JP6865239B2 - How to transdermally absorb hydrophilic drugs - Google Patents

Description

The present invention relates to a method for percutaneously absorbing a hydrophilic drug using a low molecular weight lipid peptide type compound, which is useful as a base material for a percutaneous absorption preparation.

Administration of the active ingredient by percutaneous absorption is a method widely adopted together with oral administration and injection administration because it is non-invasive and the dose can be adjusted. In the percutaneous absorption preparation, a method of blending a percutaneous absorption promoter with a percutaneous absorption base material is generally adopted in order to promote the absorption of the active ingredient.
In recent years, from the viewpoint that active ingredients with different parent / hydrophobicity and transdermal absorption promoters can be blended at the same time, and it can be expected to improve the solubility and activity of the active ingredients, gelled products applying microemulsion technology have been used. Attention is being paid to its application to skin-absorbing preparations. For example, w / o microemulsion gels using lecithin [Non-Patent Documents 1 and 2] and o / w microemulsion gels using thickeners such as carboxypolymer and xanthan gum [Non-Patent Document 3] have been proposed. ..

On the other hand, hydrogel is useful as a gel with high biocompatibility because it uses water as a medium, and is used in a wide range of fields including applications for disposable diapers, cosmetics, and daily necessities of air fresheners.
Examples of conventional hydrogels include polymer gels formed by cross-linking polymer chains to form a three-dimensional network structure, which forms a non-covalent bond with a medium such as water and swells. Further, in recent years, hydrogels composed of self-assembly of organic compounds having a relatively low molecular weight have been discovered and various studies have been conducted. There have been many proposals for a low molecular weight gelling agent which is an amphipathic compound combining a long-chain alkyl group which is a hydrophobic part and a hydrophilic part. For example, the hydrophilic part is an amino acid [Non-Patent Document 4], a peptide [Patent Documents 1 and 2], a monopolysaccharide [Non-Patent Documents 5 and 6], or a polyol [Non-Patent Document 7]. Can be mentioned. In addition, a low molecular weight gelling agent [Non-Patent Document 8] has also been proposed, which utilizes the fact that a peptide composed of valine easily takes a β-sheet structure.

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

S. Murdan, Expert Opin. Drag Deliv. 2 (3) 489-505 (2005) S. Kantaria, G.M. D. Rees, M.M. J. lawrence, J. et al. Controlled Release 60 344-365 (1999) H. Chen, X. Chang, D.C. Du, L. Li, H. Xu, X. Yang, International J. et al. Pharm. , 315, 52-58 (2006) Suzuki, Masahiro. Yumoto, Mariko. Mutsumi, Shirai. Hirofusa, Hanabusa, Kenji. Chemistry Letters, 33 (11), 1496-1497. Jong Hwa Jung, Georeg John, Mitsutosh Mausda, Kaname Yoshida, Seiji Shinnkai, and Toshimi Shimizu 721, I. Hamachi, S.A. Kiyonaka, S.A. Shinkai, Tetrahedron Letter. , 2001, 42, 6141. I. Hamachi, S.A. Kiyonaka, S, Shinaki, Chem. Commun. , 2000, 1281. Masahiro Suzuki, Sanae Owa, Hirofusa Shirai and Kenji Hanabusa, Tetrahedron 2007 63 7302-7308. Yoko Matsuzawa, Katsuyuki Ueki, Masahiko Yoshida, Nobuyuki Tamaoki, Tohru Nakamura, Hideki Sakai, and Maki. Funct. Mater. 2007, 17, 1507-1514

Many of the w / o or o / w microemulsion gels proposed so far are made of a polymer compound as a gelling agent, and when applied to the skin, they become sticky or wrinkled after a lapse of time (residue of the polymer compound). ) May occur.
Further, when the transdermal preparation using the above microemulsion gel is applied to the skin, the transdermal absorbability of the active ingredient is also a problem.

An object of the present invention is to provide a method for transdermally absorbing a hydrophilic drug, which uses a low molecular weight gelling agent to improve not only the feeling of use but also the transdermal absorbability.

As a result of diligent research to solve the above problems, the present inventors transdermally transdermal hydrophilic drugs by using a lipid peptide-type compound consisting of a low-molecular-weight lipid peptide or a pharmaceutically usable salt thereof. The discovery that it can be absorbed has led to the completion of the present invention.
In addition, the present inventors have adopted a lipid peptide-type compound consisting of a low-molecular-weight lipid peptide or a pharmaceutically usable salt thereof as a gelling agent for a gel constituting a transdermal absorption substrate, thereby providing a hydrophobic component. It has been found that a stable o / w emulsion gel containing the above can be obtained.
And even if it is a hydrophilic drug whose skin permeability is inhibited by the barrier function of the stratum corneum (stratum corneum) located in the outermost layer of the epidermis, it is a hydrophobic component such as isopropyl myristate (transdermal absorption promoter). ) Disturbs the structure of the stratum corneum, which improves the permeability to the skin. That is, by adopting a hydrophobic component such as isopropyl myristate as one component of the transdermal absorption substrate, the active ingredient. It was found that it is a useful gel as a transdermal absorption base material, which is expected to increase the amount of permeation into the skin.

（式中、Ｒ^１は炭素原子数９乃至２３の脂肪族基を表し、Ｒ^２は水素原子、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のアルキル基を表し、Ｒ^３は−（ＣＨ_２）_ｎ−Ｘ基を表し、ｎは１乃至４の数を表し、Ｘはアミノ基、グアニジノ基、−ＣＯＮＨ_２基、又は窒素原子を１乃至３個有し得る５員環若しくは６員環又は５員環と６員環から構成される縮合複素環を表す。）

（式中、Ｒ^４は炭素原子数９乃至２３の脂肪族基を表し、Ｒ^５乃至Ｒ^７はそれぞれ独立して水素原子、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−（ＣＨ_２）_ｎ−Ｘ基を表し、ｎは１乃至４の数を表し、Ｘはアミノ基、グアニジノ基、−ＣＯＮＨ_２基、又は窒素原子を１乃至３個有し得る５員環若しくは６員環又は５員環と６員環から構成される縮合複素環を表す。）

（式中、Ｒ^８は炭素原子数９乃至２３の脂肪族基を表し、Ｒ^９乃至Ｒ^１２はそれぞれ独立して水素原子、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−（ＣＨ_２）_ｎ−Ｘ基を表し、ｎは１乃至４の数を表し、Ｘはアミノ基、グアニジノ基、−ＣＯＮＨ_２基、又は窒素原子を１乃至３個有し得る５員環若しくは６員環又は５員環と６員環から構成される縮合複素環を表す。）
第２観点として、さらに、炭素原子数８乃至２０の脂肪酸のエステル、スクワラン、オリーブ油、プロピレングリコールジカプリレート及び流動パラフィンからなる群から選択される少なくとも一種の経皮吸収促進剤を用いる、第１観点に記載の方法に関する。
第３観点として、前記経皮吸収促進剤は、ミリスチン酸イソプロピルである、第２観点に記載の方法に関する。 That is, the present invention uses, as a first aspect, a lipid peptide-type compound consisting of at least one of the compounds represented by the following formulas (1) to (3) or pharmaceutically usable salts thereof. The present invention relates to a method for transdermally absorbing a hydrophilic drug.

(In the formula, R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms. , R ³ represents a − (CH ₂ ) _n −X group, n represents a number from 1 to 4, X represents an amino group, a guanidino group, −CONH ₂ groups, or 1 to 3 nitrogen atoms. Represents a possible 5-membered or 6-membered ring or a fused heterocycle composed of a 5-membered ring and a 6-membered ring.)

(In the formula, R ⁴ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{5 to} R ⁷ each independently have a hydrogen atom and a branched chain having 1 or 2 carbon atoms. 1 to 4 alkyl groups _{or-(CH 2} ) _n- X groups, n represents numbers 1 to 4, X represents amino groups, guanidino groups, -CONH ₂ groups, or nitrogen atoms 1 to 3 It represents a 5-membered ring or a 6-membered ring or a fused heterocycle composed of a 5-membered ring and a 6-membered ring.

(In the formula, R ⁸ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{9 to} R ¹² are independently hydrogen atoms and the number of carbon atoms capable of having a branched chain having 1 or 2 carbon atoms, respectively. 1 to 4 alkyl groups _{or-(CH 2} ) _n- X groups, n represents numbers 1 to 4, X represents amino groups, guanidino groups, -CONH ₂ groups, or nitrogen atoms 1 to 3 It represents a 5-membered ring or a 6-membered ring or a fused heterocycle composed of a 5-membered ring and a 6-membered ring.
As a second aspect, further, at least one transdermal absorption promoter selected from the group consisting of esters of fatty acids having 8 to 20 carbon atoms, squalane, olive oil, propylene glycol dicaprelate and liquid paraffin is used. Regarding the method described in the viewpoint.
As a third aspect, the transdermal absorption promoter is isopropyl myristate, according to the method according to the second aspect.

The specification of the present application also discloses the inventions relating to the percutaneous absorption substrates of the following [1] to [3]. [1] A lipid peptide-type compound consisting of at least one of the compounds represented by the formulas (1) to (3) or pharmaceutically usable salts thereof, and an ester of a fatty acid having 8 to 20 carbon atoms. A transdermal substrate comprising, at least one percutaneous absorption enhancer selected from the group consisting of, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin, and water.
[3] The transdermal absorption substrate according to [1], wherein the transdermal absorption promoter is isopropyl myristate.
[3] The transdermal base material according to [1] or [2], further containing polyoxyethylene (20) sorbitan monolaurate (CAS Registry Number 9005-64-5).

According to the present invention, a hydrophilic drug can be prepared by using a lipid peptide type compound consisting of at least one of the compounds represented by the above formulas (1) to (3) or pharmaceutically usable salts thereof. It can be absorbed transdermally.
The transdermal absorption substrate using the above lipid peptide type compound is a group consisting of a hydrophobic compound (ester of a fatty acid having 8 to 20 carbon atoms such as isopropyl myristate, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin). It is an o / w emulsion gel in which an o / w emulsion composed of water and (at least one selected from) is stably gelled with a gelling agent (lipid peptide type compound). Therefore, even when a substance having different hydrophilicity / hydrophobicity, for example, a transdermal absorbent and an active ingredient are mixed at the same time, a stable o / w emulsion gel can be formed by the gelling agent, and it can be used as a transdermal absorbent base material. It is useful.
The percutaneous absorption base material using the above lipid peptide type compound contains a compound such as isopropyl myristate, which is a percutaneous absorption promoter. Hydrophobic compounds such as isopropyl myristate, when applied to the skin, disturb the structure of the stratum corneum (stratum corneum) located in the outermost layer of the epidermis, thus improving the permeability of hydrophilic compounds (active ingredients). It is thought that. Therefore, the transdermal preparation in which the active ingredient is blended in the base material can be made excellent in the permeability of the active ingredient blended with the hydrophobic compound such as isopropyl myristate into the skin.

Further, the lipid peptide type compound used for the transdermal absorption base material using the above lipid peptide type compound is a very safe artificial low molecular weight compound composed of only lipid and peptide, and has high biosafety. In particular, from the viewpoint of high safety required for medical materials, cosmetic materials, and the like, it is very useful as a transdermal absorbent substrate in the above applications.
Further, the above-mentioned lipid peptide type compound can form a gel by gelling an o / w emulsion without using, for example, a conventionally proposed synthetic polymer type gel, which is required at the time of forming a cross-linking agent or the like. Therefore, problems such as residual unreacted substances such as unreacted cross-linking agents do not occur in the obtained gel. Moreover, the lipid peptide-type compound contained in the transdermal absorption substrate can form a gel with an addition amount of only about 1% by mass, and the load is small when taken up in the environment or in the living body.

The transdermal base material using the above lipid peptide type compound is a gel that can be formed even while stirring under relatively mild conditions of less than 100 ° C., and is an additive for cosmetics that wants to eliminate the influence of heat as much as possible. Even when an agent or an additive for a quasi-drug is added, a transdermal base material can be produced without modifying these additives.

FIG. 1 is an external view showing the presence or absence of gel formation of five types of o / w emulsions in which the blending amount of isopropyl myristate (IPM) prepared in Example 1 was changed. FIG. 2 is a diagram showing the time variation of the FNa release rate (%) released into PBS from three kinds of o / w emulsion gels in which the blending amount of isopropyl myristate (IPM) prepared in Example 3 was changed. Is. FIG. 3 is a diagram showing a photograph before the FNa release test and a photograph after 24 hours of three kinds of o / w emulsion gels in which the blending amount of isopropyl myristate (IPM) prepared in Example 3 was changed. .. FIG. 4 is a conceptual diagram of the device used in the skin permeability test of Example 4. FIG. 5 shows the amount of FNa in the skin extract after the skin permeability test conducted using three types of o / w emulsion gels in which the blending amount of isopropyl myristate (IPM) prepared in Example 4 was changed. It is a figure which shows. FIG. 6 is a fluorescence micrograph of a skin section after a skin permeability test performed using three types of o / w emulsion gels in which the amount of isopropyl myristate (IPM) prepared in Example 4 was changed. It is a figure which shows. FIG. 7 shows the skin carried out using 6 types of o / w emulsion gels (Pal-GH-containing gels) and carbopole-containing gels (IPM blended) in which the transdermal absorption promoter prepared in Example 5 was variously changed. It is a figure which shows the amount of FNa of the skin extract after the permeability test. FIG. 8 shows the skin after a skin permeation test performed using three types of o / w emulsion gels (Pal-GH-containing gels) in which the amounts of the carbopole-containing gel and squalane prepared in Example 6 were changed. It is a figure which shows the amount of fluorescent hyaluronic acid of the extract of.

The method of the present invention relates to a method for transdermally absorbing a hydrophilic drug, which comprises using the above-mentioned lipid peptide type compound.
Further, the invention relating to the transdermal base material disclosed in the present specification is an ester of the above-mentioned lipid peptide type compound and an ester of a fatty acid having 8 to 20 carbon atoms such as isopropyl myristate, squalane, olive oil, and propylene glycol dicaprylate. An o / w emulsion gel containing at least one transdermal absorption accelerator selected from the group consisting of and liquid paraffin, and water, and specifically containing these.
In the method for percutaneously absorbing the hydrophilic drug of the present invention, for example, the above-mentioned lipid peptide-type compound can be used as the form of the above-mentioned transdermal absorption base material. Therefore, components that can be used for the transdermal absorption substrate described later can also be used in the method of the present invention.

[Lipid peptide type compound]
As the lipid peptide type compound used in the method of the present invention and used as a transdermal absorption substrate, the compounds represented by the following formulas (1) to (3) (lipid peptides) or their pharmaceutically usable compounds can be used. A salt (a low molecular weight compound having a lipid part which is a hydrophobic part and a peptide part which is a hydrophilic part) can be used.

In the above formula (1), R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and preferably R ¹ is a linear chain having 11 to 23 carbon atoms capable of having 0 to 2 unsaturated bonds. It is preferably an aliphatic group.
R ¹ is and lipid portion constituted by the adjacent carbonyl group Examples of the (acyl groups), lauroyl group, a dodecyl group, a myristoyl group, tetradecyl group, palmitoyl group, Marugaroiru group, oleoyl group, elaidoyl Groups, linoleoyl groups, stearoyl groups, baccenoyl groups, octadecylcarbonyl groups, arachidoyl groups, eicosylcarbonyl groups, behenoyl groups, ercanoyle groups, docosylcarbonyl groups, lignosail groups, nervonoyl groups and the like can be mentioned as particularly preferable. , Lauroyl group, myristoyl group, palmitoyl group, carbonyl group, stearoyl group, oleoyl group, elelideyl 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 which can have a branched chain having 1 or 2 carbon atoms.
The alkyl group having 1 to 4 carbon atoms which can 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. It means an alkyl group that can have, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group or a tert-butyl group. And so on.

R ² is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which can have a branched chain having 1 carbon atom, and more preferably a hydrogen atom.
An alkyl group having 1 to 3 carbon atoms capable of having a branched chain having 1 carbon atom is an alkyl group having 1 to 3 carbon atoms in the main chain and capable of having a branched chain having 1 carbon atom. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an i-butyl group, a sec-butyl group, and the like, preferably a methyl group, an i-propyl group, and the like. It is 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 above- (CH ₂ ) n-X group, n represents a number of 1 to 4, and X is a 5-membered cyclic compound having 1 to 3 _{amino groups, guanidino groups, -CONH 2 groups, or nitrogen atoms.} Represents a group or a 6-membered cyclic group, or a fused heterocyclic group composed of a 5-membered ring and a 6-membered ring.
Representing the ^{R 3} - In _(CH 2) n-X group, X is preferably an amino group, a guanidino group, a carbamoyl group (-CONH ₂ group), a pyrrole group, an imidazole group, a pyrazole group or indole group, more It is preferably an imidazole group. Further, in the- (CH ₂ ) n-X group, n is preferably 1 or 2, and more preferably 1.
Therefore, the- (CH ₂ ) n- group is preferably an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, or a 3-carbamoyl group. Represents a butyl group, a 2-guanidinoethyl group, a 3-guanidinobutyl group, a pyrrolmethyl group, a 4-imidazole methyl group, a pyrazolemethyl group, or a 3-indolemethyl group, more preferably a 4-aminobutyl group or a carbamoylmethyl group. , 2-Carbamoylethyl group, 3-guanidinobutyl group, 4-imidazole methyl group or 3-indolemethyl group, more preferably 4-imidazole methyl group.

Among the compounds represented by the above formula (1), a particularly suitable lipid peptide as a lipid peptide type compound is a compound formed from the following lipid part and peptide part (amino acid assembly part). The abbreviations for amino acids include alanine (Ala), asparagine (Asn), glutamine (Gln), glycine (Gly), histidine (His), isolosin (Ile), leucine (Leu), lysine (Lys), and tryptophan (Trp). ), Valine. : 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; Millistyl-Gly-His, Millistyl-Gly-Gln, Millistyl-Gly-Asn, Millistyl-Gly-Trp, Millistyl-Gly-Lys, Millistyl-Ala-His, Millistyl-Ala -Gln, Millistyl-Ala-Asn, Millistyl-Ala-Trp, Millistyl-Ala-Lys; Palmitoyl-Gly-His, Palmitoyl-Gly-Gln, Palmitoyl-Gly-Asn, Palmitoyl-Gly-Trp, Palmitoyl-Gly , Palmitoyl-Ala-His, Palmitoyl-Ala-Gln, Palmitoyl-Ala-Asn, Palmitoyl-Ala-Trp, Palmitoyl-Ala-Lys; Stearoyl-Gly-His, Stearoyl-Gly-Gln, Stearoyl-Gly-Asn -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 can be mentioned.

In the above formula (2), R ⁴ represents an aliphatic group having 9 to 23 carbon atoms, and a preferable specific example thereof is the same group as defined in ^{R 1 described above.}
In the above formula (2), R ^{5 to} R ⁷ are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms, or-(. represents CH ₂₎ n-X group, preferably at least one or more of ^{R 5} to ^{R 7} - represents a _(CH 2) n-X group. n represents a number from 1 to 4, and X is a 5- or 6-membered cyclic group or 5-membered ring that may have 1 to 3 _{amino groups, guanidino groups, -CONH 2 groups, or nitrogen atoms.} Represents a fused heterocyclic group composed of a 6-membered ring. Here, preferred specific examples ^{of R 5 to} R ⁷ include the same groups as those defined in ^{R 2} and R ^{3 described above.}

In the compound represented by the above formula (2), a suitable lipid peptide is a compound formed from the following lipid part and peptide part (amino acid assembly part). Millistyl-Gly-Gly-His, Millistyl-Gly-Gly-Gln, Millistyl-Gly-Gly-Asn, Millistyl-Gly-Gly-Trp, Millistyl-Gly-Gly-Lys, Millistyl-Gly-Ala-His, Millistyl- Gly-Ala-Gln, Millistyl-Gly-Ala-Asn, Millistyl-Gly-Ala-Trp, Millistyl-Gly-Ala-Lys, Millistyl-Ala-Gly-His, Millistyl-Ala-Gly-Gln, Millistyl-Ala- Gly-Asn, Millistyl-Ala-Gly-Trp, Millistyl-Ala-Gly-Lys, Millistyl-Gly-His-Gly, Millistyl-His-Gly-Gly, Palmitoyl-Gly-Gly-His, Palmitoyl-Gly-Gly- Gln, Palmitoyl-Gly-Gly-Asn, Palmitoyl-Gly-Gly-Trp, Palmitoyl-Gly-Gly-Lys, Palmitoyl-Gly-Ala-His, Palmitoyl-Gly-Ala-Gln, Palmitoyl-Gly-Al Palmitoyl-Gly-Ala-Trp, Palmitoyl-Gly-Ala-Lys, Palmitoyl-Ala-Gly-His
, Palmitoyl-Ala-Gly-Gln, Palmitoyl-Ala-Gly-Asn, Palmitoyl-Ala-Gly-Trp, Palmitoyl-Ala-Gly-Lys, Palmitoyl-Gly-His-Gly, Palmitoyl-His-Gly-Gly.

Of these, the most preferred are lauroyl-Gly-Gly-His, myristoyl-Gly-Gly-His, palmitoyl-Gly-Gly-His, palmitoyl-Gly-His-Gly, palmitoyl-His-Gly-Gly, stearoyl. -Gly-Gly-His can be mentioned.

In the above formula (3), R ⁸ represents an aliphatic group having 9 to 23 carbon atoms, and a preferable specific example thereof is the same group as defined in ^{R 1 described above.}
In the above formula (3), R ^{9 to} R ¹² are independently hydrogen atoms or alkyl groups having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms, or-(. CH ₂ ) represents an n-X group, preferably at least one or more of ^{R 9 to} R ¹² _{represents a-(CH 2} ) n-X group. n represents a number from 1 to 4, and X is a 5- or 6-membered cyclic group or 5-membered ring that may have 1 to 3 _{amino groups, guanidino groups, -CONH 2 groups, or nitrogen atoms.} Represents a fused heterocyclic group composed of a 6-membered ring. Here, preferred specific examples ^{of R 9 to} R ¹² include the same groups as those defined in ^{R 2} and R ^{3 described above.}
Therefore, in the compound represented by the above formula (3), as a suitable lipid peptide type compound, particularly suitable lipid peptide is lauroyl-Gly-Gly-Gly-His, myristyl-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.

In the percutaneous absorption base material disclosed in the present specification, the blending amount of the lipid peptide type compound is, for example, 0.01 to 30% by mass, preferably 0.01 to 30% by mass, based on the total mass of the obtained gel (transdermal absorption base material). Is 0.05 to 10% by mass, more preferably 0.1 to 5% by mass.
The lipid peptide-type compound used in the present invention comprises at least one of the compounds (lipid peptides) represented by the above formulas (1) to (3) or pharmaceutically usable salts thereof, and is also a gel. As the agent, these compounds can be used alone or in combination of two or more.

[Transdermal absorption promoter]
The method of the present invention further uses at least one compound selected from the group consisting of esters of fatty acids having 8 to 20 carbon atoms, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin as a transdermal absorption promoter. be able to. Further, the transdermal absorption base material disclosed in the present specification uses the above-mentioned transdermal absorption promoter.
Examples of the ester of the fatty acid having 8 to 20 carbon atoms include isopropyl myristate, isopropyl palmitate, myristyl myristate, and octyldodecyl myristate.
Examples thereof include cetyl palmitate.
Among these transdermal absorption promoters, isopropyl myristate is preferably used.
In the percutaneous absorption base material disclosed in the present specification, the blending amount of the above compound is, for example, 1 to 50% by mass, preferably 10 to 50% by mass, based on the total mass of the obtained gel (transdermal absorption base material). It is 50% by mass.

In addition to the above compounds, compounds that have been conventionally recognized to promote absorption in the skin can be used or added as long as the effects of the present invention are not impaired. For example, capric acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol. , Diethanolamide laurate, methyl salicylate, ethylene glycol salicylate, stearic acid, methyl silicate, cresol, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, geraniol, timol, eugenol, terpineol, L-menthol, borneolol , D-Limonen, Isoeugenol, Isobornol, Nerol, dl-Camfur, Glycerin Monocaprylate, Glycerin Monoca Plate, Glycerin Monolaurate, Glycerin Monooleate, Solbitan Monolaurate, Sucrose Monolaurate, Polysorbate 20, Propropylene glycol monolaurate, propylene glycol monocaprilate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, jojoba oil, silicon oil, n-methyl-2-pyrrolidone, Examples include dl-camfur, peppermint oil and the like.

[Surfactant]
In the preparation of the transdermal absorption substrate disclosed in the present specification, that is, the o / w emulsion gel, the stability of the emulsion itself over time can be improved, and uniform droplets of the transdermal absorption accelerator in the emulsion It is preferable to add a surfactant to the o / w emulsion because it facilitates formation.

As the above-mentioned surfactant, a less toxic agent, particularly a non-toxic agent is preferable. The HLB of the surfactant is preferably in the range of 1.0 to 20.0, more preferably 2.0 to 17.0, and even more preferably 8.0 to 17.0. When the HLB of the surfactant is within the above range, the dispersibility of the o / w emulsion can be improved.
Specific examples of such surfactants include sorbitan monolaurates [Sorbitan monofatty acid esters such as "Span20" (registered trademark) HLB = 8.6, manufactured by Wako Pure Chemical Industries, Ltd .; polyoxyethylene (20) sorbitan. Monolaurate [“Tween 20” (registered trademark) manufactured by Wako Pure Chemical Industries, Ltd., HLB = 16.7], polyoxyethylene (4) sorbitan monostearate (HLB = 9.6), polyoxyethylene (5) ) Sorbitan monooleate (HLB = 10.0), polyoxyethylene (4) sorbitan tristearate (HLB = 10.5), polyoxyethylene (4) sorbitan trioleate (HLB = 11.0), polyoxy Polyoxyethylene sorbitan fatty acid esters such as ethylene (20) sorbitan monostearate (HLB = 14.9); and the like can be mentioned.
Of these, polyoxyethylene (20) sorbitan monolaurate is most preferable.
The blending amount of the surfactant is, for example, 0.1 to 20% by mass, preferably 0.5 to 10% by mass, based on the total mass of the obtained gel (transdermal absorption base material).

[Premix]
The transdermal base material (that is, o / w emulsion gel) disclosed in the present specification is a gelling agent in an o / w emulsion containing the above-mentioned specific transdermal absorption promoter, water, and optionally a surfactant. It is obtained by adding a lipid peptide type compound which is the above, stirring them at an increased temperature to uniformly disperse them, and then allowing them to stand at room temperature (about 25 ° C.).
However, the transdermal base material disclosed in the present specification is milder from the viewpoint of thermal stability of the ingredients to be blended as the active ingredient of the transdermal preparation, considering the application to cosmetics or quasi-drugs. It is preferable to prepare under the above conditions.
That is, the preparation step can be carried out under lower temperature conditions, specifically, the above lipid peptide type compound can form an o / w emulsion gel at a temperature of less than 100 ° C., and the gel can be formed while stirring during cooling. It is desirable to have the conditions that can be formed.
Considering these conditions, the lipid peptide type compound is not added to the o / w emulsion as it is, but is once dissolved and dispersed in a solvent having high solubility of the compound to prepare a solution (dispersion liquid), which is called a gel. It is preferable to produce a transdermal absorption base material by blending it in an o / w emulsion as a premix of the chemical material. By using such a premix, an o / w emulsion gel can be obtained even under the mild conditions described above.

The above premix has high solubility capable of dissolving a lipid peptide type compound at a high concentration, and among them, alcohol: 1,2-alkane, which is a highly safe solvent approved for use in non-pharmaceutical products and cosmetics, etc. It is preferable to mix diol, 1,3-alkanediol or ethylene glycol monoalkyl ether with a high molecular weight emulsifier such as alginate ester which enables gel formation at low temperature and stirring. Further, from the viewpoint of improving the heat resistance of the gel, a heat resistance improving agent such as fatty acid may be blended.

<Alcohol>
Specific examples of the 1,2-alkanediol include 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, and 1,2-decanediol. Preferred are 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol. More preferably, it is 1,2-pentanediol or 1,2-hexanediol.
Specific examples of the above 1,3-alkanediol include 2-ethyl-1,3-hexanediol and 1,3-butanediol. Preferably, it is 2-ethyl-1,3-hexanediol.
Further, as the above-mentioned ethylene glycol monoalkyl ether, an alkyl ether having an alkyl group of a methyl group, an ethyl group, a propyl group or a butyl group is preferable, that is, a monoethyl ether of ethylene glycol, a monopropyl ether or a monobutyl ether can be mentioned. Be done. More preferably, it is ethylene glycol monopropyl ether or ethylene glycol monobutyl ether.

The blending amount of the alcohol is, for example, 1 to 20% by mass, more preferably 2 to 5% by mass, based on the total mass of the obtained hydrogel.
The alcohol is at least one of the above-mentioned alcohol groups, and these alcohols can be used alone or in combination of two or more.

<Polymer emulsifier>
By adding a polymer emulsifier to the above premix, the gel can be given even when stirring is performed during the gel preparation. As this polymer emulsifier, at least one selected from the group consisting of a graft polymer compound in which a hydrophobic site is grafted on a hydrophilic main chain and a block polymer compound composed of a hydrophobic constituent unit and a hydrophilic constituent unit. High molecular weight compounds can be blended.

Examples of the graft polymer compound in which a hydrophobic site is grafted on the hydrophilic main chain include xanthan gum, alginate ester, cellulose derivative and the like.
Examples of the block polymer compound composed of the hydrophobic constituent unit and the hydrophilic constituent unit include acrylic acid / alkyl methacrylate copolymer and the like.
In particular, as the polymer compound, a compound selected from the group consisting of carboxymethyl cellulose and alginate ester is preferable, and propylene glycol alginate is particularly preferable.

The blending amount of the polymer emulsifier is, for example, 0.1 to 5% by mass, more preferably 0.2 to 0.5% by mass, based on the total mass of the obtained hydrogel.
The polymer emulsifier is at least one selected from the group consisting of graft polymer compounds and block polymer compounds, and these polymer compounds can be used alone or in combination of two or more.

<Heat resistance improver>
Fatty acids can be added to the premix as a heat resistance improver.
Examples of the fatty acids include saturated fatty acids, unsaturated fatty acids and salts thereof listed below: capric acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid. , Margaric acid, stearic acid, nonadecanic acid, arachidic acid and other linear saturated fatty acids and salts thereof; 2-butyl-5-methylpentanoic acid, 2-isobutyl-5-methylpentanoic acid, dimethyloctanoic acid, dimethylnonanoic acid , 2-Butyl-5-methylhexanoic acid, methylundecanoic acid, dimethyldecanoic acid, 2-ethyl-3-methylnonanoic acid, 2,2-dimethyl-4-ethyloctanoic acid, methyldocanoic acid, 2-propyl-3-methylnonanic acid Acid, methyltridecanoic acid, dimethyldodecanoic acid, 2-butyl-3-methylnonanoic acid, methyltetradecanoic acid, ethyltridecanoic acid, propyldodecanoic acid, butylundecanoic acid, pentyldecanoic acid, hexylnonanoic acid, 2- (3-methylbutyl ) -3-Methylnonanoic acid, 2- (2-methylbutyl) -3-methylnonanoic acid, butylethylnonanoic acid, methylpentadecanoic acid, ethyltetradecanoic acid, propyltridecanoic acid, butyldodecanoic acid, pentylundecanoic acid, hexyldecanoic acid, heptylnonan Acids, dimethyltetradecanoic acid, butylpentylheptanic acid, trimethyltridecanoic acid, methylhexadecanoic acid, ethylpentadecanoic acid, propyltetradecanoic acid, butyltridecanoic acid, pentyldodecanoic acid, hexylundecanoic acid, heptyldecanoic acid, methylheptylnonanoic acid, Dipentylheptanic acid, methylheptadecanoic acid, ethylhexadecanoic acid, ethylhexadecanoic acid, propylpentadecanoic acid, butyltetradecanoic acid, pentildedecanoic acid, hexyldecanoic acid, heptylundecanoic acid, octyldecanoic acid, dimethylhexadecanoic acid, methyloctylnonanoic acid , Methyl octadecanoic acid, ethyl heptadecanoic acid, dimethyl heptadecanoic acid, methyl octyl decanoic acid, methyl nonadecanic acid, methyl nonadecanic acid, dimethyl octadecanoic acid, butyl heptyl nonanoic acid and other branched saturated fatty acids and salts thereof; octenoic acid, nonene Acids, decanoic acid, caproleic acid, undecilenic acid, linderic acid, toucacic acid, lauroreic acid, tridecenoic acid, tsuzuic acid, myristoleic acid, pentadecenoic acid, hexedecenoic acid, palmitoleic acid, heptadecenoic acid, octa Linear monounsaturated fatty acids such as decenoic acid, oleic acid, nonadecenoic acid, gondonic acid and salts thereof; methylheptenoic acid, methylnonenic acid, methylundecenoic acid, dimethyldecenoic acid, methyldodecenoic acid, methyltridecenoic acid, dimethyldodecene Branched unsaturated monofatty acids such as acids, dimethyltridecenoic acid, methyloctadecenoic acid, dimethylheptadecenoic acid, ethyloctadecenoic acid and salts thereof; linoleic acid, linoelysinic acid, eleostearic acid, linolenic acid, Linear di-unsaturated fatty acids such as linolene-ellaic acid, pseudoeleostaic acid, parinaric acid, arachidonic acid and linear tri-unsaturated fatty acids and salts thereof; , Tridecic acid, tetradecic acid, pentadecic acid, heptadecic acid, octadecic acid, nonadecinic acid, acetylenoic acid such as dimethyloctadecinic acid, and salts thereof.
Here, examples of the above-mentioned fatty acid salt include sodium salt and potassium salt.

Among the above fatty acids, preferably at least one selected from the group consisting of saturated fatty acids and unsaturated fatty acids having 10 to 20 carbon atoms and salts of those fatty acids, preferably capric acid, undecanoic acid, lauric acid, and the like. Examples thereof include tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, and stearic acid. More preferred are capric acid, lauric acid, myristic acid, palmitic acid and stearic acid.

The blending amount of the heat resistance improver is, for example, 0.05 to 0.10% by mass with respect to the total mass of the obtained hydrogel.
The heat resistance improver is at least one selected from the fatty acid group, and these fatty acids can be used alone or in combination of two or more.

<Manufacturing method of premix>
In the premix, alcohol is added to the above-mentioned lipid peptide type compound, and the mixture is stirred at room temperature or higher and lower than 100 ° C., preferably 50 ° C. to 90 ° C., more preferably 60 ° C. to 90 ° C., for example 80 ° C., if desired. After that, it can be produced by adding a heat resistance improver, an additive for cosmetics and / or a quasi-drug, and stirring.

[Other additives]
Additives that can be generally used as cosmetic additives and quasi-drug additives can be used and blended with the method of the present invention and the transdermal base material, if necessary. Examples of additive components such as physiologically active substances and functional substances contained in skin external preparations such as cosmetics or non-pharmaceutical products include oily bases, moisturizers, feel improvers, surfactants, polymers, and thickeners.・ Gelling agents, solvents, antioxidants, reducing agents, oxidizing agents, preservatives, antibacterial agents, bactericides, chelating agents, pH adjusters, acids, alkalis, powders, inorganic salts, ultraviolet absorbers, whitening agents, Vitamin and its derivatives, hair growth agents, blood circulation promoters, stimulants, hormones, anti-wrinkle agents, anti-aging agents, tightening agents, cold sensation agents, warming agents, wound healing promoters, irritation relievers, pain relievers Agents, cell activators, plant / animal / microbial extracts, antipruritic agents, keratin exfoliating / dissolving agents, antiperspirants, refreshing agents, astringents, enzymes, nucleic acids, fragrances, pigments, colorants, dyes, pigments, anti-inflammatory agents, Examples thereof include anti-inflammatory agents, anti-asthma, anti-chronic obstructive pulmonary disease, anti-allergic agents, immunomodulators, anti-infective agents and antifungal agents.

Examples of these additive components include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, araquil alcohol, behenyl alcohol, jojoba alcohol, chimil alcohol, ceracyl alcohol, and batyl as oily bases. Higher (polyvalent) alcohols such as alcohols, hexyldecanol, isostearyl alcohol, 2-octyldodecanol, dimerdiol; aralkyl alcohols such as benzyl alcohol and derivatives thereof; lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid , Bechenic acid, undecylene acid, 12-hydroxystearic acid, palmitooleic acid, oleic acid, linoleic acid, linoleic acid, erucic acid, docosahexaenoic acid, eikosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long chain Higher fatty acids such as branched fatty acids, dimer acids and hydrogenated dimer acids, and metal soaps such as aluminum salts, calcium salts, magnesium salts, zinc salts, potassium salts and sodium salts thereof, and nitrogen-containing derivatives such as amides; Liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalane, vaseline, solid paraffin and other hydrocarbons; candelilla wax , Carnauba wax, rice wax, wood wax, mitsuro, montan wax, ozokerite, selecin, paraffin wax, microcrystallin wax, petrolatum, Fishertropch wax, polyethylene wax, ethylene / propylene copolymer and other waxes; palm oil, palm oil , Palm kernel oil, saflower oil, olive oil, sunflower oil, avocado oil, sesame oil, tea oil, evening primrose oil, wheat germ oil, macadamia nut oil, hazelnut oil, kukui nut oil, rose hip oil, meadowfoam oil, persic oil, tea tree Oil, peppermint oil, corn oil, rapeseed oil, sunflower oil, wheat germ oil, flaxseed oil, cottonseed oil, soybean oil, peanut oil, rice bran oil, cacao butter, shea butter, hydrogenated palm oil, hydrogenated paraffin oil, jojoba oil , Vegetable fats and oils such as hydrogenated jojoba oil; Animal fats and oils such as beef fat, milk fat, horse fat, egg yolk oil, mink oil, turtle oil; whale wax, lanolin, orange ruff Animal waxes such as oil; liquid lanolin, reduced lanolin, adsorption purified lanolin, lanolin acetate, liquid acetate lanolin, hydroxylanolin, polyoxyethylene lanolin, lanolin fatty acid, hard lanolin fatty acid, lanolin alcohol, lanolin alcohol acetate, acetic acid Lanolins such as (cetyl lanolyl) ester; sphingolin lipids such as lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, phospholipids such as phosphatidic acid, lysolecithin; hydrogenated soybean phosphorus Fatty acids, partially hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, partially hydrogenated egg yolk phospholipids and other phospholipid derivatives; cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid and other sterols; Saponins; cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate, cholesteryl isostearate, cholesteryl oleate, di-lauroyl-L-glutamate (cholesteryl / behenyl / octyldodecyl), di-lauroyl-L-glutamate (cholesteryl / Octyldodecyl), di-lauroyl-L-glutamate (phytosteryl / behenyl / octyldodecyl), di-lauroyl-L-glutamate (phytosteryl / octyldodecyl), acylsarcosine alkyl esters such as N-lauroylsarcosin isopropyl, 12- Cholesteryl hydroxystearate, macademia nut oil fatty acid cholesteryl, macadamia nut oil fatty acid phytosteryl, phytosteryl isostearate, soft lanolin fatty acid cholesteryl, hard lanolin fatty acid cholesteryl, long-chain branched fatty acid cholesteryl, long-chain α-hydroxy fatty acid cholesteryl and other sterol esters; -Fatty acid complexes such as cholesterol complex, phospholipid-phytosterol complex; octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl pariminate, octyldodecyl palmitate, cetyl octanate, hexyldecyl octanate, Isotridecyl isononanoate, isononyl isononanoate, octyl isononanoate, isotridecyl isononanoate, isodesyl neopentate, isotridecyl neopentanoate , Isostearyl neopentate, octyldodecyl neodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl ricinoleate, octyldodecyl lanolin fatty acid, hexyldecyl dimethyloctanoate, octyldodecyl erucate, hardened castor oleate, ethyl oleate , Avocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebatate, diisopropyl sebatate, dioctyl sebatate, diisopropyl adipate, dibutyl octyl sebatate, diisobutyl adipate , Monoalcoholic carboxylic acid esters such as dioctyl succinate, triethyl citrate; oxyacid esters such as cetyl lactate, diisostearyl malate, hydrogenated castor oil monoisostearate; glyceryl trioctanoate, glyceryl trioleate, tri Glyceryl isostearate, glyceryl diisostearate, tri (caprylic acid / capric acid) glyceryl, tri (caprylic acid / capric acid / myristic acid / stearic acid) glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum) ), Glyceryl dicosanate behate, Trimethylol propane trioctanoate, Trimethylol propane triisostearate, Neopentyl glycol dioctanoate, Neopentyl glycol dicaprate, 2-Butyl-2-ethyl-1,3-propanediol dioctanoate , Propylene glycol dioleate, Pentaerythrityl tetraoctanoate, Hydrogenated rosin pentaerythricyl, Ditrimethylol propane triethylhexanoate, Ditrimethylol propane (isostearic acid / sebacic acid), Pentaerythrityl triethylhexanoate, (Hydroxystearic acid / Steeric acid / logonic acid) dipentaerythrityl, diglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl nonaisostearate-10, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligo Ester, glycol distearate (ethylene glycol distearate), 3-methyl-1,5-pentanediol dineopentanoate, di Polyhydric alcohol fatty acid esters such as neopentanoic acid 2,4-diethyl-1,5-pentanediol; diisopropyl dimerdilinolate, diisostearyl dimerserinolate, di (isostearyl / phytosteryl) dimerdilinolate, dies Dimerginolic acid (phytosteryl / behenyl), dimerdilinolic acid (phytosteryl / isostearyl / cetyl / stearyl / behenyl), dimerdilinoleic acid dimerglinoleil, diisostearate dimerglinoleil, dimerglinoleil hydrogenated rosin condensation Dimeric acid or derivatives of dimeric acid or dimerdiol such as dimerdylinoic acid-hardened castor oil, hydroxyalkyl dimerdinorail ether; coconut oil fatty acid monoethanolamide (cocamide MEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acid. Monoethanolamide (lauramide MEA), lauric acid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitate monoethanolamide (partamide MEA), palmitate diethanolamide (partamide DEA), palm oil fatty acid methyl Fatty acid alkanolamides such as ethanolamide (cocamidomethyl MEA); dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyl Dimethicone, phenyldimethicone, stearoxypropyldimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, aminomodified silicones such as aminopropyldimethicone and amodimethicone, cation-modified silicones, Polyether-modified silicones such as dimethicone copolyol, polyglycerin-modified silicones, sugar-modified silicones, carboxylic acid-modified silicones, phosphate-modified silicones, sulfate-modified silicones, alkyl-modified silicones, fatty acid-modified silicones, alkyl ether-modified silicones, amino acid-modified silicones, Peptide-modified silicones, fluorine-modified silicones, cationic-modified and polyether-modified silicones, amino-modified and polyether-modified silicones, alkyl-modified and polyether-modified Silicones such as silicones and polysiloxane / oxyalkylene copolymers; fluorine-based oils such as perfluorodecane, perfluorooctane and perfluoropolyether are preferable.

Moisturizers / feeling improvers 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 copolymers and their polymers; diethylene glycol monoethyl ether Glycolalkyl ethers such as (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dibutyl ether; water-soluble such as (eicosandioic acid / tetradecanedioic acid) polyglyceryl-10, polyglyceryl-10 tetradecanedioate Esters; sugar alcohols such as sorbitol, xylitol, erythritol, mannitol, martitol; glucose, fructose, galactose, mannose, treose, xylose, arabinose, fucose, ribose, deoxyribose, maltose, trehalose, lactose, raffinose, gluconic acid , Glucronic acid, cyclodextrins (α-, β-, γ-cyclodextrin, and modified cyclodextrins such as maltosylated and hydroxyalkylated), β-glucan, chitin, chitosan, heparin and derivatives, pectin, arabino Sugars such as galactan, dextrin, dextran, glycogen, ethyl glucoside, glucosyl ethyl methacrylate polymer or copolymer and derivatives thereof; hyaluronic acid, sodium hyaluronate; sodium chondroitin sulfate; mucoitin sulfate, caronine sulfate, keratosulfate, dermatane Sulfate; white jellyfish extract, white jellyfish polysaccharide; fucoidan; tuberose polysaccharide or naturally occurring polysaccharide; organic acids such as citric acid, tartaric acid, lactic acid and salts thereof; urea and its derivatives; 2-pyrrolidone-5-carboxylic acid and its derivatives. Salts such as sodium; betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, tyrosine, β-alanine, threonine, glutamate, glutamine, asparagine, aspartic acid, cysteine , Amino acids such as cysteine, methionine, leucine, isoleucine, valine, tryptophan, histidine, taurine and salts thereof; collagen, fish-derived collagen, atelocollagen, gelatin, elastin, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolysis Collagen, elastin-degrading peptide, keratin-degrading peptide, hydrolyzed keratin, conchiolin-degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, wheat proteolytic peptide, hydrolyzed wheat Protein peptides such as proteins, casein-degrading peptides and acylated peptides and their derivatives; acylated peptides such as palmitoyl oligopeptide, palmitoyl pentapeptide and palmitoyl tetrapeptide; silylated peptides; lactic acid bacteria culture solution, yeast extract, eggshell Membrane protein, submandibular gland mutin, hypotaurine, sesame lignan glycoside, glutathione, albumin, lactose; choline chloride, phosphorylcholine; placenta extract, aerastin, collagen, aloe extract, hamamelis water, hechima water, chamomile extract, citrus Animal / plant extracts such as extracts, comfrey extracts, silk extracts, Izayoi rose extract, sycamore extract, eucalyptus extract, melilot extract, natural ceramides (types 1, 2, 3, 4, 5, 6), hydroxyceramides, Preferred are ceramides such as pseudo-ceramides, sphingoglycolipids, ceramides and sugar ceramide-containing extracts.

As the surfactant, anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants, polymer surfactants and the like are preferable. Examples of preferred surfactants include fatty acid salts such as potassium laurate and potassium myristate; alkyl sulphates such as sodium lauryl sulphate, triethanolamine lauryl sulphate and ammonium lauryl sulphate; Polyoxyethylene alkyl sulfates such as sodium laureth sulphate and triethanolamine laureth sulphate; sodium cocoyl methyl taurine, potassium cocoyl methyl taurine, sodium lauroyl methyl taurine, sodium myristyl methyl taurine, sodium lauroyl methyl alanine, sodium lauroyl sarcosin, lauroyl sarcosintri Acyl N-methyl amino acid salts such as ethanolamine, sodium methylalanine lauroyl glutamate; sodium cocoyl glutamate, triethanolamine cocoyl glutamate, sodium lauroyl glutamate, sodium myristyl glutamate, sodium stearoyl glutamate, ditriethanolamine palmitoyl aspartate, cocoylalanine triethanol Acylamino acid salts such as amines; Polyoxyethylene alkyl ether acetates such as sodium laureth acetate; Sulfonic acid ester salts such as lauroyl monoethanolamide sodium succinate; Fatty acid alkanolamide ether carboxylates; Acyl late; Polyoxyethylene fat Amin sulfate; fatty acid alkanolamide sulfate; hardened coconut oil fatty acid fatty acid glyceride sulfate such as sodium glycerin sulfate; alkylbenzene polyoxyethylene sulfate; olefin sulfonate such as α-olefin sulfonate; sodium lauryl sulfosuccinate, Alkyl sulfosuccinates such as dioctyl sodium sulfosuccinate; alkyl ether sulfosuccinates such as laures disodium sulfosuccinate, sodium monolauroyl monoethanolamide polyoxyethylene sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate; sodium tetradecylbenzene sulfonate, Alkylbenzene sulfonates such as tetradecylbenzene sulfonic acid triethanolamine; alkylnaphthalene sulfonates; alkane sulfonates; α-sulfo fatty acid methyl ester salts; acyl citeionates; alkyl glycidyl ether sulfonates; alkyl sulfoacetates; Laures Alkyl ether phosphates such as sodium phosphate, sodium dilaures phosphate, sodium trilaureth phosphate, sodium monoolesphosphate; alkyl phosphates such as potassium lauryl phosphate; sodium caseinate; alkylaryl ether phosphate; fatty acid amide Ether phosphate; phospholipids such as phosphatidylglycerol, phosphatidylinositol, phosphatidic acid; silicone-based anionic surfactants such as carboxylic acid-modified silicone, phosphoric acid-modified silicone, sulfate-modified silicone; as nonionic surfactants Laures (polyoxyethylene lauryl ether), ceteth (polyoxyethylene cetyl ether), steares (polyoxyethylene stearyl ether), behenes (polyoxyethylene behenyl ether), isosteares (polyoxyethylene isostearyl ether) ), Polyoxyethylene alkyl ethers with various polyoxyethylene additions such as octyldodeceth (polyoxyethylene octyldodecyl ether); polyoxyethylene alkylphenyl ether; polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, Polyoxyethylene hydrogenated castor oil monoisostearate, polyoxyethylene hydrogenated castor oil triisostearate, polyoxyethylene hydrogenated castor oil monopyroglutamic acid monoisostearic acid diester, polyoxyethylene hydrogenated castor oil maleic acid and other castor oils and cured Himasi oil derivative; polyoxyethylene phytosterol; polyoxyethylene cholesterol; polyoxyethylene cholestanol; polyoxyethylene lanolin; polyoxyethylene reduced lanolin; polyoxyethylene / polyoxypropylene cetyl ether, polyoxyethylene / polyoxypropylene 2- Polyoxyethylene / polyoxypropylene alkyl ethers such as decyltetradecyl ether, polyoxyethylene / polyoxypropylene monobutyl ether, polyoxyethylene / polyoxypropylene hydrogenated lanolin, polyoxyethylene / polyoxypropylene glycerin ether; polyoxyethylene; -Polyoxypropylene glycol; (poly) glycerin polyoxypropylene glycol such as PPG-9 diglyceryl; glyceryl stearate, glyceryl isostearate, glyceryl palmitate, millis Partial esters of glycerin fatty acids such as glyceryl phosphate, glyceryl oleate, coconut oil fatty acid glyceryl, monocotton seed oil fatty acid glycerin, monoerucate glycerin, sesquioleate glycerin, α, α'-pyroglutamate oleate glycerin, monostearate glycerin malic acid, etc. Kind: Polyglyceryl-2 stearate-2, 3, 4, 5, 5, 8, 8, 10, polyglyceryl distearate-6, 10, polyglyceryl tristearate-2, polyglyceryl decastearate-10, isostearic acid Polyglyceryl-2 acid, 3, 4, 4, 5, 6, 8, 10, 10, polyglyceryl diisostearate-2 (diglyceryl diisostearate), 3, 10, 10, polyglyceryl triisostearate-2, tetraisostearate. Polyglyceryl-2 acid, polyglyceryl-10 decaisostearate, polyglyceryl-2 oleate, 3, 4, 5, 6, 6, 8, polyglyceryl dioleate-6, polyglyceryl trioleate-2, decaolein Polyglycerin fatty acid ester such as polyglyceryl-10 acid; ethylene glycol monofatty acid ester such as ethylene glycol monostearate; propylene glycol monofatty acid ester such as propylene glycol monostearate; pentaerythritol partial fatty acid ester; sorbitol partial fatty acid ester; martitol Partial fatty acid ester; multitoll ether; sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, dipenta-2-ethylhexylate Sorbitane fatty acid esters such as glycerol sorbitan and diglycerol sorbitan tetra-2-ethylhexylate; sugar derivative partial esters such as sucrose fatty acid ester, methyl glucoside fatty acid ester and trehalose undecylate; alkyl glucosides such as caprylyl glucoside; alkyl polyglycoside; Lanoline alcohol; reduced lanoline; polyoxyethylene fatty acid monos and diesters such as polyoxyethylene distearate, polytylene glycol diisostearate, polyoxyethylene monooleate, and polyoxyethylene dioleate; polyoxyethylene / propylene glycol Fatty acid ester; poly Polyoxyethylene glycerin fatty acid esters such as polyoxyethylene monooleate such as oxyethylene glycerin monostearate, polyoxyethylene glycerin monoisostearate, polyoxyethylene glycerin triisostearate; polyoxyethylene sorbitan monolaurate, poly Polyoxyethylene sorbitan fatty acid esters such as oxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetraoleate; polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol Polyoxyethylene sorbitol fatty acid esters such as monooleate, polyoxyethylene sorbitol pentaoleate, polyoxyethylene sorbitol monostearate; polyoxyethylene methyl glucoside fatty acid esters; polyoxyethylene alkyl ether fatty acid esters; polyoxyethylene sorbitol mitsuro, etc. Polyoxyethylene animal and vegetable oils and fats; alkyl glyceryl ethers such as isostearyl glyceryl ether, chimyl alcohol, ceracyl alcohol, and batyl alcohol; polyhydric alcohol alkyl ether; polyoxyethylene alkylamine; tetrapolyoxyethylene / tetrapolyoxy Propropylene-ethylenediamine condensates; natural surfactants such as saponin and sophorolipid; polyoxyethylene fatty acid amide; coconut oil fatty acid monoethanolamide (cocamide MEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acid monoethanolamide (Lauramide MEA), Lauric Acid Diethanolamide (Lauramide DEA), Lauric Acid Monoisopropanolamide (Lauramide MIPA), Palmitic Acid Monoethanolamide (Partamide MEA), Palmitic Acid Diethanolamide (Partamide DEA), Palm Oil Fatty Acid Methylethanolamide (Lauramide MEA) Fatty acid alkanolamides such as cocamide methyl MEA); alkyldimethylamine oxides such as lauramine oxide, cocamine oxide, stearamine oxide, behenamine oxide; alkylethoxydimethylamine oxides; polyoxyethylene alkyl mercaptans; Polyether-modified silicone, polysiloxane / oxyalkylene copolymer, polyethylene Silicone-based nonionic surfactants such as liglyserine-modified silicones and sugar-modified silicones; as cationic surfactants, alkyls such as behentrimonium chloride, stealtrimonium chloride, cetrimonium chloride, and lauryltrimonium chloride. Trimethylammonium chloride; alkyltrimethylammonium bromide such as stearyltrimonium bromide; dialkyldimethylammonium chloride such as distealyl dimonium chloride and dicocodimonium chloride; fatty acid amidamines such as stearamide propyl dimethylamine and stearamide ethyl diethylamine and salts thereof; Alkyl ether amines such as stearoxypropyl dimethylamine and salts or quaternary salts thereof; fatty acid amide type tetra such as ethyl sulfate long chain branched fatty acids (12-31) aminopropyl ethyl dimethyl ammonium, ethyl sulfate lanolin fatty acids aminopropyl ethyl dimethyl ammonium Secondary ammonium salts; polyoxyethylene alkylamines and their salts or quaternary salts; alkylamine salts; fatty acid amide guanidium salts; alkyl etheraminemonium salts; alkyltrialkylene glycol ammonium salts; benzalconium salts; benzethonium salts; chlorides Pyridinium salts such as cetylpyridinium; imidazolinium salts; alkylisoquinolinium salts; dialkylmoriphonium salts; polyamine fatty acid derivatives; amino-modified silicones such as aminopropyldimethicone and amodimethicone, cation-modified silicones, cation-modified and polyethers. Silicone-based cationic surfactants such as modified silicones, amino-modified and polyether-modified silicones; as amphoteric surfactants, N-alkyl-N, N-dimethyl amino acids such as lauryl betaine (lauryl dimethylaminoacetic acid betaine) Betain; fatty acid amide alkyl-N, N-dimethylamino acid betaine such as cocamidopropyl betaine and lauramidopropyl betaine; imidazoline type betaine such as sodium cocoamphoacetate and sodium lauroamphoacetate; alkylsulfobetaine such as alkyldimethyltaurin; alkyldimethylamino Sulfate-type betaine such as ethanol sulfate ester; Phosphate-type betaine such as alkyldimethylaminoethanol phosphate; Sphingoli such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, etc. Phospholipids, lysolecithin, hydrogenated soybean phospholipids, partially hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, partially hydrogenated egg yolk phospholipids, phospholipids such as lecithin hydroxide; As the surfactant, polyvinyl alcohol, sodium alginate, starch derivative, tragant gum, acrylate / alkyl methacrylic acid copolymer; various silicone-based surfactants are preferable.

Polymers, thickeners and gelling agents include guar gum, locust bean gum, queens seed, carrageenan, galactan, arabic gum, tara gum, tamarind, farseleran, karaya gum, trolley aoi, cara gum, tragant gum, pectin, pectic acid and sodium. Salts such as salts, salts such as alginic acid and sodium salts, mannan; starches such as rice, corn, potatoes, wheat; xanthan gum, dextran, succinoglucan, curdran, hyaluronic acid and its salts, zansangum, purulan, gellan gum, chitin , Chitosan, agar, casso extract, chondroitin sulfate, casein, collagen, gelatin, albumin; methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts such as sodium thereof, methyl hydroxypropyl cellulose, cellulose sulfate Cellulose such as sodium, dialkyldimethylammonium sulfate cellulose, crystalline cellulose, cellulose powder and its derivatives; starch-based polymers such as soluble starch, carboxymethyl starch, methylhydroxypropyl starch and methyl starch, hydroxypropyltrimonium chloride starch, octenyl succinic acid. Steel derivatives such as corn starch aluminum; alginic acid derivatives such as sodium alginate and propylene glycol alginate; polyvinylpyridone (PVP), polyvinyl alcohol (PVA), vinylpyridone / vinyl alcohol copolymer, polyvinylmethyl ether; polyethylene glycol, polypropylene glycol, Polyoxyethylene / polyoxypropylene copolymer; amphoteric methacrylic acid ester copolymer such as (methacryloyloxyethyl carboxybetaine / alkyl methacrylate) copolymer, (acrelites / stearyl acrylate / ethylamine acrylate) copolymer; (dimethicone /) Vinyl Dimethicone) Crosspolymer, (alkyl Acrylate / Diacetoneacrylamide) Copolymer, (alkyl Acrylate / Diacetoneacrylamide) Copolymer AMP; Polyvinyl acetate partially saponified product, Maleic acid copolymer; Vinylpyrrolidone / Dialkylaminoalkyl methacrylate Copolymer; Acrylic Resin Alkanolamine; Polye Steal, water-dispersible polyester; polyacrylamide; polyacrylic acid ester copolymer such as ethyl polyacrylate, carboxyvinyl polymer, salt such as polyacrylic acid and sodium salt thereof, acrylic acid / methacrylic acid ester copolymer; Acrylic acid / alkyl methacrylic acid copolymer; cationized cellulose such as polyquaternium-10, diallyldimethylammonium chloride / acrylamide copolymer such as polyquaternium-7, acrylic acid / diallyldimethylammonium chloride copolymer such as polyquaternium-22. , Polyquaternium-39 and other acrylic acid / diallyldimethylammonium chloride / acrylamide copolymers, acrylic acid / cationized methacrylic acid ester copolymers, acrylic acid / cationized methacrylic acid amide copolymers, polyquaternium-47 and the like. Acrylic acid / methyl acrylate / methacrylic acid propyltrimethylammonium copolymer, choline methacrylate polymer; cationized polysaccharides such as cationized oligosaccharide, cationized dextran, guarhydroxypropyltrimonium chloride; polyethyleneimine; Cationic polymer; polymer of 2-methacryloyloxyethyl phosphorylcholine such as polyquaternium-51 and polymer with butyl methacrylate copolymer and the like; acrylic resin emulsion, ethyl polyacrylate emulsion, polyacrylic alkyl ester emulsion, vinyl acetate Polymer emulsions such as resin emulsions, natural rubber latex, synthetic latex; nitrocellulose; polyurethanes and various copolymers; various silicones; various silicone-based copolymers such as acrylic-silicone graft copolymers; various fluoropolymers; Polymers; 12-hydroxystearic acid and salts thereof; dextrin fatty acid esters such as dextrin palmitate and dextrin myristinate; silicic anhydride, fuming silica (ultrafine anhydrous silicic acid), aluminum magnesium silicate, magnesium sodium silicate, metal Preferred are soaps, dialkyl phosphate metal salts, bentonite, hectrites, organically modified clay minerals, sucrose fatty acid esters, and fructo-oligosaccharide fatty acid esters. Among the above examples, cellulose and its derivatives, alginic acid and its salts, polyvinyl alcohol, hyaluronic acid and its salts, or collagen are preferable.

Examples of the solvent include lower alcohols such as ethanol, 2-propanol (isopropyl alcohol), butanol and isobutyl alcohol; glycols such as propylene glycol, 1,3-butylene glycol, diethylene glycol, dipropylene glycol and isopentyldiol; diethylene glycol mono. Glycol ethers such as ethyl 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, etc. Classes; glycol ether esters such as ethylene glycol monoethyl ether acetate, diethylene glycol monoethyl ether acetate and propylene glycol monoethyl ether acetate; glycol esters such as diethoxyethyl succinate and ethylene glycol disuccinate; benzyl alcohol and benzyloxy. Ethanol, propylene carbonate, dialkyl carbonate, acetone, ethyl acetate, N-methylpyrrolidone; toluene and the like are preferable.

Antioxidants include tocopherol derivatives such as tocopherol (vitamin E) and tocopherol acetate; BHT, BHA; bisulfite derivatives such as propyl bisulfite; vitamin C (ascorbic acid) and / or its derivatives; erythorbic acid and its derivatives; Sulfites such as sodium sulfite; hydrogen sulfites such as sodium hydrogen sulfite; thiosulfites such as sodium thiosulfite; metahydrosulfites; thiotaurine, hypotaurine; thioglycerol, thiourea, thioglycolic acid, cysteine hydrochloride are preferable. Is listed as.

As the reducing agent, thioglycolic acid, cysteine, cysteamine and the like are preferable.

As the oxidizing agent, hydrogen peroxide solution, ammonium persulfate, sodium bromate, percarbonate and the like are preferable.

Examples of preservatives, antibacterial agents, and bactericidal agents include hydroxybenzoic acids such as methylparaben, ethylparaben, propylparaben, and butylparaben and salts thereof or esters thereof; salicylic acid; sodium benzoate; phenoxyethanol; methylchloroisothiazolinone, methylisothiazo. Isothiazolinone derivatives such as linone; imidazolinium urea; dehydroacetic acid and salts thereof; phenols; bisphenol halides such as triclosan, acid amides, quaternary ammonium salts; trichlorocarbanide, zincpyrythion, benzalconium chloride, chloride Benzethonium, sorbic acid, chlorhexidine, chlorhexidine gluconate, halocarban, hexachlorophene, hinokithiol; other phenols such as phenol, isopropylphenol, cresol, timol, parachlorophenol, phenylphenol, sodium phenylphenol; phenylethyl alcohol, photosensitizer Phenols, antibacterial phenols, and silver ions are preferred.

Examples of the chelating agent include edetates (ethylenediaminetetraacetate) such as EDTA, EDTA2Na, EDTA3Na, and EDTA4Na; hydroxyethylethylenediaminetriacetate such as HEDTA3Na; pentetate (diethylenetriaminepentaacetate); phytate; ethidroic acid and the like. Phosphonic acid and salts such as sodium salts thereof; sodium oxalate; polyamino acids such as polyaspartic acid and polyglutamic acid; sodium polyphosphate, sodium metaphosphate, phosphate; sodium citrate, citric acid, alanine, dihydroxyethylglycine , Gluconic acid, ascorbic acid, succinic acid, tartrate acid are preferred.

As pH adjusters / acids / alkalis, citric acid, sodium citrate, lactic acid, sodium lactate, potassium lactate, glycolic acid, succinic acid, acetic acid, sodium acetate, malic acid, tartrate 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, ammonium carbonate are preferred.

Powders include mica, talc, kaolin, cericite, montmorillonite, kaolinite, mica, white mica, gold mica, synthetic mica, red mica, black mica, permiculite, magnesium carbonate, calcium carbonate, aluminum silicate, silicic acid. Barium, calcium silicate, magnesium silicate, strontium silicate, metal tungrate, magnesium, zeolite, barium sulfate, calcined calcium sulfate, calcium phosphate, fluoroapatite, hydroxyapatite, ceramic powder, bentonite, smectite, clay, mud, metal Soap (eg zinc myristate, calcium palmitate, aluminum stearate), calcium carbonate, red iron oxide, iron yellow oxide, iron black oxide, ultramarine, dark blue, carbon black, titanium oxide, fine and ultrafine titanium oxide, zinc oxide, Fine and ultrafine zinc oxide, alumina, silica, fumigant silica (ultrafine anhydrous silicic acid), mica titanium, fish scale foil, boron nitride, photochromic pigment, synthetic fluorine gold mica, fine particle composite powder, gold, aluminum, etc. Inorganic powders of various sizes and shapes, and these are treated with silicones such as hydrogen silicone and cyclic hydrogen silicone or other surface treatment agents such as silane or titanium coupling agents to make them hydrophobic or hydrophilic. Inorganic powder such as sterilized powder; starch, cellulose, nylon powder, polyethylene powder, polymethyl methacrylate powder, polystyrene powder, styrene and acrylic acid copolymer resin powder, polyester powder, benzoguanamine resin powder, polyethylene terephthalate. Polymethylmethacrylate laminated powder, polyethylene terephthalate / aluminum / epoxy laminated powder, etc., urethane powder, silicone powder, Teflon (registered trademark) powder, and other organic powders and surface-treated powders of various sizes and shapes, organic-inorganic composites Powders are preferred.

Inorganic salts include sodium chloride-containing salts such as salt, normal salt, rock salt, sea salt, and natural salt; potassium chloride, aluminum chloride, calcium chloride, magnesium chloride, ginger, zinc chloride, ammonium chloride; sodium sulfate, aluminum sulfate, etc. Aluminum / potassium sulfate (myoban), aluminum / ammonium sulfate, barium sulfate, calcium sulfate, potassium sulfate, magnesium sulfate, zinc sulfate, iron sulfate, copper sulfate; sodium phosphates such as 1Na / 2Na / 3Na phosphate, phosphoric acid Potassiums, calcium phosphates and magnesium phosphates are preferred.

Examples of the ultraviolet absorber include paraaminobenzoic acid, paraaminobenzoic acid monoglycerin ester, N, N-dipropoxyparaaminobenzoic acid ethyl ester, N, N-diethoxyparaaminobenzoic acid ethyl ester, and N, N-dimethylparaaminobenzoate ethyl. Benzophenone-based UV absorbers such as esters, N, N-dimethylparaaminobenzoic acid butyl esters, N, N-dimethylparaaminobenzoic acid ethyl esters; Anthranilic acid-based UV absorbers such as homomentyl-N-acetylanthranilate; salicylic acid And its sodium salts amyl salicylate, menthyl salicylate, homomentyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate and other salicylic acid-based UV absorbers; octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl- 2,5-Diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate, isoamyl-p-methoxy cinnamate Mate, 2-ethylhexyl p-methoxycinnamate (octyl paramethoxysilicate), 2-ethoxyethyl-p-methoxycinnamate (sinoxate), cyclohexyl-p-methoxycinnamate, ethyl-α-cyano-β-phenylcinna Ceramic acid-based UV absorbers such as mate, 2-ethylhexyl α-cyano-β-phenylcinnamate (octocrine), glycerylmono-2-ethylhexanoyl-diparamethoxycinnamate, ferulic acid and derivatives thereof; 2,4 -Dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2', 4,4'-tetrahydroxybenzophenone, 2-hydroxy-4 −methoxybenzophenone (oxybenzophenone-3), 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone, 2-ethylhexyl-4'- Benzophenones such as phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone UV absorbers; 3- (4'-methylbenziliden) -d, l-camfur, 3-benziliden-d, l-camphr; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5- Methylphenylbenzotriazole; 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole; 2- (2'-hydroxy-5'-methylphenylbenzotriazole;dibenzalazine;dianisoilmethane; 5- (3) , 3-Dimethyl-2-norbornylidene) -3-pentan-2-one; dibenzoylmethane derivatives such as 4-t-butylmethoxydibenzoylmethane; octylriazone; urocanic acid derivatives such as urocanic acid and ethyl urocanate; 2- (2'-Hydroxy-5'-methylphenyl) benzotriazole, 1- (3,4-dimethoxyphenyl) -4,4-dimethyl-1,3-pentandione, dimethoxybenzilidendioxoimidazolidinepropionic acid 2 Preferable examples include hydantin derivatives such as ethylhexyl, phenylbenzimidazolol sulfonic acid, terephthalylidene dicanfursulfonic acid, drometrizole trisiloxane, methyl anthranilate, rutin and its derivatives, oryzanol and its derivatives.

Examples of the whitening agent include hydroquinone glycosides such as arbutin and α-arbutin and their esters; ascorbic acid, ascorbic acid phosphate sodium salt, ascorbic acid phosphate ester magnesium salt and the like, ascorbic acid phosphate ester salt, ascorbic acid. Ascorbic acid fatty acid ester such as tetraisopalmitic acid ester, ascorbic acid alkyl ether such as ethyl ether ascorbic acid, ascorbic acid glucoside such as ascorbic acid-2-glucoside and its fatty acid esters, ascorbic acid sulfate ester, tocopheryl ascorbyl phosphate Ascorbic acid derivatives such as: kodic acid, ellagic acid, tranexamic acid and its derivatives, ferulic acid and its derivatives, placenta extract, glutathione, oryzanol, butylresorcinol, oil-soluble chamomile extract, oil-soluble kanzo extract, Nishikawayanagi extract, Yukinoshita extract Ascorbic acid is preferred.

Examples of vitamins and derivatives thereof include vitamin A such as retinol, retinol acetate, and retinol palmitate; thiamine hydrochloride, thiamine sulfate, riboflavin, riboflavin acetate, pyridoxin hydrochloride, pyridoxin dioctanoate, pyridoxin dipalmitate, etc. Vitamin B group such as flavin adenin dinucleotide, cyanocobalamine, folic acid, nicotinic acid such as nicotinic acid amide / benzyl nicotinate, choline; vitamin C such as ascorbic acid and its sodium salt; vitamin D; α, Vitamin E such as β, γ, δ-tocopherol; other vitamins such as pantothenic acid and biotin; ascorbic acid phosphate ester salt such as ascorbic acid phosphate sodium salt and ascorbic acid phosphate ester magnesium salt, tetra ascorbic acid Ascorbic acid fatty acid ester such as isoparmic acid ester, ascorbic stearate, ascorbic palmitate, ascorbic dipalmitate, alkyl ether ascorbic acid such as ethyl ether ascorbic acid, ascorbic acid glucoside such as -2-glucoside ascorbic acid and its fatty acid ester. , Ascorbic acid derivatives such as tocopheryl ascorbic acid; tocopherol nicotinate, tocopherol acetate, tocopherol linoleate, tocopherol ferulate, tocopherol derivatives such as tocopherol phosphate, and other vitamin derivatives, tocotrienol, and other various vitamin derivatives are preferable. Is listed as.

As hair growth agents, blood circulation promoters, and stimulants, plant extracts and tinctures such as senburi extract, togarashi tincture, ginger tincture, ginger extract, and cantalis tincture; capsaicin, nonylate valenylamide, zingerone, ictamol, and tannic acid. , Borneol, cyclanderate, cinnaridine, trazoline, acetylcholine, verapamil, cepharanthin, γ-oryzanol, vitamin E and derivatives such as tocopherol nicotinate / tocopherol acetate, γ-orizanol, nicotinic acid and nicotinic acid amide / nicotinic acid benzyl ester. Derivatives such as inositol hexanicotinate and nicotine alcohol, allantin, photosensitizer 301, photosensitizer 401, capronium chloride, pentadecanoic acid monoglyceride, flavanonol derivative, stigmasterol or stigmasterol and its glycosides, minoxidil are listed as preferable. Be done.

As the hormones, estradiol, estrone, ethinyl estradiol, cortisone, hydrocortisone, prednisone and the like are preferable. Other medicinal agents such as anti-wrinkle agents, anti-aging agents, tightening agents, cold sensitizers, warming agents, wound healing promoters, stimulant relievers, analgesics, cell activators, etc. include retinols, retinoic acids, retinoins. Tocopheryl acid; derivatives such as lactic acid, glycolic acid, gluconic acid, fruit acid, salicylic acid and its glycosides / esterified products, hydroxycapric acid, long-chain α-hydroxy fatty acid, long-chain α-hydroxy fatty acid cholesteryl and other α- or β-Hydroxy acids and their derivatives; γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid; carnitine; carnosin; creatin; ceramides, spingosins; caffeine, xanthin and its derivatives; coenzyme Q10, carotene, lycopene , Astaxanthin, lutein, α-lipoic acid, platinum nanocolloids, fullerene and other antioxidant / active oxygen scavengers; catechins; quercetin and other flavones; isoflavones; gallic acid and ester sugar derivatives; tannins, sesamine, proto Polyphenols such as anthocyanidin, chlorogenic acid, apple polyphenols; derivatives such as rutin and glycosides; derivatives such as hesperidin and glycosides; lignan glycosides; Aroma substances such as menthol and sedrol and derivatives thereof; insect repellents such as capsaicin, vanillin and derivatives; insect repellents such as diethyl toluamide; complexes of physiologically active substances and cyclodextrins are preferable. ..

Plant / animal / microbial extracts include iris extract, acitaba extract, asunaro extract, asparagus extract, avocado extract, flaxseed extract, almond extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo extract. , Inchikou extract, Uikyo extract, Ukon extract, Woolong tea extract, Uwaurushi extract, Agetsu extract, Echinashi leaf extract, Enmeisou extract, Ogon extract, Oubaku extract, Ouren extract, Omugi extract, Otanenjinjin extract, Otogirisou extract, Odori kosou extract, Ononis extract , Dutch mustard extract, orange extract, dried seawater, seaweed extract, oyster leaf extract, oyster extract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk, cucumber extract, chamomile extract, oil-soluble chamomile extract, carrot extract, kawarayomogi Extract, crow wheat extract, calcade extract, kanzo extract, oil-soluble kanzo extract, kiwi extract, kiou extract, kikurage extract, kina extract, cucumber extract, kiri leaf extract, guanosine, guava extract, kujin extract, cutinashi extract, kumazasa extract, clara extract, walnut Extract, chestnut extract, grapefruit extract, clematis extract, black rice extract, brown sugar extract, black vinegar, chlorella extract, quail extract, gentiana extract, gennoshouko extract, tea extract, yeast extract, koboku extract, coffee extract, gobo extract, rice extract, rice Fermented extract, fermented rice bran extract, rice germ oil, comfrey extract, collagen, moss peach extract, saishin extract, psycho extract, saitai extract, saffron extract, salvia extract, sabonsou extract, sasa extract, sanzashi extract, sansha extract, sansho Extract, Shiitake extract, Jio extract, Shikon extract, Shiso extract, Shinanoki extract, Shimotsukesou extract, Jatoba extract, Shakuyaku extract, Shokyu extract, Shobu root extract, Shirakaba extract, White chrysanthemum extract, Sugina extract, Stevia extract, Stevia fermented product, Nishikawayanagi extract, Seiyoukizuta extract, Seiyousanzashi extract, Seiyouniwatoko extract, Seiyounokogirisou extract, Seiyouhakka extract, Sage extract, Zeniaoi extract, Senkyu extract, Senburi extract, Souhakuhi extract, Daiou extract, Dai Zu extract, Taisou extract, Thyme extract, Dandelion extract, Local clothing extract, Tea extract, Chouji extract, Chigaya extract, Chinpi extract, Tea tree oil, Jincha extract, Togarashi extract, Touki extract, Tokinsenka extract, Tounin extract, Tohi extract, Dokudami extract, Tomato Extract, Natto extract, Carrot extract, Carrot extract, Novara extract, Hibiscus extract, Bakumondou extract, Hass extract, Parsley extract, Birch extract, Honey, Hamamelis extract, Paris etalia extract, Hikiokoshi extract, Bisaborol, Hinoki extract, Bifizus bacterium extract, Biwa extract, Fukitanpopo extract, Fukinotou extract, Bukuryo extract, Butcher bloom extract, Grape extract, Grape seed extract, Propolis, Hechima extract, Benibana extract, Peppermint extract, Bodaiju extract, Button extract, Hop extract, Maikaika extract, Pine extract, Maronie extract , Mizubasho extract, Mukuroji extract, Melissa extract, Mozuku extract, Peach extract, Yagurumagiku extract, Eucalyptus extract, Yukinoshita extract, Yuzu extract, Yuri extract, Yokuinin extract, Yomogi extract, Lavender extract, Green tea extract, Eggshell membrane extract, Apple extract, Louis Boss tea extract , Reishi extract, lettuce extract, lemon extract, lotus extract, lotus extract, rose extract, rosemary extract, roman chamomile extract, royal jelly extract, crackle extract and the like are preferable.

Examples of the antipruritic agent include diphenhydramine hydrochloride, chlorpheniramine maleate, camphor, substance-P inhibitor and the like.

Examples of the exfoliating / dissolving agent include salicylic acid, sulfur, resorcin, selenium sulfide, pyridoxine and the like.

Examples of the antiperspirant include chlorohydroxyaluminum, aluminum chloride, zinc oxide, zinc paraphenol sulfonate and the like.

Examples of the refreshing agent include menthol and methyl salicylate.

Examples of the astringent include citric acid, tartaric acid, lactic acid, aluminum / potassium sulfate, tannic acid and the like.

Examples of the enzymes include superoxide dismutase, catalase, lysozyme chloride, lipase, papain, pancreatin, protease and the like.

Preferred examples of nucleic acids include ribonucleic acid and a salt thereof, deoxyribonucleic acid and a salt thereof, and disodium adenosine triphosphate.

Fragrances include acetylsedrene, amylcinnamaldehyde, allylamylglycolate, β-ionone, isoe super, isobutylquinolin, iris oil, iron, indol, ylang ylang oil, undecanal, undecenal, γ-undecalactone, Estragor, eugenol, oak moss, opoponax resinoid, orange oil, eugenol, aurantiol, galactosolid, carbachlor, L-carboxylic, camphor, cannon, carrot seed oil, clove oil, methyl silicate, geraniol, geraniol nitrile , Isobornyl acetate, geraniol acetate, dimethylbenzylcarbinate acetate, styralyl acetate, sedrill acetate, terepinel acetate, pt-butylcyclohexyl acetate, vetiveryl acetate, benzyl acetate, linalyl acetate, isopentyl salicylate, benzyl salicylate, sandalwood oil, Santa Roll, cyclamenaldehyde, cyclopentadecanolide, methyl dihydrojasmonate, dihydromilsenol, jasmine absolute, jasmine lactone, cis-jasmon, citral, citronenol, citroneral, cinnamon bark oil, 1,8-cineol, cinnamaldehyde, Styrax resinoid, cedarwood oil, sedrene, sedrol, celery seed oil, thyme oil, damascon, damasenon, timol, tuberose absolute, decanal, decalactone, terpineol, γ-terpinen, triplar, nerol, nonanal, 2,6-nonadienol, nonalactone. , Pacholi alcohol, vanilla absolute, vanillin, basil oil, pachori oil, hydroxycitronellal, α-pinene, piperitone, phenethyl alcohol, phenylacetaldehyde, petitgrain oil, hexyl cinnamaldehyde, cis-3-hexenol, peruvian balsam, benzyl oil , Vetiberol, peppermint oil, pepper oil, heliotropin, bergamot oil, benzylbenzoate, borneol, milresinoid, muskketone, methylnonylacetaldehyde, γ-methylyonone, menthol, L-menthol, L-mentonone, eucalyptus oil, β-yonone, Synthetic fragrances and natural scents such as lime oil, lavender oil, D-limonene, linalool, linal, lilial, lemon oil, rose absolute, rose oxide, rose oil, rosemary oil, various essential oils, etc. Agents and various blended fragrances are preferred.

As pigments / colorants / dyes / pigments, brown 201, black 401, purple 201, purple 401, blue 1, blue 2, blue 201, blue 202, blue 203, blue 204 , Blue 205, Blue 403, Blue 404, Green 201, Green 202, Green 204, Green 205, Green 3, Green 401, Green 402, Red 102, Red 104-1 , Red 105-1, Red 106, Red 2, Red 201, Red 202, Red 203, Red 204, Red 205, Red 206, Red 207, Red 208, Red 213 , Red 214, Red 215, Red 218, Red 219, Red 220, Red 221, Red 223, Red 225, Red 226, Red 227, Red 228, Red 230-1 , Red 230-2, Red 231 and Red 232, Red 3, Red 401, Red 404, Red 405, Red 501, Red 502, Red 503, Red 504, Red 505. , Red 506, Orange 201, Orange 203, Orange 204, Orange 205, Orange 206, Orange 207, Orange 401, Orange 402, Orange 403, Yellow 201, Yellow 202-1 , Yellow 202-2, Yellow 203, Yellow 204, Yellow 205, Yellow 4, Yellow 401, Yellow 402, Yellow 403-1, Yellow 404, Yellow 405, Yellow 406, Yellow Legal dyes such as No. 407 and Yellow No. 5; other acidic dyes such as Acid Red 14; Arianor Sienna
Brown, Arianor Madder Red, Arianor Steel
Basic dyes such as Blue and Arianor Straw Yellow; HC Yellow 2, HC Yellow 5, HC Red 3,4-hydoxypropylamino-3-nitrophenol, N, N'-bis (2-hydroxythyl) -2-nitro-pigment Nitro dyes such as HC Blue 2 and Basic Blue 26; Dispersion dyes; Inorganic white pigments such as titanium dioxide and zinc oxide; Inorganic red pigments such as iron oxide (Bengala) and iron titanate; Inorganic brown pigments such as γ-iron oxide Pigments; Inorganic yellow pigments such as yellow iron oxide and ocher; Inorganic black pigments such as black iron oxide and lower titanium oxide; Inorganic purple pigments such as mango violet and cobalt violet; Chromium oxide, chromium hydroxide, titanium Inorganic green pigments such as cobalt acid; Inorganic blue pigments such as ultramarine and dark blue; Titanium oxide coated mica, titanium oxide coated bismuth oxychloride, titanium oxide coated talc, colored titanium oxide coated mica, bismuth oxychloride, fish scale foil, etc. Pearl pigments; metal powder pigments such as aluminum powder, copper powder and gold; surface-treated inorganic and metal powder pigments; organic pigments such as zirconium, barium or aluminum lake; surface-treated organic pigments; anthracinones such as astaxanthin and alizarin, anthocyanidins, naphthoquinones such as β-carotene, catenal, capsantin, chalcone, calsamine, quercetin, crocin, chlorophyll, curcumin, cochineal, shikonin, bixins, flavones, betacyanidine, henna, hemoglobin, lycopene, riboflavin, rutin and other natural pigments Dyes; p-phenylenediamine, toluene-2,5-diamine, o-, m-, or p-aminophenol, m-phenylenediamine, 5-amino-2-methylphenol, resorcin, 1-naphthol, 2,6 -Oxidation dye intermediates and couplers such as diaminopyridine and salts thereof; automatic oxidation dyes such as indolin; dihydroxyacetones are preferred.

Anti-inflammatory and anti-inflammatory agents include glycyrrhizic acid and its derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokithiol, guaiazulene, allantin, indomethacin, ketoprofen, ibuprofen, diclofenac, loxoprofen, selecosikib, infliximab, etanelcept, zinc oxide, hydro. , Prednisone, diclofenac hydrochloride, chlorpheniramine maleate; plant extracts such as peach leaf extract and honoha extract are preferred.

Anti-asthma, anti-chronic obstructive pulmonary disease, anti-allergy, immunomodulators include aminophilin, theophylline, steroids (fluticasone, bechrometazone, etc.), leukotriene antagonists, thromboxane inhibitors, intal, β2-agonists Kinds (formoterol, salmeterol, albuterol, turobterol, clembuterol, epinephrine, etc.), thiotropium, ipratropium, dextrometholphan, dimemorphan, bromhexin, tranilast, ketotiphen, azelastine, cetylidine, chlorpheniramine, mequitalim , Salmeterol regulators, interferon, omalizumab, protein / antibody preparations are preferred.

Preferable examples of the anti-infective agent and the antifungal agent include oseltamivir, zanamivir, and itraconazole. In addition to these, cosmetic raw material standards, compounding ingredient standards by cosmetic type, Japanese Cosmetic Industry Association ingredient display name list, INCI dictionary (The International Cosmetic Ingredient Handbook), non-pharmaceutical raw material standards, Japanese pharmacy standards, pharmaceutical additive standards , Ingredients described in Food Additives Official Regulations, etc., and Japanese and foreign patent gazettes and patent publication gazettes (including publication gazettes and republications) whose international patent classification IPC belongs to the classification of A61K7 and A61K8. It is possible to contain known cosmetic ingredients, pharmaceutical ingredients, food ingredients, etc. in known combinations, blending ratios, and blending amounts.

[Preparation of transdermal base material]
The transdermal base material can be prepared by the following steps using the above-mentioned premix (that is, containing a lipid peptide type compound, a specific alcohol, a polymer emulsifier, a heat resistance improver, and a desired component). Is.
a) A step of adding the above-mentioned specific transdermal absorption accelerator and, if desired, a surfactant to water, and heating and stirring at a temperature of room temperature or more and less than 100 ° C. to produce an o / w emulsion b) The above-mentioned o / w emulsion. And the above-mentioned premix and heated at a temperature of room temperature or more and less than 100 ° C. c) A step of cooling while stirring until the temperature becomes lower than the temperature in the above-mentioned heating step to form a gel. The cosmetic additive and the non-pharmaceutical additive can be added at the same time as the premix in the step b).

In the steps a) and b) above, 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 preferably performed while heating.
b) The heating and stirring time in the step is not particularly limited, but for example, the heating time can be appropriately selected from immediately after the addition of the dispersant to 6 hours, preferably from 10 minutes to 3 hours after the addition of the dispersant.

b) Following the step, cooling is performed while stirring until the liquid temperature becomes lower than the temperature in the b) step (c).
Here, the cooling temperature is room temperature to 80 ° C., preferably room temperature to 40 ° C.

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

[Synthesis Example 1: Synthesis of Lipid Peptide (N-Palmityl-Gly-His)]
In this example, the lipid peptide used as the gelling agent was placed in a 500 mL four-necked flask synthesized by the method shown below in an amount of 14.2 g (91.6 mmol) of histidine and 30.0 g of N-palmitoyl-Gly-methyl. (91.6 mmol) and 300 g of toluene were added, 35.3 g (183.2 mmol) of a 28% methanol solution of sodium methoxide as a base was added, and the mixture was heated to 60 ° C. in an oil bath and stirred for 1 hour. Then, the oil bath was removed, the mixture was allowed to cool to 25 ° C., and this solution was reprecipitated with 600 g of acetone and collected by filtration. 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 to neutralize the solid, and the solid was precipitated and filtered. Next, the obtained solid was dissolved in a mixture 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. Then, the precipitated solid was filtered. Further, the obtained solid was dissolved in a solvent of 120 g of tetrahydrofuran and 60 g of acetonitrile, heated to 60 ° C., stirred for 1 hour, cooled and filtered. The solid obtained here was washed with 120 g of water, filtered and dried under reduced pressure to obtain 26.9 g (yield 65) of white crystals of N-palmitoyl-Gly-His-free form (hereinafter, also simply referred to as Pal-GH). %) Was obtained.

[Production Example 1: Preparation of premix]
In a sample tube (No. 7, manufactured by Maruemu Co., Ltd.), Pal-GH, propylene glycol alginate (also referred to as PG alginate), 1,2-hexanediol, stearic acid and water obtained in the above synthetic example are shown. Weighed and charged so as to have the composition (mass%) shown in 1, and heated and stirred at 80 ° C. to obtain a Pal-GH dispersion (premix). The stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE Corporation.

[Example 1: Gelation of o / w emulsion]
Pure water is placed in a 300 mL tall beaker, and isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd. (also referred to as IPM)) has a concentration of 10% by mass, 20% by mass, 30% by mass, 40% by mass, or 50%. The mixture was added so as to be in mass%, and the mixture was heated and stirred at 80 ° C. for 10 minutes to prepare an o / w emulsion. The stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE Corporation.
Next, to each of the obtained o / w emulsions, the premix prepared in Production Example 1 heated to 70 ° C. was added so that the concentration of the o / w emulsion and the premix with respect to the total mass was 10% by mass. Further, heating and stirring were performed for 10 minutes (70 ° C., 200 rpm).
After the stirring was completed, the mixture was allowed to cool at room temperature (about 25 ° C.), and the presence or absence of gel formation was confirmed. The gel formation was confirmed by the test tube inversion method, and the state in which the fluidity of the dispersion was lost and the liquid did not flow down even when the tall beaker was inverted was judged as "gelation (○)", leading to gelation. Those that did not exist were evaluated as "x". The results obtained are shown in Table 2 and FIG.

[Example 2: Gelation of o / w emulsion to which Tween 20 is added]
Pure water is placed in a 300 mL tall beaker, and isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd. (also referred to as IPM)) has a concentration of 10% by mass, 20% by mass, 30% by mass, 40% by mass, or 50%. The mixture was added so as to be in mass%, and the mixture was heated and stirred at 80 ° C. for 10 minutes to prepare an o / w emulsion. The stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by AS ONE Corporation.
Next, for each of the obtained o / w emulsions, the premix prepared in Production Example 1 heated to 70 ° C. was prepared so that the concentration of the premix prepared in Production Example 1 was 10% by mass with respect to the total mass of the o / w emulsion, the premix and Tween 20. In addition, Tween 20 (manufactured by Wako Pure Chemical Industries, Ltd.) was further added so as to have a content of 0.5% by mass, and heating and stirring were carried out for 10 minutes (70 ° C., 200 rpm).
After the stirring was completed, the mixture was allowed to cool at room temperature (about 25 ° C.), and the presence or absence of gel formation was confirmed by the above-mentioned test tube inversion method. The results obtained are shown in Table 2.

As shown in Table 2, when Tween 20 was not added to the o / w emulsion, phase separation occurred without gelation when the IPM concentration was 50% by mass.
On the other hand, when Tween 20 was added to the o / w emulsion, gel formation was confirmed even when the IPM concentration was 50% by mass.

[Example 3: Sustained release test of o / w emulsion gel]
In the composition shown in Table 3, the premix prepared in Production Example 1, isopropyl myristate (IPM, concentration changes from 0 to 50% by mass), Tween 20, water, and sodium fluorescein (FNa) were added to a sample tube (No.). .7, It was put into a product manufactured by Maruemu Co., Ltd., heated and stirred (70 ° C., 10 minutes, 200 rpm), and then allowed to cool at room temperature (about 25 ° C.) to form a gel (formed gel: 500 mg). ).
To this, 10 mL of phosphate buffered saline (PBS, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was shaken at 37 ° C. and 30 rpm.
50 μL of PBS was collected over time, and the amount of FNa released into PBS from the o / w emulsion gel was quantified with a fluorometer. The fluorometer was measured at an excitation wavelength of 495 nm and a measurement wavelength of 521 nm. The FNa release rate (%) from the gel was calculated from the measured amount of FNa. The obtained results are shown in FIG. In addition, a photograph of each gel 24 hours after the start of this test is shown in FIG.

As shown in FIG. 2, regardless of the composition of the gel, 90% or more (almost 100%) release of FNa was confirmed by 3 hours after the addition of PBS and shaking. This result showed that FNa was encapsulated in a gel and could be sufficiently released under the condition of being in PBS.
In addition, even if the isopropyl myristate (IPM) concentration was changed, there was almost no change in the release behavior of FNa. This result indicated that the IPM encapsulated in the gel did not inhibit the release of FNa.
Then, as shown in FIG. 3, the gel immersed in PBS maintained the gel structure even after the lapse of 24 hours, and the result was obtained that the prepared o / w emulsion gel was a highly stable gel.

[Example 4: Skin permeability test of o / w emulsion gel (1)]
In the composition shown in Table 4, the premix prepared in Production Example 1, isopropyl myristate (IPM, concentration changes from 0 to 50% by mass), Tween 20, water, and sodium fluorescein (FNa) were added to a sample tube (No.). .7, It was put into (manufactured by Maruemu Co., Ltd.), heated and stirred (70 ° C., 10 minutes, 200 rpm), and then allowed to cool at room temperature (about 25 ° C.) to form a gel.

Yucatan Micro Pig (YMP) skin stored at -80 ° C (Japan Charles River Co., Ltd.) is thawed at room temperature (approximately 25 ° C) and then fat is removed (the thickness of the skin after fat removal is approximately 25 ° C). 2 mm), about 2 cm square YMP skin was prepared. 5.0 mL of phosphate buffered saline (PBS: pH 7.4 ° C., stirred at 500 rpm) was added to the receiver phase of the vertical Franz type diffusion cell (effective area: 0.785 cm ^{3), and the YMP skin was described.} (PBS skin surface temperature: 32.5 ° C.) was set. Each gel (500 mg) shown in Table 4 was placed in the donor phase of the vertical Franz type diffusion cell (see FIG. 4).
After 24 hours, the skin was taken out, the skin was finely chopped with a utility knife, 5 mL of distilled water was added thereto, ultrasonic waves were applied for 5 minutes, and FNa in the skin was extracted as an extract. The amount of FNa in the extract thus obtained was quantified with a fluorometer. The fluorometer was measured at an excitation wavelength of 495 nm and a measurement wavelength of 521 nm. The obtained results are shown in FIG. In addition, a skin section after 24 hours was observed using a fluorescence microscope. The obtained results are shown in FIG.

As shown in FIGS. 5 and 6, the use of lipid peptide-type compounds has resulted in FNa penetrating into the skin.
Then, as shown in FIG. 5, the result was obtained that the permeation amount of FNa into the skin increased as the IPM content in the gel increased.
Further, as shown in FIG. 6, it was confirmed that the fluorescence intensity in the skin section increased with the increase in the IPM content in the gel. This result can be said to support the result shown in FIG. 5, that is, the result that the permeation amount of FNa into the skin increases as the amount of IPM increases.

[Example 5: Skin permeability test of o / w emulsion gel (2)]
With the composition shown in Table 5, the premix prepared in Production Example 1, the transdermal absorption accelerator [isopropyl myristate (IPM), isopropyl palmitate (IPP), squalane (SQ), propylene glycol dicaprylate (GPD)). , Liquid paraffin (LP) and olive oil (OO), 30% by mass]), Tween20, water, and sodium fluorescein (FNa) were put into a sample tube (No. 7, manufactured by Maruemu Co., Ltd.) and heated and stirred (No. 7, manufactured by Maruemu Co., Ltd.). 70 ° C
After 10 minutes (200 rpm), the mixture was allowed to cool at room temperature (approximately 25 ° C.) to form a gel.
Separately, 0.75% by mass of carbopole, 30% by mass of isopropyl myristate (IPM), 0.1% by mass of sodium fluorescein (FNa), 0.5% by mass of Tween20, 68.65% by mass of water are sample tubes (No. .7, It was put into (manufactured by Maruemu Co., Ltd.), heated and stirred (70 ° C., 10 minutes, 200 rpm), and then allowed to cool at room temperature (about 25 ° C.) to form a gel.

Following the procedure shown in Example 4, a skin permeability test was carried out using a vertical Franz type diffusion cell. The FNa in the skin after 24 hours was extracted as an extract, and the amount of FNa in this extract was similarly quantified with a fluorometer. The obtained results are shown in FIG.
As shown in FIG. 7, the use of the lipid peptide type compound has obtained the result that FNa penetrates into the skin.
Then, as shown in FIG. 7, isopropyl myristate (IPM), isopropyl palmitate (IPP), squalane (SQ), propylene glycol dicaprylate (GPD), and liquid paraffin are used as transdermal absorption promoters in the Pal-GH-containing gel. Both of the gels using (LP) and olive oil (OO) were found to have an increased amount of FNa permeating into the skin as compared with the carbo-mer-containing gel (CE gel, IPM added).

[Example 6: Skin permeability test of o / w emulsion gel (3)]
With the composition shown in Table 6, the premix prepared in Production Example 1, squalane (concentration change from 0 to 30% by mass), Room20, water, and fluorescently labeled hyaluronic acid were added to a sample tube (No. 7, Co., Ltd.). (Manufactured by Maruem Co., Ltd.), heated and stirred (70 ° C., 10 minutes, 200 rpm), and then allowed to cool at room temperature (about 25 ° C.) to form a gel.
Separately, 0.75% by mass of carbopole, 0.1% by mass of fluorescently labeled hyaluronic acid, 0.5% by mass of Tween20, and 98.65% by mass of water were placed in a sample tube (No. 7, manufactured by Maruemu Co., Ltd.). The mixture was charged, heated and stirred (70 ° C., 10 minutes, 200 rpm), and then allowed to cool at room temperature (about 25 ° C.) to form a gel.

Yucatan Micro Pig (YMP) skin stored at -80 ° C (Japan Charles River Co., Ltd.) is thawed at room temperature (approximately 25 ° C) and then fat is removed (the thickness of the skin after fat removal is approximately 25 ° C). 2 mm), about 2 cm square YMP skin was prepared. 5.0 mL of phosphate buffered saline (PBS: pH 7.4 ° C., stirred at 500 rpm) was added to the receiver phase of the vertical Franz type diffusion cell (effective area: 0.785 cm ^{3), and the YMP skin was described.} (PBS skin surface temperature: 32.5 ° C.) was set. Each gel and carbopole gel (200 mg) shown in Table 5 were placed in the donor phase of the vertical Franz type diffusion cell (see FIG. 4). A 2: 2: 1 (v / v / v) mixture of PBS, acetonitrile and methanol was prepared and used as an extract.
After 24 hours, the skin was taken out, the skin was washed with the extract, and the extract was wiped off with Kimwipe (registered trademark). Then, the skin was cut into 16 parts with a utility knife, placed in a light-shielding microtube, 5 mL of the extract was added thereto, and the mixture was stirred with a vortex mixer for 3 hours to extract the fluorescently labeled hyaluronic acid in the skin. The amount of fluorescently labeled hyaluronic acid in the extract from which the fluorescently labeled hyaluronic acid was extracted was quantified with a fluorometer. Specifically, the extract is taken in a syringe, the filtrate passed through a polytetrafluoroethylene (PTFE) filter (0.45 μm) is stored in a light-shielding microtube until the time of measurement, and the fluorescence intensity of the filtrate is adjusted. The measurement was performed using a fluorescence spectrophotometer LS-55 (manufactured by Perkin Elmer, excitation wavelength: 495 nm, measurement wavelength: 521 nm).
The obtained results are shown in FIG.

As shown in FIG. 8, it has been obtained that hyaluronic acid permeates the skin by using the lipid peptide type compound.
As shown in FIG. 8, the Pal-GH-containing gel has a significantly increased amount of hyaluronic acid permeated into the skin and a significantly increased squalane content in the gel as compared with the carbo-mer (CP) -containing gel. As a result, the skin penetration amount of hyaluronic acid was further increased.
The results show that the transdermal base material (gel) of the present invention relaxed the barrier function of the stratum corneum and promoted the penetration of hyaluronic acid into the skin, and that the combination of squalane further enhanced the barrier function of the stratum corneum. It suggested that it enhances relaxation and further promotes hyaluronic acid penetration.

Claims (3)

A lipid peptide-type compound consisting of at least one of the compound represented by the following formula (1) or a pharmaceutically usable salt thereof, a polymer emulsifier, and an ester of a fatty acid having 8 to 20 carbon atoms, squalane, and olive oil. A transdermal absorption-promoting composition containing at least one transdermal absorption-promoting agent selected from the group consisting of propylene glycol dicaprylate and liquid paraffin.

(In the formula, R ¹ represents an aliphatic group having 15 carbon atoms ^{, R 2} represents a hydrogen atom, R ³ represents a − (CH ₂ ) _n −X group, n represents a number of 1, and X. Represents a 5-membered ring that may have two nitrogen atoms.) The transdermal absorption-promoting composition according to claim 1, wherein the transdermal absorption-promoting agent is isopropyl myristate. The transdermal absorption promoting composition according to claim 1, further comprising at least one alcohol selected from the group consisting of 1,2-alkanediol, 1,3-alkanediol and ethylene glycol monoalkyl ether.

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