JP7636867B2 - Cosmetics or skin preparations - Google Patents

Description

The present invention relates to a cosmetic or topical skin preparation.

Enzymes called matrix metalloproteinases (MMPs) exist in the body that break down extracellular matrix (ECM) such as collagen and elastic fibers. MMPs are proteolytic enzymes that require metal ions, and more than 25 types have been identified. MMP activity is strictly controlled by their respective expression levels, activation mechanisms, and molecular balance with MMP inhibitors (TIMPs, tissue inhibitors of metalloproteinases).

MMP-14 indirectly binds to MMP-2 via TIMP-2 and activates MMP-2. Activated MMP-2 is known to degrade various components that make up the dermal matrix, such as gelatin, collagen types IV, V, VII, and XI, and elastin. Several plant extracts are known to have the effect of suppressing the activity of MMP-14 and MMP-2 (Patent Documents 1 to 5).

On the other hand, Rosa multiflora is the fruit of the Rosaceae family or a related plant, and it has been proposed to use Rosa multiflora extract as the active ingredient of an elastase inhibitor (Patent Document 6).

The roots of carrots (also called ginseng, scientific name: Panax ginseng) are used as raw materials for herbal medicines and health foods, and it has been proposed to use ginseng extract as an active ingredient in elastin production promoters (Patent Document 7). Furthermore, compound K, a metabolite of Panax ginseng, has been shown to restore the expression level of type I collagen, suggesting that compound K has anti-aging and moisturizing effects and may be used in cosmetics to protect the skin from ultraviolet rays and increase the moisture content of the skin (Non-Patent Document 1). It has also been reported that ginsenosides derived from Korean red ginseng suppress the expression of MMP-13 in articular cartilage and prevent the breakdown of cartilage (Non-Patent Document 2).

JP 2009-29708 A JP 2013-177439 A Special Publication No. 2010-235548, JP 2009-29710 A JP 2012-193121 A JP 2000-119189 A JP 2012-56933 A

Eunji Kim et al., Journal of Ginseng Research 2018;42:218-224 Je Hyeong Lee et al., European Journal of Pharmacology 2014;724:145-151

There is a demand for the development of anti-aging cosmetics and topical anti-aging skin preparations. To achieve anti-aging, it would be desirable to have ingredients that can inhibit the decomposition of various dermal matrices.

The inventors discovered that both star anise extract and carrot extract have the effect of suppressing MMP-14 expression, and thus completed the present invention.

The present invention provides the following:
[1] A dermal matrix decomposition inhibitor comprising one or more extracts selected from a star anise fruit extract and a carrot extract.
[2] An MMP-2 activity inhibitor comprising one or more extracts selected from a star anise fruit extract and a carrot extract.
[3] An MMP-14 activity inhibitor comprising one or more extracts selected from a star anise fruit extract and a carrot extract.
[4] The agent according to 3, wherein the inhibition of MMP-14 activity is achieved by suppressing expression of the MMP-14 gene.
[5] The agent according to any one of items 1 to 4, for use in an amount of 0.3 to 1.5 μg/ml of one or more selected from a Radix Root extract and a Carrot extract.
[6] A composition comprising one or more extracts selected from a star anise fruit extract and a carrot extract at a concentration of 0.3 to 1.5 μg/ml.
[7] A composition comprising one or more extracts selected from a star anise extract and a carrot extract, the composition having a concentration of 0.3 to 1.5 μg/ml when used.
[8] The composition according to 6 or 7, for any one selected from the group consisting of inhibition of dermal matrix degradation, inhibition of MMP-2 activity, inhibition of MMP-14 activity, and inhibition of MMP-14 gene expression.
[9] The composition according to any one of items 6 to 8, which is a cosmetic or an external skin preparation.

The present invention provides ingredients and compositions that are expected to have anti-aging effects, etc.

1 is a graph showing the expression level of the MMP-14 gene. The expression level of the MMP-14 gene was significantly decreased by the addition of the star anise extract and the carrot extract. * indicates a significant difference at p<0.05. 1 is a graph showing the expression level of the MMP-14 gene. The addition of star fruit extract did not show any inhibitory effect on the expression of the MMP-14 gene.

[Active ingredient]
The present invention relates to an agent and a composition containing, as an active ingredient, one or more extracts selected from a star anise fruit extract and a carrot extract.

Rosa multiflora is the fruit of Rosaceae or related plants. The Rosa multiflora extract used in the present invention may be obtained by squeezing the fruit or by extracting it with a solvent. The raw fruit may be fresh or may have been treated by drying, defatting, bleaching, fermentation, or the like.

Carrot (scientific name: Panax ginseng) is sometimes called ginseng. Its roots are well known as the raw material for the herbal medicine ginseng. In the present invention, the carrot extract may be from any part of the carrot, including flowers, leaves, stems, and roots, but is preferably an extract made from carrot roots. The carrot extract used in the present invention may be one obtained by squeezing, or may be one extracted using a solvent. The raw material may be raw, or may have been treated by drying, defatting, bleaching, fermentation, or the like.

The extract of A. japonica and the extract of Ginseng can be obtained under various extraction conditions. Examples of the extraction solvent include water, alcohols (for example, lower alcohols such as methanol and ethanol, or polyhydric alcohols such as propylene glycol (propane-1,2-diol), 1,3-butylene glycol, and glycerin), ketones such as acetone, esters such as diethyl ether, dioxane, acetonitrile, and ethyl acetate, organic solvents such as xylene, benzene, and chloroform, animal oils, vegetable oils, and supercritical carbon dioxide. These solvents can be used alone, or two or more of them may be used in any combination. A preferred example of the extraction solvent is any one selected from the group consisting of water, alcohols, and mixed solvents thereof. In a particularly preferred embodiment, water or a mixed solvent of water and ethanol, propylene glycol, 1,3-butylene glycol, or glycerin is used as the extraction solvent. This is because the components having the desired effect can be sufficiently extracted by these. When using a mixed solvent with water, the ratio can be appropriately adjusted. In this invention, when the concentration of an aqueous solvent is expressed as a percentage, it is a value based on volume unless otherwise specified. For example, a 90% ethanol solution refers to 90 ml of ethanol with water added to make a total volume of 100 ml.

The ratio of raw material to solvent during extraction can be adjusted as appropriate. Specifically, for example, the following method can be used. That is, the plant raw material or dried matter is finely crushed, 1 to 100 times the amount of extraction solvent is added, and the mixture is left to stand at room temperature under normal pressure for about 1 hour to 2 weeks, or extracted at a temperature below the boiling point of the extraction solvent for about 10 minutes to 10 days, and then filtered. The filtrate obtained is concentrated, dried under reduced pressure, or freeze-dried as necessary to obtain a plant extract.

The extract obtained as described above can be used as it is, but if necessary, it may be purified by deodorization, decolorization, etc., to the extent that the desired effect is not impaired. Such purification may be carried out by any conventional means selected at will, for example, filtration or the use of ion exchange resins or activated carbon columns for adsorption, decolorization, purification, etc. Furthermore, purified products in the form of a solution, paste, gel, or powder can be obtained by freeze-drying or concentration processing, etc.

[Application]
The present invention provides an MMP-14 activity inhibitor containing one or more selected from a star anise extract and a ginseng extract. In relation to the present invention, when the activity of MMPs is inhibited, unless otherwise specified, it includes various cases in which the activity of the MMP, which is an enzyme protein, is inhibited, and is not limited to cases in which the activity is inhibited by a specific mechanism. Specifically, the inhibition of MMP activity includes the inhibition of the expression of the MMP gene and the inhibition of the activity of the MMP protein. The inhibition of the expression of the MMP gene includes the inhibition of the transcription from the MMP gene to mRNA and the inhibition of the translation from the MMP mRNA to protein.

In a preferred embodiment, the MMP-14 activity inhibitor of the present invention is an inhibitor of MMP-14 gene expression.

Whether or not a certain component has an effect of suppressing the expression of MMP-14 can be confirmed, for example, as follows.
Human fibroblasts are cultured under normal medium conditions, and the target component is added to the culture medium. After several hours to several days have passed since the addition, the cells are harvested, and RNA is extracted from the cells. cDNA is reverse transcribed from the RNA, and real-time PCR is performed on the obtained cDNA to measure the amount of MMP-14 cDNA. As a control, the same measurement is performed on cells cultured without the addition of the component, and by comparing the two, it is determined whether the target component has an inhibitory effect on MMP-14m expression. Commercially available kits can be used to extract RNA from cells, synthesize cDNA, and perform PCR.

MMP-14 is classified as a membrane-bound matrix metalloproteinase and is known as an enzyme that breaks down type I collagen, type II collagen, and type III collagen, which are the main components of the dermal matrix of the skin. Other known substrates for MMP-14 include proMMP-2, proMMP-13, ADAM9, gelatin, fibronectin, vitronectin, laminin-1, -2/4 and -5, fibrin/fibrinogen, α1PI, perlecan, CD44, ICAM-1, tTG, LRP1, syndecan-1, αv-integrin, C3b, EMMPRIN, ApoE, MICA, betaglycan, IL-8, SLP1, CTGF, DR6, DJ-1, galectin-1, Hsp90α, pentraxin 3, progranulin, Cyr61, peptidyl-prolyl cis-trans isomerase A, dickkopf-1, KiSS-1, and Dll1 (see, for example, Yoshifumi Itoh et al., Matrix Biology, 2015;44-46:207-223).

In addition, the expression of MMP-14 is greatly increased by exposure to ultraviolet light, which is thought to be one of the causes of the decrease or denaturation of collagen due to ultraviolet light, and is one of the major factors in the formation of wrinkles in the skin. Therefore, it is believed that the MMP-14 activity inhibitor of the present invention can be used to treat skin aging such as the formation of wrinkles and loss of elasticity.

MMP-14 indirectly binds to MMP-2 via TIMP-2 and activates MMP-2. Activated MMP-2 is known to degrade various components that make up the dermal matrix, such as gelatin, collagens IV, V, VII, and X, and elastin. Therefore, the MMP-14 activity inhibitor of the present invention can also be used as an MMP-2 activity inhibitor and an inhibitor of dermal matrix degradation. In addition, fibronectin and proteoglycan core protein are known to be substrates for MMP-2 (see, for example, Robert E. Hewitt et al., Trends in Glycoscience and Glycotechnology, 1996;8(39):23-36).

Carrot extract has been known to promote elastin production (see Patent Document 7). However, elastin accounts for 2-5% of the dry weight of the dermis, whereas collagen, which is the substrate for MMP-14 or MMP-2, which is involved in the present invention, accounts for 70% of the dry weight.
Therefore, the present invention relating to the inhibition of MMP-14 activity can widely protect the dermal matrix containing collagen other than elastin from degradation, and can treat wrinkles and loss of firmness and elasticity caused by ultraviolet rays and aging more effectively than before.

In addition, the decrease in type I collagen, which is the majority of dermal fiber components, due to aging and ultraviolet rays is the main cause of the decrease in dermal density and loss of skin elasticity. Wrinkles caused by decreased elasticity tend to occur in areas of flexion due to changes in facial expression, such as the corners of the eyes, around the mouth, and forehead, while the decrease in dermal density and elasticity causes fine wrinkles and unevenness on the entire broad surface of the skin, which also causes the skin to look dark. In addition, the decrease in proteoglycan, a gel-like interstitial component that exists to fill the gaps between collagen, elastin, and other fibers, leads to the loss of skin flexibility.
Therefore, the present invention, which relates to the inhibition of MMP-14 activity, can protect type I and type III collagen and proteoglycan, which account for the majority of dermal fiber components, from degradation, and can maintain the firmness and flexibility of the skin. Furthermore, the present invention can treat fine wrinkles and irregularities that appear over a wide area due to a decrease in dermal density and loss of firmness, thereby improving the overall impression of brightness of the skin.

Conventionally, the inhibitory effect of extracts of A. sieboldii on elastase activity has been known (Non-Patent Document 6, supra). However, there are several types of elastase, such as neutrophil elastase and fibroblast elastase, and the elastase known for extracts of A. sieboldii is derived from fibroblasts. It has been revealed that fibroblast-derived elastase activity is rather decreased in the elderly group of 60 years old and above, compared to the young group of about 15 to 38 years old (Skin 1987, 29, (5), P793-797 "Measurement of elastase-like enzyme activity derived from cultured human fibroblasts"). Therefore, it is considered that the effect of inhibiting fibroblast-derived elastase is limited on wrinkles and sagging skin, which become more serious after middle age. On the other hand, if the activity of MMP-14 can be suppressed, the activation of MMP-2, which increases with age, can be suppressed.
Therefore, the present invention relating to the inhibition of MMP-14 activity can effectively treat age-related wrinkles, sagging skin, and loss of firmness and elasticity, which become more severe after middle age.

Furthermore, since collagen and laminin, which are substrates for MMP-14, are components of the basement membrane at the boundary between the epidermis and dermis, the present invention relating to the inhibition of MMP-14 activity is expected to inhibit the degradation of the basement membrane structure. Furthermore, type VII collagen, which is a substrate for MMP-14, is called anchoring fibril and functions to connect the basement membrane structure and dermal collagen fibers, so inhibition of MMP-14 activity is expected to protect the anchoring fibril and strengthen the connection between the dermis and epidermis. Furthermore, since MMP-14 is involved in the infiltration of cancer cells and angiogenesis in the cornea, the present invention may also be useful in the development of pharmaceuticals for the treatment of cancer and corneal angiogenesis.

In relation to the present invention, the term "treatment" includes actions other than medical procedures, and also includes preventing the target symptoms from appearing (sometimes referred to as reducing the risk of onset, or prevention), and suppressing the target symptoms (sometimes referred to as anti-symptoms, or treatment). Suppressing the target symptoms includes improving the target symptoms and inhibiting their progression.

[Agents and compositions]
The composition of the present invention is not particularly limited, but specific examples thereof include cosmetics, pharmaceuticals, beverages, foods, etc. The pharmaceuticals are not particularly limited, but specific examples thereof include skin external preparations, internal medicines, injections, etc.
The agent of the present invention can be used as an ingredient of various compositions, specifically cosmetics or skin external preparations. The content of the active ingredient in the agent of the present invention or a composition containing the agent of the present invention (the total content of the extract of A. serrata and the extract of ginseng when the extract of A. serrata and the extract of ginseng are contained) is preferably 0.0000001 to 0.5% by mass (hereinafter simply indicated as "%)", more preferably 0.0001 to 0.3%, and even more preferably 0.0005 to 0.1% as solid content. From the viewpoint of more fully exerting the intended effect, the content is preferably 0.03 to 5 μg/ml, more preferably 0.3 to 1.5 μg/ml, and even more preferably 0.3 to 0.7 μg/ml of the extract of A. serrata and 1.3 to 1.5 μg/ml of the extract of ginseng. Within this range, the active ingredients can be stably blended and exhibit high effects.

Cosmetics or topical skin preparations to which the agent of the present invention has been added may contain ingredients that are acceptable for use in cosmetics or topical skin preparations and have an effect on the skin, provided that the effects of the agent of the present invention are not impaired. Examples of such ingredients include whitening agents, UV protection agents, antibacterial agents, anti-inflammatory agents, cell activators, active oxygen removers, moisturizers, and ingredients that maintain skin homeostasis.

In addition to the agent of the present invention, various additives that are acceptable for use in cosmetics or topical skin preparations can be blended into the cosmetic or topical skin preparation to the extent that they do not impair the effects of the present invention. Examples of such additives include water (purified water, hot spring water, deep sea water, etc.), surfactants (emulsifiers, suspending agents, stabilizers, etc.), antioxidants, preservatives, gelling agents, alcohols, film-forming agents, colorants, fragrances, deodorants, salts, pH adjusters, cooling agents, chelating agents, keratolytic agents, enzymes, vitamins, etc.

Cosmetics or topical skin preparations can also be prepared in various dosage forms, such as solids, semi-solids, and liquids, depending on the intended use. More specifically, the cosmetics of the present invention can be used in the following forms: skin care cosmetics, such as cleansers, face washes, lotions, milky lotions, creams, massage products, pack products, serums and gels, and lip care products; base makeup cosmetics, such as foundations, face powders, makeup bases, and concealers; point makeup cosmetics, such as lipsticks, lip glosses and liners, cheek products, eye shadows, eyeliners, mascaras, and eyebrow products; body care cosmetics, such as soaps, liquid cleansers, sunscreen creams, and bath additives; and hair care cosmetics, such as shampoos, rinses, hair treatments, hair styling products, hair tonics, hair growth agents, and scalp treatments. More specifically, the topical skin preparation of the present invention can be a plaster, ointment, cataplasm, liniment, lotion, liniment, patch, aerosol (spray medicine), microneedle array, or iontophoresis.

The cosmetic or topical skin preparation may also be a packaged product. These aspects may include, in addition to the cosmetic or topical skin preparation, something that describes how to use the product or the intended effects and efficacy as described above (e.g., a box, container, label, instructions for use, tag).

[Production Example 1: Production of Star Anemone Extract]
1000g of 50vol% 1,3-butylene glycol aqueous solution was added to 100g of dried fruit of Rosa multiflora Thunberg. The mixture was extracted and filtered to obtain a rose extract. The dry solid content was 0.6%.

[Production Example 2: Production of carrot extract]
100 kg of ginseng roots were crushed, and 1000 L of 90 vol% ethanol solution was added to the crushed roots and extracted at room temperature for 5 days. The extract was then filtered to remove sediment and precipitate, and the ethanol content of the extract was adjusted to 50%, to obtain a carrot extract with a dry solid content of 2.8%.

[Production Example 3: Production of star fruit extract]
Approximately 100 L of 80 vol% ethanol was added to 10 kg of finely chopped Averrhoa carambola L. leaves, and the mixture was filtered. The resulting components were dissolved in 30% 1,3-butylene glycol solution to obtain a star fruit extract with a dry solid content of 1%.

[Production Example 4: Production of Star Anemone Extract]
The radish was cut into small pieces, 50g of which was added to 500ml of water and left to soak at room temperature for 2 days. It was then filtered to obtain the radish extract. When this radish extract was concentrated, its dry solid content was 2.28%.

[Production Example 5: Production of carrot extract]
Carrot leaves were cut into thin strips, and 50 g of the leaves were added to 500 ml of an aqueous solution (a homogeneous mixture of 250 ml of water and 250 ml of 1,3-butylene glycol) and soaked at room temperature for 3 days. The mixture was filtered to obtain a carrot extract. When the carrot extract was concentrated, its dry solid content was 2.35%.

.
[Test Example: MMP-14 Expression Inhibition Test]
Human fibroblasts (provided by RIKEN) were seeded onto a 6-well plate at 1.6×10 ⁵ cells/well. The cells were cultured at 37° C. in 5% CO ₂ .

Seeding was done on the first day, and the extracts were added on the second day. The addition was done so that the final concentration of the lyophilized material in the medium was 0.5 μg/ml for the Atractylodes oryzae extract of Production Example 1, and 1.4 μg/ml for the carrot extract of Production Example 2.

On the third day, cells were harvested and RNA was extracted using the Rneasy Plus Mini Kit (Qiagen) according to the kit's protocol. Distilled water was added to the cells as a control. The extracted RNA was stored at -80°C.

cDNA was synthesized from the extracted RNA using the iScrip Advanced cDNA Synthesis Kit for RT-qPCR (BioRAD) according to the kit's protocol. Real-time PCR was then performed using Sso Advanced SYBER GREEN Super Mix (BioRAD) according to the kit's protocol to measure the amount of MMP-14 cDNA.

The results are shown in Figure 1. The amount of MMP-14 cDNA was expressed as a relative value to the control. The addition of the Chinese berry extract and the carrot extract statistically significantly reduced the expression level of the MMP-14 gene. In other words, the addition of the Chinese berry extract and the carrot extract suppressed the expression of MMP-14.

[Comparative Example: Confirmation of the effect of star fruit in suppressing MMP-14 expression]
As in the test example, the extract from star fruit (Averrhoa carambola L.) (Production Example 3) was used for the test. In Japanese Patent Application Laid-Open No. 2003-300893, it has been recognized that star fruit extract has a hyaluronic acid production promoting effect, an elastase inhibitory effect, and a collagenase inhibitory effect.

The results are shown in Figure 2. Star fruit extract did not show any inhibitory effect on MMP-14 expression.

[Prescription Example]
<Emulsion (oil-in-water type)>
(Component) (%)
1. Polyoxyethylene (20 E.O.) Sorbitan Monostearate 1.0
2. Polyoxyethylene (20E.O.) Sorbitan Trioleate 0.5
3. Glyceryl monostearate 1.5
4. Stearic acid 0.5
5. Behenyl alcohol 0.5
6. Squalane 8.0
7. Carboxyvinyl polymer 0.1
8. Methyl parahydroxybenzoate 0.1
9. Sodium hydroxide 0.05
10. Purified water Remaining amount 11. Star anise extract (Production Example 4) 0.03
12. Ethyl alcohol 5.0
13. Fragrance 0.05

(Production method)
A: Mix ingredients 1 to 6 uniformly and dissolve at 70°C.
B: Dissolve ingredients 7 to 10 uniformly and heat to 70°C.
C: Add B to A and emulsify.
D: After cooling to room temperature, add ingredients 11 to 13 and mix uniformly to obtain an emulsion.

<Ointment>
(Component) (%)
1. Stearic acid 18.0
2. Cetanol 4.0
3. dl-α-tocopherol acetate 0.2
4. Triethanolamine 2.5
5. Glycerin 5.0
6. Dipotassium glycyrrhizinate 0.5
7. Carrot extract (Production Example 5) 5.0
8. Pentylene glycol 0.1
9. Remaining purified water

(Production method)
A. Heat ingredients 1 to 3 together and maintain at 75°C.
B. Mix ingredients 4 through 9 and maintain at 75°C.
C. Gradually add B to A to obtain an ointment.

<Lotion>
(Component) (%)
1. Polyoxyethylene (20 E.O.) Sorbitan Monolaurate 1.2
2. Ethyl alcohol 8.0
3. Ethyl parahydroxybenzoate 0.1
4. Glycerin 5.0
5. 1,3-butylene glycol 6.5
6. Para-butyryloxycinnamic acid 0.1
7. Star anise extract (Production Example 4) 0.03
8. Carrot extract (Production Example 2) 0.001
9. Remaining purified water

(Production method)
A. Mix ingredients 1 to 3 and dissolve.
B. Mix ingredients 4 to 9 and dissolve.
C. Mix A and B until homogenous to obtain a lotion.

<Liquid foundation (oil-in-water cream type)>
(Component) (%)
1. 1,3-butylene glycol 5.0
2. Hydrogenated soybean phospholipids 0.5
3. Titanium dioxide 5.0
4. Bengala 0.1
5. Yellow iron oxide 1.0
6. Black iron oxide 0.05
7. Stearic acid 0.9
8. Glyceryl monostearate 0.3
9. Cetostearyl alcohol 0.4
10. Polyoxyethylene (20E.O.) Sorbitan Monooleate 0.2
11. Polyoxyethylene (20E.O.) sorbitan trioleate 0.2
12. Diethylamino hydroxybenzoyl hexyl benzoate 2.0
13. Acrylic acid/alkyl methacrylate copolymer (※4) 0.5
14. Triethanolamine 1.5
15. Glycerin 5.0
16. Phenoxyethanol 0.3
17. Purified water remaining amount 18. Star anise extract (Production Example 1) 1.0
19. Fragrance 0.02
*4 Pemulen TR-2 (manufactured by NOVEON)

(Production method)
A: Disperse components 1 to 6.
B: Add ingredients 7 to 12 to A and mix uniformly at 70°C.
C: Ingredients 13 to 17 are mixed uniformly at 70°C.
D: Add B to C, emulsify, and cool to room temperature.
E: Components 18 and 19 are added to D and mixed uniformly to obtain an oil-in-water type creamy liquid foundation.

The various cosmetic compositions or topical skin preparations prepared above suppress the activity of MMP-14, so by applying them to the skin, it is expected that they will have an anti-aging effect that improves skin texture, firmness, and wrinkles.

<Tablets>
(Component) (%)
1. Lactose 24.0
2. Microcrystalline cellulose 20.0
3. Cornstarch 15.0
4. Carrot extract (Production Example 2) 0.5
5. Glycerin fatty acid ester 5.0
6. Silicon dioxide 1.0
7. Dextrin remaining amount

A. Mix ingredients 1 to 7 uniformly and obtain tablets according to conventional methods.

<Soft drinks>
(Component) (%)
1. Fructose glucose liquid sugar 30.0
2. Emulsifier 0.5
3. para-acetoxycinnamic acid 1.0
4. Star anise extract (Production Example 1) 0.1
5. Fragrance: appropriate amount 6. Purified water: remaining amount

A. Mix ingredients 1 to 6 uniformly and obtain a soft drink in the usual manner.

These foods and beverages are expected to have MMP-14 activity suppression effects, anti-aging effects, etc.

Claims (6)

An MMP-14 activity inhibitor containing an extract of Rosa multiflora, which is an extract of the fruit of Rosaceae . The agent according to claim 1 , containing the extract of star anise and the extract of carrot. The agent according to claim 1 or 2 , wherein the inhibition of MMP-14 activity is achieved by suppressing expression of the MMP-14 gene. The agent according to any one of claims 1 to 3 , wherein the extract of A. japonica is used at a concentration of 0.3 to 1.5 μg/ml. The agent according to any one of claims 1 to 4 , which is to be added to a cosmetic or a skin external preparation. The agent according to any one of claims 1 to 5 , for improving wrinkles, firmness, and loss of elasticity due to aging.

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