WO2015005219A1 - 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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- WO2015005219A1 WO2015005219A1 PCT/JP2014/067802 JP2014067802W WO2015005219A1 WO 2015005219 A1 WO2015005219 A1 WO 2015005219A1 JP 2014067802 W JP2014067802 W JP 2014067802W WO 2015005219 A1 WO2015005219 A1 WO 2015005219A1
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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 to contain a lipid peptide type compound useful as a low molecular weight gelling agent such as lipid dipeptide or lipid tripeptide, and a dissolution accelerator capable of dissolving the lipid peptide type compound more easily at a lower temperature. It is to provide a dispersion.
- 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. It exhibits high solubility and high dispersibility at lower temperature conditions than before, and it can be a suitable dispersion as a gel premix raw material and antifreeze thickener. I found it.
- a polymer emulsifier to a dispersion obtained by dissolving a lipid peptide type compound in the above-mentioned solvent, 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. Furthermore, by using a dissolution promoter, a good gel is formed even when the amount of lipid peptide type compound consisting of a low molecular lipid peptide necessary for gelation or a pharmaceutically usable salt thereof is reduced. I found out.
- the present invention provides, as a first aspect, a lipid in which a peptide part formed by repeating at least two identical or different amino acids is bound to a lipid part composed of an aliphatic group having 10 to 24 carbon atoms.
- the present invention relates to a dispersion comprising a peptide-type compound, a dissolution accelerator having a hydrophilic part and a hydrophobic part in the molecule, and the hydrophilic part having a betaine structure, and water.
- the lipid peptide type compound comprises 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 one 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 wherein the dissolution accelerator is at least one selected from lauryldimethylaminoacetic acid betaine, lauric acid amidopropyl betaine, lauryl hydroxysulfobetaine, stearyl betaine, and lysophosphatidylcholine.
- the dispersion liquid as described in any one of the 1st viewpoint thru
- the dispersion liquid As a 6th viewpoint, it is related with the dispersion liquid as described in a 5th viewpoint which is a premix for preparation of cosmetics or a quasi-drug. As a 7th viewpoint, it is related with the dispersion liquid as described in any one of the 1st viewpoint thru
- 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.
- the dispersion liquid according to the fifth aspect or the sixth aspect which is at least one polymer compound.
- the dispersion liquid as described in an 8th viewpoint which contains a heat resistance improver is at least one higher alcohol or higher fatty acid ester selected from the group consisting of saturated and unsaturated having 10 to 20 carbon atoms.
- the said heat resistance improver is cetanol, myristyl alcohol, and glyceryl monostearate.
- a twelfth aspect relates to the dispersion according to the eighth aspect, in which the polymer compound is selected from the group consisting of carboxymethyl cellulose and an alginate.
- a thirteenth aspect relates to the dispersion according to the twelfth aspect, in which the polymer compound is propylene glycol alginate.
- the step of adding the dispersion liquid according to any one of the fifth aspect, the sixth aspect, and the eighth aspect to the thirteenth aspect to water and heating to a temperature of room temperature to less than 100 ° C. It is related with the manufacturing method of hydrogel including the process of cooling with stirring until it becomes temperature lower than the temperature in a heating process, and forming a gel.
- the present invention relates to a hydrogel formed using the dispersion liquid according to any one of the fifth to sixth aspects and the eighth to thirteenth aspect. .
- the dispersion of the present invention dissolves and disperses the lipid peptide type compound in a relatively short time by stirring the lipid peptide type compound and the dissolution accelerator, etc. under a relatively mild temperature condition such as 80 ° C. Can be prepared.
- 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 liquid of this invention can obtain favorable hydrogel by mix
- 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 a dissolution accelerator having a hydrophilic part and a hydrophobic part in the molecule.
- 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 is capable of forming 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 composition with high dissolution promotion 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 of all, we examined a safe dissolution accelerator that can dissolve lipid peptide-type compounds at a high concentration.
- a safe dissolution accelerator approved for use in quasi-drugs, cosmetics, etc. It was found that a compound having a hydrophobic part and a hydrophilic part having a betaine structure is 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 was 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 a higher alcohol or higher fatty acid ester 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 part formed by repeating at least two identical or different amino acids is bound to a lipid part composed of an aliphatic group having 10 to 24 carbon atoms. Further, the present invention relates to a dispersion containing a mixed solution of a water accelerator having a hydrophilic part and a hydrophobic part in a molecule, and the hydrophilic part having a betaine structure.
- lipid peptide type compound examples include compounds represented by the following formulas (1) to (3) (lipid peptides) or pharmaceutically usable salts thereof (lipid part which is a hydrophobic site) And a low molecular compound having a peptide moiety which is a hydrophilic portion).
- 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, Myristoyl- 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
- 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, and more preferably 0.05 to 10% 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. More preferably, it is 0.1 to 10% by mass.
- 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 hydrogelated. These compounds can be used alone or in combination of two or more as an agent.
- the dissolution promoter used in the dispersant of the present invention is a compound having a hydrophilic part and a hydrophobic part in the molecule, and the hydrophilic part having a betaine structure (hereinafter also referred to as a betaine compound).
- betaine compounds as described above include N-alkyl-N, N-dimethylamino acid betaines such as lauryldimethylaminoacetic acid betaine (lauryl betaine); fatty acid amide alkyl-N such as cocamidopropyl betaine and lauramidopropyl betaine.
- N-dimethylamino acid betaine N-dimethylamino acid betaine; imidazoline-type betaines such as sodium cocoamphoacetate and sodium lauroamphoacetate; alkylsulfobetaines such as laurylhydroxysulfobetaine and alkyldimethyltaurine; sulfate-type betaines such as alkyldimethylaminoethanol sulfate; alkyldimethylaminoethanol Known betaine compounds such as phosphate-type betaines such as phosphate esters can be used as amphoteric surfactants.
- betaine compounds include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidic acid and other glycerophospholipids; lysophosphatidylcholine (lysolecithin), lysophosphatidylethanolamine, Examples thereof include lysoglycerophospholipids such as serine, lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidic acid; sphingophospholipids such as sphingomyelin; and hydrogenated products thereof.
- phospholipids may be derived from animals and plants such as soybeans and egg yolks, or may be synthesized by a chemical or enzymatic method.
- betaine compounds preferably lauryldimethylaminoacetic acid betaine, lauric acid amidopropyl betaine, lauryl hydroxysulfobetaine, stearyl betaine, lysophosphatidylcholine (lysolecithin), lysophosphatidylethanolamine, lysophosphatidylserine, lysophosphatidylinositol, lyso
- Examples include phosphatidylglycerol, lysophosphatidic acid, and more preferably lauryldimethylaminoacetic acid betaine, lauric acid amidopropyl betaine, lauryl hydroxysulfobetaine, stearyl betaine, and lysophosphatidylcholine (lysolecithin).
- the blending amount of the dissolution accelerator is, for example, 0.01 to 1% by mass, and more preferably 0.10 to 0.50% by mass with respect to the total mass of the resulting hydrogel.
- the compounding quantity of the said dissolution promoter is 1 thru
- polyhydric alcohol By blending the polyhydric alcohol with the dispersion of the present invention, a good gel can be obtained even when the blending amount of the lipid peptide type compound as a gelling agent is reduced.
- the polyhydric alcohol used in the dispersion of the present invention is at least one selected from the group consisting of 1,3-butylene glycol, propylene glycol, and glycerin. Preferred is glycerin or 1,3-butanediol, and more preferred is 1,3-butanediol.
- the polyhydric alcohol is at least one of the above-described alcohol groups, and these alcohols can be used alone or in combination of two or more.
- the compounding quantity of the said polyhydric alcohol is 0.1 to 10 mass% with respect to the total mass of the hydrogel obtained, More preferably, it is 1 to 5 mass%.
- the blending amount of the polyhydric alcohol is, for example, 5 to 30% by mass, preferably 15 to 25% by mass with respect to the total mass of the obtained dispersion.
- a dispersion containing the lipid peptide type compound, the dissolution accelerator and the polyhydric 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 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 blending amount of the polymer emulsifier is, for example, 0.1 to 5% by mass, and more preferably 0.2 to 0.5% by mass, with respect to the total mass of the resulting hydrogel.
- the dispersion containing the lipid peptide type compound as a gelling agent and containing a polymer emulsifier in addition to the dissolution accelerator and the polyhydric alcohol is a preparation of cosmetics or 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 a dissolution accelerator and a polyhydric alcohol to a lipid peptide-type compound and at room temperature to less than 100 ° C, preferably 50 ° C to 90 ° C, more preferably 60 ° C to 90 ° C, for example, 80 ° C. It can be manufactured by stirring and, if desired, subsequently adding a heat resistance improver, an additive for cosmetics and / or quasi drugs and stirring.
- Heat resistance improver As the heat resistance improver used in the dispersion of the present invention, a higher alcohol or a higher fatty acid ester can be added.
- the higher alcohol include saturated and unsaturated higher alcohols listed below: lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol, hexadecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyldodecanol.
- Octyldodecanol cetostearyl alcohol-2-decyltetradecinol, cholesterol, phytosterol, sitosterol, lanosterol, POE cholesterol ether, monostearyl glycerol ether (batyl alcohol) and the like.
- higher alcohols preferably at least one selected from the group consisting of saturated and unsaturated higher alcohols having 10 to 20 carbon atoms, preferably lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, Examples include behenyl alcohol, oleyl alcohol, isostearyl alcohol, cholesterol, phytosterol, sitosterol, lanosterol, monostearyl glycerol ether (batyl alcohol) and the like. More preferably, lauryl alcohol, palmityl alcohol, and myristyl alcohol are raised.
- higher fatty acid esters include the following saturated and unsaturated higher fatty acid esters: diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, N-alkyl monoisostearate Glycol, Isocetyl isostearate, Trimethylolpropane triisostearate, Ethylene glycol 2-ethylhexanoate-2-Cetyl triethylhexanoate, Trimethylolpropane tri-2-ethylhexanoate, Pentaerythritol tetra-2-ethylhexanoate , Cetyl octanoate, octyl dodecyl gum ester, oleyl oleate, octyl dodecyl oleate, decyl oleate, neopentyl glycol dicap
- higher fatty acid esters preferably at least one selected from the group consisting of saturated higher fatty acid esters having 10 to 20 carbon atoms, preferably N-alkyl glycol monoisostearate and glyceride monostearate. It is done. More preferred is glyceryl monostearate (glyceryl monostearate).
- the compounding quantity of the said heat resistance improver is 0.01 to 0.30 mass% with respect to the total mass of the hydrogel obtained, Preferably it is 0.02 to 0.10 mass%.
- the amount of the heat resistance improver is, for example, 0.2 to 1.0% by mass, preferably 0.1 to 0.5% by mass, based on the total mass of the obtained dispersion. is there.
- 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 touch improver, a surfactant, a polymer, a thickening 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
- Polyglyceryl ethers polyoxyethylene alkylamines; tetrapolyoxyethylene / tetrapolyoxypropylene-ethylenediamine condensates; natural surfactants such as saponins and sophorolipids; polyoxyethylene fatty acid amides; Palm oil fatty acid monoethanolamide (cocamide MEA), palm oil fatty acid diethanolamide (cocamide DEA), lauric acid monoethanolamide (Lauramide MEA), lauric acid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acid monoethanolamide (partamide MEA), palmitic acid diethanolamide (partamide DEA), palm oil fatty acid methylethanolamide ( Fatty acid alkanolamides such as cocamidomethyl MEA); alkyldimethylamine oxides such as lauramine oxide, cocamamine oxide, stearamine oxide, and behenamine oxide; alkylethoxydimethylamine oxide; polyoxyethylene al
- Nonionic surfactants of silicone, etc .; cationic surfactants 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 ethers such as stearoxypropyldimethylamine Amine and its salts or quaternary salts; ethyl sulfate long chain branched fatty acid (12-31) aminopropylethyldimethylammonium, ethyl Fatty acid amide type quaternary ammonium salts such as lanolin fatty acid aminopropylethyldimethylammonium; polyoxyethylene alkylamines and salts or quaternary salts thereof; alkylamine salts; fatty acid amidoguanidinium salts; alkyl etheraminemonium salts; Benzalkonium salts; benz
- Silicone-based cationic surfactants such as amino-modified silicone, cation-modified silicone, cation-modified and polyether-modified silicone, amino-modified and polyether-modified silicone
- amphoteric surfactant etc N-alkyl-N, N-dimethylamino acid betaines such as lauryl betaine (lauryldimethylaminoacetic acid betaine); fatty acid amide alkyl-N, N-dimethylamino acid betaines such as cocamidopropyl betaine and lauramidopropyl betaine; sodium cocoamphoacetate; Imidazoline-type betaines such as sodium lauroamphoacetate; alkylsulfobetaines such as alkyldimethyltaurine; sulfate-type betaines such as alkyldimethylaminoethanol sulfate; phosphate-type betaines such as alkyldimethylaminoethanol phosphate; phosphati
- 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 salicylic acid such as amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate External line absorbent: octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl
- Benzophenone UV 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)
- hydantoin derivatives phenylbenzimidazolazosulfonic acid, terephthalylidene dicamphor Preferred are sulfonic acid, drometrizole trisiloxane, methyl anthranilate, rutin and derivatives thereof, oryzanol and derivatives thereof.
- 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.
- ⁇ Hydrogel formation method> using the above-mentioned dispersion, that is, a dispersion containing a lipid peptide type compound, a dissolution accelerator, a polyhydric alcohol and a polymer emulsifier, and a dispersion containing a heat resistance improver, the following steps are performed.
- 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 70 ° C. or 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.
- 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.
- the composition of Pal-GH obtained in the above synthesis example and various dissolution accelerators shown in Table 1 are as shown in Table 1 (mass: g).
- the mixture was weighed and charged, and heated and stirred in a water bath at a preset temperature of about 80 ° C. to obtain a Pal-GH dispersion.
- a sample in which Pal-GH powder is uniformly dispersed in a solvent (a transparent solution can be obtained) is obtained, and Pal-GH is not used. What was uniformly dispersed (becomes a cloudy dispersion with a lump of powder) was evaluated visually as x.
- the obtained results are also shown in Table 1.
- Table 2 shows the sample tube (No. 7, manufactured by Marum Co., Ltd.), the Pal-GH obtained in the above synthesis example, and the dissolution accelerator, polyhydric alcohol and heat resistance improver shown in Table 2.
- a composition (mass: g) was weighed and added, and heated and stirred in a water bath at a preset temperature of about 80 ° C. to obtain a Pal-GH dispersion.
- Examples 11 and 12 Gelation test using a combination of Pal-GH dispersion and propylene glycol alginate
- pure water and propylene glycol alginate also referred to as alginate PG
- the mixture was heated and stirred at 70 ° C.
- Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE.
- 1.00 g of the Pal-GH dispersion of Example 1 or Example 4 heated to 70 ° C. was added, and further heated and stirred for 5 minutes. After completion of heating, the solution was stirred and cooled until the liquid temperature reached about 40 ° C., and the presence or absence of gel formation was confirmed.
- Example 13 to Example 16 Confirmation of effect of heat resistance improver
- pure water and propylene glycol alginate were placed in a 300 mL tall beaker, and the mixture was heated and stirred at 70 ° C. Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE.
- the Pal-GH dispersions of Examples 7 to 10 heated to 70 ° C. were added so as to have the amounts shown in Table 4, and further heated and stirred for 5 minutes. After completion of heating, the solution was stirred and cooled until the liquid temperature reached about 40 ° C., and the presence or absence of gel formation was confirmed. Confirmation of gel formation is performed by the test tube inversion method.
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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。
さらに、溶解促進剤を用いることで、ゲル化に必要な低分子脂質ペプチド又はその薬学的に使用可能な塩からなる脂質ペプチド型化合物の添加量を少なくした場合にも、良好なゲルを形成することを見出した。
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一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、さらに多価アルコールを含有する、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、前記溶解促進剤が、ラウリルジメチルアミノ酢酸ベタイン、ラウリン酸アミドプロピルベタイン、ラウリルヒドロキシスルホベタイン、ステアリルベタイン及びリゾホスファチジルコリンから選択される少なくとも一種である、第3観点に記載の分散液に関する。
第5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観点乃至第4観点のうち何れか一項に記載の分散液に関する。
第6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5観点に記載の分散液に関する。
第7観点として、不凍液の増粘剤として用いられる、第1観点乃至第4観点のうち何れか一項に記載の分散液に関する。
第8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5観点又は第6観点に記載の分散液に関する。
第9観点として、さらに耐熱性向上剤を含有する、第8観点に記載の分散液に関する。
第10観点として、前記耐熱性向上剤が炭素原子数10乃至20の飽和及び不飽和からなる群から選択される少なくとも1種の高級アルコールまたは高級脂肪酸エステルである、第9観点に記載の分散液に関する。
第11観点として、前記耐熱性向上剤がセタノール、ミリスチルアルコール、モノステアリン酸グリセリルである、第10観点に記載の分散液に関する。
第12観点として、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8観点に記載の分散液に関する。
第13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12観点に記載の分散液に関する。
第14観点として、第5観点及び第6観点並びに第8観点乃至第13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に関する。
第15観点として、第5観点及び第6観点並びに第8観点乃至第13観点のうち何れか一項に記載の分散液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促進が高い組成に一旦溶解・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溶解促進剤を検討したところ、分子内に親水部と疎水部を有し、かつ該親水部がベタイン構造を有する化合物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、高級アルコールまたは高級脂肪酸エステル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10乃至24の脂肪族基からなる脂質部に、少なくとも2つ以上の同一の又は異なるアミノ酸の繰り返しにより形成されたペプチド部が結合された脂質ペプチド型化合物と、分子内に親水部と疎水部を有し、かつ該親水部がベタイン構造を有する溶解促進剤と、水との混合溶液とを含有する、分散液に関する。
本発明の分散液において用いる脂質ペプチド型化合物としては、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(疎水性部位である脂質部と親水性部位であるペプチド部とを有する低分子化合物)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。より好ましくは0.1乃至10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一種からなり、ヒドロゲル化剤としてこれら化合物を単独で、或いは二種以上を組み合わせて用いることができる。
本発明の分散剤に使用される溶解促進剤は分子内に親水部と疎水部を有し、かつ該親水部がベタイン構造を有する化合物(以下、ベタイン系化合物とも称する)である。
上述のようなベタイン系化合物としては、例えばラウリルジメチルアミノ酢酸ベタイン(ラウリルベタイン)等のN-アルキル-N,N-ジメチルアミノ酸ベタイン;コカミドプロピルベタイン、ラウラミドプロピルベタイン等の脂肪酸アミドアルキル-N,N-ジメチルアミノ酸ベタイン;ココアンホ酢酸ナトリウム、ラウロアンホ酢酸ナトリウム等のイミダゾリン型ベタイン;ラウリルヒドロキシスルホベタイン、アルキルジメチルタウリン等のアルキルスルホベタイン;アルキルジメチルアミノエタノール硫酸エステル等の硫酸型ベタイン;アルキルジメチルアミノエタノールリン酸エステル等のリン酸型ベタイン等、両性界面活性剤として既知のベタイン系化合物を使用出来る。
また、上記ベタイン系化合物として、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジルグリセロール、ジホスファチジルグリセロール(カルジオリピン)、ホスファチジン酸などのグリセロリン脂質;リゾホスファチジルコリン(リゾレシチン)、リゾホスファチジルエタノールアミン、リゾホスファチジルセリン、リゾホスファチジルイノシトール、リゾホスファチジルグリセロール、リゾホスファチジン酸などのリゾグリセロリン脂質;スフィンゴミエリンなどのスフィンゴリン脂質;およびこれらの水素添加物などが挙げられる。これらのリン脂質は、大豆、卵黄などの動植物由来のものでもよく、化学的もしくは酵素的方法により合成されたものでもよい。
上記ベタイン系化合物の中でも、好ましくは、ラウリルジメチルアミノ酢酸ベタイン、ラウリン酸アミドプロピルベタイン、ラウリルヒドロキシスルホベタイン、ステアリルベタイン、リゾホスファチジルコリン(リゾレシチン)、リゾホスファチジルエタノールアミン、リゾホスファチジルセリン、リゾホスファチジルイノシトール、リゾホスファチジルグリセロール、リゾホスファチジン酸などが挙げられ、さらに好ましくは、ラウリルジメチルアミノ酢酸ベタイン、ラウリン酸アミドプロピルベタイン、ラウリルヒドロキシスルホベタイン、ステアリルベタイン、リゾホスファチジルコリン(リゾレシチン)が挙げられる。
これらは一種単独で、或いは二種以上を組み合わせて用いることができる。
また本発明において、上記溶解促進剤の配合量は、得られる分散液の総質量に対して、例えば1乃至30質量%、好ましくは、5乃至25質量%である。
本発明の分散液に多価アルコールを配合することで、ゲル化剤である前記脂質ペプチド型化合物の配合量を減らした場合においても、良好なゲルを得ることができる。
本発明の分散液に使用される多価アルコールは、1,3-ブチレングリコール、プロピレングリコール、グリセリンからなる群から選択される少なくとも1種である。好ましくは、グリセリン又は1,3-ブタンジオールであり、さらに、好ましくは、1,3-ブタンジオールである。
上記多価アルコールは上述のアルコール群の少なくとも一種であり、これらアルコールを単独で、或いは二種以上を組み合わせて用いることができる。
また本発明において、上記多価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5乃至30質量%、好ましくは、15乃至25質量%である。
本発明の分散液に高分子乳化剤を添加することで、ゲル調製時に撹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。
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、或いは二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、溶解促進剤、多価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、高級アルコールまたは高級脂肪酸エステルを添加することができる。
上記高級アルコールとしては、以下に挙げる飽和、不飽和高級アルコールを挙げることができる:ラウリルアルコール、ミリスチルアルコール、パルミチルアルコール、ステアリルアルコール、ベヘニルアルコール、ヘキサデシルアルコール、オレイルアルコール、イソステアリルアルコール、ヘキシルドデカノール、オクチルドデカノール、セトステアリルアルコール-2-デシルテトラデシノール、コレステロール、フィトステロール、シトステロール、ラノステロール、POEコレステロールエーテル、モノステアリルグリセリンエーテル(バチルアルコール)等が挙げられる。
また本発明において、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0.2乃至1.0質量%、好ましくは、0.1乃至0.5質量%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、或いは二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。
ラウリルベタイン(ラウリルジメチルアミノ酢酸ベタイン)等のN-アルキル-N,N-ジメチルアミノ酸ベタイン;コカミドプロピルベタイン、ラウラミドプロピルベタイン等の脂肪酸アミドアルキル-N,N-ジメチルアミノ酸ベタイン;ココアンホ酢酸ナトリウム、ラウロアンホ酢酸ナトリウム等のイミダゾリン型ベタイン;アルキルジメチルタウリン等のアルキルスルホベタイン;アルキルジメチルアミノエタノール硫酸エステル等の硫酸型ベタイン;アルキルジメチルアミノエタノールリン酸エステル等のリン酸型ベタイン;ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、スフィンゴミエリン等のスフィンゴリン脂質、リゾレシチン、水素添加大豆リン脂質、部分水素添加大豆リン脂質、水素添加卵黄リン脂質、部分水素添加卵黄リン脂質、水酸化レシチン等のリン脂質類;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、溶解促進剤、多価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。
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に示す各種溶解促進剤を、表1に示す組成(質量:g)となるように秤量して投入し、設定温度約80℃の水浴で加熱撹拌を行い、Pal-GH分散液を得た。
また、80℃加熱撹拌後のPal-GHの分散性について、Pal-GHの粉末が溶媒に対して均一に分散している(透明な溶解液を得られる)ものを○、Pal-GHが不均一に分散しているもの(粉の塊がある白濁分散液となる)ものを×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。
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2に示す溶解促進剤、多価アルコール及び耐熱性向上剤を、表2に示す組成(質量:g)となるように秤量して投入し、設定温度約80℃の水浴で加熱撹拌を行い、Pal-GH分散液を得た。
また、80℃加熱撹拌後のPal-GHの分散性について、Pal-GHの粉末が溶媒に対して均一に分散している(透明な溶解液を得られる)ものを○、Pal-GHが不均一に分散しているもの(粉の塊がある白濁分散液となる)ものを×として目視により評価した。
得られた結果を表2にあわせて示す。
300mLトールビーカーに、表3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)を入れ、70℃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、70℃に加熱した上記実施例1又は実施例4のPal-GH分散液1.00g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3に示す。
300mLトールビーカーに、表4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を入れ、70℃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、70℃に加熱した上記実施例7乃至実施例10のPal-GH分散液を表4記載の量となるように加え、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4に示す。
また、得られたゲルをサンプル管No.7(マルエム社)に一部取り出し、40℃、一晩保管を行った後、ゲル中の不溶物の有無を目視にて確認し、不溶物がない場合を「40℃熱安定性あり(○)」、不溶物がある場合を「40℃熱安定性なし(×)」として評価した。得られた結果を表4にあわせて示す。
Claims (15)
- 炭素原子数10乃至24の脂肪族基からなる脂質部に、少なくとも2つ以上の同一の又は異なるアミノ酸の繰り返しにより形成されたペプチド部が結合された脂質ペプチド型化合物と、分子内に親水部と疎水部を有し、かつ該親水部がベタイン構造を有する溶解促進剤と水とを含有する、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一種からなることを特徴とする、請求項1に記載の分散液。
- さらに多価アルコールを含有する、請求項1又は請求項2に記載の分散液。
- 前記溶解促進剤が、ラウリルジメチルアミノ酢酸ベタイン、ラウリン酸アミドプロピルベタイン、ラウリルヒドロキシスルホベタイン、ステアリルベタイン及びリゾホスファチジルコリンから選択される少なくとも一種である、請求項3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乃至請求項4のうち何れか一項に記載の分散液。
- 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5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乃至請求項4のうち何れか一項に記載の分散液。
- 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5又は請求項6に記載の分散液。
- さらに耐熱性向上剤を含有する、請求項8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の飽和及び不飽和からなる群から選択される少なくとも1種の高級アルコールまたは高級脂肪酸エステルである、請求項9に記載の分散液。
- 前記耐熱性向上剤がセタノール、ミリスチルアルコール、モノステアリン酸グリセリルである、請求項10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8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12に記載の分散液。
- 請求項5及び請求項6並びに請求項8乃至請求項13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5及び請求項6並びに請求項8乃至請求項13のうち何れか一項に記載の分散液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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US9782331B2 (en) | 2017-10-10 |
BR112016000274B1 (pt) | 2021-01-05 |
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