JP7154089B2 - Skin cosmetic composition - Google Patents

Description

The present invention is in the field of cosmetic compositions for skin.

The health condition of the skin deteriorates due to external stimuli such as ultraviolet rays and dryness, internal stimuli such as self-immune action due to stress and the like. For example, one of the deterioration of skin conditions that has become a problem is a decrease in skin barrier function, which leads to sensitive skin, rough skin, and the like.

A number of polymer materials are known as application materials to improve this condition, but water-soluble polymers with a high improvement effect have weak skin adsorption, and have problems such as being dissolved in water in the first place (Patent document 1). In addition, in the case of hydrophobic polymers, there is a report that processing them into particles to improve skin barrier properties (Patent Document 2), but in this invention as well, the effect of mixing particles rather than the effect of particles alone is reported. It is difficult to say that the effect of the polymer particles alone is due to the inclusion of an oil agent, which merely enhances the effect.

In addition, although Patent Document 3 discloses cationic gel particles made using a cationic polymerization initiator, it does not describe that the gel particles can be used to improve or protect skin health. do not have.

JP-A-9-315949 JP 2011-521890 A WO2017/043484

The present inventors have found that cationic gel particles made using a cationic polymerization initiator exhibit high adsorption to skin and can improve or protect skin health. The present invention is based on this finding.

Accordingly, the present invention provides a skin cosmetic composition capable of ameliorating or protecting skin health conditions that are deteriorating or that are in deteriorating environments.

［式中、
Ｙは、単結合またはＣＲ^８５を表し、
Ｚは、単結合またはＣＲ^８６を表し、
Ｒ^７２、Ｒ^７３、Ｒ^７５、Ｒ^７６、Ｒ^７７、Ｒ^７８、Ｒ^８５およびＲ^８６は、それぞれ独立して、水素原子、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニル、フェニルおよびヒドロキシからなる群から選択され、ここで前記Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニルおよびフェニルは、さらにＣ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニル、フェニルおよびヒドロキシからなる群から選択される１または２個の置換基で置換されていてもよく、
Ｒ^７２およびＲ^７３は、さらに、それぞれ独立して、アダマンチル、またはＳｉ（ＯＣＨ_３）_２（ＣＨ_３）で置換されたＣ_１－６アルキルを表してもよく、
あるいは、Ｒ^７５およびＲ^７６、またはＲ^７７およびＲ^７８は、一緒になって－（ＣＨ_２）_３－５－を形成してもよく、
Ｒ^８１、Ｒ^８２、Ｒ^８３、およびＲ^８４は、Ｃ_１－４アルキル、Ｃ_１－４アルキルカルボニル、およびＣ_１－３アルコキシからなる群から選択される置換基であり、ここで前記Ｃ_１－４アルキルは一つのＣ_１－３アルコキシ基で置換されていてもよく、および
Ｒ^７１およびＲ^７４は、それぞれ独立して、Ｃ_１－３アルキル基であり、
Ｘ_ｆ ^－はカウンターアニオンである］
の化学構造を有する化合物である、（１）または（２）に記載の皮膚用化粧料組成物。
（４）前記カチオン性重合開始剤が、２，２’－アゾビス－（２－（１，３－ジメチル－４，５－ジヒドロ－１Ｈ－イミダゾール－３－イウム－２－イル））プロパン トリフレート（ＡＤＩＰ）である、（１）～（３）のいずれかに記載の皮膚用化粧料組成物。
（５）前記炭素－炭素二重結合を含んでなるモノマーが、ビニル系化合物モノマーである、（１）～（４）のいずれかに記載の皮膚用化粧料組成物。
（６）前記炭素－炭素二重結合を含んでなるモノマーが、アクリルアミド類、メタクリルアミド類、アクリル酸類、アクリル酸類のエステル類、メタクリル酸類、メタクリル酸類のエステル類、スチレン類、および酢酸ビニルモノマーからなる群より選択される１または２以上の化合物である、（１）～（５）のいずれかに記載の皮膚用化粧料組成物。
（７）前記炭素－炭素二重結合を含んでなるモノマーが、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＭ）および／またはメタクリル酸メチル（ＭＭＡ）である、（１）～（６）のいずれかに記載の皮膚用化粧料組成物。
（８）前記架橋剤が、Ｎ，Ｎ’－メチレンビスアクリルアミド（ＭＢＡＭ）および／またはジビニルベンゼンである、（２）～（７）のいずれかに記載の皮膚用化粧料組成物。
（９）皮膚表面からの水分損失を低減または防止するための、（１）～（８）のいずれかに記載の皮膚用化粧料組成物。 The present invention includes the following inventions.
(1) A cosmetic composition for skin comprising gel particles whose surfaces are covered with positive charges, wherein the gel particles contain a cationic polymerization initiator and a monomer comprising a carbon-carbon double bond. A cosmetic composition for skin, which is a copolymer comprising structural units derived from.
(2) The skin cosmetic composition according to (1), wherein the copolymer contains a structural unit derived from a cross-linking agent.
(3) The cationic polymerization initiator has the general formula (I):

[In the formula,
Y represents a single bond or ^CR85 ;
Z represents a single bond or ^CR86 ;
R ⁷² , R ⁷³ , R ⁷⁵ , R ⁷⁶ , R ⁷⁷ , R ⁷⁸ , R ⁸⁵ and R ⁸⁶ are each independently a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl is selected from the group consisting of carbonyl, phenyl and hydroxy, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl and phenyl are further C _1-6 alkyl, C _1-6 alkoxy, optionally substituted with 1 or 2 substituents selected from the group consisting of C _1-6 alkylcarbonyl, phenyl and hydroxy;
R ⁷² and R ⁷³ may also each independently represent C _1-6 alkyl substituted with adamantyl or Si(OCH ₃ ) ₂ (CH ₃ );
Alternatively, R ⁷⁵ and R ⁷⁶ or R ⁷⁷ and R ⁷⁸ may together form —(CH ₂ ) _3-5 —,
R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are substituents selected from the group consisting of C _1-4 alkyl, C _1-4 alkylcarbonyl and C _1-3 alkoxy, wherein said C _{1 -4} alkyl is optionally substituted with one C _1-3 alkoxy group, and R ⁷¹ and R ⁷⁴ are each independently a C _1-3 alkyl group,
X _f ^- is the counter anion]
The skin cosmetic composition according to (1) or (2), which is a compound having the chemical structure of
(4) the cationic polymerization initiator is 2,2′-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl))propane triflate (ADIP), the skin cosmetic composition according to any one of (1) to (3).
(5) The skin cosmetic composition according to any one of (1) to (4), wherein the monomer containing a carbon-carbon double bond is a vinyl compound monomer.
(6) the monomer comprising a carbon-carbon double bond is from acrylamides, methacrylamides, acrylic acids, esters of acrylic acids, methacrylic acids, esters of methacrylic acids, styrenes, and vinyl acetate monomers; The skin cosmetic composition according to any one of (1) to (5), which is one or more compounds selected from the group consisting of:
(7) The skin according to any one of (1) to (6), wherein the monomer comprising a carbon-carbon double bond is N-isopropylacrylamide (NIPAM) and/or methyl methacrylate (MMA). cosmetic composition.
(8) The skin cosmetic composition according to any one of (2) to (7), wherein the cross-linking agent is N,N'-methylenebisacrylamide (MBAM) and/or divinylbenzene.
(9) The skin cosmetic composition according to any one of (1) to (8), for reducing or preventing moisture loss from the skin surface.

The present invention is advantageous in that it can provide skin cosmetic compositions that are less cytotoxic and less irritating. In addition, since the gel particle surface is covered with covalent cationic groups, it is chemically stable and does not elute compounds that cause irritation, which is advantageous in that it is highly safe as a skin cosmetic composition. be. The present invention is also advantageous in that it provides skin cosmetic compositions that are effective in reducing or preventing water loss from the skin surface. In particular, a cationic gel synthesized using a hydrophobic polymer is advantageous in that it can improve the skin barrier function when applied to rough skin.

FIG. 1 is a graph showing the amount of adsorption of fluorescent cationic NIPAM gel and fluorescent anionic NIPAM gel to porcine skin. The vertical axis is the average fluorescence intensity of 3 samples, and the error bar is the standard deviation.

Specific description of the invention

1. Cosmetic Composition for Skin The cosmetic composition for skin of the present invention comprises gel particles whose surfaces are covered with positive charges, and the gel particles contain a structural unit derived from a cationic polymerization initiator and a carbon- It is a copolymer comprising structural units derived from a monomer comprising a carbon double bond. Due to this feature, the skin cosmetic composition of the present invention has the effect of reducing or preventing water loss from the skin surface.

Furthermore, in order to improve the chemical stability of the gel particles, the copolymer preferably contains a crosslinked structure. Therefore, according to a preferred embodiment of the present invention, the skin cosmetic composition of the present invention has comprises gel particles coated with a positive charge, the gel particles comprising a structural unit derived from a cationic polymerization initiator, a structural unit derived from a monomer comprising a carbon-carbon double bond, and a cross-linking agent. A copolymer containing structural units derived from

である。本発明で用いられるゲル粒子の形状は、好ましくは略楕円球形状であり、さらに好ましくは略球形状である。このようなゲル粒子の好ましい構造や製法は、国際公開第２０１７／０４３４８４号に記載されている。 2. Gel Particles Covered with Positive Charges on the Surface The gel particles contained in the skin cosmetic composition of the present invention are gel particles of any shape covered with positive charges on the surface:

is. The shape of the gel particles used in the present invention is preferably approximately ellipsoidal, more preferably approximately spherical. Preferred structures and manufacturing methods for such gel particles are described in WO2017/043484.

の構造を有する。 According to one preferred embodiment, the gel particles are

has the structure

3. Method for Producing Gel Particles Surface-Covered with Positive Charges The above gel particles are produced, for example, by preparing a polymer in which at least one of the two ends or a unit near it is positively charged. be able to. According to one preferred embodiment, the gel particles used in the present invention are produced by performing a radical polymerization reaction using a cationic polymerization initiator and a monomer containing a carbon-carbon double bond. Further, according to a preferred embodiment of the present invention, the gel particles are produced by a polymerization reaction using a cross-linking agent in addition to a cationic polymerization initiator and monomers comprising carbon-carbon double bonds.

(1) Cationic polymerization initiator The cationic polymerization initiator used in the present invention is (a) stable at room temperature, (b) water-soluble, and (c) capable of producing radicals that cause a radical polymerization reaction. and (d) the end of the polymer after the radical polymerization reaction has a positive charge over a wide pH range, at least around neutrality.

Here, the cationic polymerization initiator preferably retains a positive charge in cells. The pH in most cells is between 2 and 9, and in the more common animal, plant and microbial cells is between 4 and 8. Therefore, it is desirable that the cationic polymerization initiator retains a positive charge within this pH range.

Moreover, the cationic polymerization initiator is desirably cationic on the skin surface. In other words, the state of the skin surface changes, such as a wet and moist environment or a dry environment. It is desirable to retain the positive charge under either condition in order to exhibit the effect for a long time. In other words, in water, water acts as a Bronsted acid, so amines and the like tend to be cationic, but it is desirable that they be cationic even in an environment without moisture. Specifically, it is desirable to have, for example, a quaternary ammonium structure instead of a proton-added cationic structure.

［式中、
Ｙは、単結合またはＣＲ^８５を表し、
Ｚは、単結合またはＣＲ^８６を表し、
Ｒ^７２、Ｒ^７３、Ｒ^７５、Ｒ^７６、Ｒ^７７、Ｒ^７８、Ｒ^８５およびＲ^８６は、それぞれ独立して、水素原子、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニル、フェニルおよびヒドロキシからなる群から選択され、ここで前記Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニルおよびフェニルは、さらにＣ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニル、フェニルおよびヒドロキシからなる群から選択される１または２個の置換基で置換されていてもよく、
Ｒ^７２およびＲ^７３は、さらに、それぞれ独立して、アダマンチル、またはＳｉ（ＯＣＨ_３）_２（ＣＨ_３）で置換されたＣ_１－６アルキルを表してもよく、
あるいは、Ｒ^７５およびＲ^７６、またはＲ^７７およびＲ^７８は、一緒になって－（ＣＨ_２）_３－５－を形成してもよく、
Ｒ^８１、Ｒ^８２、Ｒ^８３、およびＲ^８４は、Ｃ_１－４アルキル、Ｃ_１－４アルキルカルボニル、およびＣ_１－３アルコキシからなる群から選択される置換基であり、ここで前記Ｃ_１－４アルキルは一つのＣ_１－３アルコキシ基で置換されていてもよく、および
Ｒ^７１およびＲ^７４は、それぞれ独立して、Ｃ_１－３アルキル基であり、
Ｘ_ｆ ^－はカウンターアニオンである］
の化学構造を有する。 The cationic polymerization initiator used in the present invention has, for example, general formula (I):

[In the formula,
Y represents a single bond or ^CR85 ;
Z represents a single bond or ^CR86 ;
R ⁷² , R ⁷³ , R ⁷⁵ , R ⁷⁶ , R ⁷⁷ , R ⁷⁸ , R ⁸⁵ and R ⁸⁶ are each independently a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl is selected from the group consisting of carbonyl, phenyl and hydroxy, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl and phenyl are further C _1-6 alkyl, C _1-6 alkoxy, optionally substituted with 1 or 2 substituents selected from the group consisting of C _1-6 alkylcarbonyl, phenyl and hydroxy;
R ⁷² and R ⁷³ may also each independently represent C _1-6 alkyl substituted with adamantyl or Si(OCH ₃ ) ₂ (CH ₃ );
Alternatively, R ⁷⁵ and R ⁷⁶ or R ⁷⁷ and R ⁷⁸ may together form —(CH ₂ ) _3-5 —,
R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are substituents selected from the group consisting of C _1-4 alkyl, C _1-4 alkylcarbonyl and C _1-3 alkoxy, wherein said C _{1 -4} alkyl is optionally substituted with one C _1-3 alkoxy group, and R ⁷¹ and R ⁷⁴ are each independently a C _1-3 alkyl group,
X _f ^- is the counter anion]
has a chemical structure of

The "counter anion" in the cationic polymerization initiator is not particularly limited as long as it is an anion that is commonly used as a counter anion for organic compounds in the technical field of organic chemistry. , fluoride ion, iodide ion), conjugate bases of organic acids (eg, acetate ion, trifluoroacetate ion), nitrate ion, sulfate ion, carbonate ion, and the like. Preferred counter anions in the present invention include, for example, trifluoromethanesulfonate ion (triflate), chloride ion, nitrate ion and the like.

As will be readily understood by those skilled in the art, when the counter anion is divalent or higher, it forms ionic bonds with the corresponding number of ionic functional groups.

In one embodiment of the invention Y and Z of formula (I) represent a single bond.

In another embodiment, R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ of formula (I) each independently consist of methyl, ethyl, methylcarbonyl, isobutyl, and 2-methyl-2-methoxy-propyl. selected from the group.

In another embodiment, ^R71 and ^R74 of formula (I) are methyl groups.

In another embodiment, R ⁷² , R ⁷³ , R ⁷⁵ , R ⁷⁶ , R ⁷⁷ , R ⁷⁸ , R ⁸⁵ and R ⁸⁶ of Formula (I) are each independently a hydrogen atom, a C _1-6 alkyl , C _1-6 alkoxy, C _1-6 alkylcarbonyl, phenyl and hydroxy.

In another embodiment, R ⁷⁵ and R ⁷⁶ or R ⁷⁷ and R ⁷⁸ of formula (I) are taken together to form -(CH ₂ ) ₄ -.

According to a preferred embodiment of the present invention, R ⁷² and R ⁷³ , R ⁷⁵ and R ⁷⁷ , R ⁷⁶ and R ⁷⁸ , R ⁸¹ and R ⁸⁴ , R ⁸² and R ⁸³ , and R ⁷¹ and R of formula (I) ⁷⁴ each represent the same substituent, and Y and Z represent the same substituent or both a single bond.

According to a further preferred embodiment of the cationic polymerization initiator used in the present invention, R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ , R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ in formula (I) are methyl group, R ⁷⁵ , R ⁷⁶ , R ⁷⁷ and R ⁷⁸ are hydrogen atoms, and Y and Z are single bonds.

The method for synthesizing the compound of formula (I) is not particularly limited, but it can be synthesized, for example, as follows.

を適当な溶媒に溶解し、過剰量のメタノール存在下、室温で塩化水素ガスを通じることによって、活性なイミノエステル誘導体：

を得ることができる。なお、本明細書において構造式中のＭｅはメチル基を意味する。次に、当該イミノエステル誘導体に、エチレンジアミンなどのアルキレンジアミン誘導体：

を過剰量加え、撹拌することによって環状構造になった化合物：

を得ることができる。さらに、ジクロロメタンに生成物を溶解し、室温、脱酸素条件下において、２．１当量のトリフルオロエタンスルホン酸エステルＲ^７1ＯＴｆもしくはＲ^７４ＯＴｆを反応させることにより、Ｎアルキル化反応が起こり、式（Ｉ）に表される目的の化合物を得ることができる。 First, α,α'-azobisisobutyronitrile (AIBN) derivative:

in a suitable solvent and passing hydrogen chloride gas at room temperature in the presence of excess methanol to give the active imino ester derivative:

can be obtained. In this specification, Me in structural formulas means a methyl group. Next, the iminoester derivative is added with an alkylenediamine derivative such as ethylenediamine:

A compound with a cyclic structure by adding an excess amount of and stirring:

can be obtained. Furthermore, by dissolving the product in dichloromethane and reacting with 2.1 equivalents of trifluoroethanesulfonic acid ester R ⁷¹ OTf or R ⁷⁴ OTf at room temperature under deoxygenating conditions, an N-alkylation reaction takes place. The objective compound represented by (I) can be obtained.

According to a preferred embodiment of the present invention, the compound of formula (I) above is 2,2′-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium -2-yl)) propane triflate (ADIP).

(2) Monomer In the present invention, any monomer can be used as a raw material for the radical polymerization reaction as long as it is a compound having a carbon-carbon double bond. In addition, those skilled in the art can appropriately select one suitable for filling or chemically bonding a desired component or compound among them. In addition, those skilled in the art can appropriately select suitable ones from the viewpoint of biocompatibility, degradability, and the like. Furthermore, among them, those skilled in the art can appropriately select from the viewpoints of efficiency, economy, safety, etc. of the radical polymerization reaction.

In one embodiment of the present invention, for example, when the component or compound to be filled has a low molecular weight of 1000 or less, gel particles with a high cross-linking agent concentration and a small pore size can be selected. In addition, since low-molecular-weight molecules tend to diffuse out of the mesh of gel particles, the hydrophobicity and charge of low-molecular-weight molecules are used to promote interaction with gel particles as described below. It is desirable to select monomers that are capable of directly bonding to the gel particles, either through a covalent bond or through a covalent bond. On the other hand, in the case of a polymer with a relatively large molecular weight, the network can be controlled by appropriately selecting the concentration of the cross-linking agent.

In another embodiment, monomers such as PEG are used when biocompatibility is important.

In another embodiment, if the component or compound to be filled has a charge, a monomer with an ionic group to counter the charge can be selected. For example, if the component or compound to be filled has a negative charge, a monomer having a positively charged side chain such as an amine may be used, and if the component or compound to be filled has a positive charge, a carboxylic acid, etc. and a monomer having a negatively charged side chain.

In another embodiment, the monomer can be selected according to the hydrophobicity/hydrophilicity of the filling component or compound. For example, if the component or compound to be filled is a highly hydrophobic molecule, a monomer that does not contain a hydroxyl group, an amine group, or an ionic group in the side chain and has a large number of carbon atoms may be mentioned. If the compound has a structure containing a benzene ring, by selecting a monomer having a phenyl group in the side chain, interaction can maintain the stability of the filling component in the gel particles. On the other hand, if the component or compound to be filled is a highly hydrophilic molecule that is easily soluble in water, a monomer containing a hydroxyl group, an amine group and an ionic group in its side chain can be used.

In another embodiment, when a component or compound is covalently bonded to the gel particles, the compound is synthesized by covalently bonding an acrylamide-based monomer or the like to a target low-molecular-weight or high-molecular-weight gel particle. It can be used as a monomer.

In another embodiment, when considering releasing the filling component or compound out of the gel particles in response to pH, a monomer that changes its chemical structure in response to pH can be selected. , the pore size of the gel particles and the strength of their interaction with the filling component or compound can be controlled. Examples of such monomers include monomers containing carboxylic acids and amines in their side chains.

In another embodiment, when considering releasing the filling component or compound out of the gel particles in response to temperature, it is possible to select a monomer that changes the polymer structure in response to temperature. , the pore size of the gel particles and the strength of their interaction with the filling component or compound can be controlled. Such monomers include acrylamide-based monomers.

In another embodiment, when considering releasing the filling component or compound out of the gel particles in response to light such as ultraviolet light, the structure of a portion of the monomer is cleaved in response to UV. By selecting a suitable monomer, the structure of the gel particles can be greatly changed, and the filling component or compound can be released out of the gel particles. PEG-photo-MA (Murayama, Shuhei, et al. “NanoPARCEL: a method for controlling cellular
behavior with external light. "Chemical Communications 48.67 (2012): 8380-8382.).

According to a preferred embodiment of the present invention, monomers containing carbon-carbon double bonds used in the present invention include vinyl compound monomers. For example, if the monomers are classified by the Q value when using the Qe scheme based on the Alfrey, Price formula, which is an empirically useful index for the synthesis of copolymers, Q ≥ 0.2 Conjugated monomers include acrylamides, methacrylamides, acrylic acids, esters of acrylic acids, methacrylic acids, esters of methacrylic acids, styrenes, and the like. Examples include vinyl monomers. Since it is known that monomers with similar Q values are easy to copolymerize, copolymers in these categories can be easily produced.

According to a particularly preferred embodiment of the present invention, the monomer containing a carbon-carbon double bond used in the present invention includes N-isopropylacrylamide (NIPAM), N-isopropylmethacrylamide (NIPMAM), methyl methacrylate. (MMA), or vinyl acetate monomers, more preferably N-isopropylacrylamide (NIPAM) and/or methyl methacrylate (MMA).

(3) Cross-linking agent In the present invention, when a cross-linking agent is used as a starting material for the radical polymerization reaction, the cross-linking agent is a monomer containing two or more vinyl groups in the molecule and is commonly used as a cross-linking agent. It is not particularly limited as long as it exists. Specific examples of the cross-linking agent include N,N'-methylenebisacrylamide, N,N'-ethylenebisacrylamide, N,N'-methylenebismethacrylamide, N,N'-ethylenebismethacrylamide, ethylene Glycol diacrylate, ethylene glycol dimethacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, divinylbenzene and the like.

The amount of the cross-linking monomer used in the present invention is not particularly limited, but for example, an amount of 0.1 to 20 mol % can be used with respect to the monomer containing a carbon-carbon double bond.

According to a particularly preferred embodiment of the present invention, N,N'-methylenebisacrylamide (MBAM) or divinylbenzene is used as the crosslinker used in the present invention.

(4) Reaction Conditions The gel particles used in the present invention can be synthesized based on common knowledge in the technical field of polymer synthesis, and can be obtained as polymers by, for example, radical polymerization.

One example of the method for producing gel particles used in the present invention is as follows.

The polymerization initiator is used in an amount of 0.01 mol % or more based on the amount of the monomers used, and an appropriate amount can be selected within the concentration range at which radical synthesis proceeds. For example, 0.1 mol % or more, preferably 1 mol % or more of polymerization initiator can be used.

The reaction solvent used in the polymerization reaction is not particularly limited, and examples thereof include water, methanol, acetone, and mixed solvents thereof. An emulsion polymerization system in which water is used as a solvent and the system is stirred to carry out the polymerization reaction is preferred. Radical polymerization is not particularly limited, but can be carried out at a reaction temperature of, for example, 0 to 100° C., preferably 50 to 70° C., and for a reaction time of, for example, 1 to 48 hours, preferably 2 to 16 hours.

The copolymerization reaction when using a cross-linking monomer can be carried out by a method commonly used in the technical field.

The reaction solvent used in the copolymerization reaction is not particularly limited, but examples thereof include surfactants (e.g., sodium dodecyl sulfate, sodium dodecylbenzene sulfate, sodium pentadecane sulfate, Bromide, N-cetyl-N,N,N-trimethylammonium bromide, Triton X-100, etc.) can be used.

The size of the copolymer nanogel (nano-sized gel microparticles) can be adjusted by the stirring efficiency in the copolymerization reaction, the reaction temperature, the amount of surfactant used, the amount of reaction initiator used, and the amount of cross-linking monomer used. can be done. For example, nanogels with a small size can be obtained by increasing the amount of surfactant and/or initiator used. The size of the obtained nanogel can be appropriately adjusted by those skilled in the art to which the present invention belongs, and the size of the nanogel of the copolymer of the present invention is, for example, 5 to 100 nm.

The copolymerization reaction conditions are not particularly limited, but include, for example, a reaction temperature of 0 to 100° C., preferably 50 to 70° C., and a reaction time of, for example, 1 to 48 hours, preferably 2 to 16 hours.

Further, based on common knowledge in the technical field of polymer synthesis, a polymerization reaction can be caused by UV irradiation, if necessary.

According to a preferred embodiment of the invention the polymerization reaction is carried out under mechanical agitation. In addition, in order to produce gel particles using a hydrophobic monomer, it is preferable to carry out the polymerization reaction using a solvent that is highly compatible with water, such as water, methanol, acetone, or a mixture thereof. Furthermore, even when gel particles are produced using a water-soluble monomer, if the resulting polymer is poorly soluble in water, a solvent highly compatible with water, such as water , methanol, acetone, or mixtures thereof. In the case of producing gel particles using a water-soluble monomer, if the resulting polymer is readily soluble in water, a water-in-oil emulsion is formed from an aqueous solution of the water-soluble monomer, followed by cationic polymerization. Gel particles can be produced by adding an initiator and performing a polymerization reaction. Furthermore, if a cross-linking agent is used when producing gel particles, gel particles can be formed using monomers with various properties, and the chemical stability of the resulting gel particles can be improved.

4. Other Ingredients The cosmetic composition for skin of the present invention may optionally contain ingredients other than those mentioned above within a range that does not substantially impair the effects of the present invention. Examples of such components include liquid oils such as olive oil, camellia oil, macadamia nut oil, and castor oil; solid oils; waxes such as carnauba wax, candelilla wax, jojoba oil, beeswax, and lanolin; stearyl alcohol, cetyl alcohol, behenyl alcohol; Higher alcohols such as isostearyl alcohol; Higher fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid and isostearic acid; Hydrocarbon oils such as liquid paraffin, paraffin, vaseline, ceresin, microcrystalline wax and squalane; Isopropyl myristate , 2-octyldodecyl myristate, cetyl 2-ethylhexanoate, diisostearyl malate, and other ester oils; methylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, amino-modified or polyether-modified silicone oils, etc. Silicone oil; moisturizing agents such as glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, sorbitol, sodium 2-pyrrolidone-5-carboxylate, sodium hyaluronate; cationized cellulose, cationization Cationic polysaccharides such as guar gum and cationized locust bean gum, synthetic cationic polymers such as polyquaternium-7, water-soluble polymers such as amphoteric polymers such as polyquaternium-39; trichlorocarbanilide, sulfur, zinc pyrithione, Antidandruff agents such as isopropylmethylphenol; vegetable thickeners, microbial thickeners, animal thickeners, cellulose thickeners, starch thickeners, alginic acid thickeners, vinyl polymers , Thickeners such as high molecular weight polyethylene glycol; Viscosity modifiers; Emulsifiers; Sequestering agents; UV absorbers; Antioxidants; Preservatives such as octanediol and methylisothiazolinone; mica, talc, kaolin, calcium carbonate, magnesium carbonate, silicic anhydride, aluminum oxide, barium sulfate, red iron oxide, yellow iron oxide, black iron oxide, chromium oxide, ultramarine blue, Prussian blue , carbon black, titanium dioxide, zinc oxide, mica titanium, fish scale foil, bismuth oxychloride, boron nitride, photochromic pigment, synthetic fluorine phlogopite, iron-containing synthetic fluorine phlogopite, powder components such as fine particle composite powder; Red No. 106 ,is Pigments such as Orange No. 205, Yellow No. 4, Green No. 3, Blue No. 1; lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, polymer emulsions, various extracts, blood circulation promoters, Hair growth agents such as hair follicle activators, antiandrogenic agents, antiseborrheic agents, keratolytic agents, bactericides, antioxidants, antioxidant aids, antiphlogistic agents, skin nutrients, vitamins, crude drug extracts, pH Adjusting agents, fragrances, etc. can be mentioned, and these can be appropriately blended according to need and can be produced by a conventional method according to the desired dosage form.

The skin cosmetic composition of the present invention can be produced according to a method according to the dosage form and form to be selected. It is manufactured by dissolving in a solvent of The product forms of the skin cosmetic composition of the present invention include lotions, creams, ointments, powders, sheets, sprays and the like.

EXAMPLES The present invention will be described in more detail by showing Examples below, but the present invention is not limited to these Examples.

EXPERIMENTAL PROCEDURES Zeta potential was measured using a Zetasizer Nano ZS (Malvern). The gel particle size was measured based on the dynamic light scattering method (DLS) using ELS-8000 (Otsuka Electronics) or Zetasizer Nano ZS (Malvern).

N-(2-{[7-(N,N-dimethylaminosulfonyl)-2,1,3-benzothiadiazole-4, which is one of the monomers (fluorescent units) necessary for the synthesis of the copolymer -yl]-(methyl)amino}ethyl)-N-methylacrylamide (DBThD-AA) was carried out according to the method described in Document A (Chemistry A European Journal 2012, Vol. 18, pp. 9552-9563). .

Similarly, 2,2'-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazole-3- Ium-2-yl))propane triflate (ADIP) was carried out according to the method described in literature B (Angewandte Chemie International Edition 2018, 57, 5413-5417).

Example 1-1: Preparation of cationic N-isopropylacrylamide (NIPAM) gel (MH028) and anionic NIPAM gel (MH020)
(1) Synthesis of cationic NIPAM gel MH028 226.33 mg NIPAM (100 mM), 3.08 mg N,N'-methylenebisacrylamide (MBAM) (1 mM), 7.7 mg DBThD-AA (acrylamide group-fluorescence dye) (1 mM), and 12.16 mg of cetyltrimethylammonium chloride (1.9 mM) were dissolved in 19 mL of ultrapure water. Dissolved oxygen was expelled with nitrogen gas for 30 minutes while stirring at 70°C. The reaction was initiated by the dropwise addition of 339.79 mg of cationic initiator ADIP (28 mM) and 6.74 mg of tetramethylethylenediamine (TEMED) (2.9 mM) dissolved in 1 mL of ultrapure water. The reaction was carried out at 70° C., 1 hr, 170 rpm. The resulting reaction solution was dialyzed for one week using ultrapure water as the external solution, and then freeze-dried. A yellow powder was obtained with a yield of 11%.

(2) Synthesis of anionic NIPAM gel MH020 226.42 mg NIPAM (100 mM), 3.13 mg MBAM (1 mM), 5.65 mg DBThD-AA (1 mM), and 72.57 mg SDS (12.6 mM) was dissolved in 45 mL of ultrapure water. Dissolved oxygen was expelled with nitrogen gas for 30 minutes while stirring at 70°C. The reaction was initiated by the dropwise addition of 127.89 mg ammonium persulfate (28 mM) and 6.74 mg TEMED (2.9 mM) dissolved in 5 mL ultrapure water. The reaction was carried out at 70° C., 1 hr, 170 rpm. The resulting reaction solution was dialyzed for 8 days using water as the external solution, and then freeze-dried. A yellow powder was obtained with a yield of 51%.

(3) Zeta potential measurement The synthesized sample was dissolved in ultrapure water at a concentration of 0.1%, and the zeta potential was measured at 45°C (Zetasizer Nano ZS, Malvern). It was found that gels with anionic and anionic surfaces were formed.

Example 1-2: Evaluation of cationic N-isopropylacrylamide (NIPAM) gel (MH028) adsorptivity to pig skin Pig skin (Charles River) was partially thawed and the fat part was excised. The obtained skin was arranged on a sheet of 1 cm square. A perforated 96-well plate was sandwiched between skins from above and below so that the black surface of the skin faced upward, and a weight was placed thereon. Phosphate buffer saline (PBS: 137 mM NaCl, 2.7 mM KCl, 81 mM Na ₂ HPO ₄ , 14.7 mM KH ₂ PO ₄ ) was placed in a metal vat, and a 96-well plate sandwiched between skins was placed in PBS. Each 100 μL of various aqueous gel solutions prepared so as to have a concentration of 0.1 (w/v) % from the skin surface was placed on the gel. Cover with plastic wrap so as not to evaporate, react at 25° C. for 2 hours, wash twice with 100 μL of PBS, and detect gel-derived fluorescence with a stereoscopic fluorescence microscope (excitation 470 nm (LED), fluorescence 560 nm or more (SC56 filter)). Observed. All the parts on which the samples were placed were photographed, the entire sample-applied parts were surrounded by image analysis software ImageJ, the brightness was quantified, and the average value was calculated.

FIG. 1 shows the results of quantifying the amount of fluorescence remaining on the pig skin surface. As shown in FIG. 1, the positively charged NIPAM gel was found to strongly adsorb to the skin surface.

Example 2-1: Cationic polymerization initiator 2,2′-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl))propane triflate Preparation of methyl methacrylate (MMA) gels (TT060, AK046) and N-isopropylacrylamide (NIPAM) gels (AK030) using (ADIP)
(1) Synthesis of cationic methyl methacrylate (MMA) gel (TT060) Prepare 500 mL of ultrapure water (manufactured by Millipore's ultrapure water production equipment) in which dissolved oxygen is removed by bubbling nitrogen gas for 30 minutes. did. The mixture was heated to 60° C. while nitrogen bubbling was performed under stirring at 450 rpm. Then, 2880 mg (64 mM) of methyl methacrylate (MMA) and 559.5 mg (2.05 mM) of cationic polymerization initiator 2,2′-azobis-(2-(1,3 -dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl))propane triflate (ADIP) was added dropwise to initiate the reaction. The mixture was reacted at 60° C. for 6 hours with propeller stirring at 450 rpm. The reaction solution was purified by dialysis for 2 days using ultrapure water as an external solution to obtain a copolymer compound TT060 having a solid content of 0.56 (w/v) %.

AK046 was synthesized by the same method and concentrated by centrifugation at 20400 xg for 20 minutes. After centrifugation, 1 mL of the supernatant was removed and dissolved in 5 mL of ultrapure water. This gave 1.83 (w/v) % of copolymer compound AK046.

Mean particle size and mean zeta potential measurements were performed at 25° C. for TT060 and AK046.

For TT060, to be used as a 24-hour occlusive human patch test sample, concentration by centrifugation was performed according to the following procedure. 40 mL of TT060 suspension was centrifuged at 20400 xg for 20 minutes. All but 5 mL of the supernatant was removed and centrifuged again at 20400 xg for 6 minutes. After that, the supernatant was removed except for 1 mL, and dissolved in 5 mL of ultrapure water. Thus, an aqueous TT060 solution with a concentration of 1.0 (w/v)% was prepared.

(2) Synthesis of cationic N-isopropylacrylamide (NIPAM) gel (AK030) 500 mL of ultrapure water in which dissolved oxygen has been expelled by bubbling nitrogen gas for 30 minutes (manufactured by an ultrapure water production apparatus manufactured by Millipore) Got ready. 5658 mg (100 mM) of N-isopropylacrylamide (NIPAM) and 325 mg (5 mM) of divinylbenzene (DVB) were added to 480 mL of ultrapure water and stirred at 300 rpm and 70° C. for 30 minutes. Then 8493 mg (28 mM) of the cationic polymerization initiator 2,2′-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium) dissolved in 20 mL of ultrapure water -2-yl))propane triflate (ADIP) was added and allowed to react for 1 hour. After the reaction, the solution was ice-cooled, aggregates were removed with a filter paper, and then sodium chloride was added in a saturated amount or more for salting out. The precipitate was collected by filtration through a glass filter and dissolved in ultrapure water to obtain an aqueous solution. The solution was dialyzed through a 3.5 kDa dialysis membrane. A few mL samples were collected after 3 days of dialysis, and after centrifugation at 20400×g for 20 minutes, mean particle size and mean zeta potential were measured at 45°C.

Table 2 shows the characteristics of each gel particle synthesized according to the method described above. Since the surface zeta potential is positive in both cases, we were able to synthesize particles with cationic properties.

Example 2-2: Safety evaluation by 24-hour occlusive human patch test of cationic methyl methacrylate (MMA) gel (TT060) and N-isopropylacrylamide (NIPAM) gel (AK030) 1 produced in Example 2-1 0 (w/v)% TT060 and 1.0 (w/v)% AK030 prepared with ultrapure water were used as test samples. The test was conducted according to the human patch test (p.176) in Chapter 4 of "Cosmetics/Quasi-drugs Manufacturing and Marketing Guidebook 2011-12". There were 20 subjects, Japanese males and females aged 20 to 59, and evaluation was performed by a 24-hour occlusive human patch test. The inner upper arm was used as the treatment area. Appropriate amounts of test specimens were applied to a patch test unit (“Allegies Patch Test Chamber” (manufactured by Smart Practice Japan Co., Ltd.), and these were applied to appropriate treatment sites to form occluded patches.

The results of the 24-hour occlusive human patch test performed in the manner described above are shown in Tables 3 and 4 below.

From the results shown in Tables 3 and 4, 1.0 (w/v)% cationic methyl methacrylate (MMA) gel and 1.0 (w/v)% cationic N-isopropylacrylamide (NIPAM) gel All of them were classified as "safe products" with very little irritation.

Example 2-3: Immediate barrier improvement action evaluation test evaluation using cationic methyl methacrylate (MMA) gel (AK046) )% concentration. As a control, 0.1 (w/v)% hyaluronic acid, which has been used as a moisturizing agent, was used. The test was performed in the evaluation room of the testing facility (room temperature 20±2° C., relative humidity 50±10%). The transepidermal water loss (TEWL (g/m ² /h)) was measured three times or more with a cyclone water loss meter AS-CT1 (Nippon Ash Co., Ltd.), and the average value of three stable measurements. was used. The initial value of TEWL was measured after acclimating the inner forearm of 5 subjects (mean age 33.8±7.7) with the designated cleanser for 20 minutes after washing. After that, a 2 (w/v) % sodium dodecyl sulfate (SDS) aqueous solution patch was applied to the test site for 2 hours to prepare a simulated rough skin, and TEWL was measured. Five subjects were subjects who confirmed that the average TEWL measurement value immediately after application/removal of the SDS aqueous solution patch increased from the initial value. After that, 10 μL of the test product was applied to each test area on the inner side of the forearm, and the TEWL value was measured at the application site 1 hour and 2 hours after application.

Analysis of the measured values, as described in JP-A-2007-246459, is defined as rough skin when the increase in TEWL value after application of SDS increases by 25% or more from the initial value, and is 25% or more. When no increase was observed, it was excluded from analysis. Also, the difference (ΔTEWL value) between the TEWL value after 1 hour and 2 hours after application and the TEWL value after application of SDS was calculated. For each subject, the ΔTEWL value at the time of water application at each treatment time was standardized as 1, the average value of the subjects was calculated, and tested by Welch's t-test. Table 5 shows the results.

From these results, in the group to which the cationic PMMA gel was applied, the skin barrier property was significantly improved in 1 hour compared to the water application, and there was a tendency for improvement even in 2 hours (P=0.069). Furthermore, it was found that significant skin barrier properties were maintained for up to 2 hours compared to hyaluronic acid, which is used as a moisturizing agent.

Claims (5)

A skin cosmetic composition comprising gel particles having a surface covered with positive charges, wherein the gel particles have a structure derived from a cationic polymerization initiator and a monomer comprising a carbon-carbon double bond. A copolymer comprising the unit
The copolymer contains a structural unit derived from a cross-linking agent,
A cosmetic composition for skin , wherein the monomer comprising a carbon-carbon double bond is N-isopropylacrylamide (NIPAM) and/or methyl methacrylate (MMA) . The cationic polymerization initiator has the general formula (I):

[In the formula,
Y represents a single bond or ^CR85 ;
Z represents a single bond or ^CR86 ;
R ⁷² , R ⁷³ , R ⁷⁵ , R ⁷⁶ , R ⁷⁷ , R ⁷⁸ , R ⁸⁵ and R ⁸⁶ are each independently a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl is selected from the group consisting of carbonyl, phenyl and hydroxy, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl and phenyl are further C _1-6 alkyl, C _1-6 alkoxy, optionally substituted with 1 or 2 substituents selected from the group consisting of C _1-6 alkylcarbonyl, phenyl and hydroxy;
R ⁷² and R ⁷³ may also each independently represent C _1-6 alkyl substituted with adamantyl or Si(OCH ₃ ) ₂ (CH ₃ );
Alternatively, R ⁷⁵ and R ⁷⁶ or R ⁷⁷ and R ⁷⁸ may together form —(CH ₂ ) _3-5 —,
R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are substituents selected from the group consisting of C _1-4 alkyl, C _1-4 alkylcarbonyl and C _1-3 alkoxy, wherein said C _{1 -4} alkyl is optionally substituted with one C _1-3 alkoxy group, and R ⁷¹ and R ⁷⁴ are each independently a C _1-3 alkyl group,
X _f ^- is the counter anion]
The skin cosmetic composition according to claim 1 , which is a compound having the chemical structure of The cationic polymerization initiator is 2,2′-azobis-(2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl))propane triflate (ADIP) The cosmetic composition for skin according to claim 1 or 2 , which is The skin cosmetic composition according to any one of claims 1 to 3 , wherein said cross-linking agent is N,N'-methylenebisacrylamide (MBAM) and/or divinylbenzene. The skin cosmetic composition according to any one of claims 1 to 4 , for reducing or preventing water loss from the skin surface.

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