JPS5838209A - Tannin-containing composition for skin for external application - Google Patents

Abstract

PURPOSE:The titled composition that contains a tannin having a specific group such as hexahydroxydiphenoyl as an active ingredient, thus developing good effect of preventing and treating dermatitis by the strong antiplasmic action of the tannin. CONSTITUTION:A tannin containing groups selected from hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl, preferably ellagitannin or elm tannin, is added as an active ingredient, preferably by 0.05-5wt% based on the total amount of the composition, to give the objective composition for external application for preventing skin inflammation caused by stimulation such as ultraviolet rays, curing or restoring inflamed skins such as rough skin, sun burn, heat burn, or eczema with no problems on irritation of skins and discomfort on application.

Description

[Detailed description of the invention]

The present invention provides a tannin-containing skin external preparation composition, more specifically, it prevents skin inflammation caused by stimulation such as ultraviolet rays,
This invention relates to an external skin preparation composition containing tannins that normalizes and treats irritated skin such as rough skin, sunburn, burns, and eczema. Various kinds of skin external preparation compositions have been known for a long time, such as ultraviolet absorbers such as 1-day burn nihahara aminobenzoic acid-anthranilic acid, salicylic acid, talc, zinc white, etc. A compound containing a light scattering agent is used. However – they are skin irritating, stable and persistent. There are problems with skin sensitization. Another day burnt. For inflammation such as burns and eczema, use astringent vitamins such as calamine, vitamins such as vitamin C, disinfectants such as sulfadiazine, antihistamines such as diphenhydramine, antibiotics such as bacitracin, corticosteroids such as fluoronolone acetonide, Compositions containing appropriate anti-inflammatory agents such as azulene are used to condition the skin and treat inflammation. It is not always satisfactory in terms of safety and effectiveness in application. In general, skin inflammation is well known to be related to plasmin, a proteolytic enzyme that leaps into the fibrinolytic system in the body, and is associated with skin diseases such as acne, sunburn, burns, eczema, contact dermatitis, and lupus erythematosus. Increased plasmin activity is believed to be one of the causes. In order to obtain a skin external preparation composition that eliminates the above-mentioned problems and disadvantages and has preventive and therapeutic effects on skin inflammation, the present inventors have conducted research from the viewpoint of suppressing plasmin activity, and have discovered certain We have discovered that certain tannins obtained from crude drugs and other plants have extremely excellent antiplasmin activity and are medicinal agents suitable for inclusion in external skin preparation compositions. Tannins are divided into hydrolyzable tannins and condensed tannins, and those with a galloyl group or its derivatives bound to sugar or cyclic polyhydric alcohol, and condensates of flavan-3-ols such as catechin and shrimp catechin have a structure. It is distinguished from what is the basis of. The former can be further divided into gallotannins, which have only galloyl groups bonded to them, and tannins, which have -hexahydroxydiphenoyl, dehydrohexahydroxydiphenoyl, etc., or their analogues bonded to them. It is generally believed that tannins have a protein-adsorbing effect, thereby exerting a hemostatic effect, but it is necessary to clearly classify tannins and elucidate the functions and effects of specific tannins. I can't find many examples of this. The present inventors have focused on the fact that there are herbal medicines that exhibit proteolytic enzyme inhibitory effects, such as those found in plants that have a high tannin content, and have investigated the relationship between the type and content of these tannins and their anti-plasmin activity. As a result, herbal medicines and plants with high tannin content tend to exhibit strong anti-plasmin activity, but the tannin content and the strength of anti-plasmin activity do not necessarily match, and various tannin cavities and hexahydroquine diphenoyl groups It has a dehydrohexahydroxydiphenoyl group. Terchebin, cheblinic acid obtained from interest. Chebulagic acid -
What can you get from 7 turtle wrinkles? Ross S/7 acid (mall
otusinic acid) punicalagin, which is also found in otusinic acid and pomegranate;
iin), ellagitannins such as geraniin obtained from gennoshoko and geraniin, and geraniin tannins obtained from elms show particularly strong antiplasmin activity compared to their protein adsorption activity (tannin quantitative value). As a result, it has been found to have excellent preventive and therapeutic effects on skin inflammation. The present invention was completed based on such knowledge, and
Provided is a composition for external use on the skin, which contains as an active ingredient one or more tannins containing a group selected from the group consisting of hexahydroquine diphenoyl group and dehydrohexahydroxydiphenoyl group. The skin external preparation composition of the present invention exhibits excellent skin conditioning and anti-inflammatory effects due to the action of the blended tannins, and has no problems in terms of skin irritation or feeling of use, and is effective against sunburn,
Prevents rough skin, sunburn, rough skin, and burns. It is extremely useful in normalizing and treating inflamed skin such as eczema. Next, we will show the results of comparing the anti-plasmin activities of tannins derived from various herbal medicines. The anti-plasmin activity of each tannin was determined by measuring the ratio of the anti-plasmin activity to the hemoglobin adsorption strength (quantitative value of tannin) of each tannin as follows, and comparing it with one pharmacopoeial tannic acid as 1. In addition, the anti-plasmin activity of raw crude drug crude extracts was also compared in the same manner. (1) Preparation of samples (1) Raw materials, crude drugs, plants: terkevin, chebric acid. Dry leaves of Akamega sinensis were used for kepradiic acid, malotsic acid, and punicalagin, dried leaves of Acanthus japonica were used for alnusiin, and dry leaves of Gennoshoko and Casuarina were used for geraniin. In addition, Jiyu was used for Jiyu tannin, Nakhu Karasu was used for Hekukarasu tannin, and Seinae and Shinshu Ohga were used for Dainae tannin. Additionally, Peony bark, Xun medicine, and Ephedra were also tested. (11) Preparation of crude extract: 10g of each raw medicinal plant in water.
It was soaked in an acetone (1:1) mixture, extracted for 15 minutes at room temperature while homogenizing with a mixer, and filtered. This operation was repeated three times, and the furnace liquids were combined and concentrated to dryness to prepare a crude extract. 011) Preparation of edzitannin: The crude extract obtained in (1) was dissolved in water, washed with ethyl ether, extracted 10 times with ethyl acetate, and the entire extract was concentrated and dried at 40°C under reduced pressure. Hardened. The residue was dissolved in n-butanol-acetic acid-water (4:1).
:5) The mixed solution was subjected to droplet countercurrent partition chromatography and developed using an ascending method to separate both fractions. For each fraction, the tannin quantitative value was measured according to the method described below, and the fraction that showed a high quantitative value was concentrated to dryness at 40°C under reduced pressure.
The desired ethugitannin was obtained. In addition, each obtained edgitannin was identified by IR, HMR, and HPLC. Preparation of condensed tannins: The crude extract obtained in (1) was treated in the same manner as in the previous section to obtain an ethyl acetate extract.The residue was chromatographed on Sephadex LH-20, Low-molecular-weight polyphenols were eluted with ethanol. Next, elution was continued with an ethanol-water mixture.
Gradually increase the proportion of water until it reaches 30%.
Furthermore, add acetone, gradually increase the proportion, and gradually reduce ethanol to form ethanol-water-acetone (
Elution was continued until the ratio was 8:8:4). The tannin quantitative value of each separated fraction was measured, and both fractions showing high quantitative values were concentrated to dryness to obtain the desired condensed tannin. (2) Measurement of antiplasmin activity Each sample was dissolved in 0.01M phosphate buffer (p
H7, 8) to prepare sample solutions of various concentrations. Wallen et al. Haemostasis 4. 110 (1975)
], agaro-y, 100”f was adjusted to 0.1
0.01M phosphate buffer with 5M sodium chloride (pH 7,8) 10
After heating and dissolving in rnl, cool to 40°C. This includes plasminogen removal fibrinogen (Daiichi Chemical)
Dissolve 20W and thrombin solution

After dropping 100 units/-1 Mochida Pharmaceutical 30.1 it, place it in a petri dish (diameter 91: W
). After cooling at room temperature, a hole with a diameter of 6H is made in the center to prepare a plasminogen-depleted fibrin plate. Ambrus et al. Pediatrics, 82. 10 (1968)
”), add 0.1- of plasmin solution (0.4 units/1n!, Sigma) to 0.1- of sample solutions of various concentrations prepared above, and after 30 minutes, remove plasminogen. 20μl each into the holes made in the fibrin plate.
Inject one by one. After standing at 37°C for 20 hours, the area of dissolution is measured. The 50% inhibitory concentration (ID50) of plasmin activity was calculated by comparing with the dissolution area when no sample was added, and the ratio to the ID50 of pharmacopoeial tannic acid (RIp) was calculated according to the following formula.
). (3) The amount of adsorbed hemoglobin in each sample is measured as follows, according to the method of Tannin Quantitative Value Collection, et al. [Pharmacy Journal, 96, 1143 (1976)]. Add each sample to 0.2 M 'J acid buffer [6. Dispersed in O]. Prepare sample solutions of various concentrations by dissolving. Sample mH2
mt, hemoglobin solution

[Fresh human blood was hemolyzed by adding water to give 0D57B = 2.5] 2- and 0.2M phosphoric acid solution (-pH 6,0) 1- were mixed. Stir and let stand for 1 hour. Then, 1200 Orp, m
The supernatant was centrifuged for 10 trays, the absorbance of the supernatant was measured at 578 nm, and the amount of adsorbed hemoglobin was determined from the difference from the absorbance when no hemoglobin was added. 50% adsorption concentration (ID5) compared to the amount of hemoglobin when no sample is added
0) and calculate the ED 5 of pharmacopoeial tannic acid according to the following formula:
Find the ratio (RA)-i with respect to 0. The ID50 results for each sample are shown in Table 1 below. Table 1 Table 1

[continued]

As shown in Table 1, edzi tannins and eligi tannins having a hexahydroxydiphenoyl group or a dehydrohexahydroxydiphenoyl group have strong antiplasmin activity equal to or greater than that of pharmaceutical tannic acid. Thus, 1. The skin external preparation composition of the present invention contains tannins having a group selected from hexahydroxydiphenoyl group and dehydrohexahydroxydiphenoyl group, typically edzi tannin and jiyue tannin as an active ingredient. do. As the ethugitannin used, the above-mentioned interest is used. Extracted from herbal medicines such as Akamegashiwa, Obayashapun, and Gennon Yoko, teρkevin, keprinic acid, kepraziic acid, malotunnic acid, punicalazin, alnuciin,
In addition to geraniin, pomegranate granatin
n) A and B-punicalin
), Choji, San7 Yuyu's Terima Grunge y (tel
limagrandin) l and I, isofNl
soterchebin, casuarinin of Casuarina, casualictin, 5LricLinin, and pedunculagin, which is also found in eucalyptus.
n)% Gennoshoko dehydrogeraniin (deh
hydro-granin), furosin (furosin),
in ), etc. The method for extracting the natural tannin and the natural tannin used in the present invention is not particularly limited, but is generally used. First, raw herbal medicines and plants are sufficiently extracted with a 30-70% acetone aqueous solution or a 30-100% alcohol aqueous solution. These extraction solvents can be selected as appropriate depending on the degree of dryness of the raw materials, but in general, for crude drugs, acetone-water (1:11 mixture) is preferred.The amount of extraction solvent is used in a ratio of 2 to 10 times the raw materials, and Extraction at ~60°C for 15 minutes to 1 hour, repeated 3 times, is sufficient.In particular, thorough extraction at room temperature while homogenizing with a mixer prevents tannin decomposition and improves the overall yield. This is preferable for the purpose of increasing the concentration of tannins.Then, the entire extract is concentrated at 60°C or below and dried to obtain a crude extract containing tannins.This crude extract can be dissolved in water, or the previously obtained extract can be dissolved in water. The solution from which acetone and alcohol/l' have been removed is washed with about the same amount of ethyl ether.This solution is thoroughly extracted with ethyl acetate.Usually, 3 to 30% of the solution is extracted with ethyl acetate, which is less than half the volume of the solution.
Extract 20 times. All the extracts are combined and concentrated to dryness below 60'C to obtain a purified extract containing a large amount of tannins. Note that during this extraction, an extract containing a large amount of desired tannins can be obtained by appropriately adjusting the pH of the aqueous solution. For example, Terkepin% with voice 6, Geraniin with voice 5,
At pH 2, capric acid or malotsic acid is mainly obtained. Next, this extract is subjected to chromatography to separate the tannin fraction. Although such separation method is not particularly limited, countercurrent partition chromatography and natural tannin separation/I/p filtration method are preferable for edge tannin. For example, for edzitannin, the extract is dissolved in the lower layer of an ethyl acetate-〇-furopanol-water system or n-butanol-acetic acid-water system solvent, and the upper layer is used as a mobile phase and developed by the ascending method, or a methanol-water system solvent is used. The desired edgitannins are fractionated by development using a descending method. Sephadex LH, 20 is used for eldest tannin,
After removing low-molecular polyphenols by elution with ethanol, the total tannin fraction is obtained by elution with a 50-70% acetone aqueous solution. This fraction was concentrated and chromatographed again on Sephadex LH-20, eluting with an ethanol-water-acetone mixture. By varying the ratio of ethanol and acetone, it is possible to obtain elm tannin with a desired molecular weight. Each eluate is concentrated to dryness at 60°C or below, preferably at 40°C to obtain each of the original tannins and the district inspection tannins. The resulting tannins may be used individually or separately. Two or more types can be used in combination. In addition, two or more kinds of raw materials, herbal medicines, and plants are mixed in advance. The tannins may then be extracted. Moreover, these tannins may be used in the form of the above-mentioned crude extract or purified extract. The blending amount of these tannins in the skin external preparation composition of the present invention can be appropriately selected depending on the actual dosage form, etc., but in general, it is 0.05 to 5% (wt%, same hereinafter) based on the total amount of one composition ( In the case of a crude extract, the desired effect can be sufficiently exhibited by blending the crude extract at a ratio of about 0.1 to 10%. The skin external preparation composition of the present invention can be applied to cosmetics such as creams, milky lotions, lotions, cleansers, pack-soaps, ointments, paste preparations, lotions, tinctures, liniments, etc. in accordance with the actual use. It can be made into a dosage form similar to a topical drug such as a jelly or an aerosol. Other ingredients may be any commonly used ingredients, and other medicinal agents may also be used in combination. Next, the present invention will be explained in more detail with reference to reference examples and examples. Reference example 1 Commercially available Termilla chebura R
etzius) fruit powder 1 kq to methanol-IV2
! After stirring for 1 hour at room temperature, the extract was filtered. This operation is repeated three times, and the entire extract is concentrated to dryness under reduced pressure at 60° C. or lower to obtain a crude extract. This extract was dissolved in 1j of water, cooled to 10°C, and an aqueous IN sodium hydroxide solution was added with stirring.
Adjust to. Continuous extraction with ethyl acetate under reduced pressure for 4 days,
The solvent is distilled off from the extract under reduced pressure at a temperature below 40°C. The residue was dissolved in 0.61 g of water, extracted continuously with ethyl ether for 12 hours, and then, after removing the ether, the aqueous layer was extracted under reduced pressure.
Concentrate to dryness at 60°C or below to obtain 70 g of a refined extract containing a large amount of tannins. 10 g of this extract was subjected to droplet countercurrent partition chromatography, and ethyl acetate/I/-n-propano--water (4:2
Develop using the ascending method with a mixture of 1 and 2. Collect fractions between 0.4 and 0.71. %40°C under reduced pressure
Concentrate as follows, dissolve the concentrate in ethanol, add water, and collect the precipitate in a furnace to obtain 0.1 g of Terkevin in the form of a light brown powder. Reference Example 2 1 kg of dried Kennoshoko powder leaves was mixed with methanol-water (1 kg).
:1) Mixed liquid 5! Homogenize with a mixer for 1 hour and divide the extract. Repeat this operation 3 times. The entire extract was concentrated to dryness at below 60°C, and the crude extract 25
Obtain 0g. 200 g of this extract is dissolved in 1/2 of water, ethyl ether N11 is added thereto, shaken well, and the ethyl ether layer is removed. After repeating this operation three times, 10.81 tL of ethyl acetate is added to the remaining aqueous layer, shaken well, and extracted. After repeating this operation 10 times, combine the extracts and
Concentrate to dryness under reduced pressure at below 0°C to obtain 5.5 g of purified extract. 3 g of this extract was subjected to droplet countercurrent partition chromatography using chloroform-methanol-water (45:50:2.
1) Develop by descending method using the mixed solution. 0.31~0
．． 41 fractions were collected under reduced pressure. Concentrate at 40°C and collect the precipitate separated from the water. Add 0.2 g of yellow powdered geraniin. Reference example 3: 1 kg of fresh leaves of Akamegashiwa with water and acetone

[3 Near] Mixed liquid 5! and extracted in the same manner as in Reference Example 2. The obtained extract was concentrated to 1j, to which was added ethyl ether 1j, and treated in the same manner as in Reference Example 2 to obtain 40 g of purified extract. 10 g of this extract was subjected to droplet countercurrent partition chromatography and developed using a mixture of n-butanol-acetic acid-water (4:1:5) in an ascending manner. Collect fractions 4 to 5j, fi
Concentrate to dryness under positive pressure at 60°C or lower, and add ethyl acetate to the residue to dissolve. to this. Petroleum benzine is added and the resulting precipitate is collected to obtain 0.14 g of malotsic acid in the form of pale yellow powder. Reference example 4 Commercially available elm (Sangnisorba efficiru)
lis L, var. carnea, Reg, ) (D dried root 1 #e Mix water-acetone (1:1) in the same manner as in the above reference example G! 3
Extract with /. A purified extract is obtained in the same manner. Dissolve 50g of this extract in ethanol/l/200-
Sephadex LH-20 gel chromatography (
Wet volume 1.57) and elute with ethanol 101. Then, it was eluted with 70% acetone and the 21 fractions were collected and concentrated to dryness under reduced pressure at -40'C to obtain 10 g of total tannin. 5 g of total tannin was subjected to Sephadex LH, 20 gel chromatography (wet volume 150 m/), and after elution with ethanol-water (7:3) mixed HAl, ethanol-
Elute with water-acetone (65:80:5), the fraction 0
．． Collect 2/i. This eluate was concentrated to dryness at 40°C under reduced pressure to obtain 0.5 g of light brown elm tannin A. Example 1 A milky lotion containing Terkevin obtained in Reference Example 1 to relieve hot flashes after sunburn and snowburn was produced by a conventional method according to the following formulation. Ingredients % Stearic acid 2.0 cetanol) V Q・5
Lanolin 2.0 Isopropyl myristate 2.0 Squalene 3.0 Liquid paraffin 8.0 Polyoxyethylene cetyl ether/L' 1.7 Sorbitan monostearate 0.8 Terkevin 1.0 Triethanolamine 1.0 Glycerin
4.0 Fragrances and Preservatives
appropriate amount of water
Adjustment to 100% Example 2 A suntan lotion was prepared by blending the purified extract of red mulberry wrinkle obtained in Reference Example 3 and the red mulberry total tannin obtained in reference example 4 according to the following recipe using a conventional method. Ingredients % Carboxypolymethylene (Sil 940) 1
．． 5 Polyethylene glycol/L/600 5
．． 0 dihydroxyacetone 1.
0 Diisopropaturamine (appropriate amount) Fragrance (appropriate amount) Purified extract of Akamega wrinkles 0.5 Diisopropaturamine total tannins 0.5 Water
Adjust this lotion to 100% 18-2
The results were investigated by 10 2-year-old girls who applied the product to their backs while bathing in the sea. No skin irritation or inflammatory reaction was observed in any of the patients. Furthermore, after sunburn, the emulsion of Example 1 was applied to the arm to examine its effect, and as a result, no skin irritation or inflammatory reaction was observed. Example 3 A cream for rough skin containing the malotsic acid obtained in Reference Example 3 was produced by a conventional method according to the following formulation. Ingredients % Beeswax 10.0 Paraffin wax 6.0 Lanolin 3.0 Iso7”
Lopyrumiris f) 6.0 Squalene 8.0 Liquid paraffin 25.0 Polyoxyethylene sorbitan monostearate 1
．． 8 So 7 Levitan mononutearate 4
．． 2 Malotsic acid 0.2
Preservatives Appropriate amount of propylene glycol 2.0 urea
2.0 water
Adjustment to 100% Example 4 Afternap Lotion e was manufactured according to the following recipe using a conventional method. Ingredients % Ethyl alcohol/L'
55.0 dipropylene glycol
1.0 Horioxyethylene hydrogenated castor oil 0.5 Obayashishabushi and Gennoshoko mixed extract 0.5
Fragrance 0.5 water
Adjustment to 100% Example 5 An ointment for the treatment of burns and trauma was prepared according to the following formulation in a conventional manner. Ingredients Polyethylene glycol/I/400 53.8 Polyethylene glycol 1500 19.0 Polyethylene glycol 4000 21.0 Carbopol 9B4
1.0 Ako purified extract
5.0 Acryno) Li fine powder
0.2 Apply 1 to 2 pieces of this cartilage to one location.
As a result of applying it to the burn area of 9 patients who suffered from degree burns,
Eight of the nine patients had no blisters or pain, and the treatment was excellent. ,
One patient felt pain, but no blisters were observed and the treatment was effective. Example 6 A zinc oxide liniment was obtained by a conventional method according to the following recipe, and a liniment effective for treating eczema, insect bites, and pruritic skin diseases was produced. Ingredients % Liquid phenol/l/
2.2 Tragacanth
5.0 Glycerin 3.0 Zinc oxide fine powder 10.0 Alnuciin 1.0 Water
Adjustment to 100% Example 7 An aerosol for treating burns containing the District Examination Tannin A obtained in Reference Example 4 was produced according to the following recipe using a conventional method. Ingredients % Mentor/l/
0.1 chlorobutano/L'
0.3 hexachlorophene
0.3 Elm tannin A2.0 Dipropylene glycol 19.1 Isopropanol 13.2 Propellant
65.0 Patent applicant Sunstar Co., Ltd.? υ) 1 person Patent attorney Aoyama
2 other masters, continuation amendment (shu) November 20, 1980 Commissioner of the Japan Patent Office Tono 1 Indication of the case 1982 Patent Application No. 135771 2 Name of the invention Tannin-containing skin external preparation composition 3 Person making the amendment Relationship to the case Patent applicant, Address: 3-1 Asahi-cho, Takatsuki-shi, Osaka Name: Sunstar Co., Ltd. (and one other person) 4. Address: Inside Honmachi Building, 2-10 Honmachi, Higashi-ku, Osaka-shi, Osaka Name: Patent attorney ( 6214) Aoyama Ao et al. 7, Contents of the amendment (1) Mei M, page 15, bottom 7th line “I will expand, but)
I/-L J was corrected to ``Develop, but chloroform-methanol''. (2) In the 7th line from the bottom of page 18 of the circular, the phrase ``terminal dry leaves of gennoshouko'' has been corrected to ``undried leaves of gennoshouko.''that's all

Claims (4)

[Claims] (1) A skin external preparation characterized by containing as an active ingredient one or two tannins containing a group selected from the group consisting of hexahydroxydiphenoyl group and dehydrohexahydroquine diphenoyl group. Composition. (2) The above-mentioned (1), wherein the tannin is ellagitasonine.
A composition for external use on the skin. (3) The tannin is ground elm tannin (see (1) above)
A composition for external use on the skin. (4) The skin external preparation composition according to any one of items (1) to (3) above, which contains the tannin in an amount of 0.05 to 5% by weight based on the total amount of the composition.