JPH09208480A - Substance p-antagonizing medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a substance P-antagonizing medicine containing a plant such as Avena sativa Linne or its extract as an active ingredient and useful as an analgesic, etc. SOLUTION: This substance P-antagonizing medicine contains one or more kinds of plants selected from Avena sativa Linne, Polygoni multiflori, Crataegus cuneata, Lemna polyrrhiza, Curcuma zedoaria, Artemisia apiacea, Cinnamomum cassia and Schizandra chinensis and their extracts as an active ingredient. The extraction of the plant is carried out with water and/or a water-soluble organic solvent (e.g. methanol) by a conventional method. The solvent is, if necessary, heated to approximately 50 deg.C to enhance the extraction yield. The plant or its extract has an action to inhibit the exacerbation of skin vascular permeability, and is especially useful as a therapeutic medicine for various inflammatory syndromes in skins. The substance P-antagonizing medicine is administered at a daily dose of 10-5000mg, preferably 50-2000mg, as the plant extract (dry weight) for an adult in one to four portions. When used as a bath agent, the extract obtained from 0.001-1000g of the powder of the plant raw material per 150-200 liter of the bath water is used.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to substance P antagonists, and more particularly to substance P antagonists useful as analgesics and the like.

[0002]

BACKGROUND OF THE INVENTION Substance P is a peptide consisting of 11 amino acids, which is known to have an ileal contractile action, a salivary secretion promoting action, a pain stimulating action and the like. This substance P has recently been positioned as a kind of tachykinins.

[0003] This substance P is known to act in a wide range of diseases such as digestive diseases, nervous system diseases, and circulatory system diseases. In particular, Huntington's disease, carcinoid syndrome, chronic pain, and cutaneous blood vessels It is thought to be deeply involved in permeability enhancement and the like.

[0004] Various substance P antagonists have been reported for the purpose of developing therapeutic agents for these diseases involving substance P (MM Chang, SE Leeman, HD Nia).
ll, Nature New Biol., 232, 86 (1971), Hugan RM et
al, Br. J. Pharmacol., 99 (Suppl.), 62P (1990)).

[0005]

However, since these conventional substance P antagonists are synthetic peptides and have an agonistic action and an antigenicity to humans, they have not been developed as pharmaceuticals from the viewpoint of safety.
Therefore, an object of the present invention is to provide a drug having an excellent substance P antagonistic action and high safety.

[0006]

Means for Solving the Problems The present inventors have studied the pharmacological action of plant extracts widely to solve the above-mentioned problems. Alternatively, the inventors have found that the extract has an excellent substance P antagonistic effect particularly on the skin, and have completed the present invention.

That is, the present invention is based on oats, hemp,
The present invention provides a substance P antagonist comprising, as an active ingredient, one or two or more kinds of plants selected from Yamageko, Fuyu, Gautu, Ginkgo, cinnamon, and Gomiza.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The plant used in the present invention refers to one or more of the whole plant or its leaves, stems, roots, fruits, seeds, and flowers (hereinafter referred to as "protozoa"). ) Or dried and crushed, and the plant extract is
Various solvent extracts obtained by drying the raw material or pulverizing without drying, extracting with a solvent at room temperature or under heating, or using an extraction device such as a Soxhlet extractor, and diluents thereof , Its concentrated liquid, or its dried powder. In the present invention, oats are seeds, Heisei crow is tuberous roots, Yamako is mature fruits, leopards are whole plants, cajuts are rhizomes, eucommia is whole plants, cinnamon bark, schizandra is a dried product of mature fruits or an extract thereof. Is preferred. In the present invention, one or more of these plants or extracts thereof can be used.

[0009] Extraction from these plants requires the use of water and / or a water-soluble organic solvent in order to obtain an effective ingredient efficiently. Examples of the water-soluble organic solvent used here include methanol, ethanol, propanol, butanol, propylene glycol, 1,3-
Examples thereof include butylene glycol, and among them, ethanol, butanol, propylene glycol, and 1,3-butylene glycol are preferred. The water-soluble organic solvent may be used singly or as a mixture of two or more kinds, and is preferably combined with water. The amount of the solvent for the plant is 1 to 20.
It is preferable to make the weight times.

[0010] On the other hand, it is preferable that the plant as a raw material is coarse powder or powder, rather than used for extraction as it is.
The plant may be immersed in the above-mentioned extraction solvent and extraction may be performed by a conventional method. However, if necessary, the plant may be heated to about 50 ° C. to increase the extraction efficiency. If the extract is directly or concentrated and then fractionated with a solvent, and only an effective fraction is taken out, a higher effect can be expected with a smaller amount. Here, as the solvent used for fractionation, water and ethyl acetate are preferable, and this water fraction is preferably used.

[0011] The above-mentioned plant or its extract has the effect of suppressing the increase in cutaneous vascular permeability caused by substance P.
Therefore, the substance P antagonist of the present invention containing the above-mentioned plant or its extract as an active ingredient is particularly useful as a therapeutic agent for various inflammatory symptoms in the skin.

The substance P antagonist of the present invention may be in any form as long as it contains the above-mentioned plant or its extract, but preparations for oral administration such as tablets, granules and capsules; injections; ointment creams, lotions, It can be used as an external preparation such as a gel; a bath preparation and the like. To prepare these formulations, the plant or its extract and excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants,
It can be produced by appropriately combining and formulating a buffering agent, a preservative, a flavoring agent, a flavoring agent, a coating agent and the like. In addition to these additives, in addition to these additives, inorganic salts,
Carbon dioxide gas and carbon dioxide gas generation products can be mixed.

The dose of the substance P antagonist of the present invention is
Although it varies depending on the symptoms, administration route, etc., it is generally 10 to 5,0 as the above plant extract (dry weight) for adults.
It is preferable to administer 00 mg, particularly 50 to 2,000 mg, usually in 1 to 4 times per day. When used as a bathing agent, it is not particularly limited, but standard bath water 150
~ 200 L per powder of the above-mentioned plant drug substance (bulk powder) 0.0
The amount of extract obtained from 01 to 1,000 g is preferable, and the amount of extract obtained from 0.01 to 100 g of bulk powder is more preferable.

[0014]

INDUSTRIAL APPLICABILITY Since the substance P antagonist of the present invention is highly safe and has a strong substance P antagonistic action, it is useful as a therapeutic agent for diseases involving substance P, particularly analgesics and skin inflammation symptoms.

[0015]

Next, the present invention will be described with reference to examples and test examples, but the present invention is not limited to these examples.

Production Example 1 Extract from oat seeds (1) 2 kg of 1,3-butylene glycol: purified water (1 volume: 1 volume) mixed solution was added to 1 kg of coarse powder of oat ( Avena sativa Linne) seeds, and 50 Extract by stirring at 0 ° C. for 10 hours. After the solid matter was filtered, the filtrate was allowed to stand at 5 ° C. for several days, and the precipitated precipitate was removed by filtration to obtain 0.98 kg of a slightly yellowish clear extract. Although the recovery rate of the extract was about 50%, 1 g of the extract in this Production Example corresponds to about 0.5 g of oat seeds from the ratio of the amount of oat seeds charged and the amount of extraction solvent.

Production Example 2 Extract from oat seeds (2) 5 kg of a mixed solution of ethanol: purified water (1 volume: 1 volume) was added to 1 kg of coarse powder of oat ( Avena sativa Linne) seeds, and 5
Extract with stirring at 0 ° C. for 10 hours. After filtering solids, the filtrate was concentrated under reduced pressure at 60 ° C or lower until the total amount became about 1/10 volume, 0.5 kg of ethyl acetate was added, and the mixture was sufficiently stirred and allowed to stand, and the lower layer portion was separated. To get A brown viscous substance obtained by concentrating the lower layer under reduced pressure (1 kg of oats seeds →
0.10 kg) was obtained. To this, 100 g of pharmacopoeial dextrin and an appropriate amount of purified water were added and dissolved, and a trace amount of insoluble matter was filtered with a filter paper, and then spray-dried to obtain 200 g of a dried matter. 1 g of this product corresponds to 5 g of oats seeds.

Production Examples 3 and 4 Fractionation of Extract from Oat Seeds 1 kg crude powder of oat ( Avena sativa Linne) seeds was added with 5 kg of a mixed solution of ethanol: purified water (1 volume: 1 volume), and 5
Extract with stirring at 0 ° C. for 10 hours. After filtering the solids, the filtrate was concentrated under reduced pressure at 60 ° C or lower until the total amount became about 1/10 volume, 0.5 kg of ethyl acetate was added, and the mixture was sufficiently stirred and allowed to stand, and the liquid was separated into the lower layer. Get the part. A brown viscous substance obtained by concentrating the lower layer under reduced pressure (1 kg of oats seeds →
0.10 kg) was obtained. 100 g of the extract from this oat seed was dispersed in 1 kg of water, added with 1 kg of ethyl acetate, and fractionated by a separating funnel according to a conventional method. To the extract distributed in water, 1 kg of butanol was added, and the mixture was fractionated with a separating funnel to concentrate water, butanol, and soluble matter. Water-soluble fraction: 26 g (Production Example 3), butanol-soluble fraction Min: 40 g (Production Example 4) of a fractionated product was obtained. Each 1 g of this fraction is approximately 38 g of oat seeds and 25 g of oat seeds, respectively.
g.

Production Examples 5, 6, 7 Fractionation of extract from oat seeds 1 kg crude powder of oat ( Avena sativa Linne) seeds was successively extracted with the following solvents to form a mixture and concentrated. Acetone 2L, methanol 2L, 50% methanol 2L (room temperature extraction), acetone 2L, methanol 2L, 50% methanol 2L (50 ° C extraction), purified water 2L (room temperature extraction). The concentrated mixture was dispersed in 2 L of water and extracted with 2 L of ethyl acetate to obtain an ethyl acetate-soluble matter, which was concentrated to obtain an ethyl acetate-soluble fraction: 34 g (Production Example 5). 2 L of butanol was added to the extract mixed with water, fractionated with a separating funnel, water and butanol soluble matter were concentrated, and water-soluble fraction: 26 g (Production Example 6), butanol-soluble fraction: 40 g (Production Example 7) was obtained.

Production Example 8 Radish root extract ( Polygonum miltiflorum ) tuberous root was shredded , and 10 g thereof was mixed with water and ethanol (50:50).
100 ml was added and immersed. This was filtered to obtain an extract of Ginseng crow.

Production Example 9 Yamako extract extract Mature fruits of hawthorn ( Crataegus cuneata ) are finely chopped ,
A mixture of water and ethanol (70:30)
0 ml was added and immersed. This was filtered to obtain a Yamajiko extract.

Production Example 10 Leopard extract Lewna ( Lemna polyrrhiza )
To 0 g, 100 ml of a mixed solution of water and ethanol (50:50) was added and immersed. This was filtered to obtain a leopard extract.

Production Example 11 Gazitu extract Rhizome of Gakujutsu ( Curcuma zedoaria ) was finely chopped.
To 0 g, 100 ml of a mixed liquid of water and ethanol (60:40) was added and immersed. This was filtered to obtain a zedoary extract.

Production Example 12 Gypsophila radix extract Whole plants of Japanese ginseng ( Artemisia apiacea ) were shredded , and 10 g thereof was mixed with water and ethanol (50:50).
100 ml was added and immersed. This was filtered to obtain an extract of ginseng.

Preparation Example 13 Cinnamomum cassia Bark of Cinnamomum cassia
100 g of a mixed solution of water and ethanol (50:50) was added to g, and the mixture was immersed. This was filtered to obtain a cinnamon bark extract.

Production Example 14 Gomiza extract Mature fruits of Schizandra chinensis were shredded and 10 g thereof was mixed with water and ethanol (50:
50) 100 ml was added and immersed. This was filtered to obtain a Schisandra chinensis extract.

Test Example 1 The back of a guinea pig was shaved and a test substance solution (diluted with physiological saline to a concentration of 500 μg (solid content weight) / ml) was used.
μl administered intradermally, and 6 hours later, Evans blue (dissolved in physiological saline, 5 mg / ml, 0.5 per 1 kg of guinea pig body weight)
ml) was administered intravenously. Next, 50 μl of the test substance solution and 50 μl of the substance P solution (10 ⁻⁵ M) were intradermally administered to the intradermal administration site of the test substance. After 20 minutes, the skin on the back of the guinea pig was peeled off, and the area where the dye (Evans blue) leaked from the back side was measured. As a result, Table 1
As shown in FIG. 5, it can be seen that the plant extract of the present invention suppresses the action of substance P to enhance vascular permeability.

[0028]

[Table 1]

Test Example 2 Pain Suppressing Effect of Plant Extract The plant extract of the present invention was evaluated by the Randall-Selitto method. That is, in a 5-week-old SD male rat, Mycobacterium butyricum 0.6 mg / 0.1 ml suspended in liquid paraffin in the plantar skin of the left hind leg under ether anesthesia
/ Head (day 0). On the 14th day, the pain threshold value of the right hind limb was measured (using a pain threshold value measuring device manufactured by UGO BASILE) and grouped so that the average values were almost uniform,
From that day, the plant extract was applied to the right hind leg once a day every day. On the 28th day, the pain threshold value of the right hind limb was measured again, and the analgesic effect was evaluated by the difference in weighted value at which pain was felt. As a result, it was confirmed that the plant extract of the present invention had an excellent pain-suppressing effect.

[0030]

[Table 2]

Example 1 (Tablet) A tablet having the following composition was produced by direct compression molding. Oat extract (Production Example 5) 100 mg Crystalline cellulose 393 mg Lactose 100 mg Hydroxypropyl cellulose-L 4 mg Magnesium stearate 3 mg Total amount 500 mg

Example 2 (Granule) The following ingredients were uniformly mixed, kneaded, granulated by an extrusion granulator and sieved to obtain a granule. (Component) (g) Gomiza extract (Production Example 14) 10 Crystalline cellulose 50 10% Hydroxypropyl cellulose 40 Total 100

Example 3 (Spray Agent) A spray agent containing the following components in one cylinder was produced by a conventional method. (Ingredient) (g) Heishou crow extract (Production Example 8) 1 Oleic acid 3 Freon 11 1.2 Freon 12 2.5 Freon 114 1.3 Total 9

Example 4 (Ointment) The following ingredients were uniformly mixed to obtain an ointment. (Component) (g) Yamashiko extract (Production Example 9) 10 Squalane 20 Glycerin 20 Cetyl alcohol 5 Magnesium stearate 3 Propylene glycol 5 Water 20 Ethanol 7 Total 90

Example 5 (Capsule) The following ingredients were uniformly mixed to obtain a capsule. (Ingredient) (g) Leopardaceae extract (Production Example 10) 100 Crystalline cellulose 100 Lactose 150 Light anhydrous silicic acid 20 Total 370

Example 6 (Cream) The following ingredients were uniformly mixed to obtain a cream. (Components) (g) Gautu extract (Production Example 11) 1 Cholesterol 0.5 Cholesteryl isostearate 1 Polyether-modified silicone 1.5 Cyclic silicone 20 Methylphenylpolysiloxane 2 Methylpolysiloxane 2 Magnesium sulfate 0.5 55% Ethanol 5 Carboxymethyl chitin 0.5 Purified water 66 Total 100

Example 7 (Skin lotion) (Component) (g) Seiko extract (Production Example 12) 2 Glycerin monostearate 1 Ethanol 15 Propylene glycol 4 Isopropyl palmitate 3 Lanolin 1 Methyl paraoxybenzoate 0.1 Ceramide 1 Fragrance, pigment Micro- purified water Fuel gauge 100.0

Example 8 (Skin lotion) (Component) (g) Cinnamon extract (Production Example 13) 2 Glycerin monostearate 1 Ethanol 15 Propylene glycol 4 Isopropyl palmitate 3 Lanolin 1 Methyl paraoxybenzoate 0.1 Ceramide 1 Fragrance, pigment Micro- purified water Fuel gauge 100.0

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display area A61K 7/00 A61K 7/00 K W 7/48 7/48 (72) Inventor Satoshi Kanazawa Tochigi Prefecture 2606 Akabane, Kaiba-cho, Haga-gun Inside Kao Institute of Stock Companies (72) Inventor Yoshinori Nishizawa 2606 Akabane, Kai-cho, Haga-gun, Tochigi Inside Kao Institute of Stock Companies

Claims (3)

[Claims] 1. A substance P antagonist comprising, as an active ingredient, one or two or more kinds of plants selected from oats, hemp crows, yamageko, fuhyo, gautu, ginkgo, cinnamon and sardines. 2. The substance P antagonist according to claim 1, wherein the plant extract is an extract extracted from the plant with water and / or a water-soluble organic solvent. 3. The substance P antagonist according to claim 1, wherein the plant extract is a water fraction obtained by fractionating water and / or an extract extracted with a water-soluble organic solvent with water and ethyl acetate. Agent.