物からなるゲルだけでなく、比較的低分子量の有機化合物の自己集合化からなるヒドロゲルが見出され、種々検討されている。
こうした低分子ヒドロゲル化剤は、該ヒドロゲル化剤と媒体である水とをおよそ100℃の温度条件にて加熱撹拌して、ゲル化剤を水に溶解・分散させた後、この溶液を室温に静置することにより、ヒドロゲルを形成することができる。
また本発明はより簡便な方法にて、且つより温和な条件(低温)にてヒドロゲルが形成可能であり、また得られたゲルが高い熱安定性を有するゲルとなる分散液及びゲルの形成方法を提供することにある。
また、上述の溶媒に脂質ペプチド型化合物を溶解させた分散液に対して、高分子乳化剤を添加することにより、該分散液を用いてゲル調製を行う際、撹拌冷却を行った場合においてもゲルを良好に形成できること、そして該分散液が化粧品又は医薬部外品に使用可能なゲルのプレミックスとして有用であることを見出した。さらにこの分散液に耐熱性向上剤を添加することで、該分散液を用いて得られるゲルに対して高い熱安定性を与えることを見出し、本発明の完成に至った。
1,2-アルカンジオール、1,3-アルカンジオール及びエチレングリコールモノアルキルエーテルからなる群から選択される少なくとも1種のアルコール又は該少なくとも1種のアルコールと水との混合溶液とを含有する、分散液に関する。
第2観点として、前記脂質ペプチド型化合物が、下記式(1)乃至式(3)で表される化合物又はその薬学的に使用可能な塩のうちの少なくとも1種からなることを特徴とする、第1観点に記載の分散液に関する。
第3観点として、ゲル化剤として上記脂質ペプチド型化合物を含有し、さらに高分子乳化剤を含有する、第1観点又は第2観点に記載の分散液に関する。
第4観点として、化粧品又は医薬部外品の調製のためのプレミックスである、第3観点に記載の分散液。
第5観点として、不凍液の増粘剤として用いられる、第1観点又は第2観点に記載の分散液に関する。
第6観点として、前記高分子乳化剤が、親水性の主鎖に疎水性部位をグラフトさせたグラフト高分子化合物及び疎水性構成単位と親水性構成単位からなるブロック高分子化合物からなる群から選択される少なくとも1種の高分子化合物である、第3観点又は第4観点に記載の分散液に関する。
第7観点として、さらに耐熱性向上剤を含有する、第6観点に記載の分散液に関する。
第8観点として、前記耐熱性向上剤が炭素原子数10乃至20の飽和脂肪酸及び不飽和脂肪酸並びにそれら脂肪酸の塩からなる群から選択される少なくとも1種の脂肪酸である、第7観点記載の分散液に関する。
第9観点として、前記耐熱性向上剤がカプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸又はステアリン酸である、第8観点に記載の分散液に関する。
第10観点として、前記高分子化合物が、カルボキシメチルセルロース及びアルギン酸エステルからなる群から選択される、第6観点乃至第9観点のうち何れか一項に記載の分散液に関する。
第11観点として、前記高分子化合物が、アルギン酸プロピレングリコールである、第10観点に記載の分散液に関する。
第12観点として、第3観点及び第4観点並びに第6観点乃至第11観点のうち何れか一項に記載の分散液を水に添加し、室温以上100℃未満の温度に加熱する工程、
前記加熱工程よりも低い温度になるまで撹拌しながら冷却し、ゲルを形成させる工程、を含むヒドロゲルの製造方法に関する。
第13観点として、第3観点及び第4観点並びに第6観点乃至第11観点のうち何れか一項に記載の分散液を用いて形成されるヒドロゲルに関する。
さらに本発明の分散液は、例えば従来提案されている合成高分子型のゲルを形成時に必要とされた架橋剤等を用いずに、水をゲル化させてゲルを形成することができるため、得られるヒドロゲルにおいて未反応の架橋剤などの未反応物質の残存といった問題が起こらない。しかも分散液に含まれる脂質ペプチド型化合物は、わずか1質量%程度の添加量にてヒドロゲルを形成でき、環境や生体内で取り込まれた際に負荷が少ない。
さらに上述のように、低分子化合物である脂質ペプチドから得られたゲルは、外部環境中で、例えば土中で使用する場合、土壌細菌などによって容易に分解され、また生体内で使用する場合には代謝酵素によって容易に分解されるため、環境・生体に対する負荷が少ない。
そして本発明のゲルは、比較的温和な条件下で形成可能なゲルであり、熱の影響が懸念される添加剤を配合可能なゲルである。
従来提案された低分子ゲル化剤、例えば親水性部がペプチドのもの(脂質ペプチド、特許文献1,2)は溶媒に対する溶解性が低く、溶媒をゲル化させるためにはまずゲル化させたい溶媒を100℃といった高温に加熱し、ゲル化剤を溶解・分散させる必要があった。
また上記脂質ペプチド低分子ゲル化剤は、分子間の弱い相互作用(ファンデルワールス相互作用等)によってマクロな分子集合体を形成することによってゲル形成に至るとされ、こうした分子集合体の破壊はゲル形成を妨げることとなる。このため、ゲルを形成させるには、高温加熱して調製したゲル化剤分散液の冷却時に静置させる必要があり、冷却時に撹拌をするとゲル形成に至らないことがあった。
そしてこうした課題に対して、本発明者らは、脂質ペプチド型化合物を該化合物の溶解性が高い溶媒に一旦溶解・分散させて溶液(分散液)とし、これを謂わばゲル化材料のプレミックスとして溶媒(水等)に配合することによるゲル形成法を検討した。
そしてまず、脂質ペプチド型化合物を高濃度で溶解できる高い溶解性を有し、中でも、医薬部外品や化粧品等に使用が認められる安全性の高い溶媒を検討したところ、1,2-アルカンジオール、1,3-アルカンジオール及びエチレングリコールモノアルキルエーテルが好適であることを見出した。
続いて本発明者らは、上記プレミックスを用い、低温・撹拌下でのゲル形成を可能とすべく種々検討したところ、アルギン酸エステル等の高分子乳化剤の配合により、プレミックスを溶媒に配合した際の溶解・分散性並びにゲルの強度を確保でき、また、脂肪酸等の耐熱性向上剤の配合により形成したゲルの耐熱性を向上できることを見出した。
以上の経緯により本発明を完成するに至った。
本発明の分散液は、炭素原子数9乃至23の脂肪族基からなる脂質部に、アミノ酸の繰り返し結合構造を有するペプチド部が結合された脂質ペプチド型化合物と、1,2-アルカンジオール、1,3-アルカンジオール及びエチレングリコールモノアルキルエーテルからなる群から選択される少なくとも1種のアルコール又は該少なくとも1種のアルコールとの混合溶液とを含有する。
本発明において脂質ペプチド型化合物とは、脂肪族基からなる脂質部に、アミノ酸の繰り返し結合構造を有するペプチド部が結合された低分子化合物を示す。
本発明の分散液において用いる脂質ペプチド型化合物は、脂質部が炭素原子数9乃至23の脂肪族基からなる構造であることが好ましい。
また、本発明の分散液において用いる脂質ペプチド型化合物は、好ましくは、アミノ酸の繰り返し結合構造を複数個、好ましくは2乃至4個有し、末端にカルボン酸又はその塩を有し、そして、反対側の末端に炭素原子数9乃至23の脂肪族基を含む構造であることが好ましい。
本発明の分散液における脂質ペプチド型化合物としてより好ましくは、下記式(1)乃至式(3)で表される化合物(脂質ペプチド)又はその薬学的に使用可能な塩を用いることができる。
R1は及び隣接するカルボニル基で構成される脂質部(アシル基)の具体例としては、ラウロイル基、ドデシルカルボニル基、ミリストイル基、テトラデシルカルボニル基、パルミトイル基、マルガロイル基、オレオイル基、エライドイル基、リノレオイル基、ステアロイル基、バクセノイル基、オクタデシルカルボニル基、アラキドイル基、エイコシルカルボニル基、ベヘノイル基、エルカノイル基、ドコシルカルボニル基、リグノセイル基、ネルボノイル基等を挙げることができ、特に好ましいものとして、ラウロイル基、ミリストイル基、パルミトイル基、マルガロイル基、ステアロイル基、オレオイル基、エライドイル基及びベヘノイル基が挙げられる。
上記炭素原子数1若しくは2の分岐鎖を有し得る炭素原子数1乃至4のアルキル基とは、主鎖の炭素原子数が1乃至4であり、かつ炭素原子数1若しくは2の分岐鎖を有し得るアルキル基を意味し、その具体例としては、メチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、i-ブチル基、sec-ブチル基又はtert-ブチル基などが挙げられる。
炭素原子数1の分岐鎖を有し得る炭素原子数1乃至3のアルキル基とは、主鎖の炭素原子数が1乃至3であり、かつ炭素原子数1の分岐鎖を有し得るアルキル基を意味し、その具体例としては、メチル基、エチル基、n-プロピル基、i-プロピル基、i-ブチル基又はsec-ブチル基などが挙げられ、好ましくはメチル基、i-プロピル基、i-ブチル基又はsec-ブチル基である。
上記R3を表す-(CH2)n-X基において、Xは好ましくはアミノ基、グアニジノ基、カルバモイル基(-CONH2基)、ピロール基、イミダゾール基、ピラゾール基又はインドール基であり、より好ましくはイミダゾール基である。また、上記-(CH2)n-X基において、nは好ましくは1又は2であり、より好ましくは1である。
従って、上記-(CH2)n-基は、好ましくはアミノメチル基、2-アミノエチル基、3-アミノプロピル基、4-アミノブチル基、カルバモイルメチル基、2-カルバモイルエチル基、3-カルバモイルブチル基、2-グアニジノエチル基、3-グアニジノブチル基、ピロールメチル基、4-イミダゾールメチル基、ピラゾールメチル基、又は3-インドールメチル基を表し、より好ましくは4-アミノブチル基、カルバモイルメチル基、2-カルバモイルエチル基、3-グアニジノブチル基、4-イミダゾールメチル基又は3-インドールメチル基を表し、さらに好ましくは4-イミダゾールメチル基である。
上記式(2)において、R5乃至R7は、それぞれ独立して、水素原子、又は炭素原子数1若しくは2の分枝鎖を有し得る炭素原子数1乃至4のアルキル基、又は-(CH2)n-X基を表し、且つR5乃至R7のうち少なくとも一つ以上が-(CH2)n-X基を表す。nは1乃至4の数を表し、Xはアミノ基、グアニジノ基、-CONH2基、又は窒素原子を1乃至3個有し得る5員環式基若しくは6員環式基、又は5員環と6員環から構成される縮合複素環式基を表す。ここでR5乃至R7の好ましい具体例としては、前出のR2及びR3で定義したものと同じ基が挙げられる。
上記式(3)において、R9乃至R12は、それぞれ独立して、水素原子、又は炭素原子数1若しくは2の分枝鎖を有し得る炭素原子数1乃至4のアルキル基、又は-(CH2)n-X基を表し、且つR9乃至R12のうち少なくとも一つ以上が-(CH2)n-X基を表す。nは1乃至4の数を表し、Xはアミノ基、グアニジノ基、-CONH2基、又は窒素原子を1乃至3個有し得る5員環式基若しくは6員環式基、又は5員環と6員環から構成される縮合複素環式基を表す。ここでR9乃至R12の好ましい具体例としては、前出のR2及びR3で定義したものと同じ基が挙げられる。
したがって上記式(3)で表される化合物において、好適な脂質ペプチド型化合物として、特に好適な脂質ペプチドとしては、ラウロイル-Gly-Gly-Gly-His、ミリストイル-Gly-Gly-Gly-His、パルミトイル-Gly-Gly-Gly-His、パルミトイル-Gly-Gly-His-Gly、パルミトイル-Gly-His-Gly-Gly、パルミトイル-His-Gly-Gly-Gly、ステアロイル-Gly-Gly-Gly-His等が挙げられる。
本発明において、脂質ペプチド型化合物の配合量は、得られる分散液の総質量に対して、例えば0.1乃至40質量%、好ましくは、0.1乃至30質量%である。
なお本発明において用いられる脂質ペプチド型化合物は、上記式(1)乃至式(3)で表される化合物(脂質ペプチド)又はその薬学的な使用可能な塩のうちの少なくとも1種からなり、ヒドロゲル化剤としてこれら化合物を単独で、或いは2種以上を組み合わせて用いることができる。
本発明の分散液に使用されるアルコールは、1,2-アルカンジオール、1,3-アルカンジオール及びエチレングリコールモノアルキルエーテルからなる群から選択される少なくとも1種である。
上記1,2-アルカンジオールの具体例としては、1,2-ペンタンジオール、1,2-ヘキサンジオール、1,2-オクタンジオール及び1,2-デカンジオールなどが挙げられる。好ましくは、1,2-ペンタンジオール、1,2-ヘキサンジオール、1,2-オクタンジオールが挙げられる。さらに好ましくは、1,2-ペンタンジオール又は1,2-ヘキサンジオールである。
上記1,3-アルカンジオールの具体例としては、2-エチル-1,3-ヘキサンジオール及び1,3-ブタンジオールなどが挙げられる。好ましくは、2-エチル-1,3-ヘキサンジオールである。
また上記エチレングリコールモノアルキルエーテルとしては、アルキル基がメチル基、エチル基、プロピル基又はブチル基のアルキルエーテルが好ましいものとして挙げられ、すなわちエチレングリコールのモノエチルエーテル、モノプロピルエーテル又はモノブチルエーテルが挙げられる。さらに好ましくは、エチレングリコールモノプロピルエーテル又はエチレングリコールモノブチルエーテルである。
本発明において、上記アルコールの配合量は、得られる分散液の総質量に対して、例えば50%~90%、好ましくは70~90%である。
なお本発明において用いられる上記アルコールは上述のアルコール群の少なくとも1種であり、これらアルコールを単独で、或いは2種以上を組み合わせて用いることができる。
本発明の分散液に高分子乳化剤を添加することで、ゲル調製時に攪拌を行った場合でもゲルを与えることができる。この高分子乳化剤として、親水性の主鎖に疎水性部位をグラフトさせたグラフト高分子化合物及び疎水性構成単位と親水性構成単位からなるブロック高分子化合物からなる群から選択される少なくとも1種の高分子化合物を配合し得る。
前記疎水性構成単位と親水性構成単位からなるブロック高分子化合物としては、例えばアクリル酸・メタクリル酸アルキル共重合体等が挙げられる。
特に前記高分子化合物としては、カルボキシメチルセルロース及びアルギン酸エステルからなる群から選択される化合物が好ましく、特にアルギン酸プロピレングリコールが好ましい。
本発明において、上記高分子乳化剤の配合量は、得られる分散液の総質量に対して、例えば1.0乃至20.0%、好ましくは1.0乃至10.0%である。
なお本発明において用いられる上記高分子乳化剤は、グラフト高分子化合物及びブロック高分子化合物からなる群から選択される少なくとも1種であり、これら高分子化合物を単独で、或いは2種以上を組み合わせて用いることができる。
上記プレミックスは、脂質ペプチド型化合物にアルコールを添加し、室温以上100℃未満、好ましくは50℃乃至90℃、より好ましくは60℃乃至90℃、例えば80℃にて撹拌し、所望により、その後、耐熱性向上剤、化粧品用及び/又は医薬部外品用の添加剤を加えて撹拌することにより、製造可能である。
本発明の分散液に使用される耐熱性向上剤として、脂肪酸を添加することができる。
上記脂肪酸としては、以下に挙げる飽和脂肪酸、不飽和脂肪酸並びにそれらの塩を挙げることができる:カプリル酸、ペラルゴン酸、カプリン酸、ウンデカン酸、ラウリン酸、トリデカン酸、ミリスチン酸、ペンタデカン酸、パルミチン酸、マルガリン酸、ステアリン酸、ノナデカン酸、アラキジン酸等の直鎖飽和脂肪酸並びにそれらの塩;2-ブチル-5-メチルペンタン酸、2-イソブチル-5-メチルペンタン酸、ジメチルオクタン酸、ジメチルノナン酸、2-ブチル-5-メチルヘキサン酸、メチルウンデカン酸、ジメチルデカン酸、2-エチル-3-メチルノナン酸、2,2-ジメチル-4-エチルオクタン酸、メチルドコサン酸、2-プロピル-3-メチルノナン酸、メチルトリデカン酸、ジメチルドデカン酸、2-ブチル-3-メチルノナン酸、メチルテトラデカン酸、エチルトリデカン酸、プロピルドデカン酸、ブチルウンデカン酸、ペンチルデカン酸、ヘキシルノナン酸、2-(3-メチルブチル)-3-メチルノナン酸、2-(2-メチルブチル)-3-メチルノナン酸、ブチルエチルノナン酸、メチルペンタデカン酸、エチルテトラデカン酸、プロピルトリデカン酸、ブチルドデカン酸、ペンチルウンデカン酸、ヘキシルデカン酸、ヘプチルノナン酸、ジメチルテトラデカン酸、ブチルペンチルヘプタン酸、トリメチルトリデカン酸、メチルヘキサデカン酸、エチルペンタデカン酸、プロピルテトラデカン酸、ブチルトリデカン酸、ペンチルドデカン酸、ヘキシルウンデカン酸、ヘプチルデカン酸、メチルヘプチルノナン酸、ジペンチルヘプタン酸、メチルヘプタデカン酸、エチルヘキサデカン酸、エチルヘキサデカン酸、プロピルペンタデカン酸、ブチルテトラデカン酸、ペンチルトリデカン酸、ヘキシルドデカン酸、ヘプチルウンデカン酸、オクチルデカン酸、ジメチルヘキサデカン酸、メチルオクチルノナン酸、メチルオクタデカン酸、エチルヘプタデカン酸、ジメチルヘプタデカン酸、メチルオクチルデカン酸、メチルノナデカン酸、メチルノナデカン酸、ジメチルオクタデカン酸、ブチルヘプチルノナン酸等の分枝状飽和脂肪酸並びにそれらの塩;オクテン酸、ノネン酸、デセン酸、カプロレイン酸、ウンデシレン酸、リンデル酸、トウハク酸、ラウロレイン酸、トリデセン酸、ツズ酸、ミリストレイン酸、ペンタデセン酸、ヘキセデセン酸、パルミトレイン酸、ヘプタデセン酸、オクタデセン酸、オレイン酸、ノナデセン酸、ゴンドイン酸等の直鎖モノ不飽和脂肪酸並びにそれらの塩;メチルヘプテン酸、メチルノネン酸、メチルウンデセン酸、ジメチルデセン酸、メチルドデセン酸、メチルトリデセン酸、ジメチルドデセン酸、ジメチルトリデセン酸、メチルオクタデセン酸、ジメチルヘプタデセン酸、エチルオクタデセン酸等の分枝状不飽和モノ脂肪酸並びにそれらの塩;リノール酸、リノエライジン酸、エレオステアリン酸、リノレン酸、リノレンエライジン酸、プソイドエレオステアリン酸、パリナリン酸、アラキドン酸等の直鎖ジ不飽和脂肪酸又は直鎖トリ不飽和脂肪酸並びにそれらの塩;オクチン酸、ノニン酸、デシン酸、ウンデシン酸、ドデシン酸、トリデシン酸、テトラデシン酸、ペンタデシン酸、ヘプタデシン酸、オクタデシン酸、ノナデシン酸、ジメチルオクタデシン酸等のアセチレン酸並びにそれらの塩など。
ここで上述の脂肪酸の塩とは、例えばナトリウム塩、カリウム塩が挙げられる。
上記脂質エステル型化合物が溶媒である水に投入され、溶解・分散されると、2つの脂質エステル型化合物の脂質部同士が疎水的に分子間非共有結合を形成して対を形成し、さらにこの対の結合部分に対して外側に存在するペプチド部が水素結合によって他の対のペプチド部と分子間非共有結合を形成し得る。すなわち、2つの脂質エステル型化合物から形成される対が、ペプチド部の水素結合を介して多数の対の集合体を形成、謂わばラメラ状集合体を形成することが予想される。そして、複数のラメラ状集合体が連なることによりネットワーク構造を形成し、ラメラ状集合体の外側表面に存在するペプチド部(親水性)によってネットワーク間に存在する溶媒(水)が保持され、ゲル形態が保たれると考えられる。しかし、温度の上昇によって脂質ペプチド型化合物のアルキル鎖の運動性が上昇し、複数のラメラ状集合体の外側表面に存在するペプチド部同士が接近・水素結合を形成して凝集し、ラメラ間に存在していた水が排除されると、ゲル状態を保てなくなり、脂質ペプチド型化合物が析出することとなることが考えられる。
このとき、ラメラ状集合体間で静電反発を生じさせることにより、複数のラメラ状集合体の接近・水素結合の形成を防止することができると考えられる。静電反発を生じさせるには、例えばあるラメラ状集合体の外側表面に存在するペプチド部と非共有結合を形成し得、且つ、別のラメラ状集合体の外側表面に存在するペプチド部とは結合を形成しない(反発を生じる)構造を有する化合物の添加が有効であると考えられる。すなわち長鎖脂肪酸や長鎖アルコールといった分子内に疎水性部と親水性部とを有する化合物の添加により、温度を上昇させた場合においても、形成されたゲルにおいて析出物を生じさせることなく、安定にゲル状態を保つことができると考えられる。
本発明において、上記耐熱性向上剤の配合量は、得られる分散液の総質量に対して、例えば0.5乃至2.0%、好ましくは0.5乃至1.0%である。
なお本発明において用いられる上記耐熱性向上剤は、上記脂肪酸群から選択される少なくとも1種であり、これら脂肪酸を単独で、或いは2種以上を組み合わせて用いることができる。
該組成物に、必要に応じて一般的に化粧品用添加剤及び医薬部外品用添加剤として使用可能な添加剤を配合することができる。化粧品又は医薬部外品等の皮膚外用剤に配合される生理活性物質及び機能性物質等の添加成分としては、例えば油性基剤、保湿剤、感触向上剤、界面活性剤、高分子、増粘・ゲル化剤、溶剤、噴射剤、酸化防止剤、還元剤、酸化剤、防腐剤、抗菌剤、殺菌剤、キレート剤、pH調整剤、酸、アルカリ、粉体、無機塩、紫外線吸収剤、美白剤、ビタミン類及びその誘導体類、育毛用薬剤、血行促進剤、刺激剤、ホルモン類、抗しわ剤、抗老化剤、ひきしめ剤、冷感剤、温感剤、創傷治癒促進剤、刺激緩和剤、鎮痛剤、細胞賦活剤、植物・動物・微生物エキス、鎮痒剤、角質剥離・溶解剤、制汗剤、清涼剤、収れん剤、酵素、核酸、香料、色素、着色剤、染料、顔料、消炎剤、抗炎症剤、抗喘息、抗慢性閉塞性肺疾患、抗アレルギー、免疫調整剤、抗感染症剤及び抗真菌剤等が挙げられる。
等のリン脂質類;シリコーン系両性界面活性剤等;高分子界面活性剤としては、ポリビニルアルコール、アルギン酸ナトリウム、デンプン誘導体、トラガントガム、アクリル酸・メタアクリル酸アルキル共重合体;シリコーン系各種界面活性剤が好ましいものとして挙げられる。
本発明において、前述の分散液、すなわち、脂質ペプチド型化合物、特定のアルコール及び高分子乳化剤を含有する分散液、そしてさらに耐熱性向上剤を含有する分散液を用いて、下記工程によりヒドロゲルを形成可能である。
a)上記分散剤を水に添加し、室温以上100℃未満の温度で加熱する工程
b)前記加熱工程における温度よりも低い温度になるまで撹拌しながら冷却し、ゲルを形成させる工程
また、前述の化粧品用添加剤及び医薬部外品用添加は、前記a)工程において、分散剤とともに同時に添加することができる。
a)工程における加熱及び撹拌時間は、特に限定されないが、例えば加熱時間としては分散剤を添加直後から6時間、好ましくは分散剤を添加後30分後から3時間までの間で適宜選択できる。
前記a)工程において、添加する分散液の量は、得られるヒドロゲルの総質量に対して、例えば5乃至40質量%、好ましくは、5乃至20質量%、より好ましくは5乃至10質量%である。
ここで、冷却温度は、室温乃至80℃、好ましくは室温乃至40℃である。
上述の分散液を用いて形成されるヒドロゲル、並びに上述の製造方法により得られるゲルもまた本発明の対象である。
本実施例において、ゲル化剤として用いた脂質ペプチドは、以下に示す方法で合成した。
500mLの4つ口フラスコに、ヒスチジン14.2g(91.6mmol)、N-パルミトイル-Gly-メチル30.0g(91.6mmol)、トルエン300gを投入し、塩基であるナトリウムメトキサイド 28%メタノール溶液35.3g(183.2mmol)を加え、油浴で60℃に加熱し1時間撹拌を続けた。その後、油浴を外し、25℃まで放冷し、この溶液をアセトン600gで再沈殿させ、濾取した。ここで得られた固体を、水600gとメタノール750gの混合溶液に溶解し、ここに6規定塩酸30.5ml(183.2mmol)を加えて中和し固体を析出させ、ろ過した。次に、得られた固体をテトラヒドロフラン120gと水30gの混合液に60℃で溶解させ、酢酸エチル150gを加え、60℃から30℃まで冷却した。その後、析出した固体をろ過した。さらに得られた固体を、テトラヒドロフラン120gとアセトニトリル60g溶剤中に溶解し、60℃に加熱し、1時間撹拌した後に冷却し、ろ過した。ここで得られた固体を水120gで洗浄し、ろ過後に減圧乾燥を行いN-パルミトイル-Gly-Hisフリー体(以下、単にPal-GHとも称する)の白色の結晶、26.9g(収率65%)を得た。
サンプル管(No.7、(株)マルエム社製)に、上記合成例で得られたPal-GH、及び表1に示す各種アルコール及び/又は水を、表1に示す組成(質量%)となるように秤量して投入し、80℃で加熱撹拌を行い、Pal-GH分散液を得た。
また、80℃加熱撹拌後のPal-GHの分散性を、Pal-GHの粉末が溶媒に対して均一に分散しているものを○、Pal-GHが不均一に分散しているもの(粉の塊があるものなど)を×として目視により評価した。
得られた結果を表1にあわせて示す。
300mLトールビーカーに、表2に示すように純水、及びアルギン酸プロピレングリコール(アルギン酸PGとも称する)又はキサンタンガムを入れ、80℃で加熱撹拌を行った。なお撹拌はアズワン(株)製のLABORATORY HIGH MIXERを用いて、200rpmで行った。
次いで、80℃に加熱した上記実施例1乃至実施例5のPal-GH分散液5.0gを加え、さらに加熱撹拌を5分間行った。
加熱終了後、液温が約40℃程度になるまで撹拌冷却し、ゲル形成の有無を確認した。ゲル形成の確認は試験管倒置法により行い、分散液の流動性が失われて、トールビーカーを倒置しても液が流れ落ちない状態を「ゲル化(○)」と判定し、ゲル化に至らなかったものを「×」として評価した。ゲル化試験後の最終的な組成と、得られた試験結果を表2に示す。
300mLトールビーカーに純水80gを入れ、80℃で加熱撹拌を行った。なお撹拌はアズワン(株)製のLABORATORY HIGH MIXERを用いて、200rpmで行った。
次いで、80℃に加熱した実施例11又は実施例12のプレミックス20gを加え、さらに加熱撹拌を5分間行った(80℃、200rpm)。
加熱撹拌終了後、液温が約40℃程度になるまで撹拌冷却し、ゲル形成の有無を確認した。ゲル形成の確認は前述の試験管倒置法により行いゲル化の有無を判断した。得られた試験結果を表4に示す。
300mLトールビーカーに純水を入れ、80℃で加熱撹拌を行った。なお撹拌はアズワン(株)製のLABORATORY HIGH MIXERを用いて、200rpmで行った。
一方、80℃に加熱した実施例11のプレミックス20gに、脂肪酸(ラウリン酸、パルミチン酸又はステアリン酸)を加え、加熱溶解させた。この脂肪酸含有プレミックスを、先に80℃で加熱撹拌している純水に加え、さらに加熱撹拌を5分間行った(80℃、200rpm)。
加熱終了後、液温が約40℃程度になるまで撹拌冷却し、ゲル形成の有無を確認した。ゲル形成の確認は前述の試験管倒置法により行いゲル化の有無を判断した。得られた試験結果並びにゲル化試験後の最終的な組成を表5に示す。
また調製したゲルを40℃恒温槽内に1晩保存してゲルの熱安定性を評価した。保存後に目視にて析出物や離水が殆ど確認されなかったものを「○」、多量の析出物や離水が確認されたものを「×」として評価した。得られた結果を表5にあわせて示す。
Claims (13)
- 炭素原子数9乃至23の脂肪族基からなる脂質部に、アミノ酸の繰り返し結合構造を有するペプチド部が結合された脂質ペプチド型化合物と、
1,2-アルカンジオール、1,3-アルカンジオール及びエチレングリコールモノアルキルエーテルからなる群から選択される少なくとも1種のアルコール又は該少なくとも1種のアルコールと水との混合溶液とを含有する、分散液。 - 前記脂質ペプチド型化合物が、下記式(1)乃至式(3)で表される化合物又はその薬学的に使用可能な塩のうちの少なくとも1種からなることを特徴とする、請求項1に記載の分散液。
- ゲル化剤として上記脂質ペプチド型化合物を含有し、さらに高分子乳化剤を含有する、請求項1又は請求項2に記載の分散液。
- 化粧品又は医薬部外品の調製のためのプレミックスである、請求項3に記載の分散液。
- 不凍液の増粘剤として用いられる、請求項1又は請求項2に記載の分散液。
- 前記高分子乳化剤が、親水性の主鎖に疎水性部位をグラフトさせたグラフト高分子化合物及び疎水性構成単位と親水性構成単位からなるブロック高分子化合物からなる群から選択される少なくとも1種の高分子化合物である、請求項3又は請求項4に記載の分散液。
- さらに耐熱性向上剤を含有する、請求項6に記載の分散液。
- 前記耐熱性向上剤が炭素原子数10乃至20の飽和脂肪酸及び不飽和脂肪酸並びにそれら脂肪酸の塩からなる群から選択される少なくとも1種の脂肪酸である、請求項7記載の分散液。
- 前記耐熱性向上剤がカプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸又はステアリン酸である、請求項8に記載の分散液。
- 前記高分子化合物が、カルボキシメチルセルロース及びアルギン酸エステルからなる群から選択される、請求項6乃至請求項9のうち何れか一項に記載の分散液。
- 前記高分子化合物が、アルギン酸プロピレングリコールである、請求項10に記載の分散液。
- 請求項3及び請求項4並びに請求項6乃至請求項11のうち何れか一項に記載の分散液を水に添加し、室温以上100℃未満の温度に加熱する工程、
前記加熱工程における温度よりも低い温度になるまで撹拌しながら冷却し、ゲルを形成させる工程、を含むヒドロゲルの製造方法。 - 請求項3及び請求項4並びに請求項6乃至請求項11のうち何れか一項に記載の分散液を用いて形成されるヒドロゲル。
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EP2865442A4 (en) | 2016-01-06 |
CN104582826B (zh) | 2018-06-05 |
EP3296013A1 (en) | 2018-03-21 |
KR102091794B1 (ko) | 2020-03-20 |
CN108635240B (zh) | 2021-09-14 |
CN104582826A (zh) | 2015-04-29 |
EP2865442A1 (en) | 2015-04-29 |
US10421055B2 (en) | 2019-09-24 |
US20150202586A1 (en) | 2015-07-23 |
KR20150024916A (ko) | 2015-03-09 |
ES2660484T3 (es) | 2018-03-22 |
CN108635240A (zh) | 2018-10-12 |
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