JP7047261B2 - Compositions with vesicles containing acylproline - Google Patents

Description

The present invention relates to a vesicle composition containing a vesicle having a constituent film containing a specific acylproline and an amphipathic substance, and a cosmetic containing the composition.

Active ingredients with low affinity for the skin have poor skin permeability, and in order to obtain the effect, a method of promoting penetration into the skin must be used. It has been reported that a vesicle having a closed vesicle structure formed by aggregation of amphipathic molecules has an aqueous phase inside and contains the above-mentioned active ingredients and the like to improve skin permeability. (For example, Patent Documents 1 and 2, Non-Patent Document 1). The technology for promoting skin penetration using vesicles requires high penetration amount and skin retention (skin concentration), but the effect is often insufficient depending on the vesicle composition and inclusions, and depending on the vesicle component. It has also been reported that permeation is suppressed. The use of additives in the vesicles to promote the penetration of the active ingredient has also been considered, but some additives may destroy the vesicle structure, and especially in the case of surfactants, the membrane may be destroyed by desorption. It is known that the encapsulated drug leaks out of the vesicle and greatly affects the stability (Non-Patent Document 2). In addition, the additives often impair the usability, which is important for cosmetics.

Further, it is generally known that when a lipophilic substance is used together with a vesicle preparation, it is easily distributed (easily incorporated) into a membrane. In the cosmetic composition, in addition to the active ingredients that have the above-mentioned effects on the skin, preservatives are essential for the purpose of preventing the decay of the preparation, but parabens and phenoxyethanol, which are typical preservatives, are vesicles. Easy to be distributed to. Therefore, in the vesicle preparation, the concentration of the preservative in the aqueous layer tends to decrease (Non-Patent Document 3), and the preservative effect may not be sufficiently obtained. On the other hand, some preservatives cause skin irritation, and some preservatives, such as benzoic acid and salicylic acid, have low stability due to precipitation at low pH and low temperature. Has many challenges. In addition, due to the growing safety consciousness in recent years, the image of preservatives has deteriorated, and various preservatives that have been conventionally used in the market have become shunned by consumers. There was also concern about the permeability due to the increase in the amount of preservatives and the distribution (uptake) to vesicles as described above.

WO2014 / 069631 Special Table 2007-522205

Journal of Society of Cosmetic Chemists Vol. 48 (2014) No. 2, p. 104-108 Biochimicaet Biophysica Acta 1241 (1995) 269-292 Chem Pharm Bull Vol.34 No.8 Page.3415-3422 (1986.08)

The subject of the present invention is that the inclusions such as the active ingredient do not leak out, the vesicle structure is maintained, the skin permeability of the active ingredient is improved, and the uptake of the preservative into the vesicle is suppressed, so that the feeling of use is excellent. Is to provide a vesicle composition.

As a result of diligent studies to solve the above problems, the present inventors have made an inclusion such as an active ingredient into a vesicle containing an acylproline having a specific chain length or a salt thereof and an amphoteric substance as a membrane component. We have found that it is possible to improve the skin permeability of the active ingredient and suppress the uptake of preservatives into the vesicles while maintaining the vesicle structure without leaking, and completed the present invention.

That is, the present invention is as follows.
[1] (A) General formula (I):

(In the formula, the acyl group represented by R1 ^- CO- indicates an acyl group derived from a saturated or unsaturated fatty acid having 4 to 18 carbon atoms), and acylproline or a salt thereof, and (. B) A vesicle composition containing a vesicle having a constituent film containing an amphipathic substance.
[2] The composition according to [1], wherein the acyl group represented by R1 ^- CO- is an acyl group derived from a saturated or unsaturated fatty acid having 6 to 14 carbon atoms.
[3] The composition according to [1] or [2], wherein (B) is an amphipathic molecule having a hydrophobic chain having 8 or more carbon atoms and 24 or less carbon atoms.
[4] The composition according to [3], wherein (B) is an amphipathic molecule having two hydrophobic chains having 8 or more carbon atoms and 24 or less carbon atoms.
[5] The composition according to any one of [1] to [4], wherein the constituent film further contains (C) a vesicle forming aid.
[6] Described in [5], wherein (C) is at least one selected from the group consisting of sterols and their fatty acid esters or alkyl ethers, as well as saturated and unsaturated linear and branched long chain fatty acids. Composition.
[7] The composition according to any one of [1] to [6], further containing (D) the active ingredient.
[8] (D) is a whitening agent, an antioxidant, an antibacterial agent, an ultraviolet absorber, an anti-inflammatory agent, an astringent agent, a refreshing agent, a sebum inhibitor, a keratin remover, an anti-aging agent, a hair restorer, and a blood flow promoting agent. The composition according to [7], which is at least one selected from the group consisting of agents, cell activators, slimming agents, antiallergic agents, active oxygen scavengers and plant-derived components.
[9] The composition according to any one of [1] to [8], which contains 0.01 to 30 parts by weight of (A) with respect to 1 part by weight of (B).
[10] The composition according to any one of [1] to [9], further containing (E) a preservative.
[11] The composition according to any one of [7] to [10] for promoting skin penetration of the active ingredient.
[12] A cosmetic comprising the composition according to any one of [1] to [11].
[13] (A) A vesicle composition containing an active ingredient in a vesicle having a constituent membrane containing an acylproline or a salt thereof represented by the above general formula (I) and (B) an amphipathic substance is applied to the skin. A method of promoting skin penetration of an active ingredient, which comprises the steps of

According to the present invention, since the inclusions such as the active ingredient in the vesicle do not leak out, it is possible to provide a vesicle composition containing a desired amount of the active ingredient.
According to the present invention, it is possible to provide a vesicle composition having a high skin-penetrating action of an active ingredient and having an excellent usability.
According to the present invention, it is possible to provide a vesicle composition with a minimum amount of preservatives.

FIG. 1 shows a transmission electron microscope image of Example 2. FIG. 2 shows a transmission electron microscope image of Comparative Example 1. FIG. 3 shows a polarizing micrograph of a multilamella vesicle structure (Example 6). FIG. 4 shows a transmission electron microscope image of Example 5.

The present invention is a vesicle composition containing (A) a vesicle having a constituent membrane containing an acylproline or a salt thereof represented by the following general formula (I) and (B) an amphipathic substance (with the composition of the present invention). (Sometimes abbreviated).

In the present invention, "vesicle" means an endoplasmic reticulum composed of a lipid bilayer membrane containing (A) and (B), and the endoplasmic reticulum has an aqueous core.

[Ingredient (A)]
The component (A) in the present invention is an acylproline represented by the general formula (I) and / or a salt thereof.

(In the formula, the acyl group represented by R1 ^- CO- indicates an acyl group derived from a saturated or unsaturated fatty acid having 4 to 18 carbon atoms).

In general formula (I)

Is also referred to herein as R1 ^- CO-.
The acyl group represented by R1 ^- CO- is an acyl group derived from a saturated or unsaturated fatty acid having 4 to 18 carbon atoms, that is, an acyl residue of the fatty acid, and the number of carbon atoms of the fatty acid is It is preferably 6 or more, more preferably 8 or more, and even more preferably 10 or more. The number of carbon atoms of the fatty acid is preferably 18 or less, more preferably 14 or less, and particularly preferably 11 or less.

Examples of the acyl group represented by R1 ^- CO- include a butanoyl group, an isobutanoyl group, a sec-butanoyl group, a tert-butanoyl group, a pentanoyl group, a sec-pentanoyl group, a tert-pentanoyl group and an isopentanoyl group. Hexanoyl group, heptanoyle group, octanoyl group, 2-ethylhexanoyl group, tert-octanoyl group, nonanoyl group, isononanoyl group, decanoyl group, isodecanoyl group, undecanoyl group, lauroyl group, undecilenoyl group, myristoyl group, palmitoyl group, stearoyl group. And oleoyl groups.

The long-chain acyl group represented by ^R1 -CO-is a naturally-derived mixture of coconut oil fatty acid, castor oil fatty acid, olive oil fatty acid, palm oil fatty acid, etc., in addition to the acyl group derived from a single composition acid. It may be an acyl group derived from a fatty acid or a fatty acid obtained by synthesis (including a branched fatty acid). One of these may be used, or two or more selected from the above group may be mixed and used.

The acyl group represented by ^R1 -CO-is preferably an acyl group derived from a fatty acid having 6 to 18 carbon atoms, and is an acyl group derived from a fatty acid having 8 to 14 carbon atoms. Is more preferable, and an acyl group derived from a fatty acid having 10 to 11 carbon atoms is more preferable, and a decanoyle group is most preferable. These fatty acids may be saturated or unsaturated, that is, the acyl group represented by ^R1 -CO-is either an acyl group derived from a saturated fatty acid or an acyl group derived from an unsaturated fatty acid. However, from the viewpoint of storage stability, an acyl group derived from a saturated fatty acid is preferable.

Examples of the salt of acylproline represented by the general formula (I) include pharmaceutically acceptable salts, and alkali metal salts such as lithium salt, sodium salt, and potassium salt; calcium salt, magnesium salt, and the like. Alkaline earth metal salts; ammonium salts; basic organic salts and the like can be mentioned. Of these, from the viewpoint of solubility, sodium salt, potassium salt and ammonium salt are preferable, sodium salt and potassium salt are more preferable, and sodium salt is further preferable.

Further, the acylproline represented by the general formula (I) may be any of a hydrate, a non-hydrate, a non-solvent and a solvate.

The method for producing the component (A) is not particularly limited, and it can be easily produced by combining known methods. Specifically, it can be produced by the Schotten-Baumann method by simultaneously dropping a base such as acid chloride and sodium hydroxide to proline. The proline used in the production of the component (A) may be any of L-form, D-form and a mixture thereof, but is preferably L-form.

The composition of the present invention may contain at least one selected from the acylproline represented by the general formula (I) and a salt thereof as the component (A), but may contain two or more thereof. ..

The content of the component (A) in the composition of the present invention is usually 0.03% by weight or more with respect to the total amount of the composition of the present invention. From the viewpoint of suppressing the uptake of the above, it is preferably 0.05% by weight or more, more preferably 0.07% by weight or more, and further preferably 0.1% by weight or more.
Further, the content is usually 4% by weight or less with respect to the total amount of the composition of the present invention, the generation of a peculiar odor and the action on the skin are milder, and the leakage of inclusions such as active ingredients is caused. From the viewpoint of suppressing, it is preferably 2% by weight or less, more preferably 1% by weight or less, and particularly preferably 0.7% by weight or less.

[Component (B)]
The component (B) in the present invention is an amphipathic substance and is a structural component of the constituent membrane of the vesicle, that is, the lipid bilayer membrane.
The amphipathic substance is not particularly limited as long as it is an amphipathic substance capable of forming a vesicle, but an amphipathic substance having a hydrophobic chain having 8 or more and 24 or less carbon atoms is preferable, and 14 or more and 22 or less hydrophobic substances are preferable. An amphipathic substance having a chain is more preferable, and an amphipathic substance having a hydrophobic chain of 14 or more and 18 or less is particularly preferable.
Of these, a bihydrophobic chain amphipathic molecule having two hydrophobic chains is more preferable. The carbon atoms of the two hydrophobic chains may be the same or different.
Specific components (B) include phospholipids, ceramides, sugar fatty acid esters, acyl amino acid metal salts, polyoxyethylene hydrogenated castor oil derivatives, polyoxyethylene castor oil ethers, alkyl polyglycerin ethers, alkyl glucosides, and glycerin. Examples thereof include fatty acid esters, polyglycerin fatty acid esters, glyceryl ethers, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, gemini-type surfactants, biosurfactants and the like.

Examples of phospholipids include egg yolk phospholipids, soybean phospholipids, and hydrogenated products thereof. Specifically, phosphatidylcholine (eg, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, etc.), phosphatidylglycerin, phosphatidylethanolamine (eg, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, etc.) Examples thereof include phosphatidylserine (for example, dipalmitoylphosphatidylserine, dipalmitoylphosphatidylserine sodium, etc.), phosphatidylic acid, phosphatidylinositol, phosphatidyllipid (sphingomierin) and the like.

Examples of ceramides include natural ceramides, synthetic ceramides and pseudoceramides (synthetic pseudo-ceramides). Specific examples thereof include N-acylsphingosine, N-hydroxyacylphytosphingosine, N-acylphytosphingosine, and type 1 to 7 ceramides. Of these, N-stearoyl sphingosine (ceramide 2), ceramide NP (ceramide 3), ceramide AP (ceramide 6), ceramide EOP (ceramide 1), and ceramide NG are preferable.

Examples of the sugar fatty acid ester include sucrose fatty acid ester, maltitol fatty acid ester, trehalose fatty acid ester and the like, and sucrose fatty acid ester having a carbon chain of C12 to C22 is preferable, and specifically, sucrose monolauric acid ester and sucrose ester. Sugar dilauric acid ester, sucrose monomyristic acid ester, sucrose dimyristic acid ester, sucrose monopalmitic acid ester, sucrose dipalmitic acid ester, sucrose monostearic acid ester, sucrose distearic acid ester, sucrose monosteare Examples thereof include acid esters, sucrose diisostearic acid esters, sucrose monooleic acid esters, and sucrose dioleic acid esters.

The acyl amino acid metal salt has an acyl group derived from a saturated or unsaturated fatty acid having 8 to 22 carbon atoms, and the amino acids are glutamic acid, aspartic acid, glycine, alanine, threonine, methylalanine, sarcosine, lysine, and arginine. , Proline, hydroxyproline, phenylalanine and the like, preferably glutamic acid, lysine, sarcosine, proline, hydroxyproline, and acyl amino acid metal salts of metal salts such as sodium salt and potassium salt (component (A) in the present invention. )except for). Specifically, N-lauroyl-L sodium glutamate, N-stearoyl-L glutamate sodium, N-stearoylmethyl taurine sodium, oleoyl glutamate sodium, dioleoyl glutamate sodium lysine, dilauroyl glutamate sodium bis (N ^ε- ). Examples thereof include lauroyl-L-lysine) ^{cevacoylamide} disodium, bis (Nε-octanoyl-L-lysine) cevacoylamide disodium, dipalmitoyl hydroxyproline and the like.

As the polyoxyethylene hydrogenated castor oil derivative, a derivative having an average addition molar number (E) of 10 to 30 of ethylene oxide (EO) is preferable, and polyoxyethylene (10) cured castor oil and polyoxyethylene (20) cured castor oil are preferable. Examples include oil and lyoxyethylene (30) hardened castor oil.

Examples of the glycerin fatty acid ester include glyceryl monooleate, glyceryl isostearate, glyceryl monoerkaate, glyceryl oleate, glyceryl monostearate, glyceryl monohydroxystearate, and glyceryl monolinolate.
Examples of the polyglycerin fatty acid ester include diglycerin monooleic acid ester, diglycerin monostearic acid ester, diglycerin monoisostearic acid ester, decaglycerin monooleic acid ester, decaglycerin monostearic acid ester, decaglycerin monoisostearic acid ester, and deca. Examples thereof include glycerin pentaoleic acid ester, decaglycerin pentastearic acid ester, decaglycerin pentaisostearic acid ester, polyglyceryl monostearate, polyglyceryl monooleate, polyglyceryl distearate, and polyglyceryl dioleate.
Examples of the glyceryl ether include batyl alcohol, isostearyl glyceryl ether, hexadecyl glyceryl ether and the like.
Examples of the polyoxyethylene alkyl ether include polyoxyethylene stearyl ale.
Examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan stearate.
Examples of biosurfactants include mannosyl erythritol lipids (MML), mannosyl sorbitol lipids (MSL), MEL-A, MEL-B, MEL-C and MEL-D and the like.

One or more amphipathic substances can be used.
Of these, phospholipids, ceramides, acyl amino acid metal salts, glycerin fatty acid esters, and glyceryl ethers are preferable from the viewpoints of usability, versatility, and vesicle formation, and N-stearoyl sphingosine, ceramide NP, ceramide AP, and sodium dilauroyl glutamate are preferable. , Bis (N ^ε -lauroyl-L-lysine) Sevacoylamide disodium, Bis ( ^Nε -octanoyl-L-lysine) Sevacoylamide disodium, dipalmitoyl hydroxyproline, glyceryl monooleate, batyl alcohol, isostearyl Glyceryl ether is more preferred.

The content of the component (B) in the composition of the present invention is usually 0.01% by weight or more with respect to the total amount of the composition of the present invention, and is preferably 0.02% by weight from the viewpoint of usability and stability. % Or more, more preferably 0.04% by weight or more. The content is usually 30% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less, still more preferably 5% by weight or less, based on the total amount of the composition of the present invention. Is.

In the composition of the present invention, the component (B) is usually 0.01 to 30 parts by weight, preferably 0.05 to 20 parts by weight, preferably 0.1, based on 1 part by weight. Up to 18 parts by weight is more preferable, and 0.5 to 15 parts by weight is particularly preferable.

Further, from the viewpoint of exerting an efficient permeation effect, the total weight of the components (A) and (B) is usually 0.02% by weight or more, preferably 0.05% by weight or more, based on the total weight of the composition. More preferably, it is 0.3% by weight or more. The upper limit is usually 15% by weight or less, preferably 10% by weight or less, further preferably 8% by weight or less, and particularly preferably 5% by weight or less, from the viewpoint of affinity for the skin and influence on the formulation.

The component (C) vesicle forming aid may be added to the composition of the present invention from the viewpoint of helping to form the vesicle structure and improving the stability of the obtained vesicle structure.

[Component (C)]
Vesicle-forming aids are components that improve vesicle formation and stability over time, including sterols and their fatty acid esters or alkyl ethers, as well as saturated and unsaturated linear and branched long-chain fatty acids. , Some amino acids such as arginine.
Examples of sterols include cholesterol, stigmasterol, lanosterol, ergosterol, phytosterol (β-sitosterol, campesterol, stigmasterol, brushcasterol, etc.), dihydrocholesterol, cholesterol sulfate ester and its salt, cholesterol phosphate ester and its salt. And so on.

Examples of fatty acid esters of sterols include cholesteryl oleate, isostearic cholesterol ester, N-acylamino acid sterol ester (for example, N-lauroyl-L-glutamate di (cholesteryl / behenyl / octyldodecyl), N-lauroyl-L-glutamic acid). Di (phytosteryl / behenyl / 2-octyldodecyl), di-lauroyl-L-glutamate (cholesteryl / octyldodecyl), di-lauroyl-L-glutamate (phytosteryl / 2-octyldodecyl) or N-lauroyl-L- Examples thereof include diglutamate (phytosteryl / behenyl / 2-octyldodecyl / isostearyl), N-myristoyl-N-methyl-β-alanine phytosteryl), macadamian nut oil fatty acid cholesteryl, and macadamian nut oil fatty acid phytosteryl.
The alkyl group in the fatty acid ester of sterols and the alkyl ether of sterols is preferably 10 to 26 carbon atoms in order to assist vesicle formation, and more preferably a linear or branched chain having 12 to 22 carbon atoms. , A straight chain or a branched chain having 14 to 22 carbon atoms is particularly preferable.
As the saturated and unsaturated linear and branched long-chain fatty acids, those having 10 to 26 carbon atoms are preferable, and those having 12 to 22 carbon atoms are particularly preferable. Specific examples thereof include lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid.
These can be used alone or in combination of two or more.

Among them, cholesterol, phytosterol, cholesterol sulfate ester and its salts, isostearic acid cholesterol ester, N-acylamino acid sterol ester, straight chain or branched fatty acid having 12 to 22 carbon atoms from the viewpoint of usability, versatility and stability. Preferably, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol sulfate ester, isostearic acid cholesterol ester, N-lauroyl-L-glutamate di (phytosteryl / behenyl / 2-octyldodecyl), N-lauroyl-L-glutamate di. (Phytosteryl / 2-octyldodecyl) or di-lauroyl-L-glutamate (phytosteryl / behenyl / 2-octyldodecyl / isostearyl), N-myristyl-N-methyl-β-alanine phytosteryl) is more preferred.

The content of the component (C) in the composition of the present invention is usually 0.001% by weight or more, preferably 0.01% by weight or more, more preferably 0, based on the total amount of the composition of the present invention. It is .04% by weight or more, and particularly preferably 0.1% by weight or more. The content is usually 30% by weight or less, preferably 20% by weight or less, more preferably 10% by weight or less, still more preferably 4% by weight or less, based on the total amount of the composition of the present invention. Is.

In the composition of the present invention, the component (B) is usually 0.01 to 20 parts by weight, preferably 0.05 to 18 parts by weight, while the component (B) is 1 part by weight. 14 parts by weight is more preferable, and 0.1 to 14 parts by weight is particularly preferable.

From the viewpoint of usability and stability, the total weight of the components (A) to (C) is usually 0.05% by weight or more, preferably 0.08% by weight or more, based on the total weight of the composition. It is preferably 0.1% by weight or more, more preferably 0.2% by weight or more. The upper limit is usually 30% by weight or less, preferably 15% by weight or less, further preferably 10% by weight or less, and particularly preferably 5% by weight or less, from the viewpoint of affinity for the skin and influence on the formulation.

The composition of the present invention may further contain (D) an active ingredient (physiologically active substance).

[Component (D)]
The "active ingredient" in the present specification is not limited as long as it is an active ingredient applicable to conventional liposomes and multilamella vesicles.
The active ingredient may be any of a water-soluble, oil-soluble, and amphipathic substance, but a water-soluble or amphipathic substance is preferable, and a water-soluble active ingredient is more preferable, in that permeation can be efficiently promoted. ..

In the present invention, the "water-soluble" active ingredient means an active ingredient having a low octanol / water partition coefficient (LogP), and has an octanol / water partition coefficient (LogP) of 3 or less in that permeation can be efficiently promoted. The active ingredient of is preferable, 1 or less is more preferable, and 0 or less is particularly preferable.
The octanol / water partition coefficient (LogP) is the concentration ratio of the chemical substance in the two solvent phases of 1-octanol and water when the chemical substance is added to the two solvent phases to reach an equilibrium state. Is. The lower the octanol / water partition coefficient (LogP), the easier it is to be partitioned into water.
Regarding the method of measuring the partition coefficient between 1-octanol and water, in principle, OECD Test Guideline (OECD Board Decision "C (81) 30 Final Attachment 1") 107 or Japanese Industrial Standard Z7260-107 (2000) "Distribution" Measurement of coefficient (1-octanol / water) -Measure according to the flask shaking method.

Active ingredients include whitening agents, antioxidants, antibacterial agents, anti-inflammatory agents, astringents, refreshing agents, warming agents, sebum inhibitors, keratin removers, anti-aging agents, hair growth agents, blood flow promoters, cells. Examples thereof include those having at least one action selected from the group consisting of activators, slimming agents, anti-allergic agents and plant-derived components.
The composition of the present invention may contain the above-mentioned component (D) alone or in combination of two or more.

Examples of the whitening agent include arbutine, kodiic acid, ascorbic acid, and ascorbic acid derivatives (for example, ascorbyl tetra2-hexyldecanoate, phosphate phosphate, ascorbylethyl, ascorbyl magnesium phosphate, ascorbyl phosphate 3Na, askovyl tetraisopalmitate (VC)). -IP), L-ascorbic acid 2-glucoside, etc.), tranexamic acid, hinokityl, N-acetyl-2-methylthiazolin-2,4-dicarboxylic acid-2-ethyl ester (hereinafter referred to as acetylethylcarboxymethylthiazolidincarboxylic acid). , Nonapeptide-1, Hexapeptide-2, Undecylenoylphenylalanine, Placenta and the like.
Examples of the antioxidant include vitamin E derivatives such as acetyltripeptide-1, prolinamide ethylimidazole, vitamin E and tocopherol acetate, retinol derivatives such as retinol and retinol palmitate, and γ-orizanol.
Examples of the antibacterial agent include Phellodendron amur extract, bis (2-pyridylthio-1-oxide) zinc, resorcin, azulene, salicylic acid, zinc pyrithione and the like.
Anti-inflammatory agents include glycyrrhizinic acid, glycyrrhizinic acid derivatives, allantoin, azulene, guaiazulene, aminocaproic acid, hydrocortisone, clarinone, glabridin, hinokithiol, acetylhexapeptide-1, glutamilamide ethylimidazole, glutamilamide ethylindole, dipeptide-2, Examples thereof include palmitoyl tripeptide-8.
Examples of the astringent agent include zinc compounds such as zinc oxide, zinc sulfate, PCA zinc and zinc chloride, allantoin hydroxyaluminum, aluminum chloride, zinc sulfocarbonate and tannic acid, and glycylglycine.
Examples of the refreshing agent include menthol and camphor.
Examples of the sebum inhibitor include estradiol, estrone, ethinyl estradiol, vitamin B6 and the like.
Examples of the exfoliating agent include sulfur, salicylic acid, resorcin, and selenium sulfide.
As the anti-aging agent, an anti-inflammatory agent and an antioxidant may be used, but in addition, amino acids (ectin) and peptides (for example, (arginine / lysine) polypeptide, acetylglutamyl) exhibiting an anti-aging effect may be used. Peptide-1, Acetylcitruluamide Arginine, Acetyldipeptide-1 Cetyl, Acetyldecapeptide-3, Acetyltetrapeptide-2, Acetyltetrapeptide-5, Acetyltetrapeptide-9, Acetyltetrapeptide-11, Acetylpentapeptide- 1, Ergothioneine, Octapeptide-2, Oligopeptide-20, Oligopeptide-24, Oligopeptide-6, Caproyltetrapeptide-3, Carnosin, Glycyltyrosine, Hexanoyldipeptide-3 Norleucine, Tetrapeptide-1, Tetrapeptide-5, Trifluoroacetyltripeptide-2, Tripeptide-1, Tripeptide-1 Copper, Tripeptide-3, Tripeptide-10 Citrulin, Biotinoyl Tripeptide-1, Human Oligopeptide-1, Human Oligopeptide-2, Human Oligopeptide-3, Human Oligopeptide-4, Human Oligopeptide-13, Hydroxyproline, Hexapeptide-3, Hexapeptide-9, Hexapeptide-10, Hexapeptide-11, Acetylhexapeptide- 8. Diacetate dipeptide aminobutylbenzylamide, dipeptide-4, decarboxycarnosin HCl, pentapeptide-3, dipeptide-9 (glutamyllysine), etc.), flavonoids such as vitamins and rutin, retinol, retinol acetate, retinol palmitate, etc. Retinol derivatives, α-hydroxyic acid and the like can be mentioned.
Examples of the hair restorer include pantothenyl ethyl ether, biotinoyl tripeptide-1, minoxidil and the like.
Blood flow promoters include sembri extract, cepharanthin, vitamin E and its derivatives, gamma-orizanol, capsaicin, syrup tincture, cantalis tincture, nicotinic acid benzyl ester, l-menthol, menthol derivative, dl-camfur, nonyl acid. Examples thereof include vanillyl amide, capsaicin, vanillyl butyl ether, arnica extract, sodium polyethylene sulfonate, and tincture extract.
Examples of the cell activator include arginine, acetylcitrulamide arginine, dipeptide-9 (glutamyllysine) and the like.
Slimming agents include decapeptide-2, siloxane triol alginate, caffeine, carnitine, hydroxycitrate palmitate, carnitine palmitate, cacao extract, turkey leaf extract (asiaticoside, asiatic acid, madecasinic acid), uncaliatomentosa extract. , Chrysanthemum indikum extract, Tsunogeshi leaf extract, Euglena extract, Mishima psycho root extract, Deleceria sanguinea extract, Darth extract, Hydrolyzed red algae extract, Algae extract, Ethylarginoate acetamide metionamide HCl, Chrismum maritimum extract , Pyroglutamylamide ethyl indol, sphaceraria scoparia extract, papaya fruit extract, sanshomodoki seed extract, laminaria diguitarta extract, filacanta fibrosa extract and the like.
Examples of the antiallergic agent include cycloheptazine hydrochloride, sodium cromoglycate, ketotifen and the like.

Further, the above active ingredients may be used in combination of two or more.
In the present invention, the active ingredients include amino acids such as arginine, hydroxyproline, ectin, and peptides and their derivatives (excluding the above-mentioned components (A) and (B)), vitamins such as niacinamide and pantenol, and derivatives thereof. Examples include vitamin-like substances such as inositol, choline, α-lipoic acid, ubiquinone, pangamic acid, and carnitine, sphingolipids such as water-soluble sphingolipids such as sugar ceramide, hydroquinone glycosides such as arbutin, and esters thereof. Pantothenyl ethyl ether, arginine, lysine, histidine, proline, hydroxyproline, ectin, glycylglycine, glutamyllysine, alanylglutamine, glycyltyrosine, valyltryptophan, pyridoxylserine, inositol, carnosin, niacinamide are preferred. , Pantothenyl ethyl ether, arginine, proline, hydroxyproline, glutamillysine, niacinamide are more preferred.

The content of the component (D) in the composition of the present invention is usually 0.001% by weight or more with respect to the total amount of the composition of the present invention, and is preferably 0.01% by weight from the viewpoint of the action of the active ingredient. % Or more, more preferably 0.05% by weight or more. The content is usually 10% by weight or less based on the total amount of the composition of the present invention, preferably 7% by weight or less, more preferably 5% by weight or less, and particularly, from the viewpoint of stability. It is preferably 4% by weight or less.
As used herein, the term "content of component (D)" refers to the content of one component (D) when the composition of the present invention contains only one component (D). This means that when the composition of the present invention contains two or more components (D), it means the total content of all the components (D) contained.

As the component (D), any of those extracted and purified from naturally occurring animals and plants, or those obtained by a chemical synthesis method, a fermentation method, an enzymatic method or a gene recombination method may be used. Further, a commercially available product may be used.

The weight ratio (A + B: D) between the contents of the components (A) and (B) and the content of the component (D) in the composition of the present invention can be appropriately changed depending on the type of the component (D), but is stable. From the viewpoint of the properties and the effect of the present invention being efficiently exhibited, it is preferably 0.01 to 500: 1, more preferably 0.01 to 200: 1, and further preferably 0.05 to 100 :. It is 1, and particularly preferably 0.1 to 80: 1.

The weight ratio (A + B + C: D) between the contents of the components (A) to (C) and the content of the component (D) in the composition of the present invention can be appropriately changed depending on the type of the component (D), but is stable. From the viewpoint of the properties and the effect of the present invention being efficiently exhibited, it is preferably 0.01 to 800: 1, more preferably 0.01 to 500: 1, and further preferably 0.05 to 200 :. It is 1, and particularly preferably 0.1 to 150: 1.

The composition of the present invention may contain (E) a preservative, if necessary.

[Ingredient (E)]
Examples of the preservative in the composition of the present invention include aromatic alcohols such as parabens, benzyl alcohol, phenoxyethanol and phenethyl alcohol, benzoic acid and its salts, and organic acids such as sorbic acid and its salts. It is preferable that the octanol / water partition coefficient (LogP) is 1 or more in that the effect of the present invention is more exhibited.
As a general rule, the partition coefficient between 1-octanol and water is OECD Test Guideline (OECD Board decision "C (81) 30 final attachment 1") 107 or Japanese Industrial Standard Z7260-107 (2000) "Partition coefficient (1-). It is an actually measured value measured according to "Measurement of octanol / water) -flask shaking method", but it may be a predicted value calculated by In-Silico. For each individual partition coefficient, for example, the measured value and / or the predicted value can be searched from the homepage of the US Environment Agency (URL; https://www.epa.gov/).
Examples of preservatives having an octanol / water partition coefficient (LogP) of 1 or more include methylparaben (LogP = 1.96), butylparaben (LogP = 3.57), phenoxyethanol (LogP = 1.16), and benzyl alcohol (LogP = 1.16). 1.10), benzoic acid (LogP = 1.87), sorbic acid (LogP = 1.33), salicylic acid (LogP = 2.26), anisic acid (LogP = 1.96), octanohydroxamic acid (LogP). Predicted value = 1.66) and the like. Of these, methylparaben, benzoic acid, and phenoxyethanol are preferable.

The content of the component (E) in the composition of the present invention is usually 0.001% by weight or more with respect to the total amount of the composition of the present invention, and is preferably 0.01% by weight from the viewpoint of preservative of the composition. That is all. The content is usually 2% by weight or less, preferably 1% by weight or less, and more preferably 0.5% by weight or less, based on the total amount of the composition of the present invention.

Further, the composition of the present invention may contain a dispersion solvent in addition to the above components (A) to (E).
The dispersion solvent in the present invention is not particularly limited as long as it can be used for foods, cosmetics and the like. For example, purified water, sterile water, tap water, hard water, soft water, natural water, seawater, deep ocean water, electrolytic alkaline ionized water, electrolytically acidic ionized water, ionized water, cluster water and other water, ethanol, 1,3-butylene. Examples thereof include water-soluble solvents such as glycol, propylene glycol, and dipropylene glycol. Of these, water, dipropylene glycol, propylene glycol and the like are preferable. One or more of these may be used.

The content of water in the composition of the present invention is appropriately determined depending on the content of the components (A) to (D), but is usually 8 to 99.6% by weight based on the total amount of the composition of the present invention. It is preferably 20 to 99.6% by weight, more preferably 35 to 80% by weight.

The content of the water-soluble solvent other than water in the composition of the present invention is appropriately determined depending on the content of the components (A) to (D), but is usually 0.1 to 40 with respect to the total amount of the composition of the present invention. By weight%, 0.1 to 30% by weight is preferable, and 0.5 to 25% by weight is more preferable.

The pH (25 ° C.) of the composition of the present invention is usually pH 3.5 or more and pH 9 or less, and is preferably pH 4.0 to 8.5 from the viewpoint of irritation and stability of the component (A) in the composition. , More preferably pH 4.0 to 7.5, and particularly preferably pH 4.5 to 6.5.

In the present invention, the average particle size of the vesicle is usually 25 to 5000 μm, preferably 50 to 3000 μm, and more preferably 80 to 2500 μm.
The average particle size is a conventional method and can be obtained by measuring the particle size distribution by a laser diffraction method, a dynamic light scattering (DLS) method, or an image imaging method using an electron microscope.

The structure of the vesicle may be a uni-lamella vesicle (ULV) or a multi-lamella vesicle (MLV) in which a double layer film is stacked, but MLV is preferable.

The method for producing the composition of the present invention includes, but is not limited to, the following.
For example, a solvent (water, polyol, etc.) that has been mixed in advance after heating the component (B) and, if necessary, the component (C) or the lipophilic active ingredient (D) to completely and uniformly dissolve and mix them. If necessary, the hydrophilic active ingredient (D) is heated to the same temperature as the oil-soluble ingredient, and slowly added dropwise to the oil phase. Then, after stirring so as to be uniform while maintaining the temperature, the temperature in the system is gradually cooled while stirring slowly, and then the component (A) and, if necessary, the component (E) are added. The component (A) may be added even during heating or after cooling. Examples of the stirring device include a paddle mixer, a homodisper, and a homogenizer.
The multilamella vesicle preparation produced by the above-mentioned method can prepare minute vesicles by an extruder, a high-pressure emulsifier, ultrasonic waves, or the like, if necessary.
Other methods include a method in which the components (B) and components (C) constituting the vesicle are sufficiently swollen in water at a Tc temperature (gel-liquid crystal transition temperature) or higher, and then stirred and mixed, or an organic solvent is used. After forming a thin film made of the component (B) and the component (C), a solvent such as water (including the active ingredient (D) if necessary) is added, and the film is microscopically irradiated or used with an extruder. A vesicle composition can also be obtained by adding the component (A) and incorporating the component (A) into a membrane after obtaining a basic vesicle by using a method commonly used in the past, such as a method for obtaining a vesicle. The component (A) may be added either before or after the membrane formation, but a method of adding the component (A) after the membrane formation is preferable in terms of suppressing the uptake of the preservative into the membrane and increasing the permeability of the active ingredient. ..

As for the method of confirming the vesicle formation, the presence or absence of a Martese cross image under orthogonal Nicol is confirmed using a polarizing microscope, and the peak is confirmed and transmitted by measuring the small-angle X-ray scattering spectrum using the high-intensity small-angle X-ray scattering device SAXS. It can be performed by an electron microscope (TEM), a freeze breaking method, a low temperature transmission electron microscope (cryo-TEM), dynamic light scattering (DLS), or the like.

The form of the composition of the present invention is not particularly limited, and examples thereof include liquid, emulsified, paste, gel, solid, and powder.

The composition of the present invention can be incorporated into cosmetics or medicines (including quasi-drugs), or the compositions of the present invention themselves as cosmetics or medicines (including quasi-drugs). May be good.

When the composition of the present invention is blended into a cosmetic, or when the composition of the present invention itself is used as a cosmetic, examples of the cosmetic include basic cosmetics (eg, cosmetic water, milky lotion, makeup base, beauty liquid). , Night cream, pack, makeup remover products (cleansing gel, etc.), BB cream, CC cream, nail cream, etc.), Sun care products (eg, sunscreen, tanned skin lotion, etc.), hair treatment agents (eg, hair) Treatments, out bath treatments, hair styling products, split hair coatings, etc.), hair styling products (eg brushing lotion, curler lotion, pomade, tic, set hair spray, hair mist, hair liquid, styling foam, hair gel, water Grease, etc.), shaving products (eg, shaving cream, after-shave broth, etc.), makeup cosmetics (eg, foundation (solid, cream, liquid, etc.), concealer, lipstick, lip gloss, eye shadow, eyeliner, teak, etc.) , Mascara, bronzer, etc.), perfume, lip cream, antiperspirant, oral cosmetics, toothpaste, bath cosmetics (eg, bathing agents, bath salt, etc.) and the like.

When the composition of the present invention is blended into a cosmetic, or when the composition of the present invention itself is used as a cosmetic, the cosmetic may contain an ingredient which may be usually added to the cosmetic to bring about the effect of the present invention. It may be blended within a range that does not inhibit it. Specific examples of the component include oils, chelating agents, surfactants, powders, sugar alcohols and alkylene oxide adducts thereof, lower alcohols, animal and plant extracts, nucleic acids, enzymes, anti-inflammatory agents, bactericides, and isotonicization. Examples thereof include agents, antioxidants, ultraviolet absorbers, antiperspirants, pigments, pigments, oxidative dyes, organic and inorganic powders, pH adjusters, pearlizing agents, wetting agents and the like.

When the composition of the present invention is added to a cosmetic, the content of the composition of the present invention is usually 0.01% by weight or more, preferably 0.05% by weight or more, based on the total amount of the cosmetic composition. , Usually 50% by weight or less, preferably 30% by weight or less.

The pH (25 ° C.) of the cosmetic composition in the present invention is usually pH 3.5 or more and pH 9 or less, and is preferably pH 4.0 to 8 from the viewpoint of irritation and stability of the component (A) in the composition. It is 5.5, more preferably pH 4.0 to 7.5, and particularly preferably pH 4.5 to 6.5.

When the composition of the present invention is blended into a medicine (including a non-medicinal product), or when the composition of the present invention itself is a medicine (including a non-medicinal product), the dosage form of the medicine is as follows. For example, coating agents such as ointments (water-based ointments, oily ointments, etc.), creams, liquids, emulsions, gels, lotions, liniments, pasta, etc .; Such as patches; aerosols, sprays such as sprays; suppositories and the like.

When the composition of the present invention is blended with a drug (including quasi-drugs), or when the composition of the present invention itself is a drug (including quasi-drugs), the drug is pharmacologically applicable. A carrier, an excipient, a diluent, a soothing agent, an antioxidant and the like that are acceptable to the above may be blended as long as the effects of the present invention are not impaired.

The composition of the present invention is preferably for the skin, and is preferably blended with a skin cosmetic or a skin medicine (including a quasi-drug for the skin), or the composition of the present invention itself is used for skin makeup. It is preferable to use a drug or a skin medicine (including quasi-drugs for skin). Here, "skin" is a concept that includes not only the epidermis of the body (for example, face, head, neck, chest, abdomen, hips, back, buttocks, arms, legs, hands, etc.) but also the mucous membrane.

Examples of the application target of the composition of the present invention include, but are limited to, mammals (for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, pigs, monkeys, etc.). It is not something that is done.

The dose of the composition of the present invention and the number of times it is applied to a subject can be appropriately adjusted according to the type of the component (D), the form of the composition, the subject to which the composition is applied, and the like.

The compositions of the present invention are used to promote skin penetration of the active ingredient. Each component, content, etc. are as described above.

Further, the vesicle composition containing the active ingredient in a vesicle having a constituent film containing (A) acylproline represented by the above general formula (I) or a salt thereof, and (B) an amphoteric substance is applied to the skin. Also included in the invention are methods of promoting skin penetration of the active ingredient, including steps. The step of applying to the skin varies depending on the dosage form of the composition and the like, and examples thereof include a step of applying, affixing, and spraying an effective amount of the active ingredient to the target skin. Each component, content, etc. are as described above.

Hereinafter, the present invention will be described in more detail based on Synthetic Examples and Examples, but the present invention is not limited to these Synthetic Examples and Examples, and can be changed without departing from the scope of the present invention. You may. In addition, the reagents, devices, and materials used in the present invention are commercially available unless otherwise specified. Unless otherwise specified,% indicates weight%.

<Synthesis Example 1> Synthesis of decanoyle proline sodium salt After dissolving 34.54 g of proline (manufactured by Ajinomoto Co., Inc.) in 100 g of water, 52.01 g of decanoyle chloride (manufactured by Tokyo Kasei Co., Ltd.) and 25% sodium hydroxide aqueous solution are added at pH 12 Added while adjusting to. After neutralizing by adding 75% sulfuric acid and removing the aqueous layer, water and ethyl acetate were further added to remove the aqueous phase. Ethyl acetate was distilled off under reduced pressure to obtain 68.12 g of decanoylproline. The obtained decanoylproline was suspended in an appropriate amount of water, and then the pH was neutralized to 7 with sodium hydroxide to obtain a decanoylproline sodium salt.

<Test Example 1>
(Preparation of vesicle preparation 1)
For the vesicle preparation 1, a thin film is obtained using 0.4 g of ceramide II, 0.25 g of cholesterol, 0.25 g of palmitic acid, and 0.1 g of cholesterol sulfate, and then Phosphate Buffered Saline (PBS) buffer (manufactured by Takara Bio Co., Ltd.) 99. 0.0 g was mixed with a thin film, peeled off with a vortex mixer, and then irradiated with ultrasonic waves to prepare vesicle preparation 1.

(Preparation of Compositions of Examples 1 to 3 and Comparative Examples 1 to 5)
The vesicle preparation 1 prepared above was added to a mixture of the components shown in Table 1 other than the vesicle preparation 1 in advance to obtain each composition. The unit of composition shown in Table 1 is% by weight. In addition, in the table, the display of% is omitted, and only the numerical value indicating the blending amount is displayed.

(Evaluation of the amount of preservative distributed to vesicles)
The preservative concentration contained in the prepared compositions (Example 3 and Comparative Example 2) was quantified by HPLC, and it was confirmed that the preservative concentrations in each composition were equivalent. Separately, the composition is separated into vesicles using an ultracentrifuge (Himac CS100GXII manufactured by Hitachi Koki Co., Ltd., rotor: S55A2 angle rotor), and the concentrations of preservatives contained in the supernatant and solid content (vesicles) are determined by HPLC, respectively. Quantified in.
Compared with the amount of the preservative distributed to the vesicle membrane of Comparative Example 2 containing no component (A), the amount of the preservative distributed to the vesicle membrane of Example 3 was reduced by 19%, and the preservative in the aqueous phase was reduced. It was confirmed that the agent concentration was increasing. Therefore, it was found that the component (A) suppresses the distribution of the preservative to the vesicle membrane.
In Comparative Examples 3, 4, and 5, ultracentrifugation was performed under the same conditions as above, but the amount of solid content was only slightly separated.

(Vesicle confirmation test-1)
After storing Example 2 and Comparative Example 1 for 3 weeks, a sample was prepared by a freeze-breaking replica method, and the shape was observed with a transmission electron microscope (JEM-1010). As a result, FIGS. 1 (Example 2) and FIG. 2 As in (Comparative Example 1), the same vesicle structure was confirmed even after the addition of the component (A).

<Test Example 2>
(Preparation of Calcein-encapsulated vesicle preparation 1)
In order to examine the effect of the component (A) and the comparative component (A') on the vesicle membrane, the vesicle having the same composition as the vesicle preparation 1 was evaluated using a preparation in which calcein, which is a fluorescent substance, was encapsulated.
That is, a PBS buffer solution containing 75 mM calcein was added to a thin film prepared with the same composition as the above vesicle membrane (0.4 g of ceramide II, 0.25 g of cholesterol, 0.25 g of palmitic acid, and 0.1 g of cholesteryl sulfate). After peeling with a vortex mixer, it is irradiated with ultrasonic waves and thawed, and finally the calcein not contained in the vesicle is removed by an ultracentrifugator (Himac CS100GXII manufactured by Hitachi Koki Co., Ltd., rotor: S55A2 angle rotor, 150,000 xg). To obtain a vesicle preparation 1 in which calcein was encapsulated.

(Effects on vesicle membrane (leakage of inclusions))
Using the calcein-encapsulated vesicle preparation 1 described above in place of the vesicle preparation 1 shown in Table 1, the fluorescence of calcein 60 minutes after the addition to each component other than the premixed calcein-encapsulated vesicle preparation 1 (F). [Sample]) was measured using a fluorescence spectrophotometer (Jasco Support FP-6500DS). However, the fluorescence of Comparative Example 1 at that time was F [control]. Subsequently, the fluorescence of calcein leaked when 1% Triton-X100 was mixed with each composition was defined as the complete leakage amount (F [triton]). In addition, the leakage rate of calcein in each composition was calculated from the obtained fluorescence intensity from the following formula.
Leakage rate (%) = (F [sample] -F [control]) / (F [triton] -F [control]) x 100
As shown in Table 1, it was confirmed that the composition containing the component (A) had a clearly lower leakage rate of the vesicle inclusions and had a smaller effect on the vesicle membrane than the composition containing the comparative component (A'). Was done.

<Test Example 3>
(Preparation of arbutin-added vesicle preparation 1)
Arbutin (component (D)) as an active ingredient is added to a thin film prepared with the same composition as the above-mentioned vesicle film (ceramide II 0.4 g, cholesterol 0.25 g, palmitic acid 0.25 g, and cholesterol sulfuric acid 0.1 g). 98.0 g of PBS buffer containing 0.0 g was added to prepare arbutin-added vesicle preparation 1 by the same method as in Test Example 1. A PBS buffer solution and 0.7 g of the component (A) were further added to this vesicle preparation, and the composition was prepared as Example 4 with a total amount of 200 g.
For comparison, a composition not containing the component (A) (Comparative Example 8) and 0.7 g of acylproline having a chain length not contained in the component (A) are blended in place of the component (A). The composition (Comparative Example 6) and the composition containing 0.7 g of PEG-60 hydrogenated castor oil (Comparative Example 7) were also prepared in the same manner. Further, as Reference Example 1, a composition composed of only the component (A), the component (D) and the PBS buffer solution (composition not containing the vesicle membrane) is prepared, and as Reference Example 2, a composition containing only the component (D) is prepared. Each was used for the following evaluation of skin permeability.

(Evaluation of skin permeability)
For the skin permeability of the active ingredient (D) of the composition prepared as described above, a horizontal diffusion cell (average diffusion area: 0.64 cm ² ) and a Strat-M membrane (25 mm, manufactured by Merck Group) were used as a skin model. It was evaluated by the in vitro permeability test.
Specifically, after the Strat-M membrane was attached to the horizontal diffusion cell and fixed, the sample composition was added to the cell on the donor side, and water or PBS buffer was added to the cell on the receiver side, and each was 37 ° C. (± 0). .2 ° C.) was stirred, and a certain amount of sampling was performed from the cell on the receiver side over time to obtain a sample to be analyzed. The obtained sample was quantitatively measured for the component (D) by a liquid chromatograph according to a conventional method, and the cumulative permeation amount (μg / cm ² ) of the component (D) was determined.

Compared with the composition not containing the component (A) (Comparative Example 8), the composition containing the component (A) (Example 4) has a cumulative permeation amount of the component (D) 6 hours after the start of the test. It was confirmed that the improvement was 2.1 times and the permeability of the component (D) was improved. On the other hand, in Comparative Example 6 using acylproline having a chain length not included in the component (A) and Comparative Example 7 containing other comparative components, there was almost no difference or a decrease in the permeation amount of Comparative Example 8. .. Further, in the composition containing the component (A) and not containing the vesicle film (Reference Example 1), an increase in the permeation amount of the component (D) was confirmed as compared with the composition containing only the component (D) (Reference Example 2). Was not done. From these, it was confirmed that the component (A) improves the permeability of the component (D) when combined with the vesicle preparation.

<Test Example 4>
(Preparation of composition of vesicle preparation 2, Example 5 and Comparative Example 9)
Di (phytosteryl / octyldodecyl) 0.5% lauroyl glutamic acid and 4.0% isostearic cholesterol ester were dissolved at 80 ° C. and mixed uniformly, and then arginine (Arg): palmitic acid: dipalmitoyl hydroxyproline: To 10% of the aqueous solution mixed at a ratio of water = 1: 1: 3: 45, 10% of dipropylene glycol (DPG) and 1.0% of pantothenyl ethyl ether as the active ingredient (D) were added and added to 80 ° C. After warming, it was added dropwise to the oil-soluble component. After stirring at 80 ° C. for 5 minutes using Homo Disper (manufactured by PRIMIX Corporation), the mixture was cooled to around 40 ° C. while stirring, and this was used as vesicle preparation 2. An aqueous solution in which the component (A) and the preservative were dissolved was added thereto, and the mixture was uniformly stirred to prepare a composition (Example 5). Further, as Comparative Example 9, a composition containing no component (A) was prepared by the same method as described above.

(Preparation of composition of vesicle preparation 3, Example 6 and Comparative Example 10)
The vesicle preparation 3 is replaced with an aqueous solution of Arg: palmitic acid: dipalmityl hydroxyproline: water = 1: 1: 3: 45 of the above vesicle preparation 2 with lysine Na dilauroyl glutamate (1%). It was prepared in the same manner using water (9%). An aqueous solution in which the component (A) and the preservative were dissolved was added thereto, and the mixture was uniformly stirred to prepare a composition (Example 6). Further, as Comparative Example 10, a composition containing no component (A) was prepared by the same method as described above.

(Vesicle confirmation test-2: Multilamella vesicle)
The presence or absence of a Martese cloth image was observed using a polarizing microscope (manufactured by Nikon Corporation, magnification 400 times) for each sample that had been allowed to stand at room temperature for one day after production. As shown in FIG. 3, those in which the Martese cloth image could be confirmed were judged to form a multilamella vesicle structure and evaluated according to the following evaluation criteria.
⊚: The image of Martese Cross was confirmed on the whole.
◯: The Martese cross image was partially confirmed.
X: The Martese Cross image could not be confirmed.

(Reduced amount of preservative distribution to vesicles)
The concentration of the preservative contained in the supernatant and the solid content (vesicle) was quantified by the same method as in Test Example 1 described above, and Comparative Example 9 was used as a reference in Example 5 and 10 was used as a reference in Example 6. , The increase / decrease in the amount of preservative distributed to the vesicles, and the concentration of preservatives in the aqueous phase were evaluated according to the following criteria.
⊚: Distribution of preservatives of 15% or more to vesicles was suppressed, and the concentration in the aqueous phase increased.
◯: Distribution of preservatives of 5% or more and less than 15% to vesicles was suppressed, and the concentration in the aqueous phase increased.
Δ: Distribution of preservatives equal to or more than 5% to vesicles was suppressed, and the concentration in the aqueous phase increased.
X: Less than equivalent, that is, the distribution of the preservative to the vesicle membrane increased and the concentration in the aqueous phase decreased.

(Evaluation of skin permeability)
The cumulative permeation amount (μg / cm ² ) of the component (D) was determined by the same procedure as the evaluation of the skin permeability of Test Example 1 described above, and the skin permeability was evaluated. In the case of Example 5, Comparative Example 9 was compared with Comparative Example 10, and the cumulative permeation amount of the component (D) 4 hours and 24 hours after the start of the test was evaluated according to the following criteria.
Compared as a corresponding composition (Comparative Examples 9, 10) containing no component (A);
⊚: 2 times or more ○: 1.5 times or more and less than 2 times △: Equivalent or more and less than 1.5 times ×: Less than equivalent

In Examples 5 and 6, the same Martese cloth image as in Comparative Examples 9 and 10 was observed. Further, when the shape of Example 5 was observed with a transmission electron microscope by the same method as in Test Example 1 vesicle confirmation test-1, a multilamella vesicle was confirmed as shown in FIG.
The distribution of the preservative to the vesicle membrane was suppressed by 21% in Example 5 as compared with Comparative Example 9, and was suppressed by 19% in Example 6 as compared with Comparative Example 10. Therefore, the component (A) suppressed the distribution of the preservative to the vesicle. It was confirmed that the distribution to was reduced.

Regarding the permeability of the active ingredient (D), in Example 5 and Example 6, the permeability of the component (D) after 4 hours and 24 hours is more than doubled as compared with Comparative Example 9 and Comparative Example 10, respectively. It was confirmed that it would improve. When the cumulative permeation amount of Comparative Examples 9 and 10 was tested with respect to the cumulative permeation amount of the component (D) in Reference Example 3 carried out as a reference, the difference was equal to or less than or almost the same in both after 4 hours and after 24 hours. It was confirmed that there was no such thing. Therefore, it was confirmed that the permeability of the active ingredient can be improved by the combination of the ingredient (A) and the vesicle preparation.

<Test Example 5>
(Evaluation of usability)
Five panelists applied 40 μL of the compositions of Example 5 and Comparative Example 9 to the skin within 8 cm × 2 cm on the inside of the forearm, respectively. After scoring as described above, the average score of 5 people was calculated and evaluated based on the following criteria.

(Score of spread and spread during application and smoothness of skin after application)
5: Very good 4: Good
3: Usually 2: Somewhat bad
1: Bad

(Score of skin familiarity during application)
5: Very good for skin familiarity 4: Feels familiar with skin 3: Normal 2: Does not feel familiar with skin very much 1: Does not feel familiar with skin

(Score of smoothness and non-stickiness of the skin immediately after application)
5: No stickiness, skin is very silky 4: Little stickiness is felt, skin is silky 3: Normal 2: Slightly sticky 1: Feels sticky

(Evaluation criteria)
⊚: Average score is 4.0 or more ○: Average score is 3.0 or more and less than 4.0 △: Average score is 2.0 or more and less than 3.0 ×: Average score is less than 2.0

<Test Example 6>
(Preparation of evaluation sample (cosmetics))
The vesicle compositions described in Example 5 and Comparative Example 9 were blended with cosmetics and subjected to an antiseptic test. Cosmetic formulations were prepared according to known methods. That is, Na hyaluronate (FCH-120) 0.1% and sorbitol 5.0%, pyrrolidone carboxylate Na 1.5%, glycerin 5.0%, ethanol 1% and methylparaben 0.14% and water at 70 ° C. After stirring until uniform while heating and cooling to around room temperature, 60% of the vesicle preparation of Example 5 or Comparative Example 9 was added, then the pH was adjusted to 6.5 with a pH adjuster, and finally the amount of water was adjusted. The sample adjusted to 100% was evaluated as Example 6 and Comparative Example 10 by the following method. Further, as a reference, a cosmetic containing 0.2% of methylparaben and containing no vesicle (Reference Example 4), or a composition in which the same amount of acetylproline is added to the vesicle preparation 2 instead of the component (A) of Example 5. A cosmetic (Reference Example 5) similarly prepared using (Acetylproline-containing composition) was also evaluated.

(Preservative test)
(1) Aspergillus brasiliensis (Ab) bacterial solution was added to ¹ mL of the cosmetic prepared as described above so that the initial number of bacteria was 105 per mL.
(2) The formulation of (1) was stored at 25 ° C. for 7 days.
(3) After 7 days, 10 μL of the formulation and 190 μL of the following medium were well mixed on a 96-well plate, stored at 25 ° C. for 1 day, and then the degree of mold growth was visually evaluated according to the following criteria.
Medium composition: GPLP medium "Daigo" (manufactured by Wako Pure Chemical Industries, Ltd.) 3.65 g, lecithin: Wako first grade 1.15 g, polysorbate 80: Wako biochemical use 8.05 g, ion-exchanged water 250 g

Mold growth evaluation criteria:
0: No mold growth 1: Slight growth 2: Growth, less than 1/3 of the well 3: Growth, 1/3 or more of the well 4: During breeding, the well is mostly covered with fungi

(4) This experiment was repeated 3 times, and the average of the evaluation values of 3 times was calculated as A. It was obtained as the growth status score of b.

In the cosmetic containing 0.2% of methylparaben without containing vesicles (Reference Example 4), the growth score was 0, but Comparative Example 10 containing 0.2% of vesicles and methylparaben in the composition was used. With cosmetics, the growth score was 3, and remarkable mold growth was confirmed. On the other hand, in the cosmetic using Example 6, which contained the component (A) in addition to 0.2% of vesicle and methylparaben in the composition, the growth score was 0 and the growth of mold was not confirmed. It was found that mold growth was also confirmed in a cosmetic using a composition (Reference Example 5) containing the same amount of acetylproline instead of the component (A) of Example 5. The results are shown in Table 5.

According to the present invention, it is possible to provide a vesicle composition having improved permeability of an active ingredient, containing a minimum necessary preservative, and having an excellent usability.

Claims (10)

(A) Decanoylproline or its salt,
A vesicle composition containing (B) an amphipathic substance and (C) a vesicle having a constituent film containing a vesicle forming aid.
Further containing (D) active ingredient and (E) preservative ,
(B) is N-lauroyl-L sodium glutamate, N-stearoyl-L glutamate sodium, N-stearoylmethyl taurine sodium, oleoyl glutamate sodium, dioleoyl glutamate sodium lysine, dilauroyl glutamate sodium bis (N ^ε ). -At least one selected from the group consisting of lauroyl-L-lysine) cevacoylamide disodium, bis ( Nε-octanoyl-L-lysine) ^{cevacoylamide} disodium and dipalmitoylhydroxyproline .
(C) is at least one selected from the group consisting of sterols and their fatty acid esters or alkyl ethers, as well as saturated and unsaturated linear and branched long chain fatty acids.
(D) is a whitening agent, an antioxidant, an antibacterial agent, an ultraviolet absorber, an anti-inflammatory agent, an astringent agent, a refreshing agent, a sebum inhibitor, a keratin remover, an anti-aging agent, a hair restorer, a blood flow promoter, and cells. A composition that is at least one selected from the group consisting of activators, slimming agents, anti-allergic agents, active oxygen scavengers and plant-derived components, and has an octanol / water distribution coefficient (LogP) of (D) of 3 or less. thing. The composition according to claim 1 , wherein (B) is at least one selected from the group consisting of sodium dilauroyl glutamate and dipalmitoyl hydroxyproline . (C) is palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol sulfate ester, isostearic acid cholesterol ester, N-lauroyl-L-glutamic acid di (phytosteryl / behenyl / 2-octyldodecyl), N-lauroyl-L-. It consists of di-glutamate (phytosteryl / 2-octyldodecyl) , di-lauroyl-L-glutamate (phytosteryl / behenyl / 2-octyldodecyl / isostearyl) and N-myristoyl-N-methyl-β-alanine phytosteryl). The composition according to claim 1 or 2 , which is at least one selected from the group. The composition according to any one of claims 1 to 3 , wherein the octanol / water partition coefficient (LogP) of (D) is 1 or less. The composition according to any one of claims 1 to 4 , wherein (D) is at least one selected from the group consisting of arbutin, pantothenyl ethyl ether, arginine, proline, hydroxyproline, glutamillysine and niacinamide. thing. (B) The composition according to any one of claims 1 to 5 , which contains 0.01 to 30 parts by weight of (A) with respect to 1 part by weight. The composition according to any one of claims 1 to 6, wherein the octanol / water partition coefficient (LogP) of (E) is 1 or more. The composition according to any one of claims 1 to 7 , for promoting skin penetration of the active ingredient. A cosmetic comprising the composition according to any one of claims 1 to 8 . A step of applying to the skin a vesicle composition containing an active ingredient in a vesicle having a constituent membrane containing (A) decanoylproline or a salt thereof, (B) an amphipathic substance and (C) a vesicle forming aid. A method of promoting skin penetration of the active ingredient
(B) is N-lauroyl-L sodium glutamate, N-stearoyl-L glutamate sodium, N-stearoylmethyl taurine sodium, oleoyl glutamate sodium, dioleoyl glutamate sodium lysine, dilauroyl glutamate sodium bis (N ^ε ). -Lauroyl-L-lysine) Sevacoylamide disodium, bis ( Nε-octanoyl-L-lysine) ^{Sevacoylamide} disodium and dipalmitoyl hydroxyproline are at least one selected from the group .
(C) is at least one selected from the group consisting of sterols and their fatty acid esters or alkyl ethers, as well as saturated and unsaturated linear and branched long chain fatty acids.
Active ingredients are whitening agents, antioxidants, antibacterial agents, UV absorbers, anti-inflammatory agents, astringents, refreshing agents, sebum inhibitors, keratin removers, anti-aging agents, hair growth agents, blood flow promoters, cell activation. A method that is at least one selected from the group consisting of agents, slimming agents, antiallergic agents, active oxygen scavengers, and plant-derived ingredients, and has an octanol / water partition coefficient (LogP) of 3 or less as an active ingredient .

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