Matrix metalloproteinase 1 expression inhibitor and topical skin preparation

Abstract

It suppresses the expression of matrix metalloproteinase 1. [Solution] The disclosed matrix metalloproteinase 1 expression inhibitor contains as an active ingredient at least one selected from the group consisting of Saxifraga stolonifera, Saxifraga stolonifera extract, Rosemary, Rosemary extract, Licorice, Licorice extract, Melissa, Melissa extract, Wild thyme, Wild thyme extract, Hops, and Hops extract.

Description

Technical Field

[0001] The present disclosure relates to an inhibitor for suppressing matrix metalloproteinase 1 expression and a topical skin preparation.

Background Art

[0002] The formation of wrinkles is caused by the degradation of collagen or hyaluronic acid in the dermis. Patent Documents 1 and 2 disclose skin care techniques related to this point. Specifically, Patent Document 1 discloses the use of Nilewan, which is a neutrophil elastase inhibitory component, for resolving skin problems. Nilewan penetrates into the dermis, acts on neutrophils, and suppresses the elastase produced by neutrophils.

[0003] Patent Document 2 discloses the application of retinol to skin cosmetics. Retinol acts on keratinocytes to exhibit an effect of promoting hyaluronic acid synthesis, and exhibits a wrinkle improvement effect by increasing the moisture content of the stratum corneum.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] As described above, the breakdown of collagen is a major cause of wrinkle formation. However, it has not been known to suppress wrinkle formation by focusing on MMP-1, an enzyme that breaks down collagen. The inventors of this invention have discovered a new technology to suppress the expression of MMP-1.

[0007] One aspect of this disclosure is a matrix metalloproteinase 1 (MMP-1) expression inhibitor. The MMP-1 expression inhibitor of the disclosure contains as an active ingredient at least one selected from the group consisting of Saxifraga stolonifera, Saxifraga stolonifera extract, Rosemary, Rosemary extract, Licorice, Licorice extract, Melissa, Melissa extract, Wild thyme, Wild thyme extract, Hops, and Hops extract. The inventors have experimentally found that the aforementioned plants or their extracts suppress MMP-1 expression.

[0008] The disclosed MMP-1 expression inhibitor suppresses MMP-1 expression by inhibiting the activity of protein kinase C delta (PKCδ). Non-patent document 1 discloses that the activity of protein kinase C (PKC) is involved in UV-induced MMP-1 expression. However, focusing on a specific subtype of PKC to suppress wrinkle formation has not been done conventionally.

[0009] The inventors experimentally revealed that PKCδ, among several subtypes of PKC expressed in the skin, is involved in the MMP-1 expression pathway. Furthermore, the inventors revealed that the MMP-1 expression inhibitor suppresses MMP-1 expression by inhibiting the activity of PKCδ. The MMP-1 expression inhibitor can suppress MMP-1 expression by acting on PKCδ. In other words, PKCδ acts as the site of action to suppress MMP-1 expression. Therefore, it is preferable that the MMP-1 expression inhibitor contains a PKCδ inhibitor as an active ingredient. Note that the MMP-1 expression inhibitor (PKCδ inhibitor) may indirectly inhibit the activity of PKCδ by acting upstream of PKCδ in the MMP-1 expression mechanism, which includes PKCδ.

[0010] Another aspect of this disclosure is a topical skin preparation. The topical skin preparation of the disclosure contains the MMP-1 expression inhibitor. The topical skin preparation of the disclosure suppresses skin wrinkles by suppressing the expression of MMP-1.

[0011] Further details will be described in the embodiments below. [Brief explanation of the drawing]

[0012]

Figure 1

Figure 2

Figure 3

Figure 4

[0013] <1. Mechanism of MMP-1 expression>

[0014] MMP-1, also known as interstitial collagenase, is an enzyme involved in tissue breakdown and tissue reconstruction. MMP-1 expression increases with age and UV exposure, and it specifically cleaves the helical regions of dermal collagen. Therefore, MMP-1 plays a significant role in wrinkle formation. Consequently, suppressing MMP-1 expression can inhibit wrinkle formation.

[0015] The inventors of the present invention have experimentally clarified the expression mechanism of MMP-1. Figure 1 shows the expression mechanism of MMP-1 clarified by the inventors. The experiment was conducted by irradiating HaCaT (epidermal keratinocyte cell line established from a human adult under special ca2 + concentration and temperature conditions) with ultraviolet light (UVA).

[0016] When UVA irradiation is performed on HaCaT, the expression level of MMP-1 increases in an irradiation dose-dependent manner. However, when HaCaT is irradiated with UVA after pretreatment with the PKCδ inhibitor rotterlin added to HaCaT, the expression of MMP-1 is significantly suppressed. Therefore, it was clarified that PKCδ is involved in the expression pathway of MMP-1.

[0017] In addition, when the expression level of MMP-1 increases due to UVA irradiation, ERK (extracellular signal-regulated kinase) and MEK (mitogen-activated protein kinase kinase), which are proteins downstream of PKCδ, also increase. However, when HaCaT is irradiated with UVA after pretreatment with the PKCδ inhibitor rotterlin added to HaCaT, the induction of the expression of phosphorylation of ERK and MEK is suppressed. Therefore, it was clarified that the activity of PKCδ induces the phosphorylation of MEK and ERK downstream thereof and promotes the expression of MMP-1 via c-Jun and the like.

[0018] According to the expression mechanism shown in Figure 1, it can be seen that in order to suppress the expression of MMP-1, it is more effective to negatively control the activity of PKCδ. By negatively controlling the activity of PKCδ, the expression of MMP-1 (formation of wrinkles) due to aging or ultraviolet light can be effectively suppressed.

[0019] <2. MMP-1 Expression Inhibitor>

[0020] The MMP-1 expression inhibitor according to the embodiment contains, as an active ingredient, a plant or an extract thereof described below. As the plant, for example, at least one or more parts selected from the group consisting of leaves, stems, roots, flowers, and fruits are used. The plant may be used as an active ingredient, for example, in the form of a pulverized product or a dried pulverized product of the plant itself.

[0021] The plant contained as an active ingredient in the MMP-1 expression inhibitor according to the embodiment is at least one selected from the group consisting of Saxifraga stolonifera, rosemary, licorice, Melissa officinalis, wild thyme, and hops.

[0022] As the active ingredient of the MMP-1 expression inhibitor, the extract of the above-mentioned plant is preferably used. The extract is extracted from the plant into a solvent using a known extraction method. The form of the extract may be liquid or powder (dry powder). For the production of the extract, at least one or more parts selected from the group consisting of leaves, stems, roots, flowers, and fruits of the plant are used.

[0023] The extract contained as an active ingredient in the MMP-1 expression inhibitor according to the embodiment is at least one selected from the group consisting of an extract of Saxifraga stolonifera, an extract of rosemary, an extract of licorice, an extract of Melissa officinalis, an extract of wild thyme, and an extract of hops.

[0024] Saxifraga stolonifera is a plant of the genus Saxifraga in the family Saxifragaceae and is an evergreen perennial herb. Rosemary is a plant of the genus Rosmarinus in the family Lamiaceae and is an evergreen shrub. Licorice is a plant of the genus Glycyrrhiza in the family Fabaceae and is a perennial herb. Melissa officinalis is a plant of the genus Melissa in the family Lamiaceae and is a perennial herb. Melissa officinalis is also called lemon balm, lemon mint, or balm mint. Wild thyme is a plant of the genus Thymus in the family Lamiaceae and is a perennial plant. Wild thyme is also called creeping thyme. Hops are plants of the genus Humulus in the family Cannabaceae and are climbing perennial herbs.

[0025] The aforementioned plants or their extracts suppress the expression of MMP-1. That is, the aforementioned plants or their extracts are suitable as active ingredients for MMP-1 expression inhibitors. By suppressing the expression of MMP-1, the aforementioned plants or their extracts suppress wrinkle formation. If an MMP-1 expression inhibitor suppresses the expression of MMP-1 by inhibiting the activity of PKCδ, then the MMP-1 expression inhibitor is also a PKCδ inhibitor.

[0026] The plant or its extract may be used as an MMP-1 expression inhibitor on its own, or it may be included as an active ingredient in a liquid or paste-like formulation, for example. The proportion of the plant or its extract in the MMP-1 expression inhibitor is not particularly limited, but is preferably 0.01% by mass or more and 20% by mass or less, more preferably 0.1% by mass or more and 10% by mass or less, and even more preferably 0.5% by mass or more and 5% by mass or less.

[0027] <3. Topical skin preparations>

[0028] The topical skin preparation according to this embodiment contains the aforementioned MMP-1 expression inhibitor. Here, "contains an MMP-1 expression inhibitor" means that the topical skin preparation may partially contain the MMP-1 expression inhibitor. That is, the topical skin preparation may contain the MMP-1 expression inhibitor and other components. Alternatively, the topical skin preparation may consist solely of the aforementioned MMP-1 expression inhibitor. That is, the MMP-1 expression inhibitor itself may be used as a topical skin preparation.

[0029] Here, "topical skin preparations" refers to skincare preparations in a broad sense, and may be for cosmetic or therapeutic purposes. Topical skin preparations are suitably used, for example, as cosmetics, quasi-drugs, or pharmaceuticals. Topical skin preparations contain an active ingredient and a base. The active ingredient is at least one selected from the group consisting of Saxifraga stolonifera, Saxifraga stolonifera extract, Rosemary, Rosemary extract, Licorice, Licorice extract, Melissa, Melissa extract, Wild thyme, Wild thyme extract, Hops, and Hop extract. The base is, for example, an oily base, a water-soluble base, an emulsion base, or a lotion base. Topical skin preparations for cosmetic purposes are used, for example, as lotions, emulsions, serums (including emulsion types), or creams.

[0030] <3. Experiment 1>

[0031] The first experiment was conducted to search for plant extracts (traditional Chinese medicine extracts) that have anti-MMP-1 activity. Multiple plant extracts were used in the first experiment. The multiple plant extracts used in the first experiment were extracts of Saxifraga stolonifera, rosemary, licorice, lemon balm, wild thyme, hops, linden, and mugwort (artemisia princeps).

[0032] For the Saxifraga stolonifera extract, we used "Saxifraga stolonifera Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Saxifraga stolonifera Extract" is an extract derived from the whole Saxifraga stolonifera plant. For the rosemary extract, we used "Rosemary Extract-J" manufactured by Maruzen Pharmaceutical Co., Ltd. "Rosemary Extract-J" is an extract derived from the leaves of rosemary.

[0033] For the licorice extract, we used "Licorice Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Licorice Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the roots of licorice. Note that "roots" may include the rhizome. For the lemon balm extract, we used "Melissa Extract-J" manufactured by Maruzen Pharmaceutical Co., Ltd. "Melissa Extract-J" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the leaves of lemon balm (European mint). For the wild thyme extract, we used "Wild Thyme Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Wild Thyme Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the above-ground parts of wild thyme (European thyme). For the hop extract, we used "Hop Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Hop Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the flowers of hops.

[0034] For the linden tree extract, we used "Linden Tree Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Linden Tree Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the flowers of the winter linden tree. Artemisia princeps is a perennial plant belonging to the Artemisia genus of the Asteraceae family. The herbal medicine made from the leaves of artemisia princeps is called Gaiyou. For the artemisia princeps extract (Gaiyou extract), we used "Gaiyou Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. "Gaiyou Extract" manufactured by Maruzen Pharmaceutical Co., Ltd. is an extract derived from the leaves of artemisia princeps.

[0035] In the first experiment, several plant extracts were each diluted 100-fold with phosphate-buffered saline (PBS(-)). 50 μL of the diluted plant extract was added to HaCaT, incubated for 1 hour, and then irradiated with UVA. The UVA dose was 16 J, the irradiation time was 13 minutes and 18 seconds, and the irradiation distance was 20 cm. Cells were harvested 24 hours after irradiation and subjected to qPCR to investigate the effect of each plant extract on MMP-1 expression.

[0036] Figure 2 shows the results of the first experiment. The graph in Figure 2 shows the MMP-1 expression level when the MMP-1 expression level of the group to which ethanol (EtOH) was added to HaCaT (without UVA irradiation) is set to 1. In Figure 2, "EtOH+non" represents the group to which ethanol (EtOH) was added to HaCaT (without UVA irradiation). In Figure 2, "non" represents the group of HaCaT without added ethanol (without UVA irradiation). In Figure 2, "EtOH+16J" represents the group to which ethanol (EtOH) was added to HaCaT and irradiated with 16J of UVA. In Figure 2, "non", "EtOH+non", and "EtOH+16J" did not contain any plant extracts. In Figure 2, "Saxifraga stolonifera", "Rosemary", "Licorice", "Melissa", "Wild Thyme", "Hop", "Tilia cordata", and "Artemisia princeps" represent groups to which their extracts were added and irradiated with 16J of UVA.

[0037] As shown in Figure 2, the MMP-1 expression level in "EtOH+16J" was approximately 2.4 times higher than that in "EtOH+non," indicating a significant increase. In contrast, when each plant extract was added, the MMP-1 expression level was suppressed. In particular, "Saxifraga stolonifera," "Rosemary," "Licorice," "Melissa," "Wild Thyme," and "Hop" showed sufficient suppression of MMP-1 expression compared to "EtOH+16J." The MMP-1 expression levels of "Saxifraga stolonifera," "Rosemary," "Licorice," "Melissa," "Wild Thyme," and "Hop" remained at approximately 1.8 times or less than that of "EtOH+non." Therefore, "Saxifraga stolonifera," "Rosemary," "Licorice," "Melissa," "Wild Thyme," and "Hop" are suitable as active ingredients for MMP-1 expression inhibitors.

[0038] In particular, "Saxifraga stolonifera" and "Rosemary" show that their MMP-1 expression levels are about half or less compared to "EtOH+16J," making them especially suitable. "Saxifraga stolonifera" and "Rosemary" have MMP-1 expression levels that are about 1.2 times or less than those of "EtOH+non," indicating that the effects of UVA are significantly reduced.

[0039] <4. Experiment 2>

[0040] In the second experiment, the effects of plant extracts on mice were investigated. In the second experiment, from among "Saxifraga stolonifera," "Rosemary," "Licorice," "Melissa officinalis," "Wild Thyme," and "Hop," "Saxifraga stolonifera," which showed the greatest effect on MMP-1 expression in the first experiment, and "Hop," which showed the least effect on MMP-1 expression, were used.

[0041] In the second experiment, the hair on the backs of 15-week-old WT (Wild Type) mice was shaved, and 100 μL of 4% sodium dodecyl sulfate (SDS) was applied and allowed to dry for 30 minutes. Then, 100 μL each of 10-fold diluted extracts of Saxifraga stolonifera and hops, as well as ethanol as a control, were applied, and the mice were irradiated with UVA for two weeks. UVA irradiation was performed seven times over two weeks at a dose of 30 J each time, for a total of 210 J of irradiation. Subsequently, tissue solubilization was prepared from the mouse skin tissue, and MMP-1 expression was examined by western-blotting.

[0042] Figure 3 shows the results of the second experiment. The graph in Figure 3 shows the MMP-1 expression level compared to the MMP-1 expression level of UVA-free mice, which is set to 1. In Figure 3, "no" represents UVA-free mice. In Figure 3, "UV+EtOH" represents mice coated with ethanol as a control and irradiated with UVA, "UV+Saxifraga" represents mice coated with Saxifraga extract and irradiated with UVA, and "UV+Hop" represents mice coated with hop extract and irradiated with UVA.

[0043] As shown in Figure 3, the MMP-1 expression level of "UV+EtOH" is approximately three times that of "no," indicating a significant increase. In contrast, the MMP-1 expression levels of "UV+Saxifraga" and "UV+Hop" are sufficiently lower compared to "UV+EtOH." Therefore, it was confirmed that Saxifraga and Hop are effective in suppressing MMP-1 expression in mice. Among "Saxifraga," "Rosemary," "Licorice," "Melissa," "Wild Thyme," and "Hop," "Hop," which had the smallest effect on MMP-1 expression in the first experiment, also showed an MMP-1 suppression effect in mice. Therefore, it can be concluded that "Rosemary," "Licorice," "Melissa," and "Wild Thyme" also exhibit MMP-1 suppression effects in mice.

[0044] <5. Experiment 3>

[0045] In the third experiment, similar to the second experiment, mice were treated with extracts of Saxifraga stolonifera, hop extract, and ethanol as a control, and then irradiated with UVA. After UVA irradiation, tissue solubilization solutions were prepared from the mouse skin tissue, and PKCδ phosphorylation was examined by western blotting.

[0046] Figure 4 shows the results of the third experiment. The graph in Figure 4 shows the PKCδ phosphorylation level when the PKCδ phosphorylation level of UVA-free mice is set to 1. In Figure 4, "no" represents UVA-free mice. In Figure 4, "UV+EtOH" represents mice coated with ethanol as a control and irradiated with UVA, "UV+Saxifraga" represents mice coated with Saxifraga extract and irradiated with UVA, and "UV+Hop" represents mice coated with hop extract and irradiated with UVA.

[0047] As shown in Figure 4, the PKCδ phosphorylation level of "UV+EtOH" is approximately 2.2 times that of "no," indicating a significant increase. In contrast, the PKCδ phosphorylation levels of "UV+Saxifraga" and "UV+Hop" are sufficiently lower compared to "UV+EtOH." Therefore, Saxifraga and Hop suppress PKCδ phosphorylation. From this, it was found that Saxifraga and Hop inhibit PKCδ activity and act as PKCδ inhibitors. In other words, Saxifraga and Hop suppress MMP-1 expression by inhibiting PKCδ activity. These results suggest that rosemary, licorice, lemon balm, and wild thyme have a similar mechanism of action. [Examples]

[0048] Cosmetics with the following compositions were prepared as MMP-1 expression inhibitors. In each example, the "plant extract" is one of the following: Saxifraga stolonifera extract, rosemary extract, licorice extract, lemon balm extract, wild thyme extract, and hop extract. A total of six types, each using a different extract, were prepared in each of the following examples. However, the present invention is not limited to the following examples.

[0049] First example (Lotion A) Component Name Composition (mass%) Plant extracts 1.000 Glycerin 3,000 Propanediol 3.000 PCA-Na 0.200 Serine 0.032 Glycine 0.022 Glutamic acid 0.017 Alanine 0.009 Ricin 0.007 Lysine HCl 0.003 Arginine 0.008 Threonine 0.005 Proline 0.003 Leucine 0.002 Histidine HCl 0.002 Valine 0.002 Sodium aspartate 0.001 Isoleucine 0.001 Phenylalanine 0.001 Allantoin 0.001 Sodium hyaluronate 0.030 Ethylhexylglycerin 0.200 Betaine 0.600 Sorbitol 0.084 Taurine 0.027 Xanthan gum 0.003 Carbomer 0.200 Phenoxyethanol 0.500 Water Remainder Total 100,000

[0050] Second example (Lotion B) Component Name Composition (mass%) Plant extracts 1.000 Glycerin 3,000 Propanediol 3.000 Sodium ascorbyl phosphate 1.000 PCA-Na 0.200 Serine 0.032 Glycine 0.022 Glutamic acid 0.017 Alanine 0.009 Ricin 0.007 Lysine HCl 0.003 Arginine 0.008 Threonine 0.005 Proline 0.003 Leucine 0.002 Histidine HCl 0.002 Valine 0.002 Sodium aspartate 0.001 Isoleucine 0.001 Phenylalanine 0.001 Allantoin 0.001 Sodium hyaluronate 0.030 Ethylhexylglycerin 0.200 Betaine 0.600 Sorbitol 0.084 Taurine 0.027 Xanthan gum 0.003 Carbomer 0.200 Sodium citrate 0.050 Phenoxyethanol 0.500 Water Remainder Total 100,000

[0051] Third example (emulsion) Component Name Composition (mass%) Plant extracts 1.000 Octyldodecanol 10,000 Glycerin 4,000 Propanediol 4.000 Sorbitan monostearate 1,000 Polyoxyethylene hydrogenated castor oil 0.800 Cetanol 0.300 Stearyl alcohol 0.200 Methylparaben 0.150 Potassium hydroxide 0.100 Carbomer 0.250 Sodium citrate 0.050 Fragrance 0.100 Water Remainder Total 100,000

[0052] Fourth embodiment (Serum A) Component Name Composition (mass%) Plant extract 1,000 Glycerin 3,000 Propanediol 3.000 1,3-Butylene glycol 1.000 PCA-Na 0.200 Serine 0.032 Glycine 0.022 Glutamic acid 0.017 Alanine 0.009 Ricin 0.007 Arginine 0.008 Threonine 0.005 Proline 0.003 Sodium hyaluronate 0.030 Ethylhexylglycerin 0.200 Betaine 0.600 Sorbitol 0.084 Xanthan gum 0.003 Carbomer 0.200 (Acrylates / Beheneth-25 Methacrylate) Copolymer 0.400 K hydroxide 0.060 Sodium citrate 0.050 Phenoxyethanol 0.500 Water Remainder Total 100,000

[0053] Fifth example (Serum B: Emulsion type) Component Name Composition (mass%) Plant extracts 1.000 Glycerin 3,000 Propanediol 3.000 1,3-Butylene glycol 1.000 Ceramide 1 0.00003 Ceramide 2 0.035 Ceramide 3 0.100 Ceramide 5 0.005 Ceramide 6II 0.030 Phytosphingosine 0.025 Cholesterol 0.055 Phytosterols 0.020 PCA-Na 0.200 Serine 0.032 Glycine 0.022 Glutamic acid 0.017 Alanine 0.009 Ricin 0.007 Arginine 0.008 Threonine 0.005 Proline 0.003 Sodium hyaluronate 0.030 Ethylhexylglycerin 0.200 Betaine 0.600 Sorbitol 0.084 Xanthan gum 0.130 Carbomer 0.100 (Acrylates / Beheneth-25 Methacrylate) Copolymer 0.400 Sodium citrate 0.050 K hydroxide 0.060 Phenoxyethanol 0.500 Water Remainder Total 100,000

[0054] Sixth embodiment (Cream A) Component Name Composition (mass%) Plant extracts 1.000 Squalane 5,000 Glycerin 3,000 Propanediol 3.000 Shea butter 2,000 Jojoba seed oil 2,000 Macadamia seed oil 1,000 Octyldodecanol 1,000 Meadowfoam oil 0.500 PCA-Na 0.200 Serine 0.032 Glycine 0.022 Glutamic acid 0.017 Alanine 0.009 Ricin 0.007 Arginine 0.008 Threonine 0.005 Proline 0.003 Sodium hyaluronate 0.030 Ethylhexylglycerin 0.200 Betaine 0.600 Sorbitol 0.084 Xanthan gum 0.600 Agar 0.400 Carbomer 0.300 Tocopherol 0.100 Sodium citrate 0.050 K hydroxide 0.060 Phenoxyethanol 0.500 Water Remainder Total 100,000

[0055] Seventh example (Cream B) Component Name Composition (mass%) Plant extracts 1.000 Triethylhexanoin 20,000 Jojoba seed oil 10,000 Glycerin 5,000 Propanediol 5.000 Hexa(hydroxystearic acid / stearic acid / rosinic acid) Dipentaerythrityl 1.000 (PEG-240 / Desulfetradeceth-20 / HDI) Copolymer 1.000 Polysorbate 60 0.500 (Acrylates / C10-30 Alkyl Acrylate) Crosspolymer 0.050 K hydroxide 0.100 Phenoxyethanol 0.500 Water Remainder Total 100,000

Claims

1. It contains at least one selected from the group consisting of Saxifraga stolonifera, Saxifraga stolonifera extract, Rosemary, Rosemary extract, Licorice, Licorice extract, Melissa, Melissa extract, Wild thyme, Wild thyme extract, Hops, and Hop extract as an active ingredient. A matrix metalloproteinase 1 expression inhibitor.

2. By inhibiting the activity of protein kinase C delta, it suppresses the expression of matrix metalloproteinase 1. The matrix metalloproteinase 1 expression inhibitor according to claim 1.

3. A matrix metalloproteinase 1 expression inhibitor according to claim 1 or claim 2 is contained A topical skin preparation.

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