JP4197194B2 - Oral administration agent for intercellular adhesion suppression - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an orally administered agent for inhibiting adhesion between cells, which comprises a natural product extract as an active ingredient and is useful for treatment / amelioration of skin diseases and prevention / improvement of stratum corneum troubles.
[0002]
[Prior art]
The epidermis is composed of various types of cells, and keratinocytes are the majority. As this keratinocyte grows and moves to the upper layer, the outermost stratum corneum is formed by the differentiation process (keratinization). Epidermal cells play an important role in the normal keratinization and maintenance of the stratum corneum.
[0003]
It is also said that the abnormal cell adhesion of keratinocytes in the epidermis is a cause of skin diseases such as blistering and certain keratosis. In addition, it is known that stratum corneum troubles such as acne, dandruff and sunburn are caused by the stratification of the stratum corneum due to enhanced cell adhesion.
[0004]
Desmosome is a representative example of an adhesion function device for the epidermis including these stratum corneum. Desmosomes are protein aggregates that are involved in adhesion between epidermal cells and corneocytes, and among these proteins that are directly involved in adhesion are desmoglein and desmocollin, particularly desmoglein.
[0005]
So far, an increase in desmosome protein has been observed in exfoliated horny layer produced by rough lips, desquamation of horny layer caused by sunburn and drying, acne inner horny layer, and dandruff. Therefore, these stratum corneum troubles are thought to be caused by an abnormality of the stratum corneum adhesion function due to an increase in desmosome protein, and it is considered effective to control the cell adhesion function by desmosome to prevent and improve the stratum corneum trouble It is done.
[0006]
As a method for controlling the amount of the desmosomal protein, a method for improving acne, dandruff and desquamation by degrading the desmosomal protein accumulated in the stratum corneum with a protease has been reported so far (Japanese Patent Publication No. 7-505383, WO93 / 19732, WO95 / 07687, WO95 / 07688).
[0007]
[Problems to be solved by the invention]
However, in recent years, consumers tend to desire natural products in the fields of pharmaceuticals, cosmetics, foods, etc., and use such natural products as active ingredients, and effectively inhibit cell-cell adhesion by a simple method such as oral administration. An agent was sought.
[0008]
Accordingly, an object of the present invention is to provide an orally administered agent containing a natural product-derived component as an active ingredient and suppressing cell-cell adhesion due to desmosomes, particularly cell-cell adhesion of desmosomes that cause horny layer troubles in the skin. And
[0009]
[Means for Solving the Problems]
Therefore, as a result of intensive studies to achieve the above object, the inventors of the present invention have found that among natural product extracts, licorice extract, purple extract, tocon extract, auren extract, abalone extract, clove extract, camellia extract, body extract, propolis extract. Alternatively, the present inventors have found that if the soap extract is orally administered, cell-cell adhesion can be effectively suppressed, and the present invention has been completed.
[0010]
That is, the present invention provides one or more kinds of natural product extracts selected from licorice extract, purple extract, tocon extract, auren extract, agate extract, clove extract, camellia extract, bodaiju extract, propolis extract and soap blossom extract as active ingredients. An oral administration agent for suppressing cell-cell adhesion is provided.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The licorice extract used in the present invention may be extracted from licorice with a polar solvent, extracted with a polar solvent and then insoluble in an organic solvent, or extracted from licorice with an organic solvent. . Examples of polar solvents include lower alcohols such as methanol and ethanol, polyhydric alcohols such as propylene glycol and butylene glycol, aliphatic ketones such as acetone and methyl ethyl ketone, water, or a mixture of two or more of these, organic solvents Examples thereof include esters such as ethyl acetate, hydrocarbon solvents such as pentane, hexane, heptane, nonane and decane, or mixtures of two or more thereof. In particular, those extracted with a mixed solvent of ethanol and water and then dissolved in ethyl acetate are preferred.
There are many types of licorice, and any species can be used for extraction, but Glycyrrhiza glabra Linne, Glyoyrrhiza ularensis Fisher, Glycyrrhizainflata Bat. Or other homologous species are preferred, especially for roots and underrunning stems. It is preferable to use it.
[0012]
The purple extract used in the present invention is extracted from purple (Lithospermum erythrorhizon), Macrotomia euchroma or other purple family, and the extraction site is not particularly limited, but the root or rhizome is preferred. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0013]
The tocon extract used in the present invention is extracted from Cephaelis ipecacuanha or a plant belonging to the same genus, and the extraction site is not particularly limited, but a root or rhizome is preferred. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0014]
The auren extract used in the present invention is extracted from Coptis japonica or a plant belonging to the same genus, and the extraction site is not particularly limited, but a root or rhizome is preferred. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0015]
The buckwheat extract used in the present invention is extracted from Phellodendron amurense or a plant belonging to the same, and the extraction site is not particularly limited, but bark is preferable. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0016]
The clove extract used in the present invention is extracted from Syzygium aromaticum or a plant belonging to the same genus, and the extraction site is not particularly limited, but cocoon is preferred. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0017]
The camellia extract used in the present invention is extracted from snow flora (Centella asiatica) or its genus plants, and the extraction site is not particularly limited, but leaves or stems are preferred. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0018]
The body extract used in the present invention is extracted from a plant body (Tilia cordata), a tree plant (Tilia platyphyllos) or a plant belonging to the same genus, and the extraction site is not particularly limited, but a flower is preferable. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0019]
The propolis extract used in the present invention is extracted from propolis, which is a resinous substance collected by bees from neighboring plants, and the extraction solvent can be the same as the above licorice extract, and is not particularly limited. However, what extracted water, ethanol, propylene glycol, and butylene glycol individually or in mixture of 2 or more types is preferable.
[0020]
The soap extract used in the present invention is extracted from Quillaya saponaria or its genus plant, and the extraction site is not particularly limited, but bark is preferable. The extraction solvent can be the same as the licorice extract described above, and is not particularly limited, but is preferably water, ethanol, propylene glycol and butylene glycol extracted alone or in a mixture of two or more. .
[0021]
Among these natural product extracts, licorice extract, particularly licorice extract extracted with a mixed solvent of ethanol and water and then dissolved in ethyl acetate is preferable.
[0022]
The oral administration agent for suppressing cell-cell adhesion of the present invention is useful for various diseases caused by enhanced cell-cell adhesion, particularly blistering, keratosis, keratosis, acne, dandruff, rough skin, It is particularly effective against diseases caused by increased cell-cell adhesion in the skin such as rough lips. The oral administration agent for inhibiting cell-cell adhesion of the present invention may be a natural product extract itself, or a solid preparation such as powder, granule, capsule, pill, tablet, or solution, suspension, emulsion. It may be formulated into a liquid such as. When formulating natural product extracts, excipients, binders, disintegrants, lubricants, coating agents, bases, suspending agents, emulsifiers, humectants, preservatives commonly used for oral administration , Stabilizers, surfactants, flavoring agents and the like can be added and produced according to conventional methods. The natural product extract is preferably blended as a dry solid, for example, in an amount of 0.001 to 30% by weight, particularly 0.01 to 10% by weight, in an oral administration agent for inhibiting adhesion between cells. When administered orally, natural product extracts or preparations may be mixed, dissolved and dispersed in food. The daily dose of the natural product extract per adult is preferably, for example, 1 to 1000 mg, particularly 10 to 500 mg as a dry solid content.
[0023]
【Example】
EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these Examples at all.
[0024]
Production Example 1 Licorice Extract Preparation Method:
The roots of licorice (Glycyrrhiza glabra Linne) were chopped, and 15 ml of a mixture of water and ethanol (5:95) was added to 5 g of the licorice and immersed. This was filtered, and the resulting extract was concentrated to obtain 325 mg of a solid content. To this was added 10 ml of ethyl acetate, and filtration was performed again to remove insoluble matter, thereby obtaining a licorice extract. When this licorice extract was concentrated, the solid content was 56 mg.
[0025]
Production Example 2 Murasaki Extract Preparation Method:
Murasaki (Lithospermum erythrorhizon Siebold et Zuccarini root) was cut into small pieces, and 15 ml of ethanol was added to 5 g of the cut and immersed. This was filtered to obtain a purple extract. When this sicon extract was concentrated, the solid content was 228 mg.
[0026]
Production Example 3 Tocon extract preparation method:
The root (Cephaelis ipecacuanha A. Richard's root) was cut into small pieces, and 15 ml of a mixture of water and ethanol (2: 8) was added to 5 g of the root and immersed. This was filtered to obtain a tocon extract. When this tocon extract was concentrated, the solid content was 169 mg.
[0027]
Production Example 4 Method for preparing auren extract:
The roots and rhizomes of auren (Coptis japonica) were cut into small pieces, and 10 ml of a mixed solution of water and ethanol (70:30) was added to 1 g thereof and immersed. This was filtered to obtain an aurene extract.
[0028]
Production Example 5 Method for preparing a buckwheat extract:
A bark of Phellodendron amurense was chopped, and 10 ml of a mixture of water and ethanol (50:50) was added to 1 g of the bark and immersed. This was filtered to obtain a buckwheat extract.
[0029]
Production Example 6 Clove extract preparation method:
A cocoon of Syzygium aromaticum was cut into small pieces, and 10 ml of a mixture of water and ethanol (70:30) was added to 1 g of the cocoon and immersed. This was filtered to obtain a clove extract.
[0030]
Production Example 7 Method of preparing centella extract:
The leaves and stems of snow flora (Centella asiatica) were chopped, and 10 ml of a mixed solution of water and propylene glycol (50:50) was added to 1 g thereof and immersed. This was filtered, and the resulting extract was concentrated to obtain a snowy grass extract.
[0031]
Production Example 8 Bodaige Extract Preparation Method:
A flower of Tilia cordata was chopped, and 10 ml of a mixture of water and propylene glycol (58:42) was added to 1 g of the flower and immersed. This was filtered to obtain a body extract.
[0032]
Production Example 9 Propolis extract preparation method:
To 1 g of propolis, 10 ml of a mixed solution of water and ethanol (30:70) was added and immersed. This was filtered to obtain a propolis extract.
[0033]
Production Example 10 Preparation method for soap extract:
The bark of Quillaya saponaria was cut into small pieces, and 10 ml of a mixture of water and propylene glycol (50:50) was added to 1 g of the bark and immersed. This was filtered to obtain a soap extract.
[0034]
Test Example 1 Quantification of desmoglein in the stratum corneum:
The licorice extract solid obtained in Production Example 1 was dissolved in olive oil to give a 1% solution. Six female 8-week-old hairless rats were divided into two groups of three, and the above-mentioned 1% solution was orally administered to the first group once a day using a sonde for 0.5 months. After the administration was completed, 600 mJ (equivalent to about 2 MED) of UVB was irradiated to one half of the back. The second group was orally administered with 0.5 ml of olive oil once a day for 1 month using a sonde, and the same treatment as in the first group was performed. Three days after UVB irradiation, a cyanoacrylate adhesive was applied to a slide glass (10 × 20 mm), and the stratum corneum was stripped by pressing against the UVB irradiated part and the non-irradiated part. Next, the adhesive was dissolved in dimethylformamide and freeze-dried to obtain a dry stratum corneum sample. Tris-HCl buffer (9 M urea, 2% SDS, 5% 2-mercaptoethanol, 10 mM p-APMSF [(p-amidinophenyl) methanesulfonyl fluoride], 100 μM aprotinin, pH 9.0) 500 μl And incubated at 37 ° C. for 12 hours to extract the protein. Subsequently, the protein extract was subjected to SDS electrophoresis, transferred to a membrane, Western blotted with an anti-desmoglein antibody, the detection band was quantified, and the amount of desmoglein per extracted protein was measured. The results are shown in FIG.
[0035]
Compared with the UVB non-irradiated part of the second group, the amount of desmoglein in the first group UVB non-irradiated part decreased by about 35% on average. In the second group, the amount of desmoglein is about 1.5 times that of the UVB irradiated part in comparison with the non-UVB irradiated part, whereas in the first group, the UVB irradiated part and the UVB non-irradiated part. There was almost no difference in the amount of desmoglein. From this, in the licorice extract administration group (first group), it was confirmed that the desmoglein amount decreased when UVB was not irradiated, and the desmoglein amount did not increase even when UVB was irradiated.
[0036]
Test Example 2 Tissue observation by HE staining:
A HE-stained section of rat skin obtained in Test Example 1 was prepared, and the epidermal tissue was observed. As a result, in the UVB non-irradiated part, no significant difference was observed between the first group and the second group. On the other hand, in the UVB irradiation part, in the second group, the epidermis was thickened and partial enhancement of the stratum corneum was observed, whereas in the first group, the thickening of the epidermis and the increased adhesion of the stratum corneum were observed in the second group. It was suppressed more than the case.
[0037]
Example 1
Licorice extract (solid content) 500g, hydroxypropylcellulose 800g, light anhydrous silicic acid 200g, lactose 500g, crystalline cellulose 500g and talc 500g were made into a tablet having a diameter of 9 mm and a weight of 200 mg by a conventional method.
[0038]
Example 2
1000 g of purple extract (solid content), 1000 g of crystalline cellulose, 1500 g of lactose and 200 g of light anhydrous silicic acid were used as capsules by a conventional method.
[0039]
Example 3
200 g of tocon extract (solid content), 200 g of lactose, 300 g of hydroxypropylcellulose and 15 g of talc were granulated by a conventional method.
[0040]
【The invention's effect】
The oral administration agent for suppressing intercellular adhesion of the present invention is treatment / improvement of various skin diseases such as blistering, keratosis, keratosis insufficiency, acne, dandruff, rough skin, rough lips, and prevention / improvement of stratum corneum troubles. It is effective for.
[Brief description of the drawings]
FIG. 1 is a diagram showing the amount of desmoglein when a licorice extract solution or the like is orally administered to hairless rats and UVB irradiation or non-irradiation is performed.

Claims (1)

After extraction with a mixed solvent of a lower alcohol and water than licorice, ethyl acetate, pentane, hexane, heptane, in the skin shall be the transfer dissolution and active ingredient licorice equi scan obtained with an organic solvent selected from the nonane and decane The oral dosage for intercellular adhesion-suppressing.

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