Radical reactive polymer micelle

Abstract

The present disclosure provides a composition in which a radical reaction-imparting substance and a polymer micelle that encapsulates a hydrophobic substance are uniformly mixed.

Description

Radical-reactive polymer micelles

[0001] The present invention relates to a composition comprising a polymeric micelle encapsulating a hydrophobic substance and a radical reactivity imparting substance, a cosmetic composition or a topical skin composition comprising said composition, and a method for producing said composition.

[0002] Skin is the largest organ, located at the outermost layer of the body, and is susceptible to oxidative stress and damage caused by reactive oxygen species (radical species) generated by external conditions. However, reactive oxygen scavenging enzymes exist within skin cells, protecting them from damage caused by reactive oxygen species unless the number of reactive oxygen species exceeds their scavenging capacity. However, during the day outdoors or indoors where sunlight shines in, strong ultraviolet rays can easily generate a large number of reactive oxygen species in the skin. Furthermore, it is known that the activity of reactive oxygen scavenging enzymes within skin cells declines with age. Therefore, when the reactive oxygen scavenging enzymes are no longer able to scavenge all the reactive oxygen species, skin cells become oxidized, accelerating aging.

[0003] To support the defense of skin cells by ROS-scavenging enzymes, ROS scavengers and antioxidants have been investigated, and cosmetics, quasi-drugs, pharmaceuticals, and foods containing ROS-scavenging enzymes such as SOD and catalase, and ROS scavengers and antioxidants such as SOD-like active substances, have been developed. However, when applying the above-mentioned cosmetics or topical preparations to the skin during sunny days, the release of the active ingredients, ROS scavengers and antioxidants, onto the skin begins immediately after application. Therefore, to maintain the effect, they must be applied immediately before going out, limiting the timing of application. Furthermore, once applied, the release onto the skin cannot be stopped midway. Even when indoors, excessive release occurs. However, when needed, the active ingredient may be depleted and lose its effectiveness, requiring reapplication, which is inconvenient. The applicant has previously reported polymer micelles (Patent Document 1) capable of encapsulating and sustaining the release of active ingredients that can be used in cosmetics and quasi-drugs, but the problem of controlling the timing of active ingredient release remains unresolved.

[0004] Japanese Patent Application Laid-Open No. 2009-275007

[0005] Therefore, an object of the present disclosure is to provide, for example, a composition capable of releasing an active ingredient in response to radical species generated on the skin, etc., a cosmetic composition and a topical skin composition containing the composition, and a method for producing the composition.

[0006] In order to achieve the above object, the composition of the present disclosure comprises: (A) a hydrophobic substance; (B) a polymer micelle containing the hydrophobic substance and including a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2); and (C) a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group, n is an integer of 10 to 2500, x is an integer of 10 to 300, and y is an integer of 1 or 2.

[0007] The method for producing the composition of the present disclosure includes the following steps: (1) mixing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), a hydrophobic substance, and a dispersion medium; and (2) mixing the polymer micelles obtained in step (1) with a radical reaction-imparting substance. [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group, n is an integer of 10 to 2500, x is 1 or an integer of 0 to 300, and y is an integer of 1 or 2.

[0008] According to the present disclosure, it is possible to provide a composition capable of releasing an active ingredient in response to radical species generated on the skin, a cosmetic composition and a topical skin composition containing the composition, and a method for producing the composition.

[0009] FIG. 1 is a graph showing the particle size distribution of polymer micelles of the present disclosure and comparative polymer micelles. The horizontal axis shows particle size (nm), and the vertical axis shows relative scattering intensity. FIG. 2 is a graph showing the inhibition rate of the WST-1 formazan production reaction of polymer micelles of the present disclosure and comparative polymer micelles. The vertical axis shows the inhibition rate (%) of the WST-1 formazan production reaction. *: p<0.005

[0010] (Composition of the Present Disclosure) The present disclosure provides a composition (composition of the present disclosure) comprising the following (A) to (C): (A) a hydrophobic substance (the hydrophobic substance of the present disclosure). (B) a polymeric micelle (the polymeric micelle of the present disclosure) comprising the hydrophobic substance. (C) a radical reaction-imparting substance (the radical reaction-imparting substance of the present disclosure).

[0011] The inventors conducted extensive research to achieve the above-mentioned objectives. They prepared polymer micelles encapsulating a hydrophobic substance (comparative polymer micelles) and polymer micelles prepared by treating the comparative polymer micelles with a platinum colloid solution (polymer micelles of the present disclosure). Their radical reactivity was then examined, revealing that the polymer micelles of the present disclosure were able to release a greater amount of hydrophobic substance. Furthermore, measurements of the average particle size, particle size distribution, and zeta potential of the polymer micelles of the present disclosure and the comparative polymer micelles revealed that, although there was no difference in particle size between the two, the polymer micelles of the present disclosure had a larger absolute value of zeta potential and superior dispersibility compared to the comparative polymer micelles. Therefore, by applying the polymer micelles of the present disclosure encapsulating a desired hydrophobic substance (active ingredient) to the skin in advance, the active ingredient is released in response to radical species generated on the skin by UV rays or other factors, thereby effectively scavenging the radical species. Furthermore, the polymer micelles of the present disclosure also have the secondary effect of superior dispersibility.

[0012] (A) Hydrophobic Substance The hydrophobic substance of the present disclosure is not particularly limited as long as it has an oil-water partition coefficient (LogPow) of 0 or more in 1-octanol and water. Substances with a partition coefficient of 0 or more are defined as fat-soluble, while substances with a partition coefficient of 0 or less are defined as water-soluble. Therefore, any substance with an oil-water partition coefficient of 0 or more falls under the category of the hydrophobic substance of the present disclosure.

[0013] The hydrophobic substance of the present disclosure is not limited as long as it satisfies the above conditions, but preferred examples thereof include substances that are commonly used as cosmetic additives and / or pharmaceutical ingredients. Examples of such substances include, but are not limited to, pigmentation inhibitors, tyrosinase activity inhibitors, melanin production inhibitors, and antioxidants. In view of the radical reactivity of the polymer micelles of the present disclosure, antioxidants are preferred.

[0014] Antioxidants include vitamin A group, retinol or its salts and derivatives thereof (unsaturated retinol fatty acid esters such as retinol palmitate, retinol linoleate, retinol linolenate, retinol oleate, and retinol arachidonic acid), retinal or its salts and derivatives thereof, dehydroretinal or its salts and derivatives thereof, retinoic acid or its salts and derivatives thereof, retinoic acid analogs, carotene or its salts and derivatives thereof, and lycopene or its salts and derivatives thereof.

[0015] Examples of antioxidants other than vitamin A include vitamin C and derivatives thereof, vitamin E and derivatives thereof, vitamin D and derivatives thereof, bakuchiol, superoxide dismutase, catalase and other endogenous active oxygen decomposing enzymes, ascorbic acid, butylhydroxyanisole, dibutylhydroxytoluene (BHT), propyl gallate, ubidecaquinone (ubiquinone), rutin, rutin glucoside, and γ-oryzanol.

[0016] (B) Polymeric Micelles The polymeric micelles of the present disclosure are polymeric micelles containing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), which are block copolymers consisting of a hydrophilic segment (polyethylene glycol) and a hydrophobic segment (polyamino acid). In each of the above formulas, R １ and R ３each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group; n is an integer of 10 to 2500; x is an integer of 10 to 300; and y is an integer of 1 or 2.

[0017] R in each of the above formulas １ and R ３ The lower alkyl group in the formula (I) refers to a straight-chain or branched-chain alkyl group having 7 or less carbon atoms, preferably 4 or less carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl groups. The optionally protected functional group includes hydroxyl groups, acetals, ketals, aldehydes, and sugar residues. The sugar residues can be selected from monosaccharides, disaccharides, and oligosaccharides, and are not particularly limited. Specific examples include glucosides, mannosides, fructosides, galactosides, maltosides, rutinosides, rhamnosides, deoxymannosylglucosides, and deoxygalactosylglucosides.

[0018] L in each of the above formulas １ and L ２are each independently a linking group, and are not limited and may vary depending on the method for producing the block copolymer. １ is -NH-, -O-, -O-Z-NH-, -CH ２ -, -O-Z-S-Z-, and -OCO-Z-NH- (where Z is C １ ~C ４ represents an alkylene group; ２ are -CO-, -OCO-Z-CO-, and -NHCO-Z-CO- (where Z is C １ ~C ４ and a group selected from the group consisting of: an alkylene group;

[0019] Among the block copolymers represented by the above formulas contained in the polymer micelles of the present disclosure, particularly preferred block copolymers are polyethylene glycol-poly(β-benzyl-L-aspartic acid) block copolymer and polyethylene glycol-poly(γ-benzyl-L-glutamic acid) block copolymer.

[0020] R in each of the above formulas ５ The hydrogen atoms in the amino acid units account for 0-60% of the total amino acid units, and groups other than hydrogen atoms (phenyl groups, C １ ~C ８ It is necessary that the proportion of R is in the range of 40 to 100%. ５ is 0 to 50% (the ratio of groups other than hydrogen atoms is 50 to 100%), particularly preferably 0 to 20% (the ratio of groups other than hydrogen atoms is 80 to 100%), and most preferably 0% (the ratio of groups other than hydrogen atoms is 100%). This is because the hydrophobic interaction between the hydrophobic segment molecules for supporting the hydrophobic substance is ５ The smaller the ratio of hydrogen atoms in the entire amino acid unit, the greater the strength of the micelle, and therefore the more stable and higher the concentration of the hydrophobic substance that can be supported within the micelle.

[0021] The polymeric micelles of the present disclosure are micelles formed by placing the hydrophobic segment (polyamino acid) of the block copolymer represented by each of the formulas above on the inside and the hydrophilic segment (polyethylene glycol) on the outside. Because the interior of the polymeric micelles of the present disclosure is hydrophobic, the hydrophobic substance of the present disclosure can be contained therein.

[0022] The amount of hydrophobic substance contained in the polymer micelles of the present disclosure is not particularly limited, but is usually adjusted to 0.0001 to 20% by weight relative to the total weight of the polymer micelles of the present disclosure, and from the viewpoint of the efficiency of encapsulating the hydrophobic substance within the polymer micelles, 0.01 to 10% by weight is particularly preferred.

[0023] The particle size of the polymeric micelles containing the hydrophobic substance of the present disclosure and coexisting with the radical reaction-imparting substance described below is not particularly limited, but may be specifically 40 to 600 nm, and may be, for example, 40 to 200 nm, which is considered to be a size that allows high infiltration into biological tissue (e.g., the stratum corneum of the skin) and does not migrate from biological tissue into the inside of blood vessels. The particle size of the polymeric micelles can be measured by a measurement means known in the art, for example, using a dynamic light scattering photometer (DLS-7000DH, Otsuka Electronics Co., Ltd.).

[0024] The zeta potential of polymer micelles containing the hydrophobic substance of the present disclosure and coexisting with a radical reaction-imparting substance (described below) is not particularly limited, but is typically 0 to -30 mV, preferably -5 to -30 mV, and more preferably -10 to -30 mV. The polymer micelles of the present disclosure exhibit excellent dispersibility due to the coexistence of the radical reaction-imparting substance, which increases the absolute value of the zeta potential compared to polymer micelles in the absence of the radical reaction-imparting substance. The zeta potential of the polymer micelles can be measured by any known measurement method in the field, for example, using a zeta potential analyzer (ZETASIZER Nano, Spectris).

[0025] The amount of polymer micelles contained in the composition of the present disclosure is not particularly limited, but is usually adjusted to, for example, within the range of 0.01 to 50 wt %, preferably 0.01 to 20 wt %, and more preferably 0.01 to 10 wt %, relative to the total weight of the composition of the present disclosure.

[0026] (C) Radical Reaction-Providing Substance The radical reaction-providing substance of the present disclosure (e.g., a component having antioxidant activity) is not particularly limited as long as it is a substance that provides the polymer micelles containing the hydrophobic substance of the present disclosure with the function of releasing the hydrophobic substance in the presence of radicals.

[0027] A radical is an atom or molecule that has an unpaired electron, such as superoxide or hydroxyl radical.

[0028] The radical reaction-imparting substance of the present disclosure is not particularly limited as long as it has the above-described properties, and examples thereof include noble metal nanoparticles.

[0029] Examples of the noble metal nanoparticles include platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles, and preferably platinum nanoparticles and silver nanoparticles. The noble metal nanoparticles may be any one of the above nanoparticles or a combination of two or more types. When two or more types are combined, any combination may be used. For example, when two types are combined, platinum nanoparticles may be selected as the first type and silver nanoparticles may be selected as the second type and combined. When the noble metal nanoparticles contain two or more types of the above nanoparticles, the blending ratio may be any.

[0030] Precious metal nanoparticles can be prepared by methods known in the art, such as pulverizing bulk precious metals (pulverization method) or generating precious metal nanoparticles through chemical reactions (chemical reaction method). The chemical reaction method is preferred because it allows for easy particle size control of the precious metal nanoparticles. Examples of chemical reaction methods include dry and wet methods. In the dry method, aggregates of precious metal atoms can be obtained by heating and vaporizing the precious metal in an inert gas or vacuum, or by sputtering. In the wet method, precious metal nanoparticles can be obtained by reducing a precious metal salt in a liquid or by thermally decomposing a metal complex. Precious metal nanoparticles may also be purchased commercially (e.g., platinum colloid solution (JOHZEN)).

[0031] The particle size of the noble metal nanoparticles used as the radical reaction-imparting substance of the present disclosure is not particularly limited, but is, for example, 70 nm to 90 nm (e.g., 80 nm). The particle size of the noble metal nanoparticles can be measured by the same method as the method for measuring the particle size of polymer micelles.

[0032] The radical reaction imparting substance of the present disclosure may be contained in the composition of the present disclosure itself, or may be contained in the composition of the present disclosure as a composition containing the radical reaction imparting substance. When the composition is a solid or liquid, it may be in a liquid form, since it is preferable that the radical reaction imparting substance of the present disclosure is uniformly dispersed in the composition of the present disclosure. Examples of liquid dosage forms include colloids. When the composition containing the radical reaction imparting substance of the present disclosure is a colloid, examples of the dispersion medium include water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, etc., and preferably water.

[0033] The radical reaction-imparting substance of the present disclosure, in the case where it is not a precious metal nanoparticle, may be, for example, a plant extract exhibiting antioxidant activity (e.g., Akebia japonica (Kodo) extract, Amacha (Amacha) extract, Oolong tea extract, Hollandaise extract, Kanran extract, Kumquat extract, Gobaisho extract, Geranium herb extract, sesame extract, sesame culture cell extract, Scrophulariaceae (Scrophulariaceae) extract, rice bran extract, pomegranate extract, Japanese pepper (Zanthoxylum piperitum) extract, European pear extract, Rhubarb (Rhubarb) extract, tomato extract, Nandina (Nandina fruit) extract, Thistle (Chinese thistle) extract, Rosa multiflora (Rhododendron multiflora) extract, paprika extract, Pisum sativum (Pistachio) extract, Examples of effective extracts include tachio extract, loquat extract, betel nut (betel nut peel), butterbur extract, Japanese quince extract, narrow-leaved euphorbia extract, ephedra extract, mimosa extract, basil extract, willow extract, willow polygonum extract, cotton deutzia extract, chlamydomonas extract, sedge extract, sea fan extract, sea fan extract, hypericum extract, hamamelis extract, clove extract, melissa extract, emmeiso extract, white birch extract, salvia extract, rosemary extract, nandina fruit extract, ginkgo extract, green tea extract, and clove extract.

[0034] The amount of the radical reaction-imparting substance contained in the composition of the present disclosure is not particularly limited, but is usually adjusted to be in the range of 0.2 to 50 wt %, preferably 1 to 10 wt %, based on the total weight of the composition of the present disclosure.

[0035] The composition of the present disclosure, which includes the hydrophobic substance, the polymer micelles, and the radical reaction-imparting substance, is a composition in which the polymer micelles contain the hydrophobic substance in their internal hydrophobic regions, and the polymer micelles and the radical reaction-imparting substance are uniformly mixed. The polymer micelles contained in the composition of the present disclosure have the ability to release the encapsulated hydrophobic substance depending on the presence of radicals, due to the radical reaction-imparting substance. Furthermore, the polymer micelles contained in the composition of the present disclosure have a larger absolute value of zeta potential than polymer micelles in a composition not containing the radical reaction-imparting substance, and therefore have excellent dispersibility.

[0036] (d) Sustained-Release-Promoting Substance The composition of the present disclosure may further contain a sustained-release-promoting substance. Here, the sustained-release-promoting substance refers to a substance that weakens the hydrophobic interaction between the hydrophobic segment molecules of the block copolymer that the polymer micelle has to support the hydrophobic substance, thereby creating a certain amount of void space between the molecules, thereby significantly improving the sustained release of the hydrophobic substance outside the polymer micelle. The sustained-release-promoting substance is not particularly limited as long as it has the above function, but examples include butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol, and preferably butylene glycol, glycerin, and propanediol. The sustained-release-promoting substance may be any one of the above substances or a combination of two or more of them. When the sustained-release-promoting substance contains two or more of the above substances, the blending ratio may be arbitrary.

[0037] The sustained-release-promoting substance can be prepared by known methods such as chemical synthesis, fermentation, or extraction.

[0038] The amount of the sustained-release-promoting substance contained in the composition of the present disclosure is not particularly limited, but is usually adjusted to be in the range of 1 to 70% by weight, preferably 10 to 50% by weight, based on the total weight of the composition of the present disclosure.

[0039] (e) Dispersion Medium The composition of the present disclosure may further contain a dispersion medium. The dispersion medium is not particularly limited as long as the polymer micelles of the present disclosure contain the hydrophobic substance of the present disclosure and maintain the ability to release the hydrophobic substance in the presence of radicals. Examples of such dispersion mediums include water, methanol, ethanol, isopropyl alcohol, acetone, and ethyl acetate, and preferably water.

[0040] The amount of the dispersion medium contained in the composition of the present disclosure is not particularly limited, but is usually adjusted to be in the range of 50 to 80 wt %, preferably 60 to 70 wt %, based on the total weight of the composition of the present disclosure.

[0041] (Cosmetic composition or topical skin composition of the present disclosure) The present disclosure also provides a cosmetic composition or topical skin composition (the cosmetic composition or topical skin composition of the present disclosure) by further adding a base, cosmetic additive ingredient, or skin drug or additive ingredient to the composition of the present disclosure.

[0042] The cosmetic composition or topical skin composition of the present disclosure refers to any dosage form that can be applied to the skin, and specifically may be in any dosage form, such as a solid, liquid, gel, foam, emulsion, cream, ointment, sheet, mousse, or aerosol. The cosmetic composition or topical skin composition of the present disclosure is preferably in a dosage form that is optimal for application to the skin, and examples thereof include cosmetics and quasi-drugs such as lotions, emulsions, creams, lotions, packs, soaps, body shampoos, facial cleansers, lipsticks, and foundations. Also included are pharmaceuticals and quasi-drugs such as ointments, patches, lotions, poultices, and liniments.

[0043] The amount of the cosmetic composition or topical skin composition of the present disclosure to be applied is not particularly limited, depending on the concentration and the condition of the area to which it is applied, but it is generally preferable to apply it once to several times a day, at a rate of about 0.01 to 10 g per application. The method of applying the cosmetic composition or topical skin composition of the present disclosure is also not particularly limited, and examples include ordinary application methods using fingers or a tool (e.g., a spatula), as well as methods such as direct application from a pump-type, spray-type, or tube-type container, and compress application.

[0044] The cosmetic composition or topical skin composition of the present disclosure can be further enhanced with a variety of functionalities by optionally selecting and using other components as additives, as long as they do not inhibit the radical reactivity of the composition of the present disclosure. The content of other components in the composition is not particularly limited, but may typically be in the concentration range of 0.0001 to 50 wt.%.

[0045] (Method for producing a composition of the present disclosure) The present disclosure also provides a method for producing a composition of the present disclosure (method for producing a composition of the present disclosure 1), which comprises the step of mixing (A) a hydrophobic substance of the present disclosure, (B) a polymeric micelle of the present disclosure, and (C) a radical reaction-imparting substance of the present disclosure. The hydrophobic substance of the present disclosure, the polymeric micelle of the present disclosure, and the radical reaction-imparting substance of the present disclosure used in method for producing a composition of the present disclosure 1 may be the same as those contained in the composition of the present disclosure.

[0046] In the first method for producing a composition of the present disclosure, the step of mixing (A) a hydrophobic substance of the present disclosure, (B) polymeric micelles of the present disclosure, and (C) a radical reaction-imparting substance of the present disclosure is not particularly limited, as long as the mixing results in a composition in which the polymeric micelles of the present disclosure encapsulating the hydrophobic substance of the present disclosure and the radical reaction-imparting substance of the present disclosure are uniformly mixed. Specifically, for example, retinol palmitate (the hydrophobic substance of the present disclosure), polymeric micelles containing polyethylene glycol-poly(γ-benzyl-L-glutamic acid) block copolymer (polymeric micelles of the present disclosure), and platinum nanoparticles (the radical reaction-imparting substance of the present disclosure) are dispersed in water, followed by stirring for a sufficient time at an appropriate temperature, e.g., 4°C to room temperature, to obtain a composition in which the polymeric micelles encapsulating retinol palmitate and the platinum nanoparticles are uniformly mixed. A sustained-release-promoting substance may also be included in the above step.

[0047] The method for producing a composition according to the present disclosure, method 1, may further include a step of filtering the composition obtained by the above step. By filtering the composition obtained by the above step, the particle size of the polymer micelles contained in the composition according to the present disclosure can be adjusted. Filtration can be carried out by means known in the art, such as filtration methods using a membrane filter or an ultrafilter. When a membrane filter or an ultrafilter is used, the pore size thereof can be, for example, 0.2 μm to 1.0 μm.

[0048] Another method for producing the composition of the present disclosure includes a method (Production Method 2 of the Composition of the Present Disclosure) comprising the following steps: (1) mixing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), a hydrophobic substance of the present disclosure, and a dispersion medium; (2) mixing the polymer micelles containing the hydrophobic substance of the present disclosure obtained in step (1) with a radical reaction-imparting substance of the present disclosure; In each of the above formulas, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group; n is an integer of 10 to 2500; x is an integer of 10 to 300; and y is an integer of 1 or 2.

[0049] In the second method for producing a composition of the present disclosure, the block copolymer represented by Formula (1), the block copolymer represented by Formula (2), the hydrophobic substance, and the dispersion medium used in step (1) may be the same as those contained in the composition of the present disclosure. Step (1) is not limited to the above method. For example, polyethylene glycol-poly(γ-benzyl-L-glutamic acid) block copolymer and retinol palmitate (the hydrophobic substance of the present disclosure) are placed in a container, and the mixture is stirred for a sufficient period of time, for example, at 80°C to 85°C. The resulting homogeneous mixture is then added to water separately heated to 80°C to 85°C while stirring, and the mixture is then stirred while heating to obtain polymer micelles encapsulating retinol palmitate. Step (1) may further include a sustained-release-promoting substance.

[0050] The method for producing a composition according to the present disclosure, method 2, may include a step of microparticulating the polymer micelles obtained in step (1) after step (1) and before step (2). For example, the polymer micelles obtained in step (1) can be microparticulated using a Nanomizer at a processing pressure of 150 MPa. Commercially available Nanomizers (e.g., NanoVeida (Yoshida Kikai Kogyo Co., Ltd.)) can be used.

[0051] In the second method for producing a composition of the present disclosure, the radical reaction-imparting substance used in step (2) may be the same as that contained in the composition of the present disclosure. For example, but not limited to, in step (2), platinum nanoparticles (the radical reaction-imparting substance of the present disclosure) are added to the polymer micelles encapsulating retinol palmitate obtained in step (1), and the mixture is stirred for a sufficient time at an appropriate temperature, for example, 4°C to room temperature, to obtain a composition in which the polymer micelles encapsulating retinol palmitate and platinum nanoparticles are uniformly mixed.

[0052] Next, examples of the present invention will be described. However, the present invention is not limited to the following examples. Commercially available reagents were used according to their protocols unless otherwise specified.

[0053] (Manufacturing Example) Preparation of Polymeric Micelles The polymeric micelles of the present disclosure were prepared according to the following procedure. 1 g of polyethylene glycol-poly(γ-benzyl-L-glutamic acid) block copolymer, 30 g of 1,3-butylene glycol, and 0.5 g of Riken A Palmitate 1000(E) were mixed and homogenized at 80-85°C. 63.5 g of purified water heated to 80-85°C was gradually added to the homogenized mixture while stirring, and the mixture was heated and mixed until homogenized. The resulting mixture was micronized using a Nanomizer (150 MPa, 3 passes, water cooling) without cooling. The solvent evaporated during the above procedure was added with purified water until the total volume reached 95 g, and the mixture was mixed. 5 g of platinum colloid solution (Johzen) was then added and stirred at room temperature overnight. The resulting mixture was filtered through 0.45 μm MF Acetate to prepare polymeric micelles of the present disclosure for use in the following examples. Comparative polymeric micelles were prepared according to the same procedure as above, except that the platinum colloid solution was not used. A control without any inclusions (hereinafter referred to as empty polymeric micelles) was prepared according to the same procedure as above, except that the platinum colloid solution and Riken A Palmitate 1000(E) were not used. The compositions of the polymeric micelles of the present disclosure, the comparative polymeric micelles, and the empty polymeric micelles are shown in Table 1.

[0054]

[0055] Example 1 Measurement of Particle Size Distribution and Average Particle Size The particle size distribution and average particle size of the polymer micelles of the present disclosure, the polymer micelles of the comparative example, the empty polymer micelles, and the platinum colloid solution prepared in the Production Examples were measured using a dynamic light scattering photometer. As a result, there was no difference in particle size distribution and average particle size between the polymer micelles of the present disclosure and the polymer micelles of the comparative example, confirming that the platinum colloid solution does not affect the particle size of the polymer micelles. The particle size distribution is shown in Figure 1, and the average particle size is shown in Table 2.

[0056]

[0057] Example 2: Measurement of Zeta Potential The zeta potentials of the polymer micelles of the present disclosure prepared in the Production Examples, the polymer micelles of the Comparative Examples, the empty polymer micelles, and the platinum colloid solution were measured using a dynamic light scattering photometer. The zeta potential is the potential of the slip plane (the limit plane at which the surface charge affects ions outside of it) on the outer surface of the microparticles. Measuring the zeta potential allows the stability of the dispersion state of the microparticles to be estimated. Specifically, the greater the absolute value of the zeta potential, the stronger the electrical repulsion between the microparticles, resulting in a more stable dispersion state. Conversely, the smaller the absolute value of the zeta potential, the weaker the electrical repulsion between the microparticles, making the microparticles more prone to aggregation. As a result of the above measurements, the zeta potential of the polymer micelles of the present disclosure was lower than that of the polymer micelles of the Comparative Examples, suggesting that the platinum colloid solution can impart stability to the dispersion of the polymer micelles. The zeta potentials are shown in Table 3.

[0058]

[0059] Example 3 Verification of Radical Responsiveness The polymer micelles of the present disclosure prepared in the Production Examples and the polymer micelles of the Comparative Examples were verified for their ability to release encapsulated retinol palmitate in a radical responsive manner.

[0060] (1) Encapsulation Rate of Retinol Palmitate Prior to testing radical responsiveness, we confirmed that there was no difference in the encapsulation rate of retinol palmitate between the polymer micelles of the present disclosure and the polymer micelles of the comparative example. The quantification of retinol palmitate was performed according to the Vitamin A Quantification Method (Method 1) described in the Quasi-Drug Raw Materials Standards 2021. Specifically, 0.5 g of Riken A Palmitate 1000(E), which was used in preparing the polymer micelles of the present disclosure and the polymer micelles of the comparative example, was precisely weighed and dissolved in vitamin A quantification isopropanol to make a 250 mL solution. This solution was accurately diluted with vitamin A quantification isopropanol to obtain a sample solution with an absorbance of approximately 0.5 at 326 nm with a layer length of 10 mm, and the wavelength at which the absorption maximum was measured. In addition, absorbance was measured at wavelengths of 300 nm, 310 nm, 320 nm, 326 nm, 340 nm, and 350 nm at a depth of 10 mm above the layer, and the absorbance ratio at each wavelength was calculated, assuming the absorbance at 326 nm was 1.000. Because there was a maximum absorption at wavelengths of 325 to 328 nm and the absorbance ratios obtained at each wavelength were within ±0.030 of the values ​​in Table 4, the vitamin A (retinol palmitate) units in 1 g of Riken A Palmitate 1000(E) were calculated from the absorbance A at a wavelength of 326 nm, and this was used as the quantitative value of vitamin A (retinol palmitate) for the polymer micelles of the present disclosure and the polymer micelles of the comparative example at the time of preparation. Vitamin A (retinol palmitate) units in 1g = E1% 1cm(326nm) x 1900 E1% 1cm(326nm) = (A / W) x (V / 100) A: absorbance at wavelength 326nm V: total volume of sample solution (mL) W: weight of sample in VmL of sample solution (g)

[0061]

[0062] Next, approximately 1 mL of each of the polymer micelles of the present disclosure and the polymer micelles of the comparative example was taken and subjected to ultracentrifugation (1.04 million G, 1 hour, 4°C). The vitamin A content in the supernatant was then quantitatively evaluated using the Vitamin A Quantitation Method (Method 1) described in the Standards for Quasi-Drug Ingredients (2006). The encapsulation rate of vitamin A (retinol palmitate) was calculated by subtracting the quantitation value of vitamin A (retinol palmitate) contained in the supernatant of the polymer micelles of the present disclosure and the comparative example from the quantitation value of vitamin A (retinol palmitate) at the time of preparation. The encapsulation rate of vitamin A (retinol palmitate) in the polymer micelles of the present disclosure and the comparative example was 89.11% and 87.94%, respectively, showing no significant difference between the two.

[0063] (2) Radical responsiveness In the reaction system of the SOD Assay Kit-WST (DOJINDO), WST-1, a tetrazolium salt, reacts with superoxide (O2 -) is converted into chromogenic WST-1 formazan and O2. On the other hand, in the presence of antioxidants such as vitamins and polyphenols, superoxide is converted into O2 and H2O2 by the antioxidants and eliminated. Therefore, when WST-1 and antioxidants coexist in the same reaction system, they compete for superoxide, resulting in a decrease in the amount of WST-1 formazan produced compared to when antioxidants are not present, resulting in a lower absorbance of the reaction system. In other words, the inhibition rate of the WST-1 formazan production reaction is higher. Therefore, using the SOD Assay Kit-WST, the inhibition rate of the WST-1 formazan production reaction by the polymer micelles of the present disclosure and the comparative polymer micelles was measured. Each solution was prepared as follows: (WST working sol.) 1 mL of WST sol. was diluted with 19 mL of buffer sol. to prepare WST working sol. (Enzyme working sol.) Enzyme sol. was prepared into a uniform suspension by pipetting or other means. 15 μL of enzyme solution was taken and diluted with 2.5 mL of dilution buffer to prepare enzyme working solution. (Sample solution) 50 ppm of the polymer micelles of the present disclosure and the comparative example were diluted to 5 ppm with empty polymer micelles to prepare 200 μL of sample solution for each group. WST working solution was used as a control.

[0064] The sample solution obtained above was dispensed in 20 μL aliquots into each well (N=3) of a 96-well microplate. Next, 200 μL of WST working sol. was added to each well and mixed thoroughly using a plate mixer. 20 μL of Dilution Buffer was added to each enzyme (-) well, and 20 μL of Enzyme Working sol. was added to each enzyme (+) well. The 96-well microplate was incubated at 37°C for 20 minutes, after which the absorbance at 450 nm was measured using a plate reader. The inhibition rates of the WST-1 formazan production reaction by the polymeric micelles of the present disclosure and the comparative polymeric micelles were calculated from the absorbance values ​​obtained for the control, the polymeric micelles of the present disclosure, and the comparative polymeric micelles. The results showed that the polymeric micelles of the present disclosure exhibited a higher inhibition rate than the comparative polymeric micelles. This result suggests that the polymeric micelles of the present disclosure release more of the antioxidant retinol palmitate than the polymeric micelles of the comparative example due to radicals such as superoxide present in the reaction system. Therefore, the polymeric micelles of the present disclosure obtained by treating the polymeric micelles of the comparative example with a platinum colloid solution are radical-responsive polymeric micelles with an improved ability to release encapsulated substances in response to radicals compared to the polymeric micelles of the comparative example. The inhibition rates are shown in Table 5 and Figure 2. As also shown in Table 5, the values ​​shown in Figure 2 are 45.250% for the group of polymeric micelles of the comparative example and 61.325% for the group of polymeric micelles of the present disclosure.

[0065]

[0066] Although the present invention has been described above with reference to the embodiments, the present disclosure is not limited to the above embodiments. Various modifications that can be understood by those skilled in the art can be made to the configuration and details of the present disclosure within the scope of the present disclosure.

[0067] The patents, patent applications, and publications cited herein are incorporated by reference into this specification in their entirety as if the contents were specifically set forth herein.

[0068] This application claims priority based on Japanese Patent Application No. 2024-094310, filed June 11, 2024, the disclosure of which is incorporated herein in its entirety by reference.

[0069] <Supplementary Notes> Some or all of the above embodiments and examples can be described as in the following supplementary notes, but are not limited to the following: (Supplementary Note 1) A composition comprising: (A) a hydrophobic substance; (B) a polymer micelle containing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), the polymer micelle containing the hydrophobic substance; and (C) a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２each independently represent a linking group, n is an integer from 10 to 2500, x is an integer from 10 to 300, and y is an integer of 1 or 2. (Appendix 2) The composition according to Appendix 1, wherein the radical reaction-imparting substance is a noble metal nanoparticle. (Appendix 3) The composition according to Appendix 2, wherein the noble metal nanoparticles are one or more selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles. (Appendix 4) The composition according to any one of Appendixes 1 to 3, wherein the composition contains a sustained-release-promoting substance. (Appendix 5) The composition according to Appendix 4, wherein the sustained-release-promoting substance is one or more selected from the group consisting of butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol. (Appendix 6) The composition according to any one of Appendices 1 to 5, wherein the composition comprises a dispersion medium. (Appendix 7) The composition according to Appendices 6, wherein the dispersion medium is one or more selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, and ethyl acetate. (Appendix 8) A cosmetic composition comprising the composition according to any one of Appendices 1 to 7. (Appendix 9) A composition for external use on skin comprising the composition according to any one of Appendices 1 to 7. (Appendix 10) A method for producing a composition, comprising the steps of mixing (A) a hydrophobic substance, (B) polymer micelles comprising a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), and (C) a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represent a linking group, n is an integer of 10 to 2500, x is 1 or an integer of 0 to 300, and y is an integer of 1 or 2. (Appendix 11) The production method according to Appendix 10, wherein the radical reaction-imparting substance is a noble metal nanoparticle. (Appendix 12) The production method according to Appendix 11, wherein the noble metal nanoparticles are at least one selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles. (Appendix 13) The production method according to any one of Appendices 10 to 12, comprising a step of filtering the composition. (Appendix 14) The production method according to Appendices 10 to 13, wherein the polymer micelles contain a sustained-release-promoting substance. (Appendix 15) The method for producing a composition according to Appendix 14, wherein the sustained-release-promoting substance is one or more selected from the group consisting of butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol. (Appendix 16) A method for producing a composition, comprising the following steps: (1) mixing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), a hydrophobic substance, and a dispersion medium, (2) mixing the polymer micelles obtained in step (1) with a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２each independently represents a linking group, n is an integer of 10 to 2500, x is 1 or an integer of 0 to 300, and y is an integer of 1 or 2. (Appendix 17) The production method according to Appendices 16, further comprising a step of microparticulating the polymer micelles obtained in step (1) between steps (1) and (2). (Appendix 18) The production method according to Appendices 16 or 17, further comprising a sustained-release-promoting substance in step (1). (Appendix 19) The production method according to Appendices 18, wherein the sustained-release-promoting substance is one or more selected from the group consisting of butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol. (Appendix 20) The production method according to any of Appendices 16 to 19, wherein the dispersion medium is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, and ethyl acetate. (Appendix 21) The manufacturing method according to any one of Appendices 16 to 20, wherein the radical reaction-imparting substance is a noble metal nanoparticle. (Appendix 22) The manufacturing method according to Appendices 21, wherein the noble metal nanoparticles are at least one selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles. (Appendix 23) The manufacturing method according to any one of Appendices 16 to 22, comprising a step of filtering the composition.

[0070] By applying the polymer micelles of the present disclosure, which encapsulate a desired hydrophobic substance as an active ingredient, to the skin in advance, the active ingredient is released in response to radical species generated on the skin by ultraviolet rays, etc., thereby effectively eliminating the radical species. Furthermore, the polymer micelles of the present disclosure also have the secondary effect of excellent dispersibility.

Claims

1. A composition comprising: (A) a hydrophobic substance; (B) a polymer micelle containing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2) containing the hydrophobic substance; and (C) a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group, n is an integer of 10 to 2500, x is an integer of 10 to 300, and y is an integer of 1 or 2.

2. The composition according to claim 1, wherein the radical reaction-imparting substance is a noble metal nanoparticle.

3. The composition according to claim 2, wherein the noble metal nanoparticles are one or more selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles.

4. The composition of any one of claims 1 to 3, wherein the composition comprises a sustained release-promoting substance.

5. The composition of claim 4, wherein the sustained-release promoting substance is one or more selected from the group consisting of butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol.

6. The composition according to any one of claims 1 to 5, wherein the composition comprises a dispersion medium.

7. The composition according to claim 6, wherein the dispersion medium is one or more selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, and ethyl acetate.

8. A cosmetic composition comprising the composition according to any one of claims 1 to 5.

9. A composition for external use on the skin, comprising the composition according to any one of claims 1 to 5.

10. A method for producing a composition, comprising the steps of mixing (A) a hydrophobic substance, (B) polymer micelles containing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), and (C) a radical reaction-imparting substance: [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group, n is an integer of 10 to 2500, x is 1 or an integer of 0 to 300, and y is an integer of 1 or 2.

11. The method according to claim 10, wherein the radical reaction-donating substance is a noble metal nanoparticle.

12. The manufacturing method according to claim 11, wherein the noble metal nanoparticles are at least one selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles.

13. The method of any one of claims 10 to 12, further comprising filtering the composition.

14. A method for producing a composition, comprising the following steps: (1) mixing a block copolymer represented by formula (1) and / or a block copolymer represented by formula (2), a hydrophobic substance, and a dispersion medium; and (2) mixing the polymer micelles obtained in step (1) with a radical reaction-imparting substance. [In each formula, R １ and R ３ each independently represents a hydrogen atom or a lower alkyl group which is unsubstituted or substituted with an optionally protected functional group; R ２ is a hydrogen atom, saturated or unsaturated C １ ~C ２９ represents an aliphatic carbonyl group or an arylcarbonyl group, R ４ is a hydroxyl group, saturated or unsaturated C １ ~C ３０ represents an aliphatic oxy group or an aryl-lower alkyloxy group, R ５ represents a hydrogen atom, a phenyl group, C １ ~C ８ represents an alkyl group or a benzyl group (provided that R ５ can be arbitrarily selected for each amino acid unit in one block copolymer. ５ The hydrogen atoms in the amino acid units account for 0 to 60% of the total amino acid units, and when present, are present randomly. １ and L ２ each independently represents a linking group, n is an integer of 10 to 2500, x is 1 or an integer of 0 to 300, and y is an integer of 1 or 2.

15. The method of claim 14, further comprising a step of microparticulating the polymer micelles obtained in step (1) between step (1) and step (2).

16. The method of claim 14 or 15, wherein step (1) further comprises the inclusion of a sustained-release promoting substance.

17. The method of manufacturing according to claim 16, wherein the sustained-release-promoting substance is one or more selected from the group consisting of butylene glycol, glycerin, propanediol, diglycerin, dipropylene glycol, propylene glycol, polypropylene glycol, pentylene glycol, and hexylene glycol.

18. The method of any one of claims 14 to 17, wherein the dispersion medium is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, and ethyl acetate.

19. The method according to any one of claims 14 to 18, wherein the radical reaction-donating substance is a noble metal nanoparticle.

20. The manufacturing method according to claim 19, wherein the noble metal nanoparticles are at least one selected from the group consisting of platinum nanoparticles, gold nanoparticles, silver nanoparticles, palladium nanoparticles, ruthenium nanoparticles, rhodium nanoparticles, iridium nanoparticles, and osmium nanoparticles.

21. The method of any one of claims 14 to 20, further comprising filtering the composition.

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