JPH0995420A - Preparation for external use for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for external use for skin having both excellent tyrosinase and elastase inhibitory effect, thus effective for preventing skin whitening and aging. SOLUTION: This preparation contains 0.0005-20 (pref. 0.001-10)wt.%, on a dry basis, of an extract from a plant belonging to Theaceae Schima (e.g. Bunga cangkok, scientific name: Schima wallichii (DC) Korth) which grows esp. in the arid grassland and pastureland in Indonesia. The extracts can be obtained by immersing the leaves, stems, flowers, barks, seeds, fruits, whole grass, etc., of the plant in an extraction solvent (e.g. methanol) or refluxing them in the presence of the solvent under heating followed by filtration and then concentration. The preparation is obtained in the form of ointment, cream, milky lotion, lotion, pack, bathing agent, etc. The preparation is excellent in color fading ability for pigmentation after suntan, spots, freckles, chloasma, etc., and in ability for skin whitening, and is effective for retaining fresh skin through preventing skin aging by recovering and maintaining skin firmness and elasticity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has an effect of inhibiting tyrosinase activity which is effective for preventing and improving pigmentation, spots, freckles, chloasma, etc. after sunburn by incorporating an extract of a specific plant. A skin that not only has an excellent effect on whitening the skin, but also suppresses the activity of elastase and restores and maintains the firmness and elasticity of the skin to prevent skin aging and maintain a youthful skin condition. Regarding external preparations.

[0002]

BACKGROUND OF THE INVENTION Although there are some unclear points about the mechanism of the generation of skin spots and the like, it is generally caused by hormonal abnormalities and irritation of ultraviolet rays from sunlight. It is believed that melanin pigment is formed, which is abnormally deposited in the skin. This melanin pigment, which causes skin coloring, is produced in the melanin-producing granules (melanosomes) in the melanocytes (melanocytes) between the epidermis and the dermis, and the produced melanin diffuses into adjacent cells by osmotic action. . The biochemical reaction in this melanocyte is presumed to be as follows.

That is, tyrosine, which is an essential amino acid, is converted into dopaquinone by the action of the enzyme tyrosinase, which is converted into black melanin via a red pigment and a colorless pigment by an enzymatic or non-enzymatic oxidative action in the process of producing melanin pigment. is there. Therefore, suppressing the action of tyrosinase, which is the first step of the reaction, is important for suppressing melanin production.

However, the compounds that suppress the action of tyrosinase, except for hydroquinone, exhibit their effects very slowly, so that the effect of improving skin pigmentation is not sufficient. On the other hand, although hydroquinone is recognized as having an effect, its use is generally restricted because of its sensitizing properties. In order to improve the safety, attempts have been made to use monoesters or alkyl monoethers of higher fatty acids (Japanese Patent Application Laid-Open No. 58-154507), but the esters are decomposed by hydrolytic enzymes in the body. For this reason, it is not always safe to say, and ethers have not been obtained that are sufficiently satisfactory in terms of safety.

On the other hand, in recent years, research on aging has been advanced, and as a cause of skin aging, aging is an important factor from a macroscopic viewpoint, and further, drying, oxidation, and sunlight (ultraviolet rays).
The effects of the above have also been cited as direct factors related to skin aging. As a concrete phenomenon of skin aging,
It is known that collagen and elastin are reduced in the dermis of the skin, mucopolysaccharides such as hyaluronic acid are reduced, and cell damage by ultraviolet rays is caused. Of these, elastin forms a cross-link with each other and contributes to the elasticity of tissues.However, elastin, which is an elastin-disrupting enzyme, is overexpressed by UV exposure and aging, and elastin is denatured and destroyed. However, it is thought to lead to a decrease in skin elasticity. Therefore, it is important to prevent aging of the skin by suppressing the action of elastase and preventing the degeneration and destruction of elastin which gives elasticity and firmness to the skin.

[0006]

In view of the above circumstances, the present inventors have investigated a tyrosinase inhibitory action and an elastase inhibitory action on a wide variety of substances. As a result, the genus Schima of the Theaceae family is found. It was found that the plant extract of (1) has excellent tyrosinase inhibitory action and elastase inhibitory action, and completed the present invention. There has been no report on tyrosinase inhibitory action and elastase inhibitory action of a plant extract of the genus Schima of Theaceae family. unknown. The present inventors have completed the present invention based on the above findings.

That is, the present invention is an external preparation for skin characterized by containing an extract of a plant of the genus Schima of Theaceae family. The external preparation for skin of the present invention is preferably a tyrosinase inhibitor or an anti-aging agent, and is preferably an elastase inhibitor among anti-aging agents.

Hereinafter, the configuration of the present invention will be described in detail. The Theaceae family, Schim, used in the present invention.
a) As a genus plant, Bunga cangkok
, Scientific name: Schima wallichii (DC) Korth) is suitable. These are plants that especially grow in Indonesian dry grasslands and pastures. The extract used in the present invention includes leaves, stems, plants of the genus Schima of the family Camellia (Theaceae),
It is obtained by soaking or heating and refluxing flowers, bark, seeds or fruits, whole plants, etc. with an extraction solvent, filtering and concentrating. The extraction solvent used in the present invention may be any solvent as long as it is a solvent usually used for extraction, in particular, alcohols such as methanol and ethanol, hydrous alcohols, acetone,
Organic solvents such as ethyl acetate can be used alone or in combination.

In the present invention, the compounding amount of the plant extract of the genus Schima of the family Theaceae is based on the total amount of the external preparation.
The dry matter is 0.0005 to 20.0% by weight, preferably 0.001 to 10.0% by weight. If the amount is less than 0.0005% by weight, the effects of the present invention cannot be sufficiently exerted, and if it exceeds 20.0% by weight, it is difficult to formulate the composition, which is not preferable. Further, even if the content is 10.0% by weight or more, the effect is not so much improved.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, components that are usually used in external preparations for skin such as cosmetics and pharmaceuticals, for example, other whitening agents, moisturizing agents, antioxidants,
An oily component, an ultraviolet absorber, a surfactant, a thickener, an alcohol, a powder component, a coloring material, an aqueous component, water, various skin nutritional agents and the like can be appropriately blended as necessary.

Other metal 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 fruits of fire thorns, various crude drugs, tocopherol acetate,
Drugs such as glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate,
Other whitening agents such as ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, mannose,
Sugars such as sucrose and trehalose can also be appropriately blended.

The external preparation for skin of the present invention may be any ointment, cream, milky lotion, lotion, pack, bath agent or the like as long as it is a conventional external preparation for skin, and its form is not particularly limited.

[0013]

Next, the present invention will be described in more detail by way of examples. The present invention is not limited to this. The blending amount is% by weight. Prior to the Examples, the test method and the result of the tyrosinase inhibitory effect and the elastase inhibitory effect of the plant extract of the present invention will be described.

Test method for tyrosinase inhibitory activity and its effect 1. Sample preparation (1) Bunga cangkok Scientific name: Schima w
allichii (DC) Korth) extract 50g of Bunga cangkok fruit
Was immersed in methanol at room temperature for 4 days and the extract was concentrated to obtain 5.37 g of a methanol extract. This extract was dissolved in DMSO at 1%, the concentration was adjusted by diluting this solution, and the following experiment was performed using this.

2. Cell culture method B16 melanoma cultured cells derived from mice were used. 1
0% FBS and theophylline (0.09 mg / ml)
Was cultured in a CO2 incubator (95% air, 5% carbon dioxide) at 37 ° C. in an Eagle MEM medium containing After 24 hours of culture, the sample solution is added to a final concentration (concentration in terms of dry extract) of 10-2 to 10-5% by weight, and the culture is further continued for 3 days, and the tyrosinase activity inhibitory effect is measured by the following method did.

3. Test method and its results (1) Visual measurement of melanin amount Place a diffusion plate on the lid of the well plate and observe the intracellular melanin amount with an inverted microscope. ). Table 1 shows the results.
Displayed in. In addition, as a reference example, the same test as above was carried out on an extract of Kaigai (Lamiaceae, Odorikosou Subfamily), which is already known to have an action of suppressing melanin production. Table 1 also shows the results. Further, in the table, "toxic" means that it is cytotoxic.

<Judgment Criteria> ◯: White (amount of melanin) Δ: Slightly white (amount of melanin) ×: Reference (amount of melanin)

(2) Measurement of tyrosinase activity Prior to measurement, the medium in the wells was removed and the wells were washed twice with 100 μl of PBS. 45 μl of 1% Triton-X in each well
(Rohm and Haas product name, surfactant) containing PBS is added. Shake the plate for 1 minute, break the cell membrane well, and use a microplate reader for 475n.
The absorbance at m was measured, and this was taken as the absorbance at 0 minutes. Then, 5 μl of 10 mM L-DOPA solution was quickly added, and the mixture was transferred to an incubator at 37 ° C. and reacted for 60 minutes. The plate was shaken for 1 minute, and the absorbance (475 nm) at 60 minutes was measured. The tyrosinase activity ratio (%) was defined as the ratio of the absorbance difference of the sample with the plant extract to the absorbance difference between the time of 0 minute and the time of 60 minutes in the case of the sample to which no plant extract was added (control). Table 1 shows the results. In addition, as a reference example, the same test as described above was conducted on an ethanol extract of a scallop (Lamiaceae: Subfamily Lamiaceae) already known to have a tyrosinase activity inhibitory action. Table 1 also shows the results.
In the table, "toxic" means that cytotoxicity was observed, and "-" means that no significant difference was observed within a risk rate of 5% as compared with the control.

[0019]

[Table 1] ──────────────────────────────────── Test melanin production Visual evaluation Tyrosinase activity rate ( %) Concentration (% by weight 10-5 10-4 10-3 10-2 10-5 10-4 10-3 10-2 ──────────────────── ──────────────── Bunga kankoku extract △ ○ ○ Toxicity 64 72 8 Toxicity Kaigai extract × × × × − − − 55 ────────── ──────────────────────────

(3) Whitening effect test [Test method] 40 subjects exposed to summer sunlight for 4 hours (2 hours per day for 2 days) were exposed to sunlight on the skin of the upper arm inner part. After 5 days, each sample was applied once a morning and evening for 4 weeks. The panel was divided into 8 groups, and 5 groups were prepared, and the tests were conducted according to the formulations shown below. (Alcohol phase) 95% ethyl alcohol 55.0% by weight Polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 Antioxidant / preservatives Appropriate amount Perfume Appropriate amount Drug (Table 2) (Aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Appropriate amount Ion-exchange water Residue <Production method> Prepare an aqueous phase and an alcohol phase, respectively, and then mix and solubilize both.

[Evaluation Method] The lightening effect after use was judged based on the following judgment criteria. <Judgment criteria> ：: When the ratio showing significant effect and effectiveness among the subjects is 80% or more 割 合: The ratio showing significant effect and effectiveness among the subjects is 50% or more
Less than 80% △: The proportion of the test subjects showing excellent and effective is 30% or more
When less than 50% x: When the ratio of markedly effective or effective among the subjects is less than 30%

Samples having the blending composition described in the above test method were prepared and the whitening effect was compared using the agents shown in Table 2.
The results are shown in Table 2.

[0023]

[Table 2] ─────────────────────────── Drugs Compounding amount (% by weight) Effect ────────── ────────────────── Additive- × Hydroquinone 1.0 △ Bunga kankoku extract 0.1 ○ Bunga kankoku extract 1.0 ○ Bunga kankoku extract 10.0 ◎ ───────────────────────────

The Bunga kankoku extract shown in Table 2 is
It was obtained by heating and reducing the whole plant grass in ethanol, filtering, concentrating and drying.

As is clear from Table 2, the effect after exposure to sunlight is that the addition of the Bunga kankoku extract prevents the deposition of an excessive melanin pigment and prevents darkening. Admitted.

Test Method for Elastase Inhibitory Activity and Results 1. Preparation of sample 50 g of Bunga cangkok fruit
Was immersed in ethanol at room temperature for 1 week, and the extract was concentrated to obtain 4.8 g of an ethanol extract. This extract is D
The solution was dissolved in MSO at a concentration of 1%, the solution was diluted with a reaction buffer to adjust the concentration to 100 ppm, and the following experiment was conducted using this.

2. Test Method and Results The elastase activity was measured as follows according to the method of Fujie et al. In addition, as a reaction buffer, 0.1 MH
It was performed using EPES, 0.5 M NaCl (pH 7.4). Methoxy-succinyl-ala as an elastase substrate
nyl-alanyl-prolyl-valine-p-nitroanilide (BACH
EMFEINCHEMIKALIENAG), 80m
It was dissolved in DMSO to give M, dispensed in 20 μl aliquots, and stored frozen (−80 ° C.). At the time of use, it was diluted with a reaction buffer solution to 8 mM before use.

Elastase is an elastase derived from human leukocytes (ELASTINPRODUCTCO., INC.)
Was dissolved in a reaction buffer at a concentration of 200 μg / ml, dispensed in 10 μl aliquots, and stored frozen (-80 ° C.). At the time of use, it was diluted with the reaction buffer to 5 μg / ml before use. 96-well plate (CORNING
25860), and 2 mM of 8 mM elastase substrate, respectively.
Dispense 5 μl each and add 50 μl of inhibitor (concentration: 1
00 ppm) was added. Then, 25 μl of 5 μg / ml elastase was added on ice and immediately incubated at 37 ° C. for 20 minutes. Then, the absorbance was measured at 415 nm. However, the inhibition rate depends on the following function.

[0029]

## EQU1 ## Inhibition rate (%) = 100- (in the presence of inhibitor / without inhibitor) × 100

The results are shown in Table 3. Further, as a reference example, the same test as above was carried out on a soybean extract (trade name Elhibin; manufactured by Pentafarm Co.), which is already known to have elastase inhibitory activity. The results are also shown in Table 3.

[0031]

[Table 3] ──────────────────────────── Elastase inhibition rate (%) ───────────── ─────────────── Bunga kankoku extract 88.5 soybean extract 84.2 ───────────────────── ───────

Examples of the formulation of the external preparation for skin according to the present invention in various dosage forms will be described below as examples.

Example 1 Cream (Formulation) Stearic acid 5.0% by weight Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Bunga cancocum methanol extract 0.01 Caustic potassium 0.2 Sodium bisulfite 0.01 Preservative Suitable amount Perfume Suitable amount Ion-exchanged water Residual (manufacturing method) Dissolve propylene glycol, Bunga cancocum methanol extract and caustic potash in ion-exchanged water,
Heat and maintain 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 a reaction. After that, homogenize with a homomixer,
Cool to 30 ° C with good stirring.

Example 2 Cream (Formulation) Stearic acid 2.0% by weight 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 ester 2.0 Propylene glycol 5.0 Bunga cancocc ethanol extract 0.05 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Perfume suitable amount Ion-exchanged water Residue (production method) Propylene in ion-exchanged water Add glycol,
Heat and maintain 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 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 wt% 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 Bunga cancoke acetone extract 0.05 Bunga cancook ethanol extract 0.05 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Perfume proper amount Ion-exchanged water Residue (production method) Ion Soap powder and borax are added to exchanged water, and the mixture is heated and melted and kept 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 wt% Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 3. 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Brand name: Carbopol 941, BFGoodrich Chemical company) Bunga cancoccacetic acid ethyl ester extract 0.01 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Fragrance Ion Exchanged water Residue (production method) A carboxyvinyl polymer is dissolved in a small amount of ion exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and kept 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 water phase to perform preliminary emulsification, the phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

Example 5 Emulsion (formulation) Microcrystalline wax 1.0% by weight Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 moles) ) Sorbitan monooleate 1.0 Propylene glycol 7.0 Bunga cancoccacetone extract 10.0 Sodium hydrogen sulfite 0.01 Ethyl paraben 0.3 Fragrance Ion-exchanged water Residual (production method) Propylene glycol is added to ion-exchanged water In addition,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C with good stirring.

Example 6 Jelly (formulation) 95% ethyl alcohol 10.0% by weight 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 Bunga kankoku 50% ethanol aqueous solution extract 7.0 2-Hydroxy-4-methoxybenzophenone sodium sulfonate 0.05 Ethylenediaminetetraacetate-3 sodium-2 Water 0.05 Methylparaben 0.2 Perfume Suitable amount Ion-exchanged water Residue (production method) Carbopol 940 is uniformly dissolved in ion-exchanged water, while Bunga Kankoku 50 in 95% ethanol is used.
% Ethanol aqueous solution extract, polyoxyethylene (50
Mol) oleyl alcohol ether is dissolved and added to the aqueous phase. Next, after adding other components, 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 Weight Polyoxyethylene (20 mol) Octyldodecanol 1.0 Pantotenyl Ethyl Ether 0.1 Bunga Cancokumethanol Extract 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: Carbo Pole 940, BFGoodrich Chemical company) Purified water Residual (production method) Phases A and C are uniformly dissolved, and A is added to phase C
Add phase and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (formulation) (Phase A) 5.0% by weight dipropylene glycol Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) Bunga cancoccm methanol extract 0.01 Olive oil 5 0.0 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 Residue (Manufacturing method) Phase A, phase B, and phase C are uniformly dissolved,
Phase B is added to the phase to solubilize it. Next, this is added to the C phase and then filled.

Example 9 Solid Foundation (Formulation) Talc 43.1% by weight 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 octoate 2.0 Bunga kankoku ethanol extract 1.0 preservative appropriate amount perfume appropriate amount (manufacturing process) Talc to black iron oxide powder component is sufficient with a blender After mixing, an oily component of squalane to isocetyl octoate, an extract of Bunga cancocc ethanol, an antiseptic and a fragrance are added and kneaded well, and then filled into a container and molded.

Example 10 Emulsion Foundation (Cream Type) (Prescription) (Powder Part) Titanium Dioxide 10.3% by Weight 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 Bunga -Kangoku ethanol extract 1.5 Sorbitan sesquioleate 3.0 Preservative proper amount Perfume proper amount (Production method) After heating and stirring the aqueous phase, the powder portion thoroughly mixed and pulverized is added and treated with a homomixer. Further, the oil phase mixed by heating is added, and the mixture is treated with a homomixer. Then, a fragrance is added with stirring, and the mixture is cooled to room temperature.

[0043]

As described above, the external preparation for skin of the present invention has excellent tyrosinase inhibitory action and elastase inhibitory action, and it is possible to reduce pigmentation, stains, freckles, and liver spots after sunburn. In addition to having an excellent whitening effect, it also has the effect of preventing skin aging and maintaining a youthful skin condition by suppressing the activity of elastase and restoring and maintaining the firmness and elasticity of the skin. is there.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 35/78 ADA A61K 35/78 ADAC ADS ADSC AED AEDC // C12N 9/99 C12N 9/99 ( 72) Inventor Eiichiro Yagi, 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Within Shiseido Daiichi Research Center, Inc. (72) Inventor Masako Naganuma 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Stock company Shiseido Daiichi Research Center

Claims (5)

[Claims] 1. The department of Schace, the department of Theaceae.
A skin external preparation characterized by containing an extract of a genus plant. 2. The department of the family Theaceae, Schima.
The extract of the genus plant is Bunga cangkok,
Scientific name: Schima wallichii (DC) Korth), The external preparation for skin according to claim 1. 3. The external preparation for skin according to claim 1, which is a tyrosinase inhibitor. 4. The external preparation for skin according to claim 1, which is an anti-aging agent. 5. The external preparation for skin according to claim 4, which is an elastase inhibitor.