JPH04169514A - Skin medicine for external use - Google Patents

Abstract

PURPOSE:To obtain a skin medicine for external use, containing a protease inhibitor and a ketose, capable of preventing and improving skin roughening, further excellent in beautifying and whitening effects and having high safety. CONSTITUTION:The objective substance is obtained by including 0.0001-10wt.% protease inhibitor (e.g. tranexamic acid) and 0.01-10wt.% ketose (e.g. fructose) as essential ingredients, further suitably blending the aforementioned essential ingredients with various ingredients, aqueous ingredients, humectants, thickeners, ultraviolet light absorbers, preservatives, antioxidants, perfumes, colorants, medicines, etc., normally used in cosmetics, quasi-drugs, medicines, etc., and preparing a skin medicine for external use according to a conventional method. The aforementioned skin medicine can be prepared into the form of a solubilized system such as toilet water, an emulsified system such as milky lotion or cream, an ointment, a powder dispersion system, a two-layer water-oil system, a three-layer water-oil-powder system, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a skin preparation for external use, and more specifically, to a skin preparation for external use that prevents and improves rough skin, has an excellent whitening effect on the skin, and is highly safe.

[Prior Art 1 Various medicinal ingredients are blended into external preparations for the skin. Among these, the effects of preventing rough skin, improving skin roughness, and whitening effects are also among the medicinal effects, and there has been a demand for external skin preparations such as cosmetics for these purposes.

Under these circumstances, various raw materials extracted from natural products, such as proteins, polysaccharides, extracted extracts, natural polymers, etc., have traditionally been incorporated into external skin preparations because of their distinctive effects.

[Problems to be Solved by the Invention] However, the effects are not sufficient, and there has been a long-awaited development of medicinal agents with better effects.

The present invention has been made in view of the problems of the prior art, and its purpose is to provide a skin preparation for external use that is more effective in preventing and improving skin roughness, and also has a whitening effect.

In order to achieve the above object, the present inventors have conducted extensive research to obtain a substance that is particularly effective in preventing and improving skin roughness, and also has a whitening effect, from among substances with excellent safety. As a result, the combination of one or more protease inhibitors and one or more ketoses is extremely effective against proliferative acanthosis, dryness accompanied by erythema, and flaking changes. It has been found that it also effectively prevents and improves pigmentation.

The present inventors have completed the present invention based on the above findings.

[Means for Solving the Problems] That is, the present invention is an external skin preparation characterized by containing one or more selected from protease inhibitors and one or more selected from ketoses. .

The configuration of the present invention will be explained below.

Protease or proteolytic enzyme is a general name for enzymes that catalyze the hydrolysis of peptide bonds. This protease is classified into peptidases and proteases. The former is an enzyme that cleaves peptide bonds from the outside of the amino or carboxyl terminal of a protein or peptide chain, while the latter proteinase is an enzyme that cleaves specific bonds within the peptide chain. In addition, this proteinase is often called by the broad name "protease", and depending on the nature of its active site, it can be divided into 1) serine system, 2) thiol (cysteine) system, 3) carboxyl system, and 4) protease system. ) There are four types of metalloproteinases, each of which has a specific inhibitor.

The protease inhibitor in the present invention means any chemical substance that can reversibly or irreversibly inhibit the hydrolysis action of the protease or proteolytic enzyme.

The main substances are listed below.

(1) Compounds derived from animals or plants, preferably bovine pancreatic basic trypsin inhibitor, aprotinin, soybean trypsin inhibitor, lima bean protease inhibitor, corn protease inhibitor, etc.

(2) Compounds derived from microorganisms Preferably, there are antipain, plasminostrebutin, and compounds collectively called leupeptin represented by the following general formula.

RI-R2-R3-NH-CH-(CH2) 3-NH
-CH-NR21■ CHO"NR2 R1=CH3CO, CH3CH2C0 R2"L-Leu, L-11e, L-ValR3=L-
Leu+ L-11e, L-Val (Leu: leucine Ile: inleucine Val: valine) (
3) Benzamidine and its derivatives preferably benzamidine, p-aminobenzamidine, m
-aminobenzamidine, phenylguanosine, (2R,
4R)-4-methyl-1-[N2-(3-methyl-1,
2,3,4-tetrahydro-8-quinolinesulfonyl)
-L-arginyl-2-piperidine carboxylic acid monohydrate, dandylarginine N-(
Examples include 3-ethyl-1,5-bentanedyl)amide.

(4) Acetamide and derivatives thereof Preferable examples include acetamide, 2-phenylacetamide, and cyclohexylkaioxamide.

(5) Guanidine and its derivatives Preferred examples include phenylguanidine and cyclohexylguanidine.

(6) ω-Amino acids preferably tranexamic acid, p-amitumedelbenzoic acid, 4-aminomethylbicyclo(2,2°2,)octane-1-carboxylic acid, 5-[trans-4(aminomethyl)cyclo xylcotetrazole, 3-[trans-4
(aminomethyl)cyclohexyl-2-oxopropionate, trans-4-(aminomethyl)cyclohexyl glyoxal monohydrate, trans-4-(
(aminomethyl) cyclohexane hydroxamic acid or a substance having a carbon chain in which n=1 to 8 in the general formula below.

N R2(CR2)nC00H Among these ω-amino acids, tranexamic acid and p-
Particularly excellent effects are observed with aminomethylbenzoic acid.

(7) Fluorophosphoric acid and derivatives thereof, preferably diisopropylfluorophosphoric acid.

(8) Fluorosulfonic acid and its derivatives Preferred examples include phenylmethanesulfonyl fluoride, [(p-amidinobenyl)methanesulfonyl fluoride, and the like.

(9) Guanidinobenzoic acid and its derivatives preferably p-nitrophenyl-po-guanidinobenzoic acid, 3°
, 6゛-bis(4-guanidinobenzoyloxy)-5-
(N'-4-carboxyphenyl)thiouridospiro[isobenzofuran-1(3H), 9°-(9H)xanzene]-3-one and the like.

(10) Lysine and its derivatives Preferably there are compounds represented by the following general formula.

R1-NH-(CH2)4-CH-CO-R2N R1; H, Phe-Ala, Ala-PheR2”OH
, CH2Cl R3=H, 5O2--CH5 (Phe: phenylalanine Ala: alanine) Among these lysine and its derivatives, R2=C82C1 is particularly preferred, although the present invention is not limited thereto.

(11) Arginine and its derivatives Preferably there are compounds represented by the following general formula.

R+=H, D-Phe-Pro, Glu-Gly,
l1e-Glu-Gly.

Pro-Phe, Aha-Phe R2=OH, CH2Cl R3"H, 5O2--CH5 (Phe: Phenylalanine Pronibroline
Glu: glutamate Gly nigericine Ile: isoleucine Ala: alanine) Among the above arginine and its derivatives, R2=CH2C1 is particularly preferred.

Ketoses used in the present invention include erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and the like.

In the present invention, by using one or more of the above-mentioned protease inhibitors in combination with one or more ketoses, the effects of preventing, improving, and whitening skin can be further improved.

In the present invention, the amount of the protease inhibitor added to the skin external preparation is preferably 0.0001 to 10% by weight, more preferably 0.001 to 5% by weight based on the total amount of the composition. 0゜0
If it is less than 0.001% by weight, the effect of the present invention is not sufficient;
If it exceeds 0% by weight, it is not preferred in terms of formulation and is also disadvantageous in terms of cost. The amount of ketose used in combination is preferably 0.01 to 10% by weight based on the total amount of the skin external preparation.

In addition to the above-mentioned essential ingredients, the external skin preparation of the present invention may optionally include various ingredients commonly used in cosmetics, quasi-drugs, pharmaceuticals, etc., and aqueous ingredients, within the range that does not impair the effects of the present invention. Moisturizers, thickeners, ultraviolet absorbers, preservatives, antioxidants, fragrances, coloring agents, drugs, herbal medicines, etc. can be added.

Moreover, the dosage form of the skin external preparation of the present invention is arbitrary, and for example, a solubilized system such as a lotion, an emulsified system such as a milky lotion, a cream, an ointment, a powder dispersion system, a water-oil bilayer system, a water-oil system, etc. Any dosage form may be used, such as a one-powder, three-layer system.

[Example] Next, the present invention will be explained in detail with reference to Examples. Note that the present invention is not limited to this.

Prior to Examples, the test methods and evaluation methods used in the present invention will be explained.

Practical use test The effect of applying the external skin preparation according to the present invention to the skin was evaluated from the improvement rate for rough skin, razor burn, and pigmentation.

1) Tests were conducted on 60 subjects each who suffered from rough skin or hot flashes after sunburn.The lotion with the composition shown in Table 1 was applied to the face, and the skin condition was visually observed after 2 weeks. It was judged. Immediately after shaving, a lotion having the composition shown in Table 1 was applied to 60 male test subjects who shaved their heads, and its effect on shaving was evaluated. The criteria for each evaluation were as follows.

Effect: Symptoms have disappeared Effective: Symptoms have weakened Slightly effective: Symptoms have weakened slightly Ineffective: No change in symptoms has been observed Use razors Stem Effect: Razor curls have disappeared Effective: Razor curls have greatly improved Slightly effective: Razor curls have improved slightly Invalid: No change in razor curls (judgment) 0: Subjects have markedly improved, effective, and slightly effective 80% or more (effective rate): O: The proportion (effective rate) of subjects showing excellent, effective, and somewhat effective is 50% or more and less than 80% △: Subjects show excellent, effective, and somewhat effective The ratio (effective rate) is 30% or more
Less than 50% x: The percentage of subjects who found excellent efficacy, effective efficacy, and moderate efficacy (effectiveness rate) was less than 30% (blank below) As is clear from Table 2, the lotion of the present invention containing tranexamic acid and fructose It showed better improvement effects on rough skin and razor bumps than blank lotion.

Differences in skin roughness: Using the lotions obtained in Examples 1 to 3 and Comparative Example 1, a rough skin improvement effect test was conducted on a human body panel.

That is, a skin replica of the skin surface morphology of a healthy female person (face) is taken using the replica method using Millisne resin and observed under a microscope (17x magnification). Rough skin evaluation 1, 2 based on the criteria shown in Table 3 based on the condition of the skin pattern and the peeling condition of the stratum corneum.
The lotions obtained in Examples 1 to 3 and Comparative Example 1 were applied to the left and right half of the face of 20 people who were judged to be rough skin (skin panel).
was applied once a day for 2 weeks. Two weeks later, the skin condition was observed again using the replica method described above and evaluated according to the criteria in Table 3.

(The following is a blank space) As can be seen from Table 4, the lotion of the present invention was found to have a remarkable effect on improving rough skin compared to the blank lotion.

Anti-pigmentation pharmacological effect test>1' and -1 8M0P treatment phototoxic pigmentation Weiser Maple
Using GP, 50 μL of the test sample was applied once a day to an area of approximately 4 cm2 on the shaved back for 8 weeks.
The anti-pigmentation effect and the degree of pigment enhancement that occurred as a side effect were expressed using the 4-point evaluation method shown in Table 5 (10 is a depigmenting effect, - is a side effect).

The samples used were an ascorbic acid aqueous solution and a mixed aqueous solution of tranexamic acid and fructose.

(Left below) ゛ As is clear from Table 6, long-term use of ascorbic acid causes pigmentation as a side effect;
A mixed aqueous solution of tranexamic acid and fructose had an excellent decolorizing effect and did not cause any side effects due to long-term use.

Practical use test> A panel of 100 subjects with pigmentation on the face was used, 25 subjects each received Examples 1 to 3, and the remaining 25 subjects received Comparative Example 1 two to three times a day. After 3 months of continuous use, a doctor visually evaluated the lightening effect.

(Left below) *The effectiveness rate in the table is the percentage of all cases with "slight improvement" or better.

As is clear from the results in Table 7, the anti-pigmentation agent containing tranexamic acid and fructose is effective against ovarian spots, melasma,
It was suggested that it has a remarkable effect on various pigmentation diseases such as senile pigment spots.

Example 4 Lotion Weight% (1) Tranexamic acid 0.001 (2) Glycerin 1.0 (3) Fructose
4,0(4) ethanol
7.0(5) Polyoxyethylene
0.5 (20 mol) Oleyl Alcohol Ether (6) Methylparaben 0.05 (7)
Citric acid 0.01(8) Sodium citrate 0.1(9) Flavoring
0.01 (10) Purified water
Residue (manufacturing method) Dissolve (1), (2), (3), (7), and (8) in purified water. Separately in ethanol (5) , (6) , (9)
This was added to the purified aqueous solution, dissolved, and filtered to obtain a lotion.

Example 5 Cream Weight % (1) Cetostearyl alcohol 3.5 (2) Squalane 30.0 (3) Beeswax
3.0(4) Reduced lanolin
5.0(5) Ethylparaben
0.3(6) Polyoxyethylene 2
．． 0 (20 moles) Oleyl alcohol ether (7) Stearic acid monoglyceride 2.0 (8) Tosyl lysine chloromethyl ketone 0.1 (9) Fragrance
0.03 (10) Eltrulose 5.0 (11) Glycerin
15.0 (12) Purified water
Remaining (1), (2), (3), (4), (5), (6
), (7), (8) and (9) were heated and melted and kept at 75°C.
Add to 2) while stirring. The mixture was cooled while stirring and emulsifying with a homomixer to obtain cream.

Example 6 Pack Weight % (1) Tranexamic acid 5.0 (2) Polyvinyl alcohol 10.0 (3) Sorbose
3.0(4) Propylene glycol
7.0(5) Ethanol
10.0(6) Methylparaben 0
．． 05(7) Erythritol 5.0
(8) Fragrance 0.05 (9
) Purified water (3) to the remainder (9)
, (4), (6), and (7) and stir to dissolve.

Next, (2) was added and heated and stirred to dissolve (8) and (5).
and (1) were added and dissolved with stirring to obtain a bag.

Example 7 Solid white powder Weight % (1) Talc 85.4 (2) Stearic acid 1.5 (3) Lanolin
5.0(4) Squalane
5.0 (5) Sorbitan Sesqui
2.0 Oleic acid ester (6) Triethanolamine 1.0 (7)
Fructose 5.0 (8) Tosyl arginine Chloromethyl ketone 0.1 (9) Pigment
Appropriate amount (10) fragrance
Thoroughly mix appropriate amounts of talc and pigment in a kneader. (Powder part) Add triethanolamine to 50% equivalent amount of purified water and keep at 70°C. (Aqueous phase) Other ingredients except fragrance are mixed, heated and dissolved, and kept at 70°C. (oil phase)
The oil phase is added to the water phase and uniformly emulsified using a homomixer, and this is added to the powder portion and kneaded using a kneader, after which water is evaporated and the mixture is processed using a pulverizer. While stirring the mixture well, spray the fragrance evenly and compression mold.

Example 8 Lipstick Weight % (1) Microcrystalline wax 1.0 (2) Beeswax
2.0(3) Lanolin
2.0(4) Liquid paraffin
20.0(5) Squalane
10.0 (6) Sorbitan Sesqui 4.
0 Oleic acid ester (7) Polyoxyethylene 4.0 (20
Mol) Sorbitan monooleate (8) Fructose 1.0 (9)
Leupeptin 0.001 (10)
Tranexamic acid 1.0 (11) Preservative/antioxidant Appropriate amount (12) Flavoring
Appropriate amount (13) Ion exchange water
An emulsion composition is prepared by a conventional method.

Example 9 Lotion Weight% (1) 95
% Ethanol 25.0 (2) Polyoxyethylene 4.0 (40 mol) Hydrogenated castor oil (3) Preservatives/antioxidants Appropriate amount (4) Flavoring Appropriate amount (5) Dipropylene glycol 12.0 (6) Glycerin
5.0 (7) Arabitol
7.0(8) Leupeptin
0.1 (9) Fructose 2.
0 (10) Ion-exchanged water Solubilizes the remaining aqueous phase and alcohol phase as a regulator.

Examples 4 to 9 were highly safe, having excellent effects on preventing and improving skin roughness, and also having an excellent whitening effect on the skin.

Patent applicant: Shiseido Co., Ltd.

Claims (1)

[Claims] (1) A skin external preparation characterized by containing one or more protease inhibitors and one or more ketoses.