Uses of ozone oxidation reaction products containing cyclic peroxides, and cosmetics and topical skin preparations

Abstract

To provide uses of ozone oxidation reaction products containing cyclic peroxides, and to provide cosmetics and topical skin preparations.SOLUTION: A profilaggrin mRNA expression promoter contains a cyclic peroxide represented by the following chemical formula (1), and also contains an ozone oxidation reaction product of glycerin obtained by ozone-oxidizing glycerin at a concentration of 75 wt.% to 98.5 wt.% for 24 hours or more, and has the effect of promoting the expression of profilaggrin mRNA, which generates profilaggrin from profilaggrin genes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to uses of ozone oxidation reaction products containing cyclic peroxides, as well as to cosmetics and topical skin preparations. [Background technology]

[0002] Peroxides, such as hydrogen peroxide, are industrially utilized due to their oxidizing properties. In the field of drug discovery, hydrogen peroxide has been known to be a TRP channel activator. TRP channels (TRP receptors) are ionotropic receptors present in cell membranes and are used as targets for drug discovery.

[0003] In the field of dermatology, the amount and quality of melanin contained in the skin are considered to be important factors in determining skin color. Therefore, whitening agents that suppress melanin production or reduce melanin in the skin have been developed as whitening ingredients. Patent Document 1 describes the use of plant extracts such as peppermint and lemon balm as whitening ingredients that promote melanin decomposition.

[0004] Furthermore, in the field of dermatology, it is known that the barrier function of the skin declines with age, and this decline in the barrier function of the skin is known to be associated with skin diseases such as atopic dermatitis (Non-Patent Document 1).

[0005] Furthermore, in the field of physical aging, it is known that glycation (Maillard reaction) is an enzyme-independent reaction in which proteins and carbohydrates such as reducing sugars combine, ultimately producing advanced glycation end products (AGEs). When proteins containing AGEs are produced from proteins through the glycation reaction in the body, the proteins are unable to perform their original functions in the body due to the inclusion of AGEs. For this reason, AGEs are said to be related to the aging phenomenon. It has also been suggested that the accumulation of AGEs in the skin can cause sagging, wrinkles, age spots, etc. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2020-059656 [Non-patent literature]

[0007] [Non-Patent Document 1] Hironori Ishizuka, "Skin barrier formation and skin diseases associated with barrier dysfunction," 2017, Jpn. J. Clin. Immunol., 40(6), pp. 416-427 Summary of the Invention [Problem to be solved by the invention]

[0008] However, in the field of drug discovery, hydrogen peroxide has safety issues such as being highly irritating and potentially explosive due to its high reactivity.

[0009] Furthermore, in the field of dermatology, no composition is known that induces the expression of genes related to the skin barrier function, nor is it known that a compound containing a structure with oxidizing power contributes to the induction of the expression of genes related to the skin barrier function and the improvement of the skin barrier function.

[0010] Furthermore, as mentioned above, in the field of physical aging, it is known that when proteins containing AGEs are produced from proteins in the body through the glycation reaction, the proteins are unable to perform their original functions in the body due to the inclusion of AGEs. For this reason, AGEs are said to be related to the aging phenomenon. It has also been suggested that the accumulation of AGEs in the skin can cause sagging, wrinkles, age spots, etc.

[0011] Therefore, an object of the first aspect of the present invention is to provide a highly safe cyclic peroxide, an oxidation reaction product, and a method for producing the oxidation reaction product.

[0012] The second object of the present invention is to provide a whitening composition and a whitening agent containing a new whitening ingredient.

[0013] The third aspect of the present invention aims to provide a composition for inducing the expression of skin barrier function-related genes, which contains a novel component for inducing the expression of skin barrier function-related genes, and an inducer of the expression of skin barrier function-related genes.

[0014] The fourth aspect of the present invention aims to provide an anti-glycation composition and an anti-glycation agent containing a novel anti-glycation component. [Means for solving the problem]

[0015] [Means for solving the problems in the first invention] In order to solve the above-mentioned safety problem, the cyclic peroxide in the first aspect of the present invention is characterized by being represented by the following chemical formula (I). [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0016] The oxidation reaction product in the first aspect of the present invention is an oxidation reaction product obtained by oxidizing an alcohol and characterized by containing a cyclic peroxide.

[0017] The method for producing an oxidation reaction product according to the first aspect of the present invention is a method for producing an oxidation reaction product according to the present invention, which comprises an alcohol oxidation step of oxidizing the alcohol.

[0018] [Means for solving the problem in the second invention] In order to provide a whitening composition and a whitening agent containing a new whitening ingredient, the whitening composition according to the second aspect of the present invention comprises glycerin and / or a glycerin derivative and a whitening ingredient, The whitening ingredient contains, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0019] The skin whitening agent of the second invention of the present invention contains a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0020] [Means for solving the problems in the third invention] In order to provide a novel composition for inducing the expression of skin barrier function-related genes containing an expression-inducing component for skin barrier function-related genes and an inducer of skin barrier function-related genes, the composition for inducing the expression of skin barrier function-related genes in the third aspect of the present invention comprises glycerin and / or a glycerin derivative and an expression-inducing component for skin barrier function-related genes, The component for inducing the expression of a skin barrier function-related gene contains, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0021] The composition for improving skin barrier function in the third invention of the present invention comprises the composition for inducing the expression of a skin barrier function-related gene described in the third invention of the present invention.

[0022] The expression inducer of a skin barrier function-related gene according to the third aspect of the present invention comprises a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0023] The skin barrier function improver according to the third aspect of the present invention comprises the skin barrier function-related gene inducer according to the third aspect of the present invention.

[0024] A composition for inducing expression of an antioxidant stress response gene according to a third aspect of the present invention comprises glycerin and / or a glycerin derivative and a component for inducing expression of an antioxidant stress response gene, The component for inducing expression of an antioxidant stress response gene contains, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0025] The expression inducer of an antioxidant stress response gene according to the third aspect of the present invention comprises a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0026] The anti-inflammatory composition according to the third aspect of the present invention comprises glycerin and / or a glycerin derivative and an anti-inflammatory component, The anti-inflammatory component contains, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0027] The anti-inflammatory agent according to the third aspect of the present invention comprises a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0028] [Means for solving the problems in the fourth invention] In order to provide an anti-glycation composition and an anti-glycation agent containing a novel anti-glycation component, the anti-glycation composition (hereinafter also referred to as "composition") according to the fourth aspect of the present invention comprises glycerin and / or a glycerin derivative and an anti-glycation component, The anti-glycation component contains, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different. Includes things.

[0029] The anti-glycation agent according to the fourth aspect of the present invention comprises a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different. [Effects of the Invention]

[0030] [Effects of the first invention] According to the first aspect of the present invention, it is possible to provide a highly safe cyclic peroxide, an oxidation reaction product, and a method for producing an oxidation reaction product.

[0031] [Effects of the second invention] According to the second aspect of the present invention, it is possible to provide a whitening composition and a whitening agent containing a new whitening ingredient.

[0032] [Effects of the third invention] According to the third aspect of the present invention, it is possible to provide a composition for inducing the expression of skin barrier function-related genes, which contains a new component for inducing the expression of skin barrier function-related genes, and an inducer of the expression of skin barrier function-related genes.

[0033] [Effects of the fourth invention] According to the fourth aspect of the present invention, it is possible to provide an anti-glycation composition and an anti-glycation agent containing a novel anti-glycation component. [Brief explanation of the drawings]

[0034] [Figure 1-1] Figure 1-1 shows the 1H NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-2] Figure 1-2 shows the 13C NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-3] Figure 1-3 shows the 13C DEPT135 NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-4] Figure 1-4 shows the COSY NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-5] Figure 1-5 shows the HSQC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-6] Figure 1-6 shows the HMBC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 1-7] Figure 1-7 shows total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) of a sample prepared (diluted) from the reaction mixture (TLC 1 spot product) to approximately 3% by mass with acetonitrile, and a blank. [Figure 1-8] FIG. 1-8 is a mass spectrum diagram of peaks F, G and H (F fraction, G fraction and H fraction) in FIG. 1-7. [Figure 1-9] FIG. 1-9 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). [Figure 1-10] FIG. 1-10 shows the mass spectrum (after improved separation) of peaks 1 to 3 in FIG. 1-9. [Figure 1-11] FIG. 1-11 is a diagram showing the mass spectrum (after improved separation) of peaks 4 to 6 in FIG. 1-9. [Figure 1-12] FIG. 1-12 is a diagram showing the mass spectrum (after improved separation) of peaks 7 and 8 in FIG. 1-9. [Figure 1-13] FIG. 1-13 shows the microscopic Raman spectra of a sample obtained by fractionating peak 2 (Mw=180) in FIG. 1-9 and an ozonide standard. [Figure 1-14] FIG. 1-14 is a 1H NMR spectrum of peak 2 (Mw=180) in FIG. 1-9. [Figure 1-15] FIG. 1-15 is a 13C NMR spectrum of peak 2 (Mw=180) in FIG. 1-9. [Figure 1-16] FIG. 1-16 is a two-dimensional (1H-13C COSY) NMR spectrum of peak 2 (Mw=180) in FIG. 1-9. [Figure 1-17] FIG. 1-17 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of FIG. 1-9. [Figure 1-18] FIG. 1-18 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed phase HILIC conditions. [Figure 1-19] FIG. 1-19 is an enlarged view of a portion of FIG. 1-18. [Figure 1-20] FIG. 1-20 shows the ESR spectrum of the TLC 1 spot product and peak 2 (Mw=180) in FIG. 1-9. [Figure 1-21] Figure 1-21 shows the ESR spectrum of ozonated methyl linolenate. [Figure 1-22] FIG. 1-22 is an ESR spectrum diagram of peaks 1 to 8 in FIG. 1-9. [Figure 1-23] FIG. 1-23 shows the results of measuring the activities of peaks 1 to 8 in FIG. 1-9 by chemiluminescence. [Figure 1-24] Figure 1-24 shows the effects of adding G (glycerin), OG (ozonized glycerin), LOG (ozonated oxide), and HOG (heat-treated ozonized glycerin) to TRPM2 (expressing cells) and Vector (TRPM2 non-expressing cells). [Figure 1-25] FIG. 1-25 shows the TRP channel activity of G and OG against TRPM2 (expressing cells) under the same conditions as in FIG. 1-24, except that the aqueous solution concentration (mass %) was changed. [Figure 1-26]FIG. 1-26 shows the TRP channel activity of G, OG, LOG, and HOG against TRPM2 (expressing cells). [Figure 1-27] Figure 1-27 shows the TRP channel activity of LOG and OG against TRPM2 (expressing cells) under the same conditions as in Figure 1-24, except that 500 units / ml of catalase was added, and compared with the results when no catalase was added. [Figure 1-28] FIG. 1-28 shows the TRP channel activity of OG and LOG against TRPM2 (expressing cells) under the same conditions as in FIG. 1-24, except that the aqueous solution concentration (mass %) was changed. [Figure 1-29] Figure 1-29 shows the TRP channel activity of TRPM2 (expressing cells) measured under the same conditions as Figure 1-24, except that 100 units / ml of catalase or 1 μm of PJ34 (trade name of Chemscene) was added at 0.1% LOG by mass, and compared the results with the results when no catalase or PJ34 was added. [Figure 1-30] Figure 1-30 shows the TRP channel activity for TRPM2 (expressing cells) at 0.1% LOG by mass under the same conditions as Figure 1-24, except that 100 μm of dipyridyl (α,α'-dipyridyl) was added, and compared with the case when dipyridyl was not added. [Figure 1-31] Figure 1-31 shows the TRP channel activity of LOG in each cell type under the same conditions as in Figure 1-24, except that the concentration (mass%) of the aqueous solution was changed and TRPM1 HEK (expressing cells) or HEK (expressing cells) was used instead of TRPM2 (expressing cells). [Figure 1-32] FIG. 1-32 shows the TRP channel activity of F7 at various concentrations in TRPM2 (expressing cells) and TRPMA1 (expressing cells) examined in the same manner as in FIG. 1-31. [Figure 1-33] FIG. 1-33 shows the TRP channel activity of F7 at various concentrations in TRPM2 (expressing cells) and TRPMA1 (expressing cells) examined in the same manner as in FIG. 1-31. [Figure 2-1] FIG. 2-1 is a graph showing the results of melanin measurement over time in Example 2-1. [Figure 2-2] FIG. 2-2 is a graph showing the change in melanin measurement value over time in Example 2-1. [Figure 2-3] Figure 2-3 shows the 1H NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-4] Figure 2-4 shows the 13C NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-5] Figure 2-5 shows the 13C DEPT135 NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-6] Figure 2-6 shows the COSY NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-7] Figure 2-7 shows the HSQC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-8] Figure 2-8 shows the HMBC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 2-9] Figure 2-9 shows total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) of a sample prepared (diluted) from the reaction mixture (TLC 1 spot product) to approximately 3% by mass with acetonitrile, and a blank. [Figure 2-10] FIG. 2-10 is a mass spectrum diagram of peaks F, G, and H (F fraction, G fraction, and H fraction) in FIG. 2-9. [Figure 2-11] FIG. 2-11 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). [Figure 2-12] FIG. 2-12 is a diagram showing the mass spectrum (after improved separation) of peaks 1 to 3 in FIG. 2-11. [Figure 2-13] FIG. 2-13 is a diagram showing the mass spectrum (after improved separation) of peaks 4 to 6 in FIG. 2-11. [Figure 2-14] FIG. 2-14 is a diagram showing the mass spectrum (after improved separation) of peaks 7 and 8 in FIG. 2-11. [Figure 2-15] FIG. 2-15 shows the microscopic Raman spectra of a sample obtained by separating peak 2 (Mw=180) in FIG. 2-11, and an ozonide standard. [Figure 2-16] FIG. 2-16 is a 1H NMR spectrum of peak 2 (Mw=180) in FIG. 2-11. [Figure 2-17] FIG. 2-17 is a 13C NMR spectrum of peak 2 (Mw=180) in FIG. 2-11. [Figure 2-18] FIG. 2-18 is a two-dimensional (1H-13C COSY) NMR spectrum of peak 2 (Mw=180) in FIG. 2-11. [Figure 2-19] FIG. 2-19 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of FIG. 2-11. [Figure 2-20] FIG. 2-20 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed phase HILIC conditions. [Figure 2-21] FIG. 2-21 is an enlarged view of a portion of FIG. 2-20. [Figure 2-22] FIG. 2-22 shows the ESR spectrum of the TLC 1 spot product and peak 2 (Mw=180) in FIG. 2-9. [Figure 2-23]Figure 2-23 shows the ESR spectrum of ozonated methyl linolenate. [Figure 2-24] FIG. 2-24 is an ESR spectrum diagram of peaks 1 to 8 in FIG. 2-11. [Figure 2-25] FIG. 2-25 shows the results of measuring the activities of peaks 1 to 8 in FIG. 2-11 by chemiluminescence. [Figure 3-1] FIG. 3-1 is a graph showing the expression levels of skin barrier function-related genes in Example 3-1. [Figure 3-2] FIG. 3-2 is a graph showing the expression levels of antioxidant stress response genes in Example 3-1. [Figure 3-3] FIG. 3-3 is a graph showing the amount of glutathione peptide in Example 3-1. [Figure 3-4] FIG. 3-4 is a graph showing the cell viability in Example 3-1. [Figure 3-5] FIG. 3-5 is a graph showing the amount of IL-1α produced in Example 3-1. [Figure 3-6] FIG. 3-6 is a graph showing the amount of prostaglandin E2 produced in Example 3-1. [Figure 3-7] Figure 3-7 shows the 1H NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-8] Figure 3-8 shows the 13C NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-9] Figure 3-9 shows the 13C DEPT135 NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-10] Figure 3-10 shows the COSY NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-11] Figure 3-11 shows the HSQC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-12] Figure 3-12 shows the HMBC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 3-13] Figure 3-13 shows total ion chromatograms (ESI-negative mode) in the precision preparative LC (liquid chromatography) of a sample prepared (diluted) from the reaction mixture (TLC 1 spot product) to approximately 3% by mass with acetonitrile, and a blank. [Figure 3-14] FIG. 3-14 is a mass spectrum diagram of peaks F, G, and H (F fraction, G fraction, and H fraction) in FIG. 3-13. [Figure 3-15] FIG. 3-15 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). [Figure 3-16] FIG. 3-16 is a diagram showing the mass spectrum (after improved separation) of peaks 1 to 3 in FIG. 3-15. [Figure 3-17] FIG. 3-17 is a diagram showing the mass spectrum (after improved separation) of peaks 4 to 6 in FIG. 3-15. [Figure 3-18] FIG. 3-18 is a diagram showing the mass spectrum (after improved separation) of peaks 7 and 8 in FIG. 3-15. [Figure 3-19] FIG. 3-19 shows the microscopic Raman spectra of a sample obtained by fractionating peak 2 (Mw=180) in FIG. 3-15, and an ozonide standard. [Figure 3-20] FIG. 3-20 is a 1H NMR spectrum of peak 2 (Mw=180) in FIG. 3-15. [Figure 3-21] FIG. 3-21 is a 13C NMR spectrum of peak 2 (Mw=180) in FIG. 3-15. [Figure 3-22]FIG. 3-22 is a two-dimensional (1H-13C COSY) NMR spectrum of peak 2 (Mw=180) in FIG. 3-15. [Figure 3-23] FIG. 3-23 is a diagram showing HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of FIG. 3-15. [Figure 3-24] FIG. 3-24 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed phase HILIC conditions. [Figure 3-25] FIG. 3-25 is an enlarged view of a portion of FIG. 3-24. [Figure 3-26] FIG. 3-26 shows the ESR spectrum of the TLC 1 spot product and peak 2 (Mw=180) in FIG. 3-9. [Figure 3-27] Figure 3-27 shows the ESR spectrum of ozonated methyl linolenate. [Figure 3-28] FIG. 3-28 is an ESR spectrum diagram of peaks 1 to 8 in FIG. 3-15. [Figure 3-29] FIG. 3-29 shows the results of measuring the activities of peaks 1 to 8 in FIG. 3-15 by chemiluminescence. [Figure 4-1] FIG. 4-1 is a graph showing the anti-glycation rate in Example 4-1. [Figure 4-2] Figure 4-2 shows the 1H NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 4-3] Figure 4-3 shows the 13C NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 4-4] FIG. 4-4 shows the 13C DEPT135 NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27° C.) using DMSO-d6 as a solvent. [Figure 4-5] Figure 4-5 shows the COSY NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 4-6] Figure 4-6 shows the HSQC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 4-7] Figure 4-7 shows the HMBC NMR spectrum of the reaction mixture (TLC 1 spot product) of the ozone oxidation of glycerin, measured at a temperature of 300 K (27°C) using DMSO-d6 as a solvent. [Figure 4-8] Figure 4-8 shows total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) of a sample prepared (diluted) from the reaction mixture (TLC 1 spot product) to approximately 3% by mass with acetonitrile, and a blank. [Figure 4-9] FIG. 4-9 is a mass spectrum diagram of peaks F, G, and H (F fraction, G fraction, and H fraction) in FIG. 4-8. [Figure 4-10] Figure 4-10 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). [Figure 4-11] FIG. 4-11 is a diagram showing the mass spectrum (after improved separation) of peaks 1 to 3 in FIG. 4-10. [Figure 4-12] FIG. 4-12 is a diagram showing the mass spectrum (after improved separation) of peaks 4 to 6 in FIG. 4-10. [Figure 4-13] FIG. 4-13 is a diagram showing the mass spectrum (after improved separation) of peaks 7 and 8 in FIG. 4-10. [Figure 4-14] FIG. 4-14 shows the microscopic Raman spectrum of a sample obtained by separating peak 2 (Mw=180) in FIG. 4-10, and that of an ozonide standard. [Figure 4-15] FIG. 4-15 is a 1H NMR spectrum of peak 2 (Mw=180) in FIG. 4-10. [Figure 4-16] FIG. 4-16 is a 13C NMR spectrum of peak 2 (Mw=180) in FIG. 4-10. [Figure 4-17] FIG. 4-17 is a two-dimensional (1H-13C COSY) NMR spectrum of peak 2 (Mw=180) in FIG. 4-10. [Figure 4-18] FIG. 4-18 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of FIG. 4-10. [Figure 4-19] FIG. 4-19 shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed phase HILIC conditions. [Figure 4-20] FIG. 4-20 is an enlarged view of a portion of FIG. 4-19. [Figure 4-21] FIG. 4-21 shows the ESR spectrum of the TLC1 spot product and peak 2 (Mw=180) in FIG. 4-4. [Figure 4-22] Figure 4-22 shows the ESR spectrum of ozonated methyl linolenate. [Figure 4-23] FIG. 4-23 is an ESR spectrum diagram of peaks 1 to 8 in FIG. 4-10. [Figure 4-24] FIG. 4-24 shows the results of measuring the activities of peaks 1 to 8 in FIG. 4-10 by chemiluminescence. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following description.

[0036] [First embodiment of the invention] First, a first embodiment of the present invention will be described, although the first embodiment of the present invention is not limited to the following description.

[0037] In the first aspect of the present invention, when a compound has isomers such as tautomers or stereoisomers (e.g., geometric isomers, conformational isomers, and optical isomers), any of the isomers can be used in the first aspect of the present invention unless otherwise specified. Furthermore, in the first aspect of the present invention, when a substance can form a salt, the salt can also be used in the first aspect of the present invention unless otherwise specified. The salt may be an acid addition salt or a base addition salt. Furthermore, the acid that forms the acid addition salt may be an inorganic acid or an organic acid, and the base that forms the base addition salt may be an inorganic base or an organic base. The inorganic acid is not particularly limited, but examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorite acid, chlorous acid, bromous acid, iodous acid, fluorine acid, chlorine acid, bromine acid, iodic acid, perfluorine acid, perchlorine acid, perbromine acid, and periodic acid. The organic acid is also not particularly limited, but examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The inorganic base is not particularly limited, but examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates, and more specifically, examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and calcium carbonate. The organic base is also not particularly limited, but examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane. The method for producing these salts is also not particularly limited, and they can be produced, for example, by adding the above-mentioned acid or base to the compound as appropriate using a known method.

[0038] In the first aspect of the present invention, examples of the aromatic ring not containing a heteroatom include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and a pyrene ring. Examples of heteroaromatic rings include a pyridine ring and a thiophene ring. The nitrogen-containing aromatic ring may or may not have a positive charge. Examples of nitrogen-containing aromatic rings not having a positive charge include a pyrroline ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a quinoline ring, an isoquinoline ring, an acridine ring, a 3,4-benzoquinoline ring, a 5,6-benzoquinoline ring, a 6,7-benzoquinoline ring, a 7,8-benzoquinoline ring, a 3,4-benzoisoquinoline ring, a 5,6-benzoisoquinoline ring, a 6,7-benzoisoquinoline ring, and a 7,8-benzoisoquinoline ring. Examples of the positively charged nitrogen-containing aromatic ring include a pyrrolinium ring, a pyridinium ring, a pyridazinium ring, a pyrimidinium ring, a pyrazinium ring, a quinolinium ring, an isoquinolinium ring, an acridinium ring, a 3,4-benzoquinolinium ring, a 5,6-benzoquinolinium ring, a 6,7-benzoquinolinium ring, a 7,8-benzoquinolinium ring, a 3,4-benzoisoquinolinium ring, a 5,6-benzoisoquinolinium ring, a 6,7-benzoisoquinolinium ring, a 7,8-benzoisoquinolinium ring, etc. Examples of the oxygen-containing aromatic ring or sulfur-containing aromatic ring include aromatic rings in which at least one carbon atom or nitrogen atom of the aromatic ring or nitrogen-containing ring not containing a heteroatom is replaced with at least one oxygen atom and / or sulfur atom.

[0039] In the first aspect of the present invention, examples of the "substituent" include a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), and an alkylthio group (-SR, where R is an alkyl group).

[0040] In the first aspect of the present invention, unless otherwise specified, chain substituents (e.g., hydrocarbon groups such as alkyl groups and unsaturated aliphatic hydrocarbon groups) may be linear or branched, and the number of carbon atoms therein is not particularly limited and may be, for example, 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 (2 or more in the case of unsaturated hydrocarbon groups). Furthermore, in the first aspect of the present invention, the number of ring members (the number of atoms constituting the ring) of cyclic groups (e.g., aryl groups, heteroaryl groups, etc.) is not particularly limited and may be, for example, 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. Furthermore, when isomers exist in a substituent or the like, any isomer may be used unless otherwise specified. For example, a simple "butyl group" may refer to an n-butyl group, a sec-butyl group, or a tert-butyl group, and a simple "naphthyl group" may refer to a 1-naphthyl group or a 2-naphthyl group.

[0041] The first invention of the present invention will be explained in more detail below with examples. However, the first invention of the present invention is not limited by the following explanation. Furthermore, the explanations in the first invention of the present invention can be mutually incorporated unless otherwise specified. In this specification, when the expression "~" is used, it is used to mean including the numerical or physical values ​​before and after it. In addition, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0042] [1. Cyclic peroxides] As described above, the cyclic peroxide of the first invention in the present invention is characterized by being represented by the following chemical formula (I). [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0043] The heteroatom refers to an atom other than carbon and hydrogen, and may be, for example, one selected from the group consisting of oxygen, nitrogen, sulfur, selenium, boron, and silicon. The substituent is not particularly limited, and may, for example, contain a hydroxyl group, or may be, for example, one selected from the group consisting of the aforementioned hydroxyl group (-OH), aldehyde group (formyl group), hydroxyalkyl group, sulfo group, nitro group, diazo group, alkyl group, unsaturated aliphatic hydrocarbon group, aryl group, heteroaryl group, halogen, mercapto group (-SH), and alkylthio group (-SR, R is an alkyl group).

[0044] The cyclic peroxide of the first invention of the present invention is, for example, a compound represented by the chemical formula (I): 100 However, it may be a cyclic structure having 5 to 10 ring members.

[0045] The cyclic peroxide of the first invention in the present invention may be, for example, a cyclic peroxide represented by the following chemical formula (II). [ka] In the chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S).

[0046] The cyclic peroxide of the first invention of the present invention is, for example, a compound represented by the formula (II) R 11wherein the substituents may be a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group).

[0047] The cyclic peroxide of the first invention in the present invention may be, for example, a cyclic peroxide represented by the following chemical formula (1): The cyclic peroxide represented by the following chemical formula (1) is a cyclic peroxide represented by the following chemical formula (II) in which all R 11 is a hydrogen atom. [ka]

[0048] The method for producing the cyclic peroxide of the first invention of the present invention is not particularly limited, and for example, the cyclic peroxide can be produced by oxidizing an alcohol by the method for producing an oxidation reaction product of the first invention of the present invention described below. In this case, for example, the produced oxidation reaction product may be used as is without purification, or only the cyclic peroxide of the first invention of the present invention may be isolated and purified and used.

[0049] The present inventors were the first to discover that cyclic peroxides can be obtained by the oxidation of alcohols, for example, the oxidation of glycerin with ozone. The mechanism by which cyclic peroxides are obtained is unclear, but it is speculated that, for example, by extending the reaction time of the alcohol oxidation reaction, as described below, a reaction product different from that obtained in conventional reactions can be obtained.

[0050] The cyclic peroxide of the first invention of the present invention is chemically stable and easy to handle compared to, for example, radicals, and therefore can be isolated and formulated.

[0051] In general, cyclic peroxides are substances that are used industrially due to their oxidizing ability, etc. In particular, artemisinin, which has a seven-membered ring (trioxolane) skeleton similar to the structure of the cyclic peroxide of the first invention of the present invention, is useful as an antimalarial agent and was awarded the Nobel Prize in 2015, and its derivatives are currently being researched.

[0052] However, extracting and purifying artemisinin from natural sources has resulted in unstable supplies. Furthermore, because artemisinin is neither water-soluble nor fat-soluble, formulation has presented many challenges. On the other hand, as mentioned above, hydrogen peroxide is a water-soluble, oxidizing substance, but it is highly reactive and unstable, and has only been used externally for disinfection.

[0053] In contrast, the first aspect of the present invention provides, for example, a cyclic peroxide and oxidation reaction product that are highly safe and have excellent water solubility, as well as a method for producing such an oxidation reaction product. The water solubility and oxidizing ability of the cyclic peroxide of the first aspect of the present invention or the oxidation reaction product of the first aspect of the present invention can be evaluated by, for example, assessing its activity against TRP channels, which are also used as targets for drug discovery, as described in Example 1 below. The mechanism by which the cyclic peroxide of the first aspect of the present invention or the oxidation reaction product of the first aspect of the present invention exhibits TRP channel activity is not particularly limited, but it is thought that, for example, the TRP channel activity is exhibited by gradual decomposition to generate hydrogen peroxide.

[0054] [2. Oxidation Reaction Products] As described above, the oxidation reaction product of the first invention of the present invention is an oxidation reaction product obtained by oxidizing an alcohol and characterized by containing a cyclic peroxide. However, the method for producing the oxidation reaction product of the first invention of the present invention is not limited to the oxidation of an alcohol, and any method for producing a substance having the same structure may be used.

[0055] The method for oxidizing the alcohol is not particularly limited. For example, the oxidation of the alcohol may be at least one of ozone oxidation and hydrogen peroxide oxidation. However, as described above, the method for producing the oxidation reaction product of the first invention of the present invention is not limited to ozone oxidation and hydrogen peroxide oxidation of the alcohol, and any production method may be used as long as the substance has the same structure.

[0056] The oxidation reaction product of the first invention in the present invention may be, for example, a mixture containing a plurality of oxidation reaction products.

[0057] The oxidation reaction product of the first aspect of the present invention may have, for example, oxidizing ability.

[0058] The oxidation reaction product of the first aspect of the present invention may have, for example, reducing ability.

[0059] The oxidation reaction product of the first aspect of the present invention may contain, for example, a TRP channel active substance.

[0060] In the oxidation reaction product of the first invention of the present invention, the alcohol used as a raw material is not particularly limited. For example, in the oxidation reaction product of the first invention of the present invention, the alcohol may be a saturated alcohol.

[0061] In the oxidation reaction product of the first invention of the present invention, for example, the alcohol may be a polyhydric alcohol.

[0062] In the oxidation reaction product of the first invention of the present invention, for example, the alcohol may be at least one of glycerin and a glycerin derivative.

[0063] The oxidation reaction product of the first aspect of the present invention may include, for example, an oxidation reaction product obtained by bonding two or more molecules of the alcohol.

[0064] The oxidation reaction product of the first invention of the present invention may contain, for example, the cyclic peroxide of the first invention of the present invention.

[0065] The alcohol used as a raw material for the oxidation reaction product of the first aspect of the present invention is not particularly limited and may be, for example, a saturated alcohol or an unsaturated alcohol as described above. The alcohol may be linear or branched, and may or may not contain a cyclic structure. The alcohol may be, for example, a polyhydric alcohol or a monohydric alcohol. The hydricity of the polyhydric alcohol is also not particularly limited and may be, for example, dihydric, trihydric, or tetrahydric. Examples of monohydric saturated alcohols include saturated alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated alcohol may be linear or branched, and may or may not contain a cyclic structure. Specific examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butyl alcohol. Examples of saturated polyhydric alcohols include saturated polyhydric alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated polyhydric alcohols may be linear or branched, and may or may not contain a cyclic structure. Specific examples include ethylene glycol (ethane-1,2-diol), propylene glycol (propane-1,2-diol), glycerin, and glycerin derivatives. The glycerin derivatives are not particularly limited, but may be, for example, glycerin polymers or compounds in which at least one hydrogen atom of glycerin is substituted with a substituent (e.g., an alkyl group). Examples of glycerin derivatives include diglycerin and polyglycerin.

[0066] The oxidation reaction product of the first invention of the present invention may be a substance with reducing ability, as described above. For example, the oxidation reaction product of the first invention of the present invention may have a reducing functional group, thereby possessing reducing ability derived from the functional group. Specifically, for example, the oxidation reaction product of the first invention of the present invention may have reducing ability due to the inclusion of an aldehyde group (formyl group), or the TRP channel active substance of the first invention of the present invention may have reducing ability due to the inclusion of a keto-enol tautomer. For example, the oxidation reaction product of the first invention of the present invention obtained in Example 1 described below contains an acetal structure in its skeleton, as confirmed by NMR, and is therefore thought to develop color in the reaction with DNPH (dinitrophenylhydrazine: ketone-aldehyde-derived) derived from ketones and aldehydes.

[0067] The oxidation reaction product of the first aspect of the present invention may be, for example, a substance obtained by bonding two or more molecules of the alcohol, as described above. Specifically, it may be, for example, a structure in which two or more molecules of the alcohol are bonded and then oxidized. The "bonding" form of the two or more alcohol molecules is not particularly limited and may be, for example, addition, condensation, or the like.

[0068] The oxidation reaction product of the first aspect of the present invention is chemically stable and easy to handle compared to, for example, radicals, and can therefore be isolated and formulated.

[0069] [3. Method for producing oxidation reaction product] As described above, the method for producing an oxidation reaction product of the first invention of the present invention is a method for producing an oxidation reaction product of the first invention of the present invention, which includes an alcohol oxidation step of oxidizing the alcohol.

[0070] The method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited. In the method for producing an oxidation reaction product of the first aspect of the present invention, for example, the alcohol may be oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation in the alcohol oxidation step.

[0071] In the method for producing an oxidation reaction product according to the first aspect of the present invention, the reaction time for the alcohol oxidation step is not particularly limited. The reaction time for the alcohol oxidation step may be, for example, 24 hours or more or 1 day or more, 48 hours or more or 2 days or more, 72 hours or more or 3 days or more, 120 hours or more or 5 days or more, or 168 hours or more or 7 days or more. The upper limit of the reaction time for the alcohol oxidation step is not particularly limited, but may be, for example, 720 hours or less or 30 days or less, or 360 hours or less or 15 days or less.

[0072] In the method for producing an oxidation reaction product of the first invention of the present invention, it is preferable to extend the reaction time of the alcohol oxidation step in order to obtain a reaction product containing the cyclic peroxide of the first invention of the present invention. For example, it is believed that extending the reaction time of the alcohol oxidation step makes it possible to produce the cyclic peroxide of the first invention of the present invention, which could not be obtained by conventional ozone oxidation reactions of glycerin, etc. In the method for producing an oxidation reaction product of the first invention of the present invention, it is preferable that the reaction time of the alcohol oxidation step is not too long in order to ensure production efficiency.

[0073] As described above, the method for producing an oxidation reaction product of the first invention of the present invention includes an alcohol oxidation step of oxidizing the alcohol. However, as described above, the oxidation reaction product of the first invention of the present invention is not limited to substances produced by this production method, and may be a substance produced by any production method as long as it has the same structure. The method for producing an oxidation reaction product of the first invention of the present invention will be described in more detail below using examples.

[0074] The following description will be given taking as an example a case where glycerin is used as the alcohol and oxidation is carried out with ozone. However, as mentioned above, the following description is merely illustrative, and the method for producing an oxidation reaction product of the first invention of the present invention is not limited to the following description. For example, the following method can be carried out in the same manner using other alcohols instead of glycerin. For example, in the method for producing an oxidation reaction product of the first invention of the present invention, the method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited and is arbitrary, and is not limited to ozone oxidation. The oxidation method may be, for example, at least one of ozone oxidation and hydrogen peroxide oxidation. Furthermore, not only the type of alcohol and the method for oxidizing the alcohol, but also the concentration of each substance, reaction temperature, reaction time, and other reaction conditions can be changed as appropriate.

[0075] The oxidation reaction product of the first invention of the present invention can be produced by a production method including, for example, a step of contacting glycerin with ozone, more specifically, a step of oxidizing glycerin by mixing glycerin with ozone (corresponding to the "alcohol oxidation step" of the first invention of the present invention). The step of oxidizing glycerin may be, for example, a step of bringing a glycerin solution into gas-liquid contact with a gas containing ozone to oxidize glycerin.

[0076] The glycerin solution preferably has a high glycerin concentration. Examples of the high-concentration glycerin solution include a glycerin solution having a glycerin concentration of 75% or more. Specific examples include a glycerin solution of 84 to 87% by weight as specified in the Japanese Pharmacopoeia, a concentrated glycerin solution of 98% by weight or more as specified in the Japanese Pharmacopoeia, and a purified glycerin solution of 98.5% by weight or more. For example, the glycerin solution can be treated with ozone at a higher concentration as the glycerin concentration is relatively higher. The solvent for glycerin in the glycerin solution is not particularly limited, and may be, for example, an aqueous solvent such as water.

[0077] The ozone-containing gas preferably has a high ozone concentration. The method for producing the gas with a high ozone concentration is not particularly limited, and for example, an ozone generator that generates ozone by silently discharging oxygen gas can be used. When oxygen gas is used, for example, a medical oxygen cylinder can be used, or oxygen gas produced by an oxygen generator can be used.

[0078] The method for bringing the glycerin solution into gas-liquid contact with the ozone-containing gas is not particularly limited, and for example, a method is available in which a high-concentration (e.g., 98% by weight or more) glycerin solution is placed in a tank and the high-ozone-concentration gas is released into the tank as fine bubbles using an air diffuser. Specifically, for example, an ozone-treated glycerin solution having an equivalent hydrogen peroxide concentration of about 4000 ppm can be produced by aerating a gas having an ozone concentration of about 37,000 ppm into the concentrated glycerin solution for about 7 days. The aeration time is not particularly limited, and for example, an ozone-treated glycerin solution containing a higher concentration of the oxidation reaction product of the first invention of the present invention can be produced by aerating the concentrated glycerin solution for a relatively long time.

[0079] The oxidation reaction product of the first invention of the present invention may be used as it is without being separated from the mixture after the reaction (for example, the ozone-treated glycerin solution), or may be used after being separated from the mixture after the reaction. The separation method is not particularly limited, and for example, the oxidation reaction product of the first invention of the present invention can be separated from the mixture after the reaction by chromatography such as preparative thin-layer chromatography.

[0080] Conventionally, the production of substances such as peroxides having oxidizing power required a complicated system. According to the method for producing an oxidation reaction product of the first aspect of the present invention, for example, an oxidation reaction product having oxidizing power can be produced in an extremely simple and easy manner.

[0081] The oxidation reaction product of the first invention of the present invention can generate, for example, hydrogen peroxide. For example, the oxidation reaction product of the first invention of the present invention can generate 1 to 4000 ppm, 10 to 4000 ppm, or 100 to 4000 ppm of hydrogen peroxide per oxidation reaction product of the first invention of the present invention, which has a hydrogen peroxide concentration of about 4000 ppm.

[0082] 4. Use of cyclic peroxides and oxidation reaction products The method of using the cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention is not particularly limited. For example, if the cyclic peroxide of the first invention of the present invention or the oxidation reaction product of the first invention of the present invention has TRP channel activity, it may be used as a TRP channel activator. In such a case, the method of use is not particularly limited and may be similar to the method of use of a general TRP channel activator. As described above, the cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention are highly safe and can be used safely. Furthermore, the cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention may be used directly without separation from the reaction mixture, or may be used after separation of the cyclic peroxide of the first invention of the present invention or the oxidation reaction product of the first invention of the present invention from the reaction mixture.

[0083] As described above, the cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention are highly safe and therefore extremely useful. The cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention can act on ion channels (e.g., TRPA1) related to itching, pain, etc., and can therefore be used in the development of pharmaceuticals, etc.

[0084] Furthermore, the uses of the cyclic peroxide of the first invention of the present invention and the oxidation reaction product of the first invention of the present invention are not limited thereto, and they can be used in a variety of applications, such as cosmetics, pharmaceuticals, foods, or supplements.

[0085] [Second embodiment of the invention] Next, a second embodiment of the present invention will be described, although the second embodiment of the present invention is not limited to the following description.

[0086] In the second invention of the present invention, when a compound has isomers such as tautomers or stereoisomers (e.g., geometric isomers, conformational isomers, and optical isomers), any of the isomers can be used in the second invention of the present invention, unless otherwise specified. Furthermore, in the second invention of the present invention, when a substance can form a salt, the salt can also be used in the second invention of the present invention, unless otherwise specified. The salt may be an acid addition salt or a base addition salt. Furthermore, the acid that forms the acid addition salt may be an inorganic acid or an organic acid, and the base that forms the base addition salt may be an inorganic base or an organic base. The inorganic acid is not particularly limited, but examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorite acid, chlorous acid, bromous acid, iodous acid, fluorine acid, chlorine acid, bromine acid, iodic acid, perfluorine acid, perchlorine acid, perbromine acid, and periodic acid. The organic acid is also not particularly limited, but examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The inorganic base is not particularly limited, but examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates, and more specifically, examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and calcium carbonate. The organic base is also not particularly limited, but examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane. The method for producing these salts is also not particularly limited, and they can be produced, for example, by adding the above-mentioned acid or base to the compound as appropriate using a known method.

[0087] In the second aspect of the present invention, examples of the aromatic ring not containing a heteroatom include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and a pyrene ring. Examples of heteroaromatic rings include a pyridine ring and a thiophene ring. The nitrogen-containing aromatic ring may or may not have a positive charge. Examples of nitrogen-containing aromatic rings not having a positive charge include a pyrroline ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a quinoline ring, an isoquinoline ring, an acridine ring, a 3,4-benzoquinoline ring, a 5,6-benzoquinoline ring, a 6,7-benzoquinoline ring, a 7,8-benzoquinoline ring, a 3,4-benzoisoquinoline ring, a 5,6-benzoisoquinoline ring, a 6,7-benzoisoquinoline ring, and a 7,8-benzoisoquinoline ring. Examples of the positively charged nitrogen-containing aromatic ring include a pyrrolinium ring, a pyridinium ring, a pyridazinium ring, a pyrimidinium ring, a pyrazinium ring, a quinolinium ring, an isoquinolinium ring, an acridinium ring, a 3,4-benzoquinolinium ring, a 5,6-benzoquinolinium ring, a 6,7-benzoquinolinium ring, a 7,8-benzoquinolinium ring, a 3,4-benzoisoquinolinium ring, a 5,6-benzoisoquinolinium ring, a 6,7-benzoisoquinolinium ring, a 7,8-benzoisoquinolinium ring, etc. Examples of the oxygen-containing aromatic ring or sulfur-containing aromatic ring include aromatic rings in which at least one carbon atom or nitrogen atom of the aromatic ring or nitrogen-containing ring not containing a heteroatom is replaced with at least one oxygen atom and / or sulfur atom.

[0088] In the second aspect of the present invention, examples of the "substituent" include a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), an alkylthio group (-SR, where R is an alkyl group), and the like.

[0089] In the second aspect of the present invention, unless otherwise specified, chain substituents (e.g., hydrocarbon groups such as alkyl groups and unsaturated aliphatic hydrocarbon groups) may be linear or branched, and the number of carbon atoms therein is not particularly limited and may be, for example, 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 (2 or more in the case of unsaturated hydrocarbon groups). Furthermore, in this specification, the number of ring members (the number of atoms constituting the ring) of cyclic groups (e.g., aryl groups, heteroaryl groups, etc.) is not particularly limited and may be, for example, 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. Furthermore, when isomers exist in a substituent or the like, any isomer may be used unless otherwise specified. For example, a simple "butyl group" may refer to an n-butyl group, a sec-butyl group, or a tert-butyl group, and a simple "naphthyl group" may refer to a 1-naphthyl group or a 2-naphthyl group.

[0090] In the second aspect of the present invention, "skin whitening" refers to the prevention and / or improvement of pigmentation. Specifically, the term "skin whitening" refers to the prevention and / or improvement of pigmentation symptoms caused by increased melanin production or production, excessive melanin accumulation, and / or abnormal melanin deposition, such as age spots, dullness, freckles, sunburn, skin inflammation, and darkening due to skin irritation; pigmentation symptoms caused by diseases that result in pigmentation, such as skin melanosis caused by drugs such as steroids; and the like.

[0091] The second invention of the present invention will be explained in more detail below with examples. However, the second invention of the present invention is not limited by the following explanation. Furthermore, the explanations in the second invention of the present invention can be mutually incorporated unless otherwise specified. In this specification, when the expression "~" is used, it is used to mean including the numerical or physical values ​​before and after it. In addition, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0092] <Whitening composition> A whitening composition (hereinafter referred to as "composition") according to a second aspect of the present invention contains glycerin and / or a glycerin derivative and a whitening ingredient, and the whitening ingredient contains a cyclic peroxide or a salt thereof as an active ingredient. The composition according to the second aspect of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described below, the cyclic peroxide is thought to promote the decomposition of melanin. Therefore, the composition according to the second aspect of the present invention can provide a whitening effect on the skin when applied to the skin, for example.

[0093] The whitening composition of the second invention of the present invention can also be described as, for example, a composition for improving age spots, dullness, or freckles, a composition for inhibiting melanin production, a composition for decomposing melanin, a composition for promoting melanin excretion, a composition for reducing skin pigmentation, a composition for skin whitening, etc.

[0094] [1. Whitening ingredients] The composition of the second invention of the present invention contains a whitening ingredient, as described above. The composition of the second invention of the present invention may contain the cyclic peroxide as the active ingredient of the whitening ingredient, or may contain an oxidation reaction product containing the cyclic peroxide, as described below, or may contain both. The cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing an alcohol, as described below.

[0095] In the composition of the second invention of the present invention, the content of the whitening ingredient is, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%, and the content of the cyclic peroxide is, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0096] [2. Cyclic Peroxides] The cyclic peroxide is represented by the following chemical formula (I): [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0097] The heteroatom refers to an atom other than carbon and hydrogen, and may be, for example, one selected from the group consisting of oxygen, nitrogen, sulfur, selenium, boron, and silicon. The substituent is not particularly limited, and may, for example, contain a hydroxyl group, or may be, for example, one selected from the group consisting of the aforementioned hydroxyl group (-OH), aldehyde group (formyl group), hydroxyalkyl group, sulfo group, nitro group, diazo group, alkyl group, unsaturated aliphatic hydrocarbon group, aryl group, heteroaryl group, halogen, mercapto group (-SH), and alkylthio group (-SR, R is an alkyl group).

[0098] The cyclic peroxide may be, for example, a compound represented by the formula (I): 100 However, it may be a cyclic structure having 5 to 10 ring members.

[0099] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (II): [ka] In the chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S).

[0100] The cyclic peroxide is, for example, R 11 wherein the substituents may be a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group).

[0101] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (1): The cyclic peroxide represented by the following chemical formula (1) is a cyclic peroxide represented by the following chemical formula (II) in which all R 11 is a hydrogen atom. [ka]

[0102] The method for producing the cyclic peroxide is not particularly limited, and for example, the cyclic peroxide can be produced by oxidizing an alcohol by the method for producing the oxidation reaction product described below. In this case, for example, the produced oxidation reaction product may be used as is without purification, or the cyclic peroxide alone may be isolated and purified and used.

[0103] The present inventors were the first to discover that cyclic peroxides can be produced by the oxidation of alcohols, for example, the oxidation of glycerin with ozone. The mechanism by which cyclic peroxides are produced is unclear, but it is speculated that, for example, by extending the reaction time of the alcohol oxidation reaction, as described below, a reaction product different from that obtained in conventional reactions can be obtained.

[0104] The cyclic peroxides are chemically stable and easy to handle compared to radicals, for example, and therefore can be isolated and formulated.

[0105] In general, cyclic peroxides are substances that are used industrially due to their oxidizing ability, etc. In particular, artemisinin, which has a seven-membered ring (trioxolane) skeleton similar to the structure of the cyclic peroxides, is useful as an antimalarial agent and was awarded the Nobel Prize in 2015, and its derivatives are currently being researched.

[0106] However, extracting and purifying artemisinin from natural sources has resulted in unstable supplies. Furthermore, because artemisinin is neither water-soluble nor fat-soluble, formulation has presented many challenges. On the other hand, hydrogen peroxide is a water-soluble, oxidizing substance, but it is highly reactive and unstable, and has only been used topically for disinfection.

[0107] In contrast, the second aspect of the present invention uses, for example, a cyclic peroxide and an oxidation reaction product that are highly safe and have excellent water solubility, making them suitable for use in living organisms. Furthermore, the second aspect of the present invention is presumed to be able to decompose melanin due to the oxidizing ability of the cyclic peroxide, thereby providing a whitening effect. The whitening effect can be evaluated in accordance with Example 2, which will be described later.

[0108] In the composition of the second invention of the present invention, the cyclic peroxide may be a salt or a solvate such as a hydrate, etc. The description of the cyclic peroxide can be applied to the description of the salt of the cyclic peroxide or the solvate thereof.

[0109] [3. Oxidation Reaction Products] As described above, the oxidation reaction product is an oxidation reaction product characterized by containing a cyclic peroxide obtained by oxidizing an alcohol, but the method for producing the oxidation reaction product is not limited to the oxidation of an alcohol, and any method for producing the oxidation reaction product may be used as long as it has the same structure.

[0110] The method for oxidizing the alcohol is not particularly limited. For example, the oxidation of the alcohol may be at least one of ozone oxidation and hydrogen peroxide oxidation. However, as described above, the method for producing the oxidation reaction product is not limited to ozone oxidation and hydrogen peroxide oxidation of the alcohol, and any production method may be used as long as the substance has the same structure.

[0111] The oxidation reaction product may be, for example, a mixture containing a plurality of oxidation reaction products.

[0112] The oxidation reaction product may have, for example, an oxidizing ability.

[0113] The oxidation reaction product may have, for example, reducing ability.

[0114] The oxidation reaction product may contain, for example, a substance having melanin decomposition activity, melanin production inhibitory activity, and / or melanin excretion promoting activity.

[0115] The alcohol used as a raw material in the oxidation reaction product is not particularly limited. For example, the alcohol in the oxidation reaction product may be a saturated alcohol.

[0116] In the oxidation reaction product, for example, the alcohol may be a polyhydric alcohol.

[0117] In the oxidation reaction product, for example, the alcohol may be at least one of glycerin and a glycerin derivative.

[0118] The oxidation reaction product may include, for example, an oxidation reaction product obtained by bonding two or more molecules of the alcohol.

[0119] The oxidation reaction product may include, for example, the cyclic peroxide.

[0120] The alcohol used as a raw material for the oxidation reaction product is not particularly limited and may be, for example, a saturated alcohol or an unsaturated alcohol as described above. The alcohol may be linear or branched, and may or may not contain a cyclic structure. The alcohol may be, for example, a polyhydric alcohol or a monohydric alcohol. The valence of the polyhydric alcohol is also not particularly limited and may be, for example, dihydric, trihydric, or tetrahydric. Examples of monohydric saturated alcohols include saturated alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated alcohol may be linear or branched and may or may not contain a cyclic structure. Specific examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butyl alcohol. Examples of saturated polyhydric alcohols include saturated polyhydric alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated polyhydric alcohols may be linear or branched, and may or may not contain a cyclic structure. Specific examples include ethylene glycol (ethane-1,2-diol), propylene glycol (propane-1,2-diol), glycerin, and glycerin derivatives. The glycerin derivatives are not particularly limited, but may be, for example, glycerin polymers or compounds in which at least one hydrogen atom of glycerin is substituted with a substituent (e.g., an alkyl group). Examples of glycerin derivatives include diglycerin and polyglycerin. The glycerin derivative may also be an oxidized form of glycerin.

[0121] The oxidation reaction product may be, for example, a substance having reducing ability, as described above. For example, the oxidation reaction product may have a functional group having reducing ability, thereby possessing reducing ability derived from the functional group. Specifically, for example, the oxidation reaction product may have reducing ability due to the inclusion of an aldehyde group (formyl group), or may be a keto-enol tautomer, thereby possessing reducing ability derived from the keto form. For example, the oxidation reaction product obtained in Example 2 described below contains an acetal structure in its skeleton, as confirmed by NMR, and is therefore thought to develop color in a DNPH (dinitrophenylhydrazine: ketone-aldehyde-derived) reaction derived from a ketone or aldehyde.

[0122] The oxidation reaction product may be, for example, a substance obtained by bonding two or more molecules of the alcohol, as described above. Specifically, for example, the oxidation reaction product may have a structure in which two or more molecules of the alcohol are bonded and then oxidized. The form of "bonding" of the two or more alcohol molecules is not particularly limited, and may be, for example, addition, condensation, or the like.

[0123] The oxidation reaction product is chemically stable and easy to handle compared to, for example, radicals, and therefore can be isolated and formulated.

[0124] [4. Method for producing oxidation reaction product] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol.

[0125] The method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited. For example, in the method for producing the oxidation reaction product, the alcohol may be oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation in the alcohol oxidation step.

[0126] In the method for producing an oxidation reaction product, the reaction time of the alcohol oxidation step is not particularly limited. The reaction time of the alcohol oxidation step may be, for example, 24 hours or more or 1 day or more, 48 hours or more or 2 days or more, 72 hours or more or 3 days or more, 120 hours or more or 5 days or more, or 168 hours or more or 7 days or more. The upper limit of the reaction time of the alcohol oxidation step is not particularly limited, but may be, for example, 720 hours or less or 30 days or less, or 360 hours or less or 15 days or less.

[0127] In the method for producing the oxidation reaction product, it is preferable to extend the reaction time of the alcohol oxidation step in order to obtain a reaction product containing the cyclic peroxide. For example, it is believed that extending the reaction time of the alcohol oxidation step makes it possible to produce the cyclic peroxide, which could not be obtained by conventional ozone oxidation reactions of glycerin, etc. In the method for producing the oxidation reaction product, it is preferable that the reaction time of the alcohol oxidation step is not too long in order to ensure production efficiency.

[0128] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol. However, as described above, the oxidation reaction product is not limited to a substance produced by this production method, and may be a substance produced by any production method as long as it has the same structure. The method for producing the oxidation reaction product will be described in more detail below using examples.

[0129] The following description will be given taking as an example a case where glycerin is used as the alcohol and oxidation is carried out with ozone. However, as mentioned above, the following description is merely an example, and the method for producing the oxidation reaction product is not limited to the following description. For example, the following method can be carried out in the same manner using other alcohols instead of glycerin. For example, in the method for producing the oxidation reaction product, the method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited and is arbitrary, and is not limited to ozone oxidation. The oxidation method may be, for example, at least one of ozone oxidation and hydrogen peroxide oxidation. Furthermore, for example, not only the type of alcohol and the method for oxidizing the alcohol, but also the concentration of each substance, reaction temperature, reaction time, and other reaction conditions can be changed as appropriate.

[0130] The oxidation reaction product can be produced by a production method including, for example, a step of contacting glycerin with ozone, more specifically, a step of oxidizing glycerin by mixing glycerin with ozone (corresponding to the "alcohol oxidation step"). The step of oxidizing glycerin may be, for example, a step of bringing a glycerin solution into gas-liquid contact with a gas containing ozone to oxidize glycerin.

[0131] The glycerin solution preferably has a high glycerin concentration. Examples of the high-concentration glycerin solution include a glycerin solution having a glycerin concentration of 75% or more. Specific examples include a glycerin solution of 84 to 87% by weight as specified in the Japanese Pharmacopoeia, a concentrated glycerin solution of 98% by weight or more as specified in the Japanese Pharmacopoeia, and a purified glycerin solution of 98.5% by weight or more. For example, the glycerin solution can be treated with ozone at a higher concentration as the glycerin concentration is relatively higher. The solvent for glycerin in the glycerin solution is not particularly limited, and may be, for example, an aqueous solvent such as water.

[0132] The ozone-containing gas preferably has a high ozone concentration. The method for producing the gas with a high ozone concentration is not particularly limited, and for example, an ozone generator that generates ozone by silently discharging oxygen gas can be used. When oxygen gas is used, for example, a medical oxygen cylinder can be used, or oxygen gas produced by an oxygen generator can be used.

[0133] The method for bringing the glycerin solution into gas-liquid contact with the ozone-containing gas is not particularly limited, and for example, a method is available in which a high-concentration (e.g., 98% by weight or more) glycerin solution is placed in a tank and the high-ozone-concentration gas is released into the tank as fine bubbles using an air diffuser. Specifically, for example, an ozone-treated glycerin solution having an equivalent hydrogen peroxide concentration of about 4000 ppm can be produced by aerating a gas having an ozone concentration of about 37000 ppm into the concentrated glycerin solution for about 7 days. The aeration time is not particularly limited, and for example, an ozone-treated glycerin solution containing the oxidation reaction product at a higher concentration can be produced by aerating the concentrated glycerin solution for a relatively longer period of time.

[0134] The oxidation reaction product may be used as it is without being separated from the reaction mixture (e.g., the ozone-treated glycerin solution), or may be used after being separated from the reaction mixture. The separation method is not particularly limited, and the oxidation reaction product can be separated from the reaction mixture by chromatography such as preparative thin-layer chromatography, for example.

[0135] Conventionally, the production of substances such as peroxides having oxidizing power has required a complicated system. According to the method for producing an oxidation reaction product, for example, an oxidation reaction product having oxidizing power can be produced in an extremely simple and easy manner.

[0136] The oxidation reaction product can generate, for example, hydrogen peroxide. For example, the oxidation reaction product can generate 1 to 4000 ppm, 10 to 4000 ppm, or 100 to 4000 ppm of hydrogen peroxide per approximately 4000 ppm of the oxidation reaction product in terms of hydrogen peroxide concentration.

[0137] [5. Glycerin] In the composition of the second invention of the present invention, the glycerin may be glycerin or the above-mentioned glycerin derivative. In the composition of the second invention of the present invention, the cyclic peroxide can be stably maintained by coexisting with the glycerin.

[0138] In the composition of the second aspect of the present invention, the content of the glycerin is, for example, 0.1 to 100 w / v %, or preferably 0.1 to 50 w / v %.

[0139] [6. Other whitening ingredients] The composition of the second invention of the present invention may contain, as the active whitening ingredient, other whitening ingredients in addition to the cyclic peroxide and / or oxidation reaction product containing the cyclic peroxide, such as arbutin, tranexamic acid, and ascorbic acid or derivatives thereof.

[0140] [7. Other Ingredients] The composition of the second invention of the present invention may contain other components added to a formulation to be applied to the skin. Specific examples of the other components include components added to topical skin preparations and components added to cosmetics (including quasi-drugs). Specific examples of the components added to topical skin preparations include pharmaceutically acceptable carriers. Specific examples of the other components include components added when applied to the skin or transdermally, such as aqueous solvents such as water, alcohols, moisturizers, oils, softeners (emollients), surfactants (solubilizers, emulsifiers), salts, thickeners, pH adjusters, UV absorbers, pharmaceuticals, buffers, colorants, preservatives, and fragrances.

[0141] 8. Dosage Form, Dosage, and Use The composition of the second invention of the present invention is, for example, a solid or liquid. Examples of the form of the composition of the second invention of the present invention include lotion formulations, emulsion formulations such as lotions and creams, oil formulations, gel formulations, ointments, packs, cleansers, etc.

[0142] The subject of use of the composition of the second invention of the present invention is a human or a non-human animal. The composition of the second invention of the present invention can be used, for example, on a part of the subject that contains melanin, specifically, the skin. The amount of the composition of the second invention of the present invention used is not particularly limited, and can be an amount normally used depending on the dosage form of the composition of the second invention of the present invention.

[0143] The composition of the second invention of the present invention can be suitably used as an external preparation for skin, such as a cosmetic.

[0144] <Whitening agent> The whitening agent of the second invention of the present invention contains a cyclic peroxide or a salt thereof. The whitening agent of the second invention of the present invention is characterized by containing a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. The cyclic peroxide is presumed to promote the decomposition of melanin. Therefore, the whitening agent of the second invention of the present invention can provide a whitening effect on the skin, for example, when applied to the skin.

[0145] The whitening agent of the second invention of the present invention can also be described as, for example, an agent for improving spots, dullness, or freckles, a melanin production inhibitor, a melanin decomposing agent, an agent for reducing skin pigmentation, a whitening agent, or the like.

[0146] In the whitening agent of the second invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0147] The explanation of the cyclic peroxide and the oxidation reaction product can be found in the explanation of the composition of the second invention of the present invention.

[0148] The explanation of the formulation and use of the whitening agent of the second invention of the present invention can be cited from the explanation of the composition of the second invention of the present invention.

[0149] <Whitening method> The whitening method of the second invention of the present invention uses the whitening composition of the second invention of the present invention and / or the whitening agent of the second invention of the present invention. The whitening method of the second invention of the present invention is characterized by using the whitening composition of the second invention of the present invention and / or the whitening agent of the second invention of the present invention, and other steps and conditions are not particularly limited. The cyclic peroxide contained in the composition and / or whitening agent of the second invention of the present invention is thought to promote the decomposition of melanin. Therefore, the whitening agent of the second invention of the present invention can provide a whitening effect on the skin, for example, when applied to the skin.

[0150] The whitening method of the second invention of the present invention can be carried out, for example, by applying the whitening composition and / or the whitening agent to the skin of the subject. More specifically, the whitening method of the second invention of the present invention can be carried out by contacting the skin of the subject with the whitening composition and / or the whitening agent.

[0151] <Use> The second invention of the present invention is a whitening composition of the second invention of the present invention and / or a whitening agent of the second invention of the present invention for use in whitening, or use thereof.

[0152] [Third embodiment of the invention] Next, a description will be given of an embodiment of the third invention of the present invention, although the third invention of the present invention is not limited to the following description.

[0153] In the third aspect of the present invention, when a compound has isomers such as tautomers or stereoisomers (e.g., geometric isomers, conformational isomers, and optical isomers), any of these isomers can be used in the present invention unless otherwise specified. Furthermore, in the third aspect of the present invention, when a substance can form a salt, the salt can also be used in the third aspect of the present invention unless otherwise specified. The salt may be an acid addition salt or a base addition salt. Furthermore, the acid that forms the acid addition salt may be an inorganic acid or an organic acid, and the base that forms the base addition salt may be an inorganic base or an organic base. The inorganic acid is not particularly limited, but examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorite acid, chlorous acid, bromous acid, iodous acid, fluorine acid, chlorine acid, bromine acid, iodic acid, perfluorine acid, perchlorine acid, perbromine acid, and periodic acid. The organic acid is also not particularly limited, but examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The inorganic base is not particularly limited, but examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates, and more specifically, examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and calcium carbonate. The organic base is also not particularly limited, but examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane. The method for producing these salts is also not particularly limited, and they can be produced, for example, by adding the above-mentioned acid or base to the compound as appropriate using a known method.

[0154] In the third aspect of the present invention, examples of the aromatic ring not containing a heteroatom include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and a pyrene ring. Examples of heteroaromatic rings include a pyridine ring and a thiophene ring. The nitrogen-containing aromatic ring may or may not have a positive charge. Examples of nitrogen-containing aromatic rings not having a positive charge include a pyrroline ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a quinoline ring, an isoquinoline ring, an acridine ring, a 3,4-benzoquinoline ring, a 5,6-benzoquinoline ring, a 6,7-benzoquinoline ring, a 7,8-benzoquinoline ring, a 3,4-benzoisoquinoline ring, a 5,6-benzoisoquinoline ring, a 6,7-benzoisoquinoline ring, and a 7,8-benzoisoquinoline ring. Examples of the positively charged nitrogen-containing aromatic ring include a pyrrolinium ring, a pyridinium ring, a pyridazinium ring, a pyrimidinium ring, a pyrazinium ring, a quinolinium ring, an isoquinolinium ring, an acridinium ring, a 3,4-benzoquinolinium ring, a 5,6-benzoquinolinium ring, a 6,7-benzoquinolinium ring, a 7,8-benzoquinolinium ring, a 3,4-benzoisoquinolinium ring, a 5,6-benzoisoquinolinium ring, a 6,7-benzoisoquinolinium ring, a 7,8-benzoisoquinolinium ring, etc. Examples of the oxygen-containing aromatic ring or sulfur-containing aromatic ring include aromatic rings in which at least one carbon atom or nitrogen atom of the aromatic ring or nitrogen-containing ring not containing a heteroatom is replaced with at least one oxygen atom and / or sulfur atom.

[0155] In the third aspect of the present invention, examples of the "substituent" include a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), an alkylthio group (-SR, where R is an alkyl group), and the like.

[0156] In the third aspect of the present invention, unless otherwise specified, chain substituents (e.g., hydrocarbon groups such as alkyl groups and unsaturated aliphatic hydrocarbon groups) may be linear or branched, and the number of carbon atoms therein is not particularly limited and may be, for example, 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 (2 or more in the case of unsaturated hydrocarbon groups). Furthermore, in this specification, the number of ring members (the number of atoms constituting the ring) of cyclic groups (e.g., aryl groups, heteroaryl groups, etc.) is not particularly limited and may be, for example, 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. Furthermore, when isomers exist in a substituent or the like, any isomer may be used unless otherwise specified. For example, a simple "butyl group" may refer to an n-butyl group, a sec-butyl group, or a tert-butyl group, and a simple "naphthyl group" may refer to a 1-naphthyl group or a 2-naphthyl group.

[0157] In the third aspect of the present invention, the term "skin barrier function" refers to the function of preventing evaporation of moisture from inside the skin and / or the function of preventing the penetration of substances into the skin from the outside.

[0158] In the third aspect of the present invention, "oxidative stress" refers to stress caused by reactive oxygen species. Specific examples of the oxidative stress include damage to biomolecules (e.g., proteins, lipids, nucleic acids, etc.) and damage to intracellular organelles caused by the reactive oxygen species.

[0159] In the third aspect of the present invention, "induction of gene expression" may mean changing from a state in which the target gene is not expressed to a state in which the target gene is expressed, or may mean increasing the expression level of the target gene.

[0160] In the third aspect of the present invention, "treatment" refers to therapeutic treatment and / or preventive treatment. As used herein, "treatment" refers to treating, curing, preventing, suppressing, ameliorating, or ameliorating a disease, pathological condition, or disorder, or halting, suppressing, reducing, or delaying the progression of a disease, pathological condition, or disorder. As used herein, "prevention" refers to reducing the likelihood of developing a disease or pathological condition, or delaying the onset of a disease or pathological condition. The "treatment" may be, for example, treatment of a patient who develops the target disease, or treatment of an animal model of the target disease.

[0161] The third invention of the present invention will be explained in more detail below with examples. However, the third invention of the present invention is not limited by the following explanation. Furthermore, the explanations in the third invention of the present invention can be mutually incorporated unless otherwise specified. In this specification, when the expression "~" is used, it is used to mean including the numerical or physical values ​​before and after it. In addition, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0162] <Composition for inducing the expression of skin barrier function-related genes> A composition for inducing the expression of skin barrier function-related genes in a third aspect of the present invention (hereinafter referred to as the "first composition") comprises glycerin and / or a glycerin derivative and an ingredient for inducing the expression of skin barrier function-related genes, and the ingredient for inducing the expression of skin barrier function-related genes comprises a cyclic peroxide or a salt thereof as an active ingredient. The first composition of the third aspect of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described below, the cyclic peroxide induces the expression of proteins important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, the first composition of the third aspect of the present invention can, for example, when applied to the skin, achieve the effect of inducing the expression of skin barrier function-related genes in the skin.

[0163] [1. Induces the expression of genes related to skin barrier function] As described above, the first composition of the third aspect of the present invention contains a component that induces the expression of skin barrier function-related genes. The first composition of the third aspect of the present invention may contain the cyclic peroxide as an active ingredient of the component that induces the expression of skin barrier function-related genes, or may contain an oxidation reaction product containing the cyclic peroxide, as described below, or may contain both. The cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing an alcohol, as described below.

[0164] In the first composition of the third invention of the present invention, the content of the component that induces the expression of skin barrier function-related genes may be an effective amount capable of inducing the expression of skin barrier function-related genes, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the first composition of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of inducing the expression of skin barrier function-related genes, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0165] [2. Cyclic Peroxides] The cyclic peroxide is represented by the following chemical formula (I): [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0166] The heteroatom refers to an atom other than carbon and hydrogen, and may be, for example, one selected from the group consisting of oxygen, nitrogen, sulfur, selenium, boron, and silicon. The substituent is not particularly limited, and may, for example, contain a hydroxyl group, or may be, for example, one selected from the group consisting of the aforementioned hydroxyl group (-OH), aldehyde group (formyl group), hydroxyalkyl group, sulfo group, nitro group, diazo group, alkyl group, unsaturated aliphatic hydrocarbon group, aryl group, heteroaryl group, halogen, mercapto group (-SH), and alkylthio group (-SR, R is an alkyl group).

[0167] The cyclic peroxide may be, for example, a compound represented by the formula (I): 100 However, it may be a cyclic structure having 5 to 10 ring members.

[0168] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (II): [ka] In the chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S).

[0169] The cyclic peroxide is, for example, R 11 wherein the substituents may be a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group).

[0170] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (1): The cyclic peroxide represented by the following chemical formula (1) is a cyclic peroxide represented by the following chemical formula (II) in which all R 11 is a hydrogen atom. [ka]

[0171] The method for producing the cyclic peroxide is not particularly limited, and for example, the cyclic peroxide can be produced by oxidizing an alcohol by the method for producing the oxidation reaction product described below. In this case, for example, the produced oxidation reaction product may be used as is without purification, or the cyclic peroxide alone may be isolated and purified and used.

[0172] The present inventors were the first to discover that cyclic peroxides can be produced by the oxidation of alcohols, for example, the oxidation of glycerin with ozone. The mechanism by which cyclic peroxides are produced is unclear, but it is speculated that, for example, by extending the reaction time of the alcohol oxidation reaction, as described below, a reaction product different from that obtained in conventional reactions can be obtained.

[0173] The cyclic peroxides are chemically stable and easy to handle compared to radicals, for example, and therefore can be isolated and formulated.

[0174] In general, cyclic peroxides are substances that are used industrially due to their oxidizing ability, etc. In particular, artemisinin, which has a seven-membered ring (trioxolane) skeleton similar to the structure of the cyclic peroxides, is useful as an antimalarial agent and was awarded the Nobel Prize in 2015, and its derivatives are currently being researched.

[0175] However, extracting and purifying artemisinin from natural sources has resulted in unstable supplies. Furthermore, because artemisinin is neither water-soluble nor fat-soluble, formulation has presented many challenges. On the other hand, hydrogen peroxide is a water-soluble, oxidizing substance, but it is highly reactive and unstable, and has only been used topically for disinfection.

[0176] In contrast, the third aspect of the present invention uses, for example, a cyclic peroxide and an oxidation reaction product that are highly safe and have excellent water solubility, making them suitable for use in living organisms. Furthermore, in the third aspect of the present invention, it is presumed that the oxidizing ability of the cyclic peroxide results in an effect of inducing the expression of skin barrier function-related genes. The effect of inducing the expression of skin barrier function-related genes can be evaluated according to Example 3 described below.

[0177] In the first composition of the third aspect of the present invention, the cyclic peroxide may be a salt or a solvate such as a hydrate. The description of the cyclic peroxide can be applied to the description of the salt of the cyclic peroxide or the solvate thereof.

[0178] [3. Oxidation Reaction Products] As described above, the oxidation reaction product is an oxidation reaction product characterized by containing a cyclic peroxide obtained by oxidizing an alcohol, but the method for producing the oxidation reaction product is not limited to the oxidation of an alcohol, and any method for producing the oxidation reaction product may be used as long as it has the same structure.

[0179] The method for oxidizing the alcohol is not particularly limited. For example, the oxidation of the alcohol may be at least one of ozone oxidation and hydrogen peroxide oxidation. However, as described above, the method for producing the oxidation reaction product is not limited to ozone oxidation and hydrogen peroxide oxidation of the alcohol, and any production method may be used as long as the substance has the same structure.

[0180] The oxidation reaction product may be, for example, a mixture containing a plurality of oxidation reaction products.

[0181] The oxidation reaction product may have, for example, an oxidizing ability.

[0182] The oxidation reaction product may have, for example, reducing ability.

[0183] The alcohol used as a raw material in the oxidation reaction product is not particularly limited. For example, the alcohol in the oxidation reaction product may be a saturated alcohol.

[0184] In the oxidation reaction product, for example, the alcohol may be a polyhydric alcohol.

[0185] In the oxidation reaction product, for example, the alcohol may be at least one of glycerin and a glycerin derivative.

[0186] The oxidation reaction product may include, for example, an oxidation reaction product obtained by bonding two or more molecules of the alcohol.

[0187] The oxidation reaction product may include, for example, the cyclic peroxide.

[0188] The alcohol used as a raw material for the oxidation reaction product is not particularly limited and may be, for example, a saturated alcohol or an unsaturated alcohol as described above. The alcohol may be linear or branched, and may or may not contain a cyclic structure. The alcohol may be, for example, a polyhydric alcohol or a monohydric alcohol. The valence of the polyhydric alcohol is also not particularly limited and may be, for example, dihydric, trihydric, or tetrahydric. Examples of monohydric saturated alcohols include saturated alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated alcohol may be linear or branched and may or may not contain a cyclic structure. Specific examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butyl alcohol. Examples of saturated polyhydric alcohols include saturated polyhydric alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated polyhydric alcohols may be linear or branched, and may or may not contain a cyclic structure. Specific examples include ethylene glycol (ethane-1,2-diol), propylene glycol (propane-1,2-diol), glycerin, and glycerin derivatives. The glycerin derivatives are not particularly limited, but may be, for example, glycerin polymers or compounds in which at least one hydrogen atom of glycerin is substituted with a substituent (e.g., an alkyl group). Examples of glycerin derivatives include diglycerin and polyglycerin. The glycerin derivative may also be an oxidized form of glycerin.

[0189] The oxidation reaction product may be, for example, a substance having reducing ability, as described above. For example, the oxidation reaction product may have a functional group having reducing ability, thereby possessing reducing ability derived from the functional group. Specifically, for example, the oxidation reaction product may have reducing ability due to the inclusion of an aldehyde group (formyl group), or may be a keto-enol tautomer, thereby possessing reducing ability derived from the keto form. For example, the oxidation reaction product obtained in Example 3 described below contains an acetal structure in its skeleton, as confirmed by NMR, and is therefore thought to develop color in a DNPH (dinitrophenylhydrazine: ketone-aldehyde-derived) reaction derived from a ketone or aldehyde.

[0190] The oxidation reaction product may be, for example, a substance obtained by bonding two or more molecules of the alcohol, as described above. Specifically, for example, the oxidation reaction product may have a structure in which two or more molecules of the alcohol are bonded and then oxidized. The form of "bonding" of the two or more alcohol molecules is not particularly limited, and may be, for example, addition, condensation, or the like.

[0191] The oxidation reaction product is chemically stable and easy to handle compared to, for example, radicals, and therefore can be isolated and formulated.

[0192] [4. Method for producing oxidation reaction product] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol.

[0193] The method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited. For example, in the method for producing the oxidation reaction product, the alcohol may be oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation in the alcohol oxidation step.

[0194] In the method for producing an oxidation reaction product, the reaction time of the alcohol oxidation step is not particularly limited. The reaction time of the alcohol oxidation step may be, for example, 24 hours or more or 1 day or more, 48 hours or more or 2 days or more, 72 hours or more or 3 days or more, 120 hours or more or 5 days or more, or 168 hours or more or 7 days or more. The upper limit of the reaction time of the alcohol oxidation step is not particularly limited, but may be, for example, 720 hours or less or 30 days or less, or 360 hours or less or 15 days or less.

[0195] In the method for producing the oxidation reaction product, it is preferable to extend the reaction time of the alcohol oxidation step in order to obtain a reaction product containing the cyclic peroxide. For example, it is believed that extending the reaction time of the alcohol oxidation step makes it possible to produce the cyclic peroxide, which could not be obtained by conventional ozone oxidation reactions of glycerin, etc. In the method for producing the oxidation reaction product, it is preferable that the reaction time of the alcohol oxidation step is not too long in order to ensure production efficiency.

[0196] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol. However, as described above, the oxidation reaction product is not limited to a substance produced by this production method, and may be a substance produced by any production method as long as it has the same structure. The method for producing the oxidation reaction product will be described in more detail below using examples.

[0197] The following description will be given taking as an example a case where glycerin is used as the alcohol and oxidation is carried out with ozone. However, as mentioned above, the following description is merely an example, and the method for producing the oxidation reaction product is not limited to the following description. For example, the following method can be carried out in the same manner using other alcohols instead of glycerin. For example, in the method for producing the oxidation reaction product, the method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited and is arbitrary, and is not limited to ozone oxidation. The oxidation method may be, for example, at least one of ozone oxidation and hydrogen peroxide oxidation. Furthermore, for example, not only the type of alcohol and the method for oxidizing the alcohol, but also the concentration of each substance, reaction temperature, reaction time, and other reaction conditions can be changed as appropriate.

[0198] The oxidation reaction product can be produced by a production method including, for example, a step of contacting glycerin with ozone, more specifically, a step of oxidizing glycerin by mixing glycerin with ozone (corresponding to the "alcohol oxidation step"). The step of oxidizing glycerin may be, for example, a step of bringing a glycerin solution into gas-liquid contact with a gas containing ozone to oxidize glycerin.

[0199] The glycerin solution preferably has a high glycerin concentration. Examples of the high-concentration glycerin solution include a glycerin solution having a glycerin concentration of 75% or more. Specific examples include a glycerin solution of 84 to 87% by weight as specified in the Japanese Pharmacopoeia, a concentrated glycerin solution of 98% by weight or more as specified in the Japanese Pharmacopoeia, and a purified glycerin solution of 98.5% by weight or more. For example, the glycerin solution can be treated with ozone at a higher concentration as the glycerin concentration is relatively higher. The solvent for glycerin in the glycerin solution is not particularly limited, and may be, for example, an aqueous solvent such as water.

[0200] The ozone-containing gas preferably has a high ozone concentration. The method for producing the gas with a high ozone concentration is not particularly limited, and for example, an ozone generator that generates ozone by silently discharging oxygen gas can be used. When oxygen gas is used, for example, a medical oxygen cylinder can be used, or oxygen gas produced by an oxygen generator can be used.

[0201] The method for bringing the glycerin solution into gas-liquid contact with the ozone-containing gas is not particularly limited, and for example, a method is available in which a high-concentration (e.g., 98% by weight or more) glycerin solution is placed in a tank and the high-ozone-concentration gas is released into the tank as fine bubbles using an air diffuser. Specifically, for example, an ozone-treated glycerin solution having an equivalent hydrogen peroxide concentration of about 4000 ppm can be produced by aerating a gas having an ozone concentration of about 37000 ppm into the concentrated glycerin solution for about 7 days. The aeration time is not particularly limited, and for example, an ozone-treated glycerin solution containing the oxidation reaction product at a higher concentration can be produced by aerating the concentrated glycerin solution for a relatively longer period of time.

[0202] The oxidation reaction product may be used as it is without being separated from the reaction mixture (e.g., the ozone-treated glycerin solution), or may be used after being separated from the reaction mixture. The separation method is not particularly limited, and the oxidation reaction product can be separated from the reaction mixture by chromatography such as preparative thin-layer chromatography, for example.

[0203] Conventionally, the production of substances such as peroxides having oxidizing power has required a complicated system. According to the method for producing an oxidation reaction product, for example, an oxidation reaction product having oxidizing power can be produced in an extremely simple and easy manner.

[0204] The oxidation reaction product can generate, for example, hydrogen peroxide. For example, the oxidation reaction product can generate 1 to 4000 ppm, 10 to 4000 ppm, or 100 to 4000 ppm of hydrogen peroxide per approximately 4000 ppm of the oxidation reaction product in terms of hydrogen peroxide concentration.

[0205] [5. Glycerin] In the first composition of the third invention of the present invention, the glycerin may be glycerin or the above-mentioned glycerin derivative. In the first composition of the third invention of the present invention, the cyclic peroxide can be stably maintained by coexisting with the glycerin.

[0206] In the first composition of the third aspect of the present invention, the content of the glycerin is, for example, 0.1 to 100 w / v %, or preferably 0.1 to 50 w / v %.

[0207] [6. Skin barrier function-related genes] The skin barrier function-related gene may be any gene encoding a protein that contributes to the skin barrier function. Examples of the skin barrier function-related gene include the profilaggrin gene, the involucrin gene, and the serine palmitoyltransferase gene. The skin barrier function-related gene whose expression is induced by the first composition of the third invention of the present invention may be, for example, one type or multiple types. Examples of the profilaggrin gene, the involucrin gene, and the serine palmitoyltransferase gene include polynucleotides consisting of base sequences identified as human genes by the following GenBank accession numbers: Profilagrin gene: NM_002016.2 Involucrin gene: NM_005547.2 Serine palmitoyltransferase gene: NM_004863.3

[0208] [7. Other Ingredients] The first composition of the third aspect of the present invention may contain other components added to a formulation for application to the skin. Specific examples of the other components include components added to topical skin preparations and cosmetics (including quasi-drugs). Specific examples of the components added to topical skin preparations include pharmaceutically acceptable carriers. Specific examples of the other components include components added when applied to the skin or transdermally, such as aqueous solvents such as water, alcohols, moisturizers, oils, softeners (emollients), surfactants (solubilizers, emulsifiers), salts, thickeners, pH adjusters, UV absorbers, pharmaceuticals, buffers, colorants, preservatives, and fragrances.

[0209] 8. Dosage Form, Dosage, and Use The first composition of the third aspect of the present invention is, for example, a solid or liquid. Examples of the form of the first composition of the third aspect of the present invention include lotion formulations, emulsion formulations such as lotions and creams, oil formulations, gel formulations, ointments, packs, cleansers, etc.

[0210] The subject of use of the first composition of the third invention of the present invention is a human or a non-human animal. The first composition of the third invention of the present invention can be used, for example, on the skin of the subject. The amount of the first composition of the third invention of the present invention used is not particularly limited, and can be a commonly used amount depending on the dosage form of the first composition of the third invention of the present invention.

[0211] The first composition of the third aspect of the present invention can be suitably used as an external preparation for skin such as a cosmetic.

[0212] <Skin barrier function-related gene expression inducer> The skin barrier function-related gene expression inducer of the third invention of the present invention (hereinafter referred to as the "first inducer") contains a cyclic peroxide or a salt thereof. The skin barrier function-related gene expression inducer of the third invention of the present invention is characterized by containing a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described above, the cyclic peroxide induces the expression of a protein important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, the first inducer of the third invention of the present invention can, for example, when applied to the skin, achieve the effect of inducing the expression of the skin barrier function-related gene in the skin.

[0213] In the first inducer of the third aspect of the present invention, the content of the skin barrier function-related gene expression inducer may be an effective amount capable of inducing the expression of the skin barrier function-related gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the first inducer of the third aspect of the present invention, the content of the cyclic peroxide may be an effective amount capable of inducing the expression of the skin barrier function-related gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0214] In the first inducer of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0215] The explanation of the cyclic peroxide and the oxidation reaction product can be found in the explanation of the first composition of the third aspect of the present invention.

[0216] The explanation of the dosage form and use of the first inducer of the third invention of the present invention can be cited from the explanation of the first composition of the third invention of the present invention.

[0217] <Composition for improving skin barrier function> A composition for improving skin barrier function according to a third aspect of the present invention (hereinafter referred to as the "second composition") comprises glycerin and / or a glycerin derivative and a skin barrier function-improving ingredient, wherein the skin barrier function-improving ingredient comprises a cyclic peroxide or a salt thereof as an active ingredient. The second composition according to the third aspect of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described above, the cyclic peroxide induces the expression of proteins important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, when applied to the skin, the second composition according to the third aspect of the present invention can induce the expression of the skin barrier function-related gene in the skin, thereby improving the skin barrier function.

[0218] In the second composition of the third invention of the present invention, the content of the skin barrier function-improving component may be an effective amount capable of improving the skin barrier function, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the second composition of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of improving the skin barrier function, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0219] In the second composition of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0220] The explanations for the cyclic peroxide, the oxidation reaction product, and glycerin can be found in the explanations for the first composition of the third invention of the present invention.

[0221] The explanation of the dosage form and use of the second composition of the third invention of the present invention can be made by referring to the explanation of the first composition of the third invention of the present invention.

[0222] The second composition of the third aspect of the present invention can improve the skin barrier function, and therefore can be suitably used for treating conditions in which the skin barrier function is impaired, such as atopic dermatitis and psoriasis vulgaris.

[0223] <Skin barrier function improver> A skin barrier function improver (hereinafter referred to as "improver") according to a third aspect of the present invention contains a cyclic peroxide or a salt thereof. The skin barrier function improver according to the third aspect of the present invention is characterized by containing a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described above, the cyclic peroxide induces the expression of proteins important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, according to the improver according to the third aspect of the present invention, for example, when applied to the skin, the effect of inducing the expression of the skin barrier function-related gene in the skin can be obtained, thereby improving the skin barrier function.

[0224] In the improving agent of the third invention of the present invention, the content of the skin barrier function improving component may be an effective amount capable of improving the skin barrier function, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the improving agent of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of improving the skin barrier function, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0225] In the improving agent of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0226] The explanation of the cyclic peroxide and the oxidation reaction product can be found in the explanation of the first composition of the third aspect of the present invention.

[0227] The explanation of the dosage form and use of the improving agent of the third invention of the present invention can be made by referring to the explanation of the first composition and the second composition of the third invention of the present invention.

[0228] <Composition for inducing expression of antioxidant stress response genes> A composition for inducing expression of antioxidant stress response genes according to a third aspect of the present invention (hereinafter referred to as the "third composition") comprises glycerin and / or a glycerin derivative and an antioxidant stress response gene expression inducer, wherein the antioxidant stress response gene expression inducer comprises a cyclic peroxide or a salt thereof as an active ingredient. The third composition according to the third aspect of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other components and conditions are not particularly limited. As described above, the cyclic peroxide induces expression of antioxidant stress response genes, such as heme oxygenase 1 gene and NAD(P)H quinone oxidoreductase 1 gene, which are proteins important in antioxidant stress response. Therefore, when applied to the skin, the third composition according to the third aspect of the present invention can induce the expression of antioxidant stress response genes in the skin, thereby improving the antioxidant stress response.

[0229] In the third composition of the third invention of the present invention, the content of the antioxidant stress response gene expression-inducing component may be an effective amount capable of inducing the expression of the antioxidant stress response gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the third composition of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of inducing the expression of the antioxidant stress response gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0230] In the third composition of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0231] The antioxidant stress response gene may be any gene encoding a protein that contributes to oxidative stress response. Examples of the antioxidant stress response gene include the heme oxygenase 1 (HO-1) gene, the NAD(P)H quinone oxidoreductase 1 (NQO-1) gene, and / or a glutathione gene. The antioxidant stress response gene whose expression is induced by the third composition of the third aspect of the present invention may be, for example, one type or multiple types. Examples of the heme oxygenase 1 gene and the NAD(P)H quinone oxidoreductase 1 gene include, as human genes, polynucleotides consisting of the nucleotide sequences identified by the following GenBank accession numbers: Heme oxygenase 1 gene: NM_002133.3 NAD(P)H quinone oxidoreductase 1 gene: NM_000903.3

[0232] The explanations for the cyclic peroxide, the oxidation reaction product, and glycerin can be found in the explanations for the first composition of the third invention of the present invention.

[0233] The explanation of the dosage form and use of the third composition of the third invention of the present invention can be cited from the explanation of the first composition of the third invention of the present invention.

[0234] The third composition of the third aspect of the present invention can improve the antioxidant stress response, and therefore can be suitably used for treating, for example, atopic dermatitis, which has a reduced antioxidant stress response.

[0235] <Antioxidative stress gene expression inducer> The antioxidant stress response gene expression inducer of the third invention of the present invention (hereinafter referred to as the "second inducer") contains a cyclic peroxide or a salt thereof. The antioxidant stress response gene expression inducer of the third invention of the present invention is characterized by containing a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described above, the cyclic peroxide induces the expression of proteins important for the antioxidant stress response, such as the antioxidant stress response genes, heme oxygenase 1 gene and NAD(P)H quinone oxidoreductase 1 gene. Therefore, the second inducer of the third invention of the present invention can induce the expression of antioxidant stress response genes in the skin, for example, when applied to the skin, thereby improving the antioxidant stress response.

[0236] In the second inducer of the third invention of the present invention, the content of the antioxidant stress response gene expression inducer may be an effective amount capable of inducing the expression of the antioxidant stress response gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the second inducer of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of inducing the expression of the antioxidant stress response gene, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0237] In the second inducer of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0238] The explanation of the cyclic peroxide and the oxidation reaction product can be found in the explanation of the first composition of the third aspect of the present invention.

[0239] The explanation of the dosage form and use of the second inducer of the third invention of the present invention can be made by referring to the explanation of the first composition and the third composition of the third invention of the present invention.

[0240] <Anti-inflammatory composition> The anti-inflammatory composition of the third invention of the present invention (hereinafter referred to as the "fourth composition") comprises glycerin and / or a glycerin derivative and an anti-inflammatory ingredient, wherein the anti-inflammatory ingredient comprises a cyclic peroxide or a salt thereof as an active ingredient. The fourth composition of the third invention of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described below, the cyclic peroxide suppresses the production of anti-inflammatory cytokines IL-1α and prostaglandin E2. Therefore, the fourth composition of the third invention of the present invention can provide an anti-inflammatory effect on the skin when applied to the skin, for example.

[0241] In the anti-inflammatory composition of the third invention of the present invention, the content of the anti-inflammatory component may be an effective amount capable of suppressing inflammation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the anti-inflammatory composition of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of suppressing inflammation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0242] In the fourth composition of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0243] The fourth composition of the third invention of the present invention, for example, suppresses the expression and / or production of the inflammatory cytokine. An example of the inflammatory cytokine is IL-1α. Therefore, the fourth composition of the third invention of the present invention can also be referred to as, for example, a composition that suppresses the expression of the IL-1α gene and / or a composition that suppresses the production of IL-1α. Furthermore, the fourth composition of the third invention of the present invention, for example, suppresses the production of a chemical mediator that induces inflammation. An example of the chemical mediator is prostaglandin E2. Therefore, the fourth composition of the third invention of the present invention can also be referred to as, for example, a composition that suppresses the production of prostaglandin E2.

[0244] The explanations for the cyclic peroxide, the oxidation reaction product, and glycerin can be found in the explanations for the first composition of the third invention of the present invention.

[0245] The explanation of the dosage form and use of the fourth composition of the third invention of the present invention can be made by referring to the explanation of the first composition of the third invention of the present invention.

[0246] The fourth composition of the third invention of the present invention can suppress inflammation. Therefore, the fourth composition of the third invention of the present invention can be suitably used for treating inflammatory diseases such as atopic dermatitis and psoriasis vulgaris. Furthermore, the fourth composition of the third invention of the present invention can suitably suppress inflammation in epidermal keratinocytes present in the skin, for example. Therefore, the fourth composition of the third invention of the present invention can also be referred to as a composition for suppressing inflammation in epidermal keratinocytes, for example.

[0247] <Anti-inflammatory agent> The anti-inflammatory agent of the third invention of the present invention contains a cyclic peroxide or a salt thereof. The anti-oxidative stress response gene expression inducer of the third invention of the present invention is characterized by containing a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described above, the cyclic peroxide suppresses the production of IL-1α, an anti-inflammatory cytokine. Therefore, the anti-inflammatory agent of the third invention of the present invention can achieve an anti-inflammatory effect on the skin, for example, when applied to the skin.

[0248] In the anti-inflammatory agent of the third invention of the present invention, the content of the anti-inflammatory component may be an effective amount capable of suppressing inflammation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Also, in the anti-inflammatory agent of the third invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of suppressing inflammation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0249] In the anti-inflammatory agent of the third invention of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the aforementioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0250] The anti-inflammatory agent of the third invention of the present invention, for example, suppresses the expression and / or production of the inflammatory cytokine. An example of the inflammatory cytokine is IL-1α. Therefore, the anti-inflammatory agent of the third invention of the present invention can also be referred to as, for example, an inhibitor of IL-1α gene expression and / or an inhibitor of IL-1α production. Furthermore, the anti-inflammatory agent of the third invention of the present invention, for example, suppresses the production of chemical mediators that induce inflammation. An example of the chemical mediator is prostaglandin E2. Therefore, the anti-inflammatory agent of the third invention of the present invention can also be referred to as, for example, an inhibitor of prostaglandin E2 production.

[0251] The explanation of the cyclic peroxide and the oxidation reaction product can be found in the explanation of the first composition of the third aspect of the present invention.

[0252] The explanation of the dosage form and use of the anti-inflammatory agent of the third invention of the present invention can be made by referring to the explanation of the first composition and the fourth composition of the third invention of the present invention.

[0253] <Method for inducing the expression of genes related to skin barrier function> A method for inducing the expression of a skin barrier function-related gene according to a third aspect of the present invention (hereinafter also referred to as the "first induction method") uses the composition for inducing the expression of a skin barrier function-related gene according to the third aspect of the present invention and / or the inducer of the expression of a skin barrier function-related gene according to the third aspect of the present invention. The first induction method according to the third aspect of the present invention is characterized by using the first composition according to the third aspect of the present invention and / or the first inducer of the third aspect of the present invention, and other steps and conditions are not particularly limited. The cyclic peroxide contained in the first composition according to the third aspect of the present invention and / or the first inducer of the third aspect of the present invention induces the expression of a protein important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, the first induction method according to the third aspect of the present invention can, for example, induce the expression of a skin barrier function-related gene on the skin when applied to the skin.

[0254] The first induction method of the third invention of the present invention can be carried out, for example, by applying the first composition and / or the first inducer to the skin of the subject. More specifically, the first induction method of the third invention of the present invention can be carried out by contacting the skin of the subject with the first composition and / or the first inducer.

[0255] The first induction method of the third invention of the present invention is, for example, in In vitro or in vivo This will be carried out.

[0256] <Methods for improving skin barrier function> A method for improving skin barrier function according to the third aspect of the present invention (hereinafter also referred to as the "improvement method") uses the composition for improving skin barrier function according to the third aspect of the present invention and / or the skin barrier function improver according to the third aspect of the present invention. The improvement method according to the third aspect of the present invention is characterized by using the second composition according to the third aspect of the present invention and / or the improver according to the third aspect of the present invention, and other steps and conditions are not particularly limited. The cyclic peroxide contained in the second composition and / or the improver according to the third aspect of the present invention induces the expression of proteins important for skin barrier function, such as the profilaggrin gene, which is a skin barrier function-related gene. Therefore, according to the improvement method according to the third aspect of the present invention, for example, when applied to the skin, the effect of inducing the expression of the skin barrier function-related gene in the skin can be obtained, thereby improving the skin barrier function.

[0257] The improvement method of the third invention of the present invention can be carried out, for example, by applying the second composition and / or the improving agent to the skin of the subject. More specifically, the improvement method of the third invention of the present invention can be carried out by contacting the skin of the subject with the second composition and / or the improving agent.

[0258] The improvement method of the third invention of the present invention can be, for example, in In vitro or in vivo This will be carried out.

[0259] <Method for inducing expression of antioxidant stress response genes> A method for inducing expression of an antioxidant stress response gene according to a third aspect of the present invention (hereinafter also referred to as the "second induction method") uses the composition for inducing expression of an antioxidant stress response gene according to the third aspect of the present invention and / or the inducer of expression of an antioxidant stress response gene according to the third aspect of the present invention. The second induction method according to the third aspect of the present invention is characterized by using the third composition according to the third aspect of the present invention and / or the second inducer of the third aspect of the present invention; other steps and conditions are not particularly limited. The cyclic peroxide contained in the third composition according to the third aspect of the present invention and / or the second inducer of the third aspect of the present invention induces the expression of proteins important for antioxidant stress response, such as heme oxygenase 1 gene and NAD(P)H quinone oxidoreductase 1 gene, which are antioxidant stress response genes. Therefore, according to the second induction method according to the third aspect of the present invention, when applied to the skin, for example, it is possible to obtain the effect of inducing expression of the antioxidant stress response gene in the skin, thereby improving the antioxidant stress response.

[0260] The second induction method of the third invention of the present invention can be carried out, for example, by applying the third composition and / or the second inducer to the skin of the subject. More specifically, the second induction method of the third invention of the present invention can be carried out by contacting the third composition and / or the second inducer to the skin of the subject.

[0261] The second induction method of the third invention of the present invention is, for example, in In vitro or in vivo This will be carried out.

[0262] <Methods for suppressing inflammation> The method for suppressing inflammation according to the third aspect of the present invention (hereinafter also referred to as the "suppression method") uses the composition according to the fourth aspect of the third aspect of the present invention and / or the anti-inflammatory agent according to the third aspect of the present invention. The suppression method according to the third aspect of the present invention is characterized by using the composition according to the fourth aspect of the third aspect of the present invention and / or the anti-inflammatory agent according to the third aspect of the present invention, and other steps and conditions are not particularly limited. The cyclic peroxide contained in the composition according to the fourth aspect of the third aspect of the present invention and / or the anti-inflammatory agent suppresses the production of IL-1α, an anti-inflammatory cytokine, and the expression of prostaglandin E2. Therefore, the suppression method according to the third aspect of the present invention can achieve an anti-inflammatory effect on the skin when applied to the skin, for example.

[0263] The suppression method of the third invention of the present invention, for example, suppresses the expression and / or production of the inflammatory cytokine. An example of the inflammatory cytokine is IL-1α. Therefore, the suppression method of the third invention of the present invention can also be referred to as, for example, a method for suppressing the expression of the IL-1α gene and / or a method for suppressing the production of IL-1α. Furthermore, the suppression method of the third invention of the present invention, for example, suppresses the production of a chemical mediator that induces inflammation. An example of the chemical mediator is prostaglandin E2. Therefore, the suppression method of the third invention of the present invention can also be referred to as, for example, a method for suppressing the production of prostaglandin E2.

[0264] The suppression method of the third invention of the present invention can be carried out, for example, by applying the fourth composition and / or the anti-inflammatory agent to the skin of the subject. More specifically, the suppression method of the third invention of the present invention can be carried out by contacting the fourth composition and / or the anti-inflammatory agent with the skin of the subject.

[0265] The suppression method of the third invention of the present invention can be, for example, in In vitro or in vivo This will be carried out.

[0266] <Method for treating inflammatory diseases> The method for treating inflammatory diseases according to the third aspect of the present invention (hereinafter also referred to as the "treatment method") comprises an administration step of administering to a subject the anti-inflammatory composition according to the third aspect of the present invention and / or the anti-inflammatory agent according to the third aspect of the present invention. The treatment method according to the third aspect of the present invention is characterized by administering the fourth composition according to the third aspect of the present invention and / or the anti-inflammatory agent according to the third aspect of the present invention (hereinafter also referred to as the "medicine"), and other steps and conditions are not particularly limited. The treatment method according to the third aspect of the present invention uses the medicine, thereby suppressing inflammation. Therefore, the treatment method according to the third aspect of the present invention can treat inflammatory diseases.

[0267] The treatment method of the third aspect of the present invention includes, for example, an administration step of administering the medicament, and specifically includes an administration step of administering the medicament to a subject. in In vitro may be administered at in vivo The subject and administration conditions of the pharmaceutical can be, for example, the same as those described for the subject and administration conditions of the first composition of the third invention of the present invention. The subject is, for example, a subject for whom treatment is desired. Specifically, the subject may be a patient suffering from the inflammatory disease, a patient predicted to suffer from the inflammatory disease, or a patient whose likelihood of suffering from the inflammatory disease is unknown.

[0268] <Use> The third invention of the present invention is a composition for inducing expression of a skin barrier function-related gene of the third invention of the present invention and / or an inducer of expression of a skin barrier function-related gene of the third invention of the present invention, for use in inducing expression of a skin barrier function-related gene, or use thereof. The third invention of the present invention is a composition for improving skin barrier function of the third invention of the present invention and / or an inducer of expression of a skin barrier function of the third invention of the present invention, for use in improving skin barrier function, or use thereof. The third invention of the present invention is a composition for inducing expression of an antioxidant stress response gene of the third invention of the present invention and / or an inducer of expression of an antioxidant stress response gene of the third invention of the present invention, for use in inducing expression of an antioxidant stress response gene, or use thereof. The third invention of the present invention is an anti-inflammatory composition of the third invention of the present invention and / or an anti-inflammatory agent of the third invention of the present invention, for use in suppressing inflammation, or use thereof. The third invention of the present invention is the anti-inflammatory composition of the third invention of the present invention and / or the anti-inflammatory agent of the third invention of the present invention, or use thereof, for use in treating an inflammatory disease.

[0269] [Fourth embodiment of the invention] Next, a fourth embodiment of the present invention will be described, although the fourth embodiment of the present invention is not limited to the following description.

[0270] In the fourth aspect of the present invention, when a compound has isomers such as tautomers or stereoisomers (e.g., geometric isomers, conformational isomers, and optical isomers), any of the isomers can be used in the fourth aspect of the present invention unless otherwise specified. Furthermore, in the fourth aspect of the present invention, when a substance can form a salt, the salt can also be used in the fourth aspect of the present invention unless otherwise specified. The salt may be an acid addition salt or a base addition salt. Furthermore, the acid that forms the acid addition salt may be an inorganic acid or an organic acid, and the base that forms the base addition salt may be an inorganic base or an organic base. The inorganic acid is not particularly limited, but examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorite acid, chlorous acid, bromous acid, iodous acid, fluorine acid, chlorine acid, bromine acid, iodic acid, perfluorine acid, perchlorine acid, perbromine acid, and periodic acid. The organic acid is also not particularly limited, but examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The inorganic base is not particularly limited, but examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates, and more specifically, examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and calcium carbonate. The organic base is also not particularly limited, but examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane. The method for producing these salts is also not particularly limited, and they can be produced, for example, by adding the above-mentioned acid or base to the compound as appropriate using a known method.

[0271] In the fourth aspect of the present invention, examples of the aromatic ring not containing a heteroatom include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and a pyrene ring. Examples of heteroaromatic rings include a pyridine ring and a thiophene ring. The nitrogen-containing aromatic ring may or may not have a positive charge. Examples of nitrogen-containing aromatic rings not having a positive charge include a pyrroline ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a quinoline ring, an isoquinoline ring, an acridine ring, a 3,4-benzoquinoline ring, a 5,6-benzoquinoline ring, a 6,7-benzoquinoline ring, a 7,8-benzoquinoline ring, a 3,4-benzoisoquinoline ring, a 5,6-benzoisoquinoline ring, a 6,7-benzoisoquinoline ring, and a 7,8-benzoisoquinoline ring. Examples of the positively charged nitrogen-containing aromatic ring include a pyrrolinium ring, a pyridinium ring, a pyridazinium ring, a pyrimidinium ring, a pyrazinium ring, a quinolinium ring, an isoquinolinium ring, an acridinium ring, a 3,4-benzoquinolinium ring, a 5,6-benzoquinolinium ring, a 6,7-benzoquinolinium ring, a 7,8-benzoquinolinium ring, a 3,4-benzoisoquinolinium ring, a 5,6-benzoisoquinolinium ring, a 6,7-benzoisoquinolinium ring, a 7,8-benzoisoquinolinium ring, etc. Examples of the oxygen-containing aromatic ring or sulfur-containing aromatic ring include aromatic rings in which at least one carbon atom or nitrogen atom of the aromatic ring or nitrogen-containing ring not containing a heteroatom is replaced with at least one oxygen atom and / or sulfur atom.

[0272] In the fourth aspect of the present invention, examples of the "substituent" include a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), an alkylthio group (-SR, where R is an alkyl group), and the like.

[0273] In the fourth aspect of the present invention, unless otherwise specified, chain substituents (e.g., hydrocarbon groups such as alkyl groups and unsaturated aliphatic hydrocarbon groups) may be linear or branched, and the number of carbon atoms therein is not particularly limited and may be, for example, 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 (2 or more in the case of unsaturated hydrocarbon groups). Furthermore, in this specification, the number of ring members (the number of atoms constituting the ring) of cyclic groups (e.g., aryl groups, heteroaryl groups, etc.) is not particularly limited and may be, for example, 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. Furthermore, when isomers exist in a substituent or the like, any isomer may be used unless otherwise specified. For example, a simple "butyl group" may refer to an n-butyl group, a sec-butyl group, or a tert-butyl group, and a simple "naphthyl group" may refer to a 1-naphthyl group or a 2-naphthyl group.

[0274] In the fourth aspect of the present invention, the term "protein" or "polypeptide" refers to a polymer composed of unmodified amino acids (natural amino acids), modified amino acids, and / or artificial amino acids. The polypeptide is, for example, a peptide having a length of 10 amino acids or more.

[0275] In the fourth aspect of the present invention, "glycation" refers to modification of proteins, polypeptides, and / or amino acids with sugars, such as reducing sugars such as glucose, fructose, and lactose.

[0276] In the fourth aspect of the present invention, the term "glycation reaction" refers to a condensation reaction (aminocarbonylation reaction) between an amino group-containing compound and a carbonyl group-containing compound. Examples of the amino group-containing compound include proteins, polypeptides, and amino acids. Examples of the carbonyl group-containing compound include reducing sugars. The glycation reaction can also be referred to as, for example, the Maillard reaction.

[0277] In the fourth aspect of the present invention, the term "glycation reaction product" refers to a substance produced by a glycation reaction. Examples of the glycation reaction product include intermediate and final products produced in the glycation reaction. Examples of the glycation reaction product include proteins or polypeptides containing AGEs; proteins or polypeptides having cross-linked structures due to AGEs; and glycated proteins produced by glycation reactions. Examples of the intermediate reaction product include substances produced during the glycation reaction, such as glyoxal, methylglyoxal, and 3-deoxyglucosone. Examples of the AGEs include pentosidine, crosslin, pyropyridine, pyrraline, carboxymethyllysine (CML), carboxyethyllysine (CEL), carboxyethyllysine, carboxymethylarginine (CMA), argpyrimidine, imidazolone compounds, glyoxal-lysine dimer (GOLD), and methyl glyoxal-lysine dimer (MOLD).

[0278] The fourth invention of the present invention will be explained in more detail below with examples. However, the fourth invention of the present invention is not limited by the following explanation. Furthermore, the explanations in the fourth invention of the present invention can be mutually incorporated unless otherwise specified. In this specification, when the expression "~" is used, it is used to mean including the numerical or physical values ​​before and after it. In addition, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0279] <Anti-glycation composition> The anti-glycation composition of the fourth invention of the present invention comprises glycerin and / or a glycerin derivative and an anti-glycation ingredient, and the anti-glycation ingredient comprises a cyclic peroxide or a salt thereof as an active ingredient. The composition of the fourth invention of the present invention is characterized by containing the cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As described below, the cyclic peroxide has the ability to decompose the cross-linked structure of AGEs. Therefore, the composition of the fourth invention of the present invention can provide an anti-glycation effect.

[0280] The composition of the fourth invention of the present invention can decompose AGEs generated by glycation reactions, for example, and therefore can be referred to as a composition for decomposing advanced glycation end products (AGEs), a composition for decomposing glycation reaction products, a composition for decomposing proteins or polypeptides having cross-linked structures due to advanced glycation end products, etc. Furthermore, the composition of the fourth invention of the present invention can repair proteins or polypeptides by removing AGEs or AGE cross-linked structures in glycated proteins, for example, and therefore can also be referred to as a composition for repairing glycated proteins or glycated peptides.

[0281] [1. Anti-glycation component] The composition of the fourth invention of the present invention contains an anti-glycation component as described above. The composition of the fourth invention of the present invention may contain the cyclic peroxide as the active ingredient of the anti-glycation component, or may contain an oxidation reaction product containing the cyclic peroxide as described below, or may contain both. The cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing an alcohol as described below.

[0282] In the composition of the fourth invention of the present invention, the content of the anti-glycation component may be an effective amount capable of anti-glycation, more specifically, an effective amount capable of decomposing AGEs, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Furthermore, in the composition of the fourth invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of anti-glycation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0283] The anti-glycation component may exhibit anti-glycation activity by, for example, inhibiting the glycation reaction, thereby inhibiting the production of AGEs or the production of cross-linked structures of AGEs, or may exhibit anti-glycation activity by degrading AGEs or cross-linked structures of AGEs produced by the glycation reaction, or may exhibit both activities.

[0284] [2. Cyclic Peroxides] The cyclic peroxide is represented by the following chemical formula (I): [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0285] The heteroatom refers to an atom other than carbon and hydrogen, and may be, for example, one selected from the group consisting of oxygen, nitrogen, sulfur, selenium, boron, and silicon. The substituent is not particularly limited, and may, for example, contain a hydroxyl group, or may be, for example, one selected from the group consisting of the aforementioned hydroxyl group (-OH), aldehyde group (formyl group), hydroxyalkyl group, sulfo group, nitro group, diazo group, alkyl group, unsaturated aliphatic hydrocarbon group, aryl group, heteroaryl group, halogen, mercapto group (-SH), and alkylthio group (-SR, R is an alkyl group).

[0286] The cyclic peroxide may be, for example, a compound represented by the formula (I): 100 However, it may be a cyclic structure having 5 to 10 ring members.

[0287] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (II): [ka] In the chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S).

[0288] The cyclic peroxide is, for example, R 11 wherein the substituents may be a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group).

[0289] The cyclic peroxide may be, for example, a cyclic peroxide represented by the following chemical formula (1): The cyclic peroxide represented by the following chemical formula (1) is a cyclic peroxide represented by the following chemical formula (II) in which all R 11 is a hydrogen atom. [ka]

[0290] The method for producing the cyclic peroxide is not particularly limited, and for example, the cyclic peroxide can be produced by oxidizing an alcohol by the method for producing the oxidation reaction product described below. In this case, for example, the produced oxidation reaction product may be used as is without purification, or the cyclic peroxide alone may be isolated and purified and used.

[0291] The present inventors were the first to discover that cyclic peroxides can be produced by the oxidation of alcohols, for example, the oxidation of glycerin with ozone. The mechanism by which cyclic peroxides are produced is unclear, but it is speculated that, for example, by extending the reaction time of the alcohol oxidation reaction, as described below, a reaction product different from that obtained in conventional reactions can be obtained.

[0292] The cyclic peroxides are chemically stable and easy to handle compared to radicals, for example, and therefore can be isolated and formulated.

[0293] In general, cyclic peroxides are substances that are used industrially due to their oxidizing ability, etc. In particular, artemisinin, which has a seven-membered ring (trioxolane) skeleton similar to the structure of the cyclic peroxides, is useful as an antimalarial agent and was awarded the Nobel Prize in 2015, and its derivatives are currently being researched.

[0294] However, extracting and purifying artemisinin from natural sources has resulted in unstable supplies. Furthermore, because artemisinin is neither water-soluble nor fat-soluble, formulation has presented many challenges. On the other hand, hydrogen peroxide is a water-soluble, oxidizing substance, but it is highly reactive and unstable, and has only been used topically for disinfection.

[0295] In contrast, the fourth aspect of the present invention uses, for example, a cyclic peroxide and an oxidation reaction product that are highly safe and have excellent water solubility, and therefore can be suitably used in living organisms. Furthermore, in the fourth aspect of the present invention, it is presumed that an anti-glycation effect is obtained due to the oxidizing ability of the cyclic peroxide. The anti-glycation effect can be evaluated in accordance with Example 4 described below.

[0296] In the composition of the fourth aspect of the present invention, the cyclic peroxide may be a salt or a solvate such as a hydrate. The description of the cyclic peroxide can be applied to the description of the salt of the cyclic peroxide or the solvate thereof.

[0297] [3. Oxidation Reaction Products] As described above, the oxidation reaction product is an oxidation reaction product characterized by containing a cyclic peroxide obtained by oxidizing an alcohol, but the method for producing the oxidation reaction product is not limited to the oxidation of an alcohol, and any method for producing the oxidation reaction product may be used as long as it has the same structure.

[0298] The method for oxidizing the alcohol is not particularly limited. For example, the oxidation of the alcohol may be at least one of ozone oxidation and hydrogen peroxide oxidation. However, as described above, the method for producing the oxidation reaction product is not limited to ozone oxidation and hydrogen peroxide oxidation of the alcohol, and any production method may be used as long as the substance has the same structure.

[0299] The oxidation reaction product may be, for example, a mixture containing a plurality of oxidation reaction products.

[0300] The oxidation reaction product may have, for example, an oxidizing ability.

[0301] The oxidation reaction product may have, for example, reducing ability.

[0302] The alcohol used as a raw material in the oxidation reaction product is not particularly limited. For example, the alcohol in the oxidation reaction product may be a saturated alcohol.

[0303] In the oxidation reaction product, for example, the alcohol may be a polyhydric alcohol.

[0304] In the oxidation reaction product, for example, the alcohol may be at least one of glycerin and a glycerin derivative.

[0305] The oxidation reaction product may include, for example, an oxidation reaction product obtained by bonding two or more molecules of the alcohol.

[0306] The oxidation reaction product may include, for example, the cyclic peroxide.

[0307] The alcohol used as a raw material for the oxidation reaction product is not particularly limited and may be, for example, a saturated alcohol or an unsaturated alcohol as described above. The alcohol may be linear or branched, and may or may not contain a cyclic structure. The alcohol may be, for example, a polyhydric alcohol or a monohydric alcohol. The valence of the polyhydric alcohol is also not particularly limited and may be, for example, dihydric, trihydric, or tetrahydric. Examples of monohydric saturated alcohols include saturated alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated alcohol may be linear or branched and may or may not contain a cyclic structure. Specific examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butyl alcohol. Examples of saturated polyhydric alcohols include saturated polyhydric alcohols having 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 carbon atoms. The saturated polyhydric alcohols may be linear or branched, and may or may not contain a cyclic structure. Specific examples include ethylene glycol (ethane-1,2-diol), propylene glycol (propane-1,2-diol), glycerin, and glycerin derivatives. The glycerin derivatives are not particularly limited, but may be, for example, glycerin polymers or compounds in which at least one hydrogen atom of glycerin is substituted with a substituent (e.g., an alkyl group). Examples of glycerin derivatives include diglycerin and polyglycerin. The glycerin derivative may also be an oxidized form of glycerin.

[0308] The oxidation reaction product may be, for example, a substance having reducing ability, as described above. For example, the oxidation reaction product may have a functional group having reducing ability, thereby possessing reducing ability derived from the functional group. Specifically, for example, the oxidation reaction product may have reducing ability due to the inclusion of an aldehyde group (formyl group), or may be a keto-enol tautomer, thereby possessing reducing ability derived from the keto form. For example, the oxidation reaction product obtained in Example 4 described below contains an acetal structure in its skeleton, as confirmed by NMR, and is therefore thought to develop color in a DNPH (dinitrophenylhydrazine: ketone-aldehyde-derived) reaction derived from a ketone or aldehyde.

[0309] The oxidation reaction product may be, for example, a substance obtained by bonding two or more molecules of the alcohol, as described above. Specifically, for example, the oxidation reaction product may have a structure in which two or more molecules of the alcohol are bonded and then oxidized. The form of "bonding" of the two or more alcohol molecules is not particularly limited, and may be, for example, addition, condensation, or the like.

[0310] The oxidation reaction product is chemically stable and easy to handle compared to, for example, radicals, and therefore can be isolated and formulated.

[0311] [4. Method for producing oxidation reaction product] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol.

[0312] The method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited. For example, in the method for producing the oxidation reaction product, the alcohol may be oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation in the alcohol oxidation step.

[0313] In the method for producing an oxidation reaction product, the reaction time of the alcohol oxidation step is not particularly limited. The reaction time of the alcohol oxidation step may be, for example, 24 hours or more or 1 day or more, 48 hours or more or 2 days or more, 72 hours or more or 3 days or more, 120 hours or more or 5 days or more, or 168 hours or more or 7 days or more. The upper limit of the reaction time of the alcohol oxidation step is not particularly limited, but may be, for example, 720 hours or less or 30 days or less, or 360 hours or less or 15 days or less.

[0314] In the method for producing the oxidation reaction product, it is preferable to extend the reaction time of the alcohol oxidation step in order to obtain a reaction product containing the cyclic peroxide. For example, it is believed that extending the reaction time of the alcohol oxidation step makes it possible to produce the cyclic peroxide, which could not be obtained by conventional ozone oxidation reactions of glycerin, etc. In the method for producing the oxidation reaction product, it is preferable that the reaction time of the alcohol oxidation step is not too long in order to ensure production efficiency.

[0315] As described above, the method for producing the oxidation reaction product includes an alcohol oxidation step of oxidizing the alcohol. However, as described above, the oxidation reaction product is not limited to a substance produced by this production method, and may be a substance produced by any production method as long as it has the same structure. The method for producing the oxidation reaction product will be described in more detail below using examples.

[0316] The following description will be given taking as an example a case where glycerin is used as the alcohol and oxidation is carried out with ozone. However, as mentioned above, the following description is merely an example, and the method for producing the oxidation reaction product is not limited to the following description. For example, the following method can be carried out in the same manner using other alcohols instead of glycerin. For example, in the method for producing the oxidation reaction product, the method for oxidizing the alcohol in the alcohol oxidation step is not particularly limited and is arbitrary, and is not limited to ozone oxidation. The oxidation method may be, for example, at least one of ozone oxidation and hydrogen peroxide oxidation. Furthermore, for example, not only the type of alcohol and the method for oxidizing the alcohol, but also the concentration of each substance, reaction temperature, reaction time, and other reaction conditions can be changed as appropriate.

[0317] The oxidation reaction product can be produced by a production method including, for example, a step of contacting glycerin with ozone, more specifically, a step of oxidizing glycerin by mixing glycerin with ozone (corresponding to the "alcohol oxidation step"). The step of oxidizing glycerin may be, for example, a step of bringing a glycerin solution into gas-liquid contact with a gas containing ozone to oxidize glycerin.

[0318] The glycerin solution preferably has a high glycerin concentration. Examples of the high-concentration glycerin solution include a glycerin solution having a glycerin concentration of 75% or more. Specific examples include a glycerin solution of 84 to 87% by weight as specified in the Japanese Pharmacopoeia, a concentrated glycerin solution of 98% by weight or more as specified in the Japanese Pharmacopoeia, and a purified glycerin solution of 98.5% by weight or more. For example, the glycerin solution can be treated with ozone at a higher concentration as the glycerin concentration is relatively higher. The solvent for glycerin in the glycerin solution is not particularly limited, and may be, for example, an aqueous solvent such as water.

[0319] The ozone-containing gas preferably has a high ozone concentration. The method for producing the gas with a high ozone concentration is not particularly limited, and for example, an ozone generator that generates ozone by silently discharging oxygen gas can be used. When oxygen gas is used, for example, a medical oxygen cylinder can be used, or oxygen gas produced by an oxygen generator can be used.

[0320] The method for bringing the glycerin solution into gas-liquid contact with the ozone-containing gas is not particularly limited, and for example, a method is available in which a high-concentration (e.g., 98% by weight or more) glycerin solution is placed in a tank and the high-ozone-concentration gas is released into the tank as fine bubbles using an air diffuser. Specifically, for example, an ozone-treated glycerin solution having an equivalent hydrogen peroxide concentration of about 4000 ppm can be produced by aerating a gas having an ozone concentration of about 37000 ppm into the concentrated glycerin solution for about 7 days. The aeration time is not particularly limited, and for example, an ozone-treated glycerin solution containing the oxidation reaction product at a higher concentration can be produced by aerating the concentrated glycerin solution for a relatively longer period of time.

[0321] The oxidation reaction product may be used as it is without being separated from the reaction mixture (e.g., the ozone-treated glycerin solution), or may be used after being separated from the reaction mixture. The separation method is not particularly limited, and the oxidation reaction product can be separated from the reaction mixture by chromatography such as preparative thin-layer chromatography, for example.

[0322] Conventionally, the production of substances such as peroxides having oxidizing power has required a complicated system. According to the method for producing an oxidation reaction product, for example, an oxidation reaction product having oxidizing power can be produced in an extremely simple and easy manner.

[0323] The oxidation reaction product can generate, for example, hydrogen peroxide. For example, the oxidation reaction product can generate 1 to 4000 ppm, 10 to 4000 ppm, or 100 to 4000 ppm of hydrogen peroxide per approximately 4000 ppm of the oxidation reaction product in terms of hydrogen peroxide concentration.

[0324] [5. Glycerin] In the composition of the fourth invention of the present invention, the glycerin may be glycerin or the above-mentioned glycerin derivative. In the composition of the fourth invention of the present invention, the cyclic peroxide can be stably maintained by coexisting with the glycerin.

[0325] In the composition of the fourth aspect of the present invention, the content of the glycerin is, for example, 0.1 to 100 w / v %, or preferably 0.1 to 50 w / v %.

[0326] [6. Other Ingredients] The composition of the fourth aspect of the present invention may contain other components added to a formulation for application to the skin. Specific examples of the other components include components added to topical skin preparations and cosmetics (including quasi-drugs). Specific examples of the components added to topical skin preparations include pharmaceutically acceptable carriers. Specific examples of the other components include components added when applied to the skin or transdermally, such as aqueous solvents such as water, alcohols, moisturizers, oils, softeners (emollients), surfactants (solubilizers, emulsifiers), salts, thickeners, pH adjusters, UV absorbers, pharmaceuticals, buffers, colorants, preservatives, and fragrances.

[0327] [7. Dosage Form, Dosage, and Use] The composition of the fourth invention of the present invention is, for example, solid or liquid. Examples of the form of the composition of the fourth invention of the present invention include lotion formulations, emulsion formulations such as lotions and creams, oil formulations, gel formulations, ointments, packs, cleansers, etc.

[0328] The subject of use of the composition of the fourth invention of the present invention is a human or a non-human animal. The composition of the fourth invention of the present invention can be used, for example, on the skin of the subject. The amount of the composition of the fourth invention of the present invention to be used is not particularly limited, and can be an amount normally used depending on the dosage form of the composition of the fourth invention of the present invention.

[0329] The composition of the fourth aspect of the present invention can be suitably used as an external preparation for skin, such as a cosmetic.

[0330] <Anti-glycation agent> The anti-glycation agent of the fourth invention of the present invention comprises a cyclic peroxide or a salt thereof. The anti-glycation agent of the fourth invention of the present invention is characterized by comprising a cyclic peroxide or a salt thereof, and other configurations and conditions are not particularly limited. As will be described later, the cyclic peroxide has the ability to decompose the cross-linked structure of AGEs. Therefore, the anti-glycation agent of the fourth invention of the present invention can provide an anti-glycation effect.

[0331] The anti-glycation agent of the fourth invention of the present invention can decompose AGEs generated by glycation reactions, for example, and therefore can also be referred to as an agent for decomposing advanced glycation end products (AGEs), an agent for decomposing glycation reaction products, an agent for decomposing proteins or polypeptides having cross-linked structures caused by advanced glycation end products, etc. Furthermore, the anti-glycation agent of the fourth invention of the present invention can repair proteins or polypeptides by removing the cross-linked structures of AGEs or AGEs in glycated proteins, for example, and therefore can also be referred to as an agent for repairing glycated proteins or glycated peptides.

[0332] In the anti-glycation agent of the fourth invention of the present invention, the content of the anti-glycation component may be an effective amount capable of anti-glycation, more specifically, an effective amount capable of decomposing AGEs, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%. Furthermore, in the anti-glycation agent of the fourth invention of the present invention, the content of the cyclic peroxide may be an effective amount capable of anti-glycation, for example, 0.001 to 10 w / v%, 0.05 to 5 w / v%, or 0.01 to 1 w / v%.

[0333] In the anti-glycation agent of the fourth aspect of the present invention, the cyclic peroxide may be a compound represented by the following chemical formula (I), or may be a cyclic peroxide contained in an oxidation reaction product obtained by oxidizing the above-mentioned alcohol. [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different.

[0334] The explanation of the cyclic peroxide and the oxidation reaction product can be cited from the explanation of the composition of the fourth invention of the present invention.

[0335] The explanation of the dosage form and use of the anti-glycation agent of the fourth invention of the present invention can be cited from the explanation of the composition of the fourth invention of the present invention.

[0336] <Anti-glycation method> The anti-glycation method of the fourth invention of the present invention uses the anti-glycation composition of the fourth invention of the present invention and / or the anti-glycation agent of the fourth invention of the present invention. The anti-glycation method of the fourth invention of the present invention is characterized by using the composition of the fourth invention of the present invention and / or the anti-glycation agent of the fourth invention of the present invention, and other steps and conditions are not particularly limited. The cyclic peroxide contained in the composition and / or anti-glycation agent of the fourth invention of the present invention has the ability to decompose the cross-linked structure of AGEs, as described below. Therefore, the anti-glycation method of the fourth invention of the present invention can obtain an anti-glycation effect.

[0337] The anti-glycation method of the fourth invention of the present invention can be carried out, for example, by applying the composition and / or the anti-glycation agent to the skin of the subject. More specifically, the anti-glycation method of the fourth invention of the present invention can be carried out by contacting the skin of the subject with the composition and / or the anti-glycation agent.

[0338] The anti-glycation method of the fourth invention of the present invention includes, for example, in In vitro or in vivo This will be carried out.

[0339] <Use> A fourth aspect of the present invention is the anti-glycation composition of the fourth aspect of the present invention and / or the anti-glycation agent of the fourth aspect of the present invention for use in anti-glycation, or use thereof. [Example]

[0340] Examples of the present invention will be described below, but the present invention is not limited to the following examples.

[0341] [Example of the first invention] First, an example of the first invention of the present invention will be described. However, the first invention of the present invention is not limited to the following examples. Commercially available reagents were used according to their protocols unless otherwise specified.

[0342] [Example 1] An oxidation reaction product containing the cyclic peroxide of the first invention of the present invention was produced by ozone oxidation of glycerin. Furthermore, the oxidizing ability and TRP channel activity of the produced oxidation reaction product were confirmed. This example corresponds to an example in which the cyclic peroxide of the first invention of the present invention was produced and used, as well as an example in which the oxidation reaction product of the first invention of the present invention was produced and used, and also corresponds to an example of a method for producing the oxidation reaction product of the first invention of the present invention.

[0343] (1) Production of an oxidation reaction product containing the cyclic peroxide of the first aspect of the present invention Concentrated glycerin and ozone were subjected to gas-liquid contact to produce an ozone-treated glycerin solution (ozone gel) containing the oxidation reaction product of the first invention of the present invention, as described below. Here, the term "concentrated glycerin" refers to glycerin having a concentration of 98% by weight or more of the Japanese Pharmacopoeia standard. Furthermore, the oxidation reaction product of the first invention of the present invention produced in this example contains the cyclic peroxide of the first invention of the present invention, as described below.

[0344] A 50 L Teflon (registered trademark) tank was used as the contact vessel. An air diffuser was installed at the bottom of the tank, allowing ozone to be supplied into the tank as fine bubbles. A silent discharge ozone generator capable of generating 100 g of ozone per hour was used, using high-concentration oxygen gas containing 90% or more by volume as the raw material.

[0345] 22 kg of the concentrated glycerin was placed in the tank, and 20 L of the high-concentration oxygen gas was fed into the ozone generator at a rate of 20 L per minute to generate a gas containing ozone. The generated gas was then released into the tank through the air diffuser for 7 days or more, yielding a glycerin solution containing dissolved ozone-oxidized glycerin at a final concentration of 4000 ppm. This ozone-oxidized glycerin corresponds to the oxidation reaction product of the first aspect of the present invention. Furthermore, as described below, this ozone-oxidized glycerin contained the cyclic peroxide of the first aspect of the present invention.

[0346] (2) Analysis of the reaction mixture Glycerin was removed from the glycerin solution containing the ozone oxidized product of glycerin prepared in the above "(1) Preparation of an oxidation reaction product containing the cyclic peroxide of the first invention of the present invention" using a silica gel column to obtain a reaction mixture containing the cyclic peroxide of the first invention of the present invention (hereinafter sometimes referred to as the "TLC1 spot product"). As described below, the cyclic peroxide of the first invention of the present invention was directly used from this TLC1 spot product without being separated, and the oxidizing ability and TRP channel activity of the cyclic peroxide of the first invention of the present invention were confirmed.

[0347] The NMR spectrum of the reaction mixture (TLC 1 spot product) was measured at a temperature of 300 K (27 °C) using DMSO-d6 as a solvent. The spectra are shown in Figures 1-1 to 1-6. Figure 1-1 shows 1 H NMR spectrum diagram. 13 C NMR spectrum diagram. Figures 1-3 are 13 C DEPT135 NMR spectrum. Figure 1-4 is a COSY NMR spectrum. Figure 1-5 is an HSQC NMR spectrum. Figure 1-6 is an HMBC NMR spectrum. As shown in Figures 1-1 to 1-6, complex peaks were observed, suggesting that the TLC1 spot product was a mixture of multiple substances. Furthermore, LCMS revealed that this TLC1 spot product contained components with m / z 198,203.

[0348] (3) Separation and analysis of the reaction mixture The reaction mixture (TLC 1 spot product) was diluted with acetonitrile to approximately 3% by mass, filtered through a membrane filter, and the filtrate was subjected to LC measurement to optimize the separation conditions. Next, the mass of the peak observed in the LC measurement under the optimized conditions was confirmed, and precision fractionation of Mw = 180 (peak 2) was performed. The obtained fraction was then freeze-dried, and the dried fraction was subjected to microscopic LR measurement and various NMR measurements. The measurement equipment (analyzer) and measurement conditions are as follows. [Measuring equipment (analyzer)] 1)Precision preparative LC: Waters, ACQUITY UPLC H-class Bio 2) Microscope LR: SNOM / AFM / Raman combined instrument WITec alpha300RSA 3)NMR:Bruker Biospin,AVANCEIII-600 with Cryo Probe [Measurement conditions] 1)Precision preparative LC Column: Shodex Asahipak NH2P-50 (4.6 mmφ × 250 mm, 5 μm) Eluent composition: Water / acetonitrile gradient Time (min): 0 5 15 20 Wed: 5 10 50 50 Acetonitrile: 95 90 50 50 Flow rate: 1.0mL / min Detector: MS (QDa) Column temperature: 40℃ Injection volume: 50μL Ionization method: ESI (NEG.) Measurement mass range (m / z): 50 to 500 2) Microscope LR Excitation wavelength: 532 nm Measurement wave number range: approx. 125 to 3800 cm -1 Objective lens: x100 Detector: EMCCD 3) NMR Observation frequency: 600MHz( 1 H), 150MHz ( 13 C) Measurement solvent: methanol-d4 Measurement temperature: 300K Chemical shift standard: measurement solvent [3.30 ppm ( 1 H), 49.80 ppm ( 13 C)]

[0349] Figure 1-7 shows the total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) for a sample prepared (diluted) with acetonitrile to approximately 3% by mass of the reaction mixture (TLC1 spot product) and a blank. In Figure 1-7, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes). In Figure 1-7, the lower row, "Synthetic OG," is a chromatogram of the TLC1 spot product sample, and the upper row is a chromatogram of the blank (acetonitrile). As shown in the figure, components A to L were confirmed in the TLC1 spot product. Components A to L were separated and tested for coloration using potassium iodide starch test paper. Component H showed the strongest coloration.

[0350] Figure 1-8 also shows the mass spectra of peaks F, G, and H (F fraction, G fraction, and H fraction) in Figure 1-7. In Figure 1-8, the vertical axis represents intensity, and the horizontal axis represents mass-to-charge ratio (m / z). As shown in the figure, it was confirmed that peak F had Mw=180, peak G had Mw=226, and peak H had Mw=256.

[0351] Furthermore, Figure 1-9 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). In Figure 1-9, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes), as in Figures 1-17 to 1-19. In Figure 1-9, the upper row is a chromatogram before separation improvement (same conditions as in Figure 1-8), and the lower row is a chromatogram after separation improvement. As shown in the figure, peaks 1 to 8 were observed after separation improvement. The molecular weights of each peak were confirmed to be those shown in Figure 1-9 using the mass spectrum described below.

[0352] Figure 1-10 shows the mass spectra (after improved separation) of peaks 1 to 3 in Figure 1-9. In Figure 1-10, the upper row is the mass spectrum of peak 1, the middle row is the mass spectrum of peak 2, and the lower row is the mass spectrum of peak 3. As shown in the figure, it was confirmed that peak 1 had Mw = 196, peak 2 had Mw = 180, and peak 3 had Mw = 240.

[0353] Figure 1-11 shows the mass spectra (after improved separation) of peaks 4 to 6 in Figure 1-9. In Figure 1-11, the upper row is the mass spectrum of peak 4, the middle row is the mass spectrum of peak 5, and the lower row is the mass spectrum of peak 6. As shown in the figure, it was confirmed that peak 4 had Mw = 240, peak 5 had Mw = 240, and peak 6 had Mw = 226.

[0354] Figure 1-12 shows the mass spectrum (after improved separation) of peaks 7 and 8 in Figure 1-9. In Figure 1-12, the upper part is the mass spectrum of peak 7, and the lower part is the mass spectrum of peak 8. As shown in the figure, both peaks 7 and 8 were confirmed to have Mw=256.

[0355] FIG. 1-13 shows the micro-Raman spectra of a sample of peak 2 (Mw=180) in FIG. 1-9 and an ozonide standard (ozonized oleic acid). In FIG. 1-13, the vertical axis represents intensity, and the horizontal axis represents Raman shift (1 / cm). As shown in FIG. 1-13, peak 2 (Mw=180) exhibited a micro-Raman spectrum similar to that of ozonide, and thus was presumed to exhibit a structure similar to that of ozonide. Furthermore, the micro-Raman spectrum of peak 2 (Mw=180) exhibited a pattern different from that of peroxide, and therefore, it was presumed that peak 2 (Mw=180) was not a peroxide. Using NMR, which will be described later, it was confirmed that peak 2 (Mw=180) was the cyclic peroxide of the first aspect of the present invention.

[0356] Figure 1-14 shows the peak 2 (Mw=180) in Figure 1-9. 1 The H NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 3.4 to 4.9 ppm. 1 Based on the H NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the following chemical formula (1). 1In the H NMR spectrum, the peaks marked with symbols A to F were assigned to the hydrogen atoms bonded to the carbon atoms marked with the same symbols A to F in the following chemical formula (1) shown in Figure 1-14. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0357] [ka]

[0358] Figure 1-15 shows the peak 2 (Mw=180) in Figure 1-9. 13 The C NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 60 to 105 ppm. 13 Based on the C NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be the cyclic peroxide represented by the above chemical formula (1). 13 In the C NMR spectrum, the peaks indicated by symbols A to F were assigned to the carbon atoms indicated by the same symbols A to F in the following chemical formula (1) shown in Figure 1-15. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0359] Figure 1-16 shows the two-dimensional ( 1 H- 13The C COSY NMR spectrum is shown. Methanol-d4 (CD3OD) was used as the measurement solvent. Based on this 2D NMR assignment, the Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the above-mentioned chemical formula (1). In the 2D NMR spectrum of Figure 1-16, the peaks indicated by symbols A to F were respectively assigned to the carbon atoms indicated by the same symbols A to F and the hydrogen atoms bonded to those carbon atoms in the following chemical formula (1) shown in Figure 1-16. It is also assumed that a small amount of the raw material glycerin remained, and that its peak was also detected.

[0360] Figure 1-17 also shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of Figure 1-9. In Figure 1-17, the "synthetic OG" in the upper row is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, under the HILIC conditions of Figure 1-9, glyceraldehyde dimer was not detected.

[0361] Figure 1-18 shows the HILIC (high-performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed-phase HILIC conditions. Figure 1-19 also shows an enlarged view of a portion of Figure 1-18. In Figures 1-18 and 1-19, the "synthetic OG" chromatogram in the upper row is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, separation of the components of the TLC1 spot product was not confirmed under reversed-phase HILIC conditions. This is likely due to the weak column retention and the fast elution time of the TLC1 spot product. However, the retention time of the glyceraldehyde dimer was slightly different from that of the TLC1 spot product (synthetic OG). This suggests that the TLC1 spot product did not contain glyceraldehyde dimer.

[0362] Figure 1-20 shows the ESR spectrum of the TLC1 spot sample and peak 2 (Mw=180) in Figure 1-9. In Figure 1-20, the vertical axis represents intensity and the horizontal axis represents magnetic flux density (G). Water was used as the measurement solvent. As shown, the spectra of the TLC1 spot sample and peak 2 (Mw=180) in Figure 1-9 almost completely overlap, and the peak positions are almost completely identical in both cases. Both the TLC1 spot sample and peak 2 (Mw=180) in Figure 1-9 showed the spectrum of DMPO (spin trap agent) characterized by six lines. This spectral pattern is similar to that of ozonide.

[0363] Figure 1-21 shows the ESR spectrum of ozonized methyl linolenate. Acetone was used as the measurement solvent. Ozonized methyl linolenate is a known ozonide. As shown in the figure, the ESR spectrum of ozonized methyl linolenate shows a spectrum with DMPO (spin trap agent) that features six lines, which are characteristic of ozonides. This spectral pattern is similar to the pattern of TLC1 spot and peak 2 (Mw=180) in Figure 1-20.

[0364] Figure 1-22 shows the ESR spectrum of peaks 1 to 8 in Figure 1-9. Water was used as the measurement solvent. The top image shows the ESR spectrum of a blank (solvent only) for comparison. As shown in the figure, it was confirmed that all of the components in peaks 1 to 8 have radical activity.

[0365] The graph in Figure 1-23 shows the results of measuring the activity of peaks 1 to 8 in Figure 1-9 by chemiluminescence. In this figure, the vertical axis represents the luminescence intensity (relative intensity) at all wavelengths. The numbers "1" to "8" on the horizontal axis represent each fraction of peaks 1 to 8. The numbers below each number represent the molecular weight of each fraction confirmed by mass spectrometry. As shown in the figure, it was confirmed that components other than the one with a molecular weight of 180 were produced that showed activity by chemiluminescence.

[0366] (4) Confirmation of TRP channel activity The TLC1 spot product produced in "(1) Production of an oxidation reaction product containing a cyclic peroxide according to the first aspect of the present invention" was used directly without fractionation (purification) to confirm TRP channel activity. Hereinafter, "G" refers to glycerin that has not been ozonized. Hereinafter, "OG" refers to glycerin ozonized using an oxygen generator (ozonized glycerin). In the production of "OG," ozonation of glycerin using an oxygen generator was carried out by converting air into a high-concentration oxygen (oxygen concentration of 70% or more) using an oxygen generator, and then ozonizing the oxygen via an ozone generator to obtain a gas with an ozone concentration of approximately 37,000 ppm, under the following conditions: A. Hereinafter, "LOG" refers to "OG" that has been further oxidized. The production of "LOG" by oxidation of "OG" was carried out under the following conditions: B, using a gas with an ozone concentration of approximately 37,000 ppm obtained by ozonizing oxygen from an oxygen cylinder (oxygen concentration of 99% or more) via an ozone generator. That is, the "LOG" below is the same as the glycerin solution in which the ozone oxidized product of glycerin is dissolved at a final concentration of 4000 ppm, which was produced in the above "(1) Production of an oxidation reaction product containing a cyclic peroxide according to the first aspect of the present invention." Therefore, the "LOG" below is the glycerin solution of the TLC 1 spot product. In addition, in the following, "HOG" refers to "OG" that was heated (heat-treated) at 80°C for 168 hours. (Condition A: Production of "OG") Glycerin with a concentration of 98% by weight or more ("G", i.e., non-ozonized glycerin) was placed in a tank. Next, using an air diffuser, the gas with an ozone concentration of approximately 37,000 ppm was aerated into "G" in the tank for approximately 7 days, resulting in a glycerin solution in which ozone-oxidized glycerin was dissolved at a final concentration of 4,000 ppm. This ozone-treated glycerin solution was used as "OG." (Condition B: Manufacturing of "LOG") The "OG" produced under the above-mentioned condition A was placed in a tank. Next, using an aeration tube, the gas with an ozone concentration of approximately 37,000 ppm was aerated into the "OG" in the tank for approximately 7 days, thereby producing an ozone-treated glycerin solution with an equivalent hydrogen peroxide concentration of 2,000 ppm. This ozone-treated glycerin solution was used as "LOG."

[0367] Figure 1-24 shows the effects of adding G, OG, LOG, and HOG to TRPM2 (expressing cells) and Vector (TRPM2 non-expressing cells). The graph on the left side of Figure 1-24 is for TRPM2 (expressing cells), and the graph on the right side is for Vector (TRPM2 non-expressing cells). The horizontal axis indicates time (seconds). G, OG, LOG, and HOG were added at 120 seconds (2 minutes). G, OG, LOG, and HOG were each used as a 10% by mass aqueous solution. The vertical axis indicates the intracellular Ca 2+ Furthermore, the graph at the bottom of Figure 1-24 shows the net intracellular Ca concentration change. 2+ As shown, G, OG, and LOG increased intracellular Ca2+ levels relative to HOG. 2+ The large increase confirmed that TRP channel activity was high, and that OG and LOG had higher TRP channel activity than G.

[0368] For G and OG, the TRP channel activity of TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that the concentration (mass%) of the aqueous solution was changed. The results are shown in Figure 1-25. The graph on the left side of Figure 1-25 shows the results for G, and the graph on the right side of Figure 1-25 shows the results for OG. The horizontal axis shows time (seconds). The vertical axis shows intracellular Ca 2+ The graph at the bottom of Figure 1-25 shows the changes in the concentrations of G and OG (horizontal axis, mass%) and the net intracellular Ca 2+ The correlation between the increase in TRP channel activity and the amount of TRP channel activity (vertical axis) is shown. As shown in the figure, G had higher TRP channel activity at high concentrations, but OG showed high TRP channel activity even at low concentrations.

[0369] For G, OG, LOG, and HOG, the TRP channel activity of TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that the aqueous solution concentration was changed from 10% by mass to 1% by mass. The results are shown in Figure 1-26. The horizontal axis represents time (seconds). The vertical axis represents intracellular Ca 2+ As shown in Figure 1-26, under these conditions, only LOG exhibited high TRP channel activity.

[0370] For LOG and OG, TRP channel activity against TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that 500 units / ml of catalase was added, and compared with the case where catalase was not added. The results are shown in Figure 1-27. The graph on the left side of Figure 1-27 shows the results for LOG, and the graph on the right side of Figure 1-27 shows the results for OG. The horizontal axis shows time (seconds), and the vertical axis shows intracellular Ca 2+ The graph at the bottom of Figure 1-27 shows the net intracellular Ca concentration change for LOG and OG with and without catalase added. 2+ The increase in TRP channel activity (ordinate) is shown. As shown in the figure, it was confirmed that the addition of catalase inactivated the TRP channel activity of both OG and LOG.

[0371] For OG and LOG, the TRP channel activity of TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that the aqueous solution concentration (mass%) was changed. The results are shown in Figure 1-28. The graph on the left side of Figure 1-28 shows the results for OG, and the graph on the right side of Figure 1-28 shows the results for LOG. The horizontal axis shows time (seconds). The vertical axis shows intracellular Ca 2+ The graph at the bottom of Figure 1-28 shows the changes in OG and LOG concentrations (horizontal axis) and intracellular Ca 2+ The correlation with concentration change (vertical axis) is shown. As shown in the figure, LOG showed high TRP channel activity even at a 1000-fold dilution, while OG at the same concentration showed no TRP channel activity.

[0372] For 0.1% LOG by mass, TRP channel activity for TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that either 100 units / ml of catalase or 1 μm of PJ34 (trade name of Chemscene) was added, and the results were compared with the results when catalase and PJ34 were not added. The results are shown in Figure 1-29. The graph in the upper left of Figure 1-29 shows the comparison results between the cases where catalase was added and not added. The graph in the lower left of Figure 1-29 shows the comparison results between the cases where PJ34 was added and not added. The horizontal axis shows time (seconds). The vertical axis shows intracellular Ca 2+ The graph in the upper right of Figure 1-29 shows the net intracellular Ca concentration change with and without catalase (Control). 2+ The graph at the bottom right of Figure 1-29 shows the net intracellular Ca increase with and without PJ34 (Control). 2+ The increase in activity (vertical axis) is shown. As shown in the figure, it was confirmed that the addition of either catalase or PJ34 inactivated TRP channel activity. PJ34 is a substance represented by the following chemical formula:

[0373] [ka]

[0374] For 0.1% LOG by mass, TRP channel activity for TRPM2 (expressing cells) was confirmed under the same conditions as in Figure 1-24, except that 100 μm of dipyridyl (α,α'-dipyridyl) was added, and compared with the case where dipyridyl was not added. The results are shown in Figure 1-30. The graph on the left side of Figure 1-30 shows the comparison results between the case where dipyridyl was added and the case where it was not added. The horizontal axis shows time (seconds), and the vertical axis shows intracellular Ca 2+ The graph on the right side of Figure 1-30 shows the net intracellular Ca concentration change with and without dipyridyl (Control). 2+ The increase in activity (vertical axis) is shown. As shown in the figure, it was confirmed that the addition of dipyridyl inactivated TRP channel activity.

[0375] Regarding LOG, TRP channel activity for each cell was confirmed under the same conditions as in Figure 1-24, except that the concentration (mass%) of the aqueous solution was changed and TRPM1 HEK (expressing cells) or HEK (expressing cells) was used instead of TRPM2 (expressing cells). The results are shown in Figure 1-31. The graph in the upper left of Figure 1-31 shows the results for TRPM1 HEK (expressing cells), and the graph on the right of Figure 1-31 shows the results for HEK (expressing cells). The horizontal axis shows time (seconds). The vertical axis shows intracellular Ca 2+ The graph at the bottom of Figure 1-31 shows the change in the LOG concentration (horizontal axis, mass%) and the net intracellular Ca 2+ The correlation between the increase in TRP channel activity and the increase in TRP channel activity (vertical axis) is shown. As shown in the figure, LOG showed TRP channel activity in TRPM1-expressing HEK cells, but showed almost no TRP channel activity in HEK cells.

[0376] The TLC1 spot product was further purified to contain a component with a molecular weight of 180 as the main component. This component was used at various concentrations to test its TRP channel activity against TRPM2 (expressing cells) and TRPMA1 (expressing cells) using the same method as in Figure 1-31. The results are shown in Figures 1-32 and 1-33. In Figures 1-32 and 1-33, "F7" denotes the component obtained by purifying the TLC1 spot product described above to contain a component with a molecular weight of 180 as the main component. As shown in Figures 1-32 and 1-33, F7 did not exhibit TRP channel activity against TRPM2, but did exhibit TRP channel activity against TRPA1 (expressing cells).

[0377] As described above, according to Example 1, a TRP channel active substance with oxidizing power could be produced from glycerin, which is not an olefin and has no double bonds, by a simple method using ozone oxidation.

[0378] The TLC spot was separated into peaks 1-8 (Figure 1-9) and dissolved in glycerin at the same concentration as OG. TRP channel activity was confirmed in the same manner. Peaks 1-8 all possessed TRP channel activity, confirming their oxidative potential. However, OG, the mixture of these peaks, possessed stronger TRP channel activity than peaks 1-8, indicating its stronger oxidative potential.

[0379] [Example of the second invention]

[0380] Next, Example 2 will be described. However, the second invention of the present invention is not limited to the following example. Commercially available reagents were used according to their protocols unless otherwise specified.

[0381] [Example 2] An oxidation reaction product containing the cyclic peroxide was prepared by ozone oxidation of glycerin. Furthermore, the whitening effect of the prepared oxidation reaction product was confirmed. This example corresponds to an example in which the cyclic peroxide was prepared and used, as well as an example in which the oxidation reaction product was prepared and used, and also corresponds to an example of a method for preparing the oxidation reaction product.

[0382] (1) Production of an oxidation reaction product containing the cyclic peroxide Concentrated glycerin and ozone were brought into gas-liquid contact to produce an ozone-treated glycerin solution (ozonized glycerin) containing the oxidation reaction product as described below. Here, concentrated glycerin refers to glycerin having a concentration of 98% by weight or more of the Japanese Pharmacopoeia standard. The oxidation reaction product of the second aspect of the present invention produced in this example contains the cyclic peroxide of the second aspect of the present invention, as described below.

[0383] A 50 L Teflon (registered trademark) tank was used as the contact vessel. An air diffuser was installed at the bottom of the tank, allowing ozone to be supplied into the tank as fine bubbles. A silent discharge ozone generator capable of generating 100 g of ozone per hour was used, using high-concentration oxygen gas containing 90% or more by volume as the raw material.

[0384] 22 kg of the concentrated glycerin was placed in the tank, and 20 L of the high-concentration oxygen gas was fed into the ozone generator at a rate of 20 L per minute to generate a gas containing ozone. The generated gas was then released into the tank through the air diffuser for 7 days or more, yielding a glycerin solution containing ozone-oxidized glycerin at a final concentration of 4000 ppm. This ozone-oxidized glycerin corresponds to the oxidation reaction product. Furthermore, as described below, this ozone-oxidized glycerin contained the cyclic peroxide. The whitening activity of the ozone-oxidized glycerin containing the peroxide was confirmed.

[0385] (2) Confirmation of whitening effect The subjects were 48 healthy women (aged 41 or over, 59 or under). Each subject was fully informed in advance based on an explanatory document (including a consent form), and written consent was obtained.

[0386] To confirm the whitening effect, test samples of Example 2-1A, Example 2-1B, Reference Example 2-1A, and Reference Example 2-1B were prepared. Specifically, the test sample of Example 2-1A was prepared by adding an equal amount of water to the ozonated glycerin of Example 2(1) to obtain a 50% ozonated glycerin aqueous solution, to which pentylene glycol and xanthan gum were further added. The test sample of Example 2-1B was prepared by adding 9 times the amount of water as the ozonated glycerin of Example 2(1) to obtain a 10% ozonated glycerin aqueous solution, to which pentylene glycol, xanthan gum, and sodium hyaluronate were further added. As a result, the final concentrations of ozone oxidants in the ozonated glycerin obtained in Example 2(1) for the test samples of Example 2-1A and Example 2-1B were 80 ppm or 800 ppm. The test samples of Reference Example 2-1A and Reference Example 2-1B were prepared in the same manner as above, except that the concentrated glycerin was used instead of the ozonized glycerin.

[0387] The subjects were divided into two groups (24 subjects per group). After washing their face twice a day (morning and night), each subject took two pumps (approximately 1 ml) of each test product and applied it to the designated half of their face. From the start of the study until its completion, none of the subjects changed any cosmetics (lotion, emulsion, whitening lotion, cream, etc.) other than the test product, and none of them started using any new facial products. The confirmation test was conducted from April to June in an environment where melanin production occurs over time. After being reviewed and approved by the Institutional Review Board, this study was conducted in compliance with the Declaration of Helsinki and ethical guidelines for medical research involving human subjects. (Test group 1) Half face: Test product of Example 2-1A Other half of the face: Test sample of Reference Example 2-1A (Test group 2) Half face: Test product of Example 2-1B Other half of the face: Test sample of Reference Example 2-1B

[0388] Additionally, melanin measurements were performed five times on the pigmented spots on each subject's left and right cheeks: on the first day of application of each test product (week 0), and at weeks 4 and 8 after the start of application. The melanin measurements were performed using a Mexameter® MX18 (Courage+Khazaka electronic GmbH, Cologne, Germany). The maximum and minimum values ​​were then removed. The average of the remaining three measurements was used as the melanin measurement for each subject. The change in melanin measurement was measured using the melanin measurement at the start of the study. Statistical testing was performed using Student's t-test, and a significant difference was determined when p<0.05. These results are shown in Figures 2-1 and 2-2.

[0389] FIG. 2-1 is a graph showing the results of melanin measurements over time. In FIG. 2-1, (A) shows the results of Example 2-1A and Reference Example 2-1A, and (B) shows the results of Example 2-1B and Reference Example 2-1B. In FIGS. 2-1(A) and (B), the horizontal axis shows the number of weeks since the start of the test, and the vertical axis shows the melanin measurement value (Melanin index). FIG. 2-2 is a graph showing the change in melanin measurement value over time. In FIG. 2-2, (A) shows the results of Example 2-1A and Reference Example 2-1A, and (B) shows the results of Example 2-1B and Reference Example 2-1B. In FIGS. 2-2(A) and (B), the horizontal axis shows the number of weeks since the start of the test, and the vertical axis shows the change in melanin measurement value (ΔMelanin index). As shown in Figure 2-1 and Figure 2-2, in the skin area to which the test product of Example 2-1A and the test product of Example 2-1B were applied, the melanin measurement value was reduced compared to the skin area to which the test product of Reference Example 2-1A and the test product of Reference Example 2-1B were applied, and the reduction amount increased over time.From these results, it was found that the cyclic peroxide contained in the ozone oxidant has the activity of reducing the amount of melanin in the skin, that is, has a whitening effect.

[0390] The compound with a molecular weight of 180 (chemical formula (1)) described below can be eliminated from ozonized glycerin by subjecting the ozonized glycerin to heat treatment. Therefore, when changes in melanin measurement values ​​were similarly examined using the ozonized glycerin after the heat treatment, the activity of reducing the melanin measurement values ​​disappeared. Therefore, it can be said that the compound with a molecular weight of 180 (chemical formula (1)) described below is an active ingredient with a whitening effect. Furthermore, since the compound with a molecular weight of 180 is a cyclic peroxide, it was presumed that it exerts a whitening effect by decomposing melanin via its oxidizing ability.

[0391] (3) Analysis of the reaction mixture In order to identify the active whitening ingredient in the ozonized glycerin, cyclic peroxides not found in glycerin were extracted from the ozonized glycerin of Example 2(1) and analyzed. Glycerin was removed from the glycerin solution containing ozone oxidized glycerin produced in "Example 2(1) Production of oxidation reaction product containing the cyclic peroxide" using a silica gel column to obtain a reaction mixture containing the cyclic peroxide (hereinafter sometimes referred to as "TLC 1 spot product").

[0392] The NMR spectrum of the reaction mixture (TLC 1 spot product) was measured at a temperature of 300 K (27 °C) using DMSO-d6 as a solvent. The spectra are shown in Figures 2-3 to 2-8. Figure 2-3 shows 1 H NMR spectrum diagrams. 13 C NMR spectrum diagram. Figures 2-5 are 13 C DEPT135 NMR spectrum. Figure 2-6 is a COSY NMR spectrum. Figure 2-7 is an HSQC NMR spectrum. Figure 2-8 is an HMBC NMR spectrum. As shown in Figures 2-3 to 2-8, complex peaks were observed, suggesting that the TLC1 spot product was a mixture of multiple substances. Furthermore, LCMS revealed that this TLC1 spot product contained components with m / z 198,203.

[0393] (4) Separation and analysis of the reaction mixture The reaction mixture (TLC 1 spot product) was diluted with acetonitrile to approximately 3% by mass, filtered through a membrane filter, and the filtrate was subjected to LC measurement to optimize the separation conditions. Next, the mass of the peak observed in the LC measurement under the optimized conditions was confirmed, and precision fractionation of Mw = 180 (peak 2) was performed. The obtained fraction was then freeze-dried, and the dried fraction was subjected to microscopic LR measurement and various NMR measurements. The measurement equipment (analyzer) and measurement conditions are as follows. [Measuring equipment (analyzer)] 1)Precision preparative LC: Waters, ACQUITY UPLC H-class Bio 2) Microscope LR: SNOM / AFM / Raman combined instrument WITec alpha300RSA 3)NMR:Bruker Biospin,AVANCEIII-600 with Cryo Probe [Measurement conditions] 1)Precision preparative LC Column: Shodex Asahipak NH2P-50 (4.6 mmφ × 250 mm, 5 μm) Eluent composition: Water / acetonitrile gradient Time (min): 0 5 15 20 Wed: 5 10 50 50 Acetonitrile: 95 90 50 50 Flow rate: 1.0mL / min Detector: MS (QDa) Column temperature: 40℃ Injection volume: 50μL Ionization method: ESI (NEG.) Measurement mass range (m / z): 50 to 500 2) Microscope LR Excitation wavelength: 532 nm Measurement wave number range: approx. 125 to 3800 cm -1 Objective lens: x100 Detector: EMCCD 3) NMR Observation frequency: 600MHz(1 H), 150MHz ( 13 C) Measurement solvent: methanol-d4 Measurement temperature: 300K Chemical shift standard: measurement solvent [3.30 ppm ( 1 H), 49.80 ppm ( 13 C)]

[0394] Figure 2-9 shows the total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) for a sample prepared (diluted) with acetonitrile to approximately 3% by mass of the reaction mixture (TLC1 spot product) and a blank. In Figure 2-9, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes). In Figure 2-9, the lower row, "Synthetic OG," is a chromatogram of the TLC1 spot product sample, and the upper row is a chromatogram of the blank (acetonitrile). As shown in the figure, components A to L were confirmed in the TLC1 spot product. Components A to L were separated and tested for coloration using potassium iodide starch test paper. Component H showed the strongest coloration.

[0395] Figure 2-10 also shows the mass spectra of peaks F, G, and H (F fraction, G fraction, and H fraction) in Figure 2-9. In Figure 2-10, the vertical axis represents intensity, and the horizontal axis represents mass-to-charge ratio (m / z). As shown in the figure, it was confirmed that peak F had Mw=180, peak G had Mw=226, and peak H had Mw=256.

[0396] Furthermore, Figure 2-11 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). In Figure 2-11, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes), as in Figures 2-19 to 2-21. In Figure 2-11, the upper row is a chromatogram before separation improvement (same conditions as in Figure 2-10), and the lower row is a chromatogram after separation improvement. As shown in the figure, peaks 1 to 8 were observed after separation improvement. The molecular weights of each peak were confirmed to be the molecular weights shown in Figure 2-11 using the mass spectrum described below.

[0397] Figure 2-12 shows the mass spectra (after improved separation) of peaks 1 to 3 in Figure 2-11. In Figure 2-12, the upper row is the mass spectrum of peak 1, the middle row is the mass spectrum of peak 2, and the lower row is the mass spectrum of peak 3. As shown in the figure, it was confirmed that peak 1 had Mw = 196, peak 2 had Mw = 180, and peak 3 had Mw = 240.

[0398] Figure 2-13 shows the mass spectra (after improved separation) of peaks 4 to 6 in Figure 2-11. In Figure 2-13, the upper row is the mass spectrum of peak 4, the middle row is the mass spectrum of peak 5, and the lower row is the mass spectrum of peak 6. As shown in the figure, it was confirmed that peak 4 had Mw = 240, peak 5 had Mw = 240, and peak 6 had Mw = 226.

[0399] Figure 2-14 shows the mass spectrum (after improved separation) of peaks 7 and 8 in Figure 2-11. In Figure 2-14, the upper part is the mass spectrum of peak 7, and the lower part is the mass spectrum of peak 8. As shown in the figure, both peaks 7 and 8 were confirmed to have Mw=256.

[0400] Figure 2-15 shows the micro-Raman spectra of a sample of peak 2 (Mw=180) in Figure 2-11 and an ozonide standard (ozonized oleic acid). In Figure 2-15, the vertical axis represents intensity, and the horizontal axis represents Raman shift (1 / cm). As shown in Figure 2-15, peak 2 (Mw=180) exhibited a micro-Raman spectrum similar to that of ozonide, and thus was presumed to have a structure similar to that of ozonide. Furthermore, the micro-Raman spectrum of peak 2 (Mw=180) exhibited a pattern different from that of peroxides, and therefore, it was presumed that peak 2 (Mw=180) was not a peroxide. NMR, described below, confirmed that peak 2 (Mw=180) was the cyclic peroxide.

[0401] Figure 2-16 shows the peak 2 (Mw=180) in Figure 2-11. 1 The H NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 3.4 to 4.9 ppm. 1 Based on the H NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the following chemical formula (1). 1 In the H NMR spectrum, the peaks marked with symbols A to F were assigned to the hydrogen atoms bonded to the carbon atoms marked with the same symbols A to F in the following chemical formula (1) shown in Figure 2-16. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0402] [ka]

[0403] Figure 2-17 shows the peak 2 (Mw=180) in Figure 2-11. 13The C NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 60 to 105 ppm. 13 Based on the C NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be the cyclic peroxide represented by the above chemical formula (1). 13 In the C NMR spectrum, the peaks indicated by symbols A to F were assigned to the carbon atoms indicated by the same symbols A to F in the following chemical formula (1) shown in Figure 2-17. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0404] Figure 2-18 shows the two-dimensional ( 1 H- 13 The C COSY NMR spectrum is shown. Methanol-d4 (CD3OD) was used as the measurement solvent. Based on this 2D NMR assignment, the Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the above-mentioned chemical formula (1). In the 2D NMR spectrum of Figure 2-18, the peaks indicated by symbols A to F were respectively assigned to the carbon atoms indicated by the same symbols A to F and the hydrogen atoms bonded to those carbon atoms in the following chemical formula (1) shown in Figure 2-18. It is also assumed that a small amount of the raw material glycerin remained, and that its peak was also detected.

[0405] Figure 2-19 also shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of Figure 2-11. In Figure 2-19, the "synthetic OG" in the upper row is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, under the HILIC conditions of Figure 2-11, glyceraldehyde dimer was not detected.

[0406] Figure 2-20 shows the HILIC (high-performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed-phase HILIC conditions. Figure 2-21 also shows an enlarged view of a portion of Figure 2-20. In Figures 2-20 and 2-21, the upper row, "Synthetic OG," is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, separation of the components of the TLC1 spot product was not confirmed under reversed-phase HILIC conditions. This is likely due to the weak column retention and the fast elution time of the TLC1 spot product. However, the retention time of the glyceraldehyde dimer was slightly different from that of the TLC1 spot product (synthetic OG). This suggests that the TLC1 spot product did not contain glyceraldehyde dimer.

[0407] Figure 2-22 shows the ESR spectrum of the TLC1 spot sample and peak 2 (Mw=180) in Figure 2-11. In Figure 2-22, the vertical axis represents intensity and the horizontal axis represents magnetic flux density (G). Water was used as the measurement solvent. As shown in the figure, the spectra of the TLC1 spot sample and peak 2 (Mw=180) in Figure 2-11 almost completely overlap, and the peak positions are almost completely identical in both cases. Both the TLC1 spot sample and peak 2 (Mw=180) in Figure 2-11 showed the spectrum of DMPO (spin trap agent) characterized by six lines. This spectral pattern is similar to that of ozonide.

[0408] Figure 2-23 shows the ESR spectrum of ozonized methyl linolenate. Acetone was used as the measurement solvent. Ozonized methyl linolenate is well known. As shown in the figure, the ESR spectrum of ozonized methyl linolenate shows a spectrum in the presence of DMPO (a spin trapping agent) that features six lines characteristic of ozonides. This spectral pattern is similar to that of the TLC1 spot and peak 2 (Mw=180) in Figure 2-22.

[0409] Figure 2-24 shows the ESR spectrum of peaks 1 to 8 in Figure 2-11. Water was used as the measurement solvent. The top image shows the ESR spectrum of a blank (solvent only) for comparison. As shown in the figure, it was confirmed that all of the components in peaks 1 to 8 have radical activity.

[0410] The graph in Figure 2-25 shows the results of measuring the activity of peaks 1 to 8 in Figure 2-11 by chemiluminescence. In this figure, the vertical axis represents the luminescence intensity (relative intensity) at all wavelengths. The numbers "1" to "8" on the horizontal axis represent each fraction of peaks 1 to 8. The numbers below each number represent the molecular weight of each fraction confirmed by mass spectrometry. As shown in the figure, it was confirmed that components other than the one with a molecular weight of 180 were produced that showed activity by chemiluminescence.

[0411] [Example of the third invention] Next, Example 3 will be described. However, the third invention of the present invention is not limited to the following example. Commercially available reagents were used according to their protocols unless otherwise specified.

[0412] [Example 3-1] An oxidation reaction product containing the cyclic peroxide was produced by ozone oxidation of glycerin. Furthermore, the effect of the produced oxidation reaction product on inducing the expression of skin barrier function-related genes was confirmed. This example corresponds to an example in which the cyclic peroxide was produced and used, as well as an example in which the oxidation reaction product was produced and used, and also corresponds to an example of a method for producing the oxidation reaction product.

[0413] (1) Production of an oxidation reaction product containing the cyclic peroxide Concentrated glycerin and ozone were brought into gas-liquid contact to produce an ozone-treated glycerin solution (ozonized glycerin) containing the oxidation reaction product as described below. Here, concentrated glycerin refers to glycerin having a concentration of 98% by weight or more of the Japanese Pharmacopoeia standard. The oxidation reaction product of the third invention of the present invention produced in this example contains the cyclic peroxide of the third invention of the present invention, as described below.

[0414] A 50 L Teflon (registered trademark) tank was used as the contact vessel. An air diffuser was installed at the bottom of the tank, allowing ozone to be supplied into the tank as fine bubbles. A silent discharge ozone generator capable of generating 100 g of ozone per hour was used, using high-concentration oxygen gas containing 90% or more by volume as the raw material.

[0415] 22 kg of the concentrated glycerin was placed in the tank, and 20 L of the high-concentration oxygen gas was fed into the ozone generator at a rate of 20 L per minute to generate a gas containing ozone. The generated gas was then released into the tank through the air diffuser for 7 days or more, yielding a glycerin solution containing ozone-oxidized glycerin at a final concentration of 4000 ppm. This ozone-oxidized glycerin corresponds to the oxidation reaction product. Furthermore, as described below, this ozone-oxidized glycerin contained the cyclic peroxide. The peroxide-containing ozone-oxidized glycerin was tested for its ability to induce the expression of skin barrier function genes.

[0416] (2) Confirmation of the induction of skin barrier function genes Using human epidermal keratinocytes, we confirmed whether the ozonized glycerin can induce the expression of skin barrier function genes. Specifically, normal human epidermal keratinocytes (NHEK: manufactured by Kurabo Industries, Ltd.) were suspended in a medium (HuMedia-KG2 (KG2), manufactured by Kurabo Industries, Ltd.), and then 2.0 × 10 4The cells were seeded into a 96-well plate at 100 μl / well and cultured for 24 hours at 37°C and 5% CO2 (the same culture conditions apply hereinafter). After the culture, the medium in each well was replaced with KG2 medium (100 μl / well) containing the ozonized glycerin described in Example 3-1(1) at a predetermined concentration (1, 2, or 4 (v / v)%), and the cells were cultured for another 24 hours. Next, the medium from each well was removed, and the cells were washed with phosphate buffer (PBS(-)). RNA was extracted using an RNA extraction kit (Ambion® Cells-to-CT™ Kits, Thermo). cDNA was synthesized from the obtained RNA by reverse transcription.

[0417] Using the cDNA, real-time PCR reagents and a PCR device (StepOne™ Real-Time PCR System, Applied Biosystems) were used to calculate the mRNA expression levels of the profilaggrin gene, involucrin gene, and serine palmitoyltransferase gene (ΔΔCt method). The following primer set was used to amplify the mRNA of each gene, and the expression level of each gene was calculated as a relative value to the mRNA expression level of the GAPDH gene. A comparative example was carried out in the same manner, except that the concentrated glycerin was used instead of the ozonized glycerin. These results are shown in Figure 3-1.

[0418] Profilaggrin gene primer set Forward primer (SEQ ID NO: 1) 5'-CATGGCAGCTATGGTAGTGCAGA-3' Reverse primer (SEQ ID NO: 2) 5'-ACCAAACGCACTTGCTTTACAGA-3' Primer set for the involucrin gene Forward primer (SEQ ID NO: 3) 5'-GCTGGAGCAGCCTGTGTTTG-3' Reverse primer (SEQ ID NO: 4) 5'-CTGGACACTGCGGGTGGTTA-3' Primer set for serine palmitoyltransferase gene Forward primer (SEQ ID NO: 5) 5'-GCCTGTCAGCAGCTCATACCAA-3' Reverse primer (SEQ ID NO: 6) 5'-GGCCTGTCCAGTAGAGGTACCAA-3' Primer set for GAPDH gene Forward primer (SEQ ID NO: 7) 5'-GCACCGTCAAGGCTGAGAAC-3' Reverse primer (SEQ ID NO: 8) 5'-TGGTGAAGACGCCAGTGGA-3'

[0419] Figure 3-1 is a graph showing the expression levels of genes related to skin barrier function. In Figure 3-1, (A) shows the expression level of the profilaggrin gene, (B) shows the expression level of the involucrin gene, and (C) shows the results for the serine palmitoyltransferase gene. In Figures 3-1(A) to (C), the horizontal axis represents the concentration of the sample, and the vertical axis represents the relative expression level of each gene. As shown in Figures 3-1(A) to (C), the ozonized glycerin-treated group (OG) showed increased expression levels of the profilaggrin gene, the involucrin gene, and the serine palmitoyltransferase gene compared to the comparative example-treated group (Glycerin). These results demonstrate that the ozonized glycerin can induce the expression of genes related to skin barrier function. As described below, when the components of the ozonized glycerin and the concentrated glycerin are compared, the ozonized glycerin differs in that it contains a compound of the chemical formula (1) described below. Therefore, it was demonstrated that the compound of chemical formula (1) contained in the ozonized glycerin induces the expression of genes related to skin barrier function.

[0420] (3) Confirmation of the induction of antioxidant stress response genes Using human epidermal keratinocytes, we confirmed whether the ozonated glycerin can induce the expression of antioxidant stress response genes. cDNA was prepared in the same manner as in Example 3-1(2). The mRNA expression levels of the heme oxygenase 1 gene and the NAD(P)H quinone oxidoreductase 1 gene were calculated for the cDNA in the same manner as in Example 3-1(2) (ΔΔCt method). The following primer sets were used to amplify the mRNA of each gene, and the expression level of each gene was calculated as a relative value to the mRNA expression level of the GAPDH gene. A comparative example was performed in the same manner, except that the concentrated glycerin was used instead of the ozonated glycerin. These results are shown in Figure 3-2.

[0421] Primer set for heme oxygenase 1 gene Forward primer (SEQ ID NO: 9) 5'-TTGCCAGTGCCACCAAGTTC-3' Reverse primer (SEQ ID NO: 10) 5'-TCAGCAGCTCCTGCAACTCC-3' Primer set for NAD(P)H quinone oxidoreductase 1 gene Forward primer (SEQ ID NO: 11) 5'-GTGGCAGTGGCTCCATGTACTC-3' Reverse primer (SEQ ID NO: 12) 5'-GAGTGTGCCCAATGCTATATGTCAG-3'

[0422] Figure 3-2 is a graph showing the expression levels of antioxidant stress response genes. In Figure 3-1, (A) shows the expression level of the heme oxygenase 1 gene, and (B) shows the expression level of the NAD(P)H quinone oxidoreductase 1 gene. In Figures 3-2(A) and 3-2(B), the horizontal axis shows the sample concentration, and the vertical axis shows the relative expression level of each gene. As shown in Figures 3-2(A) and 3-2(B), the expression levels of the heme oxygenase 1 gene and the NAD(P)H quinone oxidoreductase 1 gene were increased in the ozonized glycerin-treated group (OG) compared with the comparative group (Glycerin). These results demonstrate that the ozonized glycerin can induce the expression of antioxidant stress response genes. As described below, when the components of the ozonized glycerin and the concentrated glycerin are compared, the ozonized glycerin differs in that it contains a compound of the chemical formula (1) described below. Therefore, it was demonstrated that the compound of chemical formula (1) contained in the ozonized glycerin induces the expression of antioxidant stress response genes.

[0423] Next, the cells were cultured for 24 or 48 hours in the presence of KG2 medium containing a predetermined concentration of ozonated glycerol, as described in Example 3-1(2). After the culture, the medium was removed from each well. Next, 100 μl of 0.5% Triton® X-100 solution was added to each well to lyse the cells, preparing a cell lysate. To a new plate, 175 μl of reaction solution (0.1 mol / L phosphate buffer containing 2 mmol / L NADPH, 0.12 units / mL glutathione reductase, and 0.5 mmol / L EDTA) and 25 μl of cell lysate were added, mixed, and incubated at 37°C for 10 minutes. Then, 25 μl of coloring solution (10 mmol / l (5,5'-dithio-bis-(2-nitrobenzoic acid):DTNB)) was added to each well, and the absorbance (405 nm) was measured using an absorption spectrophotometer. The amount of glutathione was calculated from the obtained absorbance. The amount of glutathione was calculated as a relative amount to the total amount of protein used in the assay. These results are shown in Figure 3-3.

[0424] FIG. 3-3 is a graph showing the amount of glutathione peptides. In FIG. 3-3, (A) shows the amount of peptide expression after 24 hours of culture, and (B) shows the amount of peptide expression after 48 hours of culture. In FIGS. 3-3(A) and (B), the horizontal axis indicates the concentration of the sample, and the vertical axis indicates the relative amount of glutathione peptide expression. As shown in FIGS. 3-3(A) and (B), the ozonized glycerin-treated group (OG) showed an increased amount of glutathione peptide expression compared to the comparative group (Glycerin). These results demonstrate that the ozonized glycerin can induce the expression of antioxidant proteins. As described below, when the components of the ozonized glycerin and the concentrated glycerin are compared, the ozonized glycerin differs in that it contains a compound of the chemical formula (1) described below. This demonstrates that the compound of the chemical formula (1) contained in the ozonized glycerin induces the expression of glutathione, an antioxidant protein.

[0425] (4) Confirmation of cytotoxicity The lack of cytotoxicity of the ozonated glycerin was confirmed using human epidermal keratinocytes. Specifically, cells were cultured for 24 or 48 hours in KG2 medium containing a predetermined concentration of ozonated glycerin, as described in Example 3-1(3). After the culture, the medium was removed from each well. The medium was then replaced with one containing 0.003% Neutral Red (NR: Sigma-Aldrich) and cultured at 37°C for 2 hours. After washing each well with PBS(-), NR was extracted by adding 100 μl of 1 mol / L hydrochloric acid solution containing 30 (v / v)% methanol. The absorbance of the resulting extract was measured using the spectrophotometer (measurement wavelength: 550 nm, reference wavelength: 650 nm) and the cell viability was calculated. These results are shown in Figure 3-4.

[0426] Figure 3-4 is a graph showing cell viability. In Figure 3-4, the horizontal axis indicates the concentration of the sample, and the vertical axis indicates the relative expression level of glutathione. As shown in Figure 3-4, the ozonized glycerin-treated group (OG) had a cell viability equivalent to that of the comparative example-treated group (Glycerin). These results confirmed that the ozonized glycerin does not exhibit cytotoxicity.

[0427] (5) Confirmation of anti-inflammatory effect Using human epidermal keratinocytes, it was confirmed that the ozonized glycerin exhibits anti-inflammatory effects. Specifically, 3D cultured epidermis (LabCyte EPI-MODEL, manufactured by J-TEC) was placed in a 24-well plate containing 500 μL of the included assay medium and cultured overnight at 37°C in 5% CO2. After the culture, 30 μL of assay medium containing the ozonized glycerin at a predetermined concentration (0 or 1 (v / v)%) was applied to the stratum corneum side, and the cells were cultured at 37°C for 24 hours. After the culture, the assay medium containing the ozonized glycerin was removed with a cotton swab, and the stratum corneum surface was washed once with 500 μL of PBS(-). Next, the PBS(-) was removed from the stratum corneum surface with a cotton swab, and the cells were then irradiated with UVB (280-315 nm, 600 mJ / cm). 2 The three-dimensionally cultured epidermis was then transferred to a plate to which 500 μl of fresh assay medium had been added, and further cultured for 24 hours under conditions of 37° C. and 5% CO 2 .

[0428] Next, the 3D-cultured epidermis was transferred to well plates containing 500 μl of alamarBlue® Reagent (Thermo) solution (diluted 100-fold with assay medium) and further cultured for 2 hours at 37°C and 5% CO2. The fluorescence intensity of the 3D-cultured epidermis was then measured using a fluorometer (Ex / Em = 570 nm / 590 nm) to determine cell viability. Furthermore, interleukin-1α (IL-1α: R&D Systems) and prostaglandin E2 (PGE2: Cayman) were quantified by ELISA using the culture supernatant. Comparative examples were performed in the same manner except that UVB irradiation was omitted or PBS(-) or 40% glycerol-containing assay medium was used instead of the ozonized glycerol-containing assay medium. These results are shown in Figures 3-5 and 3-6.

[0429] Figure 3-5 is a graph showing the amount of IL-1α produced. Figure 3-6 is a graph showing the amount of prostaglandin E2 produced. In Figures 3-5 and 3-6, the horizontal axis represents UV treatment and the type and concentration of the sample, and the vertical axis represents the amount of IL-1α produced or the amount of PGE2 produced. As shown in Figures 3-5 and 3-6, the ozonized glycerin-treated group (OG) showed reduced amounts of IL-1α and PGE2 produced compared to the comparative group (Glycerin). These results demonstrated that the ozonized glycerin exhibits anti-inflammatory effects. As described below, when the components of the ozonized glycerin and the concentrated glycerin were compared, the ozonized glycerin differed in that it contained a compound of formula (1) described below. Therefore, it was concluded that the compound of formula (1) contained in the ozonized glycerin exhibits anti-inflammatory effects.

[0430] [Example 3-2] It was confirmed that the active ingredient in the ozonated glycerin was a cyclic peroxide.

[0431] (1) Analysis of the reaction mixture In order to identify the active ingredient in the ozonized glycerin that induces the expression of genes related to skin barrier function, cyclic peroxides not found in glycerin were extracted from the ozonized glycerin of Example 3-1(1) and analyzed. Glycerin was removed from the glycerin solution containing ozone oxidized glycerin prepared in "Example 3-1(1) Preparation of oxidation reaction product containing the cyclic peroxide" using a silica gel column to obtain a reaction mixture containing the cyclic peroxide (hereinafter sometimes referred to as "TLC1 spot product").

[0432] The NMR spectrum of the reaction mixture (TLC 1 spot product) was measured at a temperature of 300 K (27 °C) using DMSO-d6 as a solvent. The spectra are shown in Figures 3-7 to 3-12. Figure 3-7 shows 1 H NMR spectrum diagrams. 13 C NMR spectrum diagram. Figure 3-9 shows 13 C DEPT135 NMR spectrum. Figure 3-10 is a COSY NMR spectrum. Figure 3-11 is an HSQC NMR spectrum. Figure 3-12 is an HMBC NMR spectrum. As shown in Figures 3-7 to 3-12, complex peaks were observed, suggesting that the TLC1 spot product was a mixture of multiple substances. Furthermore, LCMS revealed that this TLC1 spot product contained components with m / z 198,203.

[0433] (2) Separation and analysis of the reaction mixture The reaction mixture (TLC 1 spot product) was diluted with acetonitrile to approximately 3% by mass, filtered through a membrane filter, and the filtrate was subjected to LC measurement to optimize the separation conditions. Next, the mass of the peak observed in the LC measurement under the optimized conditions was confirmed, and precision fractionation of Mw = 180 (peak 2) was performed. The obtained fraction was then freeze-dried, and the dried fraction was subjected to microscopic LR measurement and various NMR measurements. The measurement equipment (analyzer) and measurement conditions are as follows. [Measuring equipment (analyzer)] 1)Precision preparative LC: Waters, ACQUITY UPLC H-class Bio 2) Microscope LR: SNOM / AFM / Raman combined instrument WITec alpha300RSA 3)NMR:Bruker Biospin,AVANCEIII-600 with Cryo Probe [Measurement conditions] 1)Precision preparative LC Column: Shodex Asahipak NH2P-50 (4.6 mmφ × 250 mm, 5 μm) Eluent composition: Water / acetonitrile gradient Time (min): 0 5 15 20 Wed: 5 10 50 50 Acetonitrile: 95 90 50 50 Flow rate: 1.0mL / min Detector: MS (QDa) Column temperature: 40℃ Injection volume: 50μL Ionization method: ESI (NEG.) Measurement mass range (m / z): 50 to 500 2) Microscope LR Excitation wavelength: 532 nm Measurement wave number range: approx. 125 to 3800 cm -1 Objective lens: x100 Detector: EMCCD 3) NMR Observation frequency: 600MHz( 1 H), 150MHz ( 13 C) Measurement solvent: methanol-d4 Measurement temperature: 300K Chemical shift standard: measurement solvent [3.30 ppm ( 1 H), 49.80 ppm ( 13 C)]

[0434] Figure 3-13 shows the total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) for a sample prepared (diluted) with acetonitrile to approximately 3% by mass of the reaction mixture (TLC1 spot product) and a blank. In Figure 3-13, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes). In Figure 3-13, the lower row, "Synthetic OG," is a chromatogram of the TLC1 spot product sample, and the upper row is a chromatogram of the blank (acetonitrile). As shown in the figure, components A to L were confirmed in the TLC1 spot product. Components A to L were separated and tested for coloration using potassium iodide starch test paper. Component H showed the strongest coloration.

[0435] Figure 3-14 also shows the mass spectra of peaks F, G, and H (F fraction, G fraction, and H fraction) in Figure 3-13. In Figure 3-14, the vertical axis represents intensity, and the horizontal axis represents mass-to-charge ratio (m / z). As shown in the figure, it was confirmed that peak F had Mw=180, peak G had Mw=226, and peak H had Mw=256.

[0436] Furthermore, Figure 3-15 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). In Figure 3-15, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes), as in Figures 3-23 to 3-25. In Figure 3-15, the upper row is a chromatogram before separation improvement (same conditions as in Figure 3-14), and the lower row is a chromatogram after separation improvement. As shown in the figure, peaks 1 to 8 were observed after separation improvement. The molecular weights of each peak were confirmed to be the molecular weights shown in Figure 3-15 using the mass spectrum described below.

[0437] Figure 3-16 shows the mass spectra (after improved separation) of peaks 1 to 3 in Figure 3-15. In Figure 3-16, the upper row is the mass spectrum of peak 1, the middle row is the mass spectrum of peak 2, and the lower row is the mass spectrum of peak 3. As shown in the figure, it was confirmed that peak 1 had Mw = 196, peak 2 had Mw = 180, and peak 3 had Mw = 240.

[0438] Figure 3-17 shows the mass spectra (after improved separation) of peaks 4 to 6 in Figure 3-15. In Figure 3-17, the upper row is the mass spectrum of peak 4, the middle row is the mass spectrum of peak 5, and the lower row is the mass spectrum of peak 6. As shown in the figure, it was confirmed that peak 4 had Mw = 240, peak 5 had Mw = 240, and peak 6 had Mw = 226.

[0439] Figure 3-18 shows the mass spectrum (after improved separation) of peaks 7 and 8 in Figure 3-15. In Figure 3-18, the upper part is the mass spectrum of peak 7, and the lower part is the mass spectrum of peak 8. As shown in the figure, both peaks 7 and 8 were confirmed to have Mw=256.

[0440] Figure 3-19 shows the micro-Raman spectra of a sample of peak 2 (Mw = 180) in Figure 3-15 and an ozonide standard (ozonized oleic acid). In Figure 3-19, the vertical axis represents intensity, and the horizontal axis represents Raman shift (1 / cm). As shown in Figure 3-19, peak 2 (Mw = 180) exhibited a micro-Raman spectrum similar to that of ozonide, and thus was presumed to have a structure similar to that of ozonide. Furthermore, the micro-Raman spectrum of peak 2 (Mw = 180) exhibited a pattern different from that of peroxide, and therefore, it was presumed that peak 2 (Mw = 180) was not a peroxide. NMR, described below, confirmed that peak 2 (Mw = 180) was the cyclic peroxide.

[0441] Figure 3-20 shows the peak 2 (Mw=180) in Figure 3-15. 1 The H NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 3.4 to 4.9 ppm. 1 Based on the H NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the following chemical formula (1). 1In the H NMR spectrum, the peaks marked with symbols A to F were assigned to the hydrogen atoms bonded to the carbon atoms marked with the same symbols A to F in the following chemical formula (1) shown in Figure 3-20. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0442] [ka]

[0443] Figure 3-21 shows the peak 2 (Mw=180) in Figure 3-15. 13 The C NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 60 to 105 ppm. 13 Based on the C NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be the cyclic peroxide represented by the above chemical formula (1). 13 In the C NMR spectrum, the peaks indicated by symbols A to F were assigned to the carbon atoms indicated by the same symbols A to F in the following chemical formula (1) shown in Figure 3-21. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0444] Figure 3-22 shows the two-dimensional ( 1 H- 13The C COSY NMR spectrum is shown. Methanol-d4 (CD3OD) was used as the measurement solvent. Based on this 2D NMR assignment, the Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the above-mentioned chemical formula (1). In the 2D NMR spectrum of Figure 3-22, the peaks indicated by symbols A to F were respectively assigned to the carbon atoms indicated by the same symbols A to F and the hydrogen atoms bonded to those carbon atoms in the following chemical formula (1) shown in Figure 3-22. It is also assumed that a small amount of the raw material glycerin remained, and that its peak was also detected.

[0445] Figure 3-23 also shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of Figure 3-15. In Figure 3-23, the "synthetic OG" in the upper row is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, under the HILIC conditions of Figure 3-23, glyceraldehyde dimer was not detected.

[0446] Figure 3-24 shows the HILIC (high-performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed-phase HILIC conditions. Figure 3-25 shows an enlarged view of a portion of Figure 3-24. In Figures 3-24 and 3-25, the upper row, "Synthetic OG," is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, separation of the components of the TLC1 spot product was not confirmed under reversed-phase HILIC conditions. This is likely due to the weak column retention and the fast elution time of the TLC1 spot product. However, the retention time of the glyceraldehyde dimer was slightly different from that of the TLC1 spot product (synthetic OG). This suggests that the TLC1 spot product did not contain glyceraldehyde dimer.

[0447] Figure 3-26 shows the ESR spectrum of the TLC1 spot sample and peak 2 (Mw=180) in Figure 3-15. In Figure 3-26, the vertical axis represents intensity and the horizontal axis represents magnetic flux density (G). Water was used as the measurement solvent. As shown, the spectra of the TLC1 spot sample and peak 2 (Mw=180) in Figure 3-15 almost completely overlap, and the peak positions are almost completely identical in both cases. Both the TLC1 spot sample and peak 2 (Mw=180) in Figure 3-15 showed the spectrum of DMPO (spin trap agent) characterized by six lines. This spectral pattern is similar to that of ozonide.

[0448] Figure 3-27 shows the ESR spectrum of ozonized methyl linolenate. Acetone was used as the measurement solvent. Ozonized methyl linolenate is well known. As shown in the figure, the ESR spectrum of ozonized methyl linolenate shows a spectrum in the presence of DMPO (a spin trapping agent) that features six lines characteristic of ozonides. This spectral pattern is similar to that of the TLC1 spot and peak 2 (Mw=180) in Figure 3-26.

[0449] Figure 3-28 shows the ESR spectrum of peaks 1 to 8 in Figure 3-15. Water was used as the measurement solvent. The top image shows the ESR spectrum of a blank (solvent only) for comparison. As shown in the figure, it was confirmed that all of the components in peaks 1 to 8 have radical activity.

[0450] The graph in Figure 3-29 shows the results of measuring the activity of peaks 1 to 8 in Figure 3-15 by chemiluminescence. In this figure, the vertical axis represents the luminescence intensity (relative intensity) at all wavelengths. The numbers "1" to "8" on the horizontal axis represent each fraction of peaks 1 to 8. The numbers below each number represent the molecular weight of each fraction confirmed by mass spectrometry. As shown in the figure, it was confirmed that components other than the one with a molecular weight of 180 were produced that showed activity by chemiluminescence.

[0451] [Embodiment of the Fourth Invention] Next, Example 4 will be described. However, the fourth invention of the present invention is not limited to the following example. Commercially available reagents were used according to their protocols unless otherwise specified.

[0452] [Example 4-1] An oxidation reaction product containing the cyclic peroxide was produced by ozone oxidation of glycerin. Furthermore, the anti-glycation effect of the produced oxidation reaction product was confirmed. This example corresponds to an example in which the cyclic peroxide was produced and used, as well as an example in which the oxidation reaction product was produced and used, and also corresponds to an example of a method for producing the oxidation reaction product.

[0453] (1) Production of an oxidation reaction product containing the cyclic peroxide Concentrated glycerin and ozone were brought into gas-liquid contact to produce an ozone-treated glycerin solution (ozonized glycerin) containing the oxidation reaction product as described below. Here, concentrated glycerin refers to glycerin having a concentration of 98% by weight or more of the Japanese Pharmacopoeia standard. The oxidation reaction product of the fourth aspect of the present invention produced in this example contains the cyclic peroxide of the fourth aspect of the present invention, as described below.

[0454] A 50 L Teflon (registered trademark) tank was used as the contact vessel. An air diffuser was installed at the bottom of the tank, allowing ozone to be supplied into the tank as fine bubbles. A silent discharge ozone generator capable of generating 100 g of ozone per hour was used, using high-concentration oxygen gas containing 90% or more by volume as the raw material.

[0455] 22 kg of the concentrated glycerin was placed in the tank, and 20 L of the high-concentration oxygen gas was fed into the ozone generator at a rate of 20 L per minute to generate a gas containing ozone. The generated gas was released into the tank through the air diffuser for 7 days or more, yielding a glycerin solution in which ozone-oxidized glycerin was dissolved at a final concentration of 4000 ppm. This ozone-oxidized glycerin corresponds to the oxidation reaction product. Furthermore, as described below, this ozone-oxidized glycerin contained the cyclic peroxide. The AGE decomposition activity of the ozone-oxidized glycerin containing the peroxide was confirmed.

[0456] (2) Confirmation of cleavage activity of cross-linked structures of AGEs The activity of cleaving AGE cross-linked structures was measured according to Reference 1 (Sara Vasan et al. Nature, 382, ​​pp. 275-278 (1996)). Specifically, 1-phenyl-1,2-propanedione (PPD), a reaction substrate for an AGE cross-linked model with an α-diketone structure, was used as the substrate, and the activity of cleaving AGE cross-linked structures was measured by detecting the cleavage of PPD. N-phenacylthiazolium bromide (PTB), known to have the activity of cleaving AGE cross-linked structures, was used as a positive control.

[0457] 100 μL (n=5) of the following sample solution was mixed with 20 μL of 10 mmol / L PPD (solvent: 50% acetonitrile) and 80 μL of 2 mol / L phosphate buffer (pH 7.4), and the mixture was reacted at 37°C for 2 hours. After the reaction, 40 μL of 2 mol / L hydrochloric acid was added to the resulting reaction solution to terminate the reaction. After the reaction was terminated, 20 μL of 100 mmol / L sodium dehydroacetate was added to each reaction solution as an internal standard. (sample liquid) Diluted ozonized glycerin: A solution obtained by diluting the ozonized glycerin of Example 4-1(1) with water so that the concentration of ozonized glycerin becomes 10, 100, or 1000 ppm. Concentrated glycerin solution 5 or 10 mmol / l PTB (solvent: 50% acetonitrile) Hydrogen peroxide solution: A solution diluted with water to an H2O2 concentration of 1 or 10 mmol / l

[0458] The resulting mixture was then centrifuged at 3,000 × g for 10 minutes at 20°C, and 20 μl of the supernatant was collected as a measurement sample. The amount of benzoic acid in the measurement sample was analyzed by reverse-phase HPLC. The reverse-phase HPLC was performed under the following measurement conditions. Measurement samples containing known concentrations of benzoic acid were also analyzed in the same manner. (Measurement conditions for reversed-phase HPLC) Column: Cadenza CD-C18 75mm x 4.6mm ID (Imtakt Co., Ltd.) Mobile phase: 0.2% acetic acid / acetonitrile (70:30) (Contains 2mmol / l EDTA-2Na) Flow rate: 1ml / min Measurement wavelength: 230nm

[0459] A calibration curve was created using the peak area of ​​the chromatogram (benzoic acid: 2.4 minutes) obtained from measurement samples containing known concentrations of benzoic acid, and the benzoic acid content of the measurement samples from each sample solution was then quantified. Furthermore, to eliminate background benzoic acid content, each sample solution was quantified in the same manner. Since 1 mol of PPD generates 1 mol of benzoic acid, the anti-glycation rate (crosslink cleavage rate) was calculated using the following formula (1). These results are shown in Figure 4-1. Anti-glycation rate (%)={(AB) / C}×100 ···(1) A: Amount of benzoic acid in the measurement sample B: Amount of benzoic acid in the sample solution C: Amount of PPD (substrate amount) used in the reaction

[0460] Figure 4-1 is a graph showing the anti-glycation rate. In Figure 4-1, the horizontal axis indicates the type and concentration of the sample solution, and the vertical axis indicates the anti-glycation rate. As shown in Figure 4-1, the anti-glycation rate of ozonized glycerin increased in a concentration-dependent manner. Furthermore, ozonized glycerin showed an anti-glycation rate equal to or higher than that of the positive controls PTB and hydrogen peroxide (H2O2). These results demonstrate that ozonized glycerin exhibits extremely high activity in cleaving the crosslinked structures of AGEs, i.e., anti-glycation activity. Furthermore, as described below, when the components of the ozonized glycerin and the concentrated glycerin were compared, the ozonized glycerin differed in that it contained a compound of chemical formula (1) described below. Therefore, it was demonstrated that the compound of chemical formula (1) contained in the ozonized glycerin exhibits anti-glycation activity.

[0461] From the above, it was found that the oxidation reaction product containing the cyclic peroxide, i.e., the compound of chemical formula (1), produced by the ozone oxidation of glycerin exhibits anti-glycation activity.

[0462] [Example 4-2] It was confirmed that the active ingredient in the ozonated glycerin was a cyclic peroxide.

[0463] (1) Analysis of the reaction mixture In order to identify the active anti-glycation component in the ozonated glycerin, cyclic peroxides not found in glycerin were extracted from the ozonated glycerin of Example 4-1(1) and analyzed. Glycerin was removed from the glycerin solution containing ozone oxidized glycerin produced in "Example 4-1(1) Production of oxidation reaction product containing the cyclic peroxide" using a silica gel column to obtain a reaction mixture containing the cyclic peroxide (hereinafter sometimes referred to as "TLC 1 spot product").

[0464] The NMR spectrum of the reaction mixture (TLC 1 spot product) was measured at a temperature of 300 K (27 °C) using DMSO-d6 as a solvent. The spectra are shown in Figures 4-2 to 4-7. Figure 4-2 shows 1H NMR spectrum diagram. 13 C NMR spectrum. 13 C DEPT135 NMR spectrum. Figure 4-5 is a COSY NMR spectrum. Figure 4-6 is an HSQC NMR spectrum. Figure 4-7 is an HMBC NMR spectrum. As shown in Figures 4-2 to 4-7, complex peaks were observed, suggesting that the TLC1 spot product was a mixture of multiple substances. Furthermore, LCMS revealed that this TLC1 spot product contained a component with m / z 198,203.

[0465] (2) Separation and analysis of the reaction mixture The reaction mixture (TLC 1 spot product) was diluted with acetonitrile to approximately 3% by mass, filtered through a membrane filter, and the filtrate was subjected to LC measurement to optimize the separation conditions. Next, the mass of the peak observed in the LC measurement under the optimized conditions was confirmed, and precision fractionation of Mw = 180 (peak 2) was performed. The obtained fraction was then freeze-dried, and the dried fraction was subjected to microscopic LR measurement and various NMR measurements. The measurement equipment (analyzer) and measurement conditions are as follows. [Measuring equipment (analyzer)] 1)Precision preparative LC: Waters, ACQUITY UPLC H-class Bio 2) Microscope LR: SNOM / AFM / Raman combined instrument WITec alpha300RSA 3)NMR:Bruker Biospin,AVANCEIII-600 with Cryo Probe [Measurement conditions] 1)Precision preparative LC Column: Shodex Asahipak NH2P-50 (4.6 mmφ × 250 mm, 5 μm) Eluent composition: Water / acetonitrile gradient Time (min): 0 5 15 20 Wed: 5 10 50 50 Acetonitrile: 95 90 50 50 Flow rate: 1.0mL / min Detector: MS (QDa) Column temperature: 40℃ Injection volume: 50μL Ionization method: ESI (NEG.) Measurement mass range (m / z): 50 to 500 2) Microscope LR Excitation wavelength: 532 nm Measurement wave number range: approx. 125 to 3800 cm -1 Objective lens: x100 Detector: EMCCD 3) NMR Observation frequency: 600MHz( 1 H), 150MHz ( 13 C) Measurement solvent: methanol-d4 Measurement temperature: 300K Chemical shift standard: measurement solvent [3.30 ppm ( 1 H), 49.80 ppm ( 13 C)]

[0466] Figure 4-8 shows the total ion chromatograms (ESI-negative mode) obtained by the precision preparative LC (liquid chromatography) for a sample prepared (diluted) with acetonitrile to approximately 3% by mass of the reaction mixture (TLC1 spot product) and a blank. In Figure 4-8, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes). In Figure 4-8, the lower row, "Synthetic OG," is a chromatogram of the TLC1 spot product sample, and the upper row is a chromatogram of the blank (acetonitrile). As shown in the figure, components A to L were confirmed in the TLC1 spot product. Components A to L were separated and tested for coloration using potassium iodide starch test paper. Component H showed the strongest coloration.

[0467] Figure 4-9 also shows the mass spectra of peaks F, G, and H (F fraction, G fraction, and H fraction) in Figure 4-8. In Figure 4-9, the vertical axis represents intensity and the horizontal axis represents mass-to-charge ratio (m / z). As shown in the figure, it was confirmed that peak F had Mw=180, peak G had Mw=226, and peak H had Mw=256.

[0468] Furthermore, Figure 4-10 shows the results of an investigation into the improvement of separation (improvement of separation conditions) in HILIC (high performance liquid chromatography). In Figure 4-10, the vertical axis represents intensity, and the horizontal axis represents retention time (minutes), as in Figures 4-18 to 4-20. In Figure 4-10, the upper row is a chromatogram before separation improvement (same conditions as in Figure 4-9), and the lower row is a chromatogram after separation improvement. As shown in the figure, peaks 1 to 8 were observed after separation improvement. The molecular weights of each peak were confirmed to be as shown in Figure 4-10 using the mass spectrum described below.

[0469] Figure 4-11 shows the mass spectra (after improved separation) of peaks 1 to 3 in Figure 4-10. In Figure 4-11, the upper row is the mass spectrum of peak 1, the middle row is the mass spectrum of peak 2, and the lower row is the mass spectrum of peak 3. As shown in the figure, it was confirmed that peak 1 had Mw = 196, peak 2 had Mw = 180, and peak 3 had Mw = 240.

[0470] Figure 4-12 shows the mass spectra (after improved separation) of peaks 4 to 6 in Figure 4-10. In Figure 4-12, the upper row is the mass spectrum of peak 4, the middle row is the mass spectrum of peak 5, and the lower row is the mass spectrum of peak 6. As shown in the figure, it was confirmed that peak 4 had Mw = 240, peak 5 had Mw = 240, and peak 6 had Mw = 226.

[0471] Figure 4-13 shows the mass spectrum (after improved separation) of peaks 7 and 8 in Figure 4-10. In Figure 4-13, the upper row is the mass spectrum of peak 7, and the lower row is the mass spectrum of peak 8. As shown in the figure, both peaks 7 and 8 were confirmed to have Mw=256.

[0472] Figure 4-14 shows the micro-Raman spectra of a sample of peak 2 (Mw = 180) in Figure 4-10 and an ozonide standard (ozonized oleic acid). In Figure 4-14, the vertical axis represents intensity, and the horizontal axis represents Raman shift (1 / cm). As shown in Figure 4-14, peak 2 (Mw = 180) exhibited a micro-Raman spectrum similar to that of ozonide, and thus was presumed to have a structure similar to that of ozonide. Furthermore, the micro-Raman spectrum of peak 2 (Mw = 180) exhibited a pattern different from that of peroxides, and therefore, it was presumed that peak 2 (Mw = 180) was not a peroxide. NMR, which will be described later, confirmed that peak 2 (Mw = 180) was the cyclic peroxide.

[0473] Figure 4-15 shows the peak 2 (Mw=180) in Figure 4-10. 1 The H NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 3.4 to 4.9 ppm. 1 Based on the H NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the following chemical formula (1). 1 In the H NMR spectrum, the peaks marked with symbols A to F were assigned to the hydrogen atoms bonded to the carbon atoms marked with the same symbols A to F in the following chemical formula (1) shown in Figure 4-15. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0474] [ka]

[0475] Figure 4-16 shows the peak 2 (Mw=180) in Figure 4-10. 13The C NMR spectrum is shown. The measurement solvent was methanol-d4 (CD3OD). In the figure, the upper spectrum is an enlarged view of the lower spectrum around 60 to 105 ppm. 13 Based on the C NMR assignment, Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be the cyclic peroxide represented by the above chemical formula (1). 13 In the C NMR spectrum, the peaks marked with symbols A to F were assigned to the carbon atoms marked with the same symbols A to F in the following chemical formula (1) shown in Figure 4-16. It is also assumed that a small amount of the raw material glycerin remained, and its peak was also detected.

[0476] Figure 4-17 shows the two-dimensional ( 1 H- 13 The C COSY NMR spectrum is shown. Methanol-d4 (CD3OD) was used as the measurement solvent. Based on this 2D NMR assignment, the Mw=180, and other instrumental analysis data, the structure of the oxidation reaction product of peak 2 (Mw=180) was proven to be a cyclic peroxide represented by the above-mentioned chemical formula (1). In the 2D NMR spectrum of Figure 4-17, the peaks indicated by symbols A to F were respectively assigned to the carbon atoms indicated by the same symbols A to F and the hydrogen atoms bonded to those carbon atoms in the following chemical formula (1) shown in Figure 4-17. It is also assumed that a small amount of the raw material glycerin remained, and that its peak was also detected.

[0477] Figure 4-18 also shows the HILIC (high performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under the HILIC conditions of Figure 4-10. In Figure 4-18, the upper row, "Synthetic OG," is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, under the HILIC conditions of Figure 4-18, glyceraldehyde dimer was not detected.

[0478] Figure 4-19 shows the HILIC (high-performance liquid chromatography) chromatograms of the TLC1 spot product and glyceraldehyde dimer under reversed-phase HILIC conditions. Figure 4-20 shows an enlarged view of a portion of Figure 4-19. In Figures 4-19 and 4-20, the "synthetic OG" in the upper row is the HILIC chromatogram of the TLC1 spot product. The lower row is the HILIC chromatogram with glyceraldehyde dimer. As shown, separation of the components of the TLC1 spot product was not confirmed under reversed-phase HILIC conditions. This is likely due to the weak column retention and the fast elution time of the TLC1 spot product. However, the retention time of the glyceraldehyde dimer was slightly different from that of the TLC1 spot product (synthetic OG). This suggests that the TLC1 spot product did not contain glyceraldehyde dimer.

[0479] Figure 4-21 shows the ESR spectrum of the TLC1 spot sample and peak 2 (Mw=180) in Figure 4-10. In Figure 4-21, the vertical axis represents intensity and the horizontal axis represents magnetic flux density (G). Water was used as the measurement solvent. As shown in the figure, the spectra of the TLC1 spot sample and peak 2 (Mw=180) in Figure 4-10 overlap almost completely, and the peak positions are almost completely identical in both cases. Both the TLC1 spot sample and peak 2 (Mw=180) in Figure 4-10 showed the spectrum of DMPO (spin trap agent) characterized by six lines. This spectral pattern is similar to that of ozonide.

[0480] Figure 4-22 shows the ESR spectrum of ozonized methyl linolenate. Acetone was used as the measurement solvent. Ozonized methyl linolenate is a known ozonide. As shown in the figure, the ESR spectrum of ozonized methyl linolenate shows a spectrum with DMPO (spin trap agent) that features six lines, which are characteristic of ozonides. This spectral pattern is similar to that of the TLC1 spot and peak 2 (Mw=180) in Figure 4-21.

[0481] Figure 4-23 shows the ESR spectrum of peaks 1 to 8 in Figure 4-10. Water was used as the measurement solvent. The top image shows the ESR spectrum of a blank (solvent only) for comparison. As shown in the figure, it was confirmed that all of the components in peaks 1 to 8 have radical activity.

[0482] The graph in Figure 4-24 shows the results of measuring the activity of peaks 1 to 8 in Figure 4-10 by chemiluminescence. In this figure, the vertical axis represents the luminescence intensity (relative intensity) at all wavelengths. The numbers "1" to "8" on the horizontal axis represent each fraction of peaks 1 to 8. The numbers below each number represent the molecular weight of each fraction confirmed by mass spectrometry. As shown in the figure, it was confirmed that components other than the one with a molecular weight of 180 were produced that showed activity by chemiluminescence.

[0483] Although the present invention has been described above with reference to the embodiments and examples, the present invention is not limited to the above-described embodiments and examples. Various modifications that can be understood by those skilled in the art can be made to the configuration and details of the present invention within the scope of the present invention.

[0484] This application claims priority based on Japanese Patent Application No. 2021-134732 filed on August 20, 2021, Japanese Patent Application No. 2021-195536 filed on December 1, 2021, Japanese Patent Application No. 2021-202053 filed on December 13, 2021, and Japanese Patent Application No. 2021-212094 filed on December 27, 2021, the disclosures of which are incorporated herein in their entireties.

[0485] <Additional Notes> Some or all of the above-described embodiments and examples can be described as, but are not limited to, the following supplementary notes. (Appendix 1) A cyclic peroxide characterized by being represented by the following chemical formula (I): [ka] In the chemical formula (I), R100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different. (Appendix 2) In the chemical formula (I), R 100 The cyclic peroxide according to Appendix 1, wherein the ring structure has 5 to 10 ring members. (Appendix 3) A cyclic peroxide according to appendix 1 or 2, represented by the following chemical formula (II): [ka] In the above chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S). (Appendix 4) R in the above chemical formula (II) 11 wherein the substituent is a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen atom, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group). (Appendix 5) A cyclic peroxide according to any one of appendices 1 to 4, represented by the following chemical formula (1): [ka] (Appendix 6) An oxidation reaction product comprising a cyclic peroxide, the oxidation reaction product being obtained by oxidizing an alcohol. (Appendix 7) 7. The oxidation reaction product according to claim 6, wherein the alcohol is oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation. (Appendix 8) 8. The oxidation reaction product according to claim 6 or 7, which is a mixture containing a plurality of oxidation reaction products. (Appendix 9) 9. The oxidation reaction product according to any one of claims 6 to 8, having oxidizing ability. (Appendix 10) 10. The oxidation reaction product according to any one of claims 6 to 9, having reducing ability. (Appendix 11) 11. The oxidation reaction product of any one of claims 6 to 10, comprising a TRP channel active substance. (Appendix 12) 12. The oxidation reaction product according to any one of claims 6 to 11, wherein the alcohol is a saturated alcohol. (Appendix 13) 13. The oxidation reaction product according to any one of claims 6 to 12, wherein the alcohol is a polyhydric alcohol. (Appendix 14) 14. The oxidation reaction product according to any one of claims 6 to 13, wherein the alcohol is at least one of glycerin and a glycerin derivative. (Appendix 15) 15. The oxidation reaction product according to any one of claims 6 to 14, comprising an oxidation reaction product obtained by bonding two or more molecules of the alcohol. (Appendix 16) 16. The oxidation reaction product of any one of claims 6 to 15, comprising a cyclic peroxide of any one of claims 1 to 5. (Appendix 17) 17. A method for producing an oxidation reaction product according to any one of claims 6 to 16, comprising an alcohol oxidation step of oxidizing the alcohol. (Appendix 18) 18. The method for producing an oxidation reaction product according to claim 17, wherein the alcohol is oxidized by at least one of ozone oxidation and hydrogen peroxide oxidation in the alcohol oxidation step. (Appendix 19) 19. The method for producing an oxidation reaction product according to claim 17 or 18, wherein the reaction time in the alcohol oxidation step is 24 hours or longer. <Whitening composition> (Appendix 20) Contains glycerin and / or a glycerin derivative and a whitening ingredient, A whitening composition, wherein the whitening ingredient comprises, as an active ingredient, a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different. (Appendix 21) In the chemical formula (I), R 100 is a cyclic structure having 5 to 10 ring members. (Appendix 22) The whitening composition according to Appendix 20 or 21, wherein the cyclic peroxide represented by chemical formula (I) is represented by the following chemical formula (II): [ka] In the above chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S). (Appendix 23) R in the above chemical formula (II) 11wherein the substituents are a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group). (Appendix 24) A whitening composition according to any one of Appendices 20 to 23, wherein the cyclic peroxide represented by chemical formula (I) is represented by the following chemical formula (1): [ka] (Appendix 25) Contains glycerin and / or a glycerin derivative and a whitening ingredient, The whitening composition comprises, as an active ingredient, an oxidation reaction product containing a cyclic peroxide or a salt thereof obtained by oxidizing an alcohol. (Appendix 26) 26. The whitening composition according to claim 25, wherein the oxidation of the alcohol is at least one of ozone oxidation and hydrogen peroxide oxidation. (Appendix 27) 27. The whitening composition according to claim 25 or 26, which is a mixture containing multiple oxidation reaction products. (Appendix 28) 28. The whitening composition according to any one of claims 25 to 27, wherein the oxidation reaction product has oxidizing ability. (Appendix 29) 29. The whitening composition according to any one of claims 25 to 28, wherein the oxidation reaction product has reducing ability. (Appendix 30) 30. The whitening composition according to any one of claims 25 to 29, wherein the oxidation reaction product has melanin decomposition activity, melanin production inhibition activity, and / or melanin excretion promotion activity. (Appendix 31) 31. The whitening composition according to any one of claims 25 to 30, wherein the alcohol is a saturated alcohol. (Appendix 32) 32. The whitening composition according to any one of claims 25 to 31, wherein the alcohol is a polyhydric alcohol. (Appendix 33) 33. The whitening composition according to any one of claims 25 to 32, wherein the alcohol is at least one of glycerin and a glycerin derivative. (Appendix 34) 34. The whitening composition according to any one of claims 25 to 33, comprising an oxidation reaction product obtained by bonding two or more molecules of the alcohol. (Appendix 35) 35. A whitening composition according to any one of claims 25 to 34, comprising a cyclic peroxide according to any one of claims 20 to 24. (Appendix 36) A whitening composition according to any one of Appendices 20 to 35, for use on the skin. (Appendix 37) 37. A whitening composition according to any one of Appendices 20 to 36, wherein the composition is a cosmetic. <Whitening agent> (Appendix 38) A skin whitening agent comprising a cyclic peroxide represented by the following chemical formula (I) or a salt thereof: [ka] In the chemical formula (I), R 100 represents a cyclic structure having 3 or more ring members, which may be saturated or unsaturated, may be an aromatic ring or a non-aromatic ring, may or may not have a heteroatom other than the oxygen atom in the chemical formula (I) in the cyclic structure, and may be a single ring or a condensed ring, R 1 is a substituent, and may be one, multiple, or absent, and when multiple, they may be the same or different. (Appendix 39) In the chemical formula (I), R 100 is a cyclic structure having 5 to 10 ring members. (Appendix 40) The whitening agent according to Appendix 38 or 39, wherein the cyclic peroxide represented by chemical formula (I) is represented by the following chemical formula (II): [ka] In the above chemical formula (II), Each R 11 may be the same or different, and each is a hydrogen atom or a substituent. Two R 11 may be taken together to form an oxo group (=O) or a thioxo group (=S). (Appendix 41) R in the above chemical formula (II) 11 wherein the substituents are a hydroxyl group (-OH), an aldehyde group (formyl group), a hydroxyalkyl group, a sulfo group, a nitro group, a diazo group, an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a mercapto group (-SH), or an alkylthio group (-SR, where R is an alkyl group). (Appendix 42) 42. The whitening agent according to any one of Appendices 38 to 41, wherein the cyclic peroxide represented by chemical formula (I) is represented by the following chemical formula (1): [ka] (Appendix 43) A skin whitening agent comprising an oxidation reaction product containing a cyclic peroxide or a salt thereof, which is obtained by oxidizing an alcohol. (Appendix 44) 44. The skin whitening agent according to claim 43, wherein the oxidation of the alcohol is at least one of ozone oxidation and hydrogen peroxide oxidation. (Appendix 45) 45. The skin whitening agent according to claim 43 or 44, which is a mixture containing multiple oxidation reaction products. (Appendix 46) 46. ​​The whitening agent according to any one of claims 43 to 45, wherein the oxidation reaction product has oxidizing ability. (Appendix 47) 47. The whitening agent according to any one of claims 43 to 46, wherein the oxidation reaction product has reducing ability. (Appendix 48) 48. The skin whitening agent according to any one of claims 43 to 47, wherein the oxidation reaction product has melanin decomposition activity, melanin production inhibitory activity, and / or melanin excretion promoting activity. (Appendix 49) 49. The skin whitening agent according to any one of claims 43 to 48, wherein the alcohol is a saturated alcohol. (Appendix 50) 50. The whitening agent according to any one of claims 43 to 49, wherein the alcohol is a polyhydric alcohol. (Appendix 51) 51. The whitening agent according to any one of claims 43 to 50, wherein the alcohol is at least one of glycerin and a glycerin derivative. (Appendix 52) 52. The whitening agent according to any one of Appendices 43 to 51, comprising an oxidation reaction product obtained by bonding two or more molecules of the alcohol. (Appendix 53) 53. The skin whitening agent according to any one of Appendices 43 to 52, comprising a cyclic peroxide according to any one of Appendices 38 to 42. (Appendix 54) A skin whitening agent according to any one of Appendices 38 to 53, for use on the skin. <Whitening method> (Appendix 55) A method for whitening using a whitening composition according to any one of Appendices 20 to 37 and / or a whitening agent according to any one of Appendices 38 to 54. (Appendix 56) 56. The whitening method of claim 55, wherein the whitening composition and / or the whitening agent is applied to the skin of a subject. <Use> (Appendix 57) A whitening composition according to any one of Appendices 20 to 37 and / or a whitening agent according to any one ...

Claims

1. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, A profilaggrin mRNA expression promoter, characterized by having an effect of promoting the expression of profilaggrin mRNA that produces profilaggrin from the profilaggrin gene. 【Chemical 1】

2. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, An involucrin mRNA expression promoter characterized by having an effect of promoting the expression of involucrin mRNA, which produces involucrin from the involucrin gene. 【Chemistry 2】

3. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, A serine palmitoyltransferase mRNA expression promoter, characterized by having an activity of promoting the expression of serine palmitoyltransferase mRNA that produces serine palmitoyltransferase from a serine palmitoyltransferase gene. 【Chemistry 3】

4. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, A heme oxygenase 1 mRNA expression promoter, characterized by having an effect of promoting the expression of heme oxygenase 1 mRNA, which produces heme oxygenase 1 from the heme oxygenase 1 gene. 【Chemistry 4】

5. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, An NAD(P)H quinone oxidoreductase 1 mRNA expression promoter, characterized by having an effect of promoting the expression of NAD(P)H quinone oxidoreductase 1 mRNA, which produces NAD(P)H quinone oxidoreductase 1 from the NAD(P)H quinone oxidoreductase 1 gene. 【Chemistry 5】

6. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, A glutathione production promoter characterized by having an action of promoting glutathione production. 【Chemistry 6】

7. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, An IL-1α production inhibitor characterized by having an IL-1α production inhibitory effect. 【Chemistry 7】

8. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, Prostaglandin E ２ Prostaglandin E, characterized by its production inhibitory effect ２ Production inhibitor. 【Chemistry 8】

9. The present invention comprises a cyclic peroxide represented by the following chemical formula (1), and an ozone oxidation reaction product of glycerin obtained by oxidizing glycerin having a concentration of 75% by weight to 98.5% by weight with ozone for 24 hours or more, An anti-glycation agent characterized by having an effect of cleaving cross-linked structures between polypeptides and / or proteins formed by glycation reactions. 【Chemistry 9】

10. The agent according to any one of claims 1 to 9, wherein the ozone oxidation reaction product of glycerin contains the cyclic peroxide represented by chemical formula (1) and is an ozone oxidation reaction product of glycerin obtained by ozone oxidizing glycerin at a concentration of 75 wt% to 98.5 wt% for 24 hours or more and less than 7 days.

11. A cosmetic preparation containing the agent according to any one of claims 1 to 9.

12. A skin external preparation containing the agent according to any one of claims 1 to 9.

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