JPH08176003A - Arachidonic acid metabolism inhibitor - Google Patents

Abstract

PURPOSE: To provide an arachidonic acid metabolism inhibitor which contains, as active ingredients, Euphorbia lathyris L. Aqrimonia pilosa Ledeb.var. japonica, Artemisia capillaris Thumb and Tussilago farfara L. and is effective for diseases accompanied by dysbolism of arachidonic acid. CONSTITUTION: This arachidonic acid metabolism inhibitor contains, as active ingredients, one or more plants selected from Euphorbia lathyris L. Aqrimonia pilosa Ledeb.var. japonica, Artemisia capillaris Thumb and Tussilago farfara L. or their extracts. Particularly, it can be widely used in prophylaxis and treatment for bronchitis, asthma, allergic rhinitis, gout, arthritis, nephritis, hepatitis, psoriasis, urticaria, contact dermatitis, atopy dermatitis, ultraviolet inflammation. This inhibitor also can be used as a skin cosmetic. It can be applied in the form of emulsion, cream, milk cosmetic, solution cosmetic, oil cosmetic, pack, foundation or the like.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an arachidonic acid metabolism inhibitor, and more particularly to an arachidonic acid metabolism inhibitor useful for the prevention / treatment of diseases associated with increased metabolism of arachidonic acid.

[0002]

BACKGROUND ART Arachidonic acid is an unsaturated fatty acid having 20 carbon atoms that is released from cell membranes in response to various stimuli, and is converted into prostaglandins by a cyclooxygenase system and by a lipoxygenase system. It is known that it is metabolized into leukotrienes and HETEs (hydroxyeicosatetraenoic acids), and each metabolite is deeply involved in various allergic diseases and inflammatory diseases (protein, nucleic acid, enzyme, p546). -560,
35 (4) 1990; proteins, nucleic acids, enzymes, p136-
149, 33 (2) 1988; protein, nucleic acid, enzyme, p.
226-238, 33 (3) 1988).

On the other hand, in recent years, the number of patients with allergic diseases such as bronchial asthma and hay fever has increased with the occurrence of pollution such as changes in eating habits and living environment and air pollution, which is becoming a big social problem. Asthma is a condition in which patients with high airway hypersensitivity cause dyspnea due to increased vascular permeability, contraction of bronchial smooth muscle, increased secretion, etc. due to external allergens and nonspecific stimulation of the respiratory tract. Cases are fatal diseases. Steroids and antihistamines have been used as therapeutic agents for asthma, but since they have serious side effects, overcoming them is an important issue.

[0004] In recent years, with the progress of basic research on asthma, it has become clear that lipoxygenase metabolites among arachidonic acid metabolites play an important role in the pathological condition of asthma.

Further, psoriasis, which is a kind of skin disease, is an intractable chronic inflammatory keratosis which causes proliferation of epidermis and infiltration of inflammatory cells. Although the cause of psoriasis has not been clarified yet, the increase in the amount of lipoxygenase metabolites, leukotriene and HETEs, in relation to the relationship between psoriasis lesion formation and abnormal arachidonic acid metabolism. Is strongly suggested (Clinical skin, p1333-
1341, 35 (8) 1993).

Further, when the skin is exposed to ultraviolet rays, erythema (sunburn) occurs, which activates the arachidonic acid metabolic system and causes prostaglandin E ₂ and F (2α),
It is known that this is because substances such as 12-HETE are produced (Seminars in Dermat).
biology, p114-120, 11 (2) 1992;
Journal of the Japanese Dermatological Association, p645-652, 91 (6) 19
81; Photodermatology, p359-
366, 2, 1985).

As described above, arachidonic acid metabolites are considered to play an extremely important role in various allergic and inflammatory diseases. Inhibitors of these arachidonic acid metabolizing enzymes are the above-mentioned diseases accompanied by abnormal metabolism of arachidonic acid. It is considered to be useful as a therapeutic drug for various diseases.

Therefore, it is an object of the present invention to provide an arachidonic acid metabolism inhibitor which is effective in the treatment of diseases associated with abnormal arachidonic acid metabolism.

[0009]

[Means for Solving the Problems] In such a situation, the present inventor has conducted diligent studies, and as a result, a plant and its extract selected from Horthosoma japonicum, Astragalus vulgaris and subwinter winter have an excellent arachidonic acid metabolism inhibitory action. The inventors have found that they have the present invention and have completed the present invention.

That is, the present invention provides an arachidonic acid metabolism inhibitor characterized in that it contains, as an active ingredient, one or two or more kinds of plants selected from Horsanthium japonicum, Astragalus membranaceus, Spodoptera litura, and Scots winter, and extracts thereof. It is a thing.

Euphorbi used in the present invention
a lathyris L.) is a plant of Euphorbiaceae, which is widely distributed in China, and its seeds are sometimes used as laxatives.
It is also known to have an antitumor effect. Golden cypress (Aqrimonia pilosa Ledeb.var.japonica) is a perennial plant of the Rosaceae family, and is known for its hemostatic action, blood pressure raising action, and antibacterial action. Artemisia capillar
is Thumb.) is a perennial of the Asteraceae family whose main production area is China.
The seedling extract is known to have a bile action, a hypotensive action, and a diuretic action. Winter (Tussilago farfara
L.) is a perennial plant of the Asteraceae family, which is mainly produced in China, and was known to have a cough suppressant effect. However, it has not been known at all that these plants have an arachidonic acid metabolism inhibitory action.

[0012] The plant used in the present invention means one or two or more of the whole plants or leaves, barks, stems, roots, branches, fruits, seeds and flowers (hereinafter referred to as "article"). ) Or it is dried and crushed, and the plant extract is dried or crushed without drying the drug substance, and then extracted with a solvent at room temperature or under heating, or a Soxhlet extractor, etc. It means various solvent extracts obtained by extraction using an extraction device, diluted solutions thereof, concentrated solutions thereof, or dried powders thereof. It is preferable to use seeds for Holtose, whole plants for Astragalus japonicum, seedlings for Artemisia crocodile, and seedlings for the winter season, and dried roots or extracts thereof for use in the present invention.

Examples of the solvent used for extraction include water, organic solvents and mixtures thereof, with organic solvents being particularly preferred. Preferred specific examples of the organic solvent include hydrocarbons such as petroleum ether, cyclohexane, toluene and benzene; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; esters such as ether and ethyl acetate; ketones such as acetone. Alcohols such as butanol, propanol, ethanol, polyethylene glycol, propylene glycol, butylene glycol; pyridine and the like.

When, for example, aqueous alcohol is used as the organic solvent, a plant extract can be obtained by subjecting the plant to extraction treatment at 3 to 70 ° C. As a specific example of a preferable extraction method from the drug substance, 5000 ml of 70 v / v% ethanol is added to 1000 g of the dry pulverized product, extraction is performed for 7 days at room temperature with occasional stirring, and the obtained extract is filtered, The filtrate is allowed to stand at 5 ° C for 3 days and then filtered again to obtain a plant extract as a supernatant. The obtained plant extract can be used as it is as an active ingredient of the drug of the present invention, and the extract is diluted, concentrated, or lyophilized, and then prepared into powder or paste, and appropriately formulated to be used. You can also If necessary, it may be used after purification treatment such as deodorization and decolorization by a known method.

The blending amount of the above-mentioned active ingredient in the arachidonic acid metabolism inhibitor of the present invention is not particularly limited, but usually 0.1 to 0.1 as a dry solid content from the viewpoint of odor, feel, color, potency, physical properties and the like. It is preferably 70% by weight, more preferably 1 to 30% by weight.

The above plants or extracts thereof can be used as they are as anti-inflammatory agents, anti-allergic agents, etc., but oral preparations such as tablets, capsules, granules, powders, injections, suppositories, ointments, etc. It can also be formulated into a parenteral preparation for use. In the case of molding in the form of tablets, the carriers usually used for tablets can be widely used. Specific examples of such carriers include excipients such as starch, lactose, sucrose, carboxymethyl cellulose, corn starch, inorganic salts and urea; water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose. , Binders such as shellac, methylcellulose, calcium phosphate, polyvinylpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch , Disintegrants such as lactose, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, absorption enhancers such as sodium lauryl sulfate and quaternary ammonium salts; humectants such as glycerin and starch; starch Lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid; stearate,
Examples thereof include boric acid powder, purified talc, and lubricants such as polyethylene glycol. The tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multiple tablet.

In the case of molding in the form of pills, the carriers usually used in pills can be widely used. Specifically, excipients such as starch, lactose, glucose, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol;
Examples include disintegrants such as laminaran powder and agar powder.

In the case of molding in the form of suppositories, the carriers generally used in suppositories can be widely used. Specific examples thereof include cocoa butter, gelatin, polyethylene glycol, higher alcohols, esters of higher alcohols, and semisynthetic glycerides.

When prepared as an injection, it is desirable that the prepared solution, suspension and emulsion be sterilized and isotonic with blood. In preparing these forms, any of the diluents commonly used in injectable solutions can be used. Specific examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, a sufficient amount of salt, glucose, glycerin, etc. for preparing an isotonic aqueous solution may be contained in the pharmaceutical preparation, and a solubilizer, a buffering agent and a pain-relieving agent which are usually used may be included. You may add an agent etc.

When prepared as a propellant, those generally used as dispersants and propellants can be widely used. Specific examples of the dispersant include soybean lecithin, egg yolk lecithin, fatty acids such as oleic acid, linoleic acid, and linolenic acid; sorbitans such as sorbitan trioleate and sorbitan monooleate. Further, as the propellant, Freon 11, Freon 12, Freon 114
And the like non-combustible liquefied gas such as usual.

When prepared as an ointment, the compounding ingredients usually used for the preparation of ointments can be widely used. Specifically, water, ethanol, isopropyl alcohol, glycerin, polyethylene glycol, sorbitol, polyvinyl alcohol, and other polyhydric alcohols; animal fats, vegetable fats, mineral oils, hardened oils, waxes such as beeswax, etc .; liquid paraffin, paraffin wax Higher hydrocarbons such as; stearic acid and other fatty acids; emulsifiers; anionic surfactants, cationic surfactants, amphoteric surfactants and other surfactants; xanthan gum, sodium alginate, methyl cellulose, hydroxyethyl cellulose, carboxyvinylyl polymer, etc. And the water-soluble polymer compound.

These preparations may further contain coloring agents, preservatives, perfumes, flavors, sweeteners and other pharmaceuticals in the pharmaceutical preparation, if necessary.

There is no particular limitation on the method of administration of the above-mentioned preparation, and the preparation is administered according to the preparation form, conditions such as age and sex of the patient, and degree of disease of the patient. For example, tablets, pills, granules,
Capsules are administered orally, solutions, suspensions, injections such as emulsions are administered alone or mixed intravenously with usual replenishers such as glucose and amino acids, and, if necessary, intramuscularly alone, It is administered intradermally, subcutaneously or intraperitoneally. Suppositories are administered rectally, sprays are administered to the bronchi by spraying the mouth or nose, and ointments are applied directly to the lesion site.

The arachidonic acid metabolism inhibitor of the present invention can also be used as a skin cosmetic, for example, oil / water type, water / water type.
It can be used in the form of oil-based emulsified cosmetics, creams, cosmetic emulsions, lotions, oily cosmetics, packs, foundations and the like.

[0025]

INDUSTRIAL APPLICABILITY The arachidonic acid metabolism inhibitor of the present invention has an excellent arachidonic acid metabolism inhibitory effect and is useful for the prevention and treatment of diseases accompanied by accelerated arachidonic acid metabolism. Therefore, it can be widely applied to the prevention and treatment of bronchitis, asthma, allergic rhinitis, gout, arthritis, nephritis, hepatitis, psoriasis, urticaria, contact dermatitis, atopic dermatitis, ultraviolet inflammation and the like.

[0026]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Production Example 1 Production method of Spinach extract: 1 kg of crushed Holtoso seeds was immersed in 5 liters of 70% ethanol at room temperature for 1 week to extract a 70% ethanol-soluble component. The same operation was repeated for the residue obtained by separating the extract, and a total of 10 liters of extract was obtained. The solvent of this extract was distilled off, and the residue was dried under reduced pressure to give 30 g of an extract.

Production Example 2 Production method of Agrimony japonicus extract:
25 g of an extract was obtained in the same manner as in Production Example 1 except that 1 kg of ground beetle crushed product was used in Production Example 1.

Production Example 3 Production Method of Kawamura Artemisia Extract:
20 g of an extract was obtained in the same manner as in Production Example 1 except that 1 kg of Sagebrush seedlings were used in Production Example 1.

Manufacturing Example 4 Manufacturing method of subsection Winter extract: Manufacturing Example 1
Production Example 1 except that 1 kg of crushed winter roots were used in
16 g of an extract was obtained in the same manner as in.

Test Example 1 Leukotriene C ₄ production inhibitory effect evaluation test: rat basophilic leukemia cell line (Rat
Basophillic Leukemia Cell:
RBL-1) was suspended in D-PBS (+), 2 × 10 ⁵ cells were taken in each of 4 plastic tubes, and 0.0005% by weight (final concentration) of each plant extract was added as a solid content. After incubating at 37 ° C for 15 minutes,
Calcium ionophore A23187 (final concentration 2.5
μM) was added. After further incubation for 15 minutes, EDTA (final concentration 4 mM) was added and ice-cooled to 20
Centrifugation was carried out at 00 rpm for 5 minutes to collect the supernatant. Next, leukotriene C ₄ contained in this supernatant was quantified using a radioimmunoassay method to evaluate the leukotriene C ₄ production inhibitory effect. The results are shown in Table 1.

[0032]

[Table 1]

From Table 1, it was confirmed that the plant extract according to the present invention has an excellent arachidonic acid metabolism inhibitory action.

Test Example 2 Anti-inflammatory effect evaluation test: After shaving the back hair of Hartley white guinea pigs with a hair clipper and a shaver, a plant extract (2% ethanol solution, 25 μl) 2 hours before and 6 hours after induction. Was applied. 0.2% croton oil was used for the induction, and 24 hours after the induction, the degree of erythema was visually determined according to the Japanese Dermatological Association standard (scoring standard). In addition, a sample coated with ethanol alone as a control and a sample coated with croton oil for comparison were tested in the same manner as the sample. Table 2 shows the results.

-Japanese Dermatological Association Standard 0 (-): No reaction. 0.5 (±): Mild or partial erythema. 1.0 (+): Clear full-scale erythema. 2.0 (++): erythema and edema. 3.0 (+++): Erythema, edema and vesicles.

[0036]

[Table 2]

From Table 2, it was confirmed that the plant extract according to the present invention has an excellent anti-inflammatory effect.

The formulations shown in Examples 1 to 5 and the cosmetics shown in Example 6 were prepared.

Example 1 Tablet: The following ingredients were uniformly mixed and compression-molded with a tableting machine to obtain a tablet weighing 200 g.

[0040]

[Table 3] (Components) (g) Quercus cypress extract 10 Corn starch 30 Starch 30 Carboxymethyl cellulose 5 Magnesium stearate 5 Lactose 20 Total 100

Example 2 Granules: The following components were uniformly mixed, kneaded, granulated by an extrusion granulator and sieved to obtain granules.

[0042]

[Table 4] (Components) (g) Kawamura wormwood extract 10 Crystalline cellulose 50 10% Hydroxypropyl cellulose 40 Total 100

Example 3 Spray: A spray containing the following components in one cylinder was prepared by a conventional method.

[0044]

[Table 5] (Components) (g) Subsection Winter extract 1 Oleic acid 3 Freon 11 1.2 Freon 12 2.5 Freon 114 1.3 Total 9

Example 4 Ointment: The following components were uniformly mixed to obtain an ointment.

[0046]

[Table 6] (Ingredients) (g) Kawamura wormwood extract 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.

[0048]

[Table 7] (Component) (g) Quercus cypress extract 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.

[0050]

Table 8 (Components) (g) Spinach extract 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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 7/48 (72) Inventor Ichiro Tokimitsu 89-28 Takebayashi-cho, Utsunomiya-shi, Tochigi Prefecture

Claims (1)

[Claims] 1. An arachidonic acid metabolism inhibitor, which comprises, as an active ingredient, one or two or more kinds of plants or extracts thereof, which are selected from spinach, quince spruce, sagebrush, and winter.