JPH041115A - Dermal drug for external use - Google Patents

Abstract

PURPOSE:To obtain a dermal drug for external use, containing a catechol glycoside, having remarkable inhibitory action on formation of melanin, effective in preventing and treating skin pigmentation and excellent in stability and safety. CONSTITUTION:A dermal drug for external use is obtained by blending a catechol glycoside expressed by the formula (R is pentose residue, hexose residue, amino sugar residue or uronic acid residue) in an amount of 0.1-10wt.% based on the whole. Furthermore, 0.01-5wt.% each of an ultraviolet ray protectant, a wound curing agent, a metabolic promoter, or an anti-inflammatory agent, or 0.1-20wt.% humectant is preferably used together or they are preferably combined and blended. In addition, various ingredients normally used in cosmetics, medicines, etc., are slitably blended and prepared into a formulation to afford the objective substance. The agent can be prepared in the form of an ointment, a cream, a milky lotion, a lotion, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a skin external preparation, and more specifically, it is effective for the prevention and treatment of skin pigmentation disorders, and its effects can be improved by using it in combination with various active ingredients. It is an object of the present invention to provide an external preparation for skin that can significantly increase the skin function and also has excellent stability and safety.

[Conventional technology] Pigmentation caused by age spots, freckles, and sunburn is caused by a significant increase in melanin production due to the activation of pigment cells (melanocytes) present in the skin, and is a common cause of skin concerns among middle-aged and elderly people. They are one.

For the purpose of preventing and improving these skin pigment problems, external preparations containing ascorbic acid, hydrogen peroxide, glutathione, colloidal sulfur, etc., and in Europe and America, hydroquinone, are known.

In addition, in response to various changes caused by sunburn, for example, there is interest in wound healing effects, skin beautification effects, anti-inflammatory effects, and improvement in texture.

[Problem to be solved by the invention] However, regarding the prevention and improvement of skin pigmentation, ascorbic acids are easily oxidized and unstable in systems containing a lot of water such as water-containing cosmetics, and can cause discoloration. . Furthermore, hydrogen peroxide has storage stability and safety issues, and glutathione yacolloid sulfur emits a significant off-odor, so its use in products is restricted.

Furthermore, hydroquinone and catechol have safety problems such as skin irritation and allergy, and cyclic compounds have not yet been found to be fully satisfactory.

The present invention was made in view of such circumstances, and
The object of the present invention is to provide an external skin preparation that not only exhibits an excellent effect on the prevention and improvement of skin pigmentation, but also is stable in the product and has no adverse effects on the skin and can be used safely.

Furthermore, we have developed external skin preparations that take advantage of the properties of materials that enhance wound healing, materials that improve acne and increase skin moisture, materials that enhance the effects of anti-inflammatory agents, and materials that reduce the sticky feeling of moisturizers. The challenge was to blend it into the product to achieve a remarkable effect.

[Means for Solving the Problems] As a result of extensive research to solve the above problems, the present inventors have discovered that catechol glycosides are stable and highly safe compounds that have a remarkable melanin-suppressing effect. Based on this finding, the present invention was completed.

That is, the present invention is an external skin preparation characterized by containing a catechol glycoside represented by the following general formula (I>), and in a preferred embodiment, the proportion of the catechol glycoside in the total amount is It is a skin external preparation characterized by a content of 0.1 to 10!%.

Furthermore, as a preferred embodiment, catechol glycosides are used in combination with 0.01 to 5% by weight of an ultraviolet protection agent, or 0.01 to 5% by weight of a wound healing agent, or metabolic Use in combination with 0.01 to 51% by weight of an accelerator, or 0.01 to 5% by weight of an anti-inflammatory agent, or 0.1 to 20% by weight of a moisturizer, Alternatively, it is a skin external preparation characterized by a combination of these.

The present invention will be described in detail below.

The sugar residue of the catechol glycoside applied to the present invention is L
- Residues of pentose sugars such as arabinose, L-xylose, D-lipose, and lyxose; hexoses such as D-glucose, D-galactose, cyclogalactose, D-mannose, D-talose, and D-fructose; residues of amino sugars such as D-glucosamine, D-galactosamine, and sialic acid, and residues of uronic acids such as D-glucuronic acid-galacturonic acid and D-mannuron M. In terms of ease of use, stability, and safety, D-glucose residues are particularly preferred.

Examples of catechol glycosides according to the present invention include 0-hydroxyphenyl-β-D-glucoside and ○-hydroxyphenyl-D-glucosaminide, but the present invention is not limited thereto.

The blending ratio of catechol glycosides used in the present invention is preferably 0.1 to 10% by weight of the total.

In other words, when used in external skin preparations such as cosmetics intended to prevent spots, freckles, and dark skin due to sunburn, the amount of ir is 0.11% or more, and when used externally as a drug for the treatment of pigmentation disorders. When used in preparations, an effective amount of 1% by weight or more can be used. Usage amount is 0.
If it is less than 1%, the object of the present invention cannot be achieved, and if it significantly exceeds 10%, it may be undesirable from the viewpoint of safety for the skin.

Next, various experiments were conducted to evaluate the usefulness of catechol glycosides applied to the present invention.

First, the melanin production inhibiting effect of ○-hydroxyphenyl-β-D-glucoside, which is an example of a catechol glycoside, was tested. .

Experimental Example 1 Melanin production suppression test (method) 105 B cells in a plastic culture flask (25 cm)
-16 melanoma cells and containing 10% serum
The cells were cultured in a PH11640 medium under 5% carbon dioxide and 37°C. 0-hydroxyphenyl-β-D- after 58
Glucosides at concentrations in the medium: o, i, i, o.

2. The cells were added to omH and cultured for 4 days.

After culturing, the medium was removed, and after washing with phosphate buffer, the cells were collected in a glass centrifuge tube using rubber police and centrifuged at 1000 rpm. After washing the cells twice with phosphate buffer, 1N sodium hydroxide was added to the precipitate and dissolved by heating.

After cooling, chloroform was added and centrifuged again. The supernatant obtained by this was measured by absorbance at 400 nm,
The amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. In addition, the melanin amount was determined as a value per 106 cells.

(Left below) (Results) Table 1: Suppression rate of melanin production 0.1 + nHL87 ± 0.16
After storage for 22.73 months, the degree of coloration was evaluated with the naked eye.

(Evaluation) ◎: Hardly colored ○: Slightly colored △: @Color (Results) As is clear from the results in Table 1, ○-hydroxyphenyl-β-D-glucoside is effective against melanoma cells. It shows a remarkable melanin suppressing effect on the skin.

Next, the stability of catechol glycosides and external skin preparations containing them will be tested.

Experimental Example 2 Stability Test (Method) A 0.1% by weight 0-hydroxyphenyl-β-D-glucoside solution and a pyrocatechol solution as a control were prepared in a 0.1N aqueous sodium hydroxide solution. As is clear from the results in Table 2 at 37°C, ○-hydroxyphenyl-β-D-glucoside alone is stable together with the cream of Example 1 described below.

Furthermore, it can be seen that the skin external preparation of the present invention (the cream of Example 1) is also stable.

Next, we will test the safety of catechol glycosides and external skin preparations containing them.

Experimental Example 3 Safety Test (1) Cumulative Skin Irritation (Method) Hair was removed from the backs of white guinea pigs (5 animals in each group) using electric clippers, and the hair was washed with a disinfectant solution.

1% of Q-hydroxyphenyl-β-D-glucoside,
For 4 samples of 5% and 10% ethanol-water (1:1) solution and the cream of Example 1 described below, 5 o each once a day! ! rg/cli was applied, and the degree of irritation was visually measured every day.

(Results) As is clear from the results in Table 3, 0-hydroxyphenyl-β-D-glucoside did not cause skin irritation at any concentration, and the external skin preparation of the present invention (cream of Example 1) The results show that it is safe and does not cause any skin irritation.

(11) Contact sensitization (method) Using healthy guinea pigs weighing 380 to 420 g, the method of Sahara et al.
, 7, 225 (1981)).

(Samples) The test was performed on 0-hydroxyphenyl-β-D-glycoside, pyrocatechol as a control product, and three samples of Example 1 of the present invention described later.

(Judgment criteria) (Results) As is clear from the results in Table 4, the strength of contact sensitization is that pyrocatechol >> 0-hydroxyphenyl-β-D
- Cream of glucoside valve Example 1.

No sensitization was observed in ○-hydroxyphenyl-β-D-glucoside and the product of the present invention.

(The following is a blank space) Next, the ultraviolet protective agents applied to the present invention include ascorbic acid or its derivatives, isoferulic acid or its salts, glutathione or its derivatives, oxybenzone or its derivatives, p-aminobenzoic acid or its derivatives, It must be one or more selected from urocanic acid or its derivatives, cinnamic acid or its derivatives, kojic acid, titanium oxide, etc., and its blending ratio is from o, oi to 5% by weight of the total.

By using catechol glycosides and the present UV protection agent in combination, due to their synergistic effect, a remarkable healing promoting effect is observed for patients with hyperpigmentation.

The wound healing agent applied to the present invention is one or more selected from Toki extract, allantoin or its derivatives, rosemary extract, etc., and the blending ratio thereof is 0.01 to 5% by weight of the total. It is.

By using catechol glycosides and the present wound healing agent in combination, the healing of the wound surface can be significantly enhanced due to their synergistic effect.

The metabolism promoter applied to the present invention is placenta extract (
One or more types selected from water-soluble placenta extract, ), γ-oryzanol, various amino acids, vitamin E or its derivatives, etc., and the proportion of the total is o, oi ~
It is 5% by weight.

When catechol glycosides and the present metabolism promoter are used in combination, their synergistic effects can improve acne and make skin beautiful by moisturizing the skin.

The anti-inflammatory agent applied to the present invention is one or more selected from glycyrrhetinic acid or its derivatives, glycyrrhizic acid or its derivatives, bisabolol, geraniin, horse chestnut extract, aloe extract, etc., and the blending ratio thereof is 0.01 to 5% by weight of the total.

By using catechol glycosides and the present anti-inflammatory agent in combination, the anti-inflammatory effect can be increased due to their synergistic effect.

The moisturizing agent applied to the present invention includes hyaluronic acid or its salt, glycosphingolipid, collagen, elastin, mucin, sour cream, royal jelly sodium caseinate,
It is one or more selected from lecithin, chitin and chitosan, derivatives thereof, etc., and the blending ratio thereof is 0.1 to 20% by weight of the total.

By using catechol glycosides and this moisturizer together,
It is possible to improve the strong sticky feel inherent in moisturizers.

In addition, the skin external preparation of the present invention includes various ingredients commonly used in cosmetics, pharmaceuticals, etc., such as aqueous ingredients, oily ingredients, surfactants, powder ingredients, thickeners, colorants, preservatives, and antioxidants. , fragrances, thymus extract, hormones, nucleic acids, various vitamins, pantethine, and other medicinal ingredients can be blended.

Of course, these must be used within a quantitative and qualitative range that does not impair the effects of the present invention.

Furthermore, the dosage form of the skin external preparation of the present invention is arbitrary and may be any of those conventionally used for this type of skin external preparation, such as ointments, creams, milky lotions, and lotions. It will be done.

[Examples] The present invention will be explained below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

In addition, the blending amount is the heaviest part.

Examples 1-6 Cream (How to treat) As shown in Table-5.

(Production method) Uniformly dissolve A and B at 70'C while stirring each.

Gradually add B to A while stirring.

Furthermore, after uniformly emulsifying with a homo mixer,
After maintaining the temperature at 30°C, cool it to 30°C and pack it into a container to make the product.

(Margin below) First, let's talk about the pigmentation improving effect.

(Sample) The cream of Example 1 containing the ○-hydroxyphenyl-β-D-glucoside of the present invention, the cream of Example 2 containing the UV protectant in combination, and 0-hydroxyphenyl-β-D-glucoside These are four samples of the cream of Comparative Example 1, which does not contain UV protection agent, and the cream of Comparative Example 2, which contains only UV protection agent.

(Method) Forty female volunteers suffering from dark skin, age spots, and freckles were divided into four groups with statistically equal levels of pigmentation.
Each subject used the above cream for a long period of time for 3 months.

Three months later, five beauty experts evaluated the degree of improvement in dark skin, age spots, and freckles.

(Results) Table 6 Pigmentation Improving Effect As is clear from the results in Table 6, the pigmentation improving effect was Example 2>Example 1>Comparative Example 2>Comparative Example 1. It can be seen that the ○-hydroxyphenyl-β-D-glucoside of the present invention has an effect of improving pigmentation, and the effect is further enhanced when used in combination with an ultraviolet protection agent.

Furthermore, no side effects were observed in any of the creams during the test period, confirming that the products of the present invention are safe for the skin.

Next, the wound healing effect will be described.

(Samples) The cream of Example 1 containing O-hydroxyphenyl-B-D-glucoside of the present invention, the cream of Example 3 containing this in combination with a wound healing agent, and O-hydroxyphenyl-β These are three samples of the cream of Comparative Example 3 in which a wound healing agent was blended without -D-glucoside.

(Method) Forty 5-week-old SD rats were preliminarily bred for 7 days after purchase and divided into 4 groups of 10 rats each. Hair is removed from the back of the rat using electric clippers and cleaned with disinfectant solution. Then, using a circular chisel (φ111M), four skin defects are created symmetrically along the midline. The first group was treated as an untreated group, the second group was treated with the cream of Example 1 once a day after the observation, and similarly, the cream of Example 3 was applied to the third group, and the comparative example was applied to the fourth group. Apply cream from step 3. Application was 0.1 g per damaged area once a day.

Observations were made once a day, including measurement of the wound area and visual observation. The healing rate is calculated using the following formula.

(Area of the wound on day 0) Wound area on day 11 Healing rate (%) = Wound area on day 0 (results) As is clear from the results in Table 7, the wound healing rate was Example 3〉Example 1〉Comparative Example 3〉No treatment. It can be seen that the 0-hydroxyphenyl-βD-glucoside of the present invention has a wound therapeutic effect, and the effect is further improved when used in combination with a wound healing agent.

Next, we will discuss the skin beautifying effect.

(Samples) The cream of Example 1 containing O-hydroxyphenyl-β-D-glucoside of the present invention, the cream of Example 4 containing this in combination with a metabolism promoter, and O-hydroxyphenyl-β-D - Three samples of the cream of Comparative Example 4, which did not contain glucoside but contained a metabolism promoter.

(Method) Thirty female volunteers with acne on their faces were
Divided into 3 groups with statistically equivalent levels of acne;
The above cream was used for a long period of time for several months.

Three months later, five beauty experts evaluated the improvement in acne and skin moisture.

(Evaluation criteria) Skin beautification effect evaluation score (Results) As is clear from the results in Table 8, the degree of improvement in acne was
Example 4〉Comparative Example 4 to Example 1, and the bile moisture level was Example 4〉Example 1〉Comparative Example 1. By using the ○-hydroxyphenyl-β-D-glucoside of the present invention in combination with a metabolism promoter, a remarkable skin beautifying effect is observed.

Next, we will discuss the anti-inflammatory effect.

(Samples) The cream of Example 1 containing O-hydroxyphenyl-β-D-glucoside of the present invention, the cream of Example 5 containing this in combination with an anti-inflammatory agent, and the O-hydroxyphenyl-β-D - Three samples of the cream of Comparative Example 5, which contains no glucoside but contains an anti-inflammatory agent.

(Method) Thirty male volunteers in their 20s to 30s were divided into three groups and exposed to sunlight for half a day at a summer beach. Each group used each cream of Example 1.5 and Comparative Example 5 continuously for 5 days, and the anti-inflammatory effects were compared based on the feeling of satisfaction due to the reduction in the feeling of hot flashes caused by sunburn.

(Results) As is clear from the results in Table 9, the degree of reduction in the feeling of hot flashes due to sunburn was that of Example 5>Comparative Example 5 and Example 1. A remarkable anti-inflammatory effect was observed when the 0-hydroxyphenyl-β-D-glucoside of the present invention was used in combination with an anti-inflammatory agent.

Next, the effect of improving the feeling of use will be described.

(Samples) The cream of Example 1 containing uninvented 0-hydroxyphenyl-β-D-glucoside, the cream of Example 6 containing this in combination with a moisturizer, and 0-hydroxyphenyl-β-D - Three samples of the cream of Comparative Example 6 in which a humectant was blended without glucoside.

(Method) Ten female beauty experts conducted actual use tests for the usability (stickiness) of the creams of Examples 1 and 6 and the cream of Comparative Example 6.

(Evaluation Criteria) (Results) As is clear from the results in Table 10, the usability (stickiness) was that of Example 1, Example 6, and Comparative Example 6.

By using the 0-hydroxyphenyl-β-D-glucoside of the present invention in combination with a humectant, the sticky feeling inherent in the humectant could be significantly improved.

Example 7 Lotion (prescription) Ethanol 10.0 Polyoxyethylene (50) Hydrogenated castor oil 1.0 Methyl paraoxybenzoate 0.1 Fragrance
0.
1 Chitosan 1.0 Disodium edetate 0.10-Hydroxyphenyl-D-7,0 Glucosaminidopropylene glycol 5.0 Purified water 75.7 (Production method) Stir at 7 temperature to uniformly solubilize Then, pack it into a container and use it as a product.

(Leaving space below) Example 8 Packing material Example 9 Ointment for ice making 40.0 (Formulation) Ethylene rubitan (20E, O,) Beeswax 1 Titanium chloride 3.0 5.0 Relicerin 10.0 (Manufacturing method ) Disperse and dissolve A at room temperature. Add B to this and dissolve well. Pack it into a container and use it as a product.

(Production method) Heat and stir each of A and B to uniformly dissolve them.

Gradually add 8 to A while stirring. Cool to 30°C and pack into a container to make the product.

[Effects of the Invention] According to the present invention, a skin external preparation containing a catechol glycoside has a remarkable melanin-suppressing effect, has excellent stability, and has low cumulative skin irritation and contact sensitization. It is highly effective in preventing and improving skin pigmentation.

Moreover, the combined use of catechol glycosides and UV protection agents has a significant healing-promoting effect on patients with hyperpigmentation.

Further, by using a catechol glycoside and a wound healing agent together, their synergistic effect significantly enhances the healing of #I wound surface.

In addition, by using catechol glycosides and metabolism promoters in combination, their synergistic effect improves acne and moisturizes the skin, resulting in beautifying effects.

Furthermore, by using catechol glycosides and anti-inflammatory agents together, the synergistic effect increases the anti-inflammatory effect.

Furthermore, by using catechol glycosides and a humectant in combination, the usability (sticky feeling) inherent in humectants is significantly improved.

Claims (1)

[Scope of Claims] 1) An external skin preparation characterized by containing a catechol glycoside represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R represents pentose residues, hexose residues, amino sugar residues, uronic acid residues, etc. 2) The blending ratio of catechol glycosides is 0.1 to 1
The skin external preparation according to claim (1), which contains 0% by weight. 3) The skin preparation for external use according to claim 1, which contains 0.01 to 5% by weight of a UV protection agent. 4) The skin external preparation according to claim 1, which contains 0.01 to 5% by weight of a wound healing agent. 5) The external preparation for skin according to claim 1, which contains 0.01 to 5% by weight of a metabolism promoter. 6) The external preparation for skin according to claim 1, which contains 0.01 to 5% by weight of an anti-inflammatory agent. 7) The external preparation for skin according to claim 1, which contains 0.1 to 20% by weight of a humectant.