JP2003252745A - MATRIX METALLOPROTEINASE (MMPs) INHIBITOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a matrix metalloproteinase (MMPs) inhibitor capable of preventing the aging of the skin by inhibiting activities of the MMPs belonging to a gelatinase group, a stromeleicin group or a collagenase group which give a large effect on the aging of the skin. <P>SOLUTION: The matrix metalloproteinase inhibitor comprises one or more kinds of compounds of catechins, procyanidins and mangosteens. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a matrix metalloproteinase inhibitor, and more specifically, to specific matrix metalloproteinases (MMPs) that have a great influence on skin aging.
The present invention relates to a matrix metalloprotease inhibitor capable of inhibiting the activity of the skin, preventing skin aging and maintaining youthful skin, and a cosmetic containing the same. The cosmetics of the present invention can be suitably used for basic cosmetics, makeup cosmetics, hair cosmetics, bath agents and the like.

[0002]

2. Description of the Related Art Changes caused by aging of the skin, that is, wrinkles, dullness, loss of texture,
It has been known that ultraviolet rays and the decrease in female hormones that are observed in menopause are largely involved in the decrease in elasticity. From a microscopic view of these changes, dermal matrix components such as collagen and elastin are reduced and denatured, and further, basement membrane damage and epidermal thickening occur.

[0003] In recent years, studies have been made, and it has been pointed out that the matrix metalloprotease is particularly involved as a factor inducing this change. Many kinds of matrix metalloproteases are known, and although they have common structural and functional characteristics, each substrate protein is different (Kan Miyazaki, Biochemistry 68, No. 12, PP179
1-1807 (1996)). Among matrix metalloproteases, MMP1 decomposes type I and III collagens, which are the main constituents of the skin-dermal matrix, and MMP2 and 9 belonging to the gelatinase group, type IV collagens and laminin, which are basement membrane components, and dermal matrix components. Is known as an enzyme that decomposes elastin and the like and further decomposes proteoglycan, type IV collagen, laminin and the like, which belongs to the stromlysin group. Since its expression is greatly increased by, for example, irradiation with ultraviolet rays, it is considered to be one of the causes of the degeneration and modification of extracellular matrix by ultraviolet rays and one of the major factors such as the formation of skin wrinkles (V . Koivukang
as et al., Acta Derm Venereol (Stockh), 74,279−282
(1994); Gary J. Fisher et al. Nature, 379 (25), 335.
(1996); Gary J. Fisher et al. The NewEngland Journ
al of Medicine, 337 (20), 1419 (1997)). In addition to UV rays, the rapid decrease / deficiency of female hormones during menopause triggered the increase of MMP-2,9 in the skin,
It has been clarified that it is a cause of skin wrinkles, sagging, etc., similar to ultraviolet rays (Japanese Patent Application 2001-50839; N. Oc.
hiai et al., Jpn J. Dermatol., 111 (3), 532 (Abs) (20
01)). Thus, inhibition of MMPs activity is extremely important for protecting various extracellular matrices and preventing skin aging. Many conventional anti-aging agents have a mechanism of activating fibroblasts and increasing the amount of collagen produced, but only a few focus on the inhibition of each MMPs activity ( Japanese Patent Application No. 11-320747, Japanese Patent Application 1
1-358344, Japanese Patent Application 2000-5704, Japanese Patent Application 2000-5705). Therefore, in order to develop a more effective anti-aging drug, we have developed a matrix metalloprotease inhibitor having an inhibitory effect on each MMPs.

Therefore, an object of the present invention is to provide a matrix metalloprotease inhibitor which is highly safe and has excellent effects of preventing and improving skin aging by suppressing the activity of various matrix metalloproteases, and cosmetics containing the same. To do.

[0005]

In order to solve these problems, the present inventors have studied a wide variety of substances for their anti-aging action based on inhibition of MMPs activity, and as a result, catechin, epicatechin, procyanidin have been obtained. The present invention was completed by discovering that the compounds and mangosteens have excellent MMPs activity inhibitory properties. Up to now, there have been no reports on the MMPs inhibitory action of this compound. Further, it is not known at all until now that this compound has an anti-aging effect based on the inhibition of MMPs activity belonging to the gelatinase group, the inhibition of MMPs activity belonging to the stromlysin group, and further the inhibition of MMPs activity belonging to the collagenase group.

That is, the present invention is a matrix metalloprotease (MMPs) inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. Further, according to the present invention, a matrix metalloprotease (MMPs) inhibitor belonging to the gelatinase group, a matrix metalloprotease (MMPs) inhibitor belonging to the stromelysin group, and a matrix metalloprotease (MMPs) belonging to the collagenase group consisting of the above compounds. An inhibitor is provided.

In the present invention, the matrix metalloprotease (MMPs) inhibitors belonging to the gelatinase group can be applied as elastin degradation inhibitors, laminin degradation inhibitors and basement membrane degradation inhibitors. Further, as applications of matrix metalloprotease (MMPs) inhibitors belonging to the stromelysin group,
It can be applied as a proteoglycan decomposition inhibitor and a laminin decomposition inhibitor. Further, the matrix metalloprotease (MMPs) inhibitor belonging to the collagenase group can be applied as a collagen degradation inhibitor. These can also be applied as an anti-aging agent for the purpose of preventing and improving wrinkles and tarmi.

The structure of the present invention will be described in detail below. The catechins, procyanidins, and mangosteens used in the present invention are represented by the following formulas (1) to (5) and can be obtained, for example, as a component of the pericarp of mangosteen, which is a plant of the Hypericumaceae family.

[0009]

[Chemical 5]

(In the formula, the structural part of 1 represents (-)-epicatechin, the structural part of 2 represents procyanidin B-2, and the structural parts of 3 and 4 are R ¹ = OH and R ² = H. Procyanidin C-1 is shown, R ¹ ═H, R ² ═OH is shown, and procyanidin C-3 is shown, and the structural portion of 5 is R ¹ ═H, R ² ═OH.
Represents procyanidin B-1. )

[0011]

[Chemical 6]

(In the formula, the structural portion of 6 represents catechin,
Structural part of 7,8 R ¹ = H, shows the procyanidin B-3 with R ² = OH, shows the procyanidin B-4 in ^{R 1 = OH, R 2 =} H. )

[0013]

[Chemical 7]

(Wherein formula (3) is procyanidin A-1.
And formula (4) represents procyanidin A-2. )

[0015]

[Chemical 8]

(Wherein R ¹ = CH ₃ , R ² = H represents α-mangostin, R ¹ = CH ₃ , R ² = CH ₃ represents β-mangostin, and R ¹ = H, R ² = H indicates γ-mangostin.)

Of the above structural formulas, catechins include
Catechin, (−)-epicatechin (epicat)
echin) as procyanidins, procyanidins (procyanidin) A-1,2, B-1,2,3,4, C-1,3, etc. as mangosteens, α, β, γ-mangostin ( mang
ostin).

The matrix metalloprotease (MMPs) inhibitor of the present invention is preferably used as a cosmetic which can be expected to have an antiaging effect by inhibiting matrix metalloprotease (MMPs), and the compounding amount of the compound in this case is an external preparation. 0.0001-
It is 20.0 mass%, preferably 0.0001 to 10.0 mass%. If it is less than 0.0001% by mass, the effect of the present invention is not sufficiently exhibited, and if it exceeds 20.0% by mass, formulation is difficult, which is not preferable. Also, 10.0
Even if it is blended in an amount of not less than mass%, the effect is not significantly improved.

In addition to the present compound, the external preparations of the present invention, especially cosmetics, are used in addition to the present compounds, such as components usually used in external preparations for skin such as cosmetics and pharmaceuticals, such as whitening agents, moisturizers, antioxidants, oily ingredients, An ultraviolet absorber, a surfactant, a thickener, an alcohol, a powder component, a coloring agent, an aqueous component, water, various skin nutritional agents and the like can be appropriately blended as necessary.

In addition, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extraction Substance, glabridin, hot water extract of karin fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, etc. Other whitening agents, saccharides such as glucose, fructose, mannose, sucrose, trehalose, etc., vitamins A such as retinoic acid, retinol, retinol acetate, retinol palmitate, etc. can also be appropriately added.

The external preparations containing catechins, procyanidins and mangosteens used in the present invention include, for example, ointments, creams, emulsions, lotions, packs, bath agents, etc.
Any conventional skin external preparation may be used,
The dosage form is not particularly limited, but it is particularly preferably used as a cosmetic dosage form.

[0022]

The present invention will be described in more detail with reference to Examples. The present invention is not limited to this. The blending amount is% by mass. Prior to the Examples, a test method and results of the catechins, procyanidins, and mangostins used in the present invention for inhibiting the MMP9, MMP3 and MMP1 activity will be described.

1. Sample preparation (1) α-mangostin, epicatechin, procyanidin B-2 and C-1 α-mangostin, a type of mangosteen, epicatenate, a type of catechins, procyanidin B-2 and C-1 belonging to procyanidins Can be obtained, for example, by extracting the skin of mangosteen, which is a plant of the Hypericum family, with methanol, and subjecting the obtained methanol extract to silica gel column chromatography. These compounds were dissolved in DMSO at a concentration of 2%, the solution was diluted to adjust the concentration, and the following experiments were carried out using this.

2. For the test method of the MMPs activity inhibitory effect and the measurement of the results, a type IV collagenase, stromelysin-1, and type I collagenase assay kit manufactured by Yagaya Co., Ltd. were used. Dissolve the test substance in dimethyl sulfoxide to make a 2 mass% solution,
Measurement buffer (0.4M NaCl, 10 mM CaCl
_It was diluted to a predetermined concentration with 0.1 M Tris of pH 7.4 containing ₂ ). The enzyme used was MMP derived from human cells made by oysters.
3, MMP9 and MMP1. The activity inhibition rate of the test substance was measured from the ratio of the substrate degradation rate in the system containing the test substance to the substrate degradation rate in the reaction system containing no test substance. The results are shown in Tables 1, 2, and 3. In addition, as a reference example, the same test as described above was performed for ethylenediaminetetraacetic acid (EDTA), which is a substance well known to have an inhibitory action on MMPs. The results are also shown in Tables 1, 2, and 3.

[0025]

[Table 1] ────────────────────────── Sample concentration (%) Enzyme inhibition rate (%) ────────────────────────── α-mangostin 0.001 MMP9 36 procyanidin B−2 0.001 MMP9 25 epicatechin 0.001 MMP9 31 EDTA 0.005 MMP9 0 EDTA 0.05 MMP9 85 ──────────────────────────

[0026]

[Table 2] ────────────────────────── Sample concentration (%) Enzyme inhibition rate (%) ────────────────────────── α-mangostin 0.001 MMP3 23 procyanidin B−2 0.001 MMP3 18 epicatechin 0.001 MMP3 21 EDTA 0.005 MMP3 0 EDTA 0.05 MMP3 80 ──────────────────────────

[0027]

[Table 3] ────────────────────────── Sample concentration (%) Enzyme inhibition rate (%) ────────────────────────── α-mangostin 0.001 MMP1 30 procyanidin B−2 0.001 MMP1 28 epicatechin 0.001 MMP1 28 EDTA 0.005 MMP1 0 EDTA 0.05 MMP1 91 ──────────────────────────

As is clear from Tables 1 to 3, catechins, procyanidins and mangosteens MMP9, M
MP3, MMP1 inhibitory effect, EDTA MMP9, M
It was equal to or higher than the MP3 and MMP1 inhibitory effect. Hereinafter, prescription examples of the external preparation for skin of the present invention in various dosage forms will be described as examples.

Example 1 Cream (prescription) Stearic acid 5.0% by mass Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 γ-mangostin 0.01 Caustic potassium 0.1 2 Sodium bisulfite 0.01 Preservative Appropriate amount Perfume Appropriate amount Ion-exchanged water Residue (production method) Propylene glycol and γ-ma in ion-exchanged water
Add ngostin and caustic potash to dissolve, heat and keep at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause the reaction. Then, it is uniformly emulsified with a homomixer and cooled to 30 ° C. with thorough stirring.

Example 2 Cream (Formulation) Tearic Acid 2.0% by Mass Stearyl Alcohol 7.0 Hydrogenated Lanolin 2.0 Squalane 5.0 2-Octyldodecyl Alcohol 6.0 Polyoxyethylene (25 mol) Cetyl Alcohol Ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 catechin 0.05 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Perfume Ion-exchanged water Residual (production method) Add propylene glycol to ion-exchanged water,
Heat to maintain 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase to carry out preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. with thorough stirring.

Example 3 Cream (formulation) Solid paraffin 5.0% by mass Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 procyanidin C-1 0.1 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Perfume Ion-exchanged water Residual (production method) Soap powder and borax are added to ion-exchanged water and heated. Melt and keep at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is stirred into the water phase and gradually added to carry out the reaction. After the reaction is completed, the mixture is uniformly emulsified with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 4 Emulsion (formulation) Stearic acid 2.5% by mass Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) Monooleate ester 2.0 Polyethylene glycol 1500 3. 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Brand name: Carbopol 941, BFGoodrich Chemical company) epicatechin 0.01 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Fragrance Suitable amount Ion-exchanged water Residue (production method) Small amount The carboxyvinyl polymer is dissolved in the ion-exchanged water of (A phase). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, and the mixture was heated and dissolved and maintained at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase for preliminary emulsification, the phase A is added and the mixture is homogenized with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. while being well stirred.

Example 5 Emulsion (formulation) Microcrystalline wax 1.0% by mass Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) ) Sorbitan monooleate 1.0 Propylene glycol 7.0 α-mangostin 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume Ion-exchanged water Residual (production method) Add propylene glycol to ion-exchanged water,
Heat to maintain 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added to this and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C while stirring well.

Example 6 Jelly (formulation) 95% ethyl alcohol 10.0 mass% dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 1.0 (trade name: Carbopol) 940, BFGoodrich Chemical company) Caustic soda 0.15 L-Arginine 0.1 procyanidin B-3 7.0 2-Hydroxy-4-methoxybenzophenone sodium sulfonate 0.05 Ethylenediaminetetraacetate ・ 3 sodium ・ 2 water 0.05 Methylparaben 0.2 Fragrance Suitable amount Ion-exchanged water Residual (production method) Carbopol 940 is uniformly dissolved in ion-exchanged water, while procyanidin B-3 and polyoxyethylene (50 mol) oleyl alcohol ether are dissolved in 95% ethanol. , To the aqueous phase. Next, after adding other ingredients, the mixture is neutralized with caustic soda and L.arginine to increase the viscosity.

Example 7 Beauty Serum (Formulation) (Phase A) Ethyl Alcohol (95%) 10.0% by Mass Polyoxyethylene (20 mol) Octyldodecanol 1.0 Pantotenyl Ethyl Ether 0.1 β-mangostin 1 .5 Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (trade name: Carbopol 940, BFGoodrich Chemical company) Purified water Residual (manufacturing method) Dissolve Phases A and C uniformly,
Add phase and solubilize. Next, phase B is added and then filling is performed.

Example 8 Pack (formulation) (Phase A) Dipropylene glycol 5.0% by mass Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) procyanidin C-2 0.01 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (Phase C) Sodium hydrogen sulfite 0.03 Polyvinyl alcohol 13.0 (Saponification degree 90, degree of polymerization 2,000) Ethanol 7.0 Purified water Residual (manufacturing method ) A phase, B phase, and C phase are uniformly dissolved,
Phase B is added to the phase to solubilize it. Next, this is added to phase C and then filled.

Example 9 Solid foundation (formulation) Talc 43.1% by mass Kaolin 15.0 Sericite 10.0 Zinc white 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8 0.0 Isostearic acid 4.0 POE sorbitan monooleate 3.0 Isocetyl octanoate 2.0 procyanidin B-5 1.0 Preservative A suitable amount of perfume An appropriate amount (production method) Talc, a powdery component of black iron oxide is thoroughly mixed with a blender. Then, squalane, an oily component of isocetyl octanoate, procyanidin B-5, a preservative, and a fragrance are added, and the mixture is well kneaded, then filled into a container and molded.

Example 10 Emulsion type foundation (cream type) (Prescription) (Powder part) Titanium dioxide 10.3% by mass Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Bengala 0.3 Black iron oxide 0.2 (oil phase) decamethylcyclopentasiloxane 11.5 liquid paraffin 4.5 polyoxyethylene-modified dimethylpolysiloxane 4.0 (aqueous phase) purified water 50.0 1,3-butylene glycol 4.5 catechin 1.5 Sorbitan sesquioleate 3.0 Preservative Suitable amount Perfume Suitable amount (manufacturing method) After heating and stirring the aqueous phase, the powder portion thoroughly mixed and pulverized is added and treated with a homomixer. Further, the heated and mixed oil phase is added, and the mixture is treated with a homomixer. Then, the fragrance is added with stirring and the mixture is cooled to room temperature.

[0039]

As described above, the matrix metalloprotease (MMPs) inhibitor of the present invention has excellent M
MP9 activity inhibition effect and MMP3 activity inhibition and MM
It has a P1 inhibitory effect. By incorporating this matrix metalloprotease (MMPs) inhibitor into cosmetics, it is possible to prevent decomposition of skin extracellular matrix components by MMPs and maintain elastic, wrinkle- and sagging-free skin. Provided is a cosmetic that can prevent skin aging and maintain a youthful skin condition.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Shinji Inomata             2-2-1 Hayabuchi, Tsuzuki Ward, Yokohama City, Kanagawa Prefecture             Shiseido Research Center (Shin-Yokohama)             Within F-term (reference) 4C083 AA082 AA111 AA112 AA122                       AB032 AB212 AB232 AB242                       AB272 AB352 AB432 AB442                       AC012 AC022 AC072 AC102                       AC122 AC182 AC242 AC262                       AC352 AC402 AC422 AC432                       AC442 AC482 AC532 AC542                       AC582 AC792 AC841 AC842                       AD042 AD092 AD112 AD162                       AD172 AD512 AD662 BB51                       CC04 CC05 CC07 CC12 DD21                       DD22 DD23 DD27 DD31 DD41                       EE12

Claims (11)

[Claims] 1. A matrix metalloprotease (MMPs) inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 2. One or more compounds selected from catechins, procyanidins and mangosteens,
The matrix metalloprotease (MMPs) inhibitor according to claim 1, which is represented by any of the following formulas (1) to (5). [Chemical 1] (In the formula, the structural portion of 1 represents (−)-epicatechin,
The structural portion of 2 represents procyanidin B-2, and the structural portions of 3 and 4 are procyanidin C-1 with R ¹ = OH and R ² = H.
, R ¹ ═H and R ² ═OH represent procyanidin C-3, and the structural portion of 5 represents R ¹ ═H and R ² ═OH, representing procyanidin B-1. ) [Chemical 2] (Wherein structural part of the 6 shows a catechin, structural parts of 7,8 indicates R ¹ = H, procyanidin B-3 with R ² = OH, procyanidins in ^{R 1 = OH, R 2 =} H B- 4 is shown.) (In the formula, the formula (3) represents procyanidin A-1 and the formula (4) represents procyanidin A-2.) (In the formula, R ¹ = CH ₃ , R ² = H represents α-mangostin, R ¹ = CH ₃ , R ² = CH ₃ represents β-mangostin, and R ¹ = H, R ² = H represents γ. -Indicates mangosteen.) 3. The matrix metalloprotease (MMPs) according to claim 1, wherein the matrix metalloprotease belongs to the gelatinase group.
Inhibitor. 4. An elastin degradation inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 5. A laminin decomposition inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 6. A basement membrane degradation inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 7. The matrix metalloprotease (MMP) according to claim 1, wherein the matrix metalloprotease belongs to the stromelysin group.
s) inhibitors. 8. A proteoglycan degradation inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 9. The matrix metalloprotease (MMPs) according to claim 1, wherein the matrix metalloprotease belongs to the collagenase group.
Inhibitor. 10. A collagen degradation inhibitor comprising one or more compounds selected from catechins, procyanidins and mangosteens. 11. A cosmetic comprising the matrix metalloprotease (MMPs) inhibitor according to claim 1 blended therein.