JP6516083B2 - Percutaneous absorption substrate - Google Patents

Description

  The present invention relates to a percutaneous absorption substrate containing a low molecular weight lipid peptide type compound, which is useful as a substrate of a transdermal absorption preparation.

Administration of the active ingredient by means of transdermal absorption is a widely employed procedure along with oral administration and injection administration because of its advantages such as non-invasiveness and the possibility of adjusting the dose. And in the percutaneous absorption preparation, in order to promote absorption of an active ingredient, a method of blending a percutaneous absorption enhancer with a percutaneous absorption substrate is generally adopted.
In recent years, gelation products to which microemulsion technology has been applied from the viewpoint that it is possible to simultaneously mix active ingredients and transdermal absorption enhancers having different parenthesis / hydrophobicity and to improve the solubility and activity of the active ingredients. The application to skin absorption preparations has attracted attention. For example, w / o microemulsion gel [Non-patent documents 1 and 2] using lecithin and o / w microemulsion gel [Non-patent document 3] using thickeners such as carboxy polymer and xanthan gum have been proposed. .

On the other hand, hydrogels are useful as highly biocompatible gels because they use water as a medium, and they are used in a wide range of fields including disposable diapers, cosmetics, and daily necessities for fragrances.
Conventional hydrogels include polymer gels formed by cross-linking of polymer chains to form a three-dimensional network structure, which forms non-covalent bonds with media such as water and swells. Also, in recent years, hydrogels comprising self-assembly of relatively low molecular weight organic compounds have been found and variously studied. There have been many proposals for low molecular weight gelling agents which are amphiphilic compounds in which a long chain alkyl group which is a hydrophobic part and a hydrophilic part are combined. For example, those whose hydrophilic part is amino acid [Non-patent document 4], those of peptide [patent documents 1 and 2], monopolysaccharide [non-patent documents 5 and 6] or polyol [non-patent document 7] It 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.

WO 2009/005151 pamphlet WO 2009/005152 pamphlet

S. Murdan, Expart Opin. Drug Deliv. 2 (3) 489-505 (2005) S. Kantaria, G. D. Rees, M. J. lawrence, J. Controlled Release 60 344-365 (1999) H. Chen, X. Chang, D. Du, L. Li, H. Xu, X. Yang, International J. Pharm., 315, 52-58 (2006) Yumoto, Mariko. Mutsumi, Shirai. Hirofusa, Hanabusa, Kenji. Chemistry Letters, 33 (11), 1496-1497. Jong Hwa Jung, Georeg John, Mitsutosish Mausda, Kaname Yoshida, Seiji Shinnkai, and Toshimi Shimizu Langumir 2001, 17, 7229-7232 I. Hamachi, S. Kiyonaka, S. Shinkai, Tetrahedron Lett., 2001, 42, 6141. I. Hamachi, S. 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, Masaru Yoshida, Nobuyuki Tamaoki, Tohru Nakamura, Hideki Sakai, and Masahiko Abe, Adv. Funct. Mater. 2007, 17, 1507-1514

Many of the w / o or o / w microemulsion gels that have been proposed so far use a polymer compound as a gelling agent, and when applied to the skin, they stick or slip over time (residues of polymer compound It is pointed out that there is a possibility that) may occur.
In addition, when applying the percutaneously absorbable preparation using the above microemulsion gel to the skin, the percutaneous absorbability of the active ingredient also becomes a problem.

  An object of the present invention is to provide a novel percutaneous absorption substrate which uses a low molecular weight gelling agent to improve not only the feeling of use but also the percutaneous absorbability.

As a result of intensive studies to solve the above problems, the present inventors are composed of a low molecular weight lipid peptide or a pharmaceutically usable salt thereof as a gelling agent of a gel constituting a percutaneous absorption substrate. It has been found that a stable o / w emulsion gel containing a hydrophobic component can be obtained by employing a lipid peptide type compound.
In particular, even if it is a hydrophilic drug whose skin permeability has been inhibited by the barrier function of the stratum corneum (corneal layer) located in the outermost layer of the epidermis, the hydrophobic component isopropyl myristate etc. (transdermal absorption enhancer The structure of the stratum corneum is disturbed by the function of) to improve the permeability to the skin, that is, by using a hydrophobic component such as isopropyl myristate as one component of the percutaneous absorption substrate, the active component It has been found that it becomes a gel useful as a percutaneous absorption base material, which is expected to increase the amount of penetration into the skin of the present invention, leading to the completion of the present invention.

That is, according to the present invention, as a first aspect, a lipid peptide type compound comprising at least one of the compounds represented by the following formulas (1) to (3) or a pharmaceutically usable salt thereof, and a carbon atom The present invention relates to a transdermal absorption substrate containing at least one transdermal absorption enhancer selected from the group consisting of esters of fatty acids of several 8 to 20, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin, and water.
(Wherein, R ¹ represents an aliphatic group having 9 to 23 carbon atoms, R ² represents a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms) R ³ represents a — (CH ₂ ) _n —X group, n represents a number of 1 to 4, and X has 1 to 3 amino, guanidino, —CONH ₂ or 1 to 3 nitrogen atoms. Represents a fused heterocyclic ring composed of a 5-membered ring or a 6-membered ring, or a 5-membered ring and a
(Wherein, R ⁴ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{5 to} R ⁷ each independently represent a hydrogen atom, or a branched chain having 1 or 2 carbon atoms) 1 to 4 alkyl group or-(CH ₂ ) _n -X group, n is a number of 1 to 4 and X is an amino group, guanidino group, -CONH ₂ group, or 1 to 3 nitrogen atoms Represents a 5-membered ring or a 6-membered ring which may be substituted or a fused heterocyclic ring composed of a 5-membered ring and a 6-membered ring)
(Wherein R ⁸ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{9 to} R ¹² each independently represent a hydrogen atom, or a branched chain having 1 or 2 carbon atoms) 1 to 4 alkyl group or-(CH ₂ ) _n -X group, n is a number of 1 to 4 and X is an amino group, guanidino group, -CONH ₂ group, or 1 to 3 nitrogen atoms Represents a 5-membered ring or a 6-membered ring which may be substituted or a fused heterocyclic ring composed of a 5-membered ring and a 6-membered ring)

In addition, as a second aspect, the present invention relates to the percutaneous absorption base according to the first aspect, wherein the percutaneous absorption enhancer is isopropyl myristate.
And it is related with the percutaneous absorption base material as described in the 1st viewpoint or the 2nd viewpoint which further contains polyoxyethylene (20) sorbitan monolaurate (CAS registration number 9005-64-5) as the 3rd viewpoint.

The percutaneous absorption substrate of the present invention is at least selected from the group consisting of hydrophobic compounds (esters of fatty acids having 8 to 20 carbon atoms such as isopropyl myristate, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin) These o / w emulsions consist of an o / w emulsion composed of (1) and water stably gelled with a gelling agent (a lipid peptide type compound). Therefore, even when substances having different hydrophilicity / hydrophobicity, for example, a percutaneous absorption agent and an active ingredient, are simultaneously blended, a stable o / w emulsion gel can be formed by the gelling agent, and as a percutaneous absorption substrate It is useful.
The percutaneous absorption substrate of the present invention comprises a compound such as isopropyl myristate which is a percutaneous absorption enhancer. A hydrophobic compound such as isopropyl myristate, when applied to the skin, disturbs the structure of the stratum corneum (corneum) located in the outermost layer of the epidermis, thus improving the permeability of the hydrophilic compound (active ingredient) It is thought that. Therefore, the percutaneous absorption preparation in which the active ingredient is blended in the base material can be made excellent in the permeability of the active ingredient blended in the skin with a hydrophobic compound such as isopropyl myristate.

Further, the lipid peptide type compound used for the percutaneous absorption substrate of the present invention is a highly safe artificial low molecular weight compound composed of only lipid and peptide, and has high biosafety, in particular, a medical material or From the viewpoint of the high safety required for cosmetic materials and the like, it is very useful in the percutaneous absorption substrate in the above applications.
Furthermore, the dispersion liquid of the present invention may form a gel by gelling an o / w emulsion without using, for example, a conventionally proposed synthetic polymer type gel without using a cross-linking agent required at the time of formation. Since the reaction can be carried out, problems such as the remaining of unreacted substances such as unreacted crosslinking agent do not occur in the obtained gel. Moreover, the lipid peptide-type compound contained in the percutaneous absorption substrate can form a gel with an addition amount of only about 1% by mass, and has a low load when taken in the environment or in vivo.

  The percutaneous absorption substrate of the present invention is a gel which can be formed while stirring under relatively mild conditions of less than 100 ° C., and it is desired to eliminate the influence of heat as much as possible. Even when a commodity additive is added, a percutaneous absorption substrate can be manufactured without modifying the additive.

FIG. 1 is an external view showing the presence or absence of gel formation of five o / w emulsions in which the compounding amount of isopropyl myristate (IPM) prepared in Example 1 is changed. FIG. 2 is a graph showing the time-dependent change in FNa release rate (%) released into PBS from three o / w emulsion gels of varying amounts of isopropyl myristate (IPM) prepared in Example 3. It is. FIG. 3 shows a photograph before Fna release test and a photograph after a lapse of 24 hours of three o / w emulsion gels with different amounts of isopropyl myristate (IPM) prepared in Example 3. . FIG. 4 is a conceptual view of a device used for the skin permeability test of Example 4. FIG. 5 shows FNa content of skin extract after skin permeability test performed using three o / w emulsion gels with different amounts of isopropyl myristate (IPM) prepared in Example 4. FIG. FIG. 6 is a fluorescence micrograph of a skin section after skin permeability test performed using three o / w emulsion gels of varying amounts of isopropyl myristate (IPM) prepared in Example 4. FIG. FIG. 7 shows skins implemented using six o / w emulsion gels (Pal-GH-containing gel) and Carbopol-containing gel (IPM-containing gel) in which the percutaneous absorption enhancers prepared in Example 5 were variously changed. It is a figure which shows the amount of FNa of the extract of skin after a permeability test. FIG. 8 shows the skin after skin permeation test carried out using three o / w emulsion gels (Pal-GH containing gel) in which the blending amounts of the carbopol containing gel and squalane prepared in Example 6 were changed. It is a figure which shows the fluorescence hyaluronic acid amount of the extract of 1.

  The percutaneous absorption substrate of the present invention is selected from the group consisting of the aforementioned lipid peptide type compounds and esters of fatty acid having 8 to 20 carbon atoms such as isopropyl myristate, squalane, olive oil, propylene glycol dicaprylate and liquid paraffin And at least one transdermal absorption enhancer, and water, in particular, an o / w emulsion gel containing these.

[Lipid peptide type compound]
As a lipid peptide type compound used for the percutaneous absorption substrate of the present invention, compounds (lipid peptide) represented by the following formulas (1) to (3) or a pharmaceutically usable salt thereof (at a hydrophobic site) A low molecular weight compound having a certain lipid moiety and a peptide moiety which is a hydrophilic moiety 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 straight chain having 11 to 23 carbon atoms which may have 0 to 2 unsaturated bonds. It is desirable that it is an aliphatic group.
Specific examples of the lipid moiety (acyl group) composed of R ¹ and an adjacent carbonyl group include a lauroyl group, a dodecyl carbonyl group, a myristoyl group, a tetradecyl carbonyl group, a palmitoyl group, a margaroyl group, an oleoyl group, an eliidoyl group Groups, linoleoyl group, stearoyl group, baccenoyl group, octadecyl carbonyl group, arachidoyl group, eicosyl carbonyl group, behenoyl group, erkanoyl group, docosyl carbonyl group, lignoselyl group, nervonoyl group, etc., particularly preferred And lauroyl group, myristoyl group, palmitoyl group, margalloyl group, stearoyl group, oleoyl group, eliidoyl group and behenoyl group.

In the above formula (1), R ² contained in the peptide part represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms.
The alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms means 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 be possessed, 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 Etc.

The above R ² is preferably a hydrogen atom, or a C ¹ to C 3 alkyl group which may have a branched chain having 1 carbon atom, and more preferably a hydrogen atom.
An alkyl group having 1 to 3 carbon atoms which may have a branched chain having 1 carbon atom means an alkyl group having 1 to 3 carbon atoms in the main chain and having a branched chain having 1 carbon atom. And specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an i-butyl group or a sec-butyl group, preferably a methyl group, an i-propyl group, It is an i-butyl group or a sec-butyl group.

In Formula (1) above, R ³ represents a — (CH ₂ ) n —X group. In the above-(CH ₂ ) n -X group, n is a number of 1 to 4 and X is an amino group, a guanidino group, a -CONH ₂ group, or a 5-membered cyclic group having 1 to 3 nitrogen atoms A group or a 6-membered cyclic group, or a fused heterocyclic group composed of a 5-membered ring and a 6-membered ring.
In the-(CH ₂ ) n -X group representing the above R ³ , 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 an indole group, Preferably it is an imidazole group. In addition, in the above-(CH ₂ ) n -X group, n is preferably 1 or 2, and more preferably 1.
Accordingly, 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, a 3-carbamoyl group. Represents a butyl group, 2-guanidinoethyl group, 3-guanidinobutyl group, pyrrole methyl group, 4-imidazole methyl group, pyrazole methyl group, or 3-indole methyl group, more preferably 4-aminobutyl group, carbamoyl methyl group And 2-carbamoylethyl group, 3-guanidinobutyl group, 4-imidazole methyl group or 3-indolemethyl group, more preferably 4-imidazole methyl group.

  In the compound represented by the above formula (1), a lipid peptide particularly suitable as a lipid peptide type compound is a compound formed from the following lipid part and peptide part (amino acid aggregate part). In addition, as an abbreviation of an amino acid, alanine (Ala), asparagine (Asn), glutamine (Gln), glycine (Gly), histidine (His), isolocin (Ile), leucine (Leu), lysine (Lys), tryptophan (Trp) And valine (Val). Lauroyl-Gly-His, lauroyl-Gly-Gln, lauroyl-Gly-Asn, lauroyl-Gly-Trp, lauroyl-Gly-Lys, lauroyl-Ala-His, lauroyl-Ala-Gln, lauroyl-Ala-Asn, lauroyl -Ala-Trp, lauroyl-Ala-Lys; myristoyl-Gly-His, myristoyl-Gly-Gln, myristoyl-Gly-Asn, myristoyl-Gly-Trp, myristoyl-Gly-Lys, myristoyl-Ala-His, myristoyl-Ala -Gln, myristoyl-Ala-Asn, myristoyl-Ala-Trp, myristoyl-Ala-Lys; palmitoyl-Gly-His, palmitoyl-Gly-Gln, palmitoyl-Gly-A n, Palmitoyl-Gly-Trp, Palmitoyl-Gly-Lys, Palmitoyl-Ala-His, Palmitoyl-Ala-Gln, Palmitoyl-Ala-Asn, Palmitoyl-Ala-Trp, Palmitoyl-Ala-Lys; Stearoyl-Gly-His, Stearoyl-Gly-Gln, Stearoyl-Gly-Asn, Stearoyl-Gly-Trp, Stearoyl-Gly-Lys, Stearoyl-Ala-His, Stearoyl-Ala-Gln, Stearoyl-Ala-Asn, Stearoyl-Ala-Trp, Stearoyl- Ala-Lys.

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

In the above formula (2), R ⁴ represents an aliphatic group having 9 to 23 carbon atoms, and preferred specific examples include the same groups as those defined for R ^{1 described} above.
In the above formula (2), R ^{5 to} R ⁷ each independently represent a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms, or A CH ₂ ) n -X group is represented, desirably at least one or more of R ^{5 to} R ⁷ represent a-(CH ₂ ) n -X group. n represents a number of 1 to 4, and X is an amino group, a guanidino group, a -CONH ₂ group, or a 5- or 6-membered cyclic group which may have 1 to 3 nitrogen atoms, or a 5-membered ring And a fused heterocyclic group consisting of and a 6-membered ring. Here, preferred specific examples of R ^{5 to} R ⁷ are
The same groups as those defined above for R ² and R ³ can be mentioned.

  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 aggregate part). Myristoyl-Gly-Gly-His, myristoyl-Gly-Gly-Gln, myristoyl-Gly-Gly-Asn, myristoyl-Gly-Gly-Trp, myristoyl-Gly-Gly-Lys, myristoyl-Gly-Ala-His, myristoyl- Gly-Ala-Gln, myristoyl-Gly-Ala-Asn, myristoyl-Gly-Ala-Trp, myristoyl-Gly-Ala-Lys, myristoyl-Ala-Gly-His, myristoyl-Ala-Gly-Gln, myristoyl-Ala- Gly-Asn, myristoyl-Ala-Gly-Trp, myristoyl-Ala-Gly-Lys, myristoyl-Gly-His-Gly, myristoyl-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-Ala-Asn, 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.

  Among these, most preferable 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 is mentioned.

In the above formula (3), R ⁸ represents an aliphatic group having 9 to 23 carbon atoms, and preferred specific examples include the same groups as those defined for R ^{1 described} above.
In the above formula (3), R ^{9 to} R ¹² each independently represent a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms, or A CH ₂ ) n -X group is represented, desirably at least one or more of R ^{9 to} R ¹² represent a-(CH ₂ ) n -X group. n represents a number of 1 to 4, and X is an amino group, a guanidino group, a -CONH ₂ group, or a 5- or 6-membered cyclic group which may have 1 to 3 nitrogen atoms, or a 5-membered ring And a fused heterocyclic group consisting of and a 6-membered ring. Here, as preferable specific examples of R ^{9 to} R ^12, the same groups as those defined for R ² and R ^{3 above} can be mentioned.
Therefore, in the compound represented by the above formula (3), lauroyl-Gly-Gly-Gly-His, myristoyl-Gly-Gly-Gly-His, palmitoyl as a particularly preferable lipid peptide as a suitable lipid peptide type compound -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 It can be mentioned.

In the present invention, the compounding amount of the lipid peptide type compound is, for example, 0.01 to 30% by mass, preferably 0.05 to 10% by mass, with respect to the total mass of the gel (transdermal absorption substrate) to be obtained. More preferably, it is 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 gelled. As the agent, these compounds can be used alone or in combination of two or more.

[Percutaneous absorption enhancer]
The percutaneous absorption substrate of the present invention includes at least one member 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 percutaneous absorption enhancer. Use the compound.
Examples of the esters of fatty acids having 8 to 20 carbon atoms include isopropyl myristate, isopropyl palmitate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, and the like.
Among these percutaneous absorption enhancers, isopropyl myristate is preferably used.
In the present invention, the compounding amount of the above-mentioned compound is, for example, 1 to 50% by mass, preferably 10 to 50% by mass, with respect to the total mass of the obtained gel (percutaneous absorption substrate).

  Further, in addition to the above compounds, compounds which have conventionally been found to have an absorption promoting effect on the skin can be added as long as the effects of the present invention are not impaired. For example, caprylic 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 Lauric acid diethanolamide, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, propyl acetate, geraniol, thymol, eugenol, terpineol, L-menthol, borneolol , D-Limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerin monocaprylate, glycerin monocaprate, glycerin monolaurate Glycerin monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20, propylene glycol monolaurate, propylene glycol monocaprylate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene oleyl ether, poly Oxyethylene lauryl ether, jojoba oil, silicone oil, n-methyl-2-pyrrolidone, dl-camphor, mint oil and the like.

[Surfactant]
In the preparation of the transdermal absorption substrate of the present invention, that is, an o / w emulsion gel, the stability of the emulsion itself over time can be improved, and the uniform droplets of the above-mentioned transdermal absorption enhancer in the emulsion can be easily formed. In view of the above, it is preferable to incorporate a surfactant into the o / w emulsion.

As the above-mentioned surfactant, one having lower toxicity, particularly nontoxic one 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 still more preferably 8.0 to 17.0. When the HLB of the surfactant is in the above range, the dispersibility of the o / w emulsion can be improved.
Specific examples of such surfactants include sorbitan monofatty acid esters such as sorbitan monolaurate ["Span 20" (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 acid Polyoxyethyleneso, such as ethylene (20) sorbitan monostearate (HLB = 14.9) Tail fatty acid ester; and the like.
Among them, 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, with respect to the total mass of the obtained gel (transdermal absorption substrate).

[Premix]
The transdermal absorption substrate of the present invention (that is, an o / w emulsion gel) is a lipid peptide which is a gelling agent in an o / w emulsion containing the above-mentioned specific transdermal absorption promoter and water, optionally a surfactant. It is obtained by adding type compounds, stirring them at an elevated temperature, dispersing them uniformly, and leaving them to stand at room temperature (about 25 ° C.).
However, in consideration of application to cosmetics or quasi-drugs, the percutaneous absorption substrate of the present invention is more mild condition from the viewpoint of the thermal stability of the component etc. to be blended as an active ingredient of the percutaneous absorption preparation. Preferably it is prepared.
That is, the preparation process can be carried out under lower temperature conditions, specifically, the lipid peptide type compound can form an o / w emulsion gel at a temperature of less than 100 ° C., and the gel can be carried out while stirring for cooling. It is desirable to have the conditions that can be formed.
In view of these conditions, in the present invention, the lipid peptide type compound is not added as it is to the o / w emulsion, but is once dissolved and dispersed in a solvent having high solubility of the compound to form a solution (dispersion liquid) It is preferable to produce a percutaneously absorbable substrate by incorporating this into an o / w emulsion as a premix of a gelling material. By using such a premix, an o / w emulsion gel can be obtained even under the mild conditions described above.

  The above-mentioned premix has high solubility capable of dissolving the lipid peptide type compound at a high concentration, and among them, a highly safe solvent which can be used for quasi-drugs and cosmetics etc., alcohol: 1,2-alkane It is preferable to mix | blend diol, a 1, 3- alkanediol or ethylene glycol monoalkyl ether, and polymeric emulsifiers, such as an alginate ester which enables gel formation under low temperature and stirring. Further, from the viewpoint of improving the heat resistance of the gel, a heat resistance improver 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. Preferably, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol can be mentioned. More preferably, it is 1,2-pentanediol or 1,2-hexanediol.
Specific examples of the 1,3-alkanediol include 2-ethyl-1,3-hexanediol and 1,3-butanediol. Preferably, it is 2-ethyl-1,3-hexanediol.
Moreover, as said ethylene glycol monoalkyl ether, the alkyl group whose alkyl group is a methyl group, an ethyl group, a propyl group, or a butyl group is mentioned as a preferable thing, That is, monoethyl ether of ethylene glycol, monopropyl ether or monobutyl ether is mentioned. Be More preferably, ethylene glycol monopropyl ether or ethylene glycol monobutyl ether is used.

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

<Polymer emulsifier>
By adding a polymeric emulsifier to the above-mentioned premix, it is possible to give a gel even when stirring is carried out at the time of gel preparation. At least one selected from the group consisting of a graft polymer compound having a hydrophobic moiety grafted onto a hydrophilic main chain and a block polymer compound consisting of a hydrophobic constitutional unit and a hydrophilic constitutional unit as this polymeric emulsifier. A polymer compound can be blended.

Examples of the graft polymer compound having a hydrophobic site grafted to the hydrophilic main chain include xanthan gum, alginic acid ester, cellulose derivative and the like.
As a block polymer compound which consists of the said hydrophobic structural unit and a hydrophilic structural unit, an acrylic acid * alkyl methacrylate copolymer etc. are mentioned, for example.
In particular, as the polymer compound, a compound selected from the group consisting of carboxymethyl cellulose and alginic acid ester is preferable, and propylene glycol alginate is particularly preferable.

In the present invention, the blending amount of the above-mentioned high molecular weight emulsifier is, for example, 0.1 to 5% by mass, more preferably 0.2 to 0.5% by mass, with respect to the total mass of the obtained hydrogel.
The above-mentioned polymer emulsifying agent used in the present invention is at least one selected from the group consisting of graft polymer compounds and block polymer compounds, and these polymer compounds may be used alone or in combination of two or more. be able to.

<Heat resistance improver>
A fatty acid can be added to the above premix as a heat resistance improver.
The above fatty acids may include saturated fatty acids, unsaturated fatty acids and their salts listed below: caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid , Linear saturated fatty acids such as margaric acid, stearic acid, nonadecanoic acid, arachidic acid and 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, methyl docosanoic acid, 2-propyl-3-methylnonane Acid, methyl tridecanoic acid, dimethyl dodecanoic 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, heptylnonanoic acid, dimethyltetradecanoic acid, butylpentylheptanoic acid, trimethyltridecanoic acid, methyl Hexadecanoic acid, ethyl pentadecanoic acid, propyl tetradecanoic acid, butyl tridecanoic acid, pentyl dodecanoic acid, hexyl undecanoic acid, heptyl decanoic acid, methyl heptyl nonanoic acid, dipentyl heptanoic acid, methyl Putadecanoic acid, ethyl hexadecanoic acid, ethyl hexadecanoic acid, propyl pentadecanoic acid, butyl tetradecanoic acid, pentyl tridecanoic acid, hexyl dodecanoic acid, heptyl undecanoic acid, heptyl undecanoic acid, octyl decanoic acid, dimethyl hexadecanoic acid, methyl octyl nonanoic acid, methyl octa decanoic acid, ethyl Branched saturated fatty acids such as heptadecanoic acid, dimethyl heptadecanoic acid, methyl octyl decanoic acid, methyl nona decanoic acid, methyl nona decanoic acid, dimethyl octa decanoic acid, butyl heptyl nonanoic acid and salts thereof; octenoic acid, nonenic acid, decenoic acid, caproline Acid, undecylenic acid, lindelic acid, touhaku acid, lauroleic acid, tridecenoic acid, tous acid, myristoleic acid, pentadecenoic acid, hexedenic acid, palmitoleic acid, heptadecenoic acid, octa Linear monounsaturated fatty acids such as decenoic acid, oleic acid, nonadecenoic acid, gondinoic acid and salts thereof; methylheptenoic acid, methylnonenoic acid, methyl undecenoic acid, dimethyl decenoic acid, methyl dodecenoic acid, methyl tridecenoic acid, dimethyl dodecene Branched unsaturated mono-fatty acids such as acid, dimethyl tridecenoic acid, methyl octadecenoic acid, dimethyl heptadecenoic acid, ethyl octadecenoic acid and salts thereof; linoleic acid, linoleic acid, eleostearic acid, linolenic acid, Linear diunsaturated fatty acids or linear triunsaturated fatty acids such as linolenic elaidic acid, pseudoeleostearic acid, palinaric acid, arachidonic acid and salts thereof; Octic acid, nonic acid, decanoic acid, undecynic acid, dodecynic acid , Tridecynoic acid, tetradecynoic acid, pentadecynoic acid, heptadede Phosphate, octadecene acid, Nonadeshin acid, acetylene acid and their salts such as dimethyl octa decyne acid.
Here, the above-mentioned salts of fatty acids include, for example, sodium salts and potassium salts.

  Among the above fatty acids, preferred are at least one selected from the group consisting of saturated fatty acids having 10 to 20 carbon atoms and unsaturated fatty acids and salts of these fatty acids, preferably capric acid, undecanoic acid, lauric acid, Tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid and stearic acid can be mentioned. More preferably, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid are mentioned.

In the present invention, the compounding 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 used in the present invention is at least one selected from the above fatty acid group, and these fatty acids can be used alone or in combination of two or more.

<Production method of premix>
The above premix is prepared by adding an alcohol to the above-mentioned lipid peptide type compound and stirring at room temperature or more and less than 100 ° C., preferably 50 ° C. to 90 ° C., more preferably 60 ° C. Then, it can be manufactured by adding and stirring a heat resistance improver and additives for cosmetic and / or quasi drugs.

[Other additives]
In the percutaneous absorption substrate of the present invention, additives which can be generally used as cosmetic additives and additives for quasi-drugs can be blended as needed. Additives such as physiologically active substances and functional substances to be added to external preparations for skin such as cosmetics or quasi-drugs include, for example, oil base, moisturizer, touch improver, surfactant, polymer, thickening agent -Gelling agents, solvents, antioxidants, reducing agents, oxidizing agents, preservatives, antibacterial agents, bactericides, chelating agents, pH adjusters, acids, alkalis, powders, inorganic salts, ultraviolet absorbers, skin lightening agents, Vitamins and their derivatives, hair growth agents, blood circulation enhancers, stimulants, hormones, anti-wrinkle agents, anti-aging agents, anti-aging agents, cooling agents, warming agents, wound healing promoters, pain relievers, pain relief Agents, cell activators, plant / animal / microbe extracts, antipruritic agents, exfoliants, solubilizers, antiperspirants, fresheners, astringents, enzymes, nucleic acids, fragrances, dyes, colorants, dyes, pigments, anti-inflammatory agents, Anti-inflammatory agent, Anti-asthma, Anti-chronic obstructive pulmonary disease, Anti-allergy, Immunomodulator, Anti-infection Agents and antifungal agents.

Examples of these additive components include, as an oil base, cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, arachyl alcohol, behenyl alcohol, jojoba alcohol, chymyl alcohol, celakyl alcohol, batyl Higher (polyhydric) alcohols such as alcohol, 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 , Behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitooleic acid, oleic acid, linoleic acid, linoleic acid, erucic acid, docosahexene Higher fatty acids such as enoic acid, eicosapentaenoic acid, isohexadecanoic acid, anteisohenicoic acid, long chain branched fatty acid, dimer acid, hydrogenated dimer acid, and aluminum salts thereof, calcium salts, magnesium salts, zinc salts, Metal soaps such as potassium salt and sodium salt, and nitrogen-containing derivatives such as amide; liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane , Olive origin squalane, squalene, petrolatum, hydrocarbons such as solid paraffin; Candelilla wax, carnauba wax, rice wax, wax, beeswax, bee wax, montan wax, ozokerite, ceresin, paraffin wax, micro Waxes such as crystallin wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, ethylene / propylene copolymer; coconut oil, palm oil, palm kernel oil, safflower oil, olive oil, castor oil, avocado oil, sesame oil, tea oil, evening primrose oil , Wheat germ oil, macadamia oil, hazelnut oil, kucunut oil, rosehip oil, meadowfoam oil, persic oil, tea tree oil, pepper oil, corn oil, rapeseed oil, sunflower oil, sunflower oil, wheat germ oil, linseed oil, cotton seed oil, large Vegetable oils such as bean oil, peanut oil, rice bran oil, cocoa butter, shea butter, hydrogenated coconut oil, hydrogenated castor oil, jojoba oil, hydrogenated jojoba oil, etc .; tallow oil, milk fat, horse oil, egg yolk oil, mink oil, Animal fats and oils such as turtle oil; persimmon wax, lanolin, orange luff -Animal waxes such as oil; liquid lanolin, reduced lanolin, adsorbed purified lanolin, lanolin acetate, liquid lanolin acetate, hydroxyl lanolin, polyoxyethylene lanolin, lanolin fatty acid, rigid lanolin fatty acid, lanolin alcohol, lanolin alcohol acetate, acetic acid ( Lanolins such as cetyl and ranolyl esters; lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingophospholipids such as sphingomyelin, phosphatidic acid, phospholipids such as lysolecithin; hydrogenated soybean phospholipids Phospholipid derivatives such as partially hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, partially hydrogenated egg yolk phospholipids; cholesterol, dihydrocholesterol, Sterols such as sterols, dihydrolanosterols, phytosterols, cholic acid; sapogenins; saponins; cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate, cholesteryl isostearate, cholesteryl oleate, N-lauroyl-L-glutamic acid di (cholesteryl / Behenyl / octyldodecyl), N-lauroyl-L-glutamic acid di (cholesteryl / octyldodecyl), N-lauroyl-L-glutamic acid di (phytosteryl / behenyl / octyldodecyl), N-lauroyl-L-glutamic acid di (phytosteryl / octyl) Acyl sarcosine alkyl esters such as dodecyl), N-lauroyl sarcosine isopropyl, cholesteryl 12-hydroxystearate, macadamia nut oil Fatty acid cholesteryl, macadamia nut oil fatty acid phytosteryl, iso-stearate phytosteryl, soft lanolin fatty acid cholesteryl, hard lanolin fatty acid cholesteryl, long chain branched fatty acid cholesteryl, sterol esters such as long chain α-hydroxy fatty acid cholesteryl; phospholipid / cholesterol complex, phosphorus Lipid complexes such as lipid-phytosterol complex; octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl palmitate, octyldodecyl palmitate, cetyl octanoate, hexyldecyl octanoate, isotridecyl isononanoate, isononanoic acid Isononyl, octyl isononanonate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate Isostearyl neopentanoate, octyl dodecyl neodecanoate, oleyl oleate, octyl dodecyl oleate, octyl dodecyl licinoleate, octyl dodecyl lanolin fatty acid, hexyl decyl dimethyl octanoate, octyl dodecyl erbate, isostearic acid hydrogenated castor oil, ethyl oleate, Avocado oil Fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isanostearate, isopropyl lanolin fatty acid, diethyl sebacate, diisopropyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyl octyl sebacate, diisobutyl adipate, Monoalcohol carboxylic acid esters such as dioctyl succinate and triethyl citrate; Oxyates such as chill, diisostearyl malate, hydrogenated castor oil monoisostearic acid glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, 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 beicate ecosan diacetate, trimethylolpropane trioctanoate, triisostearic acid Trimethylolpropane, neopentyl glycol dioctanoate, neopentyl glycol dicaprate, 2-butyl-2-ethyl 1,3-propanediol dioctoate, dioleic acid ester Pyrene glycol, pentaerythrityl tetraoctanoate, hydrogenated rosin pentaerythrityl, ditrimethylolpropane triethylhexanoate, (isostearic acid / sebacic acid) ditrimethylolpropane, pentaerythrityl triethylhexanoate, (hydroxystearic acid / stearic acid / Rosin acid) dipentaerythrityl, diglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl nonaisostearate-10, deca (erucic acid / isostearic acid / licinoleic acid) polyglyceryl-8, (hexyl decanoic acid / sebacic acid) diglyceryl oligoester, distearin Acid glycol (ethylene glycol distearate), 3-methyl-1,5-pentanediol dineopentanoate, Polyhydric alcohol fatty acid esters such as 2,4-diethyl-1,5-pentanediol pentenoate; Diisopropyl dilinoleate, diisostearyl dimerdilinoleate, di (isostearyl / phytosteryl) dimerdilinoleate, diyne dilinoleate Merdilinoleic acid (phytosteryl / behenyl), dimerdilinoleic acid (phytosteryl / isostearyl / cetyl / stearyl / behenyl), dimer dilinoleyl dimer dilinoleate, dimer dilinoleyl diisostearate, dimer dilinoleyl hydrogenated rosin condensation , Dimer dilinoleic acid hydrogenated castor oil, derivatives of dimer acid or dimer diol such as hydroxyalkyl dimer di linoleyl 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), palmitic acid monoethanolamide (paltamide MEA), palmitic acid Fatty acid alkanolamides such as diethanolamide (paltamide DEA), coconut oil fatty acid methylethanolamide (cocamide methyl MEA); dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethyl siloxane, deca Methylcyclopentasiloxane), phenyl trimethicone, diphenyl dimethicone, phenyl dimethicone, stearoxypropyldimethylamine, ( Minoethylaminopropyl methicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino modified silicone such as aminopropyl dimethicone and amodimethicone, cationic modified silicone, polyether modified silicone such as dimethicone copolyol, polyglycerin Modified silicone, sugar modified silicone, carboxylic acid modified silicone, phosphoric acid modified silicone, sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cation modified and poly Ether modified silicone, amino modified and polyether modified silicone, alkyl modified and polyether modified Recone, silicones such as polysiloxane polyoxyalkylene copolymer; perfluorodecane, perfluorooctane, fluorine-based oils such as perfluoropolyether may be mentioned as preferred.

  Humectants and touch 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 copolymer, and polymers thereof; diethylene glycol monoethyl ether Glycol alkyl ethers such as (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dibutyl ether Water-soluble esters such as polyglyceryl-10, tetradecanedioic acid polyglyceryl-10; sugar alcohols such as sorbitol, xylitol, erythritol, mannitol, maltitol; glucose, fructose, galactose , Mannose, threose, xylose, arabinose, fucose, ribose, deoxyribose, maltose, trehalose, lactose, raffinose, gluconic acid, glucuronic acid, cyclodextrins (α-, β-, γ-cyclodextrin, and maltosylation, Modified cyclodextrins such as hydroxyalkylation), β-glucan, chitin, chitosan, heparin and derivatives, pectin, arabinogalactan, dextrin, dextran, glycogen Saccharides such as ethyl glucoside, glucosyl ethyl methacrylate polymers or copolymers and derivatives thereof; hyaluronic acid, sodium hyaluronate; chondroitin sulfate sodium; mucoitin sulfate, caronin sulfate, kerato sulfate, dermatan sulfate; Polysaccharides; fucoidan; tubevelose polysaccharides or naturally-occurring polysaccharides; organic acids such as citric acid, tartaric acid, lactic acid and their salts; urea and derivatives thereof; salts such as 2-pyrrolidone-5-carboxylic acid and its sodium; Trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, tyrosine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, Amino acids and salts thereof such as stain, methionine, leucine, isoleucine, valine, tryptophan, histidine and taurine; collagen, fish-derived collagen, atelocollagen, gelatin, elastin, collagenolytic peptides, hydrolyzed collagen, hydroxypropyl ammonium chloride hydrolyzed collagen Elastin degradation peptide, Keratin degradation peptide, Hydrolysis keratin, Conchiolin degradation peptide, Hydrolysis conchiolin, Silk protein degradation peptide, Hydrolysis silk, Lauroyl hydrolysis silk sodium, Soy protein degradation peptide, Wheat protein degradation peptide, Hydrolysis wheat protein , Protein peptides such as caseinolytic peptides, acylated peptides and derivatives thereof; palmitoyl oligopeptide, palmitoyl pentapeptide, palm Acylated peptides such as mitoyl tetrapeptide; silylated peptides; lactic acid bacteria culture solution, yeast extract, eggshell membrane protein, bovine submandibular mucin, hypotaurine, sesame lignan glycoside, glutathione, albumin, whey, choline chloride , Phosphoryl choline; placenta extract, air lastin, collagen, aloe extract, hamamelis water, lice water, kamoira extract, licorice extract, licorice extract, comfrey extract, silk extract, lice extract, yarrow extract, eucalyptus extract, meliloto extract, etc. Plant extracts, naturally occurring ceramides (types 1, 2, 3, 4, 5, 6), hydroxyceramides, pseudoceramides, glycosphingolipids, ceramides, and ceramides such as sugar ceramide-containing extracts are preferably mentioned.

As surfactant, anionic surfactant, nonionic surfactant, cationic surfactant, amphoteric surfactant, polymer surfactant etc. are mentioned as a preferable thing. As preferable examples of the surfactant, as anionic surfactants, fatty acid salts such as potassium laurate and potassium myristate; alkyl sulfate ester salts such as sodium lauryl sulfate, triethanolamine lauryl sulfate and ammonium lauryl sulfate; Polyoxyethylene alkyl sulfates such as sodium laureth sulfate and triethanolamine laureth sulfate; sodium cocoyl methyl taurine, sodium cocoyl methyl taurine, sodium lauroyl methyl taurine, sodium myristoyl methyl taurine, sodium lauroyl methyl alanine, sodium lauroyl sarcosine, lauroyl sarcosine tri Acyl N-methyl amino acid salts such as ethanolamine, lauroyl glutamic acid sodium methylalanine; cocoyl Acyl amino acid salts such as sodium rutaminate, cocoyl glutamate triethanolamine, sodium lauroyl glutamate, sodium myristoyl glutamate, sodium stearoyl glutamate, palmitoyl aspartic acid ditriethanolamine, cocoylalanine triethanolamine, etc .; polyoxyethylene alkyl ethers such as sodium laureth acetate Acetate salt; Succinate ester salts such as sodium lauroyl monoethanolamide succinate; fatty acid alkanolamide ether carboxylate salt; acyl lactate salt; polyoxyethylene fatty amine sulfate salt; fatty acid alkanolamide sulfate salt; Fatty acid glyceride sulfates such as: alkyl benzene polyoxyethylene sulfate; α-olefin Olefin sulfonates such as sodium vinesulfonate; alkyl sulfosuccinates such as disodium lauryl sulfosuccinate and dioctyl sodium sulfosuccinate; disodium laureth sulfosuccinate; sodium monolauroyl monoethanolamide polyoxyethylene sulfosuccinate sodium lauryl polypropylene glycol sulfosuccinic acid Alkyl ether sulfosuccinates such as sodium; alkylbenzene sulfonates such as sodium tetradecylbenzene sulfonate, triethanolamine tetradecylbenzene sulfonate; alkyl naphthalene sulfonates; alkane sulfonates; α-sulfo fatty acid methyl ester salts; Acyl isethionate; alkyl glycidyl ether sulfonate; alkyl sulfoacetate; laureth Alkyl ether phosphate such as sodium dilaurate phosphate, sodium trilaure phosphate, sodium monolaurate phosphate, alkyl phosphate ester salt such as potassium lauryl phosphate; casein sodium; alkyl aryl ether phosphate; fatty acid amide Ether phosphates; Phospholipids such as phosphatidyl glycerol, phosphatidyl inositol, phosphatidic acid, etc .; Silicone-based anionic surfactants such as carboxylic acid-modified silicone, phosphoric acid-modified silicone, sulfuric acid-modified silicone, etc .; As nonionic surfactants Laureth (polyoxyethylene lauryl ether), cetes (polyoxyethylene cetyl ether), steareth (polyoxyethylene stearyl ether), and behenes (polyoxyethylene lauryl ether); Polyoxyethylene alkyl ethers of various polyoxyethylene addition numbers such as ethylene behenyl ether), isosteares (polyoxyethylene isostearyl ether), octyl dodeces (polyoxyethylene octyl dodecyl ether), etc .; polyoxyethylene alkyl phenyl ether Polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil monoisostearate, polyoxyethylene hydrogenated castor oil triisostearate, polyoxyethylene hydrogenated castor oil monopyroglutamic acid monoisostearate diester, Castor oil such as polyoxyethylene hydrogenated castor oil and maleic acid and hydrogenated castor oil derivative; polyoxyethylene phytosterol; polyoxyethylene cholesterol; Ryoxyethylene cholestanol; polyoxyethylene lanolin; polyoxyethylene reduced lanolin; polyoxyethylene / polyoxypropylene cetyl ether, polyoxyethylene / polyoxypropylene 2-decyl tetradecyl ether, polyoxyethylene / polyoxypropylene monobutyl ether (Polyoxyethylene / polyoxypropylene hydrogenated lanolin, polyoxyethylene / polyoxypropylene glycerin ether, etc .; polyoxyethylene / polyoxypropylene alkyl ether; polyoxyethylene / polyoxypropylene glycol; PPG-9 diglyceryl etc.) Poly (glycerin) polyoxypropylene glycol; glyceryl stearate, glyceryl isostearate, glyceryl palmitate, myris Glyceryl folate, glyceryl oleate, coconut oil fatty acid glyceryl, mono-cottonseed oil fatty acid glycerin, glycerol monoerucate, glycerol sesquioleate, glycerol α, α'-pyroglutamate oleate, glycerol monostearate glycerine fatty acid partial ester such as malic acid Class: polyglyceryl stearate-2, 3, 4, 5, 6, 6, 8, 10, polyglyceryl-6 distearate, 10, polyglyceryl tristearate-2, polyglyceryl decastearate-10, isostearin 2, 3, 4, 5, 6, 6, 8, 10, polyglyceryl diisostearate (diglyceryl diisostearate), 3, 10, polyglyceryl triisostearate 2, tetraisostearate acid Liglyceryl-2, polyglyceryl decaisostearate-10, polyglyceryl oleate-2, 3, 4, 5, 6, 6, 8, 10, polyglyceryl-6 dioleate, polyglyceryl trioleate-2, decolein Polyglyceryl fatty acid esters such as polyglyceryl acid 10; ethylene glycol monofatty acid esters such as ethylene glycol monostearate; propylene glycol monofatty acid esters such as propylene glycol monostearate; pentaerythritol partial fatty acid esters; sorbitol partial fatty acid esters; maltitol Partial fatty acid ester; maltitol ether; sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbita Sorbitan fatty acid esters such as monostearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexyl acid, diglycerol sorbitan tetra-2-ethylhexyl acid, sucrose fatty acid ester, methyl glucoside fatty acid ester, undecylenic acid Sugar derivative partial ester such as trehalose; alkyl glucoside such as caprylyl glucoside; alkyl polyglycoside; lanolin alcohol; reduced lanolin; polyoxyethylene distearate, polythylene glycol disisostearate, polyoxyethylene monooleate, polyoxy acid Polyoxyethylene fatty acid mono and diesters such as ethylene dioleate; polyoxyethylene / propylene glycol fatty acid ester; Polyoxyethylene glycerine fatty acid esters such as polyoxyethylene monooleate such as ethylene glycol monostearate, polyoxyethylene glycerol mono isostearate, polyoxyethylene glycerol tri isostearate; polyoxyethylene sorbitan monolaurate, poly Polyoxyethylene sorbitan fatty acid esters such as oxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetraoleate, etc .; polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol Monooleate, polyoxyethylene sorbitol pentaoleate, polyoxyethylene sorbitol monoste Polyoxyethylene methyl glucoside fatty acid ester; polyoxyethylene alkyl ether fatty acid ester; polyoxyethylene sorbitol oil and fats such as polyoxyethylene sorbitol beeswax; isostearyl glyceryl ether, chymyl alcohol, sera Alkyl glyceryl ethers such as carbyl alcohol and vatyl alcohol; polyhydric alcohol alkyl ether; polyoxyethylene alkylamine; tetrapolyoxyethylene · tetrapolyoxypropylene-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 (coca DEA), lauric acid monoethanolamide (lauramide MEA), lauric acid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acid monoethanolamide (paltamide MEA), palmitic acid diethanolamide (paltamide DEA) Fatty acid alkanolamides such as coconut oil fatty acid methylethanolamide (cocamidomethyl MEA); alkyldimethylamine oxides such as lauramine oxide, cokami oxide, stearamine oxide, behenami oxide; alkyl ethoxy dimethyl amine oxide; Ethylene alkyl mercaptan; polyether modified silicone such as dimethicone copolyol, polysiloxane / oxyalkylene copolymer, polyg Silicone-based nonionic surfactants such as lysine modified silicone, sugar modified silicone, etc .; Cationic surfactants such as behentrimonium chloride, stealtrimonium chloride, cetrimonium chloride, alkyltrimethyls such as lauryltrimonium chloride Ammonium chloride; alkyltrimethyl ammonium bromide such as stearyltrimonium bromide; dialkyldimethyl ammonium chloride such as distearyldimonium chloride, dicocodimonium chloride; fatty acid amidoamines such as stearamidopropyldimethylamine, stearamidoethyl diethylamine and salts thereof; Alkyl ether amines such as roxypropyldimethylamine and salts or quaternary salts thereof; ethyl sulfate long chain branched fatty acids (12 to 31) amino Fatty acid amide type quaternary ammonium salt such as ropirethyl dimethyl ammonium, ethyl lanolin sulfate fatty acid aminopropyl ethyl dimethyl ammonium; polyoxyethylene alkylamine and its salt or quaternary salt; alkylamine salt; fatty acid amide guanidinium salt; alkyl Ether amine monium salt; alkyl trialkylene glycol ammonium salt; benzalkonium salt; benzethonium salt; pyridinium salt such as cetyl pyridinium chloride; imidazolinium salt; alkyl isoquinolinium salt; dialkyl morpholinium salt; Amino-modified silicones such as aminopropyl dimethicone and amodimethicone, cation-modified silicones, cation-modified and polyether-modified silicones, amino-modified and polyether-modified silicones Silicone-based cationic surfactants such as corn; etc .; Amphoteric surfactants such as N-alkyl-N, N-dimethyl amino acid betaines such as lauryl betaine (lauryl dimethylaminoacetic acid betaine); cocamidopropyl betaine, lauramide Fatty acid amide alkyl-N, N-dimethyl amino acid betaines such as propyl betaine; imidazoline type betaines such as sodium cocoamphoacetate, sodium lauroamphoacetate; alkyl sulfobetaines such as alkyl dimethyl taurine; sulfuric acid type betaines such as alkyl dimethylaminoethanol sulfate ester; Phosphoric acid type betaines such as alkyl dimethylamino ethanol phosphate ester; Sphingophospholipids such as phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, sphingomyelin etc Quality, lysolecithin, hydrogenated soybean phospholipids, partially hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, partially hydrogenated egg yolk phospholipids, phospholipids such as hydroxylated lecithin; silicone amphoteric surfactants etc .; polymer interface Preferred examples of the active agent include polyvinyl alcohol, sodium alginate, starch derivatives, tragacanth gum, acrylic acid / methacrylic acid alkyl copolymer, and various silicone surfactants.

Examples of polymers, thickeners and gelling agents include guar gum, locust bean gum, queen seeds, carrageenan, galactan, gum arabic, gum arabic, tara gum, tamarind, farcereran, karaya gum, troy roy, caragam, tragant gum, pectin, pectate and sodium Salts such as salts, salts such as alginic acid and sodium salts, mannan starches such as rice, corn, potato, wheat etc. xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid and its salts, xanthan gum, pullulan, gellan gum, chitin Chitosan, agar, cassava extract, chondroitin sulfate, casein, collagen, gelatin, albumin; methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy propi Cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and salts thereof such as sodium, methyl hydroxypropyl cellulose, sodium cellulose sulfate, dialkyldimethyl ammonium cellulose cellulose, crystalline cellulose, cellulose cellulose derivatives such as cellulose powder; soluble starch, carboxymethyl starch, methyl Starch polymers such as hydroxypropyl starch and methyl starch, starch derivatives such as hydroxypropyl trimonium chloride starch, corn starch aluminum octenyl succinic acid; sodium alginate, alginic acid derivative such as alginic acid propylene glycol ester, polyvinyl polyvinyl chloride (PVP), polyvinyl alcohol (PVA), vinylpydridone and vinylal Copolymer, polyvinyl methyl ether; polyethylene glycol, polypropylene glycol, polyoxyethylene / polyoxypropylene copolymer; (methacryloyloxyethyl carboxybetaine / alkyl methacrylate) copolymer, (acrylates / stearyl acrylate / ethylamine ethyl methacrylate) Oxide) Amphoteric methacrylate ester copolymer such as copolymer; (dimethicone / vinyl dimethicone) crosspolymer, (alkyl acrylate / diacetone acrylamide) copolymer, (alkyl acrylate / diacetone acrylamide) copolymer AMP; polyvinyl acetate partial chain , Maleic acid copolymer; vinyl pyrrolidone / dialkylaminoalkyl methacrylate copolymer; acrylic resin alkanolamine; Water dispersible polyester; polyacrylamide; polyacrylic acid ester copolymer such as ethyl polyacrylate, carboxy vinyl polymer, polyacrylic acid and salts thereof such as sodium salt thereof, acrylic acid / methacrylic acid ester copolymer; Acrylic acid / methacrylic acid alkyl copolymer; cationized cellulose such as polyquaternium-10, diallyldimethyl ammonium chloride / acrylamide copolymer such as polyquaternium-7, acrylic acid / diallyldimethylammonium chloride copolymer such as polyquaternium-22 Acrylic acid / diallyldimethyl ammonium chloride / acrylamide copolymer such as polyquaternium-39, acrylic acid / cationized methacrylate copolymer, acrylic acid / cationized methacrylate Acid amide copolymer, acrylic acid / methyl acrylate / methacrylamidopropyl trimethyl ammonium copolymer such as polyquaternium-47, choline chloride methacrylic acid ester polymer, cationized oligosaccharide, cationized dextran, guar hydroxypropyltrimonium Cationic polysaccharides such as chloride; polyethyleneimine; cationic polymer; polymer of 2-methacryloyloxyethyl phosphorylcholine such as polyquaternium-51 and copolymer with butyl methacrylate copolymer; acrylic resin emulsion, ethyl polyacrylate Polymer emulsions such as emulsion, polyacrylic alkyl ester emulsion, polyvinyl acetate resin emulsion, natural rubber latex, synthetic latex, etc .; nitrocellulose; And various copolymers; various silicones; various silicone-based copolymers such as acrylic-silicone graft copolymers; various fluorinated polymers; 12-hydroxystearic acid and its salts; dextrin palmitate, dextrin myristate Dextrin fatty acid esters, etc .; Silica, fumed silica (ultrafine particulate silica), magnesium aluminum silicate, sodium magnesium silicate, metal soap, metal salt of dialkyl phosphate, bentonite, hectorite, organically modified clay mineral, Sucrose fatty acid esters and fructooligosaccharide fatty acid esters are mentioned as preferred. Among the above examples, cellulose and derivatives thereof, alginic acid and salts thereof, polyvinyl alcohol, hyaluronic acid and salts thereof, or collagen are preferable.

  As the solvent, 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 isopentyl diol; diethylene glycol mono Glycol ethers such as ethyl ether (ethoxy diglycol), 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 Ethylene glycol monoethyl ether acetate Glycol ether esters such as diethylene glycol monoethyl ether acetate, propylene glycol monoethyl ether acetate; glycol esters such as diethoxyethyl succinate, ethylene glycol disuccinate; benzyl alcohol, benzyloxyethanol, propylene carbonate, dialkyl carbonate, Acetone, ethyl acetate, N-methyl pyrrolidone; toluene etc. are mentioned as a preferable thing.

  Antioxidants include tocopherols such as tocopherol (vitamin E) and tocopherol acetate; BHT, BHA; gallic acid derivatives such as propyl gallate; vitamin C (ascorbic acid) and / or its derivatives; erythorbic acid and its derivatives; Sulfites such as sodium sulfite; bisulfites such as sodium bisulfite; thiosulfates such as sodium thiosulfate; metabisulfite; thiotaurine, hypotaurine; thioglycerol, thiourea, thioglycolic acid, cysteine hydrochloride Can be mentioned as

  As a reducing agent, thioglycolic acid, cysteine, cysteamine etc. are mentioned as a preferable thing.

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

  As preservatives / antibacterial agents / bactericidal agents, hydroxybenzoic acids such as methylparaben, ethylparaben, propylparaben, butylparaben and salts or esters thereof; salicylic acid; sodium benzoate; phenoxyethanol; methyl chloroisothiazolinone, methylisothiazo Isothiazolinone derivatives such as linone; imidazolinium urea; dehydroacetic acid and salts thereof; phenols; halogenated bisphenols such as triclosan, acid amides, quaternary ammonium salts; trichlorocarbanide, zinc pyrithione, benzalkonium chloride, chloride Benzethonium, sorbic acid, chlorhexidine, chlorhexidine gluconate, halocarban, hexachlorophen, hinokitiol; phenol, isopropylphenol, cresol, Lumpur, para chlorophenol, phenylphenol, other phenols such as phenylphenol sodium; phenylethyl alcohol, photosensitive Motorui, be mentioned as antibacterial zeolite, silver ion.

  As a chelating agent, edetate (ethylenediamine tetraacetate) such as EDTA, 2Na, EDTA3Na, EDTA4Na, etc .; hydroxyethylethylenediamine triacetate such as HEDTA3Na; pentethate (diethylenetriamine pentaacetate); phytic acid; etidronate etc Salts of phosphonic acid and its sodium salt; sodium oxalate; polyamino acids such as polyaspartic acid and polyglutamic acid; sodium polyphosphate, sodium metaphosphate, phosphoric acid; sodium citrate, citric acid, alanine, dihydroxyethyl glycine Gluconic acid, ascorbic acid, succinic acid and tartaric acid are mentioned as preferred.

  pH adjusters / acids / alkalis such as citric acid, sodium citrate, lactic acid, sodium lactate, potassium lactate, glycolic acid, glycolic acid, acetic acid, sodium acetate, malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloric acid, sulfuric acid Monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, arginine Sodium hydroxide, potassium hydroxide, aqueous ammonia, guanidine carbonate and ammonium carbonate are mentioned as preferred.

As powder, mica, talc, kaolin, sericite, montmorillonite, kaolinite, mica, muscovite, phlogopite, synthetic mica, pyromica, biotite, permiculite, magnesium carbonate, calcium carbonate, aluminum silicate, silicate Barium, calcium silicate, magnesium silicate, strontium silicate, metal salt of tungstate, 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, bengara, yellow iron oxide, black iron oxide, ultramarine blue, bitumen, carbon black, titanium oxide, fine particles and ultrafine Titanium oxide, zinc oxide, fine particles and ultrafine particle zinc oxide, alumina, silica, fumed silica (ultrafine particle anhydrous silica), mica titanium, fish scale foil, boron nitride, photochromic pigment, synthetic fluorine phlogopite, fine particle composite powder Body, inorganic powder of various sizes and shapes such as gold and aluminum, and these are treated with various surface treatment agents such as silicone such as hydrogen silicone and cyclic hydrogen silicone or other silane or titanium coupling agent Inorganic powder such as powder hydrophobized or hydrophilized by conducting the above; starch, cellulose, nylon powder, polyethylene powder, polymethyl methacrylate powder,
Polystyrene powder, copolymer resin powder of styrene and acrylic acid, polyester powder, benzoguanamine resin powder, polyethylene terephthalate, polymethyl methacrylate laminate powder, polyethylene terephthalate, aluminum epoxy laminate powder, etc., urethane powder, silicone powder, Teflon (registered trademark) 2.) Preferred are organic powders of various sizes and shapes such as powders, surface-treated powders, and organic-inorganic composite powders.

  As inorganic salts, sodium chloride-containing salts such as sodium chloride, common salt, rock salt, sea salt, natural salt, etc .; potassium chloride, aluminum chloride, calcium chloride, magnesium chloride, zinc oxide, ammonium chloride; sodium sulfate, aluminum sulfate, Aluminum potassium sulfate (alum), aluminum ammonium sulfate, barium sulfate, calcium sulfate, potassium sulfate, magnesium sulfate, zinc sulfate, iron sulfate, copper sulfate; sodium phosphates such as phosphoric acid 1Na · 2Na · 3Na, phosphoric acid Preferred are potassiums, calcium phosphates and magnesium phosphates.

Examples of UV absorbers include para-aminobenzoic acid, para-aminobenzoic acid monoglycerin ester, N, N-dipropoxy-p-aminobenzoic acid ethyl ester, N, N-diethoxy-p-aminobenzoic acid ethyl ester, ethyl N, N-dimethyl-p-aminoaminobenzoate Benzoic acid ultraviolet absorbers such as esters, N, N-dimethyl paraaminobenzoic acid butyl ester, N, N-dimethyl paraaminobenzoic acid ethyl ester, etc .; anthranilic acid ultraviolet absorbers such as homomentyl-N-acetyl anthranilate; salicylic acid And salicylic acid ultraviolet rays such as sodium salt amyl salicylate, menthyl salicylate, homomentyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, etc. Absorbent; Octylcinnamate, Ethyl-4-isopropylcinnamate, Methyl-2,5-diisopropylcinnamate, Ethyl-2,4-diisopropylcinnamate, Methyl-2,4-diisopropylcinnamate, Propyl-p-methoxy Cinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, 2-ethylhexyl p-methoxycinnamate (octyl para-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate (cinoxate), cyclohexyl -P-Methoxycinnamate, ethyl-α-cyano-β-phenylcinnamate, 2-ethylhexyl α-cyano-β-phenylcinnamate (octocrine), glyceryl mono-2-ethylhexanoyl-diparamethoxy Cinnamic acid-based UV absorbers such as cinnamate, 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 (oxybenzon-3), 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone -5-sulfonate, 4-phenylbenzophenone, 2-ethylhexyl-4'-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone and the like Benzophenone UV absorber 3- (4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-methylphenylbenzo Triazole; 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole; 2- (2'-hydroxy-5'-methylphenylbenzotriazole;dibenzalazine; dianiso ylmethane; 5- (3, 3- Dibenzoylmethane derivatives such as dimethyl-2-norbornylidene) -3-pentan-2-one; 4-t-butylmethoxydibenzoylmethane; octyl triazone; urocanic acid derivatives such as urocanic acid and ethyl urocanic acid; 2'-hydroxy-5'-methylphenyl) benzotriazole, 1- (3,4-dimethoxyphen) Yl) -4,4-dimethyl-1,3-pentanedione, dimethoxybenzylidene ethylidenedioxy oxoimidazolidine acid 2-hydantoin derivatives ethylhexyl, phenyl benzimidate Serve tetrazole sulfonic acid,
Terephthalylidene dicamphorsulfonic acid, drometrizole trisiloxane, methyl anthranilate, rutin and its derivatives, oryzanol and its derivatives are mentioned as preferred.

  As a skin lightening agent, hydroquinone glycosides such as arbutin and α-arbutin and esters thereof; ascorbic acid phosphate ester salt such as ascorbic acid, ascorbic acid phosphate sodium salt and ascorbic acid phosphate magnesium salt, ascorbic acid Ascorbic acid fatty acid esters such as tetraisopalmitate esters, ascorbic acid alkyl ethers such as ascorbic acid ethyl ether, ascorbic acid glucosides such as ascorbic acid-2-glucoside and fatty acid esters thereof, ascorbic acid sulfuric acid esters, tocopheryl ascorbic acid phosphate Ascorbic acid derivatives, etc .; Kojic acid, ellagic acid, tranexamic acid and its derivatives, ferulic acid and its derivatives, placenta extract, glutathione, oryzanol, butyl resor Nord, oil-soluble Kamomiraekisu, oil-soluble licorice extract, Nishikawa willow extract, be mentioned as saxifrage extract, and the like plant extracts are preferred.

  Vitamins and derivatives thereof include vitamin A such as retinol, retinol acetate, retinol palmitate, thiamine hydrochloride, thiamine sulfate, riboflavin acetate, riboflavin acetate, pyridoxine hydrochloride, pyridoxine dioctanoate, pyridoxine dipalmitate, Flavin adenine dinucleotide, cyanocobalamin, folic acid, nicotinic acid such as nicotinamide and benzyl nicotinate, and vitamin B groups such as choline; vitamin C such as ascorbic acid and salts thereof such as sodium; vitamin D; α, α, Vitamin Es such as β, γ, δ-tocopherol; Other vitamins such as pantothenic acid, biotin etc. Ascorbic acid phosphate sodium salt Ascorbic acid phosphate sodium salt and ascorbic acid phosphate magnesium salt etc Ascorbic acid fatty acid esters such as corrubinic acid tetraisopalmitate, ascorbyl stearate, ascorbyl palmitate, ascorbyl dipalmitate, ascorbic acid alkyl ethers such as ascorbic acid ethyl ether, ascorbic acid glucosides such as ascorbic acid 2-glucoside and the like The fatty acid ester, ascorbic acid derivatives such as tocopheryl ascorbyl phosphate; vitamin derivatives such as tocopherol nicotinate such as tocopherol nicotinate, tocopherol acetate, tocopherol linoleate, tocopherol ferulate, tocopherol phosphate, tocotrienol, various other vitamin derivatives Is mentioned as a preferable thing.

  As hair growth agents, circulation enhancers and stimulants, plant extracts and tinctures such as cerebrum extract, capsicum tincture, cassava tincture, cassava extract, kanthalistinc etc .; capsaicin, nonyl valenylamide, zingerone, ictamol, tannic acid , Borneol, cyclanelate, cinnarizine, trazoline, acetylcholine, verapamil, cepharanthine, γ-oryzanol, vitamin E and tocopherol nicotinate / tocopherol acetate, etc., γ-oryzanol, nicotinic acid, nicotinic acid, nicotinic acid benzyl ester · Inositol hexanicotinate, derivatives such as nicotine alcohol, allantoin, photosensitizer 301, photosensitizer 401, capronium chloride, pentadecanoic acid monoglyceride, flavanonol derivative Conductors, stigmasterol or stigmastanol and its glycoside, minoxidil are mentioned as preferred.

As hormones, estradiol, estrone, ethynyl estradiol, cortisone, hydrocortisone, prednisone etc. are mentioned as a preferable thing. Other medicinal agents such as anti-wrinkle agent, anti-aging agent, tempering agent, cooling agent, warming agent, wound healing promoting agent, irritation reducing agent, analgesia agent, cell activator and the like include retinols, retinoic acid, retinoic acid Acid tocopheryl; lactic acid, glycolic acid, gluconic acid, fruit acid, salicylic acid and derivatives thereof such as glycosides / esterified products, hydroxycapric acid, long chain α-hydroxy fatty acid, long chain α-hydroxy fatty acid cholesteryl α- or β-hydroxy acids and derivatives thereof; γ
-Aminobutyric acid, γ-amino-β-hydroxybutyric acid; carnitine; carnosine; creatinine; ceramides, sphingosines; caffeine, xanthine etc. and derivatives thereof; Antioxidant / Reactive oxygen scavenging agents such as platinum nanocolloids and fullerenes; catechins; flavones such as quercetin; isoflavones; gallic acid and ester sugar derivatives; Derivatives such as rutin and glycosides; derivatives such as hesperidin and glycosides; lignan glycosides; licorice extract related substances such as glabridin, glabren, liquiritin, isoliquiritin; lactoferrin; Ngeroru; menthol, perfume substances and their derivatives such as cedrol; capsaicin, vanillin and derivatives thereof; insect repellent such as diethyl toluamide; complexes with physiologically active substance and cyclodextrin are mentioned as preferred.

Examples of plant / animal / microbe extracts include iris extract, ashitaba extract, asunaro extract, asparagus extract, avocado extract, amacha extract, almond extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract and ginkgo extract , Ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract, umbilical root extract, Egeria extract, Echinacea leaf extract, Einacea leaf extract, Aedesium extract, Augan extract, Auaba extract, Auaba extract, Auula extract, a barley extract, a ginseng extract, a ginseng extract, an apricot extract, an apricot extract , Dutch mustard extract, orange extract, dried sea water, seaweed extract, persimmon leaf extract, persimmon leaf extract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed Luk, Cuckin Extract, Kamomila Extract, Oil-soluble Kamomila Extract, Carrot Extract, Kawara Yomogi Extract, Oytomugi Extract, Karkade Extract, Licorice Extract, Licorice Extract, Oil-Soluble Licorice Extract, Kiwi Extract, Kiow Extract, Chrysanthemum Extract, Cinna Extract, Cucumber Extract, Kiriha Extract, Guanosine, guava extract, kudin extract, gardenia extract, mulberry extract, Clara extract, walnut extract, chestnut extract, grapefruit extract, clematis extract, black rice extract, black sugar extract, black vinegar, chlorella extract, mulberry extract, gentian extract, black tea extract Extract, yeast extract, kobo extract, coffee extract, burdock extract, rice extract, rice fermented extract, rice bran fermented extract, rice germ oil, comfrey extract, Lagen, bilberry extract, saicin extract, saiko extract, saiole extract, saffron extract, salvia extract, saffron extract, sasa extract, sashimi extract, sashimi extract, sashisho extract, shiitake extract, sicosa extract, sicense extract, Sesame extract, Sinocino extract, Sinocium extract Extract, Jatoba extract, Peony extract, Shochu extract, Shobu root extract, birch extract, White chrysanthemum extract, spinach extract, Svenia extract, Stevia extract, Stevia fermented article, Nishikawayanagi extract, Azalea extract, Azalea extract, Azalea extract, Azalea extract , Peppermint extract, sage extract, zenia extract, senkyu extract, seinburi extract, souhakuhi extract, rhubarb extract, dye Extract of rosewood extract, thyme extract, thyme extract, dandelion extract, lichen extract, tea extract, clove extract, chigaya extract, chimpanzee extract, tea tree oil, tea tree oil, persimmon tea extract, red pepper extract, toucan extract, toucan senka extract, toenin extract, spruce extract, tokudami extract, tomato Extract, Natto extract, Carrot extract, Garlic extract, Novara extract, Hibiscus extract, Bacmondo extract, Lotus extract, Lotus extract, Parsley extract, Birch extract, Honey, Hamameris extract, Parietalia extract, Hikiokoshi extract, Bisavolol, Hinoki extract, Bifidobacteria extract, Loquat extract, Fukino dandelion extract, Fukinotou extract, Bokuryou extract, butcherbroom extract, grape extract, grape seed extract, propolis, pomace extract, Scutellaria extract, peppermint extract, bodyspout extract, button extract, hop extract, mosquito extract, pine extract, marronie extract, sphagnum extract, mukuroshi extract, melissa extract, mozuku extract, peach extract, cornflower extract, eucalyptus extract, yukinoshita extract, yusu extract, lily extract, lily extract Yokinin Extract, Yomogi Extract, Lavender Extract, Green Tea Extract, Eggshell Membrane Extract, Apple Extract, Rooibos Tea Extract, Lishi Extract, Lettuce Extract, Lettuce Extract, Lemon Extract, Forsythia Extract, Scutellaria Extract, Rose Extract, Rosemary Extract, Roman Camellia Extract, Royal Jelly Extracts and extracts such as Waremochi extract are mentioned as preferred.

  As an antipruritic agent, diphenhydramine hydrochloride, chlorpheniramine maleate, camphor, substance-P inhibitor and the like can be mentioned.

  Examples of the exfoliating agent for solubilization include salicylic acid, sulfur, resorcinol, selenium sulfide, pyridoxine and the like.

  As an antiperspirant, chlorhydroxy aluminum, aluminum chloride, zinc oxide, zinc paraphenol sulfonate etc. are mentioned.

  Examples of the cooling agent include menthol, methyl salicylate and the like.

  As the astringent agent, citric acid, tartaric acid, lactic acid, aluminum potassium sulfate, tannic acid and the like can be mentioned.

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

  As nucleic acids, ribonucleic acid and its salts, deoxyribonucleic acid and its salts, and adenosine triphosphate disodium are mentioned as preferable.

  As a flavoring agent, acetyl cedrene, amyl cinnamaldehyde, allyl amyl glycolate, β-ionone, isoesuper, isobutyl quinoline, iris oil, ylone, indole, yylan oil, undecanal, undecenal, γ-undecanal, Estragole, Eugenol, Okemos, Opoponax Resinoid, Orange Oil, Eugenol, Orlanthiol, Galac Solid, Carvacrol, L-Carvone, Camphor, Cannon, Carrot Seed Oil, Clove Oil, Methyl Cyanate, Geraniol, Geranil Nitrile , Isobornyl acetate, geranyl acetate, dimethylbenzylcarbyl acetate, styrylyl acetate, cedryl acetate, heptynyl acetate, p-t-butylcyclohexyl acetate, betberryyl acetate, benzyl acetate, Linalyl acetate, isopentyl salicylate, benzyl salicylate, sandalwood oil, santarol, cyclamenaldehyde, cyclopentadecanolide, methyl dihydrojasmonate, dihydromyrsenol, jasmine absolute, jasmine lactone, cis-jasmone, citral, citronenol, citronellal , Cinnamon bark oil, 1,8-cineole, cinnamaldehyde, styrene resinoid, cedar wood oil, cedrene, cedrol, celery seed oil, thyme oil, damascone, damasenone, thymol, tuberos absolute, decanal, decalactone, terpineol, γ-terpinene , Triplar, nerol, nonanal, 2, 6 nonadienol, nona lactone, patchouli alcohol, vanilla Lute, vanillin, basil oil, patchouli oil, hydroxycitronellal, alpha-pinene, piperitone, phenethyl alcohol, phenylacetaldehyde, petit gren oil, hexyl cinnamaldehyde, cis-3-hexenol, peru balsam, vetiver oil, vetiverol, peppermint oil , Pepper oil, heliotropin, bergamot oil, benzyl benzoate, borneol, myrresinoid, musk ketone, methyl nonyl acetaldehyde, γ-methyl yonone, menthol, L-menthol, L-menthol, e-eucalyptus oil, β-ionone, lime oil, lavender oil Synthetic flavors and natural flavors such as D-limonene, linalool, rillal, lilyal, lemon oil, rose absolute, rose oxide, rose oil, rosemary oil, various essential oils, etc. Various compounded flavors are mentioned as being preferred.

As a pigment, a coloring agent, a dye and a pigment, brown 201, black 401, purple 201, purple 401, blue 1, blue 2, blue 201, blue 202, blue 203, blue 203, blue 204 , Blue 205, Blue 403, Blue 404, Green 201, Green 202, Green 204, Green 205, Green 3, Green 401, Green 402, Green 102, 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 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, Red 230 No. 1, Red 230-2, Red 231, Red 232, Red 3, No. 401, Red 404, Red 405, Red 501, Red 502, Red 503, Red 504, Red 504, Red No. 505, red No. 506, orange No. 201, orange No. 203, orange No. 204, orange No. 205, orange No. 206, orange No. 207, orange No. 401, orange No. 402, orange No. 403, yellow No. 201, yellow No. 202- No. 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 406 , Yellow No. 407, yellow No. 5 etc .; other acid dyes such as Acid Red 14; Arianor Sienna Brown, Arianor Madder Red, Arian r Steel Blue, base dyes such as Arianor Straw Yellow; HC Yellow
2. Nitro dyes such as HC Yellow 5, HC Red 3,4-hydroxypropylamino-3-nitrophenol, N, N'-bis (2-hydroxyethyl) -2-nitro-p-phenylenediamine, HC Blue 2, Basic Blue 26 and the like; Disperse dyes; Inorganic white pigments such as titanium dioxide and zinc oxide; Inorganic red pigments such as iron oxide (bengal) and iron titanate; Inorganic brown pigments such as γ-iron oxide; Inorganic yellow pigments such as yellow iron oxide and yellow earth Inorganic black pigments such as black iron oxide and low-order titanium oxide; inorganic purple pigments such as mango violet and cobalt violet; inorganic green pigments such as chromium oxide, chromium hydroxide and cobalt titanate; ultramarine blue, bituminous blue Inorganic blue pigments such as; titanium oxide coated mica, titanium oxide Pearl pigments such as bismuth oxychloride bismuth coated titanium oxide coated talc, pigmented titanium oxide coated mica, bismuth oxychloride, fish scale foil, metal powder pigments such as aluminum powder, kappa powder, gold and the like; surface treated inorganic and metal powder pigments; zirconium, barium Or organic pigments such as aluminum lake; surface-treated organic pigments; anthraquinones such as astaxanthin and alizarin; anthocyanidins; β-carotene; Natural dyes and dyes such as bixin, flavones, betacyanidin, henna, hemoglobin, lycopene, riboflavin, rutin; p-phenylenediamine, toluene-2, 5- Oxidation dye intermediates such as amines, o-, m- or p-aminophenols, m-phenylenediamines, 5-amino-2-methylphenols, resorcins, 1-naphthol, 2, 6-diaminopyridines etc. and salts thereof And couplers; autooxidative dyes such as indoline; dihydroxyacetone is mentioned as being preferred.

  Anti-inflammatory agents and anti-inflammatory agents include glycyrrhizinic acid and derivatives thereof, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, guaiazulene, allantoin, indomethacin, ketoprofen, ibuprofen, diclofenac, loxoprofen, cericosquib, infliximab, etanercept, zinc oxide, acetic acid hydrocortisone And prednisone, diphedramine hydrochloride, chlorpheniramine maleate, and plant extracts such as peach leaf extract and mulberry leaf extract are preferable.

Anti-asthma, anti-chronic obstructive pulmonary disease, anti-allergy, immuno-regulatory agents such as aminophylline, theophyllines, steroids (fluticasone, beclomethasone etc), leukotriene antagonists, thromboxane inhibitors, intal, β2 stimulant (Formoterol, salmeterol, albuterol, tulobuterol, clenbuterol, epinephrine, etc.), tiotropium, ipratropium, dextromethorphan, dimemorphane, bromhexine, tranilast, ketotifen, azelastine, chlorpheniramine, mequitazine glucidorolimus, Cytokine modulators, interferons, omalizumab, protein / antibody preparations are mentioned as preferred.

  As the anti-infective agent and antifungal agent, oseltamivir, zanamivir and itraconazole are mentioned as preferable ones. Other than these, cosmetic raw material standard, cosmetic type compounding ingredient standard, Japan Cosmetics Industry Association Association ingredient display name list, INCI dictionary (The International Cosmetic Ingredient Dictionary and Handbook), quasi-drug raw material standard, Japanese Pharmacopoeia, pharmaceutical additive standard Ingredients described in Food Additives Official Standards, etc., and in Japanese and other foreign patent publications and patent publication gazettes (including published gazettes / republications) where the 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 the known combination and blending ratio / blending amount, such as the ingredients mentioned above.

[Preparation of Transdermal Absorbent Substrate]
The percutaneous absorption substrate of the present invention comprises the above-mentioned premix (that is, a lipid peptide type compound, a specific alcohol, a high molecular weight emulsifier, a heat resistance improver and further a desired component) according to the following steps: It can be prepared.
a) adding the above-mentioned specific percutaneous absorption enhancer, optionally surfactant to water, 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 o / w emulsion And mixing the above-mentioned premix and heating at a temperature of room temperature or more and less than 100 ° C. c) cooling with stirring to a temperature lower than the temperature in the heating step to form a gel Cosmetic additives and quasi-drug additions can be added simultaneously with the premix in the step b).

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

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

  Hereinafter, the present invention will be described in detail by way of examples and test examples, but the present invention is not limited to these examples.

Synthesis Example 1: Synthesis of lipid peptide (N-palmitoyl-Gly-His)
In this example, the lipid peptide used as the gelling agent was 14.2 g (91.6 mmol) of histidine, 30.0 g of N-palmitoyl-Gly-methyl in a 500 mL four-necked flask synthesized by the following method. (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 stirring was continued for 1 hour. The oil bath was then removed and allowed to cool to 25 ° C., the solution reprecipitated with 600 g of acetone and filtered off. 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 6 N hydrochloric acid was added thereto to neutralize it to precipitate a solid, which was 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 to 60 ° C. to 30 ° C. Thereafter, the precipitated solid was filtered. Furthermore, the solid obtained was dissolved in 120 g of tetrahydrofuran and 60 g of acetonitrile, heated to 60 ° C., stirred for 1 hour, cooled, and filtered. The solid obtained here is washed with 120 g of water, filtered and dried under reduced pressure, and white crystals of N-palmitoyl-Gly-His free form (hereinafter, also simply referred to as Pal-GH), 26.9 g (yield 65) %) Got.

Production Example 1: Preparation of Premix
In a sample tube (No. 7, manufactured by Maruem Co., Ltd.), Pal-GH, propylene glycol alginate (also referred to as alginic acid PG) obtained in the above synthesis example, 1,2-hexanediol, stearic acid and water It weighed and injected so that it might become composition (mass%) shown to 1, and it heat-stirred at 80 degreeC, and obtained the Pal-GH dispersion liquid (premix). 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 put in a 300 mL tall beaker, and isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd. (also referred to as IPM)) is added thereto at a concentration of 10% by mass, 20% by mass, 30% by mass It was added so as to be% by mass, and heated and stirred at 80 ° C. for 10 minutes to prepare an o / w emulsion. 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 was 10% by mass with respect to the total mass of the o / w emulsion and the premix. Further, heating and stirring were performed for 10 minutes (70 ° C., 200 rpm).
After completion of the stirring, the mixture was allowed to cool at room temperature (approximately 25 ° C.) to confirm the presence or absence of gel formation. The gel formation is confirmed by the test tube inversion method, the fluidity of the dispersion is lost, and the state in which the liquid does not flow even if the tall beaker is inverted is judged as "gelation (○)", and gelation is reached. Those that did not exist were evaluated as "x". The obtained results are shown in Table 2 and FIG.

[Example 2: Gelation of o / w emulsion added with Tween 20]
Pure water is put in a 300 mL tall beaker, and isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd. (also referred to as IPM)) is added thereto at a concentration of 10% by mass, 20% by mass, 30% by mass It was added so as to be% by mass, and heated and stirred at 80 ° C. for 10 minutes to prepare an o / w emulsion. Stirring was performed at 200 rpm using a LABORATORY HIGH MIXER manufactured by As One Corporation.
Next, for each o / w emulsion obtained, the concentration of the premix prepared in Production Example 1 heated to 70 ° C. is 10% by mass with respect to the total mass of the o / w emulsion, premix and Tween 20. In addition to the above, Tween 20 (manufactured by Wako Pure Chemical Industries, Ltd.) was added to the same 0.5 mass%, and heating and stirring were performed for 10 minutes (70 ° C., 200 rpm).
After completion of the stirring, it was allowed to cool at room temperature (approximately 25 ° C.), and the presence or absence of gel formation was confirmed by the above-mentioned test tube inversion method. The obtained results 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: Slow Release Test of o / w Emulsion Gel]
Premix prepared in Preparation Example 1, isopropyl myristate (IPM, concentration change at 0 to 50% by mass), Tween 20, water, and sodium fluorescein (FNa) in the composition shown in Table 3 as a sample tube (No .7, made by Marumu Co., Ltd., heated and stirred (70.degree. C., 10 minutes, 200 rpm), allowed to cool at room temperature (approximately 25.degree. C.), and allowed to gel (gel formed: 500 mg) ).
To this, 10 mL of phosphate buffered saline (PBS, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and shaken at 37 ° C. and 30 rpm.
50 μl of PBS was collected over time, and the amount of FNa released from the o / w emulsion gel into PBS was quantified with a fluorometer. The fluorometer was measured at an excitation wavelength of 495 nm and a measurement wavelength of 521 nm. The percent release of FNa from the gel was calculated from the amount of FNa measured. The obtained result is shown in FIG. Moreover, the 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 (approximately 100%) release of FNa was confirmed by 3 hours after the addition of PBS and shaking. The results showed that FNa was encapsulated in a gel and was sufficiently releasable under the condition of in PBS.
In addition, even when the concentration of isopropyl myristate (IPM) was changed, almost no change was observed in the release behavior of FNa. This result indicated that IPM contained in the gel did not inhibit the release of FNa.
And as shown in FIG. 3, the gel immersed in PBS maintained the structure of the gel after 24 hours, and the result that the prepared o / w emulsion gel was a highly stable gel was obtained.

[Example 4: Skin Permeability Test of o / w Emulsion Gel (1)]
Premix prepared in Preparation Example 1, isopropyl myristate (IPM, concentration change at 0 to 50% by mass), Tween 20, water, and sodium fluorescein (FNa) in the composition shown in Table 4 as a sample tube (No .7, made by Marumu Co., Ltd., heated and stirred (70.degree. C., 10 minutes, 200 rpm), allowed to cool at room temperature (approximately 25.degree. C.), and allowed to form a gel.

Thaw Yucatan Micro Pig (YMP) skin (Nippon Charles River Co., Ltd.) stored at -80 ° C at room temperature (approximately 25 ° C), and then remove fat (the thickness of the skin after fat removal is approx. 2 mm), about 2 cm square of YMP skin was prepared. Add 5.0 mL of phosphate buffered saline (PBS: pH 7.4 ° C, stirring at 500 rpm) to the receiver phase of a vertical Franz diffusion cell (effective area: 0.785 cm ³ ) to obtain the YMP skin. (The temperature of the skin surface of PBS: 32.5 ° C.) was set. Each gel (500 mg) shown in Table 4 was placed in the donor phase of the vertical Franz diffusion cell (see FIG. 4).
After 24 hours, the skin was removed, the skin was minced with a cutter knife, 5 mL of distilled water was added thereto, and ultrasonic waves were applied for 5 minutes to extract FNa in the skin as an extract. The amount of FNa in the extract thus obtained was quantified by a fluorometer. The fluorometer was measured at an excitation wavelength of 495 nm and a measurement wavelength of 521 nm. The obtained result is shown in FIG. Moreover, the skin section after 24 hours passed was observed using a fluorescence microscope. The obtained result is shown in FIG.

As shown in FIG. 5, as the IPM content in the gel increased, the result was obtained that the amount of penetration of FNa into the skin increased.
Further, as shown in FIG. 6, an increase in fluorescence intensity in the skin section was confirmed as the IPM content in the gel increased. This result supports the result shown in FIG. 5, that is, the result that the penetration amount of FNa into the skin increases with the increase of the IPM amount.

Example 5 Skin Permeability Test of o / w Emulsion Gel (2)
Premix prepared in Preparation Example 1, percutaneous absorption enhancer [isopropyl myristate (IPM), isopropyl palmitate (IPP), squalane (SQ), propylene glycol dicaprylate (GPD), and compositions shown in Table 5] Liquid paraffin (LP) and olive oil (OO), 30% by mass], Tween 20, water, and sodium fluorescein (FNa) were introduced into a sample tube (No. 7, manufactured by Maruem Co., Ltd.), and heated and stirred ( After 70 ° C., 10 minutes, 200 rpm), it was allowed to cool at room temperature (approximately 25 ° C.) to form a gel.
Separately, 0.75% by mass of Carbopol, 30% by mass of isopropyl myristate (IPM), 0.1% by mass of sodium fluorescein (FNa), 0.5% by mass of Tween 20, 68.65% by mass of water .7, made by Marumu Co., Ltd., heated and stirred (70.degree. C., 10 minutes, 200 rpm), allowed to cool at room temperature (approximately 25.degree. C.), and allowed to form a gel.

Following the procedure set forth in Example 4, a skin penetration test was conducted using a vertical Franz diffusion cell. After 24 hours, FNa in the skin was extracted as an extract, and the amount of FNa in the extract was similarly quantified with a fluorometer. The obtained result is shown in FIG.
As shown in FIG. 7, in a Pal-GH containing gel, isopropyl myristate (IPM), isopropyl palmitate (IPP), squalane (SQ), propylene glycol dicaprylate (GPD), liquid paraffin (PIP) as a percutaneous absorption accelerator The results showed that the penetration amount of FNa to the skin was increased as compared with the Carbopol containing gel (CE gel, added with IPM) for both of the gels employing LP) and olive oil (OO).

[Example 6: Skin Permeability Test of o / w Emulsion Gel (3)]
Premix prepared in Production Example 1 with composition shown in Table 6, squalane (0 to 30% by mass
), Tween 20, water, and fluorescently labeled hyaluronic acid are introduced into a sample tube (No. 7, manufactured by Maruem Co., Ltd.), heated and stirred (70 ° C., 10 minutes, 200 rpm), and then room temperature ( The mixture was allowed to cool at approximately 25 ° C. to form a gel.
Separately, 0.75% by mass of Carbopol, 0.1% by mass of fluorescently labeled hyaluronic acid, 0.5% by mass of Tween 20, and 98.65% by mass of water in a sample tube (No. 7, manufactured by Marem Co., Ltd.) After charging and heating (70 ° C., 10 minutes, 200 rpm), the mixture was allowed to cool at room temperature (approximately 25 ° C.) to form a gel.

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

As shown in FIG. 8, in the Pal-GH-containing gel, the permeation amount of hyaluronic acid to the skin is significantly increased and the squalane content in the gel is increased, as compared to the carbopol (CP) -containing gel. As a result, the skin penetration amount of hyaluronic acid was further increased.
This result indicates that the transdermal absorption substrate (gel) of the present invention alleviates the barrier function of the stratum corneum and promotes the penetration of hyaluronic acid into the skin, and the formulation of the stratum corneum barrier function further by blending squalane. It was suggested to enhance relaxation and further promote the penetration of hyaluronic acid.

Claims (3)

A lipid peptide type compound comprising at least one of the compounds represented by the following formulas (1) to (3) or a pharmaceutically usable salt thereof:
From an o / w emulsion gel comprising at least one transdermal absorption enhancer 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, and water Become a percutaneous absorption substrate.
(Wherein, R ¹ represents an aliphatic group having 9 to 23 carbon atoms, R ² represents a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may have a branched chain having 1 or 2 carbon atoms) R ³ represents a — (CH ₂ ) _n —X group, n represents a number of 1 to 4, and X has 1 to 3 amino, guanidino, —CONH ₂ or 1 to 3 nitrogen atoms. Represents a fused heterocyclic ring composed of a 5-membered ring or a 6-membered ring, or a 5-membered ring and a
(Wherein, R ⁴ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{5 to} R ⁷ each independently represent a hydrogen atom, or a branched chain having 1 or 2 carbon atoms) 1 to 4 alkyl group or-(CH ₂ ) _n -X group, n is a number of 1 to 4 and X is an amino group, guanidino group, -CONH ₂ group, or 1 to 3 nitrogen atoms Represents a 5-membered ring or a 6-membered ring which may be substituted or a fused heterocyclic ring composed of a 5-membered ring and a 6-membered ring)
(Wherein R ⁸ represents an aliphatic group having 9 to 23 carbon atoms, and R ^{9 to} R ¹² each independently represent a hydrogen atom, or a branched chain having 1 or 2 carbon atoms) 1 to 4 alkyl group or-(CH ₂ ) _n -X group, n is a number of 1 to 4 and X is an amino group, guanidino group, -CONH ₂ group, or 1 to 3 nitrogen atoms Represents a 5-membered ring or a 6-membered ring which may be substituted or a fused heterocyclic ring composed of a 5-membered ring and a 6-membered ring) The transdermal absorption substrate according to claim 1, wherein the transdermal absorption enhancer is isopropyl myristate. The percutaneously absorbable substrate according to claim 1 or 2, further comprising polyoxyethylene (20) sorbitan monolaurate (CAS registration number 9005-64-5).