Method for suppressing expression of neutrophil adhesion promoter, method for preventing or improving wrinkle and / or flabbiness of skin, and agent for preventing or improving wrinkle and / or flabbiness of skin, and skin external composition kit

Abstract

To provide a novel technique for suppressing the expression of a neutrophil adhesion promoter and, preferably, to also provide a novel technique for preventing or improving wrinkle and / or flabbiness of skin.SOLUTION: A method for suppressing the expression of a neutrophil adhesion promoter includes applying red light onto cells or the skin.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for inhibiting the expression of a neutrophil adhesion promoting factor. [Background technology]

[0002] The skin is composed of the epidermis, dermis, and subcutaneous tissue (fatty layer). The epidermis protects the body from external dryness and foreign substances, the subcutaneous tissue cushions external shocks with subcutaneous fat, and the dermis is composed of fibroblasts and the extracellular matrix that is located outside these cells and supports the skin structure, and plays an important role in maintaining the structure of the skin. Collagen and elastin in the extracellular matrix are important components that maintain the firmness and elasticity of the skin. Due to aging and ultraviolet rays, etc., proteolytic enzymes such as matrix metalloproteinase and elastase are secreted from skin cells and neutrophils in the skin, causing the breakdown of collagen and elastin. It is widely known that this reduces the elasticity of the skin, resulting in wrinkles and sagging of the skin.

[0003] In recent years, ingredients that inhibit elastase activity have been discovered, and various cosmetics containing elastase inhibitors as active ingredients for preventing or improving the formation of wrinkles and sagging have been disclosed (Patent Documents 1 to 4). The present applicant has also reported cosmetics and topical preparations that contain an inhibitor of neutrophil elastase, which is secreted from neutrophils, and that are effective in preventing and improving the formation of wrinkles and sagging skin (Patent Document 5). Neutrophil elastase is known not only to directly degrade elastin, but also to be indirectly involved in the degradation of collagen by activating a type of matrix metalloproteinase (MAP-1 and MAP-2) (Non-Patent Document 1).

[0004] Neutrophils secrete neutrophil elastase, and infiltrate into skin tissue through multiple stages. First, neutrophils are captured by vascular endothelial cells in the skin, roll along the blood vessels, and adhere to them. They then pass through the vascular endothelial cells (transmigration), migrate out of the blood vessels (diapedesis), and infiltrate into the skin. As the captured neutrophils roll on the vascular endothelial cells, the conformation of integrins on their surfaces changes, and their affinity for ligands present on the surfaces of the vascular endothelial cells increases. As a result, the neutrophils adhere to the vascular endothelial cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are known as ligands (neutrophil adhesion promoters) on vascular endothelial cells that play an important role in this adhesion process (Non-Patent Document 2).

[0005] Incidentally, there is a mesh-like fibrous structure called the retinacula cutis in the subcutaneous tissue. It is known that the retinacula cutis is related to facial sagging (Non-Patent Document 3). It is also known that the density of the retinacula cutis is reduced in the subcutaneous tissue immediately below deep wrinkles such as the forehead and corners of the eyes (Non-Patent Document 4).

[0006] Microfibril-associated glycoprotein 4 (MFAP4) is known to be a component of the retinaculum of the skin. It is known that the amount of MFAP4 present is reduced in the subcutaneous tissue that has been subjected to photoaging. It has also been suggested that the loss of elasticity of skin tissue caused by photoaging can be prevented by improving the expression of MFAP4 or inhibiting its degradation, thereby improving wrinkles and sagging (Non-Patent Document 5).

[0007] Meanwhile, in recent years, it has become clear that light in the long wavelength region of visible light has anti-aging effects based on cell proliferation enhancement, collagen synthesis enhancement, vascular endothelial proliferation, etc. It is already widely known that ultraviolet rays, which are light rays near visible light on the shorter wavelength side than visible light, have adverse effects on the skin, and many measures have been proposed to protect the skin from ultraviolet rays. In addition, infrared rays, which are light rays near visible light on the longer wavelength side than visible light, are divided into near infrared rays (approximately 0.76 to 2.5 μm), mid infrared rays (approximately 2.5 to 4 μm), and far infrared rays (approximately 4 to 1000 μm) depending on the wavelength, and it has been confirmed that near infrared rays in particular damage the dermis and subcutaneous tissue and are deeply involved in skin aging, etc. Therefore, it is important to effectively protect the skin from near infrared rays as well as ultraviolet rays.

[0008] As a cosmetic for protecting the skin from near-infrared rays, for example, an oil-in-water emulsion cosmetic containing titanium dioxide having a specific average particle size and inorganic plate-like powder has been proposed (for example, Patent Document 6). However, with conventional near-infrared shielding technology, there was an issue that when near-infrared rays are blocked, the long wavelength region of visible light that is useful for the skin is also blocked significantly. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] JP 2002-205950 A [Patent Document 2] JP 2009-191043 A [Patent Document 3] JP 2013-006815 A [Patent Document 4] JP 2019-81726 A [Patent Document 5] International Publication No. 2017 / 221973 [Patent Document 6] JP 2015-86157 A [Non-patent literature]

[0010] [Non-Patent Document 1] Takeuchi H., et al.: “Neutrophil elastase contributes to extracellular matrix damage induced by chronic low-dose UV irradiation in a hairless mouse photoaging model”, J Dermatol Science. (2010), 60, 151-158 [Non-Patent Document 2] Journal of the Japanese Society of Clinical Immunology, vol.33, No.5, 242-248 [Non-Patent Document 3] Sakata A., et al.:”Breakthrough in improving the skin sagging with focusing on the subcutaneous tissue structure, retinacula cutis”, 23rd IFSCC, Zurich(2015) [Non-Patent Document 4] Tsukahara K. et al.,Arch Dermatol.(2012),148,39-46 [Non-Patent Document 5] Scientific Reports volume 1,Article number:164(2011) Summary of the Invention [Problem to be solved by the invention]

[0011] Neutrophils infiltrate into skin tissues from vascular endothelial cells, secrete neutrophil elastase, and directly degrade elastin and indirectly degrade collagen, causing wrinkles and sagging of the skin. As mentioned above, neutrophil adhesion promoters present on vascular endothelial cells play an important role in the firm adhesion process of neutrophil infiltration. If the expression of this neutrophil adhesion promoter can be inhibited, neutrophil infiltration can be inhibited, and thus the secretion of neutrophil elastase and the degradation of elastin and collagen after infiltration can be inhibited. In view of the above, an object of the present invention is to provide a novel technique for suppressing the expression of neutrophil adhesion promoting factor, and preferably a novel technique for preventing or improving wrinkles and sagging skin. [Means for solving the problem]

[0012] Through intensive research efforts, the present inventors have newly discovered that the expression of neutrophil adhesion promoting factor can be suppressed by applying red light, which is light in the long wavelength region of visible light, to cells or skin. The present invention was completed based on this new finding. That is, the present invention, which solves the above-mentioned problems, provides a method for inhibiting expression of a neutrophil adhesion promoting factor, which comprises applying red light to cells or skin.

[0013] In a preferred embodiment of the present invention, the neutrophil adhesion promoting factor is intercellular adhesion molecule-1 (ICAM-1) and / or vascular cell adhesion molecule-1 (VCAM-1). Application of red light can suppress the expression of ICAM-1 and / or VCAM-1, which play an important role in the adhesion of neutrophils to vascular endothelial cells.

[0014] In a preferred embodiment of the invention, the cells are vascular endothelial cells. Neutrophil adhesion promoting factor acts as a ligand when expressed on vascular endothelial cells. According to the present invention, the expression of neutrophil adhesion promoting factor that acts as a ligand on vascular endothelial cells can be inhibited.

[0015] A preferred embodiment of the present invention is a method for inhibiting neutrophil infiltration. In the adhesion process of neutrophil infiltration, neutrophil adhesion promoting factor plays an important role. According to the method of the present invention, the expression of neutrophil adhesion promoting factor, which plays an important role in the process of neutrophil infiltration, can be inhibited, and therefore, it is preferable to apply the method to inhibit neutrophil infiltration.

[0016] A preferred embodiment of the present invention is a cosmetic method for anti-aging of the skin (excluding medical procedures). Application of red light suppresses the expression of neutrophil adhesion promoters, thereby suppressing the infiltration of neutrophils into skin tissues. This suppresses the degradation of elastin and collagen by neutrophil elastase secreted by infiltrated neutrophils, which is one of the causes of skin aging (formation of wrinkles and sagging). For this reason, the present invention is preferably applied to a cosmetic method for anti-aging of the skin.

[0017] In a preferred embodiment of the present invention, red light is applied to an object by irradiating the object with light through a member having optical properties that block near-infrared light and transmit red light. By configuring the light to be irradiated through a component having the optical properties described above, a good effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained even if the irradiated light is not only red light but also near-infrared light (e.g., sunlight).

[0018] In a preferred embodiment of the present invention, an article provided with the member is attached to an object to which red light is to be applied, and light is irradiated through the member, thereby applying the red light to the object. According to this aspect of the invention, the effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained in a subject wearing the article.

[0019] In a preferred embodiment of the present invention, the article is spectacles or sunglasses having lenses made of the member. According to this aspect of the present invention, it is possible to obtain an effect of suppressing the expression of neutrophil adhesion promoting factor in the skin around the eyes that is exposed to light passing through eyeglasses or sunglasses.

[0020] In a preferred embodiment of the present invention, an object to which red light is to be applied is placed in a space in which at least a portion of the walls or ceiling are formed from the above-mentioned member, and the red light is applied to the object by irradiating the light through the above-mentioned member. According to this aspect of the present invention, it is possible to obtain an effect of suppressing the expression of neutrophil adhesion promoting factor in an application subject placed in the space.

[0021] In a preferred embodiment of the present invention, the space is an interior space or a vehicle interior space. The effect of suppressing the expression of neutrophil adhesion promoting factor can be achieved simply by being indoors or in a car.

[0022] The present invention also relates to a device for inhibiting the expression of a neutrophil adhesion-promoting factor, characterized in that the device has the optical properties of blocking near-infrared light and transmitting red light, and is used for the above-mentioned method. By irradiating light through the member of the present invention, red light can be applied to the target object, and the effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained.

[0023] The present invention also relates to an article for suppressing the expression of a neutrophil adhesion-promoting factor, which is a body wearable device comprising the above-mentioned member and is used for the method according to claim 7 or 8. When the article of the present invention is worn, red light is irradiated onto the body of the subject through the member, and the effect of suppressing the expression of neutrophil adhesion promoting factor is obtained.

[0024] In a preferred embodiment of the present invention, the body wearable device is spectacles or sunglasses having lenses made of the above-mentioned member. According to this aspect of the present invention, it is possible to obtain an effect of suppressing the expression of neutrophil adhesion promoting factor in the skin around the eyes that is exposed to light passing through eyeglasses or sunglasses.

[0025] The present invention also relates to a structure for inhibiting the expression of neutrophil adhesion promoting factor, characterized in that at least a portion of the wall or ceiling has a space formed by the above-mentioned material and is used for the above-mentioned method. By spending time in the space, the effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained.

[0026] In a preferred form of the invention, it is a building or a vehicle. By simply going about one's daily life using the building or vehicle of the present invention, the effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained.

[0027] The present invention also provides a method for treating a skin cancer, comprising: A neutrophil elastase inhibitor application step of applying a neutrophil elastase inhibitor to the skin; The present invention also relates to a method for preventing or improving wrinkles and sagging (excluding medical procedures), comprising: Irradiation with red light suppresses the expression of neutrophil adhesion promoters, which in turn suppresses the infiltration of neutrophils into skin tissue. Application of a neutrophil elastase inhibitor also suppresses the decomposition of elastin and collagen by neutrophil elastase secreted by infiltrated neutrophils. In other words, by combining the light irradiation step with the neutrophil elastase inhibitor application step, it is possible to inhibit the upstream and downstream of the series of pathways that lead to the formation of wrinkles and sagging, which include the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase.

[0028] Furthermore, the following effects can be obtained by irradiating red light. -Improves the expression of MFAP4, a component of the cutaneous retinaculum. -Suppression of the expression of matrix metalloproteinases that degrade MFAP4. - Promotes proliferation of MFAP4-producing tendon cells. In other words, the effect of strengthening the retinaculum can be obtained by irradiating the skin with red light.

[0029] As described above, the present invention, by comprising a light irradiation step and a neutrophil elastase inhibitor application step, inhibits the causes of wrinkle and sagging in a multifaceted manner, thereby effectively preventing or improving wrinkles and sagging.

[0030] In a preferred embodiment of the present invention, the neutrophil elastase inhibitor is a compound represented by the following general formula (1), an isomer thereof, and / or a pharmacologically acceptable salt thereof.

[0031] [ka]

[0032] In general formula (1), R1 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylate group having an alkyl chain having 1 to 4 carbon atoms, and R2 and R3 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

[0033] In a preferred embodiment of the present invention, the compound represented by the above general formula (1) is a compound represented by the following general formula (2), an isomer thereof, and / or a pharmacologically acceptable salt thereof.

[0034] [ka]

[0035] In general formula (2), R4 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R5 and R6 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

[0036] In a preferred embodiment of the present invention, the compound represented by the above general formula (2) is 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the following formula (3), an isomer thereof, and / or a pharmacologically acceptable salt thereof.

[0037] [ka]

[0038] By applying the compound represented by general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, more preferably the compound represented by general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof, and further preferably the compound represented by formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof, a more effective effect of preventing or improving wrinkles and sagging can be achieved.

[0039] Moreover, in recent years, it has been confirmed that infrared rays, particularly near-infrared rays, cause damage to the dermis and subcutaneous tissue and are deeply involved in skin aging, etc. Through the intensive research efforts of the present inventors, it has been discovered that application of near-infrared rays to cells increases the expression of neutrophil adhesion promoting factor. In other words, by applying red light while blocking near-infrared light, a more effective inhibitory effect on the expression of neutrophil adhesion promoting factor can be obtained. Therefore, the present invention provides a method for treating a skin cancer by using a light irradiation process, comprising: In addition to the neutrophil elastase inhibitor application step of applying a neutrophil elastase inhibitor to the skin, it is preferable to have a light scattering agent application step of applying a light scattering agent that blocks near-infrared rays to the skin.

[0040] In a preferred embodiment of the present invention, the light scattering agent is titanium oxide having an average particle size of 0.5 μm or more, In the light scattering agent application step, a) 25% by mass or more of the above-mentioned titanium oxide based on the total powder amount excluding the ultraviolet scattering agent; and b) spherical powder; A composition for external use on the skin, in which the difference between the "light shielding rate of 585 to 760 nm wavelength" and the "light shielding rate of 760 to 1310 nm wavelength" is 10% or less and the "light shielding rate of 760 to 1310 nm wavelength" is 30% or more, is applied to the skin. By using such a form, near-infrared light can be more effectively blocked and red light can be more effectively applied to the skin, thereby obtaining an even more excellent effect of suppressing the expression of neutrophil adhesion promoting factor, and ultimately an effect of preventing or improving wrinkles and sagging.

[0041] Furthermore, the following effects can be obtained by irradiating red light. -Improves the expression of MFAP4, a component of the cutaneous retinaculum. -Suppression of the expression of matrix metalloproteinases that degrade MFAP4. - Promotes proliferation of MFAP4-producing tendon cells. In other words, the effect of strengthening the retinaculum can be obtained by irradiating the skin with red light.

[0042] In a preferred embodiment of the present invention, the light irradiating step is carried out after the light scattering agent applying step, In the light irradiation step, sunlight containing the red light is irradiated. Naturally, sunlight contains red light and near infrared light. By carrying out a light irradiation step of irradiating the skin with sunlight after the light scattering agent application step, it is possible to apply red light to the skin while blocking the near infrared light contained in sunlight, thereby obtaining a more excellent effect of preventing or improving wrinkles and sagging.

[0043] In a preferred embodiment of the present invention, the expression of neutrophil adhesion promoting factor is suppressed by irradiation with red light in the light irradiation step. By inhibiting the expression of neutrophil adhesion promoting factor, it is possible to inhibit neutrophil infiltration and the subsequent degradation of elastin and collagen by neutrophil elastase, thereby obtaining the effect of preventing or improving wrinkles and sagging.

[0044] In a preferred embodiment of the present invention, the neutrophil elastase inhibitor is a compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, more preferably a compound represented by the above general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof, and even more preferably a compound represented by the above formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof.

[0045] Incidentally, the decomposition of elastin and collagen by neutrophil elastase secreted by infiltrated neutrophils is suppressed by application of the compound represented by the above general formula (1), its isomers and / or their pharmacologically acceptable salts. In addition, the expression of neutrophil adhesion promoter is suppressed by irradiation with red light, and thus the infiltration of neutrophils into skin tissue is suppressed. In other words, by using the compound represented by the above general formula (1), its isomers and / or their pharmacologically acceptable salts in the manner of "applying to the skin and then applying red light", it is possible to inhibit the upstream and downstream of a series of pathways leading to the formation of wrinkles and sagging, which are the suppression of the decomposition of elastin and collagen by neutrophil elastase and the suppression of neutrophil infiltration.

[0046] Furthermore, by applying red light, the following effects can be obtained. -Improves the expression of MFAP4, a component of the cutaneous retinaculum. -Suppression of the expression of matrix metalloproteinases that degrade MFAP4. - Promotes proliferation of MFAP4-producing tendon cells. In other words, the above-mentioned method can provide the effect of strengthening the retinaculum.

[0047] As described above, the present invention uses the compound represented by the above-mentioned general formula (1), its isomer and / or a pharmacologically acceptable salt thereof in the manner of "applying the compound to the skin and then applying red light", thereby inhibiting the factors that cause wrinkles and sagging in a multifaceted manner, and effectively preventing or improving wrinkles and sagging. As a result, the agent of the present invention exhibits a superior effect in preventing or improving wrinkles and sagging compared to known agents.

[0048] In a preferred embodiment of the present invention, the neutrophil elastase inhibitor is a compound represented by the above general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof, and more preferably a compound represented by the above formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof.

[0049] The present invention also relates to a composition comprising the above-mentioned neutrophil elastase inhibitor and A light scattering agent that blocks near infrared rays, The present invention also relates to an agent for preventing or improving wrinkles and sagging skin, which is characterized in that it is used by applying red light to the skin after application. By using the above-mentioned neutrophil elastase inhibitor in a method of applying red light after application to the skin, it is possible to inhibit the upstream and downstream of a series of pathways leading to the formation of wrinkles and sagging, including the inhibition of neutrophil infiltration and the decomposition of elastin by neutrophil elastase. In addition, by blocking near-infrared rays, the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light can be enhanced, and a more excellent effect of preventing or improving wrinkles and sagging can be obtained. In other words, the agent for preventing or improving wrinkles and sagging of the present invention has multiple components that can provide excellent effects, and therefore exerts a remarkable effect of preventing or improving wrinkles and sagging.

[0050] In a preferred embodiment of the present invention, the light scattering agent is titanium oxide having an average particle size of 0.5 μm or more, a) 25% by mass or more of the above-mentioned titanium oxide based on the total powder amount excluding the ultraviolet scattering agent; and b) spherical powder; The difference between the "light blocking rate of 585 to 760 nm wavelengths" and the "light blocking rate of 760 to 1310 nm wavelengths" is 10% or less, and the "light blocking rate of 760 to 1310 nm wavelengths" is 30% or more. By using such a form, near-infrared light can be more effectively blocked and red light can be more effectively applied to the skin, thereby obtaining an even more excellent effect of suppressing the expression of neutrophil adhesion promoting factor, and ultimately an effect of preventing or improving wrinkles and sagging.

[0051] Furthermore, by applying red light, the following effects can be obtained. -Improves the expression of MFAP4, a component of the cutaneous retinaculum. -Suppression of the expression of matrix metalloproteinases that degrade MFAP4. - Promotes proliferation of MFAP4-producing tendon cells. In other words, the above-mentioned method can provide the effect of strengthening the retinaculum.

[0052] In a preferred embodiment of the present invention, the composition is used by applying it to the skin and then irradiating it with sunlight containing red light. Naturally, sunlight contains red light and near infrared light. By applying the composition to the skin and then irradiating the skin with sunlight, it is possible to apply red light to the skin while blocking the near infrared light contained in sunlight, thereby achieving a more excellent effect in preventing or improving wrinkles and sagging.

[0053] In a preferred embodiment of the present invention, the above-mentioned application of red light is used to suppress the expression of neutrophil adhesion promoting factor. By inhibiting the expression of neutrophil adhesion promoting factor, it is possible to inhibit neutrophil infiltration and the subsequent degradation of elastin and collagen by neutrophil elastase, thereby obtaining the effect of preventing or improving wrinkles and sagging.

[0054] The present invention also relates to a first skin external composition containing the above-mentioned wrinkle prevention or amelioration agent, The present invention also relates to a skin topical composition kit, which is characterized in that it comprises a second skin topical composition containing a light scattering agent that blocks near-infrared light, and is used by applying red light to the skin after applying the first and second skin topical compositions to the skin. In a method of application in which red light is applied after application to the skin, the second skin topical composition is applied to block near-infrared rays, thereby enhancing the effect of suppressing the expression of neutrophil adhesion promoting factor by application of red light. In addition, by using the first skin topical composition containing an agent for preventing or improving wrinkles and sagging, it is possible to inhibit the upstream and downstream of a series of pathways leading to the formation of wrinkles and sagging, including the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase. In other words, the skin topical composition kit of the present invention has multiple components that can provide excellent effects, and therefore exerts a significant effect of preventing or improving wrinkles and sagging.

[0055] In a preferred embodiment of the present invention, the light scattering agent is titanium oxide having an average particle size of 0.5 μm or more, The second composition for topical application to the skin is a) 25% by mass or more of the above-mentioned titanium oxide based on the total powder amount excluding the ultraviolet scattering agent; and b) spherical powder; The difference between the "light blocking rate of 585 to 760 nm wavelengths" and the "light blocking rate of 760 to 1310 nm wavelengths" is 10% or less, and the "light blocking rate of 760 to 1310 nm wavelengths" is 30% or more. By using such a form, the near-infrared light contained in sunlight can be more effectively blocked and the red light contained in sunlight can be more effectively applied to the skin, thereby obtaining an even more excellent effect of suppressing the expression of neutrophil adhesion promoting factor, and ultimately an effect of preventing or improving wrinkles and sagging.

[0056] Furthermore, by applying red light, the following effects can be obtained. -Improves the expression of MFAP4, a component of the cutaneous retinaculum. -Suppression of the expression of matrix metalloproteinases that degrade MFAP4. - Promotes proliferation of MFAP4-producing tendon cells. In other words, the above-mentioned method can provide the effect of strengthening the retinaculum.

[0057] In a preferred embodiment of the present invention, the first and second skin topical compositions are applied to the skin, followed by application of sunlight containing red light to the skin. Naturally, sunlight contains red light and near infrared rays. By using the skin topical composition kit of the present invention in a manner in which the first and second skin topical compositions are applied to the skin and then exposed to sunlight, red light can be applied to the skin while blocking the near infrared rays contained in sunlight, and a more excellent effect of preventing or improving wrinkles and sagging can be obtained.

[0058] In a preferred embodiment of the present invention, the above-mentioned application of red light is used to suppress the expression of neutrophil adhesion promoting factor. By inhibiting the expression of neutrophil adhesion promoting factor, it is possible to inhibit neutrophil infiltration and the subsequent degradation of elastin and collagen by neutrophil elastase, thereby obtaining the effect of preventing or improving wrinkles and sagging.

[0059] The present invention also relates to a second composition for external use on the skin, comprising the above-mentioned light scattering agent that blocks near-infrared rays; The present invention also relates to a skin topical composition kit, characterized by comprising a first skin topical composition containing an agent for preventing or improving wrinkles or sagging. When the skin to which the first and second compositions for external use on the skin are applied is exposed to sunlight, the second composition for external use on the skin acts to block near-infrared radiation contained in sunlight, thereby more strongly inducing the suppression of expression of neutrophil adhesion-promoting factor by red light contained in sunlight, and effectively suppressing the infiltration of neutrophils into the skin and the subsequent degradation of elastin and collagen by neutrophil elastase. Furthermore, the first composition for external use on the skin acts to inhibit the activity of neutrophil elastase secreted from neutrophils, thereby suppressing the degradation of elastin and collagen. In other words, by simply applying the skin topical composition kit of the present invention to the skin and living a normal life exposed to sunlight, it is possible to inhibit the upstream and downstream of a series of pathways that lead to the formation of wrinkles and sagging, including the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase. In other words, the skin topical composition kit of the present invention exerts an excellent effect of preventing or improving wrinkles and sagging.

[0060] In a preferred embodiment of the present invention, the light scattering agent is titanium oxide having an average particle size of 0.5 μm or more, The second composition for topical application to the skin is a) 25% by mass or more of the above-mentioned titanium oxide based on the total powder amount excluding the ultraviolet scattering agent; and b) spherical powder; The difference between the "light blocking rate of 585 to 760 nm wavelengths" and the "light blocking rate of 760 to 1310 nm wavelengths" is 10% or less, and the "light blocking rate of 760 to 1310 nm wavelengths" is 30% or more. By using such a form, the near-infrared light contained in sunlight can be more effectively blocked and the red light contained in sunlight can be more effectively applied to the skin, thereby obtaining an even more excellent effect of suppressing the expression of neutrophil adhesion promoting factor, and ultimately an effect of preventing or improving wrinkles and sagging.

[0061] The present invention also relates to a skin topical composition kit, characterized by comprising a first skin topical composition containing a compound represented by the following general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, and a second skin topical composition containing a light scattering agent that blocks near-infrared radiation.

[0062] [ka]

[0063] In general formula (1), R1 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylate group having an alkyl chain having 1 to 4 carbon atoms, and R2 and R3 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

[0064] When the skin to which the first and second compositions for external use on the skin are applied is exposed to sunlight, the second composition for external use on the skin acts to block near-infrared radiation contained in sunlight, thereby more strongly inducing the suppression of expression of neutrophil adhesion-promoting factor by red light contained in sunlight, and effectively suppressing the infiltration of neutrophils into the skin and the subsequent degradation of elastin and collagen by neutrophil elastase. Furthermore, the first composition for external use on the skin acts to inhibit the activity of neutrophil elastase secreted from neutrophils, thereby suppressing the degradation of elastin and collagen. In other words, by simply applying the skin topical composition kit of the present invention to the skin and living a normal life exposed to sunlight, it is possible to inhibit the upstream and downstream of a series of pathways that lead to the formation of wrinkles and sagging, including the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase. In other words, the skin topical composition kit of the present invention exerts an excellent effect of preventing or improving wrinkles and sagging.

[0065] In a preferred embodiment of the present invention, the light scattering agent is titanium oxide having an average particle size of 0.5 μm or more, The second composition for topical application to the skin is a) 25% by mass or more of the above-mentioned titanium oxide based on the total powder amount excluding the ultraviolet scattering agent; and b) spherical powder; The difference between the "light blocking rate of 585 to 760 nm wavelengths" and the "light blocking rate of 760 to 1310 nm wavelengths" is 10% or less, and the "light blocking rate of 760 to 1310 nm wavelengths" is 30% or more. By using such a form, the near-infrared light contained in sunlight can be more effectively blocked and the red light contained in sunlight can be more effectively applied to the skin, thereby obtaining an even more excellent effect of suppressing the expression of neutrophil adhesion promoting factor, and ultimately an effect of preventing or improving wrinkles and sagging. Effect of the Invention

[0066] According to the present invention, the expression of neutrophil adhesion promoting factor can be suppressed. Furthermore, according to the present invention, the effect of preventing or improving wrinkles and sagging can be obtained. [Brief description of the drawings]

[0067] [Figure 1] 1 is a graph showing the results of Test Example 1. It shows the expression level of ICAM-1 when irradiated with and without red light. [Diagram 2] 1 is a graph showing the results of Test Example 1. It shows the expression level of VCAM-1 when irradiated with and without red light. [Diagram 3] 1 is a graph showing the results of Test 2-1, showing the cell proliferation ratio when red light was irradiated and not irradiated. [Figure 4] 1 is a graph showing the results of Test 2-2, illustrating the relationship between the amount of irradiation with long-wavelength visible light and mitochondrial activity. [Diagram 5] 1 is a graph showing the results of Test 2-2, illustrating the relationship between the amount of irradiation with long-wavelength visible light and the cell proliferation rate. [Figure 6] 1 shows the results of Test 2-3. FIG 1 shows the results of a microarray. [Figure 7] 1 is a graph showing the results of Tests 2-4, showing that MFAP4 is a substrate for matrix metalloproteinases. [Figure 8] 1 is a graph showing the results of Test 2-5, showing the expression level of MFAP4 when irradiated with red light and when not irradiated, and when burdock extract was added and not added. [Figure 9]1 is a graph showing the results of Test Example 3, showing the inhibitory effect of adding cyclohexylglycerin and horsetail extract on the expression of CLCL-1. [Figure 10] 1 is a graph showing the results of Test Example 3, showing the effect of suppressing IL-8 expression by the addition of cyclohexylglycerin and horsetail extract. [Figure 11] 1 is a graph showing the results of Test Example 4. It shows the inhibitory effect of the addition of an oil-soluble peach leaf extract on the expression of ICAM-1 and VCAM-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] Preferred embodiments of the present invention will be described below, however, it goes without saying that the technical scope of the present invention is not limited to the following embodiments. In the following description, unless otherwise specified, the terms used are those defined in JIS Z 8120 "Optical Terms."

[0069] [1] Method for inhibiting expression of neutrophil adhesion promoting factor The present invention relates to a method for inhibiting the expression of a neutrophil adhesion promoting factor, the method comprising applying red light to a cell or skin.

[0070] In this specification, "red light" refers to light of a wavelength that appears red to the naked eye. The red light applied is preferably light having a wavelength of any one of 610 to 780 nm, and more preferably light having a wavelength of any one of 620 to 760 nm. "Red light" includes not only light consisting of a single wavelength, but also composite light containing light of multiple wavelengths.

[0071] The light applied in the present invention may contain the above-mentioned red light. In other words, if the light applied contains a wavelength of light that appears red to the naked eye in its spectrum when it is split, it is included in the technical scope of the present invention. Therefore, for example, irradiating sunlight also falls under the "application of red light". In the present invention, as long as the above-mentioned red light is applied, there is no restriction on the presence or absence of light of other wavelengths.

[0072] It is preferable that the applied light does not include ultraviolet light. It is also preferable that the applied light does not include infrared light, more preferably, near infrared light. It is further preferable that the applied light does not include either ultraviolet light or infrared light.

[0073] The light applied may be artificial light provided by any lighting means, or may be sunlight. When applying artificial light, there is no particular limitation on the type of light source provided in the light projecting means, and it may be, for example, a light emitting diode (LED), a halogen lamp, an HID lamp, an incandescent lamp, a silica lamp, or a mini krypton lamp. Among these, it is preferable to use a light emitting diode (LED). By using a light emitting diode (LED), red light can be applied to cells or skin without damaging the cells.

[0074] When artificial light is applied, light emitted from a red LED may be applied, for example, light emitted from a red LED having a peak wavelength of 625 nm may be applied.

[0075] When sunlight is used, it is acceptable to irradiate the film with sunlight as it is, but it is preferable to block ultraviolet rays. Examples of the ultraviolet ray shielding means include any ultraviolet ray absorbing agent or ultraviolet ray scattering agent. In addition, an optical filter for shielding ultraviolet ray may be used.

[0076] In addition, when sunlight is applied, it is preferable to block infrared rays, and more preferably near-infrared rays. Examples of infrared shielding means include any infrared absorbing agent or infrared scattering agent. Specifically, the description of the second skin external composition described below can be applied. In addition, an optical filter that shields infrared rays may be used.

[0077] Alternatively, a light projecting means (solar simulator) that irradiates artificial sunlight may be used as the light source. In this case, it is preferable to install an optical filter under the light source to cut off light in a specific wavelength range and irradiate light in any wavelength range including red light. For example, it is preferable to use an optical filter to cut light in a wavelength range other than red light emitted from a solar simulator, and to use light in the red range of 620 to 760 nm. An example of a solar simulator is the XHS-8 (manufactured by Spectral Engines). Any optical filter can be used, and for example, filters from various manufacturers such as HOYA, SCHOTT, Shibuya Optical Co., Ltd. A plurality of optical filters may be used in combination.

[0078] In a preferred embodiment of the present invention, cells are irradiated with red light, more preferably light in the wavelength range of 620 to 760 nm, preferably at 10 J / cm 2 More preferably, 20 J / cm 2 More preferably, 30 J / cm 2 More preferably, 40 J / cm 2 More preferably, 50 J / cm 2 Irradiate more than this. By irradiating cells with red light within the above range, the effect of suppressing the expression of neutrophil adhesion promoting factor can be improved.

[0079] In addition, red light, more preferably light in the wavelength range of 620 to 760 nm, is applied to the cells at a dose of preferably 200 J / cm 2 Less than or equal to 150 J / cm 2 Less than 100 J / cm, more preferably 100 J / cm 2 Irradiation will be performed as follows. By irradiating the cells with red light within the above range, the effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained while reducing the burden on the cells.

[0080] The present invention involves applying red light to cells or skin, where "cells" includes cells in culture and tissue culture, as well as cells present in a living animal or human body. Note that inventions in which red light is applied to cells present in the human body do not include methods of treating humans.

[0081] Since the present invention is a method for inhibiting the expression of a neutrophil adhesion promoting factor, it is preferable to apply red light to cells expressing the neutrophil adhesion promoting factor. Therefore, in a preferred embodiment of the present invention, it is preferable to apply red light to vascular endothelial cells. It should be noted that the "vascular endothelial cells" referred to here include not only "cultured vascular endothelial cells" but also "vascular endothelial cells present in a living body."

[0082] The present invention may be implemented in a form in which red light is irradiated onto cultured vascular endothelial cells, or in a form in which red light is irradiated onto vascular endothelial cells present in a living body. When applied to a living body, it is preferable to irradiate red light onto vascular endothelial cells constituting the endothelium of blood vessels present in skin tissue. When irradiating vascular endothelial cells with red light, one method is to insert an optical fiber into the blood vessels in the skin and irradiate them directly. However, because red light penetrates deep into the skin even when irradiated to the surface of the skin, a simpler method is to irradiate the red light directly to the surface of the skin.

[0083] Specific examples of neutrophil adhesion-promoting factors whose expression is inhibited by irradiation with red light include intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). ICAM-1 and VCAM-1 are ligands expressed on vascular endothelial cells and are proteins that play an important role in neutrophil adhesion.

[0084] By suppressing the expression of neutrophil adhesion promoting factor, the adhesion process required for neutrophils to infiltrate from blood vessels into tissues is suppressed. Therefore, the present invention can be used to suppress neutrophil infiltration. More preferably, the present invention is used to suppress neutrophil infiltration into skin tissues.

[0085] Neutrophils that infiltrate into skin tissue secrete neutrophil elastase. Neutrophil elastase secreted into skin tissue breaks down elastin and collagen, which support the skin structure. This breakdown of elastin and collagen is one of the causes of changes in skin appearance associated with aging, such as a decrease in skin elasticity, loss of skin texture, wrinkles, sagging, and dullness. As mentioned above, application of red light leads to the suppression of expression of neutrophil adhesion promoting factor, thereby inhibiting neutrophil infiltration and the subsequent degradation of elastin and collagen. That is, the present invention can be applied to a cosmetic method for anti-aging of the skin.

[0086] The present invention is preferably a cosmetic method for preventing or improving one or more morphological changes of the skin selected from the group consisting of increased wrinkles and sagging of the skin, loss of firmness, and loss of elasticity of the skin. More preferably, the present invention is a method for preventing or improving wrinkles or sagging skin. Sagging skin refers to deformation of the skin caused by a decrease in the elasticity of the skin and subcutaneous tissue.

[0087] Furthermore, the present invention may be configured such that red light is applied to an application target by irradiating the target with light through a member having optical properties that block near-infrared light and transmit red light. By configuring the light to be irradiated through a component having the optical properties described above, a good effect of suppressing the expression of neutrophil adhesion promoting factor can be obtained even if the irradiated light is not only red light but also near-infrared light (e.g., sunlight).

[0088] The member used in this embodiment has "optical properties of blocking near-infrared light and transmitting red light." Here, "shielding near-infrared rays" refers to shielding at least a part of near-infrared rays, and is not limited to a near-infrared shielding rate of 100%. The near-infrared shielding rate of the member of the present invention is preferably 5% or more, more preferably 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 60% or more, even more preferably 70% or more, even more preferably 80% or more, and even more preferably 90% or more.

[0089] Furthermore, "transmitting red light" refers to transmitting at least a portion of red light, and is not limited to a red light transmittance of 100%. The red light transmittance of the member of the present invention is preferably 5% or more, more preferably 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 60% or more, even more preferably 70% or more, even more preferably 80% or more, and even more preferably 90% or more.

[0090] It is preferable to use a material that has a higher near-infrared shielding rate than red light shielding rate. In other words, it is preferable to use a material whose transmittance for red light is higher than that for near-infrared light.

[0091] There is no limitation on the material or shape of the member as long as it has the above-mentioned optical properties. The material of the member may be glass, resin, metal, metal oxide, or a combination thereof. The member may be in the form of a plate, a film, a fiber, a powder, or a combination thereof.

[0092] Examples of the member of the present invention include a resin containing a near-infrared shielding material such as hexaboride or cesium tungsten oxide, or a near-infrared absorbing organic dye such as 9,10-anthracenedione or 9,10-anthraquinone. Examples of the member of the present invention include a resin film or resin fiber formed by processing the resin. Examples of the member of the present invention include a glass material laminated with the resin film. Conventionally, the resin films have been used for car glass, window materials for houses, eyeglasses, sunglasses, etc., and the resin fibers have been used for heat-shielding curtains, etc., and these can be used as members of the present invention.

[0093] The member is preferably used as an article that can be attached to an application target. That is, an article provided with the member is attached to an application target of red light, and light is irradiated through the member. As a result, the red light that has passed through the member is incident on the application target.

[0094] When the subject of application is a human, the article is preferably a body wearable device. The body-worn device may be spectacles or sunglasses having lenses made of the above-mentioned material. In this case, the lenses are preferably made of a resin containing the above-mentioned near-infrared shielding material or near-infrared absorbing organic dye, or a glass material laminated with the resin film.

[0095] Other examples of body wearable items include sun visors with a brim made of the above-mentioned material, and fabric products (clothes, hats, masks, etc.) made of the above-mentioned material formed into a fibrous form.

[0096] The method of the present invention may be implemented by placing an object to which the red light is to be applied in a space having at least a part of a wall or a ceiling made of the material. In this case, the red light is applied to the object placed in the space by irradiating the light through the material.

[0097] The type of structure having the space is not particularly limited as long as it is a structure having a space in which at least a portion of the wall or ceiling is formed by the above-mentioned material. For example, the structure may be a building. The building may be a residential or non-residential. It is sufficient that at least one wall (including windows) or ceiling in an indoor space of the building is made of the material. By irradiating light through the material, red light can be applied to an application target in the indoor space.

[0098] The structure may be, for example, a car. Any of or all of the walls or ceiling in the interior space of the car, specifically the front window, side windows, rear window, and sunroof, may be made of the member. By irradiating light through the member, red light can be applied to the target in the interior space.

[0099] Other examples of the structure include airplanes and trains.

[0100] [2] Components, articles and structures for inhibiting the expression of neutrophil adhesion promoters The present invention also relates to a member, article or structure for inhibiting the expression of a neutrophil adhesion-promoting factor. Specific embodiments of the members, articles, and structures of the present invention are as explained above in “[1] Method for inhibiting expression of neutrophil adhesion-promoting factor.”

[0101] [3] Method for preventing or improving wrinkles and / or sagging The present invention also relates to a method for preventing or improving wrinkles and sagging (excluding medical procedures). The method of the present invention is characterized by comprising a light irradiation step and a neutrophil elastase inhibitor application step.

[0102] The light irradiation step is a step of irradiating the skin with red light. Irradiation of the skin with red light suppresses the expression of neutrophil adhesion promoting factor in vascular endothelial cells, thereby suppressing neutrophil infiltration into skin tissue.

[0103] Furthermore, irradiation with red light can have the effect of suppressing the increase and / or decrease in expression of MFAP4, a component of the retinacula cutis. Furthermore, irradiation with red light can have the effect of decreasing the expression and / or suppressing the increase in expression of matrix metalloproteases (MMP-3, MMP-7, MMP-9, MMP-12, etc.) that degrade MFAP4. Furthermore, irradiation with red light can promote the proliferation of tendon cells that produce MFAP4. In other words, the irradiation of red light can provide an effect of thickening the cutaneous retinaculum or an effect of preventing the cutaneous retinaculum from becoming thin. In other words, the effect of strengthening the cutaneous retinaculum can be obtained.

[0104] On the other hand, the neutrophil elastase inhibitor application step is a step of applying a neutrophil elastase inhibitor to the skin. Application of a neutrophil elastase inhibitor suppresses the degradation of elastin and collagen caused by neutrophil elastase secreted by neutrophils that have infiltrated into skin tissue.

[0105] By including a combination of a light irradiation step and a neutrophil elastase inhibitor application step, the present invention can inhibit the upstream and downstream of the series of pathways that lead to the formation of wrinkles and sagging, including the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase. Furthermore, as described above, the light irradiation step can provide the effect of strengthening the cutaneous retinaculum. In other words, the present invention, by comprising a light irradiation step and a neutrophil elastase inhibitor application step, inhibits the causes of wrinkle and sagging in a multifaceted manner, thereby effectively preventing or improving wrinkles and sagging.

[0106] As a specific embodiment of the light irradiation step, the matters described above in “[1] Method for suppressing expression of neutrophil adhesion-promoting factor” can be applied.

[0107] From the viewpoint of increasing the expression of MFAP4, the red light is preferably 0.5 J / cm in the light irradiation step. 2 More than 5 J / cm 2 More preferably, 15 J / cm 2 The above applies. Application of red light under the above conditions is more effective in increasing expression and / or suppressing the decrease in expression of MFAP4.

[0108] In terms of increasing the expression of MFAP4, the light irradiation step is preferably performed with red light at 100 J / cm 2 It is preferable that the following be applied. By applying red light under the above conditions, it is possible to obtain the effect of increasing and / or suppressing the decrease in MFAP4 expression without damaging cells.

[0109] There is no limitation on the type of neutrophil elastase inhibitor to be applied in the neutrophil elastase inhibitor application step, and any known neutrophil elastase inhibitor can be used. In a preferred embodiment of the present invention, a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof is used as a neutrophil elastase inhibitor.

[0110] [ka]

[0111] In general formula (1), R1 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylate group having an alkyl chain having 1 to 4 carbon atoms, and R2 and R3 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

[0112] Specific examples of preferred R1 include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, a carboxybutyl group, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, a methoxycarbonylpropyl group, a methoxycarbonylbutyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group, an ethoxycarbonylpropyl group, an ethoxycarbonylbutyl group, a propyloxycarbonylmethyl group, a propyloxycarbonylethyl group, a propyloxycarbonylpropyl group, a propyloxycarbonylbutyl group, a butyloxycarbonylmethyl group, a butyloxycarbonylethyl group, a butyloxycarbonylpropyl group, a butyloxycarbonylbutyl group, and the like, and a carboxymethyl group is more preferred.

[0113] Preferred examples of the aforementioned R2 and R3, which are each independent of each other, include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group, and more preferably an isopropyl group.

[0114] In a preferred embodiment of the present invention, the compound represented by the above general formula (1) is a compound represented by the following general formula (2), an isomer thereof, and / or a pharmacologically acceptable salt thereof.

[0115] [ka]

[0116] In general formula (2), R4 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R5 and R6 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

[0117] The above-mentioned R4 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group. Specific examples of preferred R4 include a carboxymethyl group, a 1-carboxyethyl group, a 2-carboxyethyl group, a 1-carboxypropyl group, a 2-carboxypropyl group, a 3-carboxypropyl group, a 1-carboxybutyl group, a 2-carboxybutyl group, a 3-carboxybutyl group, a 4-carboxybutyl group, and the like. A more preferred example is a carboxymethyl group. The above-mentioned R5 and R6 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples of preferred R5 and R6 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and the like. A more preferred example is an isopropyl group.

[0118] Specific examples of preferred compounds among the compounds represented by the general formula (2) include N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, and N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl] N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-Trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]ca N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4 -[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide pyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide (3(RS)-N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide), N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, its isomers and / or pharmacologically acceptable salts thereof can be preferably exemplified.

[0119] In a preferred embodiment of the present invention, the compound represented by the general formula (2) is 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-valyl-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, an isomer thereof, and / or a pharmacologically acceptable salt thereof.

[0120] More preferred is 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the following formula (3), its isomers and / or pharmacologically acceptable salts thereof.

[0121] [ka]

[0122] The compound represented by the above general formula (1), its isomer and / or pharmacologically acceptable salt thereof can be produced, for example, by the method described in JP-A-04-297446.

[0123] The compound represented by the above-mentioned general formula (1) of the present invention is an optically active compound having a plurality of asymmetric carbon atoms in its molecular structure, and therefore has enantiomers and diastereomers as its isomers. Furthermore, the compound represented by the above-mentioned general formula (1) of the present invention may be a racemate, an enantiomer, a diastereomer, or a compound in which the above-mentioned isomers are mixed in any ratio.

[0124] Examples of "pharmacologically acceptable salts" include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, etc.; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, paratoluenesulfonate, benzenesulfonate, etc.; alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, piperidine salt, etc., basic amino acid salts such as lysine salt, arginine salt, etc.; and the like.

[0125] The neutrophil elastase inhibitor is preferably applied to the skin in the form of a skin topical composition. The specific aspects of the skin topical composition containing the neutrophil elastase inhibitor are described below in relation to the first skin topical composition.

[0126] In addition, in a preferred embodiment of the present invention, the method further comprises a light scattering agent application step of applying a light scattering agent that blocks near-infrared rays to the skin. Near-infrared light has the effect of enhancing the expression of neutrophil adhesion promoter. In other words, near-infrared light has the opposite effect to red light on the expression of neutrophil adhesion promoter. Near-infrared light weakens the favorable effect of red light, so it is preferable to block it. The light scattering agent application step is a step for blocking near-infrared rays. By blocking near-infrared rays while applying red light in the light irradiation step, a more excellent effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained.

[0127] The light scattering agent is preferably applied to the skin in the form of a skin external composition. The specific embodiment of the skin external composition containing such a light scattering agent can be described in the second skin external composition section below.

[0128] The light irradiation step is preferably carried out after the light scattering agent application step. More preferably, in the light irradiation step carried out after the light scattering agent application step, sunlight containing red light is irradiated. Naturally, sunlight contains red light and near infrared light. By carrying out a light irradiation step of irradiating the skin with sunlight after the light scattering agent application step, it is possible to apply red light to the skin while blocking the near infrared light contained in the sunlight with the light scattering agent, thereby obtaining a more excellent effect of preventing or improving wrinkles and sagging.

[0129] The order of the light irradiation step and the neutrophil elastase inhibitor application step is not limited. The light irradiation step may be performed first or after the step, or these two steps may be performed simultaneously. Furthermore, the order of the light scattering agent application step and the neutrophil elastase inhibitor application step is not limited. The light scattering agent application step may be performed first or after the step, or these two steps may be performed simultaneously.

[0130] In the light irradiation step, it is preferable to apply red light to vascular endothelial cells expressing a neutrophil adhesion promoter, which can effectively inhibit neutrophil infiltration and improve the effect of preventing or improving wrinkles and sagging.

[0131] In addition, in the light irradiation step, it is preferable to apply red light to tendon cells expressing MFAP4, which can strengthen the skin retinaculum and improve the effect of preventing or improving wrinkles and sagging.

[0132] In a more preferred embodiment of the present invention, red light is applied to both vascular endothelial cells and tendon cells in the light irradiation step, which can provide an effect of inhibiting the decomposition of elastin and collagen and an effect of strengthening the skin retinaculum, thereby providing a more excellent effect of preventing or improving wrinkles and sagging. By applying red light to the skin, the red light reaches both vascular endothelial cells and tendon cells, so that this form of the invention can be implemented without any special trial and error.

[0133] [4] Agents for preventing or improving wrinkles and / or sagging The present invention also relates to an agent for preventing or improving wrinkles and / or sagging, which comprises the compound represented by the aforementioned general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof as an active ingredient. The agent for preventing or improving wrinkles and / or sagging of the present invention is characterized by being used in the manner of "application to the skin followed by application of red light."

[0134] The active ingredient of the present invention has the effect of inhibiting the activity of neutrophil elastase secreted by neutrophils that have infiltrated into skin tissue, and suppresses the decomposition of elastin and collagen caused by neutrophil elastase. On the other hand, irradiation of the skin with red light suppresses the expression of neutrophil adhesion promoting factor in vascular endothelial cells, thereby suppressing the infiltration of neutrophils into skin tissue. In other words, by using the active ingredient of the present invention in the manner of "applying it to the skin and then applying red light," it is possible to inhibit the upstream and downstream of the series of pathways that lead to the formation of wrinkles and sagging, which include suppressing neutrophil infiltration and inhibiting the decomposition of elastin and collagen by neutrophil elastase. Furthermore, as mentioned above, application of red light can have the effect of enhancing the retinaculum of the skin. In other words, the present invention inhibits the causes of wrinkle and sagging in a multifaceted manner, and effectively prevents or improves wrinkles and sagging.

[0135] In addition, in a preferred embodiment of the present invention, the method further comprises a light scattering agent application step of applying a light scattering agent that blocks near-infrared rays to the skin. As described above, in terms of controlling the expression of neutrophil adhesion promoting factor, near-infrared light has the opposite effect to red light. By including a light scattering agent that blocks near-infrared light, the near-infrared light that weakens the effect of infrared light is blocked, and the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light can be further increased.

[0136] With regard to the specific mode of usage of "applying to the skin and then applying red light," the descriptions regarding the neutrophil elastase inhibitor application step and the light irradiation step in "[3] Method for preventing or improving wrinkles and / or sagging" above can be applied as is. In other words, with regard to the method of use of the present invention, the descriptions of the neutrophil elastase inhibitor application step and the light scattering agent application step can be applied to "application to skin," and the descriptions of the light irradiation step can be applied to "application of red light."

[0137] In addition, specific embodiments of the compound represented by the above general formula (1), its isomer, and / or a pharmacologically acceptable salt thereof, which are the active ingredients of the present invention, are as described above in “[3] Method for preventing or improving wrinkles and / or sagging.”

[0138] The agent for preventing or improving wrinkles or sagging of the present invention is preferably in the form of a skin topical composition. Specific embodiments of such a skin topical composition are as described below for the first skin topical composition.

[0139] Furthermore, specific embodiments of the light scattering agent that blocks near-infrared rays, which is a component of the present invention, will be described later in the description of the second external composition for skin.

[0140] [5] Skin topical composition kit The present invention also relates to an external skin composition kit comprising a first external skin composition containing an agent for preventing or improving wrinkles or sagging, and a second external skin composition containing a light scattering agent that blocks near-infrared radiation. The first skin topical composition contains the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, while the second skin topical composition contains a light scattering agent that blocks near-infrared rays.

[0141] When the skin to which the first and second compositions for external use on the skin are applied is exposed to sunlight, the second composition for external use on the skin acts to block near-infrared radiation contained in sunlight, thereby more strongly inducing the suppression of expression of neutrophil adhesion-promoting factor by red light contained in sunlight, and effectively suppressing the infiltration of neutrophils into the skin and the subsequent degradation of elastin and collagen by neutrophil elastase.

[0142] In addition, the compound represented by the above general formula (1), its isomer and / or their pharmacologically acceptable salts contained in the first topical skin composition inhibits the activity of neutrophil elastase secreted from neutrophils, thereby suppressing the degradation of elastin and collagen.

[0143] In other words, by applying the skin topical composition kit of the present invention to the skin, even when exposed to sunlight, it is possible to inhibit the upstream and downstream of a series of pathways that lead to the formation of wrinkles and sagging, including the suppression of neutrophil infiltration and the decomposition of elastin and collagen by neutrophil elastase. In other words, the skin topical composition kit of the present invention exerts an excellent effect of preventing or improving wrinkles and sagging.

[0144] The topical skin composition kit of the present invention is preferably used in such a manner that red light is applied to the skin after the first and second topical skin compositions are applied to the skin. By using the first skin topical composition in a method of applying red light after application to the skin, it is possible to inhibit the upstream and downstream of a series of pathways leading to the formation of wrinkles and sagging, which are the decomposition of elastin and collagen by neutrophil elastase and the inhibition of neutrophil infiltration. In addition, by applying the second skin topical composition to block near-infrared rays, the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light can be enhanced, and a more excellent effect of preventing or improving wrinkles and sagging can be obtained.

[0145] With regard to the specific mode of usage of "applying to the skin and then applying red light," the descriptions regarding the neutrophil elastase inhibitor application step and the light irradiation step in "[3] Method for preventing or improving wrinkles and / or sagging" above can be applied as is. In other words, with regard to the method of use of the present invention, the descriptions of the neutrophil elastase inhibitor application step and the light scattering agent application step can be applied to "application to skin," and the descriptions of the light irradiation step can be applied to "application of red light."

[0146] Hereinafter, more detailed aspects of each of the first and second external skin compositions will be described. [5-1] First skin topical composition The first skin topical composition contains the compound represented by the above-mentioned general formula (1), its isomer, and / or a pharmacologically acceptable salt thereof. Specific embodiments of the compound represented by the general formula (1), its isomer, and / or a pharmacologically acceptable salt thereof are as described above in “[3] Method for preventing or improving wrinkles and / or sagging.”

[0147] The compound represented by the general formula (1) can be directly contained in the skin external composition, but can also be treated with a pharmacologically acceptable acid or base to convert it into a salt form and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, etc.; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, paratoluenesulfonate, benzenesulfonate, etc.; alkali metal salts such as sodium salt, potassium salt, alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, piperidine salt, etc., basic amino acid salts such as lysine salt, alginate, etc.; etc. The skin external composition of the present invention can contain one or more selected from the compound represented by the general formula (1), its isomer, and / or their pharmacologically acceptable salts.

[0148] In order to exhibit the above-mentioned effects by including the compound represented by the above-mentioned general formula (1), its isomer and / or their pharmacologically acceptable salt in the first skin topical composition, it is preferable to include 0.01% by mass to 10% by mass, more preferably 0.1% by mass to 5.0% by mass, based on the total amount of the first skin topical composition. This is because if the amount of the compound represented by the above-mentioned general formula (1), its isomer and / or their pharmacologically acceptable salt contained in the first skin topical composition is too small, the above-mentioned effects tend to decrease, and if it is too large, the above-mentioned effects tend to plateau.

[0149] The compound represented by the above general formula (1), its isomer and / or their pharmacologically acceptable salt are preferably contained in an oil gel-form skin preparation together with a partially crosslinked methylpolysiloxane.By forming the first skin composition into such a form, the skin retention is increased, wrinkle and sagging formation is inhibited, and the balance between the new formation and disappearance of wrinkles and sagging is shifted to the disappearance side, thereby improving the preventive or ameliorative effect against the formation of wrinkles and sagging.

[0150] Partially crosslinked methylpolysiloxane, which is classified as a partially crosslinked organopolysiloxane polymer, is a silicone oil having a structure in which a linear polymer formed by siloxane bonds is partially crosslinked. Note that, in the present invention, "partially crosslinked" refers to one produced by crosslinking so that the crosslinking rate, which indicates the degree of crosslinking, is about 20 to 30%.

[0151] It is preferable to use a partially crosslinked methylpolysiloxane having a consistency of 100 to 500 at 25° C. from the viewpoints of stability and usability. The viscosity of the partially crosslinked methylpolysiloxane at 25° C. can be measured in accordance with JIS K2220.

[0152] Some of the above-mentioned partially crosslinked methylpolysiloxanes are commercially available as general-purpose raw materials for cosmetics, and the partially crosslinked methylpolysiloxane of the present invention can be purchased and used as such a commercially available product.

[0153] As a commercially available product, in addition to partially crosslinked methylpolysiloxane, those containing other silicone oils such as decamethylcyclopentasiloxane, methylpolysiloxane, octamethylcyclotetrasiloxane, methylphenylpolysiloxane, etc. can be used, or those containing only partially crosslinked methylpolysiloxane can be used.

[0154] Among commercially available partially crosslinked methylpolysiloxanes, preferred ones include KSG-15 (a mixture of about 5 parts by mass of partially crosslinked methylpolysiloxane and about 95 parts by mass of decamethylcyclopentasiloxane), KSG-16 (a mixture of about 20 to 30 parts by mass of partially crosslinked methylpolysiloxane and about 70 to 80 parts by mass of methylpolysiloxane), KSG-17 (a mixture of about 5 parts by mass of partially crosslinked methylpolysiloxane and about 95 parts by mass of octamethylcyclotetrasiloxane), and KSG-18 (a mixture of about 10 to 20 parts by mass of partially crosslinked methylpolysiloxane and about 80 to 90 parts by mass of methylphenylpolysiloxane), all of which are manufactured by Shin-Etsu Chemical Co., Ltd., with KSG-16 being particularly preferred.

[0155] The first skin topical composition can contain one or more selected commercially available products containing the aforementioned partially crosslinked methylpolysiloxane, or a commercially available product containing only the partially crosslinked methylpolysiloxane can contain other silicone oils.

[0156] The partially crosslinked methylpolysiloxane acts as a gel former in the first composition for external use on the skin, and provides an effect of maintaining the oil gel structure of the first composition for external use on the skin. In order to achieve this effect, the content of the partially crosslinked methylpolysiloxane is preferably 5-25% by mass, more preferably 10-20% by mass, based on the total amount of the first composition for external use on the skin in the form of an oil gel. This is because if the content is too low, it tends to be difficult to maintain the structure, and if the content is too high, the freedom of formulation tends to be impaired.

[0157] The first composition for external use on the skin preferably contains spherical powder that enhances fat solubility, for example, by improving spreadability, etc. In addition, "spherical" includes not only a true spherical shape, but also an approximately spherical shape including irregularities on the surface.

[0158] The average particle size of such spherical powder is preferably 5 to 20 μm, because if it is less than 5 μm, a strong squeaky feeling is felt when applied, whereas if it exceeds 20 μm, the spherical powder may cause a strong sense of unevenness.

[0159] The particle size of the spherical powder can be measured using a Microtrack method (laser diffraction / scattering method, for example, a Microtrack MT3000II series manufactured by Nikkiso Co., Ltd.

[0160] Suitable examples of spherical powders to be contained in the first topical skin composition in oil gel formulation include spherical inorganic powders such as spherical silica, spherical calcium carbonate, spherical magnesium carbonate, and spherical silicates such as spherical calcium silicate and spherical magnesium silicate, and organic spherical powders such as polyamide powder, polymethyl methacrylate, and polyester powder. Among these, it is more preferable to use organic spherical powders, and it is particularly preferable to use polymethyl methacrylate. This is because the organic spherical powder has the effect of significantly increasing the skin retention of the compound represented by the general formula (1) above, its isomers and / or their pharmacologically acceptable salts, in addition to the effect of improving usability described above.

[0161] The organic spherical powder polymethyl methacrylate can be a commercially available one, and a suitable example of a commercially available one is Microsphere M330 sold by Matsumoto Yushi Seiyaku Co., Ltd. Furthermore, in order to achieve the above-mentioned effect, the spherical powder is preferably contained in a total amount of 12 to 50 mass%, more preferably 15 to 45 mass%, and particularly preferably 20 to 30 mass% relative to the total amount of the first skin topical composition in oil gel formulation. This is because if the amount is too small, the above-mentioned effect tends to decrease, and if the amount is too large, there are cases where the degree of freedom of formulation is impaired. In addition, one or more of the spherical powders described above can be selected and contained in the first skin topical composition in oil gel formulation.

[0162] Furthermore, by adding a plant extract described below to the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, the stability over time can be improved.

[0163] Examples of plant extracts that can be used in combination with the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof include peach kernel extract, morning glory extract, ginseng extract, white birch resin extract, Job's tears seed extract, Belamcanda chinensis extract, Codonopsis gracilis extract, peony extract, lotus extract, peony extract, hydrangea extract, lemongrass extract, horsetail extract, olive fruit extract, thorn extract, astragalus extract, mugwort extract, Japanese knotweed extract, shell ginger leaf extract, clove extract, centaurea cyanus extract, farrerol, and Hypericum perforatum extract.

[0164] The above-mentioned plant extract is not particularly limited to the plant part, and the whole plant can be used, but it is also possible to use only the plant body, above-ground parts, rhizomes, trunks, leaves, stems, inflorescences, flower buds, fruits, etc. As the above-mentioned plant extract, any of pressed effluent, steam distillate, distillate, and solvent extract can be used, but pressed effluent or solvent extract is particularly preferred because useful components can be selectively obtained.

[0165] The solvent used in the solvent extraction is preferably a polar solvent, such as water, alcohols such as 1,3-butanediol, ethanol, isopropanol, esters such as ethyl acetate, methyl formate, ketones such as acetone, methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran, etc., and among these, an aqueous solution containing 1,3-butanediol and / or ethanol is preferred. The content of 1,3-butanediol and / or ethanol in this case is preferably 10 to 40% by mass, more preferably 15 to 35% by mass, based on the total amount of the solvent.

[0166] For extraction, 1 to 10 parts by mass of a solvent is added to 1 part by mass of the plant body or its dried product, and the plant body or its dried product is immersed for several days at room temperature or for several hours at a temperature near the boiling point. If necessary, insoluble matter may be removed by filtration. When concentrating, the mixture may be distilled under reduced pressure. In the case of a squeezed effluent, for example, 1,3-butanediol and / or ethanol are added to the obtained fruit juice after filtering out the insoluble matter so that the final concentration is 10 to 40% by mass, preferably 15 to 35% by mass, based on the total amount of the fruit juice. Such a plant extract may be prepared as described above and used, or may be purchased and used as a commercially available product.

[0167] The first composition for external use on the skin may contain the following substances in addition to the above-mentioned plant extract. The first skin topical composition can be prepared by containing, together with the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, one or more substances selected from ascorbic acid glucoside, acetyl hexapeptide, sodium alginate sulfate, benzyl ursolate, dipotassium glycyrrhizinate, stearyl glycyrrhetinate, sodium chondroitin sulfate, sphingoglycolipids, tranexamic acid, sodium trehalose sulfate, urea, hydrogenated soybean phospholipid, 4-n-butylresorcinol, polymethacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, polyglucosyloxyethyl methacrylate, sodium polyglutamate, di(phytosteryl-2-octyldodecyl) N-lauroyl-L-glutamate, and golden silk extract.

[0168] By containing the above substance, the stability over time is increased, as described above, and the effect of the compound represented by the general formula (1), its isomer, and / or their pharmacologically acceptable salts can be stably exhibited.

[0169] The first skin topical composition may also contain an expression inhibitor of neutrophil migration-promoting factor. Neutrophil migration-promoting factor is a factor that promotes the migration of neutrophils into tissues. Neutrophil migration-promoting factor is secreted by dermal fibroblasts. When the first external skin composition contains an inhibitor of the expression of neutrophil migration-stimulating factor, a more excellent effect of preventing or improving wrinkles and sagging can be obtained.

[0170] More specifically, application of red light suppresses the expression of neutrophil adhesion promoting factor, thereby suppressing adhesion of neutrophils to vascular endothelial cells. Downstream, neutrophil migration is suppressed by an inhibitor of neutrophil migration promoting factor expression. Furthermore, neutrophil elastase secreted by infiltrating neutrophils is inhibited by the action of the compound represented by the above-mentioned general formula (1), its isomer and / or a pharmacologically acceptable salt thereof. In this way, by making the first topical skin composition contain an inhibitor of the expression of neutrophil migration-promoting factor, a series of upstream, midstream and downstream reactions, such as neutrophil adhesion and migration, and the decomposition of elastin and collagen by neutrophil elastase, can be suppressed in a multifaceted manner, thereby achieving a more effective prevention or improvement of wrinkles and sagging.

[0171] Neutrophil migration-promoting factors include CXC chemokines having an ELR (Glu-Leu-Arg) motif, such as CXCL-1 and IL-8.

[0172] Examples of inhibitors of neutrophil chemotaxis factor expression include cyclohexylglycerin and horsetail extract. These inhibitors of neutrophil migration-stimulating factor expression are particularly effective in suppressing the gene expression of CXCL-1 and IL-8. Furthermore, in a form that contains both cyclohexylglycerin and horsetail extract, the inhibitory effect on CXCL-1 gene expression is significantly increased.

[0173] Cyclohexylglycerin is a diol compound with the IUPAC name 3-(cyclohexyloxy)-1,2-propanediol.

[0174] As the cyclohexylglycerin, commercially available products can be used, for example, "ADEKA NOL CHG (manufactured by ADEKA Corporation)".

[0175] The content of cyclohexylglycerin in the entire first composition for external use on skin is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass, in terms of dry mass.

[0176] The parts of horsetail used for the extraction of the above-mentioned horsetail extract may be the plant body, above-ground parts, trunks and dried products thereof. Preferably, the whole plant is used for the extraction.

[0177] The extract can be obtained by adding 1 to 30 parts by mass of the extraction solvent described above to 1 part by mass of the extraction part described above and soaking it at room temperature for several days or at a temperature near the boiling point of the solvent for several hours. After the extraction, a step of removing insoluble matter and a step of concentrating under reduced pressure may be included as necessary. Alternatively, fractionation and purification may be carried out by column chromatography packed with silica gel or ion exchange resin.

[0178] The content of the above-mentioned horsetail extract relative to the total amount of the first external skin composition is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass, in terms of dry mass.

[0179] When the first topical skin composition contains two types of agents, cyclohexylglycerin and horsetail extract, as inhibitors of neutrophil migration-promoting factor gene expression, the mass ratio of cyclohexylglycerin to 1 part by mass of horsetail extract is preferably 0.01 to 1 part by mass, more preferably 0.02 to 0.5 parts by mass, and particularly preferably 0.04 to 0.2 parts by mass.

[0180] The first external skin composition may also contain an agent for suppressing the expression of neutrophil adhesion promoting factor. By including an inhibitor of the expression of neutrophil adhesion promoting factor in the first topical skin composition, the effect of inhibiting the expression of neutrophil adhesion promoting factor by application of red light can be further increased, thereby achieving a more excellent effect in preventing or improving wrinkles and sagging.

[0181] A suitable example of an inhibitor of neutrophil adhesion promoter expression is an oil-soluble peach leaf extract, which can be incorporated into formulations that cannot contain water and can also be formulated together with ingredients that are poorly stable in water.

[0182] The oil-soluble peach leaf extract can be obtained by extracting the fruits and / or leaves of the peach genus (Rosaceae Amygdaloideae Amygdalus) of the family Rosaceae with an organic solvent. Examples of organic solvents that can be used include aliphatic alcohols such as methanol and ethanol, aliphatic ketones such as acetone, aliphatic ethers such as dioxane and ethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, fatty acid esters such as ethyl acetate, butyl acetate, and isobutyl acetate, hydrocarbons such as hexane and benzene, and mixtures of two or more of these solvents. As the oil-soluble peach leaf extract, an extract extracted with the above-mentioned solvent, a concentrate obtained by vacuum concentration or freeze-drying, and a fractionated and purified product obtained by column chromatography filled with silica gel or ion exchange resin can be used.

[0183] The oil-based peach leaf extract may be a commercially available product, for example, "oil-soluble peach leaf extract (manufactured by Koei Kogyo Co., Ltd.)."

[0184] The content of the oil-soluble peach leaf extract in the first skin external use composition is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass, based on the total amount of the first skin external use composition.

[0185] In addition to the above-mentioned components, substances that can be used in combination with the compound represented by the above-mentioned general formula (1), its isomers and / or their pharmacologically acceptable salts include chrysanthellum indicum, conchiolin hydrolysates, terpenoids, stilbene derivatives, para-aminobenzoic acid-based UV absorbers, anthranilic acid-based UV absorbers, salicylic acid-based UV absorbers, cinnamic acid-based UV absorbers, benzophenone-based UV absorbers, sugar-based UV absorbers, 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole, and 4-methoxy-4'-t-butyldibenzoylmethane.

[0186] In addition to the above-mentioned components, the first skin topical composition may contain the following substances. There are no particular limitations on the plant extracts, so long as they are generally used in pharmaceuticals, cosmetics, etc. For example, Akebia extract, Asarum extract, Asparagus extract, Avocado extract, Almond extract, Arnica extract, Aloe extract, Apricot extract, Ginkgo extract, Fennel extract, Ajing extract, Scutellaria extract, Lamium extract, Orange extract, Kakyoku extract, Pueraria lobata extract, Chamomilla extract, Carrot extract, Artemisia capillaris extract, Licorice extract, Kiwi extract, Cucumber extract, Guava extract, Gardenia extract, Sasa veitchii extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, mulberry extract, gentian extract, geranium extract, black tea extract, burdock extract, rice extract, fermented rice extract, fermented rice bran extract, rice germ oil, cowberry extract, salvia extract, soapwort extract, bamboo extract, sansha extract, Japanese pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, linden extract, meadowsweet extract, calamus root extract, white birch extract, stevia extract, stevia fermented product, hawthorn extract, elderberry extract, peppermint Extract, sage extract, mallow extract, cnidium extract, sophora gracilis extract, rhubarb extract, taiwan extract, thyme extract, dandelion extract, tangerine extract, sweet tea extract, chili pepper extract, angelica extract, calendula extract, spruce extract, houttuynia extract, tomato extract, natto extract, garlic extract, wild rose extract, burdock root extract, parsley extract, birch extract, witch hazel extract, cypress extract, loquat extract, coltsfoot extract, butterbur sprout extract, butcher's broom extract, grape extract Preferred examples of the extracts include safflower extract, grape seed extract, loofah extract, safflower extract, peppermint extract, hop extract, pine extract, skunk cabbage extract, soapberry extract, melissa extract, mozuku extract, eucalyptus extract, saxifrage extract, lily extract, coix seed extract, lavender extract, green tea extract, apple extract, lychee extract, lettuce extract, lemon extract, forsythia extract, rose extract, Roman chamomile extract, royal jelly extract, wild thyme extract, and burnet extract.

[0187] The content of the plant extract in the first composition for external use on skin is usually 0.01 to 30% by mass, preferably 0.1 to 10% by mass, and more preferably 1 to 5% by mass.

[0188] Oily components that can be contained in the first composition for external use on skin include polar oils, silicone oils, volatile hydrocarbon oils, and the like. As polar oils, synthetic ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearyl acid, ethylene glycol di-2-ethylhexyl acid, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptylundecanoate, trimethylolpropane tri-2-ethylhexyl acid, trimethylolpropane triisostearate, pentaneerythritol tetra-2-ethylhexyl acid, ... -Ethylhexyl glycerin, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glycerin trimyristate, tri-2-heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleic acid oil, cetostearyl alcohol, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glucose Examples of such esters include 2-octyldodecyl glutamate, di-2-heptylundecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebacate, 2-ethylhexyl succinate, ethyl acetate, butyl acetate, amyl acetate, triethyl citrate, and octyl methoxycinnamate.

[0189] Examples of silicone oils include chain polysiloxanes such as dimethylpolysiloxane and diphenylpolysiloxane, cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexanesiloxane, and modified polysiloxanes such as amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes and fluorine-modified polysiloxanes.

[0190] Further, examples of natural oils include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, sasanqua oil, castor oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, Chinese tung oil, Japanese tung oil, jojoba oil, germ oil, triglycerin, glycerin trioctanoate, and glycerin triisopalmitate.

[0191] Examples of volatile hydrocarbon oils include isododecane, isohexadecane, etc. Other oily components that are commonly used in cosmetics can also be used.

[0192] Examples of surfactants include anionic surfactants such as fatty acid soaps (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, and alkyl sulfate triethanolamine ether; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide; amphoteric surfactants such as imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), and acylmethyltaurine; and sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.). , glycerin fatty acids (glycerin monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hydrogenated castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbit fatty acid esters (POE-sorbitan monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.) , POE alkyl ethers (POE 2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE·POP alkyl ethers (POE·POP 2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hydrogenated castor oil derivatives (POE castor oil, POE hydrogenated castor oil, etc.), sucrose fatty acid esters, alkyl glucosides and other nonionic surfactants.

[0193] Examples of polyhydric alcohols include polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-hexanediol, and 1,2-octanediol.

[0194] Examples of thickening agents include guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methylhydroxypropyl cellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratosulfuric acid, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, sodium polyacrylate, and polyethylene glycol.

[0195] Suitable examples of the first skin topical composition include cosmetics, quasi-drugs, and medicines, with cosmetics and quasi-drugs being more preferred since they can be used on a daily basis.

[0196] The first skin topical composition can be in any of the commonly known forms such as lotion, emulsion, essence, cream, foam, and non-aqueous formulations. As the cosmetic, any of basic cosmetic, hair cosmetic, and makeup cosmetic can be used. [5-2] Second skin topical composition The second composition for external use on the skin contains a light scattering agent that blocks near-infrared rays. Here, "blocking near-infrared rays" does not only refer to a form that blocks all of the near-infrared rays (i.e., a blocking rate of 100%), but also includes a form that blocks at least a part of the near-infrared rays.

[0197] A suitable example of a light scattering agent that blocks near-infrared rays is titanium oxide. More preferably, titanium oxide having an average particle size of 0.5 μm or more is used. Such titanium oxide has excellent near-infrared ray scattering function and provides near-infrared ray protection effect in the second skin topical composition.

[0198] As described above, the average particle size of titanium oxide is preferably 0.5 μm or more, more preferably 0.8 μm to 2.0 μm, and more preferably 1.0 μm to 1.5 μm. From the viewpoint of a good near-infrared scattering effect, it is preferable that the average particle size is within the above range.

[0199] In the present invention, the "average particle size" specifically means the volume average particle size of the particles, and can be calculated, for example, by acquiring a transmission electron microscope (TEM) image and analyzing the image.

[0200] The titanium oxide used in the cosmetic of the present invention is preferably surface-coated with an inorganic compound such as silica, alumina, etc., or an organic compound such as a surfactant such as stearic acid, isostearic acid, sodium alginate, etc., or a silicone compound such as silicone oil, etc. When a coating treatment is performed, it can be performed by a known surface treatment method.

[0201] Titanium oxide is preferably oil-dispersible. Since oil-dispersible titanium oxide is uniformly dispersed in the oil phase, the second composition for external application to skin in this form has excellent water resistance and near-infrared protection function.

[0202] A preferred example of oil-dispersible titanium oxide is titanium oxide whose surface is coated with a hydrophobic compound. Although not limited to such oil-dispersible titanium oxide, titanium oxide coated with a hydrophobic organic compound is preferably used.

[0203] Titanium oxide is not particularly limited as long as it has a near-infrared scattering effect. Such titanium oxide may be a commercially available product. Alternatively, commercially available titanium oxide may be surface-treated by a known method. In addition, titanium oxide may be blended in the second skin external composition with only one type having different particle size, or may be blended in combination of two or more types.

[0204] The content of titanium oxide in the second composition for external use on skin is usually 0.1% by mass to 15% by mass, and preferably 0.5% by mass to 10% by mass. The content of titanium oxide relative to the total amount of powder excluding the ultraviolet scattering agent is usually 25% by mass or more, and preferably 30% by mass or more. Based on this range and the examples described below, a person skilled in the art can adjust the content as appropriate, taking into consideration the feel, finish, and the like. Here, the ultraviolet scattering agent is understood in the usual sense in the fields of cosmetics, external skin preparations, etc. Although not limited, if the ultraviolet scattering agent is a fine particle metal oxide, for example, the primary average particle diameter by electron microscope observation can be 100 nm or less. In other words, the content of titanium oxide relative to the total powder amount excluding the ultraviolet scattering agent can be rephrased as the content of titanium oxide relative to the total powder amount having an average particle diameter of more than 100 nm.

[0205] A preferred embodiment of the second topical skin composition is an emulsion or oil-gel cosmetic preparation containing the following components, in which the difference between the "light shielding rate with a wavelength of 585 to 760 nm" and the "light shielding rate with a wavelength of 760 to 1310 nm" is 10% or less, and the "light shielding rate with a wavelength of 760 to 1310 nm" is 30% or more. a-1) titanium dioxide having an average particle size of 0.5 μm or more, which is 25% by mass or more of the total powder amount excluding the ultraviolet scattering agent; and b-1) Spherical powder.

[0206] The present inventors have conducted extensive research in search of a cosmetic that can protect against near-infrared rays, transmit the long wavelength region of visible light, and provide an anti-aging effect. As a result, they have found that near-infrared rays can be protected by titanium oxide with a large average particle size, specifically titanium oxide with an average particle size of 0.5 μm or more, and that the long wavelength region of visible light can be effectively transmitted by including a spherical powder as a powder to be blended in the cosmetic, that is, the difference between the "light shielding rate of 585 to 760 nm wavelength" and the "light shielding rate of 760 to 1310 nm wavelength" is 10% or less, and the "light shielding rate of 760 to 1310 nm wavelength" can be 30% or more.

[0207] It was found that the second composition for external use on the skin has the effect of preventing or improving a decrease in skin viscoelasticity, wrinkles, sagging of the skin, etc., by protecting against near-infrared rays that damage the skin and transmitting the long wavelength region of visible light that has an anti-aging care effect, and is effective as a cosmetic that imparts an anti-aging effect. The second composition for external use on the skin was designed based on such findings.

[0208] The difference between the "light blocking rate of 585 to 760 nm wavelength" and the "light blocking rate of 760 to 1310 nm wavelength", and the "light blocking rate of 760 to 1310 nm wavelength" can be measured or calculated based on known analytical methods. For example, a spectrophotometer or the like is used to measure the light transmittance of a thin film of the second composition for external use on skin in the wavelength range of 585 to 760 nm, and the average value of the transmittance in the same wavelength range is calculated. The "light shielding rate of 585 to 760 nm wavelength" can be calculated as 100-transmittance (average value). Similarly, the "light shielding rate of 760 to 1310 nm wavelength" can be calculated. The "light shielding rate of 760 to 1310 nm wavelength" can be subtracted from the "light shielding rate of 585 to 760 nm wavelength" to obtain the difference.

[0209] The formulation of the second topical skin composition is not particularly limited as long as it is a known formulation used as a cosmetic or topical skin medicine, but examples include an oil-in-water emulsion formulation, a water-in-oil emulsion formulation, an oil gel formulation, etc.

[0210] Specific uses of the second composition for external use on the skin are not particularly limited, and examples thereof include external preparations for the skin, such as milky lotion, foundation, sunscreen, lip color, lip cream, lip gloss, cheek color, eye color, spot cover, and cosmetics, etc. In such an embodiment, the effects of the present invention can be effectively utilized, and the composition can be particularly suitable for protecting the skin.

[0211] As described above, in a preferred embodiment of the second skin topical composition, the component b-1) contains spherical powder. The spherical powder has an excellent function of transmitting light on the long wavelength side of visible light in comparison with light on the short wavelength side of visible light, and imparts an anti-aging effect to the cosmetic composition of the present invention. Furthermore, the spherical powder contributes to suppressing the squeaky feeling, and imparts an excellent feeling of use.

[0212] The function of transmitting light on the long wavelength side of visible light can be specifically expressed as the ratio of the "transmittance of light with a wavelength of 585 to 760 nm" to the "transmittance of light with a wavelength of 400 to 760 nm" (hereinafter sometimes referred to as the "585 to 760 nm transmittance ratio"). The 585 to 760 nm transmittance ratio of the spherical powder used in the present invention is preferably 50% or more, more preferably 60% or more, even more preferably 65% ​​or more, and particularly preferably 68% or more.

[0213] Here, the 585-760 nm transmission ratio can be measured and calculated based on a known analysis method. For example, a spectrophotometer or the like is used to measure the amount of light transmitted through a thin film of a spherical powder dispersion in a wavelength range of 400-760 nm, and the average value of the amount of light transmitted through the thin film in the same wavelength range is calculated and defined as the "amount of light transmitted through the thin film in the wavelength range of 400-760 nm". Furthermore, the amount of light transmitted through the thin film in the wavelength range of 585-760 nm is measured, and the average value of the amount of light transmitted through the thin film in the wavelength range is calculated and defined as the "amount of light transmitted through the thin film in the wavelength range of 585-760 nm". The 585-760 nm transmission ratio can be calculated by dividing the "amount of light transmitted through the thin film in the wavelength range of 585-760 nm" by the "amount of light transmitted through the thin film in the wavelength range of 400-760 nm".

[0214] The average particle size of the spherical powder is preferably 6.0 μm or less, and more preferably 2.0 μm or less. If the average particle size of the spherical powder is within the above range, the transmittance ratio of 585 to 760 nm is high, which is preferable from the viewpoint of achieving the numerical range of the difference between the "light shielding rate with wavelengths of 585 to 760 nm" and the "light shielding rate with wavelengths of 760 to 1310 nm" in the cosmetic of the present invention.

[0215] The spherical powder used in the present invention is not particularly limited, but examples thereof include organic powders such as polymethylsilsesquioxane and crosslinked polydimethylsiloxane. Such spherical powders may be commercially available products, such as Tospearl 120A (manufactured by Momentive Corporation), MSP-N050 (manufactured by Nikko Rica Corporation) (average particle size: 0.5 to 2.0 μm), etc. The spherical powders may be blended in a cosmetic composition in one type or in a combination of two or more types.

[0216] The content of the spherical powder of component b-1) in the cosmetic of the present invention is usually 0.1% by mass to 15% by mass, preferably 0.5% by mass to 10% by mass. The content of the spherical powder of component b-1) relative to the total powder amount excluding titanium oxide and ultraviolet scattering agent of component a-1) is 2.5% by mass or more, preferably 5% by mass or more. From the viewpoint of the effect of transmitting light on the long wavelength side of visible light, it is preferable that the content of the spherical powder is within the above range. The content ratio (mass ratio) of titanium oxide of component a-1) to the spherical powder of component b-1), (a-1) / (a+b-1), is usually 0.25 or more, preferably 0.50 or more.

[0217] The second skin topical composition may contain an anti-photoaging component as component x). The anti-photoaging component refers to a component that improves and / or prevents aging caused by exposure to ultraviolet light. More specifically, the anti-photoaging component refers to a component that improves and / or prevents aging by having an effect of increasing the expression and / or suppressing the decrease in the expression of MFAP4. The anti-photoaging component also refers to a component that improves and / or prevents aging by having an effect of suppressing the expression of matrix metalloproteinases (MMP-3 and MMP-9) that degrade MFAP4.

[0218] The anti-photoaging component is preferably an extract of biological origin, and more preferably an extract of plant origin. Here, the plant extract can be prepared using plants that grow wild or are grown in Japan, or plants that are sold in Japan as raw materials for herbal medicines, or commercially available extracts sold by companies that deal in plant extracts, such as Maruzen Co., Ltd., can be purchased and used.

[0219] As the photoaging-resistant component, the following components can be preferably mentioned. Morus alba (Morus), Phellodendron amurense (Phellodendron), Orchidaceae (Orchidaceae), Citrus aurantifolia (Citrus), Rosa × coryana (Rosa), Thymus serpyllum (Thymus), Actinidia arguta (Actinidia), Rosa × damascena (Rosa), damascena, Schisandraceae (Schisandra), Schisandra chinensis, Campanulaceae (Codonopsis), Codonopsis pilosula, Oxalidaceae (Averrhoa), Averrhoa carambola, Fabaceae (Pterocarpus), Ptericarpus marsupium, Araliaceae (Panax), Panax ginseng, Lamiaceae (Perilla), Perilla frutescens, Camellia sinensis (Camellia sinensis) (Theaceae), Rosa × damascena (Rosa × damascena) (Robiaceae), Cinchona (Cinchona) (Rubiaceae), Aloe (Aloe) (Xanthorrhoeaceae), Urtica (Urtica) (Urticaceae)thunbergiana), Apiaceae Foeniculum vulgare, Asteraceae Arctium A. lappa, Royal jelly The above components may be used alone or in combination of two or more.

[0220] The above-mentioned burdock extract has a particularly large effect of increasing the expression of MFAP4, and therefore it is preferable to use burdock extract (burdock extract) as an anti-photoaging ingredient.

[0221] Furthermore, among the above-mentioned biological extracts, the effect of reducing the expression level of at least one of MMP-3 and MMP-9 is particularly large, and therefore it is preferable to use a form containing at least one of Phellodendron amurense extract, kiwi extract, Rosa damask flower extract, perilla extract, tea plant extract, and ginseng extract as an anti-photoaging component.

[0222] The content of the extract of component x) in the second skin topical composition is usually 0.00001 mass% or more, preferably 0.0001 mass% or more, and more preferably 0.001 mass% or more, based on the total amount of the cosmetic, in terms of dry solid content. In addition, the content of the extract of component x) in the second skin topical composition is usually 80% by mass or less, preferably 30% by mass or less, and more preferably 10% by mass or less, based on the total amount of the cosmetic, in terms of dry solid content. By setting the amount within the above range, anti-photoaging effects such as wrinkle improvement, sagging, prevention of loss of firmness, and prevention of loss of elasticity of the skin can be preferably achieved.

[0223] The second skin topical composition may contain, as component y), an extract whose activity is improved by light with a wavelength of 585 to 760 nm (hereinafter, sometimes simply referred to as "extract"). The extract whose activity is improved by light with a wavelength of 585 to 760 nm on the long wavelength side of visible light is preferably used in the cosmetic of the present invention in that it improves the activity in the cosmetic of the present invention and imparts good effects. Here, the activity is an activity that improves the skin, and is not particularly limited, and examples thereof include anti-inflammation, moisturizing, blood circulation promotion, antioxidant, skin cell activation, and whitening activities. Since the cosmetic of the present invention has excellent near-infrared protection and transmission in the long wavelength region of visible light, and exhibits anti-aging effects such as prevention or improvement of decreased skin viscoelasticity, wrinkles, sagging, etc., if it has such anti-aging activity, it is preferable from the viewpoint of exhibiting better effects.

[0224] The increase in activity of the extract due to light with a wavelength of 585 to 760 nm can be measured and calculated based on known analytical methods. For example, it can be confirmed by measuring and comparing the activity of the extract with and without irradiation of light with a wavelength of 585 to 760 nm.

[0225] The extract to be incorporated in the second skin external composition is not limited as long as it is an extract whose activity of improving the skin is improved by light having a wavelength of 585 to 760 nm, and may be an animal or plant-derived extract. Note that the term "extract" used herein is a general term for animal or plant-derived extracts, extract fractions, purified fractions, and solvent-removed extracts, fractions, and purified products. From the viewpoints of availability and usability, etc., preferably, an extract derived from a plant is used.

[0226] Examples of plants include extracts of wild or cultivated plants, plants sold as raw materials for herbal medicines, and commercially available extracts. In the extraction operation, the whole plant can be used, and also the plant body, above-ground parts, roots and stems, trunks, leaves, stems, inflorescences, flower buds, etc. can be used, but it is preferable to crush or chop them in advance to improve the extraction efficiency. The extraction solvent can be one or more selected from water; alcohols such as methanol, ethanol, isopropyl alcohol, butanol, etc.; polyhydric alcohols such as 1,3-butanediol, polypropylene glycol, etc.; ketones such as acetone, methyl ethyl ketone, etc.; and ethers such as diethyl ether, tetrahydrofuran, etc., polar solvents. A specific extraction method includes, for example, adding 1 to 30% by mass of a solvent to 1 mass of a part or a dried product thereof used for extraction of a plant body, etc., immersing the part at room temperature for several days or at a temperature near the boiling point for several hours, cooling to room temperature, removing insoluble matter and / or solvent as desired, and fractionating and purifying the part by column chromatography, etc.

[0227] Examples of extracts include, but are not limited to, akebia extract, asparagus extract, avocado extract, amacha extract, almond extract, arnica extract, aloe extract, aronia extract, apricot extract, ginkgo extract, indian kinoko extract, fennel extract, udo extract, eijitsu extract, eleuthero extract, enmeiso extract, scutellaria root extract, phellodendron bark extract, coptis japonica extract, ginseng extract, hypericum extract, white lamb's foot extract, orange extract, kakyoku extract, pueraria root extract, chamomile extract, carrot extract, Extract, Artemisia capillaris extract, Licorice extract, Kiwi extract, Cucumber extract, Guava extract, Sophora root extract, Gardenia extract, Sasa veitchii extract, Sophora flavescens extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, Mulberry extract, Schisandra chinensis extract, Alpinia speciosa extract, Gentiana chinensis extract, Gentiana geranium extract, Black tea extract, Burdock extract, Rice extract, Fermented rice extract, Fermented rice bran extract, Rice germ oil, Cowberry extract, Salvia extract, Soapwort extract, Bamboo grass extract, Hawthorn extract, Sanshou extract, Sanshi Root extract, Shiitake mushroom extract, Rehmannia root extract, Lithospermum root extract, Perilla extract, Tilia extract, Meadowsweet extract, Peony extract, Ginger extract, Calamus root extract, Birch extract, Horsetail extract, Stevia extract, Stevia fermentation product, Ivy extract, Hawthorn extract, Elderberry extract, Yarrow extract, Peppermint extract, Sage extract, Mallow extract, Cnidium rhizome extract, Swertia japonica extract, Soybean extract, Chinese laurel extract, Thyme extract, Dandelion extract , tea extract, clove extract, tangerine extract, sweet tea extract, chili pepper extract, angelica extract, calendula extract, peach kernel extract, spruce extract, dokudami extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, bamboo shoot extract, lotus extract, lotus germ extract, parsley extract, birch extract, witch hazel extract, Japanese knotweed extract, cypress extract, loquat extract, coltsfoot extract, butterbur bud extract, bupleurum extract, butcher's broom extract, grape extract, grape seed extract,Examples of extracts that may be included include loofah extract, safflower extract, peppermint extract, linden extract, peony extract, hop extract, pine extract, horse chestnut extract, skunk cabbage extract, soapberry extract, melissa extract, mozuku extract, peach extract, cornflower extract, eucalyptus extract, saxifrage extract, yuzu extract, lily extract, coix seed extract, mugwort extract, lavender extract, green tea extract, apple extract, rooibos tea extract, lychee extract, lettuce extract, lemon extract, forsythia extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, royal jelly extract, and burnet extract.

[0228] Such an extract may be a commercially available product. The extract may be blended in the cosmetic composition alone or in combination of two or more kinds.

[0229] The content of the extract of component y) in the second skin topical composition is preferably 0.00001 to 5% by mass, more preferably 0.0001 to 2% by mass, based on the total amount of the cosmetic, as a dry solid content. From the viewpoint of stably blending the extract and satisfactorily exerting the effect of the extract, it is preferable that the content of the extract is within the above range.

[0230] In order to protect the skin from ultraviolet rays that have a detrimental effect on the skin, a preferred embodiment of the second skin topical composition contains an ultraviolet absorbing agent and / or an ultraviolet scattering agent. By containing an ultraviolet absorbing agent and / or an ultraviolet scattering agent, the adverse effects of not only near-infrared rays but also ultraviolet rays are suppressed, making the skin topical composition particularly suitable for protecting the skin.

[0231] The type of ultraviolet absorber is not particularly limited as long as it is a known one used in the field of external skin preparations such as cosmetics, and examples thereof include cinnamic acid-based ultraviolet absorbers, benzophenone-based ultraviolet absorbers, benzoic acid-based ultraviolet absorbers, salicylic acid-based ultraviolet absorbers, dibenzoylmethane-based ultraviolet absorbers, anthranilic acid-based ultraviolet absorbers, urocanic acid-based ultraviolet absorbers, and triazine-based ultraviolet absorbers. Specifically, cinnamic acid-based ultraviolet absorbers such as paramethoxycinnamate-2-ethylhexyl, paramethoxycinnamate isopropyl, paramethoxyhydrocinnamic acid diethanolamine salt, diparamethoxycinnamate-mono-2-ethylhexanoate glyceryl, methoxycinnamate octyl, and diisopropyl cinnamate methyl; 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfuric acid, 2-hydroxy-4-methoxybenzophenone-5-sodium sulfate, 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2',4,Benzophenone-based UV absorbers such as 4'-tetrahydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone; benzoic acid-based UV absorbers such as para-aminobenzoic acid, ethyl para-aminobenzoate, butyl para-aminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, glyceryl para-aminobenzoate, octyl para-dimethylaminobenzoate, amyl para-aminobenzoate, and diethylaminohydroxybenzoylhexyl benzoate; salicylic acid-based UV absorbers such as 2-ethylhexyl salicylate, triethanolamine salicylate, homomenthyl salicylate, dipropylene glycol salicylate, methyl salicylate, ethylene glycol salicylate, phenyl salicylate, amyl salicylate, benzyl salicylate, isopropyl benzyl salicylate, and potassium salicylate; Examples of the ultraviolet absorbing agent include dibenzoylmethane, 4-isopropyldibenzoylmethane, 4-methoxydibenzoylmethane, 4-tert-butyl-4'-hydroxydibenzoylmethane, and other dibenzoylmethane-based ultraviolet absorbing agents, menthyl-O-aminobenzoate, 2-phenyl-benzimidazole-5-sulfuric acid, 2-phenyl-5-methylbenzoxazole, 3-(4-methylbenzylidene)camphor, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethyl-2-cyano-3,3'-diphenylacrylate, 2-(2'-hydroxy-5-methylphenyl)benzotriazole, and other anthranilic acid-based ultraviolet absorbing agents, such as menthyl anthranilate, and urocanic acid-based ultraviolet absorbing agents, such as ethyl urocanate; and triazine-based ultraviolet absorbing agents, such as bisethylhexyloxyphenol methoxyphenyl triazine and ethylhexyl triazone. As the ultraviolet absorbing agent, commercially available products can also be used. The ultraviolet absorbent may be blended in the cosmetic composition in one type or in a combination of two or more types.

[0232] The content of the ultraviolet absorbing agent in the second skin external composition is usually 0.01% by mass to 15% by mass, preferably 0.1% by mass to 10% by mass. When the content of the ultraviolet absorbing agent is within the above range, excellent ultraviolet absorbing ability can be exhibited.

[0233] The type of ultraviolet scattering agent is not particularly limited as long as it is a known agent used in the field of skin external preparations such as cosmetics, but is not particularly limited as long as it is, for example, a fine particle metal oxide having the function of scattering ultraviolet rays and can be blended into an emulsion composition, an oil gel composition, etc. Examples of metal oxides include titanium oxide, titanium dioxide, zinc oxide, zirconium oxide, and cerium oxide. Only one type of ultraviolet scattering agent may be blended into the cosmetic, or two or more types may be blended in combination.

[0234] The fine particle metal oxide has a particle size that is called fine particles in the relevant technical field, and for example, has a primary particle size as measured by observation with an electron microscope of usually 5 to 100 nm, preferably 10 to 80 nm.

[0235] The ultraviolet scattering agent has an excellent ultraviolet scattering effect, and therefore, the second composition for external application to skin preferably contains one or two kinds selected from fine particle titanium oxide and fine particle zinc oxide.

[0236] The ultraviolet scattering agent to be added to the second composition for external use on skin can be prepared by a conventional method such as thermally decomposing a salt of the corresponding metal in the gas phase, but a commercially available product can also be used.

[0237] The surface of the ultraviolet scattering agent is preferably coated with an inorganic compound such as silica, alumina, etc., or an organic compound such as a surfactant such as stearic acid, isostearic acid, sodium alginate, etc., or a silicone compound such as silicone oil, etc. When a coating treatment is performed, it can be performed by a known surface treatment method.

[0238] The UV scattering agent is preferably dispersible in an oil phase. Since the UV scattering agent dispersible in an oil phase is uniformly dispersed in the oil phase, the second composition for external use on the skin in this form has excellent water resistance and UV protection function.

[0239] A preferred example of the oil-dispersible ultraviolet scattering agent is an ultraviolet scattering agent whose surface is coated with a hydrophobic compound. Although not limited to such an oil-dispersible ultraviolet scattering agent, an ultraviolet scattering agent coated with a hydrophobic organic compound is preferably used.

[0240] The content of the ultraviolet scattering agent in the second skin external composition is usually 0.01% by mass to 15% by mass, preferably 0.1% by mass to 10% by mass. When the content of the ultraviolet scattering agent is within the above range, excellent ultraviolet scattering ability can be exhibited.

[0241] From the viewpoint of uniformly dispersing the ultraviolet scattering agent in the oil phase, it is preferable that the ultraviolet scattering agent is dispersed in an oily medium and then mixed with the cosmetic raw material. The dispersion of the ultraviolet scattering agent in the oily medium can be carried out based on a preparation method generally used in the field of cosmetics, etc. For example, the ultraviolet scattering agent and the oily medium can be mixed in a bead mill or the like to prepare a fluid (slurry) in which the ultraviolet scattering agent is dispersed in the oily medium, and then the ultraviolet scattering agent can be dispersed.

[0242] In the slurry obtained by stirring and mixing the ultraviolet scattering agent and the oil medium, the content of the ultraviolet scattering agent is preferably 10% by mass to 70% by mass in order to provide the slurry with appropriate fluidity.

[0243] The oil medium for dispersing the ultraviolet scattering agent is not limited, but examples thereof include silicone oils such as hydrogen dimethicone, caprylyl methicone, dimethicone, and cyclopentasiloxane; fatty acid ester oils such as lauric acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, isononanoic acid ester, isostearic acid ester, isopalmitic acid ester, oleic acid ester, and vegetable oils (macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, etc.). From the viewpoint of dispersibility, fatty acid ester oils are preferably used. The oil medium may be used alone or in combination of two or more. Among these, vegetable oils are preferred from the viewpoint of obtaining good dispersibility, and olive oil is more preferred.

[0244] The second skin external composition may contain optional ingredients that are usually used in cosmetics and the like other than the above essential ingredients. Optional ingredients include, for example, oils such as macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, and dicaprylyl carbonate; waxes such as hydrogenated coconut oil, hydrogenated oil, Japan wax, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, Japanese laurel wax, lanolin, reduced lanolin, hard lanolin, and jojoba wax; liquid paraffins such as hydrogenated polyisobutene, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum, Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, and undecylenic acid; higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, and cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, and di-2-ethyl hexanoate. Synthetic ester oils such as ethylhexyl, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, and pentane erythritol tetra-2-ethylhexanoate; linear polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, and diphenylpolysiloxane; octadecyl esters such as ethylhexyl esters, ethylhexyl esters, and ethylhexyl esters; Cyclic polysiloxanes such as methylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; oils such as silicone oils, including modified polysiloxanes such as amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, and fluorine-modified polysiloxane; anionic surfactants such as fatty acid soaps (potassium behenate, potassium stearate, sodium laurate, sodium palmitate, and the like), potassium lauryl sulfate, and alkyl sulfate triethanolamine ether;Cationic surfactants such as stearyl trimethylammonium chloride, benzalkonium chloride, laurylamine oxide, etc.; imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine-based surfactants (alkyl betaine, amido betaine, sulfobetaine, etc.), acyl methyl taurine, etc.; sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycol Serine fatty acids (glycerin monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hydrogenated castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbit fatty acid esters (POE-sorbitan monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), PO E fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE 2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP 2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hydrogenated castor oil derivatives (POE castor oil, POE hydrogenated castor oil, etc.), sucrose fatty acid esters, alkyl glycols nonionic surfactants such as coside; moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate, etc.; powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, etc., which may be surface-treated; inorganic pigments such as red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine blue, Prussian blue, zinc oxide, pigment-grade titanium oxide, etc., which may be surface-treated; pearl agents such as fish phosphorus foil, bismuth oxychloride, etc., which may be surface-treated;Organic dyes such as Red No. 202, Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, and Red No. 204, which may be laked; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomer; lower alcohols such as ethanol and isopropanol; vitamin Bs such as vitamin A or a derivative thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or a derivative thereof, vitamin B12, and vitamin B15 or a derivative thereof; Examples of such ingredients include vitamin E, such as α-tocopherol, β-tocopherol, γ-tocopherol, and vitamin E acetate, vitamin D, vitamin H, pantothenic acid, pantethine, and pyrroloquinoline quinone; antibacterial agents, such as methylparaben and phenoxyethanol; physiologically active ingredients, such as skin whitening agents, cell activators, skin roughness improving agents, blood circulation promoters, and skin astringents; pH adjusters; alcohols, such as water, methanol, ethanol, isopropyl alcohol, and 1,3-butylene glycol; thickeners, such as carboxyvinyl polymers; emulsion stabilizers, such as polyglyceryl pentastearate and sodium stearoyl lactylate; and solvents, such as benzene, toluene, tetrahydrofuran, and silicone.

[0245] The second skin topical composition can be produced by a known method used in the field of ordinary cosmetics, etc. For example, in the case of an oil-in-water emulsion, powder components including component a-1) and component b-1) are added to a heated oil phase after pulverization as necessary, and mixed and dispersed. The oil phase is added to a heated water phase, emulsified, and cooled to obtain the composition. For example, an oil gel formulation can be obtained by adding powder components containing component a-1) and component b-1), optionally pulverizing them, to a heated oil phase, mixing and dispersing them, and cooling.

[0246] The second composition for topical application on the skin is preferably in the form of an oil-in-water emulsion, and from the viewpoint of making it into a composition that combines improved water resistance and uniform film-forming properties, it is preferable that the second composition for topical application on the skin has the following configuration. a-2) Titanium dioxide having an average particle size of 0.5 μm or more and surface-treated with triethoxycaprylylsilane; b-2) ultraviolet absorbing agents and / or ultraviolet scattering agents; c-2) fatty acid salts; and d-2) oil solutions that are paste-like or solid at 25°C, excluding higher alcohols and fatty acids.

[0247] Titanium oxide with a large average particle size, specifically titanium oxide with an average particle size of 0.5 μm or more, is particularly excellent in scattering near-infrared rays. In addition, by mixing the above-mentioned titanium oxide surface-treated with triethoxycaprylylsilane with an oil phase containing a fatty acid salt, the fatty acid salt can be bonded to the titanium oxide surface, and the titanium oxide can be effectively dispersed in the oil phase. Furthermore, oils that are paste-like or solid at 25°C, except for higher alcohols and fatty acids, can improve water resistance by increasing skin adhesion and hydrophobicity of the film. Hereinafter, an embodiment of the second composition for external use on skin containing components a-2) to d-2) will be described in detail.

[0248] Component a-2) is titanium oxide having an average particle size of 0.5 μm or more and having been surface-treated with triethoxycaprylylsilane. The average particle size of the titanium oxide is as described above.

[0249] The titanium oxide of component a-2) is surface-treated with triethoxycaprylylsilane by a known surface treatment method. In the second skin topical composition in the form of an oil-in-water emulsion, the titanium oxide surface-treated with triethoxycaprylylsilane has excellent dispersibility in the oil phase.

[0250] The titanium oxide of component a-2) is not particularly limited as long as it has the specific average particle size and has been subjected to a specific surface treatment. Such titanium oxide may be a commercially available product. Alternatively, commercially available titanium oxide may be surface-treated by a known method. The titanium oxide may be blended in the composition with only one type of titanium oxide having different particle size, or may be blended in combination with two or more types of titanium oxide.

[0251] In the second skin topical composition in the form of an oil-in-water emulsion, the content of titanium oxide (component a-2) is usually 0.1% by mass to 15% by mass, preferably 0.5% by mass to 10% by mass. From the viewpoint of good near-infrared scattering effect and dispersibility, the content of titanium oxide is preferably within the above range.

[0252] In the second skin topical composition in the form of an oil-in-water emulsion, the oil phase component dispersing titanium oxide (component a-2) is not limited, but from the viewpoint of powder dispersibility, saturated or unsaturated fatty acids and the like can be mentioned. Specific examples of such fatty acids include, but are not limited to, saturated or unsaturated fatty acids having 12 to 22 carbon atoms, such as lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, and behenic acid. From the viewpoint of dispersibility, saturated fatty acids having 18 to 22 carbon atoms are more preferable, and stearic acid and behenic acid are particularly preferable. The oil phase component may be blended in the composition in one type or in a combination of two or more types.

[0253] In the oil-in-water emulsion composition of the present invention, the content of the oil phase component that disperses titanium oxide (component a-2) is usually 1% by mass to 40% by mass, preferably 5% by mass to 30% by mass, from the viewpoints of dispersibility and usability. The above content includes the fatty acid that constitutes the fatty acid salt (component c-2).

[0254] Component b-2) is an ultraviolet absorbing agent and / or an ultraviolet scattering agent. By containing an ultraviolet absorbing agent and / or an ultraviolet scattering agent, the harmful effects of not only near infrared rays but also ultraviolet rays are suppressed, making the composition particularly suitable for protecting the skin.

[0255] With regard to component b-2), the items described above apply with respect to the type of UV absorber, the content of UV absorber, the type of UV scattering agent, the preparation method or acquisition method of the UV scattering agent, the surface treatment of the UV scattering agent, the form of the oil-dispersible UV scattering agent, the content of the UV scattering agent, the means for uniformly dispersing the UV scattering agent in the oil phase, the oil-based medium in which the UV scattering agent is dispersed, etc.

[0256] Component c-2) is a fatty acid salt. By including the fatty acid salt, component a-2) titanium oxide having an average particle size of 0.5 μm or more and surface-treated with triethoxycaprylylsilane can be dispersed well in the oil phase.

[0257] The fatty acid salt may be added directly to the composition raw material as a fatty acid salt, or may be produced by reacting a fatty acid with an alkali during the production process, and its origin is not particularly limited.

[0258] The fatty acid constituting the fatty acid salt is not limited, but may be a saturated or unsaturated fatty acid having a carbon number of 12 to 22. Specific examples of the fatty acid are the same as those exemplified as the fatty acid used as the oil phase component above.

[0259] Examples of fatty acid salts include alkali metal salts (sodium fatty acid, potassium fatty acid, etc.), alkaline earth metal salts (magnesium fatty acid, calcium fatty acid, barium fatty acid, etc.), and ammonia salts (ammonium fatty acid) of the above fatty acids, as well as reaction products of the above fatty acids with organic amines such as amines, hydroxylamines, imines, guanidines, amine oxides, alkanolamines, alkoxylated amines, and alkylamines (diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, aminobutanol, aminoethylpropanediol, aminomethylpropanol, aminomethylpropanediol, isopropylamine, methylethanolamine, diisopropylamine, dipropylenetriamine, glucamine, N-methylglucamine, morpholine, tromethamine), cocamines, soyamines, oleamines, stearamines, and quaterniums. The fatty acid salt is preferably an alkali metal salt or an alkaline earth metal salt of a fatty acid, and more preferably an alkali metal salt of a fatty acid, such as a fatty acid sodium salt or a fatty acid potassium salt. The fatty acid salt may be blended in the composition alone or in combination of two or more kinds.

[0260] The content of these fatty acid salts in the second composition for external use on skin in the form of an oil-in-water emulsion is usually 0.1% by mass to 5% by mass, preferably 0.5% by mass to 3% by mass, from the viewpoint of dispersibility.

[0261] Component d-2) is an oil that is a paste or solid at 25°C, excluding higher alcohols and fatty acids (hereinafter, may be simply referred to as "oil that is a paste or solid at 25°C"). By including an oil that is a paste or solid at 25°C, it is possible to increase the skin adhesion and the hydrophobicity of the film, and improve the water resistance. One embodiment of the "oil that is a paste or solid at 25°C" is an "oil with a melting point of 30°C or higher."

[0262] The oil agent that is pasty or solid at 25°C and is used in the oil-in-water emulsion composition of the present invention may be natural or synthetic, so long as it can be incorporated into cosmetics, etc. Examples of such oil agents include tri(caprylic acid / capric acid / myristic acid / stearic acid), hydrogenated castor oil stearate, rice bran oil fatty acid phytosteryl, tetra(hydroxystearate / isostearate) dipentaerythrityl, hexahydroxystearate dipentaerythrityl, hydroxyalkyl dimer fatty acid ethers (hydroxyalkyl (C12-14) hydroxydimer dilinoleyl ether, hydroxyalkyl (C16-18) hydroxydimer dilinoleyl ether, etc.), bisdiglyceryl polyacyladipate-2, shea butter, theobroma grandiflorum, and the like. Examples of the oils include diflorum seed oil, hydrogenated coconut oil, hydrogenated oil, Japan wax, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ivoro wax, lanolin, reduced lanolin, hard lanolin, jojoba wax, hydrogenated palm oil, ozokerite, paraffin, ceresin, petrolatum, microcrystalline wax, partially hydrogenated isomerized jojoba oil, phytosteryl oleate, phytosteryl macadamiate, a mixture of vegetable triglycerides and organic fatty acids obtained by hydrogenating palm oil, palm kernel oil, coconut oil, and rapeseed oil, and an ester of dipentaerythritol and mixed fatty acids. Among the above oils, hydrogenated palm oil and hydroxyalkyl dimer fatty acid ethers are preferred from the viewpoint of improving stability and water resistance, and hydroxyalkyl dimer fatty acid ethers are more preferred. As the fatty acid constituting the dimer, unsaturated fatty acids having 16 to 20 carbon atoms are preferred. Specific examples of fatty acids include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, etc. Commercially available products may also be used. The oil agent that is pasty or solid at 25°C used in the oil-in-water emulsion composition of the present invention may be blended in the composition alone or in combination of two or more kinds.

[0263] The second skin topical composition in the form of an oil-in-water emulsion contains, in the composition, usually 0.5% by mass or more, preferably 1% by mass or more of the component (d-2) which is a paste or solid oil at 25°C, from the viewpoint of good water resistance. If the content is too high, stickiness will occur, so the content is usually 10% by mass or less. It is preferable that the content of the paste or solid oil at 25°C is within the above range.

[0264] The second skin topical composition in the form of an oil-in-water emulsion may contain a film-forming agent as component e-2). The film-forming agent is not particularly limited as long as it forms a film after the composition containing the film-forming agent is applied to the skin or the like and dried. By incorporating a film-forming agent, water resistance, durability, and stability are improved.

[0265] As component e-2), for example, a polymer compound dispersed in an aqueous solvent such as water (emulsion, etc.) that is usually used in cosmetics can be used. For example, alkyl acrylate copolymer emulsion, alkyl acrylate-styrene copolymer emulsion, polyvinyl acetate emulsion, vinylpyrrolidone-styrene copolymer emulsion, etc. can be mentioned, and alkyl acrylate copolymer emulsion is preferably used. As the film-forming agent, one or more kinds can be used as necessary.

[0266] In the present invention, the film-forming agent of component e-2) is contained in the second skin topical composition in an amount of usually 0.01% by mass to 2% by mass, preferably 0.02% by mass to 1% by mass, as a polymer solid content. From the viewpoint of good water resistance, the content of the film-forming agent is preferably in the above range.

[0267] The second composition for external use on the skin in the form of an oil-in-water emulsion may contain optional ingredients other than the above-mentioned essential ingredients that are usually used in cosmetics, etc. Specific examples of the optional ingredients are as described above.

[0268] The specific uses of the second skin topical composition in the form of an oil-in-water emulsion are not particularly limited, and examples thereof include skin topical preparations such as emulsions, sunscreens, foundations, and cosmetics, etc. In such an embodiment, the effects of the present invention can be effectively utilized, and the composition can be particularly suitable for protecting the skin.

[0269] The second composition for external use on the skin in the form of an oil-in-water emulsion can be produced by a production method including a step of mixing the above-mentioned components a-2) to d-2).

[0270] The method for producing the second skin topical composition in the form of an oil-in-water emulsion is not particularly limited as long as it includes a step of mixing components a-2) to d-2). As for the mixing method, a known method used in the field of ordinary cosmetics and the like can be appropriately adopted. For example, an alkali is heated and mixed into an oil phase containing a fatty acid and component d-2) a paste-like or solid oil agent at 25°C to form a fatty acid salt of component c-2), and a powder component containing components a-2) and b-2) is added to the oil phase after being crushed as necessary, and mixed and dispersed. The oil phase can be obtained by adding the oil phase to a heated aqueous phase, emulsifying, and cooling. After emulsification, component e-2) is added as necessary. It is preferable not to mix component a-2) in the form of a slurry, i.e., to mix the titanium oxide of component a-2) directly with the oil phase, since this allows component a-2) to be well dispersed in the oil phase. EXAMPLES

[0271] Test Example 1: Changes in expression of neutrophil adhesion factors by irradiation with red light or near-infrared light (1) Experimental procedure Using the experimental procedures detailed below, vascular endothelial cells were irradiated with red light or near-infrared light, and after 24 hours of culture, gene expression of neutrophil adhesion molecules (ICAM-1: intercellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-1) was measured using q-RT-PCR and compared with that in non-irradiated cases.

[0272] First, vascular endothelial cells (HUVEC (Kurabo)) were placed in a 24-well plate at 6.0 × 10 4 The cells were seeded at 100 cells / well and cultured overnight in an incubator (37°C, 5% CO2).

[0273] Next, the cultured vascular endothelial cells were washed with PBS(-), and then 1 mL of PBS was added to the plate.

[0274] The plate lid was opened, and an optical filter (HOYA, SCHOTT, Shibuya Optical) was placed under the light source of a solar simulator (XHS-8, Spectral Engines) to cut off transmission of wavelengths other than the target. Red light (620-760 nm) or near-infrared light (760-1440 nm) was then applied at 74 J / cm. 2 , 41J / cm 2 Irradiated. These conditions, when converted to the illuminance (annual average) on a sunny day in Japan, are equivalent to the dose of sunlight for 2.5 hours that reaches the dermis (a depth of approximately 1 mm from the skin surface).

[0275] As a control, a plate similarly seeded with vascular endothelial cells was wrapped in aluminum foil and left to stand on the same experimental bench for the same period of time.

[0276] After irradiation with red light or near-infrared light, the PBS(-) was removed from the plate, 1 mL of a medium specifically for vascular endothelial cells was added, and the cells were cultured in an incubator (37°C, 5% CO2).

[0277] Twenty-four hours after irradiation, mRNA was extracted and the expression of ICAM-1 and VCAM-1 was analyzed by q-RT-PCR. The primers used for q-RT-PCR were ICAM-1 (QIAGEN, Hs_ICAM1_1_SG QuantiTect Primer Assay) and VCAM-1 (Thermofisher custom primer). As an endogenous control, TBP (TATA binding protein) (QIAGEN, Hs_TBP_1_SG QuantiTect Primer Assay) was used.

[0278] The expression levels of ICAM-1 and VCAM-1 were divided by the expression level of TBP to determine the expression levels of ICAM-1 and VCAM-1 in each sample.

[0279] (2) Results The results of red light irradiation are shown in Table 1, Figure 1, and Figure 2. The average value of the non-irradiated group (n = 3) was set to 1, and the expression levels of ICAM-1 and VCAM-1 in the red light irradiation group (n = 3) were evaluated. The results of near-infrared irradiation are shown in Table 2. The average value of the non-irradiated group (n=3) was set to 1, and the expression levels of ICAM-1 and VCAM-1 in the near-infrared irradiated group (n=3) were evaluated.

[0280] [Table 1]

[0281] [Table 2]

[0282] As shown in Table 1, Figures 1 and 2, a decrease in the expression level of neutrophil adhesion promoters (ICAM-1, VCAM-1) in vascular endothelial cells was observed upon irradiation with red light. This result indicates that red light irradiation suppresses the expression of neutrophil adhesion-promoting factor, thereby inhibiting neutrophil adhesion to vascular endothelial cells, i.e., it is possible to suppress the infiltration of neutrophils from blood vessels into skin tissue by red light irradiation.

[0283] On the other hand, as shown in Table 2, an increase in the expression of neutrophil adhesion promoting factors (ICAM-1, VCAM-1) in vascular endothelial cells was observed following irradiation with near-infrared rays. These results indicate that near-infrared irradiation increases the expression of neutrophil adhesion-promoting factors, thereby promoting neutrophil adhesion to vascular endothelial cells and infiltration from blood vessels into skin tissue.

[0284] In daily life, there are occasions when the skin is exposed to sunlight that contains both near-infrared and red light. In this case, by applying red light to vascular endothelial cells in skin tissue while blocking the near-infrared light contained in sunlight, it is possible to more strongly suppress the expression of neutrophil adhesion promoting factor, thereby providing an effective prevention or improvement effect for wrinkles and sagging.

[0285] <Test Example 2> Test related to MFAP4 <Test Example 2-1> Evaluation of cell proliferation rate In Test 2-1, the effect of light with a wavelength of 625 nm (red light) on tendon cell proliferation was examined.

[0286] (1) Experimental procedure First, tenocytes were cultured in a 24-well plate at 2.5 x 10 4 The cells were seeded at 200 cells / mL and cultured overnight in an incubator (37°C, 5% CO2).

[0287] Next, the cultured tendon cells were washed with PBS(-), and then 300 mL of PBS(-) was added to the plate.

[0288] The lid of the plate was opened and a red light (peak wavelength: 625 nm) LED lamp was installed. As a control, a plate was wrapped in aluminum foil and placed on the same experimental bench.

[0289] 45W / m 2 3.3 minutes (0.88 J / cm 2 ) Tendon cells were illuminated with red light. Here, the light irradiation under the above conditions is equivalent to 1.4 hours of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

[0290] After irradiation, the PBS(-) was removed from the plate, 1 mL of medium specifically for tendon cells was added, and the cells were cultured overnight in an incubator (37°C, 5% CO2). Twelve hours after irradiation, cell proliferation was evaluated using a viable cell count kit (WST-8). The results are shown in Figure 3.

[0291] (2) Results and Discussion As shown in Figure 3, it was found that irradiating tendon cells with light with a peak wavelength of 625 nm (red light) improved the cell proliferation rate. Tendon cells are cells that produce MFAP4, and it was found that applying red light to the cells increased and / or decreased the expression of MFAP4.

[0292] <Test Example 2-2> Evaluation of cell proliferation rate In Test Example 2-2, the effect of long-wavelength visible light (light having a wavelength of 585 to 760 nm) on enhancing the activity of tendon cells was examined.

[0293] (1) Experimental procedure First, tenocytes were cultured in a 24-well plate at 2.5 x 10 4 The cells were seeded at 200 cells / mL and cultured overnight in an incubator (37°C, 5% CO2).

[0294] Next, the cultured tendon cells were washed with PBS(-), and then 300 mL of PBS(-) was added to the plate.

[0295] The lid of the plate was opened, and a light source capable of irradiating light in the wavelength range of 585 to 760 nm, which is close to the wavelength of sunlight, was installed using a halogen lamp, a light-cutting filter, and a plastic tray containing water. As a control, a plate was wrapped in aluminum foil and placed on the same experimental bench.

[0296] 50W / m 2 3.3 minutes (1 J / cm 2 The sample was irradiated with long-wavelength visible light (light having a wavelength of 585 to 760 nm) for 10 min. Here, the light irradiation under the above conditions is equivalent to 3.3 minutes of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

[0297] In another embodiment, 50 W / m 2 16.7 minutes (5J / cm 2 The sample was irradiated with long-wavelength visible light (light having a wavelength of 585 to 760 nm) for 10 min.

[0298] After irradiation, the PBS(-) was removed from the plate, 1 mL of medium specifically for tendon cells was added, and the cells were cultured in an incubator (37°C, 5% CO2). Mitochondrial activity and cell proliferation rate were evaluated at 0, 24, and 48 hours after irradiation.

[0299] Mitochondrial activity was measured by staining cells with JC-1 dye and Hoechst 33432. Mitochondrial activity was evaluated by calculating the red (high mitochondrial membrane potential) / green (low mitochondrial membrane potential) fluorescence ratio. When the mitochondrial membrane potential is high, red fluorescence is emitted, and when it is low, green fluorescence is emitted. Therefore, the higher the red / green fluorescence intensity value, the higher the mitochondrial activity of the cell can be evaluated. The results are shown in Figures 4 and 5.

[0300] (2) Results and Discussion As shown in Figure 4, it was found that mitochondrial activity was improved by irradiating tendon cells with light having a wavelength of 585 to 760 nm (long-wavelength visible light). Furthermore, as shown in Figure 5, it was found that the cell proliferation rate was improved by irradiating tendon cells with light having a wavelength of 585 to 760 nm (long-wavelength visible light). Tendon cells are cells that produce MFAP4, and it was found that applying red light to the cells increased and / or suppressed the decrease in MFAP4 expression.

[0301] <Test Example 2-3> In Test Example 2-3, the effect of light having a specific wavelength on gene expression of matrix metalloproteinase was examined. (1) Experimental procedure First, skin tissue (with subcutaneous tissue) from the abdomen of a Caucasian woman was cultured overnight.

[0302] Next, the cultured tendon cells were washed with PBS(-), and then 300 mL of PBS(-) was added to the plate.

[0303] The lid of the plate was opened, and an LED irradiator capable of irradiating light having a wavelength of 400 to 700 nm (visible light) was installed. As a control, a plate was prepared that was wrapped in aluminum foil and placed on the same laboratory bench. 286W / m 2 1.8 hours (190 J / cm 2 ) and irradiated with light having a wavelength of 400 to 700 nm (visible light). Here, the light irradiation under the above conditions is equivalent to 66.7 minutes of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

[0304] After irradiation, the PBS(-) was removed from the plate, 1 mL of ex vivo culture medium was added, and the cells were cultured in an incubator (37°C, 5% CO2).

[0305] 24 hours after irradiation, the tissue was immersed overnight in RNAlater RNA Stabilization Reagent (QIAGEN). After soaking, the retinaculum was cut into pieces, and RNA was extracted from the cut retinaculum using the RNeasy Fibrous Tissue Mini Kit (QIAGEN).

[0306] The extracted RNA was subjected to microarray analysis using a SurePrint G3 Human GE microarray 8x60K (Agilent Technologies) to evaluate gene expression levels of matrix metalloproteinases. The results are shown in Figure 6.

[0307] (2) Results and Discussion As shown in FIG. 6, light having a wavelength of 400 to 700 nm (visible light) decreased the expression and / or inhibited the increase in expression of matrix metalloproteinase. Here, among visible light, light that reaches subcutaneous tissue is long-wavelength visible light. That is, it was found that long-wavelength visible light has the effect of decreasing and / or suppressing the increase in expression of matrix metalloproteinases. In particular, it was found that long-wavelength visible light suppressed the expression levels of MMP-3, MMP-7, MMP-9, and MMP-12.

[0308] <Test Example 2-4> Relationship between matrix metalloproteinase and MFAP4 In Test Example 2-4, the relationship between matrix metalloproteinases and MFAP4 was examined.

[0309] (1) Experimental procedure First, matrix metalloproteases (MMP3 or MMP9) activated with chymotrypsin were mixed with MFAP4 to prepare enzyme-substrate reaction solutions.

[0310] Here, in order to confirm the change in the state of substrate decomposition due to the inhibition of enzyme activity, a system was prepared to which an MMP inhibitor (80 mM NNGH (N-hydroxy-2-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]acetamide) (solvent: DMSO)) was added. The sample containing the MMP inhibitor was prepared by adding NNGH to the above enzyme-substrate reaction solution.

[0311] The prepared enzyme-substrate reaction solution was incubated at 37°C for 24 hours with shaking.

[0312] Using Lane Marker Sample Buffer SDS (manufactured by Thermo Fisher Scientific) as a marker, samples from each system shown in FIG. 7 were loaded (applied) onto an SDS-polyacrylamide gel and electrophoresis was performed.

[0313] After electrophoresis, the samples were silver stained using 2D-Silver Stain Reagent II (Cosmo Bio) and the protein bands were quantified. The results are shown in Figure 7.

[0314] (2) Results and Discussion As shown in Figure 7, it was found that microfibril-associated glycoprotein 4 (MFAP4) is degraded in the presence of matrix metalloproteinase-3 (MMP3) and matrix metalloproteinase-9 (MMP9).

[0315] Here, as shown in Test Example 2-3, long wavelength visible light reduces and / or inhibits the increase in expression of matrix metalloproteinase. It was found that applying long-wavelength visible light to cells not only increased the production of MFAP4 associated with tendon cell proliferation, but also increased and / or inhibited the decrease in expression of MFAP4 by decreasing the expression and / or inhibiting the increase in expression of matrix metalloproteinases.

[0316] <Test Example 2-5> In Test Example 2-5, the effect on the expression level of MFAP4 by applying red light to cells and then applying an anti-photoaging component to the cells was examined.

[0317] (1) Experimental procedure First, tenocytes were cultured in a 24-well plate at 2.5 x 10 4 The cells were seeded at 37°C and 5% CO2 overnight. The cultured tendon cells were washed with PBS(-), and then 300 mL of PBS(-) was added to the plate.

[0318] The lid of the plate was opened and a red light (peak wavelength: 625 nm) LED lamp was installed. As a control, a plate was wrapped in aluminum foil and placed on the same experimental bench.

[0319] 45W / m 2 3.3 minutes (0.88 J / cm 2 ) Tendon cells were illuminated with red light. Here, the light irradiation under the above conditions is equivalent to 1.4 hours of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

[0320] After irradiation, the PBS(-) was removed from the plate, and 1 mL of a medium specifically for tendon cells containing 0.5% burdock extract was added, followed by overnight culture at 37°C and 5% CO2 (Example 2). At the same time, a system using a medium not containing burdock extract was also prepared (Example 1). In addition, a medium not containing burdock extract was also used for the control (system not irradiated with red light).

[0321] Forty-eight hours after irradiation, mRNA was extracted and MFAP4 mRNA expression was analyzed by q-RT-PCR.

[0322] The primer used for q-RT-PCR was MFAP4 (QIAGEN, Hs_MFAP4_1_SG QuantiTect Primer Assay, QT00040026). In addition, Actin-b (QIAGEN, Hs_ACTB_2_SG QuantiTect Primer Assay, QT01680476) was used as an endogenous control.

[0323] The results are shown in Table 3 and Figure 8. Here, in Table 3 and Figure 8, the measured value (average value) under control conditions was set to 1, and the expression levels (average value) of MFAP4 in Examples 1 and 2 were evaluated.

[0324] [Table 3]

[0325] (2) Results and Discussion As shown in Table 3 and Figure 8, the expression level of MFAP4 was increased by irradiation with red light (Example 1). Furthermore, the expression level of MFAP4 was further increased by applying an anti-photoaging component to the cells after applying red light to the cells (Example 2).

[0326] As described above, the results of Test Example 2 demonstrate that application of red light induces increased expression of MFAP4, thereby enhancing the cutaneous retinaculum. Considering these results together with those of Test Example 1, it was found that irradiation with red light can inhibit the infiltration of neutrophils from blood vessels into skin tissue, inhibit the degradation of elastin and collagen by neutrophil elastase secreted by neutrophils, and also achieve the strengthening of the skin retinaculum. In other words, it has been shown that irradiating the skin with red light has the effect of preventing or improving wrinkles and sagging through two mechanisms: inhibiting the breakdown of elastin and collagen, and strengthening the skin retinaculum.

[0327] <Test Example 3> Effect of cyclohexylglycerin and horsetail extract on gene expression of neutrophil chemotaxis promoting factor in dermis-derived fibroblasts Human normal dermal fibroblasts were seeded in 10% FBS / DMEM medium onto a 24-well plate at 1000 μL / well, and cultured at 37° C. in a 5% CO 2 environment for 24 hours. 24 hours after sowing, samples were prepared to which cyclohexylglycerin ("ADEKA NOL CHG", ADEKA Corporation) and horsetail extract ("Horsetail Extract UK-P", Maruzen Pharmaceuticals) were added (cyclohexylglycerin: final concentration 0.05% by mass, horsetail extract: final concentration 1% by mass), and to which both components were added (cyclohexylglycerin: final concentration 0.05% by mass, horsetail extract: final concentration 1% by mass).

[0328] After 24 hours, the medium was removed and the cells were washed with PBS. The cells were then recovered using an RNeasy Mini QiAcube kit (QIAGEN), and RNA was extracted using a QIAcube (QIAGEN). RT-PCR was performed using the QuantiTecT SYBR Green RT-PCR Kit (QIAGEN) to measure the mRNA expression levels of CXCL-1, IL-8, and TBP, an endogenous control, in each sample. The mRNA expression level of each sample was calculated by dividing the mRNA expression level of CXCL-1 and IL-8 by the mRNA expression level of TBP. The results are shown in Figures 9 and 10.

[0329] As shown in Figure 9, the expression level of CXCL-1 in the sample with added cyclohexylglycerin was reduced to approximately 57% compared to the non-additive group, and the expression level of CXCL-1 in the sample with added horsetail extract was reduced to approximately 43% compared to the non-additive group. Furthermore, as shown in FIG. 9, it was found that the expression level of CXCL-1 in the samples to which cyclohexylglycerin and horsetail extract had been added was reduced to approximately 18% compared to the control group. These results indicate that both cyclohexylglycerin and horsetail extract have the effect of suppressing the gene expression of CXCL-1, a neutrophil migration-promoting factor, and that combining these ingredients produces a synergistic effect of suppressing gene expression.

[0330] Furthermore, as shown in Figure 10, it was found that the expression levels of IL-8 in the samples with added cyclohexylglycerin, the samples with added horsetail extract, and the samples with added both ingredients were reduced to approximately 72%, approximately 69%, and approximately 70% compared to the non-additive group. These results indicate that although both cyclohexylglycerin and horsetail extract have the effect of suppressing the gene expression of IL-8, a neutrophil migration-promoting factor, combining these ingredients does not produce a synergistic effect.

[0331] From the above results, it was found that cyclohexylglycerin and horsetail extract have the effect of suppressing the gene expression of neutrophil migration-promoting factor, and have the effect of suppressing neutrophil migration.

[0332] In addition, by applying a skin topical composition containing an elastase inhibitor and components that have the effect of suppressing the gene expression of neutrophil migration-promoting factors, such as cyclohexylglycerin and horsetail extract, and then applying red light, it is possible to inhibit the upstream, middle, and downstream steps of a series of processes in the formation of wrinkles and sagging, such as neutrophil adhesion to vascular endothelial cells, neutrophil migration, and the breakdown of elastin and collagen by neutrophil elastase secreted by neutrophils, thereby achieving more effective prevention or improvement of wrinkles and sagging.

[0333] <Test Example 4> Effect of oil-soluble peach leaf extract on gene expression of neutrophil adhesion promoting factor in vascular endothelial cells Human umbilical vein endothelial cells were cultured in Endothelial Cell Growth Medium 2 Kit (Takara Bio) and plated in a 6-well plate at 3.0 × 10 5 After seeding at 10 cells / well, the cells were cultured at 37°C in a 5% CO2 environment for 24 hours. After 24 hours of culture, PBS was added to each well of the plate to wash the cells, and an oil-soluble peach leaf extract mixed with ethanol (manufactured by Koei Kogyo Co., Ltd.) was added to a final concentration of 0.2% by mass. After 24 hours, the medium was removed and the cells were washed with PBS, the solution was placed in a QIA shredder tube (QIAGEN), and the cells were collected by centrifugation.

[0334] RNA was extracted from the resulting cell lysate using an RNeasy plus micro kit (QIAGEN). RT-PCR was performed using the QuantiTecT SYBR Green RT-PCR kit (QIAGEN) to measure the mRNA expression levels of ICAM-1, VCAM-1, and the mRNA expression level of ACTB, an endogenous control. The mRNA expression level of each sample was calculated by dividing the mRNA expression level of ICAM-1 and VCAM-1 by the mRNA expression level of ACTB. The results are shown in FIG.

[0335] As shown in Figure 11, in the sample to which oil-soluble peach leaf extract was added, the expression level of ICAM-1 was reduced to approximately 20% compared to the sample to which ethanol was added (solvent control), and the expression level of VCAM-1 was reduced to approximately 60%. These results demonstrated that the oil-soluble peach leaf extract has the effect of suppressing gene expression of neutrophil adhesion promoting factor.

[0336] ICAM-1 and VCAM-1 are known to be adhesion molecules that promote the adhesion of neutrophils to vascular endothelial cells in order to allow them to infiltrate into tissues. Oil-soluble peach leaf extract, which has the effect of suppressing the gene expression levels of these adhesion molecules, suppresses the adhesion of neutrophils to the inner walls of blood vessels, the infiltration outside of blood vessels, and their arrival into skin tissues, and is therefore recognized to have the effect of preventing or improving the formation of wrinkles and sagging skin.

[0337] In addition, the results of Test Example 4 show that the combined use of oil-soluble peach leaf extract and elastase inhibitor provides beneficial effects. The action of the oil-soluble peach leaf extract suppresses the infiltration of neutrophils into skin tissue, and the action of the neutrophil elastase inhibitor inhibits the activity of neutrophil elastase released by the infiltrated neutrophils, so it is believed that the extract exerts an effect both upstream and downstream of the mechanism of wrinkle and sagging formation caused by neutrophils, and has a stronger anti-wrinkle and anti-sagging effect.

[0338] In addition, it has been shown that by applying a topical skin composition containing an oil-soluble peach leaf extract and a neutrophil elastase inhibitor followed by red light, the effect of suppressing the expression of neutrophil adhesion promoting factor is synergistically improved, resulting in more effective prevention or improvement of wrinkles and sagging.

[0339] Test Example 5: Test on near-infrared shielding (test on the second skin topical composition) <Test Example 5-1> Evaluating the compatibility of transmission of long wavelength visible light and blocking of near infrared light Oil-in-water emulsion compositions of Examples and Comparative Examples were prepared according to the formulations shown in the table below. That is, the water phase II was added to the oil phase adjusted to a temperature of 80°C to neutralize it, and the powder was dispersed using a disperser. The oil phase was added to the water phase I adjusted to a temperature of 80°C, and then the water phase III was added and homogenized using a homogenizer. The mixture was cooled to 30°C to obtain an oil-in-water emulsion composition.

[0340] The light shielding rate of a specific wavelength, the transmittance ratio of 585 to 760 nm, and the squeaking sensation of the oil-in-water emulsion composition were measured and evaluated as follows. <Coverage rate> A thin film of the oil-in-water emulsion composition was formed on a slide glass using a 1.2 mil doctor blade, and the transmittance (average value in each wavelength range) was measured using a spectrophotometer. The shielding rate was calculated as "100-transmittance", and the average shielding rate was calculated in each wavelength range of 585 to 760 nm and 760 to 1310 nm.

[0341] <585~760nm transmission ratio> A thin polymer film was prepared on a glass slide using a doctor blade, and powder was applied using a brush. Excess powder was removed using an air gun to prepare a thin film, and the amount of light transmitted at wavelengths of 400-760 nm and 585-760 nm (average value for each wavelength range) was measured using a spectrophotometer. The 585-760 nm transmittance ratio was calculated as the amount of light transmitted at wavelengths of 585-760 nm / the amount of light transmitted at wavelengths of 400-760 nm.

[0342] <Evaluation of creaking sensation> A practical test was conducted by 10 expert panelists, who scored the creaking sensation on a four-point scale and calculated the average value. Squeakiness rating scale: 1: There is a creaking sensation 2: There is a slight creaking sensation 3: Not much creaking 4: No squeaking sensation

[0343] The evaluation results are shown in the table below.

[0344] [Table 4]

[0345] As is clear from the results shown in Table 4, compositions in which the difference between the "light shielding rate of 585 to 760 nm wavelength" and the "light shielding rate of 760 to 1310 nm wavelength" is 10% or less and the "light shielding rate of 760 to 1310 nm wavelength" is 30% or more, were excellent in the effect of achieving both transmission of long wavelength region of visible light and shielding of near infrared light (Formulation Examples 1 to 6).

[0346] In addition, when spherical powder that transmits more long wavelengths of visible light than short wavelengths is contained, the effect of transmitting long wavelengths of visible light was particularly excellent (Formulation Examples 1 and 5 compared to Formulation Example 6).

[0347] Furthermore, when spherical powder having a specific average particle size was contained, the effect of transmitting the longer wavelength side of visible light was particularly excellent (Formulation Example 5 compared to Formulation Examples 1 and 6).

[0348] Formulation Examples 1 to 6 were excellent in terms of the transmission in the long wavelength region of visible light, the shielding of near-infrared light, or both, compared to the cases where titanium oxide of 0.5 μm or more was not blended (Formulation Examples 7 and 8) or where the blending amount of titanium oxide of 0.5 μm or more was small (Formulation Example 9).

[0349] <Test Example 5-2> Evaluation of Anti-Aging Effect in Consecutive Use Samples of Formulation Example 1, Formulation Examples 7 and 8 were used consecutively for 3 weeks, and the viscoelasticity of the skin was measured using Cutometer MPA580, and the rate of change (%) calculated with the value before consecutive use as 100% was measured. The evaluation results are shown in the following table.

[0350]

Table 5

[0351] As is clear from the results shown in Table 5, the water-in-oil type emulsified cosmetic of Formulation Example 1 was excellent in the effect of improving the viscoelasticity of the skin and showed an anti-aging effect.

[0352] ≪Test Example 6≫ Test on Water Resistance and Uniformity (Test on the Second Topical Composition for Skin) According to the formulation shown in the following table, a water-in-oil type emulsified composition was prepared. That is, Aqueous Phase II was added to the oil phase adjusted to 80°C to form a fatty acid salt. Then, the powder was dispersed. The oil phase was added to Aqueous Phase I adjusted to 80°C, and after adding Aqueous Phase III, it was homogenized with a homogenizer. Aqueous Phase IV was added at 45°C and cooled to 30°C to obtain a water-in-oil type emulsified composition.

[0353] The SPF value, water resistance and film uniformity of the water-in-oil type emulsified composition were evaluated as follows. <SPF Value> The SPF value was determined from the average protection spectrum obtained by measuring 10 times using an SPF analyzer.

[0354] <Water Resistance Evaluation> The oil-in-water emulsion composition was applied to the arm, dried for 15 minutes, and then the cosmetic film was photographed under a UV lamp. After running water, the cosmetic film was photographed again under the UV lamp. The rate of change in brightness was calculated by image analysis and classified into the following four categories to evaluate water resistance. The smaller the rate of change in brightness, the higher the water resistance can be evaluated. Luminance value change rate: ◎: 110% or less, ○: 125% or less, △: 126~150%, ×: 150% or more

[0355] <Uniformity evaluation> A thin film was created on a slide glass using a 1.2 mil doctor blade, and the uniformity of the powder dispersion was visually evaluated into the following three categories. Powder dispersion uniformity: ○: uniform, △: slightly non-uniform, ×: non-uniform

[0356] The evaluation results are shown in the table below.

[0357] [Table 6]

[0358] As is clear from the results shown in Table 6, the oil-in-water emulsion compositions (Formulation Examples 10 to 12) containing the following components a-2) to d-2) had excellent powder dispersion uniformity, film uniformity, and water resistance compared to the oil-in-water emulsion compositions (Formulation Examples 13 to 18) lacking any of these components. Furthermore, when a film-forming agent was included, water resistance was particularly excellent (Formulation Example 12). a-2) Titanium dioxide having an average particle size of 0.5 μm or more and surface-treated with triethoxycaprylylsilane; b-2) ultraviolet absorbing agents and / or ultraviolet scattering agents; c-2) fatty acid salts; and d-2) Oils that are paste-like or solid at 25°C, excluding higher alcohols and fatty acids. [Industrial Applicability]

[0359] The present invention can be applied to beauty methods and cosmetics for preventing or improving wrinkles and sagging.

Claims

[Claim 1] A method for inhibiting expression of neutrophil adhesion promoting factor, comprising applying red light to cells or skin.

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