JP2021194341A - 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 - Google Patents

Abstract

To provide a safe method using a visible light for suppressing an expression of a neutrophil adhesion promotor, suppressing excretion of a neutrophil elastase after being infiltrated and decomposition of elastin and collagen, and preventing or improving wrinkles and flabbiness.SOLUTION: An expression of a neutrophil adhesion promotor is suppressed by irradiating a cell or skin with a red light, which is in a wavelength range of a visible light. By applying the red light, an expression of ICAM-1 and/or VCAM-1 can be suppressed which plays a significant role in adhesion of the neutrophil onto a vascular endothelial cell.SELECTED DRAWING: Figure 1

Description

The present invention relates to a method for suppressing the expression of a neutrophil adhesion promoting factor.

The skin consists of the epidermis, dermis, and subcutaneous tissue (fat layer). The epidermis protects the body from external dryness and foreign substances, the subcutaneous tissue softens the impact from the outside with subcutaneous fat, etc., and the dermis is fibroblasts and these cells. It is composed of an extracellular matrix that is outside the skin 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 skin tension and elasticity. Due to aging, ultraviolet rays, etc., proteolytic enzymes such as matrix metalloprotease and elastase are secreted from skin cells, neutrophils, etc. in the skin, resulting in decomposition of collagen and elastin. It is widely known that this reduces the elasticity of the skin and causes wrinkles and sagging of the skin.

In recent years, a component that suppresses elastase activity has been discovered, and cosmetics for preventing or improving the formation of wrinkles and sagging containing various elastase inhibitors as active ingredients have been disclosed (Patent Documents 1 to 4).
The applicant also reports cosmetics and external preparations that contain a neutrophil elastase inhibitor secreted from neutrophils and exert an effect of preventing and improving the formation of wrinkles and sagging of the skin (Patent Documents). 5).
Neutrophil elastase not only directly degrades elastin, but also indirectly participates in collagen degradation by activating one of the matrix metalloproteinases (ММP-1 and ММP-2). It is known (Non-Patent Document 1).

Neutrophil elastase is a neutrophil that secretes elastase, which infiltrates into the skin tissue through multiple stages. Neutrophils are first captured by the vascular endothelial cells of the skin, then rolled and adhered along the blood vessels (film adaptation). It then transmigrates through vascular endothelial cells, diverges out of the blood vessels (diapedesis), and infiltrates the skin. In the process of rolling on vascular endothelial cells, the captured neutrophils change the conformation of integrins on their surface, improving their affinity for ligands present on the surface of vascular endothelial cells. As a result, neutrophils adhere to vascular endothelial cells. As ligands (neutrophil adhesion promoting factor) on vascular endothelial cells that play an important role in this adhesion process, intercellular adhesion molecule-1 (intercellural adhesion molecule-1, ICAM-1) and vascular cell adhesion molecule- 1 (vascular cell adhesion molecule-1, VCAM-1) is known (Non-Patent Document 2).

By the way, in the subcutaneous tissue, there is a network-like fibrous structure called a skin striate (retinacula cutis). The skin band is known to have a relationship with facial tarmi (Non-Patent Document 3). It is also known that the skin zonule density is reduced in the subcutaneous tissue directly under the deep wrinkle site such as the forehead and the outer corner of the eye (Non-Patent Document 4).

Microfibril-associated glycoproteins 4 (MFAP4) are known to be constituents of the skin zonules. It is known that the abundance of MFAP4 is reduced in the photoaged subcutaneous tissue. Further, it has been suggested that by improving the expression of MFAP4 and suppressing its decomposition, it is possible to prevent the decrease in elasticity of the skin tissue due to photoaging, and it is possible to improve wrinkles and tarmi (Non-Patent Document 5).

On the other hand, in recent years, it has become clear that light in the long wavelength region of visible light has an aging care effect based on cell proliferation promoting action, collagen synthesis promoting action, vascular endothelial proliferation action and the like. It is already widely known that "ultraviolet rays" in the vicinity of visible light on the shorter wavelength side of visible light have an adverse effect on the skin, and various measures for protecting the skin from ultraviolet rays have been proposed. Infrared rays, which are near visible light on the longer wavelength side than visible light, are near-infrared (about 0.76 to 2.5 μm), mid-infrared (about 2.5 to 4 μm), and far, depending on the wavelength. It is divided into infrared rays (about 4 to 1000 μm), and it has been confirmed that near infrared rays in particular damage the dermal and subcutaneous tissues and are deeply involved in skin aging and the like. Therefore, it is important to effectively protect the skin from near-infrared rays as well as UV rays.

As a cosmetic for protecting the skin from near infrared rays, for example, an oil-in-water emulsified cosmetic containing titanium dioxide having a specific average particle size and an inorganic plate-like powder has been proposed (for example, Patent Document 6). ). However, in the conventional near-infrared ray shielding technology, there is a problem that when the near-infrared ray is cut, the long wavelength region of visible light useful for the skin is also significantly cut.

Japanese Unexamined Patent Publication No. 2002-205950 Japanese Unexamined Patent Publication No. 2009-191043 Japanese Unexamined Patent Publication No. 2013-006815 Japanese Unexamined Patent Publication No. 2019-81726 International Publication No. 2017/221973 Japanese Unexamined Patent Publication No. 2015-86157

Takeuchi H. , Et al. : “Neurophil elastase contours to extracellular matrix distributed by chronic low-dose UV irradiation, neutrophil elastase mousetechnology. (2010), 60, 151-158 Journal of Japanese Society for Clinical Immunology, vol. 33, No. 5,242-248 Sakata A. , Et al. : "Breakthrough in implantation the skin sagging with focusing on the subcutaneous tissue structure, retinacula cutis", 23rd IFSCC, Zur Tsukahara K. et al. , Arch Dermatol. (2012), 148, 39-46 Scientific Reports volume 1, Article number 164 (2011)

Neutrophils infiltrate the skin tissue from vascular endothelial cells, secrete neutrophil elastase, directly decompose elastin, and indirectly decompose collagen, causing wrinkles and sagging of the skin. As described above, in the process of adhesion (film adaptation) in the process of neutrophil infiltration, the neutrophil adhesion promoting factor present on the vascular endothelial cells plays an important role. If the expression of this neutrophil adhesion promoting factor can be suppressed, the infiltration of neutrophils can be suppressed, and eventually the secretion of neutrophil elastase and the decomposition of elastin and collagen after infiltration can be suppressed. can.
Based on the above, an object to be solved by the present invention is to provide a novel technique for suppressing the expression of a neutrophil adhesion promoting factor. Further, it is preferably an object to provide a new technique for preventing or improving wrinkles and sagging.

Through diligent research efforts by the present inventors, it has been newly found that the expression of neutrophil adhesion promoting factor is suppressed by applying red light, which is light in the long wavelength region of visible light, to cells or skin. rice field. The present invention has been completed based on such novel findings.
That is, the present invention that solves the above-mentioned problems is a method for suppressing the expression of a neutrophil adhesion promoting factor, which comprises applying red light to cells or skin.

In a preferred embodiment of the present invention, the above-mentioned neutrophil adhesion promoting factor is an intercellular adhesion molecule-1 (intercellular adhesion molecule-1, ICAM-1) and / or a vascular cell adhesion molecule-1 (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.

In a preferred embodiment of the invention, the aforementioned cells are vascular endothelial cells.
Neutrophil adhesion-promoting factors act as ligands by being expressed on vascular endothelial cells. According to the present invention, it is possible to suppress the expression of a neutrophil adhesion promoting factor that acts as a ligand on vascular endothelial cells.

In a preferred embodiment of the present invention, it is a method of suppressing infiltration of neutrophils.
Neutrophil adhesion-promoting factors play an important role in the process of adhesion in neutrophil infiltration. According to the method of the present invention, since the expression of a neutrophil adhesion promoting factor that plays an important role in the process of neutrophil infiltration can be suppressed, it is preferable to apply it for suppressing neutrophil infiltration.

In a preferred embodiment of the present invention, it is a cosmetic method for anti-aging of the skin (excluding medical practice).
The application of red light suppresses the expression of neutrophil adhesion-promoting factors, thereby suppressing the infiltration of neutrophils into the skin tissue. Along with this, the decomposition 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), is suppressed.
From this, it is preferable that the present invention is applied to a cosmetic method for anti-aging of the skin.

In a preferred embodiment of the present invention, red light is applied to an application target by irradiating light through a member having optical characteristics that shields near infrared rays and transmits red light.
By irradiating light through a member having optical characteristics as described above, good neutrophil adhesion is achieved even if the irradiated light contains near infrared rays (for example, sunlight) in addition to red light. The effect of suppressing the expression of the promoting factor can be obtained.

In a preferred embodiment of the present invention, an article provided with the member is attached to an application target of red light, and the red light is applied to the application target by irradiating the light through the member.
According to the invention of such a form, the effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained in the application target to which the article is attached.

In a preferred embodiment of the invention, the article is eyeglasses or sunglasses with a lens made of the member.
According to the present invention in such a form, it is possible to obtain an effect of suppressing the expression of a neutrophil adhesion promoting factor in the skin near the eyes exposed to light through glasses or sunglasses.

In a preferred embodiment of the present invention, an application target of red light is placed in a space in which at least a part of a wall portion or a ceiling portion is composed of the member, and the application target is irradiated with light through the member to emit red light to the application target. Apply.
According to the present invention in such a form, it is possible to obtain the effect of suppressing the expression of the neutrophil adhesion promoting factor in the application target placed in the space.

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 factors can be obtained only by being indoors or in a vehicle.

The present invention is also a member for suppressing the expression of a neutrophil adhesion promoting factor, which has an optical property of shielding near infrared rays and transmitting red light, and is used for the above-mentioned method. Related.
By irradiating light through the member of the present invention, red light can be applied to the application target, and the effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained.

The present invention also relates to an article for suppressing the expression of a neutrophil adhesion promoting factor, which is a body-worn device provided with the above-mentioned member and is used for the method according to claim 7 or 8.
When the article of the present invention is attached, red light hits the body to be applied through the member, and the effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained.

In a preferred embodiment of the invention, the body wearer is glasses or sunglasses with a lens made of the member.
According to the present invention in such a form, it is possible to obtain an effect of suppressing the expression of a neutrophil adhesion promoting factor in the skin near the eyes exposed to light through glasses or sunglasses.

The present invention is a structure for suppressing the expression of a neutrophil adhesion promoting factor, which comprises a space in which at least a part of a wall portion or a ceiling portion is composed of the above-mentioned members and is used for the above-mentioned method. Also related to.
By spending time in the space, the effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained.

A preferred embodiment of the invention is a building or a car.
The effect of suppressing the expression of the neutrophil adhesion promoting factor can be obtained only by living a daily life using the building or the car of the present invention.

Further, the present invention comprises a light irradiation step of irradiating the skin with red light.
The neutrophil elastase inhibitor application step of applying the neutrophil elastase inhibitor to the skin, and
It also relates to a method for preventing or improving wrinkles and sagging (excluding medical practice), which is characterized by the provision of.
Irradiation with red light suppresses the expression of neutrophil adhesion-promoting factors, which in turn suppresses the infiltration of neutrophils into the skin tissue. In addition, the application of the neutrophil elastase inhibitor suppresses the decomposition of elastin and collagen by the neutrophil elastase secreted by the infiltrated neutrophils. In other words, by combining the light irradiation step and the neutrophil elastase inhibitor application step, suppression of neutrophil infiltration and upstream of a series of wrinkle and sagging pathways of decomposition of elastin and collagen by neutrophil elastase. And can inhibit downstream.

Furthermore, the following effects can be obtained by irradiating with red light.
-Effect of improving the expression of MFAP4, which is a component of the skin band.
-The effect of suppressing the expression of matrix metalloproteinase that decomposes MFAP4.
-Proliferation promoting effect of tendon cells that produce MFAP4.
That is, the effect of enhancing the skin band can be obtained by irradiating with red light.

As described above, the present invention effectively inhibits the factors of wrinkle and sagging formation by the configuration including the light irradiation step and the neutrophil elastase inhibitor application step, and effectively prevents or improves wrinkles and sagging. Realize.

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.

Here, in the general formula (1), R ₁ is composed of a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Substituted linear or branched alkyl groups with 1-4 carbon atoms, R ₂ and R ₃ independently represent linear or branched alkyl groups with 1 to 4 carbon atoms, respectively.

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. ..

Here, in the general formula (2), R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₅ and R ₆ each independently have 1 carbon atom. Represents a linear or branched alkyl group of ~ 4.

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

Compounds represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof, more preferably compounds represented by the general formula (2), isomers thereof and / or theirs. It is more effective by applying a pharmacologically acceptable salt, more preferably a compound represented by the formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof. The effect of preventing or improving wrinkles and sagging is exhibited.

In recent years, it has been confirmed that near-infrared rays in particular damage the dermis and subcutaneous skin and are deeply involved in skin aging. However, due to the diligent research efforts by the present inventors, near-infrared rays have been confirmed. It was found that application of neutrophils to cells increased the expression of neutrophil adhesion-promoting factors.
That is, by applying red light while shielding near infrared rays, it is possible to obtain a more excellent effect of suppressing the expression of the neutrophil adhesion promoting factor.
Therefore, the present invention comprises a light irradiation step of irradiating the skin with red light.
In addition to the neutrophil elastase inhibitor application step of applying the neutrophil elastase inhibitor to the skin, it is preferable to have a form including a light scattering agent application step of applying a light scattering agent that shields near infrared rays to the skin.

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 above-mentioned light scattering agent application process,
a) 25% by mass or more of the above-mentioned titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. The external composition for skin is applied to the skin.
With such a form, near-infrared rays can be shielded more effectively and red light can be applied to the skin more effectively, so that a more excellent effect of suppressing the expression of neutrophil adhesion promoting factor is achieved. As a result, it is possible to obtain the effect of preventing or improving wrinkles and sagging.

Furthermore, the following effects can be obtained by irradiating with red light.
-Effect of improving the expression of MFAP4, which is a component of the skin band.
-The effect of suppressing the expression of matrix metalloproteinase that decomposes MFAP4.
-Proliferation promoting effect of tendon cells that produce MFAP4.
That is, the effect of enhancing the skin band can be obtained by irradiating with red light.

In a preferred embodiment of the present invention, the above-mentioned light irradiation step is performed after the above-mentioned light scattering agent application step.
In the above-mentioned light irradiation step, sunlight including the above-mentioned red light is irradiated.
Naturally, sunlight includes red light and near infrared rays. By performing a light irradiation step of irradiating sunlight after the light scattering agent application step, red light can be applied to the skin while blocking the near infrared rays contained in the sunlight, resulting in better wrinkles and sagging. A preventive or improving effect can be obtained.

In a preferred embodiment of the present invention, in the above-mentioned light irradiation step, the expression of the neutrophil adhesion promoting factor is suppressed by irradiation with red light.
By suppressing the expression of neutrophil adhesion promoting factors, it is possible to suppress the infiltration of neutrophils and the subsequent decomposition of elastin and collagen by neutrophil elastase, and obtain the effect of preventing or improving wrinkles and sagging. Can be done.

In a preferred embodiment of the present invention, the neutrophil elastase inhibitor is a compound represented by the above-mentioned general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, more preferably the above-mentioned general formula. The compound represented by (2), its isomer and / or a pharmacologically acceptable salt thereof, more preferably the compound represented by the above formula (3), its isomer and / or their pharmacology. It is an acceptable salt.

By the way, the decomposition of elastin and collagen by neutrophil elastase secreted by infiltrated neutrophils is caused by the above-mentioned compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof. Suppressed by application. In addition, the expression of the neutrophil adhesion promoting factor is suppressed by irradiation with red light, and the infiltration of neutrophils into the skin tissue is suppressed accordingly. That is, the compound represented by the above-mentioned general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is used by applying red light after application to the skin. By using neutrophil elastase, it is possible to inhibit the upstream and downstream of the series of wrinkle and sagging pathways of suppressing the decomposition of elastin and collagen by neutrophil elastase and suppressing the infiltration of neutrophils.

Furthermore, the following effects can be obtained by the usage of applying red light.
-Effect of improving the expression of MFAP4, which is a component of the skin band.
-The effect of suppressing the expression of matrix metalloproteinase that decomposes MFAP4.
-Proliferation promoting effect of tendon cells that produce MFAP4.
That is, the effect of enhancing the skin band can be obtained by the above-mentioned usage.

As described above, the present invention is used by applying red light after application to the skin, and the compound represented by the above-mentioned general formula (1), an isomer thereof and / or a compound thereof. By using a pharmacologically acceptable salt, the factors of wrinkle and sagging formation are inhibited from various aspects, and the prevention or improvement of wrinkles and sagging is effectively realized.
As a result, the agent of the present invention exhibits a better effect of preventing or improving wrinkles and sagging than known agents.

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.

Further, the present invention comprises the above-mentioned neutrophil elastase inhibitor and the above-mentioned neutrophil elastase inhibitor.
Contains a light scattering agent that shields near infrared rays,
It also relates to a wrinkle and sagging preventive or ameliorating agent, which is characterized by being used by applying red light after application to the skin.
By using the above-mentioned neutrophil elastase inhibitor in the method of applying red light after application to the skin, the infiltration of neutrophils is suppressed and the formation of wrinkles and sagging by the decomposition of elastin by neutrophil elastase. It is possible to block upstream and downstream of a series of pathways. Further, by shielding the near infrared rays, the effect of suppressing the expression of the 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.
That is, since the agent for preventing or improving wrinkles and sagging of the present invention is provided with a structure capable of obtaining an excellent effect, it exhibits a remarkable effect of preventing or improving wrinkles and sagging.

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 with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. Is.
With such a form, near-infrared rays can be shielded more effectively and red light can be applied to the skin more effectively, so that a more excellent effect of suppressing the expression of neutrophil adhesion promoting factor is achieved. As a result, it is possible to obtain the effect of preventing or improving wrinkles and sagging.

Furthermore, the following effects can be obtained by the usage of applying red light.
-Effect of improving the expression of MFAP4, which is a component of the skin band.
-The effect of suppressing the expression of matrix metalloproteinase that decomposes MFAP4.
-Proliferation promoting effect of tendon cells that produce MFAP4.
That is, the effect of enhancing the skin band can be obtained by the above-mentioned usage.

In a preferred embodiment of the present invention, after application to the skin, it is used by irradiating it with sunlight including the red light.
Naturally, sunlight includes red light and near infrared rays. By using the method of irradiating sunlight after application to the skin, red light can be applied to the skin while blocking the near infrared rays contained in the sunlight, and better prevention or improvement of wrinkles and sagging. The effect can be obtained.

In a preferred embodiment of the present invention, it is used to suppress the expression of a neutrophil adhesion promoting factor by applying the above-mentioned red light.
By suppressing the expression of neutrophil adhesion promoting factors, it is possible to suppress the infiltration of neutrophils and the subsequent decomposition of elastin and collagen by neutrophil elastase, and obtain the effect of preventing or improving wrinkles and sagging. Can be done.

In addition, the present invention comprises a first external composition for skin containing the above-mentioned wrinkle prevention or ameliorating agent.
It is provided with a second external composition for skin containing a light scattering agent that shields near infrared rays, and is used by applying red light to the skin after application of the first and second external compositions for skin to the skin. It also relates to a composition kit for external skin, which is characterized by the above.
In the method of applying red light after application to the skin, by applying the second external composition for skin to shield near infrared rays, the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light can be obtained. Can be enhanced. In addition, by using a first external composition for skin containing a preventive or ameliorating agent for wrinkles and sagging, the infiltration of neutrophils is suppressed and the formation of wrinkles and sagging due to the decomposition of elastin and collagen by neutrophil elastase. It can block upstream and downstream of a series of pathways.
That is, since the composition kit for external skin of the present invention is provided with a structure capable of obtaining an excellent effect, it exhibits a remarkable effect of preventing or improving wrinkles and sagging.

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 above-mentioned second external composition for skin is
a) 25% by mass or more of the above-mentioned titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. Is.
With such a form, it is possible to more effectively shield the near infrared rays contained in the sunlight and more effectively apply the red light contained in the sunlight to the skin, which is further excellent. It is possible to obtain an effect of suppressing the expression of a neutrophil adhesion promoting factor and, by extension, an effect of preventing or improving wrinkles and sagging.

Furthermore, the following effects can be obtained by the usage of applying red light.
-Effect of improving the expression of MFAP4, which is a component of the skin band.
-The effect of suppressing the expression of matrix metalloproteinase that decomposes MFAP4.
-Proliferation promoting effect of tendon cells that produce MFAP4.
That is, the effect of enhancing the skin band can be obtained by the above-mentioned usage.

In a preferred embodiment of the present invention, after application of the first and second external skin compositions to the skin, sunlight containing red light is applied to the skin for use.
Naturally, sunlight includes red light and near infrared rays. By using the skin external composition kit of the present invention in a method of irradiating sunlight after applying the first and second external skin compositions to the skin, while shielding the near infrared rays contained in the sunlight. , Red light can be applied to the skin, and more excellent wrinkle and sagging prevention or improvement effects can be obtained.

In a preferred embodiment of the present invention, it is used to suppress the expression of a neutrophil adhesion promoting factor by applying the above-mentioned red light.
By suppressing the expression of neutrophil adhesion promoting factors, it is possible to suppress the infiltration of neutrophils and the subsequent decomposition of elastin and collagen by neutrophil elastase, and obtain the effect of preventing or improving wrinkles and sagging. Can be done.

Further, the present invention comprises a second external composition for skin containing the above-mentioned light scattering agent that shields near infrared rays.
It also relates to a first skin external composition kit comprising a first external composition for preventing or ameliorating wrinkles and sagging.
When the portion where the first and second external composition for skin is applied to the skin is exposed to sunlight, the near infrared rays contained in the sunlight are shielded by the action of the second external composition for skin. This strongly induces the suppression of the expression of neutrophil adhesion promoting factors by the red light contained in sunlight, and the infiltration of neutrophils into the skin and the subsequent decomposition of elastin and collagen by neutrophil elastase are effective. Is suppressed.
In addition, the action of the first external composition for skin inhibits the activity of neutrophil elastase secreted from neutrophils and suppresses the decomposition of elastin and collagen.
In other words, by applying the external composition kit for external skin of the present invention to the skin and living a life exposed to sunlight as usual, wrinkles such as suppression of neutrophil infiltration and decomposition of elastin and collagen by neutrophil elastase can be seen. It can block upstream and downstream of a series of sagging pathways. That is, the external composition kit for skin of the present invention exhibits an excellent effect of preventing or improving wrinkles and sagging.

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 above-mentioned second external composition for skin is
a) 25% by mass or more of the above-mentioned titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. Is.
With such a form, it is possible to more effectively shield the near infrared rays contained in the sunlight and more effectively apply the red light contained in the sunlight to the skin, which is further excellent. It is possible to obtain an effect of suppressing the expression of a neutrophil adhesion promoting factor and, by extension, an effect of preventing or improving wrinkles and sagging.

Further, the present invention comprises a first external composition for skin containing a compound represented by the following general formula (1), an isomer thereof and / or a pharmaceutically acceptable salt thereof, and light that shields near infrared rays. It also relates to a composition kit for external skin, which comprises a second external composition for skin containing a scattering agent.

Here, in the general formula (1), R ₁ is composed of a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Substituted linear or branched alkyl groups with 1-4 carbon atoms, R ₂ and R ₃ independently represent linear or branched alkyl groups with 1 to 4 carbon atoms, respectively.

When the portion where the first and second external composition for skin is applied to the skin is exposed to sunlight, the near infrared rays contained in the sunlight are shielded by the action of the second external composition for skin. This strongly induces the suppression of the expression of neutrophil adhesion promoting factors by the red light contained in sunlight, and the infiltration of neutrophils into the skin and the subsequent decomposition of elastin and collagen by neutrophil elastase are effective. Is suppressed.
In addition, the action of the first external composition for skin inhibits the activity of neutrophil elastase secreted from neutrophils and suppresses the decomposition of elastin and collagen.
In other words, by applying the external composition kit for external skin of the present invention to the skin and living a life exposed to sunlight as usual, wrinkles such as suppression of neutrophil infiltration and decomposition of elastin and collagen by neutrophil elastase can be seen. It can block upstream and downstream of a series of sagging pathways. That is, the external composition kit for skin of the present invention exhibits an excellent effect of preventing or improving wrinkles and sagging.

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 above-mentioned second external composition for skin is
a) 25% by mass or more of the above-mentioned titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. Is.
With such a form, it is possible to more effectively shield the near infrared rays contained in the sunlight and more effectively apply the red light contained in the sunlight to the skin, which is further excellent. It is possible to obtain an effect of suppressing the expression of a neutrophil adhesion promoting factor and, by extension, an effect of preventing or improving wrinkles and sagging.

According to the present invention, the expression of the neutrophil adhesion promoting factor can be suppressed.
Further, according to the present invention, it is possible to obtain an effect of preventing or improving wrinkles and sagging.

It is a graph which shows the result of Test Example 1. FIG. The expression level of ICAM-1 at the time of irradiation with red light and at the time of non-irradiation is shown. It is a graph which shows the result of Test Example 1. FIG. The expression level of VCAM-1 is shown with and without irradiation with red light. It is a graph which shows the result of the test 2-1. The cell proliferation ratio at the time of irradiation with red light and at the time of no irradiation is shown. It is a graph which shows the result of the test 2-2. The relationship between the irradiation amount of visible light in the long wavelength range and mitochondrial activity is shown. It is a graph which shows the result of the test 2-2. The relationship between the irradiation amount of visible light in the long wavelength range and the cell proliferation rate is shown. It is a figure which shows the result of the test 2-3. The results of the microarray are shown. It is a graph which shows the result of the test 2-4. It is shown that MFAP4 is a substrate for matrix metalloproteinase. It is a graph which shows the result of test 2-5. The expression level of MFAP4 is shown with and without irradiation of red light and with and without addition of burdock extract. It is a graph which shows the result of Test Example 3. It shows the effect of suppressing the expression of CLCL-1 by the addition of cyclohexylglycerin and horsetail extract. It is a graph which shows the result of Test Example 3. It shows the effect of suppressing the expression of IL-8 by the addition of cyclohexylglycerin and horsetail extract. It is a graph which shows the result of Test Example 4. It shows the effect of suppressing the expression of ICAM-1 and VCAM-1 by adding the oil-soluble peach leaf extract.

Hereinafter, preferred embodiments of the present invention will be described. However, it goes without saying that the technical scope of the present invention is not limited to the following embodiments.
Further, in the following description, unless otherwise specified, the terms defined in JIS Z 8120 “Optical Term” are used.

[1] Method for suppressing expression of neutrophil adhesion promoting factor The present invention is a method for suppressing expression of neutrophil adhesion promoting factor. The present invention is characterized by applying red light to cells or skin.

As used herein, "red light" refers to light having a wavelength that is visible to the naked eye as red.
The red light to be applied is preferably light having any wavelength of 610 to 780 nm, and more preferably light having any wavelength of 620 to 760 nm.
"Red light" includes not only light having a single wavelength but also complex light including light having a plurality of wavelengths.

The light applied in the present invention may include the above-mentioned red light. That is, if the spectrum includes the wavelength of light that appears red to the naked eye when the applied light is separated, it is included in the technical scope of the present invention. Therefore, for example, the form of irradiating sunlight also corresponds to "application of red light". In the present invention, as long as the above red light is applied, there is no limitation on the presence or absence of light of other wavelengths.

It is preferable that the applied light does not contain ultraviolet rays. Further, it is preferable that the applied light does not contain infrared rays, more preferably near infrared rays. Furthermore, it is preferable that the applied light does not contain either ultraviolet rays or infrared rays.

The applied light may be artificial light by any light projecting means or sunlight.
When artificial light is applied, the type of light source included in the light projecting means is not particularly limited, and may be, for example, a light emitting diode (LED), a halogen lamp, a HID lamp, an incandescent lamp, a silica lamp, or a mini krypton lamp. Above all, it is preferable to use a light emitting diode (LED). By using light emitting diodes (LEDs), red light can be applied to cells or skin without damaging the cells.

Further, when applying artificial light, light emitted from a red LED may be applied. For example, light emitted from a red LED having a peak wavelength at 625 nm can be applied.

When applying sunlight, the sunlight may be irradiated as it is, but it is preferable to shield the ultraviolet rays.
As the ultraviolet shielding means, any ultraviolet absorber or ultraviolet scattering agent can be exemplified. Further, an optical filter that shields ultraviolet rays may be used.

Further, when sunlight is applied, it is preferable to shield infrared rays, and more preferably near infrared rays.
As the infrared shielding means, any infrared absorber or infrared scattering agent can be exemplified. Specifically, the matters described regarding the second external composition for skin described later can be applied. Further, an optical filter that shields infrared rays may be used.

Further, a light projecting means (solar simulator) that irradiates pseudo-sunlight may be used as a light source. In this case, it is preferable to install an optical filter under the light source to cut light in a specific wavelength range and irradiate light in an arbitrary wavelength range including red light.
For example, it is preferable to cut the light in the wavelength range other than the red light emitted from the solar simulator with an optical filter and apply the light in the red region of 620 to 760 nm.
As a solar simulator, XHS-8 (manufactured by Spectral Engines) and the like can be exemplified.
Any optical filter can be used, and for example, those of various manufacturers such as HOYA, SCHOTT, and Shibuya Optical can be used. A plurality of optical filters may be used in combination.

In a preferred embodiment of the present invention, red light, more preferably light in the wavelength range of 620 to 760 nm, preferably 10 J / cm ² or more, more preferably 20 J / cm ² or more, still more preferably 30 J / cm, to the cells. ² or more, more preferably 40 J / cm ² or more, more preferably irradiates 50 J / cm ² or more.
By irradiating the cells with red light in the above range, the effect of suppressing the expression of the neutrophil adhesion promoting factor can be improved.

Further, the cells are irradiated with red light, more preferably light in the wavelength range of 620 to 760 nm, preferably 200 J / cm ² or less, more preferably 150 J / cm ² or less, still more preferably 100 J / cm ² or less.
By irradiating red light in the above range, it is possible to obtain the effect of suppressing the expression of the neutrophil adhesion promoting factor while reducing the burden on the cells.

The present invention includes a step of applying red light to a cell or skin, wherein the "cell" is present in a cultured cell, a cell in a cultured tissue, and a living animal or human living body. Contains cells.
The invention in which red light is applied to cells existing in a human body does not include a method for treating humans.

Since the present invention is a method for suppressing 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 the preferred embodiment of the present invention, it is preferable to apply red light to vascular endothelial cells.
The "vascular endothelial cells" referred to here include not only "cultured vascular endothelial cells" but also "vascular endothelial cells existing in a living body".

INDUSTRIAL APPLICABILITY The present invention may be a form of irradiating cultured vascular endothelial cells with red light, or a form of irradiating vascular endothelial cells existing in a living body with red light. When applied to a living body, it is preferable to irradiate the vascular endothelial cells constituting the endothelium of blood vessels existing in the skin tissue with red light.
When irradiating vascular endothelial cells with red light, there is also a method of inserting an optical fiber into the blood vessels of the skin and irradiating it directly, but since red light penetrates deep into the skin even when it is irradiated to the skin surface. More simply, a method of irradiating the skin surface with red light can be mentioned.

Specific examples of neutrophil adhesion-promoting factors that suppress expression by irradiation with red light include cell-cell adhesion molecule-1 (intercellar adhesion molecule-1, ICAM-1) and vascular cell adhesion molecule-1 (vascular cell adhesion). Molecule-1, VCAM-1) can be mentioned.
ICAM-1 and VCAM-1 are ligands expressed on vascular endothelial cells and are proteins that play an important role in the adhesion of neutrophils.

Suppression of the expression of neutrophil adhesion-promoting factors suppresses the process of adhesion required for neutrophils to infiltrate tissues from blood vessels. Therefore, the present invention can be used to suppress the infiltration of neutrophils. More preferably, the present invention is used to prevent neutrophils from infiltrating skin tissue.

Neutrophils that infiltrate the skin tissue secrete neutrophil elastase. Neutrophil elastase secreted into the skin tissue breaks down elastin and collagen that support the skin structure. This decomposition of elastin and collagen contributes to changes in skin appearance such as decreased skin elasticity, loss of texture, wrinkles, sagging, and dullness with aging.
As described above, the application of red light results in suppression of the expression of neutrophil adhesion-promoting factors, which can suppress neutrophil infiltration and subsequent degradation of elastin and collagen.
That is, the present invention can be applied to a cosmetic method for anti-aging of the skin.

The present invention is a cosmetological method for preventing or ameliorating one or more morphological changes of the skin selected from the group consisting of increased wrinkles and sagging of the skin, decreased firmness, and decreased elasticity of the skin. Is preferable.
More preferably, the present invention is a method for preventing or improving wrinkles and sagging of the skin.
The sagging of the skin refers to the deformation of the skin caused by the decrease in the elasticity of the skin and the subcutaneous tissue.

Further, the present invention may be in a form in which red light is applied to an application target by irradiating light through a member having optical characteristics that shields near infrared rays and transmits red light.
By irradiating light through a member having optical characteristics as described above, good neutrophil adhesion is achieved even if the irradiated light contains near infrared rays (for example, sunlight) in addition to red light. The effect of suppressing the expression of the promoting factor can be obtained.

The member used in this embodiment has "optical characteristics that shield near infrared rays and transmit red light".
Here, "shielding near-infrared rays" means shielding at least a part of near-infrared rays, and the shielding rate of near-infrared rays is not limited to 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, still more preferably 50. % Or more, more preferably 60% or more, still more preferably 70% or more, still more preferably 80% or more, still more preferably 90% or more.

Further, "transmitting red light" means transmitting at least a part of red light, and the transmittance of red light is not limited to 100%. The transmittance of red light 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, still more preferably 50. % Or more, more preferably 60% or more, still more preferably 70% or more, still more preferably 80% or more, still more preferably 90% or more.

It is preferable to use a member having a higher near-infrared shielding rate than a red light shielding rate.
In other words, it is preferable to use a member having a higher transmittance of red light than that of near infrared rays.

As long as it has the above-mentioned optical characteristics, the material and shape of the member are not limited.
The material of the member may be glass, resin, metal, metal oxide or a combination thereof.
Further, the shape of the member may be a plate shape, a film shape, a fiber, a powder shape, or a combination thereof.

Examples of the member of the present invention include a near-infrared shielding material such as hexaboride and cesium tungsten oxide, or a resin containing a near-infrared absorbing organic dye such as 9,10-anthracendion and 9,10-anthraquinone. Further, a resin film or a resin fiber formed by processing the resin can be mentioned. In addition, a glass material in which the resin film is laminated can be mentioned.
Conventionally, the resin film has been used for car glass, windows of houses, glasses, sunglasses, etc., and the resin fiber has been used for heat shield curtains, etc., but these are applied as members of the present invention. be able to.

The member is preferably used as an article that can be attached to an application target. That is, the article provided with the member is attached to the object to which the red light is applied, and the light is irradiated through the member. As a result, the red light transmitted through the member hits the application target.

When the object of application is a person, it is preferable that the article is a body-worn device.
Examples of the body-worn tool include glasses or sunglasses provided with a lens made of the above-mentioned member. In this case, the lens is preferably made of the above-mentioned near-infrared ray shielding material, a resin containing the near-infrared ray absorbing organic dye, or a glass material on which the resin film is laminated.

In addition, examples of the body-worn tool include a sun visor having a brim made of the member, and a cloth product (clothes, hat, mask, etc.) made of the member formed in a fibrous form.

Further, the method of the present invention may be implemented by placing an application target of red light in a space in which at least a part of a wall portion or a ceiling portion is composed of the members. In this case, by irradiating the light through the member, the red light is applied to the application target placed in the space.

The type of the structure including the space is not particularly limited, and any structure may be used as long as it has a space in which at least a part of the wall portion or the ceiling portion is composed of the members.
For example, the structure may be a building. The building may be residential or non-residential. The walls (including windows) or ceilings in at least one interior space of the building may be composed of the above-mentioned members. By irradiating light through the member, red light can be applied to the application target in the indoor space.

Further, as the structure, a car can be exemplified. The wall or ceiling in the vehicle interior space, specifically, any or all of the front window, side window, rear window, and sunroof may be composed of the above members. By irradiating light through the member, red light can be applied to the application target in the indoor space.

Other examples of the structure include airplanes and trains.

[2] Member / article / structure for suppressing expression of neutrophil adhesion promoting factor The present invention also relates to a member / article / structure for suppressing expression of neutrophil adhesion promoting factor.
Specific embodiments of the members, articles, and structures of the present invention are as described in the above "[1] Method for suppressing expression of neutrophil adhesion promoting factor".

[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 practice).
The method of the present invention is characterized by comprising a light irradiation step and a step of applying a neutrophil elastase inhibitor.

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 factors in vascular endothelial cells, and thereby suppresses the infiltration of neutrophils into the skin tissue.

Furthermore, by irradiating with red light, it is possible to obtain an effect of suppressing the expression increase and / or the expression decrease of MFAP4 which is a component of the skin zonule (retinacula cutis).
Further, by irradiation with red light, it is possible to obtain an effect of suppressing the expression decrease and / or the expression increase of the matrix metalloproteinase (MMP-3, MMP-7, MMP-9, MMP-12, etc.) that decomposes MFAP4.
Furthermore, the effect of promoting the proliferation of tendon cells producing MFAP4 can be obtained by irradiation with red light.
That is, the effect of thickening the skin band or the effect of preventing the skin band from becoming thin can be obtained by irradiating with red light. That is, the effect of enhancing the skin band can be obtained.

On the other hand, the neutrophil elastase inhibitor application step is a step of applying the neutrophil elastase inhibitor to the skin.
The application of the neutrophil elastase inhibitor suppresses the degradation of elastin and collagen by neutrophil elastase secreted by neutrophils infiltrating the skin tissue.

The present invention includes a combination of a light irradiation step and a neutrophil elastase inhibitor application step to suppress neutrophil infiltration and to form wrinkles and sagging by decomposing elastin and collagen by neutrophil elastase. It can block upstream and downstream of the pathway.
Furthermore, as described above, the effect of enhancing the skin band can be obtained by the light irradiation step.
That is, the present invention multilaterally inhibits the factors of wrinkle and sagging formation by the configuration including the light irradiation step and the neutrophil elastase inhibitor application step, and effectively realizes the prevention or improvement of wrinkles and sagging.

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

From the viewpoint of increasing the expression of MFAP4, red light is preferably applied at 0.5 J / cm ² or more, more preferably 5 J / cm ² or more, still more preferably 15 J / cm ² or more in the light irradiation step.
By applying red light under the above conditions, the effect of suppressing the expression increase and / or the expression decrease of MFAP4 is more excellent.

Further, from the viewpoint of increasing the expression of MFAP4, it is preferable that the red light is preferably applied at ^{100 J / cm 2 or less in the light irradiation step.}
By applying red light under the above conditions, it is possible to obtain the effect of suppressing the expression increase and / or the expression decrease of MFAP4 without damaging the cells.

The type of neutrophil elastase inhibitor applied in the neutrophil elastase inhibitor application step is not limited, 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.

Here, in the general formula (1), R ₁ is composed of a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Substituted linear or branched alkyl groups with 1-4 carbon atoms, R ₂ and R ₃ independently represent linear or branched alkyl groups with 1 to 4 carbon atoms, respectively.

If Specific examples of the preferred relates to the aforementioned R _1, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, carboxybutyl group, methoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylpropyl group, methoxycarbonyl butyl group, Ethoxycarbonylmethyl group, ethoxycarbonylethyl group, ethoxycarbonylpropyl group, ethoxycarbonylbutyl group, propyloxycarbonylmethyl group, propyloxycarbonylethyl group, propyloxycarbonylpropyl group, propyloxycarbonylbutyl group, butyloxycarbonylmethyl group, Butyloxycarbonylethyl group, butyloxycarbonylpropyl group, butyloxycarbonylbutyl group and the like can be preferably exemplified, and more preferably, carboxymethyl group can be exemplified.

The above-mentioned R ₂ and R ₃ are independent of each other, and specific examples thereof are preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-. A butyl group and the like can be preferably exemplified, and more preferably, an isopropyl group can be preferably exemplified.

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. ..

Here, in the general formula (2), R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₅ and R ₆ each independently have 1 carbon atom. Represents a linear or branched alkyl group of ~ 4.

The above-mentioned R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, _{and specific examples of the above-mentioned R 4} are preferable, such as a carboxymethyl group and a 1-carboxyethyl group. 2-carboxyethyl group, 1-carboxypropyl group, 2-carboxypropyl group, 3-carboxypropyl group, 1-carboxybutyl group, 2-carboxybutyl group, 3-carboxybutyl group, 4-carboxybutyl group and the like are preferable. And more preferably, a carboxymethyl group can be preferably exemplified.
Above R ₅ and R ₆ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, by way specifically those preferred relates to the aforementioned R ₅ and R _6, a methyl group, an ethyl group, N-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like can be preferably exemplified, and more preferably, an isopropyl group can be preferably exemplified.

Specific preferred compounds with respect to the compound represented by the above general formula (2) are N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3. 3-Trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3 , 3,3-Trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-alanyl-N -[3,3,3-trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L- Alanyl-N- [3,3,3-trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl ] Benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl)] Amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[( Carboxybutyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4- [[(Carboxymethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N -[4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L- Proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxo Propyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1) -Methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1 -(1-Methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-tri Fluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3 3-Trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3 , 3,3-Trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-valyl-N -[3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L- Valyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-Valyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl ] Benzoyl] -L-Valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide (3 (RS) -N- [4- [[(Carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide), N- [4-[[(( Carboxyethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4 -[[(Carboxypropyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L -Propylamide, its isomers and / or pharmaceutically acceptable salts thereof are preferably exemplified.

In a preferred embodiment of the present invention, the compound represented by the above 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.

More preferably, 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L-prolyl] amino-1,1,1-represented by the following formula (3) Trifluoro-4-methyl-2-oxopentane, an isomer thereof and / or a pharmacologically acceptable salt thereof.

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

Since 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, enantiomers and diastereomers are present as its isomers. .. Further, as the compound represented by the above-mentioned general formula (1) of the present invention, there are a racemate, an enantiomer, a diastereomer, and a compound in which the above-mentioned isomer is mixed at an arbitrary ratio.

"Pharmically acceptable salts" include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates; maleates, fumarates, oxalates, citrates. , Lactate, tartrate, methanesulfonate, paratoluenesulfonate, organic acid salts such as benzenesulfonate; alkali metal salts such as sodium salt and potassium salt, and alkaline earth metals such as calcium salt and magnesium salt. Salts; organic amine salts such as triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, piperidine salt, basic amino acid salts such as lysine salt and arginate; and the like.

The neutrophil elastase inhibitor is preferably applied by applying it to the skin in the form of an external composition for skin. As for the specific embodiment of the external composition for skin containing such a neutrophil elastase inhibitor, the description regarding the first external composition for skin described later can be applied.

Further, a preferred embodiment of the present invention further comprises a light scattering agent application step of applying a light scattering agent that shields near infrared rays to the skin.
Near infrared rays have an action of improving the expression of neutrophil adhesion promoting factors. That is, near-infrared rays have the opposite effect to red light with respect to the expression of neutrophil adhesion promoting factors. Since near-infrared rays attenuate the favorable effects of red light, it is preferable to shield them.
The light scattering agent application step is a step for shielding near infrared rays. By applying red light in the light irradiation step while shielding near infrared rays, it is possible to obtain a more excellent effect of suppressing the expression of the neutrophil adhesion promoting factor.

The light scattering agent is preferably applied by applying it to the skin in the form of a composition for external use on the skin. As for the specific embodiment of the external composition for skin containing such a light scattering agent, the description regarding the second external composition for skin described later can be applied.

The light irradiation step is preferably performed after the light scattering agent application step.
More preferably, in the light irradiation step performed after the light scattering agent application step, sunlight including red light is irradiated.
Naturally, sunlight includes red light and near infrared rays. By performing a light irradiation step of irradiating sunlight after the light scattering agent application step, it is possible to apply red light to the skin while blocking the near infrared rays contained in the sunlight by the light scattering agent, which is more excellent. It is possible to obtain the effect of preventing or improving wrinkles and sagging.

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, later, or these two steps may be performed at the same time.
Further, 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, later, or these two steps may be performed at the same time.

In the light irradiation step, it is preferable to apply red light to the vascular endothelial cells expressing the neutrophil adhesion promoting factor. Thereby, the infiltration of neutrophils can be effectively suppressed, and the effect of preventing or improving wrinkles and sagging can be improved.

Further, in the light irradiation step, it is preferable to apply red light to the tendon cells expressing MFAP4. Thereby, the skin band can be strengthened, and the effect of preventing or improving wrinkles and sagging can be improved.

In a more preferred embodiment of the invention, red light is applied to both vascular endothelial cells and tendon cells in the light irradiation step. As a result, it is possible to obtain an effect of suppressing the decomposition of elastin and collagen and an effect of enhancing the skin band, and it is possible to obtain a more excellent effect of preventing or improving wrinkles and sagging.
When red light is applied to the skin, the red light reaches both the vascular endothelial cells and the tendon cells, so that the invention of such a form can be carried out without any special trial and error.

[4] Wrinkle and / or sagging preventive or ameliorating agent The present invention contains the above-mentioned compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof as an active ingredient. Also related to wrinkle and / or sagging preventive or ameliorating agents, including.
The wrinkle and / or sagging preventive or ameliorating agent of the present invention is characterized by being used in the usage of "used by applying red light after application to the skin".

The active ingredient of the present invention has an action of inhibiting the activity of neutrophil elastase secreted by neutrophils infiltrating the skin tissue, and suppresses the decomposition of elastin and collagen by neutrophil elastase.
On the other hand, irradiation of the skin with red light suppresses the expression of neutrophil adhesion promoting factors in vascular endothelial cells, and accordingly, the infiltration of neutrophils into the skin tissue is suppressed.
That is, by using the active ingredient of the present invention in the usage of "used by applying red light after application to the skin", the infiltration of neutrophils is suppressed, and elastin and collagen by neutrophil elastase are used. It can inhibit the upstream and downstream of the series of wrinkle and sagging pathways of collagen degradation.
Furthermore, as described above, the effect of enhancing the skin band can be obtained by applying red light.
That is, the present invention multilaterally inhibits the factors of wrinkle and sagging formation, and effectively realizes prevention or improvement of wrinkles and sagging.

Further, a preferred embodiment of the present invention further comprises a light scattering agent application step of applying a light scattering agent that shields near infrared rays to the skin.
As described above, near infrared rays have an opposite effect to red light from the viewpoint of controlling the expression of neutrophil adhesion promoting factors. By containing a light scattering agent that shields near-infrared rays, near-infrared rays that attenuate the effect of infrared rays are shielded, and the effect of suppressing the expression of neutrophil adhesion promoting factors by applying red light can be further increased.

Regarding the specific embodiment of the usage of "used by applying red light after application to the skin", the application of the neutrophil elastase inhibitor in the above "[3] Method for preventing or improving wrinkles and / or sagging". The items described regarding the process and the light irradiation process can be applied as they are.
That is, among the usages of the present invention, the items described in the neutrophil elastase inhibitor application step and the light scattering agent application step can be applied to "application to the skin", and the light irradiation step to "apply red light". The items described can be applied.

In addition, specific embodiments of the compound represented by the above-mentioned general formula (1), an isomer thereof, and / or a pharmacologically acceptable salt thereof, which are the active ingredients of the present invention, are described in the above-mentioned "[3] Wrinkles. And / or how to prevent or improve sagging. "

The wrinkle and sagging preventive or ameliorating agent of the present invention is preferably in the form of an external composition for skin. As for the specific embodiment of the external composition for skin, the description regarding the first external composition for skin described later applies.

Further, a specific embodiment of the light scattering agent that shields near infrared rays, which is a component of the present invention, will be described in the description of the second external composition for skin described later.

[5] External skin composition kit The present invention comprises a first external composition for skin containing an agent for preventing or improving wrinkles and sagging, and a second external composition for skin containing a light scattering agent for blocking near infrared rays. Also related to the external composition kit provided.
The first external composition for skin contains a compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. On the other hand, the second external composition for skin contains a light scattering agent that shields near infrared rays.

When the portion where the first and second external composition for skin is applied to the skin is exposed to sunlight, the near infrared rays contained in the sunlight are shielded by the action of the second external composition for skin. This strongly induces the suppression of the expression of neutrophil adhesion promoting factors by the red light contained in sunlight, and the infiltration of neutrophils into the skin and the subsequent decomposition of elastin and collagen by neutrophil elastase are effective. Is suppressed.

In addition, it is secreted from neutrophils by the action of the compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof contained in the first external composition for skin. The activity of neutrophil elastase is inhibited, and the decomposition of elastin and collagen is suppressed.

That is, by applying the external composition kit for skin of the present invention to the skin, wrinkles and sagging formation of suppression of neutrophil infiltration and decomposition of elastin and collagen by neutrophil elastase even when exposed to sunlight. It is possible to block upstream and downstream of a series of pathways. That is, the external composition kit for skin of the present invention exhibits an excellent effect of preventing or improving wrinkles and sagging.

The external composition kit for skin of the present invention is preferably used in such a way that red light is applied to the skin after the first and second external compositions for skin are applied to the skin.
By using the first external composition for skin in the method of applying red light after application to the skin, the decomposition of elastin and collagen by neutrophil elastase and the formation of wrinkles and sagging by suppressing the infiltration of neutrophils. It is possible to block upstream and downstream of a series of pathways. In addition, by applying the second external composition for skin to shield near infrared rays, the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light is enhanced, and more excellent prevention or improvement of wrinkles and sagging is achieved. The effect of can be obtained.

Regarding the specific embodiment of the usage of "used by applying red light after application to the skin", the application of the neutrophil elastase inhibitor in the above "[3] Method for preventing or improving wrinkles and / or sagging". The items described regarding the process and the light irradiation process can be applied as they are.
That is, among the usages of the present invention, the items described in the neutrophil elastase inhibitor application step and the light scattering agent application step can be applied to "application to the skin", and the light irradiation step to "apply red light". The items described can be applied.

Hereinafter, more detailed aspects of each of the first and second external skin compositions will be described.
[5-1] First Skin External Composition The first skin external composition comprises a compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. include. Specific embodiments of the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof are described in the above-mentioned "[3] Method for preventing or improving wrinkles and / or sagging". As described in.

The compound represented by the above general formula (1) can be contained as it is in the composition for external use on the skin, but it is treated with a pharmacologically acceptable acid or base to be converted into a salt form and used as a salt. It is also possible. Inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonates and benzene sulfonates; alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts; triethylamine salts, triethanolamine salts, ammonium salts, Examples thereof include organic amine salts such as monoethanolamine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginates; The composition for external use on the skin of the present invention contains one or more selected from the compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. be able to.

In order to include the compound represented by the general formula (1), an isomer thereof and / or a pharmaceutically acceptable salt thereof in the first skin external composition, the above-mentioned effect can be exhibited. It is preferably contained in an amount of 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 external composition for skin 1. This is due to the above-mentioned effect when the amount of the compound represented by the above-mentioned general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof contained in the first external composition for skin is too small. This is because the above-mentioned effect tends to reach a plateau even if the amount is too large.

The compound represented by the above general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof is preferably contained in an oil gel dosage form for external skin preparation together with partially crosslinked methylpolysiloxane. .. By forming the first external composition for skin in such a form, the skin retention property is enhanced, wrinkles and sagging are suppressed, and the balance between the formation and disappearance of new wrinkles and sagging is inclined toward the disappearance side, and wrinkles and sagging are formed. It is possible to improve the preventive or ameliorating effect on the formation of sagging.

The partially crosslinked methylpolysiloxane classified as a partially crosslinked organopolysiloxane polymer is a silicone oil having a structure in which a linear polymer formed by a siloxane bond is partially crosslinked. The "partially crosslinked type" in the present invention refers to a product manufactured by cross-linking so that the cross-linking rate indicating the degree of cross-linking is about 20 to 30%.

As the partially crosslinked methylpolysiloxane, it is preferable to use one having a consistency of 100 to 500 at 25 ° C. from the viewpoint of stability and usability.
The consistency of the partially crosslinked methylpolysiloxane at 25 ° C. can be measured according to JIS K2220.

Some of the partially crosslinked methylpolysiloxanes as described above are commercially available as general-purpose raw materials for cosmetics. The partially crosslinked methylpolysiloxane of the present invention can be used by purchasing such a commercially available product.

As commercially available products, in addition to partially crosslinked methylpolysiloxane, those containing other silicone oils such as decamethylcyclopentasiloxane, methylpolysiloxane, octamethylcyclotetrasiloxane, and methylphenylpolysiloxane should also be used. However, those containing only partially crosslinked methylpolysiloxane can also be used.

Among the commercially available partially crosslinked methylpolysiloxanes, the preferred one is KSG-15 manufactured by Shin-Etsu Chemical Industry Co., Ltd. (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 20-30 parts by mass of partially crosslinked methylpolysiloxane and about 70-80 parts by mass of methylpolysiloxane), KSG-17 (about 5 parts by mass of partially crosslinked methylpolysiloxane and octamethylcyclotetra). Approximately 95 parts by mass of siloxane), KSG-18 (mixture of approximately 10 to 20 parts by mass of partially crosslinked methylpolysiloxane and approximately 80 to 90 parts by mass of methylphenylpolysiloxane), and the like, in particular, KSG-16. preferable.

The first external composition for skin may be selected and contained in one or more of the commercially available products containing the above-mentioned partially crosslinked methylpolysiloxane, or may be commercially available containing the partially crosslinked methylpolysiloxane alone. The product may also contain other silicone oils.

The partially crosslinked methylpolysiloxane acts as a gel-forming agent in the first external composition for skin and imparts an action of maintaining the oil gel structure of the first external composition for skin. In order to exhibit such an action, it is preferable that the content of the partially crosslinked methylpolysiloxane is 5 to 25% by mass, based on the total amount of the first external composition for skin in the form of an oil gel. It is preferably 10 to 20% by mass. This is because if the amount is too small, it tends to be difficult to maintain the structure, and if it is too large, the degree of freedom of formulation tends to be impaired.

The first external composition for skin preferably contains a spherical powder that enhances fat solubility, for example, to improve elongation. The term "spherical" includes not only a true spherical shape but also a substantially spherical shape including an uneven portion on the surface.

The average particle size of such a spherical powder is preferably 5 to 20 μm. This is because if it is less than 5 μm, a squeaky feeling may be strongly felt at the time of application, while if it exceeds 20 μm, an uneven feeling due to the spherical powder may be strongly felt.

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

The spherical powder to be contained in the first skin external composition in the form of an oil gel is a spherical inorganic substance such as spherical silica, spherical calcium carbonate, spherical magnesium carbonate, spherical silicate such as spherical calcium silicate and spherical magnesium silicate. Powders and organic spherical powders such as polyamide powder, polymethylmethacrylate, and polyester powder can be preferably exemplified. Among these, organic spherical powder is more preferable, and polymethylmethacrylate is particularly preferable.
In addition to the above-mentioned effect of improving usability, the organic spherical powder has a skin retention of the compound represented by the above-mentioned general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. This is because it has an effect of significantly enhancing sex.

As the polymethylmethacrylate of the organic spherical powder, a commercially available product can be used, and as a commercially available product, Microsphere M330 sold by Matsumoto Yushi Pharmaceutical Co., Ltd. can be preferably exemplified. Further, in order to exert the above-mentioned action, the above-mentioned spherical powder preferably contains 12 to 50% by mass in total with respect to the total amount of the first skin external composition in the form of an oil gel, 15 to 45. It is more preferably contained in an amount of 20 to 30% by mass, and particularly preferably contained in an amount of 20 to 30% by mass. This is because if the amount is too small, the above-mentioned effect tends to decrease, and if the amount is too large, the degree of freedom in prescribing may be impaired. In addition, one or more of the above-mentioned spherical powders can be selected and contained in the first skin external preparation in the form of an oil gel.

Further, by containing the plant extract described later in the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, the stability over time can be enhanced. ..

Examples of the plant extract used in combination with the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof include peach seed extract, asagao karakusa extract, ginseng extract, and white birch resin extract. , Hatomugi seed extract, Hiougi extract, Ginseng extract, Button extract, Lotus extract, Shakuyaku extract, Amacha extract, Lemongrass extract, Sugina extract, Olive fruit extract, Togenashi extract, Rengesou extract, Yomogi extract, Toyaku extract, Moon peach leaf extract, Clove extract , Yagurumagiku extract, Farreroll, Otogirisou extract can be exemplified.

In the above plant extract, the plant part is not particularly limited, and the whole plant can be used, but of course, the plant body, the above-ground part, the rhizome part, the tree trunk part, the leaf part, the stem part, the spike, and the flower bud. , It is also possible to use only parts such as fruits. As the above-mentioned plant extract, any of a squeezed effluent, a steam distillate, a distillate, and a solvent extract can be used, but the squeezed effluent or the solvent extract can selectively obtain useful components. preferable.

The solvent used for solvent extraction is preferably a polar solvent, for example, water, alcohols such as 1,3-butanediol, ethanol and isopropanol, esters such as ethyl acetate and methyl acrylate, and ketones such as acetone and methyl ethyl ketone. Ethers such as diethyl ether and tetrahydrofuran can be preferably exemplified, and among them, an aqueous solution containing 1,3-butanediol and / or ethanol can be preferably exemplified. The content of 1,3-butanediol and / or ethanol at this time is preferably 10 to 40% by mass, more preferably 15 to 35% by mass, based on the total amount of the solvent.

Extraction may be carried out by adding 1 to 10 parts by mass of a solvent to 1 part by mass of the plant or a dried product thereof, and immersing the plant for several days at room temperature and for several hours at a temperature near the boiling point. If necessary, the insoluble material may be filtered out. When it is concentrated, it may be distilled off under reduced pressure. In the case of squeezed effluent, for example, 1,3-butanediol and / or ethanol was added to the obtained juice obtained by filtering and removing the insoluble matter, and the final concentration was 10 to 40% by mass based on the total amount of the juice. , Preferably added in an amount of 15 to 35% by mass. Such a plant extract can be prepared and used as described above, or a commercially available product can be purchased and used.

The first external composition for skin can contain the following substances in addition to the above plant extract.
Along with the compound represented by the above general formula (1), an isomer thereof and / or a pharmaceutically acceptable salt thereof, ascorbic acid glucoside, acetylhexapeptide, sodium alginate sulfate, benzyl ursolate, dipotassium glycyrrhizinate, Stearyl glycyrrhetinate, sodium chondroitin sulfate, sphingoglycolipid, tranexamic acid, sodium trehalose sulfate, urea, hydrogenated soybean phospholipid, 4-n-butylresorcinol, polymethacryloxyethylphosphorylcholine, 2-methacryloyloxyethylphosphorylcholine / butylmethacrylate First, by containing one or more substances selected from copolymers, polyglucosyloxyethyl methacrylate, sodium polyglutamate, di-lauroyl-L-glutamate (phytosteryl-2-octyldodecyl), golden silk extract. Can be a composition for external use of the skin.

By containing the above-mentioned substance, the stability with time is enhanced as described above, and the effect of the compound represented by the above-mentioned general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is stabilized. Can be demonstrated.

In addition, the first external composition for skin may contain an agent for suppressing the expression of a neutrophil migration promoting factor. The neutrophil migration promoting factor is a factor that promotes the migration of neutrophils into a tissue. Neutrophil migration promoting factors are secreted by dermal fibroblasts.
When the first external composition for skin contains an agent for suppressing the expression of a neutrophil migration promoting factor, a more excellent effect of preventing or improving wrinkles and sagging can be obtained.

More specifically, the application of red light suppresses the expression of neutrophil adhesion promoting factors and suppresses the adhesion of neutrophils to vascular endothelial cells. The migration of neutrophils located downstream thereof is suppressed by an agent that suppresses the expression of neutrophil migration promoting factors. The neutrophil elastase secreted by the infiltrated neutrophils is inhibited by the action of the compound represented by the above general formula (1), its isomer and / or a pharmacologically acceptable salt thereof. ..
As described above, by forming the first external composition for skin into a form containing an agent for suppressing the expression of neutrophil migration promoting factor, it is said that neutrophil adhesion, migration, and decomposition of elastin and collagen by neutrophil elastase. By suppressing a series of reactions located upstream, midstream, and downstream from multiple aspects, it is possible to obtain a more excellent effect of preventing or improving wrinkles and sagging.

Examples of the neutrophil migration promoting factor include CXC chemokines having an ELR (Glu-Leu-Arg) motif represented by CXCL-1 and IL-8.

Examples of the agent for suppressing the expression of neutrophil migration promoting factors include cyclohexylglycerin and horsetail extract.
These neutrophil migration promoting factor expression-suppressing agents are particularly excellent in the gene expression-suppressing action of CXCL-1 and IL-8.
Further, in the form containing both cyclohexylglycerin and horsetail extract, the gene expression inhibitory effect of CXCL-1 is remarkably increased.

Cyclohexylglycerin is a diol compound called 3- (cyclohexyloxy) -1,2-propanediol by the IUPAC name.

As the cyclohexyl glycerin, a commercially available product can be used, and for example, "ADEKANOL CHG (manufactured by ADEKA Corporation)" can be used.

The content of cyclohexylglycerin in the whole first external composition for skin is preferably 0.01 to 10% by mass in dry mass, and more preferably 0.05 to 2% by mass.

As the horsetail extraction site of the above-mentioned horsetail extract, a plant body, an above-ground part, a tree trunk and a dried product thereof can be used. Preferably, the whole plant is used as the extraction site.

The extract can be obtained by adding 1 to 30 parts by mass of the above-mentioned extraction solvent to 1 part by mass of the above-mentioned extraction site and immersing the extract at room temperature for several days or at a temperature near the boiling point of the solvent for several hours. ..
After extraction, a step of removing insoluble matter and a step of concentrating under reduced pressure may be provided, if necessary.
Further, fractional purification may be performed by column chromatography or the like filled with silica gel or an ion exchange resin.

The content of the horsetail extract is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass in terms of dry mass, based on the total amount of the first external composition for skin.

When the first external composition for skin contains two kinds of cyclohexylglycerin and horsetail extract as a gene expression inhibitor of a neutrophil migration promoting factor, the mass ratio of cyclohexylglycerin to 1 part by mass of horsetail extract is preferable. Is 0.01 to 1 part by mass, more preferably 0.02 to 0.5 part by mass, and particularly preferably 0.04 to 0.2 part by mass.

In addition, the first external composition for skin may contain an agent for suppressing the expression of a neutrophil adhesion promoting factor.
When the first external composition for skin contains an agent for suppressing the expression of neutrophil adhesion promoting factor, the effect of suppressing the expression of neutrophil adhesion promoting factor by applying red light can be further increased, and more excellent wrinkles can be obtained. It is possible to obtain the effect of preventing or improving sagging.

An oil-soluble peach leaf extract can be preferably exemplified as an agent for suppressing the expression of a neutrophil adhesion promoting factor. The oil-soluble peach leaf extract can be formulated in a formulation that does not contain water, and can also be formulated with an ingredient that is not stable in water.

The oil-soluble peach leaf extract can be obtained by extracting the fruits and / or leaves of Rosaceae Amygdaloideea Amygdalus with an organic solvent.
As usable organic solvents, 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, ethyl acetate and butyl acetate, Examples thereof include fatty acid esters such as isobutyl acetate, hydrocarbons such as hexane and benzene, and mixtures of two or more of these solvents.
The oil-soluble peach leaf extract includes an extract extracted with the above solvent, a concentrate obtained by vacuum concentration or freeze-drying, and a fractionally purified product fractionally purified by column chromatography or the like filled with silica gel or an ion exchange resin. Etc. can be used.

As the oily peach leaf extract, a commercially available one can be used. For example, "oil-soluble peach leaf extract (manufactured by Koei Kogyo Co., Ltd.)" can be used.

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

Further, in addition to the above-mentioned components, chrysanthermindicum and conchiolin hydrolysis as substances to be used in combination with the above-mentioned compound represented by the general formula (1), an isomer thereof and / or a pharmaceutically acceptable salt thereof. Substances, terpenoids, stilbene derivatives, para-aminobenzoic acid-based UV absorbers, anthranylic 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 can be used.

In addition to the above-mentioned components, the following substances can be contained in the first external composition for skin. The plant extract is not particularly limited as long as it is generally used for pharmaceuticals, cosmetics and the like.
For example, akebi extract, asunaro extract, asparagus extract, avocado extract, almond extract, arnica extract, aloe extract, apricot extract, ginkgo extract, uikyo extract, agetsu extract, ginger extract, odorikosou extract, orange extract, oyster extract, cucumber extract. , Camomila extract, carrot extract, kawarayomogi extract, kanzo extract, kiwi extract, cucumber extract, guaba extract, cuttlefish extract, bear zasa extract, walnut extract, grapefruit extract, black rice extract, chlorella extract, mulberry extract, gentiana extract, gennoshoco extract, tea extract , Gobo extract, rice extract, fermented rice extract, fermented rice bran extract, rice germ oil, kokemomo extract, salvia extract, sabonsou extract, sasa extract, sansha extract, sansho extract, shiitake extract, dioe extract, shikon extract, shiso extract, shinanoki extract, shimotsukesou Extract, shobu root extract, white birch extract, stevia extract, stevia fermented product, sardine extract, sardine extract, sage extract, zegna oyster extract, senkyu extract, soybean extract, daiou extract, taiso extract, thyme extract, dandelion Extract, Chinpi extract, Jincha extract, Togarashi extract, Touki extract, Tokinsenka extract, Tohi extract, Dokudami extract, Tomato extract, Natto extract, Garlic extract, Novara extract, Bakumondou extract, Parsley extract, Birch extract, Hamamelis extract, Hinoki extract , Biwa extract, Fukitanpopo extract, Fukinotou extract, Butcher bloom extract, Grape extract, Grape seed extract, Hechima extract, Benibana extract, Peppermint extract, Hop extract, Pine extract, Mizubasho extract, Mukuroji extract, Melissa extract, Mozuku extract, Eucalyptus extract, Yukinoshita Extracts such as extract, lily extract, yokuinin extract, lavender extract, green tea extract, apple extract, reishi extract, lettuce extract, lemon extract, lotus extract, rose extract, Roman chamomile extract, royal jelly extract, wild thyme extract, and crackle extract are preferable. Is mentioned as.

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

Examples of the oily component that can be contained in the first external composition for skin include polar oils, silicone oils, and volatile hydrocarbon oils. As polar oils, synthetic ester oils include isopropyl myristate, cetyl octanate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyl dimethyl octanoate, and lactic acid. Cetyl, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearyl acid, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl dicaprate Glycol, diisostearyl malate, glycerin di-2-heptylundecanoate, trimethylolpropane tri-2-ethylhexylate, trimethylolpropane triisostearate, pentanyllithitol tetra-2-ethylhexylate, glycerin tri-2-ethylhexylate , Trimethylol propane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glycerin trimyristate, glyceride tri-2-heptylundecanoic acid, castor oil fatty acid methyl ester, oleic acid oil, cetostearyl alcohol, Acetglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamate-2-octyldodecyl ester, di-2-heptylundecyl adipate, ethyllaurate, di-2-ethylhexyl sebatate , 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebatate, 2-ethylhexyl succinate, ethyl acetate, butyl acetate, amyl acetate, triethyl citrate, octylmethoxycinnamate, etc. Can be mentioned.

Further, as the silicone oil, chain polysiloxane such as dimethylpolysiloxane and diphenylpolysiloxane, cyclic polysiloxane such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane, amino-modified polysiloxane, and polyether modification Examples thereof include modified polysiloxanes such as polysiloxanes, alkyl-modified polysiloxanes, and fluorine-modified polysiloxanes.

Also, as natural oils, 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, southern ka oil, castor oil, flaxseed oil, Saflower oil, cotton seed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, cinnamon oil, Japanese millet oil, jojoba oil, germ oil, triglycerin, glycerin trioctanoate, glycerin triisopalmitate And so on.

Examples of the volatile hydrocarbon oil include isododecane and isohexadecane. Oily ingredients normally used in other cosmetics can be used.

Examples of the surfactant include anionic surfactants such as fatty acid sekken (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine alkyl sulfate ether, stearyltrimethylammonium chloride, benzalconium chloride, laurylamine oxide. Cationic surfactants such as, imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyroxy 2-sodium salt, etc.), amphoteric surfactants such as acylmethyltaurine, sorbitan Fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (glycerin monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearate polyoxyethylene sorbitan, etc.), POE sorbit fatty acid esters (POE-sorbit monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.) Etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic (registered trademark) type , POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivative (POE castor oil, POE cured castor oil, etc.), sucrose fatty acid ester, alkyl Examples thereof include non-ionic surfactants such as glucoside.

Polyhydric alcohols include polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, martitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4. -Hexylene glycol, 1,2-hexanediol, 1,2-octanediol and the like can be mentioned.

Thickeners include guagam, quince seed, carrageenan, galactan, arabic gum, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatane sulfate, glycogen, Heparan sulfate, hyaluronic acid, sodium hyaluronate, traganth gum, keratane sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guagam, carboxymethyl gua gum, dextran, kerato sulfate, locust bean gum, succinoglucan, carronic acid, chitin, chitosan, carboxymethyl Examples thereof include chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol and the like.

As the first external composition for skin, cosmetics, quasi-drugs, pharmaceuticals and the like can be preferably exemplified, and cosmetics and quasi-drugs are more preferable because they can be used on a daily basis.

The first external composition for skin can take any of the commonly known lotion, emulsion, essence, cream, foam, and non-hydraulic forms. As the cosmetics, any of basic cosmetics, hair cosmetics, make-up cosmetics and the like can be applied.
[5-2] Second External Skin Composition The second external skin composition contains a light scattering agent that shields near infrared rays. Here, "shielding near-infrared rays" does not mean only a form that shields all near-infrared rays (that is, a shielding rate of 100%), but also includes a form that shields at least a part of near-infrared rays.

Titanium oxide can be preferably exemplified as a light scattering agent that shields near infrared rays. More preferably, titanium oxide having an average particle size of 0.5 μm or more is used. Such titanium oxide has an excellent function of scattering near-infrared rays, and imparts a near-infrared ray protective effect in the second external composition for skin.

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, the average particle size is preferably in the above range.

In the present invention, the "average particle size" specifically means the volume average particle size of the particles. For example, a transmission electron microscope (TEM) image is acquired and the image is analyzed. It can be calculated by

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

Titanium oxide is preferably oil-phase dispersible. Since the oil phase-dispersible titanium oxide is uniformly dispersed in the oil phase, the second external composition for skin in such a form is excellent in water resistance and near-infrared ray protection function.

As the oil-dispersible titanium oxide, titanium oxide whose surface is coated with a hydrophobic compound can be preferably exemplified. The oil-dispersible titanium oxide is not limited, but titanium oxide coated with a hydrophobic organic compound is preferably used.

Titanium oxide is not particularly limited as long as it has a scattering effect of near infrared rays. Such titanium oxide may be a commercially available product. Alternatively, commercially available titanium oxide, such as titanium oxide surface-treated by a known method, can be used. As for titanium oxide, only one type having different particle sizes or the like may be blended in the second external composition for skin, or two or more kinds may be blended in combination.

The content of titanium oxide in the second external composition for skin is usually 0.1% by mass to 15% by mass, preferably 0.5% by mass to 10% by mass.
The content of titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent is usually 25% by mass or more, preferably 30% by mass or more.
In addition, a person skilled in the art can appropriately adjust the content based on this range and the examples described later in consideration of 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 and the like. Although not limited, if the ultraviolet scattering agent is a fine particle metal oxide, for example, the primary average particle size as observed by an electron microscope may be 100 nm or less. That is, the content of titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent can be rephrased as the content of titanium oxide with respect to the total amount of powder having an average particle diameter of more than 100 nm.

A preferred embodiment of the second external composition for skin is an emulsified or oil gel-like cosmetic containing the following components, which are "a shielding rate of light having a wavelength of 585 to 760 nm" and "a light having a wavelength of 760 to 1310 nm". The difference in "shielding rate" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more.
a-1) Titanium oxide having an average particle size of 0.5 μm or more and 25% by mass or more based on the total amount of powder excluding the ultraviolet scattering agent; and b-1) Spherical powder.

The present inventors have studied diligently for a cosmetic that can protect near infrared rays, transmit visible light in a long wavelength region, and impart an anti-aging effect. As a result, near-infrared rays can be protected by titanium oxide having a large average particle size, specifically, titanium oxide having an average particle size of 0.5 μm or more, and further, spherical powder is contained as a powder to be blended in cosmetics. Therefore, the long wavelength region of visible light can be effectively transmitted, that is, the difference between "the shielding rate of light having a wavelength of 585 to 760 nm" and "the shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and , "Shading rate of light having a wavelength of 760 to 1310 nm" was found to be able to achieve 30% or more.

The second external composition for skin prevents or improves the decrease in skin viscous elasticity, wrinkles, sagging, etc. of the skin by protecting the near infrared rays that damage the skin and transmitting visible light having an aging care effect in the long wavelength region. It has been found that it is effective as a cosmetic that has an anti-aging effect. The second external composition for skin is designed based on such findings.

The difference between "the shielding rate of light having a wavelength of 585 to 760 nm" and "the shielding rate of light having a wavelength of 760 to 1310 nm" and "the shielding rate of light having a wavelength of 760 to 1310 nm" are based on known analytical methods. Can be measured and calculated.
For example, using a spectrophotometer or the like, the light transmittance of the thin film of the second skin external composition in the wavelength range of 585 to 760 nm is measured, and the average value of the transmittance in the same wavelength range is calculated. As 100-transmittance (average value), "shielding rate of light having a wavelength of 585 to 760 nm" can be obtained. Similarly, the "shielding rate of light having a wavelength of 760 to 1310 nm" is calculated. The difference between them can be obtained by subtracting the "shielding rate of light having a wavelength of 760 to 1310 nm" from the "shielding rate of light having a wavelength of 585 to 760 nm".

The dosage form of the second external composition for skin is not particularly limited as long as it is a known dosage form used as a cosmetic or an external medicine for skin, and for example, an oil emulsifier form in water, an emulsifier form in water in oil, an oil gel dosage form and the like. Can be mentioned.

The specific use of the second external composition for skin is not particularly limited, but for example, an external skin preparation such as emulsion, foundation, sunscreen, lip color, lip balm, lip gloss, cheek color, eye color, and spots cover, and cosmetics. And so on. In such an aspect, the effect of the present invention can be effectively utilized and it may be particularly suitable for skin protection.

As described above, in a preferred form of the second external skin composition, a spherical powder is contained as the component b-1). The spherical powder has an excellent function of transmitting light on the long wavelength side of visible light with respect to light on the short wavelength side of visible light, and imparts an anti-aging effect in the cosmetic of the present invention. Further, the spherical powder contributes to the suppression of the squeaky feeling and imparts an excellent usability.

As a function of transmitting light on the long wavelength side of visible light, specifically, the ratio of "the amount of transmitted light having a wavelength of 585 to 760 nm" to "the amount of transmitted light having a wavelength of 400 to 760 nm" (hereinafter, "" It may be referred to as "585-760 nm transmission ratio"). The permeation ratio of the spherical powder used in the present invention is preferably 50% or more, more preferably 60% or more, still more preferably 65% or more, and particularly preferably 68% or more.

Here, the 585-760 nm transmission ratio can be measured and calculated based on a known analytical method. For example, using a spectrophotometer or the like, the light transmission amount in the wavelength range of 400 to 760 nm of the thin film of the spherical powder dispersion is measured, the average value of the transmission amount in the same wavelength range is calculated, and "400 to 760 nm". The amount of light transmitted at the wavelength of Further, the transmitted amount of light in the wavelength range of 585 to 760 nm is measured, and the average value of the transmitted amount in the same wavelength range is calculated and used as "the transmitted amount of light having a wavelength of 585 to 760 nm". The transmission ratio of 585 to 760 nm can be calculated by dividing the "transmitted amount of light having a wavelength of 585 to 760 nm" by the "transmitted amount of light having a wavelength of 400 to 760 nm".

The average particle size of the spherical powder is preferably 6.0 μm or less, more preferably 2.0 μm or less.
When the average particle size of the spherical powder is in the above range, the transmission ratio of 585 to 760 nm is high, and the "shielding rate of light having a wavelength of 585 to 760 nm" and "light having a wavelength of 760 to 1310 nm" in the cosmetic of the present invention have a high transmission ratio. It is preferable from the viewpoint of achieving the numerical range of the difference of "shielding rate".

The spherical powder used in the present invention is not particularly limited, and examples thereof include organic powders such as polymethylsilsesquioxane and crosslinked polydimethylsiloxane.
Such spherical powder may be a commercially available product, for example, Tospearl 120A (manufactured by Momentive), MSP-N050 (manufactured by Nikko Rika) (average particle size: 0.5 to 2.0 μm) and the like. Can be mentioned. The spherical powder may be blended in only one type or in combination of two or more types in the cosmetic.

The content of the spherical powder of the 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 the component b-1) with respect to the total amount of the powder of the component a-1) excluding titanium oxide and the ultraviolet scattering agent 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, the content of the spherical powder is preferably in the above range. The content ratio (mass ratio) of the titanium oxide of the component a-1) and the spherical powder of the component b-1) is usually (a-1) / (a + b-1) of 0.25 or more, preferably 0. .50 or more.

The second external composition for skin may contain an anti-photoaging component as the component x). The anti-photoaging component is a component that improves and / or prevents aging caused by irradiation with ultraviolet rays. More specifically, the anti-photoaging component refers to a component that improves and / or prevents aging by having an action of increasing and / or suppressing the expression of MFAP4. Further, it refers to a component that improves and / or prevents aging by having an action of suppressing the expression of matrix metalloproteinases (MMP-3 and MMP-9) that decompose MFAP4.

The anti-photoaging component is preferably a biological extract. Among them, the anti-photoaging component is particularly preferably a plant extract.
Here, as the plant extract, a plant native or grown in Japan, an extract produced in Japan sold as a raw material for Chinese herbal medicine, etc. can be used to prepare an extract, or a plant extract such as Maruzen Co., Ltd. can be used. You can also purchase and use commercially available extracts sold by the companies that handle them.

As the anti-photoaging component, the following components can be preferably mentioned.
Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae, Rutaceae. Rutaceae (Citrus aurantifolia), Rutaceae (Rosaceae) Rosa (Rosa) Rosa × coryana, Rutaceae (Lamiaceae) Rutaceae (Thymus) Tymus Lamiaceae (Actinidia) Kiwifruit (Actinidia arguta), Labiatae (Rosaceae) Rose genus (Rosa) Rosa x damaschena, Rutaceae (Rutaceae) Lamiaceae (Rutaceae) Lamiaceae (Rutaceae) (Campanulaceae) Lamiaceae (Codonopsis) Lamiaceae (Codonopsis pilosula), Rutaceae (Oxalidaceae) Lamiaceae (Averrhoea) Gorenshi (Averrhoea carambola) (Ariaceae) Genus Tochibaninjin (Panax) Otaneninjin (Panax ginseng), Rutaceae (Lamiaceae) Lamiaceae (Perilla) Egoma (Perilla frutessens), Tsubaki (Theaceae) Tsubaki (Theaceae) ) Rosa genus Rosa × damaskena, Rutaceae, a plant species belonging to the genus Rutaceae, Rutaceae, Lamiaceae, Aloe, Aloe, Aloe, Aloe Genus Urtica (Urtica) Urtica (Urtica tunbergiana), Rutaceae (Api) aceae) Fennels genus Fennels vulgare, Asteraceae genus Arctium burdock (A.). lappa), royal jelly The above components may be used alone or in combination of two or more.

Since the above-mentioned burdock extract has a particularly large effect of increasing the expression of MFAP4, it is preferable to use burdock extract (burdock extract) as an anti-photoaging component.

In addition, among the above-mentioned biological extracts, since the effect of reducing the expression level of at least one of MMP-3 and MMP-9 is particularly large, kihada extract, kiwi extract, damask rose flower extract, perilla extract, chanoki extract, etc. It is preferable to have a form containing at least one of the Otaneninjin extract as an anti-photoaging component.

The content of the extract of the component x) in the second external composition for skin is usually 0.00001% by mass or more, preferably 0.0001% by mass or more, more preferably the total amount of the cosmetic as a dry solid content. Is 0.001% by mass or more.
The content of the extract of the component x) in the second external composition for skin is usually 80% by mass or less, preferably 30% by mass or less, more preferably 10 with respect to the total amount of the cosmetic as a dry solid content. It is less than mass%.
Within the above range, anti-photoaging effects such as wrinkle improvement, sagging improvement, firmness reduction prevention, and skin elasticity reduction prevention are exhibited.

The second external composition for skin may contain, as the component y), an extract whose activity is improved by light having a wavelength of 585 to 760 nm (hereinafter, may be simply referred to as “extract”). The extract whose activity is improved by light having a wavelength of 585 to 760 nm on the long wavelength side of visible light is preferable to the cosmetic of the present invention in that the activity is improved in the cosmetic of the present invention and a good effect is imparted. Used. Here, the activity is an activity for improving the skin, and is not particularly limited, and examples thereof include activities such as anti-inflammatory, moisturizing, blood circulation promotion, antioxidant, skin cell activation, and whitening. The cosmetic of the present invention is excellent in protection of near infrared rays and transmission of visible light in a long wavelength region, and has anti-aging effects such as reduction of skin viscoelasticity, prevention or improvement of wrinkles, sagging, etc., and thus such anti-aging. Anything that has the activity related to is preferable from the viewpoint of exhibiting a more excellent effect.

The improvement of the activity of the extract by light having a wavelength of 585 to 760 nm can be measured and calculated based on a known analytical method. For example, it can be confirmed by measuring and comparing the activity of the extract with and without light irradiation having a wavelength of 585 to 760 nm.

The extract to be blended in the second external composition for skin is not limited as long as it is an extract whose activity for improving the skin is improved by light having a wavelength of 585 to 760 nm, and examples thereof include extracts derived from animals or plants. Here, the extract is a general term for an animal or plant-derived extract, an extract fraction, a purified fraction, an extract, a fraction, a solvent-removed product of a purified product, and the like. From the viewpoint of availability, usability and the like, plant-derived extracts are preferable.

Examples of the plant include native or grown plants, extracts using those sold as raw materials for Chinese herbal medicine, and commercially available extracts.
In the extraction operation, in addition to using the whole plant part, parts such as the plant body, the above-ground part, the rhizome part, the tree trunk, the leaf part, the stem part, the spikes, and the flower buds can be used, but these are crushed or finely divided in advance. It is preferable to cut it to improve the extraction efficiency. As the extraction solvent, water; alcohols such as methanol, ethanol, isopropyl alcohol, butanol; polyhydric alcohols such as 1,3-butanediol and polypropylene glycol; ketones such as acetone and methyl ethyl ketone; diethyl ether, tetrahydrofuran and the like. One or more selected from polar solvents such as ethers can be exemplified as suitable ones. As a specific extraction method, for example, a solvent may be added in an amount of 1 to 30% by mass based on 1 mass of a part used for extraction of a plant or the like or a dried product thereof, and the temperature may be near the boiling point for several days at room temperature. For example, a method of immersing for several hours, cooling to room temperature, removing insoluble matter and / or solvent if desired, and fractionally purifying by column chromatography or the like can be mentioned.

Extracts include, but are not limited to, akebi extract, asnalo extract, asparagus extract, avocado extract, flaxseed extract, almond extract, arnica extract, aloe extract, aronia extract, apricot extract, ginkgo extract, indokino extract, uikyo extract, etc. Udo extract, Agetsu extract, Ezokogi extract, Enmeisou extract, Ogon extract, Oubaku extract, Ouren extract, Otaneninjin extract, Otogirisou extract, Odorikosou extract, Orange extract, Kakyoku extract, Kakkon extract, Camomila extract, Carrot extract, Kawarayomogi extract, Kanzo extract. , Kiwi extract, Cucumber extract, Guava extract, Kujin extract, Kuchinashi extract, Kumazasa extract, Clara extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, Kwa extract, Keiketto extract, Gettoyo extract, Gentiana extract, Gennoshoco extract, Tea Extract, Gobo extract, Rice extract, Fermented rice extract, Fermented rice bran extract, Rice germ oil, Kokemomo extract, Salvia extract, Sabonsou extract, Sasa extract, Sanzashi extract, Sansha extract, Sansho extract, Shiitake extract, Jio extract, Shikon extract, Shiso extract, Shinanoki extract, Shimotsukesou extract, Shakuyaku extract, Shokyo extract, Shobu root extract, Shirakaba extract, Sugina extract, Stevia extract, Stevia fermented product, Seiyoukizuta extract, Seiyousanzashi extract, Seiyouniwatoko extract, Seiyounokogirisou extract, Seiyouhakka extract, Sage extract, Zenia oi extract, Senkyu extract, Senburi extract, Souhakuhi extract, Daiou extract, Soybean extract, Taiso extract, Thyme extract, Dandelion extract, Tea extract, Chouji extract, Chinpi extract, Jincha extract, Togarashi extract, Touki extract, Tokinsenka extract, Tounin extract, Tohi extract, Dokudami extract, Tomato extract, Natto extract, Carrot extract, Garlic extract, Novara extract, Hibiscus extract, Bakumondou extract, Hass extract, Hass germ extract, Parsley extract, Birch extract, Hamamelis extract, Hikiokoshi extract, Hinoki extract , Biwa extract, Fukitanpopo extract, Fukinotou extract, Bukuryo extract, Butcher bloom extract, Grape extract, Grape seed extract, Hechima Extract, Benibana extract, Peppermint extract, Bodaiju extract, Button extract, Hop extract, Pine extract, Maronie extract, Mizubasho extract, Mukuroji extract, Melissa extract, Mozuku extract, Peach extract, Yagurumagiku extract, Eucalyptus extract, Yukinoshita extract, Yuzu extract, Yuri extract, Yokuinin Extract, Yomogi extract, Lavender extract, Green tea extract, Apple extract, Louis Boss tea extract, Reishi extract, Lettuce extract, Lemon extract, Renkyo extract, Rengesou extract, Rose extract, Rosemary extract, Roman chamomile extract, Royal jelly extract, Waremokou extract, etc. Extract is mentioned.

Such an extract may be a commercially available product. The extract may be blended with only one type or in combination of two or more types in the cosmetic.

The content of the extract of the component y) in the second external composition for skin 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. %. The content of the extract is preferably in the above range from the viewpoint of stably blending the extract and satisfactorily exerting the effect of the extract.

In order to protect against ultraviolet rays having an adverse effect on the skin, a preferred embodiment of the second external composition for skin includes a response containing an ultraviolet absorber and / or an ultraviolet scattering agent. By containing an ultraviolet absorber and / or an ultraviolet scattering agent, not only near-infrared rays but also the adverse effects of ultraviolet rays are suppressed, and the composition for external use on the skin is particularly suitable for protecting the skin.

The type of the 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, but it is a katsura acid-based ultraviolet absorber, a benzophenone-based ultraviolet absorber, and a benzoic acid-based ultraviolet absorber. , Salicylic acid-based UV absorber, dibenzoylmethane-based UV absorber, anthranilic acid-based UV absorber, urocanic acid-based UV absorber, triazine-based UV absorber and the like. Specifically, -2-ethylhexyl paramethoxycinerate, isopropyl paramethoxycinerate, dietanolamine salt of paramethoxyhydrokei syrup, glyceryl glyceryl mono-2-ethylhexanoate syrup, methoxy. Octyl silicate, methyl isopropyl silicate and other silicate-based ultraviolet absorbers, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfate, 2-hydroxy-4-methoxybenzophenone -5-Sodium sulfate, 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2', 4,4'- Benzophenone-based ultraviolet absorbers such as tetrahydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone, paraaminobenzoic acid, ethyl paraaminobenzoate, butyl paraaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, glyceryl paraaminobenzoate , Octyl paradimethylaminobenzoate, Amil paraaminobenzoate, hexyl diethylaminohydroxybenzoyl, benzoic acid-based ultraviolet absorbers, 2-ethylhexyl salicylate, trietanolamine salicylate, homomentyl salicylate, dipropylene glycol salicylate, methyl salicylate, salicylate Salicylic acid-based ultraviolet absorbers such as ethylene glycol, phenyl salicylate, amyl salicylate, benzyl salicylate, isopropylbenzyl salicylate, potassium salicylate, 4-tert-butyl-4'-methoxydibenzoylmethane, 4-isopropyldibenzoylmethane, 4-methoxy Dibenzoylmethane-based ultraviolet absorbers such as dibenzoylmethane and 4-tert-butyl-4'-hydroxydibenzoylmethane, menthyl-O-aminobenzoate, 2-phenyl-benzimidazole-5-sulfate, 2- Phenyl-5-methylbenzoxazole, 3- (4-methylbenzylidene) camphor, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethyl-2-cyano-3,3 Anthranilic acid-based UV absorbers such as'-diphenylacryllate, 2- (2'-hydroxy-5-methylphenyl) benzotriazol, mentyl anthranylate, urocanic acid-based UV absorbers such as ethyl urocanate; bisethyl Examples thereof include triazine-based ultraviolet absorbers such as hexyloxyphenol methoxyphenyl triazine and ethyl hexyl triazone. As the ultraviolet absorber, a commercially available product can also be used. In addition, only one kind of ultraviolet absorber may be blended in cosmetics, or two or more kinds may be blended in combination.

The content of the ultraviolet absorber in the second external composition for skin 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 absorber is within the above range, excellent ultraviolet absorbing ability can be exhibited.

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

The fine particle metal oxide has a particle size referred to as fine particles in the art, and for example, the primary particle size as observed by an electron microscope is usually 5 to 100 nm, preferably 10 to 80 nm.

The ultraviolet scattering agent has an excellent ultraviolet scattering effect. Therefore, it is preferable that the second external composition for skin contains one or two selected from fine particle titanium oxide and fine particle zinc oxide.

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

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

The ultraviolet scattering agent is preferably oil-phase dispersible. Since the oil phase-dispersible ultraviolet scattering agent is uniformly dispersed in the oil phase, the second external composition for skin in such a form is excellent in water resistance and ultraviolet protection function.

As the oil-dispersible ultraviolet scattering agent, an ultraviolet scattering agent whose surface is coated with a hydrophobic compound can be preferably exemplified. As such an oil-dispersible ultraviolet scattering agent, an ultraviolet scattering agent coated with a hydrophobic organic compound is preferably used.

The content of the ultraviolet scattering agent in the second external composition for skin 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.

From the viewpoint of being uniformly dispersed in the oil phase, the ultraviolet scattering agent is preferably dispersed in an oil-based medium and mixed with the cosmetic raw material.
The dispersion of the ultraviolet scattering agent in an oil-based medium can be performed based on the preparation method used in the field of ordinary cosmetics and the like. For example, the ultraviolet scattering agent and the oil-based medium can be mixed with a bead mill or the like to prepare and disperse a fluid (slurry) in which the ultraviolet scattering agent is dispersed in the oil-based medium.

The content of the ultraviolet scattering agent in the slurry obtained by stirring and mixing the ultraviolet scattering agent and the oil-based medium is preferably 10% by mass to 70% by mass from the viewpoint of having an appropriate fluidity of the slurry.

The oil-based medium for dispersing the ultraviolet scattering agent is not limited, and for example, silicone oils such as hydrogen dimethicone, caprylyl methicone, dimethicone, and cyclopentasiloxane; lauric acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, and the like. Isononanoic acid ester, isostearic acid ester, isopalmitic acid ester, oleic acid ester, vegetable oil (macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, Examples thereof include fatty acid ester oils such as palm oil). From the viewpoint of dispersibility, fatty acid ester oil is preferable. The oil-based medium may be used alone or in combination of two or more. Among these, vegetable oil is preferable, and olive oil is more preferable, from the viewpoint of obtaining good dispersibility.

The second external composition for skin may contain optional ingredients usually used in cosmetics and the like other than the above essential ingredients. As optional ingredients, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid lanolin, dicaprylyl carbonate and other oils. ; Waxes such as hardened coconut oil, hardened oil, mokurou, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojobaro; liquid paraffin such as hydrogenated polyisobutene, squalane, prestan, Hydrocarbons such as ozokelite, paraffin, ceresin, vaseline, microcrystalin wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl Higher alcohols such as alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebatate, lactic acid Cetyl, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentylglycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, tri-2-ethylhexane Synthetic ester oils such as trimethylolpropane acid, trimethylolpropane triisostearate, penta-2-ethylhexanoic acid pentane erythrite; chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane; octamethyl Cyclic polysiloxanes such as cyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane; silicone oils such as amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and modified polysiloxanes such as fluorine-modified polysiloxanes. Oil agents such as; fatty acid sekiken (potassium behenate, potassium stearate, sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, anionic surfactants such as trietanolamine ether, alkyl sulfate; stearyltrimethylammonium chloride, etc. Clicks on benzalconium chloride, laurylamine oxide, etc. On-surfactants; imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxyside-1-carboxyethyroxy 2-sodium salt, etc.), betaine-based surfactants (alkylbetaine, amidobetaine, sulfobetaine, etc.) Etc.), Amphoteric surfactants such as acylmethyltaurin; sorbitan fatty acid esters (sorbitan monostealate, sorbitan sesquioleate, etc.), glycerin fatty acids (glycerin monostearate, etc.), propylene glycol fatty acid esters Classes (propylene glycol monostearate, etc.), hardened castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbit fatty acids. Esters (POE-sorbit monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostelate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.) , POE alkyl esters (POE2-octyldodecylester, etc.), POE alkylphenyl esters (POE nonylphenylester, etc.), Pluronic® types, POE / POP alkyl esters (POE / POP alkyl esters, etc.) Non-ionic surface activity such as POE / POP2-decyltetradecylether), tetronics, POE castor oil / cured castor oil derivative (POE castor oil, POE cured castor oil, etc.), sucrose fatty acid ester, alkyl glucoside, etc. Agents; Moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface-treated, mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic acid anhydride (silica), oxidation Powders such as aluminum; surface-treated inorganic pigments such as red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, dark blue, zinc oxide, pigment grade titanium oxide; surface treated Esters such as fish phosphorus foil, bismuth oxychloride, etc .; Esterized, Red No. 202, Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Organics such as Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1, Green 201, Purple 201, Red 204, etc. Pigments; polyethylene powder, polymethyl methacrylate , Nylon powder, organic powders such as organopolysiloxane elastomer; lower alcohols such as ethanol and isopropanol; vitamin A or its derivatives, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or its derivatives , Vitamin B12, Vitamin B15 or derivatives thereof; Vitamin Es such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin Ds, vitamin H, pantothenic acid, pantetin, pyrroloquinolin Vitamins such as quinone; Antibacterial agents such as methylparaben and phenoxyethanol; Physiologically active ingredients such as whitening agents, cell activators, rough skin improving agents, blood circulation promoters, skin astringent agents; pH adjusters; water, methanol, ethanol, Alcohols such as isopropyl alcohol and 1,3-butylene glycol; thickeners such as carboxyvinyl polymers; emulsification stabilizers such as polyglyceryl pentastearate and stearoyl lactylate Na; solvents such as benzene, toluene, tetrahydrofuran and silicone Etc .;

As a method for producing the second external composition for skin, a known method used in the field of ordinary cosmetics and the like can be appropriately adopted. For example, in the case of an oil-in-water emulsifier type, component a-1). , The powder component containing the component b-1) is pulverized as necessary, added to the heated oil phase, and mixed and dispersed. It can be obtained by adding the same oil phase to a heated aqueous phase, emulsifying and cooling.
For example, in the case of an oil gel dosage form, it can be obtained by crushing a powder component containing components a-1) and b-1) as necessary, adding it to a heated oil phase, mixing and dispersing it, and cooling it. can.

The second external composition for skin is preferably in the form of an oil-in-water emulsifier, but from the viewpoint of obtaining a composition having both improved water resistance and uniform film forming property, the second external composition for skin is described below. It is preferable to have the configuration of.
a-2) Titanium oxide surface-treated with triethoxycaprylylsilane and having an average particle size of 0.5 μm or more;
b-2) UV absorber and / or UV scatterer;
c-2) Fatty acid salt; and d-2) Paste-like or solid oil at 25 ° C, excluding higher alcohols and fatty acids.

Titanium oxide having a large average particle size, specifically titanium oxide having an average particle size of 0.5 μm or more, is particularly excellent in the scattering effect of near infrared rays. Further, by mixing the above-mentioned titanium oxide surface-treated with triethoxycaprylylsilane with an oil phase containing a fatty acid salt, the fatty acid salt binds to the surface of titanium oxide and is effectively dispersed in the oil phase. be able to. Further, the paste-like or solid oil agent at 25 ° C., excluding higher alcohols and fatty acids, can improve the water resistance by enhancing the skin adhesion and the hydrophobicity of the film.
Hereinafter, embodiments of the second external composition for skin containing the components a-2) to d-2) will be described in detail.

The component a-2) is titanium oxide having an average particle size of 0.5 μm or more surface-treated with triethoxycaprylylsilane. As for the average particle size of the titanium oxide, the above-mentioned one is appropriate.

Titanium oxide of component a-2) is surface-treated with triethoxycaprylylsilane by a known surface treatment method. In the oil-in-water emulsifier-type second external composition for skin, titanium oxide surface-treated with triethoxycaprylylsilane is excellent in dispersion in the oil phase.

The titanium oxide of the component a-2) is not particularly limited as long as it has the above-mentioned 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, such as titanium oxide surface-treated by a known method, can be used. As for titanium oxide, only one type having different particle sizes or the like may be blended in the composition, or two or more kinds may be blended in combination.

The content of titanium oxide of the component a-2) in the oil-in-water emulsifier type second skin external composition is usually 0.1% by mass to 15% by mass, preferably 0.5% by mass to 10% by mass. Is. From the viewpoint of good near-infrared scattering effect and dispersibility, the titanium oxide content is preferably in the above range.

The oil phase component for dispersing the titanium oxide of the component a-2) in the oil-in-water emulsifier type second skin external composition is not limited, but is a saturated or unsaturated fatty acid from the viewpoint of powder dispersibility. And so on. Such fatty acids include, but are not limited to, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidic acid, behenic acid and the like. Saturated or unsaturated fatty acids having 12 to 22 carbon atoms can be mentioned. From the viewpoint of dispersibility, it is more preferably a saturated fatty acid having 18 to 22 carbon atoms, and particularly preferably stearic acid or behenic acid. Only one type of oil phase component may be blended in the composition, or two or more kinds may be blended in combination.

In the oil-in-water emulsified composition of the present invention, the content of the oil phase component that disperses titanium oxide of the component a-2) is usually 1% by mass to 40% by mass, preferably 1% by mass, from the viewpoint of dispersibility and usability. It is 5% by mass to 30% by mass. The above-mentioned content includes fatty acids constituting the fatty acid salt of the component c-2).

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

Regarding component b-2), the type of UV absorber, the content of the UV absorber, the type of UV scatterer, the method of preparing or obtaining the UV scatterer, the surface treatment of the UV scatterer, the oil-dispersible UV scatterer. The above-mentioned matters apply to the above-mentioned aspects, the content of the ultraviolet scattering agent, the means for uniformly dispersing the ultraviolet scattering agent in the oil phase, the oil-based medium for dispersing the ultraviolet scattering agent, and the like.

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

The fatty acid salt can be added as it is to the composition raw material as a fatty acid salt, or may be produced by the reaction of the fatty acid and the alkali in the production process, and the origin thereof is not particularly limited.

Fatty acids constituting the fatty acid salt include, but are not limited to, saturated or unsaturated fatty acids having 12 to 22 carbon atoms. Specific examples of the fatty acid are the same as those exemplified as the fatty acid used as the oil phase component.

Examples of the fatty acid salt include alkali metal salts of the above fatty acids (sodium fatty acid, potassium fatty acid, etc.), alkaline earth metal salts (magnesium magnesium, calcium fatty acid, barium fatty acid, etc.), ammonia salts (ammonium fatty acid, etc.), and the above fatty acids. Amines, hydroxylamines, imines, guanidines, amine oxides, alkanolamines, alkoxylated amines, and alkylamines (diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, amino Butanol, aminoethylpropanediol, aminomethylpropanol, aminomethylpropanediol, isopropylamine, methylethanolamine, diisopropylamine, dipropylenetriamine, glucamine, N-methylglucamine, morpholine, tromethamine), cocamines, soyamines, Examples of reactants with organic amines such as oleamines, stearamines and quoterniums can be exemplified. It is preferably an alkali metal salt or an alkaline earth metal salt of a fatty acid, and more preferably a sodium fatty acid salt or a potassium fatty acid which is an alkali metal salt of a fatty acid. In addition, only one type of fatty acid salt may be blended in the composition, or two or more kinds may be blended in combination.

The content of these fatty acid salts in the oil-in-water emulsifier-type second skin external composition is usually 0.1% by mass to 5% by mass, preferably 0.5% by mass to 3% by mass from the viewpoint of dispersibility. %.

The component d-2) is a paste-like or solid oil agent at 25 ° C. (hereinafter, may be simply referred to as “paste-like or solid oil agent at 25 ° C.”) excluding higher alcohols and fatty acids. By containing a paste-like or solid oil agent at 25 ° C., skin adhesion and hydrophobicity of the film can be enhanced, and water resistance can be improved. In addition, as one aspect of "paste-like or solid oil agent at 25 ° C.", "oil agent having a melting point of 30 ° C. or higher" can be mentioned.

The oil-in-water emulsified composition of the present invention, which is a paste or solid oil at 25 ° C., may be natural or synthetic as long as it can be blended in cosmetics and the like. For example, tri (capric acid / capric acid / myristic acid / stearic acid) glyceryl, stearic acid hydrogenated castor oil, rice bran oil fatty acid phytosteryl, tetra (hydroxystearic acid / isostearic acid) dipentaerythrityl, hexahydroxystearate dipentaerythrityl, hydroxyalkyl die. Marge fatty acid ether (hydroxyalkyl (C12-14) hydroxydimage linoleyl ether, hydroxyalkyl (C16-18) hydroxydimer linoleil ether, etc.), bisdiglyceryl polyacyl adipate-2, shea butter, theobroma grungeflorum Seed fat, hardened coconut oil, hardened oil, mokurou, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, hohobarou, hydrogenated palm oil, ozokerite, paraffin, ceresin, vaseline, micro Crystalin wax, partially hydrogenated isomerized jojoba oil, phytosteryl oleate, macadamia nut fatty acid phytosteryl, palm oil, palm kernel oil, palm oil, and abrana seed oil watered with vegetable triglyceride and organic fatty acids. Examples thereof include a mixture, an ester of dipentaerythritol and a mixed fatty acid, and the like. Among the above oils, hydrogenated palm oil and hydroxyalkyl dimerged fatty acid ether are preferable, and hydroxyalkyl dimerged fatty acid ether is more preferable, from the viewpoint of improving stability and water resistance. As the fatty acid constituting the dimer, an unsaturated fatty acid having 16 to 20 carbon atoms is preferable. Specific examples of the fatty acid include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid and the like. Commercially available products can also be used for these. In addition, the paste-like or solid oil agent at 25 ° C. used in the oil-in-water emulsification composition of the present invention may be blended alone or in combination of two or more.

For the second skin external composition of the oil-in-water emulsifier type, a paste-like or solid oil agent of the component (d-2) at 25 ° C. is usually added to the composition from the viewpoint of good water resistance. It contains 5% by mass or more, preferably 1% by mass or more. If the content is too large, it becomes sticky, so it is usually 10% by mass or less. The content of the paste-like or solid oil at 25 ° C. is preferably in the above range.

The oil-in-water emulsifier-type second external composition for skin may contain a film-forming agent as the 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 blending a film-forming agent, water resistance, durability, and stability are improved.

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

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

The oil-in-water emulsifier-type second external composition for skin may contain optional ingredients usually used in cosmetics and the like other than the above essential ingredients. Specific examples of the optional components are as described above.

The specific use of the oil-in-water emulsifier-type second skin external composition is not particularly limited, and examples thereof include emulsions, sunscreens, skin external agents such as foundations, and cosmetics. In such an aspect, the effect of the present invention can be effectively utilized and it may be particularly suitable for skin protection.

The oil-in-water emulsifier-type second external composition for skin can be produced by a production method including a step of mixing the above components a-2) to d-2).

The method for producing the oil-in-water emulsifier-type second external composition for skin is not particularly limited as long as it includes a step of mixing the components a-2) to d-2). As a mixing method, a known method used in the field of ordinary cosmetics and the like can be appropriately adopted. For example, fatty acid and component d-2) in an oil phase containing a paste-like or solid oil agent at 25 ° C. The alkali is heated and mixed to form the component c-2) fatty acid salt, and the powder component containing the components a-2) and b-2) is crushed as necessary, then added to the oil phase, and mixed and dispersed. do. It can be obtained by adding the same oil phase to a heated aqueous phase, emulsifying and cooling. After emulsification, component e-2) is added as needed.
Regarding the component a-2), it is not blended in the form of a slurry, that is, by directly mixing the titanium oxide of the component a-2) with the oil phase, the component a-2) is well dispersed in the oil phase. preferable.

<< Test Example 1 >> Changes in the expression level of neutrophil adhesion factor by irradiation with red light or near infrared light (1) Experimental operation The vascular endothelial cells were irradiated with red light or near infrared light by the experimental operation specifically shown below. After culturing for 24 hours, gene expression of neutrophil adhesion factor (ICAM-1: intercellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-1) was measured using q-RT-PCR and unirradiated. Compared to the case.

First, seeded so that the vascular endothelial cells (HUVEC (Kurabo Ltd.)) and 6.0 × ¹⁰ 4 cells / well in 24-well plates, incubator _{(37 ℃, CO 2 5%} ) , the cultured overnight.

Next, the vascular endothelial cells after culturing were washed with PBS (−). After washing, 1 mL PBS was added to the plate.

Open the lid of the plate, install an optical filter (HOYA, SCHOTT, Shibuya Optics) that cuts the transmission of unintended wavelengths under the light source of the solar simulator (XHS-8, Spectral Engines), and then red. light (620~760nm) or near infrared (760~1440nm) respectively ^{74J / cm 2, 41J / cm} 2 was irradiated.
These conditions correspond to the dose at which 2.5 hours of sunlight reaches the dermis (about 1 mm deep from the skin surface) when converted to the illuminance (annual average) on a sunny day in Japan.

As a control, a plate similarly seeded with vascular endothelial cells was wrapped in aluminum foil and left on the same laboratory table for the same time.

After the red light or near-infrared radiation, plates PBS (-) was removed and the vascular endothelial cells only medium was added 1 mL, incubator _{(37 ℃, CO 2 5%} ) , the cultured.

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 are ICAM-1 (manufactured by QIAGEN, Hs_ICAM1-1_SG QuantiTect Primer Assay) and VCAM-1 (custom primer manufactured by Thermo Fisher). Further, as an endogenous control, TBP (TATA binding protein) (manufactured by QIAGEN, Hs_TBP_1_SG QuantiTect Primer Assay) was used.

The value obtained by dividing the expression levels of ICAM-1 and VCAM-1 by the expression level of TBP was determined and used as the ICAM-1 and VCAM-1 expression levels of each sample.

(2) Results The results of irradiation with red light are shown in Table 1, FIG. 1, and FIG. 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 irradiated group (n = 3) were evaluated.
Table 2 shows the results of irradiation with near infrared rays. 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 irradiation group (n = 3) were evaluated.

As shown in Table 1, FIG. 1 and FIG. 2, a decrease in the expression level of neutrophil adhesion promoting factors (ICAM-1, VCAM-1) in vascular endothelial cells was observed by irradiation with red light.
This result indicates that irradiation with red light results in suppression of the expression of neutrophil adhesion-promoting factors, which can prevent neutrophils from adhering to vascular endothelial cells. That is, this result indicates that the infiltration of neutrophils from blood vessels into the skin tissue can be suppressed by irradiation with red light.

On the other hand, as shown in Table 2, an increase in the expression level of neutrophil adhesion promoting factors (ICAM-1, VCAM-1) in vascular endothelial cells was observed by irradiation with near infrared rays.
This result indicates that near-infrared irradiation increases the expression of neutrophil adhesion-promoting factors, which promotes neutrophil adhesion to vascular endothelial cells and infiltration from blood vessels into skin tissue. There is.

In daily life, the skin has the opportunity to be exposed to sunlight, including both near-infrared and red light. At this time, by applying red light to the vascular endothelial cells in the skin tissue while blocking the near infrared rays contained in sunlight, the expression of the neutrophil adhesion promoting factor can be suppressed more strongly, which is effective. It is shown that the effect of preventing or improving wrinkles and sagging can be obtained.

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

(1) Experimental Procedures First, the tendon cell seeded so as to be 2.5 × ¹⁰ 4 cells / mL in 24-well plates, incubator _{(37 ℃, CO 2 5%} ) under the conditions of, and cultured overnight.

Next, the tendon cells after culturing were washed with PBS (-). After washing, 300 mL of PBS (−) was added to the plate.

The lid of the plate was opened and a red light (peak wavelength: 625 nm) LED lamp was installed.
Here, as a control, a plate wrapped in aluminum foil and placed on the same laboratory table was prepared. It was carried out in each group n = 3.

The tendon cells were irradiated with red light for 3.3 minutes (0.88 J / cm ² ) under the condition of 45 W / m ^2.
Here, the light irradiation under the above conditions corresponds to 1.4 hours of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

After irradiation, PBS (-) on the plate was removed, 1 mL of a tendon cell-specific medium was added, and the cells were cultured overnight in an incubator (37 ° C., 25% CO).
Twelve hours after irradiation, the cell proliferation rate was evaluated using a viable cell number measurement kit (WST-8).
The results are shown in FIG.

(2) Results and discussion As shown in FIG. 3, it was found that the cell proliferation rate was improved by irradiating the tendon cells with light having a peak wavelength of 625 nm (red light).
Here, the tendon cell is a cell that produces MFAP4. Therefore, it was found that application of red light to cells suppresses the expression increase and / or expression decrease of MFAP4.

<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 the enhancement of tendon cell activity was examined.

(1) Experimental Procedures First, the tendon cell seeded so as to be 2.5 × ¹⁰ 4 cells / mL in 24-well plates, incubator _{(37 ℃, CO 2 5%} ) and cultured overnight at.

Next, the tendon cells after culturing were washed with PBS (-). After washing, 300 mL of PBS (−) was added to the plate.

The lid of the plate was opened, and a light source capable of irradiating a wavelength range of 585 to 760 nm, which was close to the wavelength of sunlight, was installed using a halogen lamp, a light cut filter, and a plastic tray containing water.
Here, as a control, a plate wrapped in aluminum foil and placed on the same laboratory table was prepared. It was carried out in each group n = 3.

The long wavelength range visible light (light having a wavelength of 585 to 760 nm) was irradiated for 3.3 minutes (1 J / cm ² ) under the condition of 50 W / m ^2.
Here, the light irradiation under the above conditions corresponds to 3.3 minutes of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

In another embodiment, long wavelength visible light (light having a wavelength of 585 to 760 nm) was irradiated for 16.7 minutes (5 J / cm ² ) under the condition of 50 W / m ^2.

After irradiation, plates PBS (-) was removed and the tendon cell dedicated medium was added 1 mL, incubator _{(37 ℃, CO 2 5%} ) were cultured at.
The mitochondrial activity and cell proliferation rate were evaluated at 0, 24, and 48 hours after irradiation.

Measurement of mitochondrial activity was performed by staining cells with JC-1 dye and Hoechst 33432. Then, the activity of mitochondria was evaluated by calculating the fluorescence red (high membrane potential of mitochondria) / green (low membrane potential of mitochondria).
When the mitochondrial membrane potential is high, it fluoresces red, and when it is low, it fluoresces green. Therefore, it can be evaluated that the larger the red / green value of the fluorescence intensity, the higher the mitochondrial activity of the cell.
The results are shown in FIGS. 4 and 5.

(2) Results and discussion As shown in FIG. 4, it was found that the mitochondrial activity was improved by irradiating the tendon cells with light having a wavelength of 585 to 760 nm (long-wavelength visible light).
Further, as shown in FIG. 5, it was found that the cell proliferation rate was improved by irradiating the tendon cells with light having a wavelength of 585 to 760 nm (long-wavelength visible light).
Here, the tendon cell is a cell that produces MFAP4. Therefore, it was found that the expression of MFAP4 can be increased and / or decreased by applying red light to the cells.

<Test Example 2-3>
In Test Example 2-3, the effect of light having a specific wavelength on the gene expression of matrix metalloproteinase was examined.
(1) Experimental operation First, a Caucasian female abdominal skin tissue (with subcutaneous tissue) was cultured overnight.

Next, the tendon cells after culturing were washed with PBS (-). After washing, 300 mL of PBS (−) was added to the plate.

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

After irradiation, plates PBS (-) was removed and the medium for ex vivo culture 1mL added incubator _{(37 ℃, CO 2 5%} ) were cultured in the conditions of.

Twenty-four hours after irradiation, the tissue was immersed in RNAlater RNA Stabilization Reagent (manufactured by QIAGEN) overnight.
After soaking, the skin band (Retinacula Cutis) was cut off. RNA was extracted from the carved skin band (Retinacula Cutis) using RNeasy Tissue Mini Kit (manufactured by QIAGEN).

The extracted RNA was microarrayed using a SurePrint G3 Human GE microarray 8x60K (manufactured by Agilent Technologies), and the gene expression level of matrix metalloproteinase was evaluated.
The results are shown in FIG.

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

<Test Example 2-4> Relationship between matrix metalloproteinase and MFAP4 In Test Example 2-4, the relationship between matrix metalloproteinase and MFAP4 was investigated.

(1) Experimental operation First, a matrix metalloproteinase (MMP3 or MMP9) activated with chymotrypsin and MFAP4 were mixed to prepare each enzyme / substrate reaction solution.

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

The prepared enzyme / substrate reaction solution was shake-mixed (incubated) at 37 ° C. for 24 hours.

Using Lane Marker Sample Buffer SDS (manufactured by Thermo Fisher Scientific) as a marker, samples of each system shown in FIG. 7 were filled (applied) into SDS-polyacrylamide gel, and electrophoresis was performed.

After electrophoresis, silver staining was performed using 2D-Silver Stein Reagent II (manufactured by Cosmo Bio) to quantify protein bands. The results are shown in FIG.

(2) Results and discussion As shown in FIG. 7, due to the presence of matrix metalloproteinase-3 (Matrixmetalloproteinase-3, MMP3) and matrix metalloproteinase-9 (MMP9), microfibril-binding protein 4 (Microfibril-) It was found that associated glycoprotein 4, MFAP4) was degraded.

Here, as shown in Test Example 2-3, long-wavelength visible light suppresses the expression decrease and / or the expression increase of the matrix metalloproteinase.
By applying long-wavelength visible light to cells, not only the production of MFAP4 increased with the proliferation of tendon cells, but also the expression of matrix metalloproteinase decreased and / or the expression of MFAP4 increased by suppressing the increase. And / or it was found to play an ability to suppress the decrease in expression.

<Test Example 2-5>
In Test Example 2-5, the effect of applying the anti-photoaging component to the cells after applying the red light to the cells was examined on the expression level of MFAP4.

(1) Experimental Procedures First, the tendon cell seeded so as to be 2.5 × ¹⁰ 4 cell / mL in 24-well plates, 37 ° C., and cultured overnight at CO ₂ 5% of the conditions.
The cultured tendon cells were washed with PBS (-). After washing, 300 mL of PBS (−) was added to the plate.

The lid of the plate was opened and a red light (peak wavelength: 625 nm) LED lamp was installed.
Here, as a control, a plate wrapped in aluminum foil and placed on the same laboratory table was prepared. It was carried out in each group n = 4.

The tendon cells were irradiated with red light for 3.3 minutes (0.88 J / cm ² ) under the condition of 45 W / m ^2.
Here, the light irradiation under the above conditions corresponds to 1.4 hours of sunlight when converted into the illuminance (annual average) on a sunny day in Japan.

After irradiation, plates PBS (-) was removed, 0.5% burdock extract containing tendon cells only medium was added 1 mL, 37 ° C., with _CO 2 5% of the conditions, and cultured overnight (Example 2).
At the same time, a system using a medium containing no burdock extract was also prepared (Example 1). In addition, a medium containing no burdock extract was used for the control (system not irradiated with red light).

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

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

The results are shown in Table 3 and FIG. Here, in Tables 3 and 8, the measured value (average value) under the control conditions was set to 1, and the expression level (average value) of MFAP4 in Examples 1 and 2 was evaluated.

(2) Results and discussion As shown in Table 3 and FIG. 8, the expression level of MFAP4 was increased by irradiation with red light (Example 1). Further, by applying the red light to the cells and then further applying the anti-photoaging component to the cells, the expression level of MFAP4 was further increased (Example 2).

As described above, the results of Test Example 2 show that the application of red light induces an increase in the expression of MFAP4, whereby the skin zonule can be enhanced.
Considering this together with the results of Test Example 1, the infiltration of neutrophils from blood vessels into the skin tissue can be suppressed by irradiation with red light, and the decomposition of elastin and collagen by neutrophil elastase secreted by neutrophils can be suppressed. Moreover, it was found that the enhancement of the skin zonule can also be achieved.
That is, it was shown that irradiation of the skin with red light brings about a preventive or ameliorating effect on wrinkles and sagging by two mechanisms of suppressing the decomposition of elastin and collagen and strengthening the skin zonules.

<< Test Example 3 >> Effect of cyclohexylglycerin and sugina extract on the gene expression level of neutrophil migration promoting factor in dermal-derived fibroblasts 1000 μL of human normal dermal fibroblasts in a 24-well plate with 10% FBS / DMEM medium The seeds were sown to form a / well and _{cultured at 37 ° C. in a 5% CO 2} environment for 24 hours.
Twenty-four hours after sowing, a sample to which cyclohexyl glycerin ("Adecanol CHG" manufactured by ADEKA Co., Ltd.) and Sugina extract ("Sugina extract UK-P" manufactured by Maruzen Pharmaceuticals Co., Ltd.) were added (cyclohexyl glycerin: final concentration 0.05% by mass, Sugina extract: final concentration 1% by mass) and a sample to which both components were added (cyclohexylglycerin: final concentration 0.05% by mass, Sugina extract: final concentration 1% by mass) were prepared.

After 24 hours, the medium was removed, the cells were washed with PBS, cells were collected using the RNeasy Mini QiAcube kit (manufactured by QIAGEN), and RNA was extracted using QIAcube (manufactured by QIAGEN).
RT-PCR was performed using the QuantiTecT SYBR Green RT-PCR Kit (manufactured by QIAGEN), and in each sample, CXCL-1 mRNA expression level, IL-8 mRNA expression level, and TBP mRNA expression, which is an endogenous control, were performed. The amount was measured.
The value obtained by dividing the mRNA expression levels of CXCL-1 and IL-8 in each sample by the TBP mRNA expression level was determined and used as the mRNA expression level of each sample. The results are shown in FIGS. 9 and 10.

As shown in FIG. 9, the expression level of CXCL-1 was reduced to about 57% in the sample to which cyclohexyl glycerin was added, and the expression level of CXCL-1 was absent in the sample to which horsetail extract was added. It was found that it decreased to about 43% compared with the addition group.
Furthermore, as shown in FIG. 9, it was found that the expression level of CXCL-1 in the sample to which cyclohexyl glycerin and horsetail extract was added was reduced to about 18% as compared with the group without addition.
From this result, both cyclohexylglycerin and horsetail extract have the effect of suppressing the gene expression of CXCL-1, which is a neutrophil migration promoting factor, and synergistic gene expression can be achieved by combining these components. It was found to have an inhibitory effect.

Further, as shown in FIG. 10, the sample to which cyclohexyl glycerin was added, the sample to which horsetail extract was added, and the sample to which both components were added had an IL-8 expression level of about 72%, about 72%, as compared with the group without addition. It was found to decrease to 69% and about 70%.
From this result, both cyclohexylglycerin and horsetail extract have the effect of suppressing the gene expression of IL-8, which is a neutrophil migration promoting factor, but even if these components are combined, a synergistic effect is obtained. It turned out that I couldn't get it.

From the above results, it was confirmed that cyclohexylglycerin and horsetail extract have an effect of suppressing gene expression of neutrophil migration promoting factor, and have an effect of suppressing neutrophil migration.

In addition, it is preferable to apply red light after applying a component for suppressing gene expression of neutrophil migration promoting factors such as cyclohexylglycerin and sugina extract and an external composition for elastase containing an elastase inhibitor. Upstream, midstream, and downstream of a series of processes in wrinkle and sagging formation: adhesion of neutrophils to vascular endothelial cells, migration of neutrophils, and decomposition of elastin and collagen by neutrophil elastase secreted by neutrophils. It is shown that more excellent wrinkle and sagging prevention or improvement effect can be obtained.

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

RNA was extracted from the obtained cell lysate using an RNeasy plus micro kit (manufactured by QIAGEN).
RT-PCR was performed using the QuantiTecT SYBR Green RT-PCR kit (manufactured by QIAGEN), and the mRNA expression levels of ICAM-1 and VCAM-1 and the mRNA expression level of ACTB, which is an endogenous control, were measured.
The value obtained by dividing the mRNA expression levels of ICAM-1 and VCAM-1 by the mRNA expression level of ACTB was determined and used as the mRNA expression level of each sample. The results are shown in FIG.

As shown in FIG. 11, in the sample to which the oil-soluble peach leaf extract was added, the expression level of ICAM-1 was reduced to about 20% as compared with the sample to which ethanol was added (solvent control), and the expression level of VCAM-1 was reduced. Was found to decrease to about 60%.
From the above results, it was clarified that the oil-soluble peach leaf extract has an effect of suppressing the gene expression of the neutrophil adhesion promoting factor.

ICAM-1 and VCAM-1 are known to be adhesion molecules that promote adhesion to vascular endothelial cells because neutrophils infiltrate tissues. This is because the oil-soluble peach leaf extract, which has the effect of suppressing the gene expression level of these adhesion molecules, suppresses the adhesion of neutrophils to the inner wall of blood vessels, the invasion to the outside of blood vessels, and the arrival into skin tissue. , It is recognized that it has a preventive or ameliorating effect on the formation of wrinkles and sagging.

In addition, the results of Test Example 4 show that an advantageous effect can be obtained by using an oil-soluble peach leaf extract in combination with an elastase inhibitor. The action of oil-soluble peach leaf extract suppresses the infiltration of neutrophils into the skin tissue, and the action of the neutrophil elastase inhibitor inhibits the activity of neutrophil elastase released by the infiltrated neutrophils. Therefore, it is considered that it exerts an effect upstream and downstream of the wrinkle and sagging formation mechanism caused by neutrophils, and has higher anti-wrinkle and anti-sagging effects.

In addition, by applying red light after applying a composition for external use to the skin containing an oil-soluble peach leaf extract and a neutrophil elastase inhibitor, the effect of suppressing the expression of neutrophil adhesion promoting factors is synergistically improved. It is shown that a better effect of preventing or improving wrinkles and sagging can be obtained.

<< Test Example 5 >> Test for shielding near infrared rays (test for a second external composition for skin)
<Test Example 5-1> Evaluation of compatibility between transmission of visible light in a long wavelength region and cut of near infrared rays The oil-in-water emulsified compositions of Examples and Comparative Examples were prepared according to the formulations shown in the table below.
That is, the aqueous phase II was added to the oil phase whose temperature was adjusted to 80 ° C. to neutralize the oil phase, and then the powder was dispersed. After adding the oil phase to the aqueous phase I whose temperature was adjusted to 80 ° C., the aqueous phase III was added and homogenized with a homogenizer. The mixture was cooled to 30 ° C. to obtain an oil-in-water emulsified composition.

The shielding rate of light of a specific wavelength, the transmission ratio of 585 to 760 nm, and the squeaky feeling of the oil-in-water emulsified composition were measured and evaluated as follows.
<Shielding rate>
A thin film of an oil-in-water emulsified composition was prepared on a slide glass with a 1.2 mil doctor blade, and the transmittance (average value in each wavelength range) was measured with a spectrophotometer. The shielding rate was calculated by "100-transmittance", and the average shielding rate in each wavelength range of 585 to 760 nm and 760 to 1310 nm was calculated.

<Transmission ratio of 585 to 760 nm>
A thin film of polymer was prepared on a slide glass with a doctor blade, and powder was applied with a brush. A thin film from which excess powder was removed was prepared with an air gun, and the amount of light transmitted at wavelengths of 400 to 760 nm and 585 to 760 nm (average value in each wavelength range) was measured with a spectrophotometer. The transmission ratio of 585 to 760 nm was calculated as the transmission amount of light having a wavelength of 585 to 760 nm / the transmission amount of light having a wavelength of 400 to 760 nm.

<Evaluation of squeaky feeling>
The squeaky feeling was scored in 4 stages and the average value was calculated by the actual use test of 10 specialized panelists.
Evaluation criteria for squeaky feeling:
1: There is a squeaky feeling 2: There is a slight squeaky feeling 3: There is not much squeaky feeling 4: There is no squeaky feeling

The evaluation results are shown in the table below.

As is clear from the results shown in Table 4, the difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and "760 to 1310 nm". A composition having a "wavelength light shielding rate" of 30% or more was excellent in the effect of achieving both transmission of visible light in a long wavelength region and shielding of near infrared rays (Prescription Examples 1 to 6).

When the spherical powder that transmits the long wavelength side more than the short wavelength side of visible light is contained, the effect of transmitting the long wavelength side of visible light is particularly excellent (Prescription Examples 1 and 2 with respect to Formulation Example 6). 5).

Further, when the spherical powder having a specific average particle size was contained, the effect of transmitting visible light on the long wavelength side was particularly excellent (Prescription Example 5 with respect to Formulation Examples 1 and 6).

In Formulation Examples 1 to 6, visible light is obtained as compared with the case where titanium oxide of 0.5 μm or more is not blended (Prescription Examples 7 and 8) and the case where the amount of titanium oxide of 0.5 μm or more is small (Prescription Example 9). It was excellent in long wavelength range transmission, near infrared shielding, or both.

<Test Example 5-2> Evaluation of anti-aging effect in continuous use The samples of Formulation Examples 1, 7 and 8 were continuously used for 3 weeks, and the viscoelasticity of the skin was measured using Cutometer MPA580, and the same as before continuous use. The rate of change (%, calculated with 100% before continuous use) was measured.
The evaluation results are shown in the table below.

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

<< Test Example 6 >> Test on water resistance and uniformity (test on the second external composition for skin)
An oil-in-water emulsified composition was prepared according to the formulation shown in the table below.
That is, the aqueous phase II was added to the oil phase whose temperature was adjusted to 80 ° C. to form a fatty acid salt. Then, the powder was dispersed in a disperser. The oil phase was added to the aqueous phase I whose temperature was adjusted to 80 ° C., the aqueous phase III was added, and then the mixture was homogenized with a homogenizer. Aqueous phase IV was added at 45 ° C. and cooled to 30 ° C. to obtain an oil-in-water emulsified composition.

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

<Water resistance evaluation>
The oil-in-water emulsified 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 UV lamp light. The rate of change of the luminance value was calculated by image analysis, classified into the following four-stage categories, and the water resistance was evaluated. It can be evaluated that the water resistance is higher when the rate of change of the luminance value is smaller.
Luminance value change rate:
⊚: 110% or less, ○: 125% or less, Δ: 126 to 150%, ×: 150% or more

<Uniformity evaluation>
A thin film was prepared on a slide glass with a 1.2 mil doctor blade, and the uniformity of powder dispersion was visually classified into the following three stages, and the uniformity of the film was evaluated.
Uniformity of powder dispersion:
○: Uniform, △: Slightly non-uniform, ×: Non-uniform

The evaluation results are shown in the table below.

As is clear from the results shown in Table 6, the oil-in-water emulsified composition (Formulation Examples 10 to 12) comprising the following components a-2) to d-2) is an oil-in-water emulsion lacking any of these components. Compared with the emulsified compositions (Prescription Examples 13 to 18), the powder was excellent in dispersion uniformity, and the film was excellent in uniform film formation property and water resistance. Further, when the film-forming agent was contained, the water resistance was particularly excellent (Prescription Example 12).
a-2) Titanium oxide surface-treated with triethoxycaprylylsilane and having an average particle size of 0.5 μm or more;
b-2) UV absorber and / or UV scatterer;
c-2) Fatty acid salt; and d-2) Paste-like or solid oil at 25 ° C, excluding higher alcohols and fatty acids.

The present invention can be applied to cosmetic methods and cosmetics for preventing or improving wrinkles and sagging.

Claims (36)

A method for suppressing the expression of a neutrophil adhesion promoting factor, which comprises applying red light to cells or skin. The neutrophil adhesion promoting factor is an intercellular adhesion molecule-1 (intercellular adhesion molecule-1, ICAM-1) and / or a vascular cell adhesion molecule-1 (vascular cell adhesion molecule-1, VCAM-1). The method according to claim 1, wherein the method is characterized by the above-mentioned method. The method according to claim 1 or 2, wherein red light is applied to vascular endothelial cells. The method according to any one of claims 1 to 3, which is a method for suppressing infiltration of neutrophils. The method according to any one of claims 1 to 4, which is a cosmetic method for anti-aging of the skin (however, excluding medical practice). Any one of claims 1 to 5, wherein red light is applied to an application target by irradiating light through a member having optical characteristics that shields near infrared rays and transmits red light. The method described in the section. The method according to claim 6, wherein the article provided with the member is attached to an application target of red light, and the red light is applied to the application target by irradiating the light through the member. The method according to claim 7, wherein the article is glasses or sunglasses including a lens made of the member. It is characterized in that an application target of red light is placed in a space in which at least a part of a wall portion or a ceiling portion is composed of the member, and the red light is applied to the application target by irradiating the light through the member. , The method according to claim 6. The method according to claim 9, wherein the space is an interior space or a vehicle interior space. A neutrophil adhesion promoting factor, which has an optical property of shielding near infrared rays and transmitting red light, and is used for the method according to any one of claims 6 to 10. Member for suppressing the expression of. An article for suppressing the expression of a neutrophil adhesion promoting factor, which is a body-worn device including the member according to claim 11 and is used for the method according to claim 7. The article for suppressing the expression of a neutrophil adhesion promoting factor according to claim 12, wherein the body-wearing tool is glasses or sunglasses including a lens made of the member. For suppressing the expression of a neutrophil adhesion promoting factor, which comprises a space in which at least a part of a wall portion or a ceiling portion is composed of the above-mentioned members and is used for the method according to claim 9 or 10. Structure. The structure for suppressing the expression of a neutrophil adhesion promoting factor according to claim 14, which is a building or a car. A light irradiation process that irradiates the skin with red light,
The neutrophil elastase inhibitor application step of applying the neutrophil elastase inhibitor to the skin, and
A method for preventing or improving wrinkles and / or sagging (excluding medical practice), which is characterized by the provision of. 16. The 16th claim, wherein the neutrophil elastase inhibitor is a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. the method of.

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Represents a linear or branched alkyl group of ~ 4, and R ₂ and R ₃ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ] Claimed that the compound represented by the general formula (1) is a compound represented by the following general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof. Item 17. The method according to Item 17.

[In the formula, R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₅ and R ₆ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, respectively. Represents a branched alkyl group. ] The compound represented by the general formula (2) is 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L-prolyl] amino represented by the following formula (3). 18. The method of claim 18, characterized in that it is -1,1,1-trifluoro-4-methyl-2-oxopentane, an isomer thereof and / or a pharmaceutically acceptable salt thereof.

The method according to any one of claims 16 to 19, further comprising a light scattering agent application step of applying a light scattering agent that shields near infrared rays to the skin. The light scattering agent is titanium oxide having an average particle diameter of 0.5 μm or more.
In the light scattering agent application step,
a) 25% by mass or more of the titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. 20. The method of claim 20, wherein the external composition for skin is applied to the skin. After the light scattering agent application step, the light irradiation step is performed.
The method according to claim 20 or 21, wherein in the light irradiation step, sunlight including the red light is irradiated. The method according to any one of claims 16 to 22, wherein in the light irradiation step, the expression of the neutrophil adhesion promoting factor is suppressed by irradiation with red light. It contains a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof as an active ingredient, and is used by applying red light after application to the skin. A characteristic wrinkle and / or sagging preventive or ameliorating agent.

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Represents a linear or branched alkyl group of ~ 4, and R ₂ and R ₃ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ] Claimed that the compound represented by the general formula (1) is a compound represented by the following general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof. Item 24. The agent for preventing or improving wrinkles and / or sagging.

[In the formula, R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₅ and R ₆ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, respectively. Represents a branched alkyl group. ] The compound represented by the general formula (2) is 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L-prolyl] amino represented by the following formula (3). 25. The wrinkles and wrinkles of claim 25, which are -1,1,1-trifluoro-4-methyl-2-oxopentane, an isomer thereof and / or a pharmaceutically acceptable salt thereof. / Or a sagging preventive or ameliorating agent.

The agent for preventing or ameliorating wrinkles and / or sagging according to any one of claims 24 to 26 and a light scattering agent for shielding near infrared rays are included, and red light is applied after application to the skin. An agent for preventing or ameliorating wrinkles and / or sagging, which is characterized by being used. The light scattering agent is titanium oxide having an average particle diameter of 0.5 μm or more.
a) 25% by mass or more of the titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. 27. The wrinkle and / or sagging preventive or ameliorating agent according to claim 27. The agent for preventing or ameliorating wrinkles and / or sagging according to claim 27 or 28, which is used by irradiating the skin with sunlight containing red light after application to the skin. The agent for preventing or improving wrinkles and / or sagging according to any one of claims 24 to 29, which is used to suppress the expression of a neutrophil adhesion promoting factor by applying the red light. .. A first external composition for skin containing the wrinkle and / or sagging preventive or ameliorating agent according to any one of claims 24 to 26, and a second external composition for skin containing a light scattering agent that shields near infrared rays. A skin external composition kit comprising a substance and a first and second external skin composition, which is used by applying red light to the skin after application to the skin. The skin external composition kit according to claim 31, wherein after application of the first and second external skin compositions to the skin, the skin is used by applying sunlight containing red light to the skin. The external composition kit for skin according to claim 31 or 32, which is used for suppressing the expression of a neutrophil adhesion promoting factor by applying the red light. A first external composition for skin containing the wrinkle and / or sagging preventive or ameliorating agent according to any one of claims 24 to 26, and a second external composition for skin containing a light scattering agent that shields near infrared rays. Things and
A composition kit for external skin, which comprises. A first external composition for skin containing a compound represented by the following general formula (1), an isomer thereof and / or a pharmaceutically acceptable salt thereof, and a second composition containing a light scattering agent that shields near infrared rays. A composition kit for external skin, which comprises.

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Represents a linear or branched alkyl group of ~ 4, and R ₂ and R ₃ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ] The light scattering agent is titanium oxide having an average particle diameter of 0.5 μm or more.
The second external composition for skin is
a) 25% by mass or more of the titanium oxide with respect to the total amount of powder excluding the ultraviolet scattering agent; and b) spherical powder;
The difference between the "shielding rate of light having a wavelength of 585 to 760 nm" and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 10% or less, and the "shielding rate of light having a wavelength of 760 to 1310 nm" is 30% or more. The external composition kit for skin according to any one of claims 31 to 35.

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