WO2016088712A1

WO2016088712A1 - Hydrogel-forming material

Info

Publication number: WO2016088712A1
Application number: PCT/JP2015/083581
Authority: WO
Inventors: 松本　圭吾
Original assignee: 日産化学工業株式会社
Priority date: 2014-12-05
Filing date: 2015-11-30
Publication date: 2016-06-09
Also published as: JPWO2016088712A1

Abstract

[Problem] To provide, by means of a simple composition, a hydrogel-forming material such that, even after the prepared hydrogel has been solated via shaking, the gel can re-form by standing at room temperature. [Solution] A hydrogel-forming material containing water, monopalmitin, and a lipid–peptide gelling agent comprising at least one substance from among compounds represented by formula (1) and pharmaceutically acceptable salts thereof. (In the formula, R¹ represents a C9–23 aliphatic group; R² represents a hydrogen atom or a C1–4 alkyl group that can have a C1–2 alkyl group as a branched chain; R³ represents a –(CH₂)_n–X group; n represents an integer from 1 to 4; and X represents an amino group, a guanidino group, a –CONH₂ group, a 5- or 6-membered ring group having 1 to 3 nitrogen atoms as atoms within the ring, or a condensed heterocyclic group formed from a 5-membered ring and a 6-membered ring.)

Description

Hydrogel forming material

The present invention relates to a hydrogel-forming material, and in particular, to a hydrogel-forming material that can form a hydrogel that can be re-formed even if it is made into a sol, and a hydrogel formed from the hydrogel-forming material.

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.
In recent years, 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.

Many of the low-molecular gelling agents that have been proposed so far are amphiphilic compounds in which a long-chain alkyl group, which is a hydrophobic part, and a hydrophilic part are combined. For example, the hydrophilic part is an amino acid (non-patent literature) 1), peptides (Patent Documents 1 and 2), sugars (Non-Patent Documents 2 and 3) or polyols (Non-Patent Document 4). In addition, a low molecular gelling agent (Non-patent Document 5) utilizing the fact that a peptide composed of valine easily takes a β-sheet structure has been proposed.

International Publication No. 2009/005151 International Publication No. 2009/005152

As described above, various gel-forming materials have been proposed so far. Among the conventionally proposed gel-forming materials, the gel can be re-formed after the formed hydrogel is made into a sol by shaking or the like. There were few things. In order to form a re-formable gel using at least the above-mentioned low molecular gelling agent disclosed by the applicant so far, for example, it has been necessary to add a basic component (WO 2014/054699). ). However, when a basic component is added, the pH of the resulting hydrogel becomes basic, so its use scene has been limited.
In view of the above, there has been a demand for a hydrogel that can re-form a gel after being made into a sol and has little pH change due to an additive.

The present invention has been made on the basis of the above circumstances, and the problem to be solved is to re-form the gel by allowing it to stand at room temperature even after the prepared hydrogel is made into a sol by shaking or the like. It is an object of the present invention to provide a hydrogel forming material.

As a result of diligent research to solve the above-mentioned problems, the present inventors have found that when forming a hydrogel from a lipid peptide-type gelling agent comprising a low-molecular lipid peptide or a pharmaceutically usable salt thereof and water. The present invention has found that by using a specific glycerin fatty acid ester, the resulting hydrogel can be re-formed by allowing it to stand at room temperature even after solification by shaking, etc. Was completed.

That is, the present invention contains, as a first aspect, a lipid peptide-type gelling agent comprising at least one of a compound represented by the following formula (1) or a pharmaceutically usable salt thereof, water and monopalmitin. The present invention relates to a hydrogel-forming material.

(Wherein R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms as a branched chain having 1 to 4 carbon atoms. R ³ represents a — (CH ₂ ) _n —X group, n represents a number of 1 to 4, and X represents an amino group, a guanidino group, a —CONH ₂ group, or a nitrogen atom in the ring It represents a 5- or 6-membered cyclic group having 1 to 3 atoms, or a condensed heterocyclic group composed of a 5-membered ring and a 6-membered ring.)
As a second aspect, the present invention relates to the hydrogel-forming material according to the first aspect, in which the ratio of the gelling agent to the monopalmitin is a molar ratio of gelling agent: monopalmitin = 9: 1 to 1: 9.
As a third aspect, in the formula (1), R ² represents a hydrogen atom, a methyl group, an i-propyl group, an i-butyl group or a sec-butyl group, and the hydrogel formation according to the first aspect or the second aspect Regarding materials.
As a fourth aspect, in the formula (1), R ³ represents a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, a 4-imidazolmethyl group, or a 3-indolemethyl group. The present invention relates to a hydrogel-forming material described in two aspects.
As a fifth aspect, in the formula (1), R ¹ represents an aliphatic group having 11 to 23 carbon atoms, R ² represents a hydrogen atom, a methyl group or an i-propyl group, and R ³ represents 4-amino The hydrogel-forming material according to the first aspect or the second aspect, which represents a butyl group, a 4-imidazolemethyl group, or a 3-indolemethyl group.
As a sixth aspect, the present invention relates to the hydrogel-forming material according to the fifth aspect, wherein R ² represents a hydrogen atom and R ³ represents a 4-imidazolemethyl group in the formula (1).
As a 7th viewpoint, it is related with the hydrogel formed using the hydrogel formation material as described in any one of a 1st viewpoint thru | or a 6th viewpoint.
As an eighth aspect, the hydrogel according to the seventh aspect, wherein the hydrogel has a pH of 7 to 9.

When the hydrogel-forming material of the present invention contains monopalmitin, it can form a gel again even when the hydrogel once formed is made into a sol state by shaking or the like and then allowed to stand at room temperature. Furthermore, since monopalmitin used is nonionic, the pH change of the obtained hydrogel is small.

The lipid peptide type gelling agent contained in the hydrogel-forming material of the present invention is a very safe artificial low molecular weight compound composed only of lipid and peptide, and monopalmitin is a general-purpose additive for foods. It is. That is, the hydrogel-forming material 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. is there.

Furthermore, the hydrogel-forming material of the present invention is a material capable of forming a hydrogel by gelling water without using, for example, a conventionally proposed cross-linking agent required for the formation of a synthetic polymer gel. There is no problem of remaining unreacted substances such as unreacted crosslinking agent in the obtained hydrogel. Moreover, the hydrogel-forming material can form a hydrogel with an addition amount of the gelling agent of only about 20 mM, and has a low load when taken up in the environment or in vivo.

And since the hydrogel of this invention can be obtained by addition of a small amount of gelatinizers compared with the former as mentioned above, it can be said that it is a hydrogel with high safety | security in both a biological surface and an environmental surface.
Furthermore, as described above, a hydrogel 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.

The present invention provides a hydrogel formation containing a lipid peptide type gelling agent comprising at least one of the compound represented by the formula (1) described in detail below or a pharmaceutically usable salt thereof, water and monopalmitin. Regarding materials.
Hereinafter, each component will be described.

[Lipid peptide type gelling agent]
As the lipid peptide type gelling agent used in the present invention, a compound (lipid peptide) represented by the following formula (1) or a pharmaceutically usable salt thereof (a lipid part which is a hydrophobic part and a hydrophilic part) A low molecular compound having a peptide portion).

In the above formula (1), 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 elideoyl group. Linoleoyl group, stearoyl group, baccenoyl group, octadecylcarbonyl group, arachidyl group, eicosylcarbonyl group, behenoyl group, ercanoyl group, docosylcarbonyl group, lignoceyl group and nerbonoyl group, and the like are particularly preferable. Examples include lauroyl group, myristoyl group, palmitoyl group, margaroyl group, stearoyl group, oleoyl group, elidoyl group, and behenoyl group.

In the above formula (1), R ² contained in the peptide portion represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms that may have a branched chain of an alkyl group having 1 or 2 carbon atoms.
The alkyl group having 1 to 4 carbon atoms, which can have the above alkyl group having 1 or 2 carbon atoms as a branched chain, has 1 to 4 carbon atoms in the main chain and 1 or 2 carbon atoms. An alkyl group that may have a branched chain as an alkyl group, 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.

R ² is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which can have a branched chain having an alkyl group having 1 carbon atom, and more preferably a hydrogen atom.
An alkyl group having 1 to 3 carbon atoms which can have an alkyl group having 1 carbon atom as a branched chain is an alkyl group having 1 to 3 carbon atoms in the main chain and having an alkyl group having 1 carbon atom. This means an alkyl group that can have a branched chain, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an i-butyl group, and a sec-butyl group, preferably A methyl group, an i-propyl group, an i-butyl group or a sec-butyl group;

In the above formula (1), R ³ represents a — (CH ₂ ) _n —X group. In the — (CH ₂ ) _n —X group, n represents a number from 1 to 4, and X is an amino group, a guanidino group, a —CONH ₂ group, or a 5-membered group having 1 to 3 nitrogen atoms as ring atoms. A cyclic group or a 6-membered ring group, or a condensed heterocyclic group composed of a 5-membered ring and a 6-membered ring is represented.
In the — (CH ₂ ) _n —X group represented by R ³ , 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. In the — (CH ₂ ) _n —X group, n is preferably 1 or 2, and more preferably 1.
Therefore, the — (CH ₂ ) _n —X group is preferably an aminomethyl group, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, carbamoylmethyl group, 2-carbamoylethyl group, 3- It represents a carbamoylbutyl group, 2-guanidinoethyl group, 3-guanidinobutyl group, pyrrolemethyl group, 4-imidazolemethyl group, pyrazolemethyl group, or 3-indolemethyl group, more preferably 4-aminobutyl group, carbamoylmethyl. Group, 2-carbamoylethyl group, 3-guanidinobutyl group, 4-imidazolemethyl group or 3-indolemethyl group, more preferably 4-imidazolemethyl group.

In the compound represented by the above formula (1), a lipid peptide particularly suitable as a lipid peptide-type gelling agent is a compound formed from the following lipid part and peptide part (amino acid assembly part). As abbreviations for 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, Palmitoyl-Gly-As , Palmitoyl-Gly-Trp, Palmitoyl-Gly-Lys, Palmitoyl-Ala-His, Palmitoyl-Ala-Gln, Palmitoyl-Ala-Asn, Palmitoyl-Ala-Trp, Palmitoyl-Ala-Lys; Stearoyl-Gly-His, Stearoyl-Gly-His -Gly-Gln, stearoyl-Gly-Asn, stearoyl-Gly-Trp, stearoyl-Gly-Lys, stearoyl-Ala-His, stearoyl-Ala-Gln, stearoyl-Ala-Asn, stearoyl-Ala-Trp, stearoyl-Ala -Lys.

Most preferred are lauroyl-Gly-His, lauroyl-Ala-His; myristoyl-Gly-His, myristoyl-Ala-His; palmitoyl-Gly-His, palmitoyl-Ala-His; stearoyl-Gly-His, stearoyl-Ala -His.

The lipid peptide type gelling agent used in the present invention comprises at least one of the compound represented by the above formula (1) (lipid peptide) or a pharmaceutically usable salt thereof. A compound can be used individually or in combination of 2 or more types.

In the hydrogel-forming material according to the present invention, the proportion of the lipid peptide-type gelling agent (the total amount when two or more lipid peptide-type gelling agents are used) is, for example, relative to the total volume of the hydrogel-forming material. 0.1 to 200 mmolar (mM, mol / m ³ ), preferably 0.5 to 100 mmolar, more preferably 1 to 50 mmolar.

[Monopalmitin]
The hydrogel-forming material of the present invention contains monopalmitin. Further, the hydrogel-forming material of the present invention can be used in combination with monopalmitin in combination with other glycerin fatty acid esters such as monocaprin, monolaurin, monomyristin, monostearin and monoolein, as long as the effects of the present invention are not impaired. it can.

In the present invention, when monopalmitin is used in combination with other glycerin fatty acid ester, the blending ratio of monopalmitin and other glycerin fatty acid ester is a molar concentration ratio, usually monopalmitin: other glycerin fatty acid ester = 9: 1 to 1: 9, preferably 9: 1 to 3: 7, more preferably 9: 1 to 5: 5.

In the hydrogel-forming material according to the present invention, the blending ratio of monopalmitin (when monopalmitin is used in combination with other glycerin fatty acid esters) is, for example, 0.1 to 200 with respect to the total volume of the hydrogel-forming material. Milli-molar, preferably 0.5 to 100 mm-molar, more preferably 1 to 50 mm-molar.

[Hydrogel forming material]
The hydrogel-forming material of the present invention contains a lipid peptide-type gelling agent comprising at least one of the compound represented by the formula (1) or a pharmaceutically usable salt thereof, water and monopalmitin. is there.

In the hydrogel-forming material, after mixing the above-mentioned components, the lipid peptide type gelling agent is easily dissolved and dispersed in water as a medium by heating at about 100 ° C., preferably with stirring. be able to.
At this time, the heating and stirring time is usually about 20 to 90 minutes, although it varies depending on the type of lipid peptide gelling agent or additive used and the amount of them.
Thus, the hydrogel-forming material in the form of a solution in which the lipid peptide type gelling agent is in a dissolved / dispersed state is cooled at about room temperature (about 25 ° C.) and allowed to stand to obtain a hydrogel.

In the hydrogel-forming material of the present invention, the blending ratio of the gelling agent and the monopalmitin is a molar concentration ratio, usually gelling agent: monopalmitin = 9: 1 to 1: 9, preferably 8: 2. To 3: 7, more preferably 7: 3 to 5: 5.

[Hydrogel]
Hydrogels formed using the hydrogel-forming materials described above are also the subject of the present invention. The resulting hydrogel is preferably a hydrogel having a pH of 7-9.

[Hydrogel formation mechanism]
The hydrogel-forming material of the present invention, particularly the low molecular weight compound (lipid peptide) represented by the above formula (1), is charged with water, dissolved and dispersed, and hydrophobic interaction and amide bond generated between alkyl chains. Intermolecular interactions such as hydrogen bonds that occur between them are self-organized using a driving force to form a molecular association state. The resulting molecular association state grows two-dimensionally to form a fibrous association.
The fibrous aggregates are intertwined to form a three-dimensional network structure, and this three-dimensional network structure reduces the fluidity of water to form a hydrogel.

As described above, the hydrogel-forming material of the present invention (and the hydrogel obtained therefrom) uses a low-molecular gelling agent or monopalmitin composed of naturally-derived raw materials such as fatty acids and amino acids as the gelling agent. It is a material with excellent biological safety.

Further, the hydrogel of the present invention can be re-formed by making it into a sol by shaking or the like and then leaving it at room temperature again.

As described above, the hydrogel-forming material of the present invention is a material that is very advantageous in actual use such as repeated use, and a cell culture substrate, a biomolecule storage material such as cells and proteins, an external substrate, It can be used for materials in various fields such as medical materials, biochemical materials, cosmetic materials, food materials, contact lenses, disposable diapers, artificial actuators, and dryland agricultural materials.

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

[Synthesis Example 1: Synthesis of lipid peptide raw material (N-palmitoyl-Gly-methyl)]
In this example, the raw material of the lipid peptide used as the gelling agent was synthesized by the method shown below according to International Publication No. 2011/027897.
A 2 L 4-necked flask was charged with 89.1 g (709 mmol) of glycine methyl ester hydrochloride, 75.2 g (709 mmol) of sodium carbonate, 750 g of water, and 450 g of toluene, and stirred. Thereafter, a solution in which 150 g (546 mmol) of palmitic acid chloride was dissolved in 900 g of toluene was added dropwise at a reaction temperature of 25 ± 5 ° C. over 2 hours. As a result, a white solid precipitated and became a slurry. After stirring at 25 ° C. for 2 hours, 750 g of water was added and stirred for 1 hour, and then filtered and washed with 150 g of water. The obtained wet product was dried under reduced pressure to obtain 150.61 g (yield 87%) of white crystals of N-palmitoyl-Gly-methyl.

[Synthesis Example 2: Synthesis of lipid peptide (N-palmitoyl-Gly-His)]
In this example, the lipid peptide used as the gelling agent was synthesized by the method shown below according to International Publication No. 2011/027897.
Into a 2 L four-necked flask, 28.4 g (183 mmol) of histidine, 60 g (183 mmol) of N-palmitoyl-Gly-methyl and 600 g of cyclohexane were added, and the mixture was heated and stirred in an oil bath. When the reaction solution reached 60 ° C., dropwise addition of 70.7 g (366 mmol) of sodium methoxide 28% methanol solution was started, and the addition was completed in 20 minutes. After completion of the dropping, the reaction was continued at about 60 ° C. for 1 hour.
Then, when the oil bath was removed and the mixture was allowed to cool to 25 ° C., it was separated into an upper layer mainly composed of cyclohexane and a lower layer mainly composed of methanol. The lower layer of the reaction solution divided into two layers was collected in Meyer using a separatory funnel, a solution obtained by mixing 180 g of water and 420 g of methanol was added to the remaining upper layer, and the solution separated into two layers was allowed to stand again for 20 minutes. . Then, the lower layer was collected by Meyer and mixed with the lower layer collected earlier.
This mixed solution was added to a mixed solution of 720 g of water, 780 g of methanol, and 36.5 mL (366 mmol) of 6N hydrochloric acid at 25 ° C. with stirring. After all the amount was added, the reaction solution was heated to 60 ° C. and stirred for 1 hour. Thereafter, the mixture was allowed to cool to 25 ° C., and the precipitated solid was collected by filtration and washed with 180 g of water.
Next, 900 g of water and 1800 g of methanol were added to the obtained solid, and the mixture was heated and stirred at 60 ° C. for 1 hour. Thereafter, the mixture was allowed to cool to 25 ° C., and the precipitated solid was collected by filtration. After repeating the same operation once more, the obtained solid was dried under reduced pressure. Next, 650 g of tetrahydrofuran was added to the dried solid and stirred at 25 ° C. for 1 hour. Thereafter, the solid was collected by filtration, and 1300 g of methanol and 650 g of tetrahydrofuran were added to the obtained solid and dissolved by heating at 60 ° C., then cooled to 0 ° C. over 2 hours and stirred at 0 ° C. overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 60.0 g (yield 72.8%) of white crystals of N-palmitoyl-Gly-His.

[Examples 1 and 2 and Reference Examples 1 and 2: N-palmitoyl-Gly-His monopalmitin-containing hydrogel-forming ability evaluation and re-formation evaluation test]
In N-palmitoyl-Gly-His prepared in the above synthesis example, the final final concentration of N-palmitoyl-Gly-His and monopalmitin in a mighty vial (No. 3, manufactured by Marum Corp.) is 20 mM (solvent: In addition, it was heated at 100 ° C. for 60 minutes with a dry bath Sahara 320 (manufactured by ASONE Co., Ltd.) and allowed to cool for one day.
As the evaluation of hydrogelation ability, the state where the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is indicated as “gelation (○)”, and the case where it flows down is indicated as “no gelation (×)”. Judged. Moreover, the pH of the prepared gel was measured with a twin pH meter (manufactured by As One Co., Ltd.).
With respect to the hydrogel whose gelation was confirmed by the above test, it was agitated with a vortex mixer (Scientific Industries Inc.) for 30 seconds to form a sol, and then allowed to stand at room temperature for one day. As an evaluation of the re-forming ability of the hydrogel, the state in which the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is “re-formation (○)”, and the state in which the solution flows down is “re-forming (×)”. It was determined.
The composition used for the hydrogelation ability evaluation and the reformation evaluation test, and the obtained test results are shown in the table below.

[Comparative Examples 1 to 5 and Reference Example 3: N-palmitoyl-Gly-His monolaurin-containing hydrogel-forming ability evaluation and re-formation evaluation test]
N-palmitoyl-Gly-His prepared in the above synthesis example was added to Mighty vial (No.3, manufactured by Marem Co., Ltd.) with a total final concentration of N-palmitoyl-Gly-His and monolaurin of 20 mM (solvent: super In addition, it was heated at 100 ° C. for 60 minutes with a dry bath Sahara 320 (manufactured by ASONE Co., Ltd.) and allowed to cool for one day.
As the evaluation of hydrogelation ability, the state where the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is indicated as “gelation (○)”, and the case where it flows down is indicated as “no gelation (×)”. Judged. Moreover, the pH of the prepared gel was measured with a twin pH meter (manufactured by As One Co., Ltd.).
With respect to the hydrogel whose gelation was confirmed by the above test, it was agitated with a vortex mixer (Scientific Industries Inc.) for 30 seconds to form a sol, and then allowed to stand at room temperature for one day. As an evaluation of the re-forming ability of the hydrogel, the state in which the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is “re-formation (○)”, and the state in which the solution flows down is “re-forming (×)”. It was determined.
The composition used for the hydrogelation ability evaluation and the reformation evaluation test, and the obtained test results are shown in the table below. In the table, “-” indicates not implemented.

[Comparative Examples 6 to 10 and Reference Example 4: N-palmitoyl-Gly-His monomyristin-containing hydrogel-forming ability evaluation and re-formation evaluation test]
N-palmitoyl-Gly-His prepared in the above synthesis example was added to a final final concentration of 20 mM (solvent: N-palmitoyl-Gly-His and monomyristin) in a mighty vial (No. 3, manufactured by Marem Co., Ltd.). In addition, it was heated at 100 ° C. for 60 minutes with a dry bath Sahara 320 (manufactured by ASONE Co., Ltd.) and allowed to cool for one day.
As the evaluation of hydrogelation ability, the state where the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is indicated as “gelation (○)”, and the case where it flows down is indicated as “no gelation (×)”. Judged. Moreover, the pH of the prepared gel was measured with a twin pH meter (manufactured by As One Co., Ltd.).
Regarding the hydrogel whose gelation was confirmed by the above test, it was agitated with a vortex mixer (Scientific Industries Inc.) for 30 seconds to form a sol, and then allowed to stand at room temperature for one day. As an evaluation of the re-forming ability of the hydrogel, the state in which the fluidity of the solution is lost and the solution does not flow down even if the vial is inverted is “re-formation (○)”, and the state in which the solution flows down is “re-forming (×)”. In the vortex treatment, those that could not be confirmed to be solated were judged as “not solylated (*)”.
The composition used for the hydrogelation ability evaluation and the reformation evaluation test, and the obtained test results are shown in the table below. In the table, “-” indicates not implemented.

From the above results, it is clear that the hydrogel-forming material of the present invention in which monopalmitin is mixed with N-palmitoyl-Gly-His forms a hydrogel and has a regeneration-forming ability. On the other hand, a hydrogel-forming material containing monolaurin or monomyristin instead of monopalmitin formed a hydrogel under certain conditions, but the hydrogel did not have the ability to reform. Moreover, the gel was not formed only with glycerol fatty acid ester.

Claims

A hydrogel-forming material comprising a lipid peptide type gelling agent comprising at least one of a compound represented by the following formula (1) or a pharmaceutically usable salt thereof, water and monopalmitin.

(Wherein R 1 represents an aliphatic group having 9 to 23 carbon atoms, and R 2 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms as a branched chain having 1 to 4 carbon atoms. R 3 represents a — (CH 2 ) n —X group, n represents a number of 1 to 4, and X represents an amino group, a guanidino group, a —CONH 2 group, or a nitrogen atom in the ring It represents a 5- or 6-membered cyclic group having 1 to 3 atoms, or a condensed heterocyclic group composed of a 5-membered ring and a 6-membered ring.)
The hydrogel-forming material according to claim 1, wherein the ratio between the gelling agent and the monopalmitin is a molar ratio of gelling agent: monopalmitin = 9: 1 to 1: 9.
The hydrogel-forming material according to claim 1 or 2, wherein in the formula (1), R 2 represents a hydrogen atom, a methyl group, an i-propyl group, an i-butyl group, or a sec-butyl group.
In the formula (1), R 3 represents a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, a 4-imidazolemethyl group, or a 3-indolemethyl group. Hydrogel forming material.
In the formula (1), R 1 represents an aliphatic group having 11 to 23 carbon atoms, R 2 represents a hydrogen atom, a methyl group or an i-propyl group, R 3 represents a 4-aminobutyl group, 4- The hydrogel-forming material according to claim 1 or 2, which represents an imidazole methyl group or a 3-indolemethyl group.
The hydrogel-forming material according to claim 5, wherein in the formula (1), R 2 represents a hydrogen atom and R 3 represents a 4-imidazolemethyl group.
A hydrogel formed using the hydrogel-forming material according to any one of claims 1 to 6.
The hydrogel according to claim 7, wherein the hydrogel has a pH of 7 to 9.