JP3323765B2 - Cell adhesion inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a cell adhesion inhibitor useful as a cancer metastasis inhibitor, an antiallergic agent, an antiinflammatory agent, a prophylactic / therapeutic agent for chronic arthritis, and a prophylactic / therapeutic agent for arteriosclerosis.

[0002]

2. Description of the Related Art In recent years, research at the molecular level regarding various inflammations, allergic reactions, immune reactions, cancer metastasis, arteriosclerosis, etc. has been advanced, and leukocytes and vascular endothelial cells and cancer cells are common to these diseases. It has become clear that adhesion between cells such as vascular endothelial cells is greatly involved.

When various stimuli (chemical substances, sunlight (ultraviolet rays), virus infection, bacterial infection, trauma, etc.) are applied to a living body,
A series of inflammatory reactions are induced, followed by vasodilation and increased vascular permeability, and then leukocytes such as neutrophils, macrophages, and T cells infiltrate into the inflammatory foci. In addition, when a foreign substance enters a living body from the outside, a series of immune reactions are induced in the living body, and a large number of leukocytes infiltrate the site, resulting in a so-called inflammatory reaction. Here, when leukocytes infiltrate into tissues from blood vessels,
It is known that leukocytes and vascular endothelial cells adhere via specific cell adhesion molecules present on their respective cell surfaces. Vascular endothelial cells are IL-1, cytokines such as TNF,
When activated by active oxygen, etc., ICAM
Adhesion molecules such as -1, ELAM-1, VCAM-1, and GMP-140 are induced. Then, leukocytes are expressed on the surface of LFA-1, Mac
-1, Sialyl Lewis X (sLe ^x ), Sialyl Lewis a (sLe ^a ), VL
It adheres to endothelial cells via molecules such as A-4, and most of the adhered leukocytes migrate directly into the tissue, and a series of inflammation and immune reactions progress. Therefore, adhesion between leukocytes and vascular endothelial cells is considered to be a very important step in the course of a series of inflammation and immune reactions as well as leukocyte infiltration.

[0004] The role of cell adhesion molecules in antigen recognition and activation of various immune cells, particularly T cells, has also been elucidated. Central to the T cell antigen recognition and subsequent activation process is the T cell receptor (TC
R) and CD3 (TCR / CD3), but TCR on T cells
To efficiently recognize a complex of an antigen peptide on an antigen presenting cell (APC) and a major histocompatibility complex (MHC), it is necessary to intervene some adhesion molecules acting on the binding between the two cells. First, LFA-1 and CD2 on T cells adhere nonspecifically to antigen by binding between TCAM and cells using ICAM-1 and LFA-3 on APC as ligands. TCR
Recognizes the antigen / MHC complex on the APC, the binding via LFA-1 is strengthened and antigen-specific adhesion occurs. This APC
The TCR on the T cell promotes the recognition of the antigen on the APC by the stable adhesion, and the TCR / CD3 complex emits a strong signal that induces the expression of T cell functions such as cytotoxicity or lymphokine production. In addition, these adhesion molecules not only enhance T cell antigen reactivity by increasing T cell-APC binding and helping TCRs to recognize antigens, but also signal themselves to regulate T cell activation. It is also clear that As described above, T cells recognize the antigen peptide presented on the APC by the TCR / CD3 complex and activate antigen-specifically.
T cells alone cannot induce sufficient proliferative differentiation by stimulation through 3 alone, but also do not respond to any subsequent stimuli in an unresponsive state or clonal anergy
Into a state called. And T cell activation requires TC
A second stimulus (co-stimulus) supplied from the APC other than the R / CD3-mediated stimulus is required. To date, the second stimulus involved in T cell activation has been CD2 on T cells / APC, respectively.
8 / B7-1, CD28 / B7-2, LFA-1 / ICAM-1, VLA-4 / VCAM-1, CD2
/ LFA-3, CD40L / CD40 and the like are known, and it has been revealed that these adhesion molecules play a very important role in regulating immune responses. Therefore, the so-called Anti-adhesion therapy, which attempts to control cell-cell adhesion and cell-cell interaction through such adhesion molecules to control inflammation and immune response,
Substances that actually inhibit cell adhesion have been applied to various animal models (ischemia-reperfusion injury, asthma, dermatitis, lung injury and kidney injury due to complement activation and immune complexes, etc.), and have good improvement effects. It recognized.

On the other hand, cancer metastasis includes (1) detachment and release of cancer cells grown in the primary focus into blood vessels and lymph vessels, (2) migration of cancer cells in blood vessels and lymph vessels, and (3) cancer cell growth. Is considered to be established through four steps: adhesion to peripheral vascular endothelium, and (4) formation of metastatic foci by infiltration of cancer cells into basement membrane and connective tissue. Of these, the cell adhesion molecule plays a major role mainly in the aspect of detachment from the primary focus and the aspect of adhesion to vascular endothelial cells and lymphatic endothelial cells. Expressed on vascular endothelial cells and known as molecules involved in cancer metastasis, such as ICAM-1, VCAM-1, ELAM-1, etc., and corresponding leukocyte side ligands are LFA-1, VLA-4, Si
alyl Lewis X (sLe ^x ) and Sialyl Lewis a (sLe ^a ) have been identified. Among malignant cells, leukemia cells frequently express these cell adhesion molecules and their ligands, and are considered to be involved in extravasation of leukemia cells. It is known that many melanomas, neuroblastomas and osteosarcomas adhere to vascular endothelial cells in the VCAM-1 / VLA-4 system. In gastric cancer, colorectal cancer, lung cancer, liver cancer, pancreatic cancer, etc., it is thought that ELAM-1 plays a leading role [`` regulation of adhesion molecule expression and clinical application ”(Medical View, 1991), Nature, Vol.364, 149-155
(1993), Science, Vol.247, 456-459 (1990), Annual Re
view Immunity 1989, 175-185, Trends in Glycoscience an
d Glycotechnology, Vol. 4, No. 19, 405-414 (1992), Experimental Medicine Vol. 10, No. 11, 1402-1413 (1992), Experimental Medicine Vo
l.11, No.16, 2168-2175 (1993), Annual Review Immunity 1
989, 175-185, Infection, inflammation, and immunity Vol. 19 (2), 129-153
(1989), Infection / Inflammation / Immunity Vol.24 (3), 158-165 (1994),
Molecular Medicine, Vol.32 (4), 348-355 (1995), History of Medicine Vol.174 (1), 41-45 (1995), Clinical Immunity Vpl.27
(11), 1302-1308 (1995), Clinical Immunity Vol. 27 (4), 388-392
(1995), Experimental Medicine Vol.10 (11), 1388-1395 (1992), Experimental Medicine Vol.12 (8), 906-964 (1994), History of Medicine Vol.16
9 (1), 108-111 (1994), History of Medicine Vol.169 (1), 103-
107 (1994), Advances in Immunology, Vol. 58, 345-41
6].

[0006] In the early stage of atherosclerosis, local aggregation of cells derived from monocyte macrophages called foam cells, which have accumulated a large amount of esterified cholesterol in the cells, is observed in the subendothelium. It is also known that atherosclerotic lesions have T lymphocytes. The involvement of cell adhesion molecules on vascular endothelial cells is also known for the accumulation of leukocytes at the site of arteriosclerosis, and is recognized as an important initial step in the onset process of arteriosclerosis.

Thus, it is clear that cell adhesion between leukocytes and cancer cells and vascular endothelial cells via cell adhesion molecules plays a very important role in inflammation, immune response, arteriosclerosis and metastasis of cancer. In addition, it has been widely shown and recognized that cell adhesion inhibitors are effective in suppressing inflammation, immune response, arteriosclerosis and cancer metastasis, both theoretically and at the level of animal experiments. Many researchers, including the present applicant, have been searching for a cell adhesion inhibitor for the purpose of suppressing or controlling inflammation, allergic reaction, immune reaction, cancer metastasis, arteriosclerosis, and the like.

[0008] So far, these substances that suppress cell adhesion include antibodies and ligands (sLe ^x ) against cell surface adhesion molecules, N- (fluorenyl-9-methoxycarbonyl) aminoacetic acid, 3-deazaadenosine and the like [ Proc. Natul.
Acad. Sci. USA, Vol. 88, 355-359 (1991), Immunopharm
acology, 23, 139-149 (1992), J. Biological Chemistr
y, Vol.267 (13), 9376-9382 (1992), J. Immunology, Vo
l. 144 (2), 653-661 (1990)].

[0009]

However, the effect has not been satisfactory. Accordingly, an object of the present invention is to provide a safe and excellent cell adhesion inhibitor which is useful as a cancer metastasis inhibitor, an antiallergic agent, an antiinflammatory agent, an agent for preventing and treating arteriosclerosis, and the like.

[0010]

Under such circumstances, the present inventors have conducted tests on the cell adhesion inhibitory effects of a large number of plant extracts, and as a result, it has been found that asunaro (Thuj
opsis dolabrata) or its extract has an excellent inhibitory effect on cell adhesion, and is useful as an antiallergic agent, antiinflammatory agent, cancer metastasis inhibitor, therapeutic agent for chronic arthritis, therapeutic agent for arteriosclerosis, etc. The present inventors have found such a fact and completed the present invention.

That is, the present invention provides a cell adhesion inhibitor containing asnaro or an extract thereof as an active ingredient.

The present invention also provides a cancer metastasis inhibitor, an antiallergic agent, an antiinflammatory agent, a prophylactic / therapeutic agent for chronic arthritis, and a prophylactic / therapeutic agent for arteriosclerosis, which contain asnaro or an extract thereof as an active ingredient. .

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Asunaro is a special product belonging to Japan and is an evergreen tree that is distributed in Honshu, Shikoku and Kyushu, and its wood is used as Wajima-coated wood. However, regarding the biological activity of asnaro, the antimicrobial effect (Japanese Unexamined Patent Publication No. 2-6280)
No. 9), a whitening effect (JP-A-5-345710) and a bone disease preventive effect (JP-A-6-340542) have been reported so far, and their cell adhesion is suppressed. No action is known at all.

In the present invention, asunaro is mainly composed of leaves,
Dry and pulverized materials such as twigs and the like (hereinafter referred to as "the raw material") can be used as they are, but it is preferable to use those extracts. Asunaro extract, mainly pulverized without drying or drying the leaves, twigs, etc. of asunaro,
It can be obtained by extraction with a solvent at room temperature or under heating, or with an extraction device such as a Soxhlet extractor. In addition, the asunaro extract in the present invention means various solvent extracts or diluents, concentrated liquids or dried powders thereof.

[0015] The solvent extract may be prepared by converting the asnalo substance or its dried powder into water, an organic solvent (a hydrocarbon solvent such as petroleum ether, n-hexane, cyclohexane, toluene and benzene; a halogen such as dichloromethane, chloroform and carbon tetrachloride). Hydrocarbons; ether solvents such as diethyl ether;
Ester solvents such as ethyl acetate; ketones such as acetone; basic solvents such as pyridine; monohydric or polyhydric alcohol solvents such as butanol, propanol, ethanol, methanol, polyethylene glycol, propylene glycol, and butylene glycol), It is usually obtained by performing an extraction treatment at 3 to 70 ° C. using aqueous alcohol or the like.

As a preferred specific example of extraction from the asnaro raw material, 100 g of dried and ground asnaro is added to ethanol 1
Immersion in a liter, extraction is performed for 7 days with occasional stirring at room temperature, the obtained extract is filtered, the filtrate is allowed to stand at 5 ° C. for 3 days, and then filtered again to obtain a supernatant. .

The above extract can be used as it is as an active ingredient of the cell adhesion inhibitor of the present invention and other pharmaceuticals. After concentrating the extract, the extract is further subjected to appropriate separation means, for example, gel filtration or silica gel column chromatography. A fraction having a high activity can be fractionated and used by a high performance liquid chromatography method or the like.

The above asnaro or its extract can be used as it is or after being diluted, concentrated or freeze-dried, prepared in powder or paste form and appropriately formulated and used. Further, if necessary, a purification treatment such as deodorization and decoloration using activated carbon or the like may be performed before use.

Asnaro or its extract has low cytotoxicity, has an excellent cell adhesion inhibitory action,
It is useful as an anti-inflammatory agent, a cancer metastasis inhibitor, an immunosuppressant, a therapeutic agent for rheumatoid arthritis and / or chronic arthritis, a therapeutic agent for preventing arteriosclerosis, and the like.

In the medicament of the present invention, in addition to asnaro or its extract, existing drugs such as anti-inflammatory agents, anti-allergic agents, anti-histamines and the like can be arbitrarily combined and compounded. Formulated in any form with excipients and other additives. Examples of such excipients and additives include lactose, kaolin,
Sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride, and the like.As liquid ones, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, Examples include propylene glycol and water.

The dosage form of the preparation of the present invention is not particularly restricted but includes, for example, tablets, powders, granules, capsules, suppositories, troches, syrups, emulsions, soft gelatin capsules, creams, gels, pastes, sprays, Injections and the like can be mentioned. The use of the preparation of the present invention is not limited to pharmaceuticals, and it goes without saying that it can be used in quasi-drugs, cosmetics, foods, beverages, and the like.

The preparation of the present invention can be orally administered depending on its dosage form.
It can be administered to humans by any route such as enteral, external, and injection. The dose varies depending on various factors such as age, body weight, sex, symptoms, therapeutic effect, administration method, treatment time and the like, and is not particularly limited. In this case, it is preferable to administer a dose of 0.1 to 2000 mg, especially 10 to 1000 mg, once a day, once a day or several times per adult. In the case of parenteral administration, it is usually 0.
It is preferable to administer the dose in the range of 1 to 2000 mg, particularly 10 to 500 mg, once to several times a day.

[0023]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Production Example 1 Production of asnaro extract (1):
1 kg of ground material of asunaro (mixture of leaves and twigs) was immersed in 8 liters of ethanol at room temperature for 7 days to extract ethanol-soluble components. Next, the same operation was performed again on the residue from which the extract was separated, to obtain a total of 16 liters of the extract. The solvent of this extract was distilled off and evaporated to dryness under reduced pressure.
I got

Production Example 2 Production of asunaro extract (2):
1 kg of ground material of asunaro (mixture of leaves and twigs) was immersed in 8 liters of ethanol at room temperature for 7 days to extract ethanol-soluble components. Next, the same operation was performed again on the residue from which the extract was separated, to obtain a total of 16 liters of the extract. After evaporating the solvent of this extract and concentrating to 1 liter, 30 g of activated carbon was added, and the mixture was stirred for 6 hours, subjected to deodorization and decolorization treatment, filtered off the activated carbon, and concentrated under reduced pressure to extract the filtrate. 65 g of the product were obtained as a syrup.

Production Example 3 Production of asunaro extract (3):
The same operation as in Production Example 1 was performed except that 8 liters of 75% aqueous ethanol was used instead of 8 liters of ethanol, to obtain 79 g of an extract.

Production Example 4 Production of Asunaro extract (4):
In Preparation Example 1, the same operation was performed except that 8 liters of n-hexane was used instead of 8 liters of ethanol.
52 g of extract were obtained.

Test Example 1 Leukocyte-Vascular Endothelial Cell Adhesion Inhibition Test: A test substance was added to human vascular endothelial cells that had become confluent on a 96-well culture plate to a final concentration of 0.0001% by weight. After 18 hours, human IL-1α was added to a final concentration of 2.5 ng / ml, and the cells were cultured for 6 hours.
After removing the culture solution, the cells were washed twice with an RPMI-1640 medium, and human peripheral leukocytes (10 ⁶ cells / m 2) previously labeled with ⁵¹ Cr.
l) was added and cultured. After 30 minutes, the non-adhered cells were removed, the adhered cells were lysed, and the radioactivity was measured. As a result, as shown in Table 1, it was found that the asnaro extract had an excellent activity of suppressing cell adhesion between leukocytes and vascular endothelial cells. Therefore, asnaro or an extract thereof is useful as a preventive or therapeutic agent for diseases caused by adhesion of leukocytes to various cells, for example, allergic diseases, inflammatory diseases, and immune diseases.

[0029]

[Table 1]

Test Example 2 Cancer Cell-Vascular Endothelial Cell Adhesion Inhibition Test: A test substance was added to a confluent human vascular endothelial cell on a 96-well culture plate to a final concentration of 0.0001% by weight. After 18 hours, human IL-1α was added to a final concentration of 2.5 ng / ml, and the cells were cultured for 6 hours.
After removing the culture solution, the cells were washed twice with an RPMI-1640 medium, and then human bone marrow tumor cells HL-60 (10 ⁶ ce) previously labeled with ⁵¹ Cr.
(lls / ml) was added and cultured. After 30 minutes, the non-adhered cells were removed, the adhered cells were lysed, and the radioactivity was measured. As a result, as shown in Table 2, it was found that the asnaro extract strongly suppressed adhesion between cancer cells and vascular endothelial cells, which is important for cancer cell metastasis.

[0031]

[Table 2]

Test Example 3 Toxicity test on vascular endothelial cells (cell morphology, DNA synthesis): Morphological changes were determined by visual inspection using an inverted microscope, and DNA synthesis was performed by ³ H-
Using the incorporation of thymidine as an index, the amount of incorporation in the last 8 hours of culture for 24 hours after the addition of the test substance was evaluated using a liquid scintillation counter. The test substance concentration was 0.
0001% by weight. As a result, as shown in Table 3, all the asnalo extracts were low toxic to vascular endothelial cells.

[0033]

[Table 3]

Test Example 4 Adjuvant arthritis inhibitory effect: After measuring the body weight and the volume of both hind limbs of Wistar rats, the rats were divided into groups so that the average of the volume and weight of the right hind limb were almost uniform, and left under ether anesthesia. Mycob on hind limb footpad
acterium butyricum / liquid paraffin (0.5mg / 0.1ml /
Was administered subcutaneously. Control group (4,40,400 mg / kg / day) with asnaro extract (the extract obtained in Production Example 1 was dissolved in ethanol so as to contain 0.8% by weight as a dry solid content. The same applies hereinafter), control Indomethacin and dexamethasone administration groups (0.4 mg / kg / da each)
y), a solvent (ethanol) administration group and an arthritis non-induction group were provided, and each test substance was intraperitoneally administered once a day for 21 days from the day of adjuvant arthritis induction. On day 22, the right hind limb volume was measured. The suppression rate was calculated. As a result, as shown in Table 4, it was found that asnaro extract had a strong adjuvant arthritis inhibitory effect.

[0035]

[Table 4]

Test Example 5 Inhibitory effect on type II collagen arthritis: After measuring the weight of Wistar rats and the volume of both hind limbs, the rats were divided into groups so that the average of the volume and weight of the right hind limb were almost uniform, and on the day and on the 14th Subsequent subcutaneous ridge subcutaneous II
100 μl of type II collagen (2 mg / ml 0.01 N acetic acid) was administered.
Asunalo extract administration group (4,40,400 mg / kg / day), indomethacin administration group as control drug, dexamethasone administration group (0.4 mg / kg / day each), solvent (ethanol) administration group and non-arthritis induction group were established. Each test substance was intraperitoneally administered once a day for 21 days from the day when collagen arthritis was induced. On the 22nd day, the volume of both hind legs was measured and the arthritis inhibition rate was calculated. As a result, as shown in Table 5, it was found that asnaro extract had a strong collagen arthritis inhibitory effect.

[0037]

[Table 5]

Test Example 6 Cell adhesion inhibitory effect in rabbit atherosclerosis model: New Zealand white rabbits were used. High cholesterol diet (1% cholesterol, 9
% Coconut oil, 1% corn oil; 200g / day
Feeding) induced leukocyte adhesion to the arterial endothelium, referred to as the first stage of sclerotic lesion formation in the arteries. The asunalo extract administration group (4,40,400 mg / kg / day), the control drug probucol administration group (4 mg / kg / day), the solvent (ethanol) administration group, and the normal diet group were established. Orally once daily. Six weeks later, the aortic arch was collected, and the number of leukocytes adhered to arterial endothelial cells (number / mm ² ) was calculated under an optical microscope. As a result, as shown in Table 6, it was found that asunaro extract has a strong cell adhesion inhibitory effect.

[0039]

[Table 6]

Test Example 7 Effect of suppressing fibrosis and atherosclerosis in a rabbit arteriosclerosis model: New Zealand white rabbits were used. High cholesterol diet (1% cholesterol, 9% coconut oil, 1% corn oil; 20
0g / day feeding) induced atherosclerotic foci and atherosclerosis, a pre-stage thereof. The asunalo extract administration group (4,40,400 mg / kg / day), the control drug probucol administration group (4 mg / kg / day), the solvent (ethanol) administration group, and the normal diet group were established. 1 per day
Oral administration was performed. Thirty weeks later, the aortic arch was harvested, collagen fiber staining of paraffin-embedded sections and lipid staining of the aortic lumen were performed, and the collagen fiber staining positive area (%) and fat staining positive area (%) were determined under a light microscope. Calculated. As a result, as shown in Tables 7 and 8, it was found that asnaro extract had a strong fibrosis and atherosclerosis inhibitory effect.

[0041]

[Table 7]

[0042]

[Table 8]

Example 1 Tablets 9 mm in diameter and 200 mg in weight using the following ingredients according to a conventional method.
Tablets were produced.

Example 2 Filling Agent for Hard Capsules A filling agent for hard capsules was produced according to a conventional method using the following components.

Example 3 Granules Granules were produced using the following components according to a conventional method.

Example 4 Cream A cream was prepared by mixing the following ingredients according to a conventional method. (Composition) (% by weight) Asnalo extract obtained in Production Example 1 1.0 Cholesterol 0.5 Cholesteryl isostearate 1.0 Polyether-modified silicone 1.5 Cyclic silicone 20.0 Methylphenylpolysiloxane 2.0 Methylpolysiloxane 2.0 Magnesium sulfate 0.5 55% ethanol 5.0 Carboxymethyl Chitin 0.5 Purified water Fuel gauge 100.0

Example 5 Ointment The following components were mixed in a conventional manner to produce an ointment. (Composition) (% by weight) Asnaro extract obtained in Production Example 1 3 Cholesteryl isostearate 3 Liquid paraffin 10 Glyceryl ether 1 Glycerin 10 White petrolatum 73 Total 100

Example 6 Cream The following ingredients were mixed in a conventional manner to produce a cream. (Composition) (% by weight) Asnalo extract obtained in Production Example 1 1.0 Cholesterol 0.5 Cholesteryl isostearate 1.0 Polyether-modified silicone 1.5 Cyclic silicone 20.0 Methylphenylpolysiloxane 2.0 Methylpolysiloxane 2.0 Magnesium sulfate 0.5 55% ethanol 5.0 Carboxymethyl Chitin 0.5 Dipotassium glycyrrhizinate 0.5 Purified water Fuel gauge 100.0

Example 7 Cream According to the following formulation, components (1) to (5) were dissolved by heating and mixed.
Keep at 70 ° C to make oil phase. Minutes (6) to (12) are evenly dispersed in (14), and kept at 75 ° C. to obtain an aqueous phase. The aqueous phase was added to the oil phase to emulsify and disperse. The component (13) was added and the mixture was cooled to 30 ° C. with stirring to produce a cream. (Composition) (% by weight) (1) Asnaro extract obtained in Preparation Example 1.0 (2) Squalane 11.5 (3) Cetyl alcohol 2.5 (4) Polyoxyethylene (20) sorbitan monostearate 1.0 (5) Polyoxy Ethylene (20) cetyl ether 2.5 (6) 1,3-butylene glycol 4.0 (7) Propylene glycol 3.5 (8) Titanium dioxide 7.0 (9) Bengala 0.5 (10) Yellow iron oxide 0.2 (11) Black iron oxide 0.1 (12) ) Methyl paraoxybenzoate 0.3 (13) Fragrance 0.1 (14) Purified water Fuel gauge 100.0

Example 8 Cream According to the following formulation, components (1) to (9) were dissolved by heating and mixed.
Keep at 70 ° C to make oil phase. Components (10) to (12) are uniformly dispersed in (14), and kept at 75 ° C. to form an aqueous phase. The aqueous phase was added to the oil phase to emulsify and disperse. The component (13) was added and the mixture was cooled to 30 ° C. with stirring to produce a cream. (Composition) (% by weight) (1) Asnaro extract obtained in Production Example 2 1.0 (2) Squalane 5.5 (3) Olive oil 3.0 (4) Stearic acid 2.0 (5) Beeswax 2.0 (6) Octyldodecyl myristate 3.5 ( 7) Polyoxyethylene (20) cetyl ether 3.0 (8) Behenyl alcohol 1.5 (9) Glycerin monostearate 2.5 (10) 1,3-butylene glycol 8.5 (11) Methyl parahydroxybenzoate 0.2 (12) Ethyl paraoxybenzoate 0.2 (13) Fragrance 0.1 (14) Purified water Fuel gauge 100.0

Example 9 Cream (Oil-in-Water Emulsion) The following components were mixed according to a conventional method to produce a cream. (Composition) (% by weight) Asnaro extract obtained in Production Example 2 0.25 Glyceride stearate 2.00 Polysorbate 60 (Tween 60 manufactured by ICI) 1.00 Stearic acid 1.40 Metronidazole 1.00 Triethanolamine 0.70 Carbomer 0.40 Liquid component of carite nut butter 12.00 Vaseline oil 12.00 Antioxidant 0.05 Perfume 0.50 Preservative 0.30 Purified water Fuel gauge 100.00

Example 10 Cream (Oil-in-Water Emulsion) The following components were mixed according to a conventional method to produce a cream. (Composition) (% by weight) Asnaro extract obtained in Production Example 2 0.25 Glyceride stearate 2.00 Polysorbate 60 (Tween 60 manufactured by ICI) 1.00 Stearic acid 1.40 Glycyrrhetinic acid 2.00 Triethanolamine 0.70 Carbomail 0.40 Liquid component of carite nut butter 12.00 Sunflower oil 10.00 Antioxidant 0.05 Fragrance 0.50 Preservative 0.30 Ceramide 0.10 Purified water Fuel gauge 100.00

Example 11 Tablets Tablets were produced according to a conventional method using the following components.

Example 11 Tablet The following ingredients were uniformly mixed, and compression-molded with a tableting machine to form one tablet.
200 mg tablets were produced.

Example 12 Tablets According to the following formulation, a part of (1), (4) and (2) was uniformly mixed, compression-molded, pulverized, and the remaining amount of (3) and (2) was added. Then, the mixture was compression-molded with a tableting machine to produce a tablet of 200 mg per tablet.

Example 13 Granules The following components were uniformly mixed, kneaded, granulated by an extrusion granulator, dried, and sieved to produce granules.

Example 14 Capsules The following ingredients were mixed uniformly, and 200 mg was filled in No. 2 capsule.

Example 15 Injection According to the following formulation, (5) was dissolved in (1) and (3), and
And the solution of (4) was added and emulsified to produce an injection.

[0059]

EFFECT OF THE INVENTION Asnaro or asnaro extract has low cytotoxicity and has an excellent cell adhesion inhibitory effect, and is an antiallergic agent, an antiinflammatory agent, a cancer metastasis inhibitor, a prophylactic / therapeutic agent for chronic arthritis, an arteriosclerosis prevention Useful as a therapeutic. Therefore,
A preparation containing this as an active ingredient is based on its cell adhesion inhibitory action and other actions, and is based on bronchitis, asthma, allergic rhinitis, gout, chronic arthritis, nephritis, psoriasis, urticaria, contact dermatitis, atopic dermatitis Widely used in the prevention and treatment of UV inflammation, hay fever, ischemia-reperfusion injury, acute respiratory distress syndrome, arteriosclerosis, ulcerative colitis, septic shock, trauma, burns, various types of cancer metastasis, acute alveolar injury, etc. Can be.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 19/02 A61P 19/02 29/00 29/00 35/04 35/04 37/08 37/08 43/00 101 43 / 00 101 (72) Inventor Yoshinori Nishizawa 2606 Kabane-cho, Akaga-cho, Haga-gun, Tochigi Pref. In the Kao Co., Ltd. 63-150208 (JP, A) JP-A-4-139125 (JP, A) JP-A-9-315960 (JP, A) Biol. Pharm. Bull, 1993, Vol. 16, No. 5, pp. 521-523 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 35/78 A61K 7/00 BIOSIS (DIALOG) CA (STN) MEDLINE (STN)

Claims (6)

(57) [Claims] 1. A cell adhesion inhibitor comprising asnaro or an extract thereof as an active ingredient. 2. A cancer metastasis inhibitor comprising asnaro or an extract thereof as an active ingredient. 3. An antiallergic agent comprising asnaro or an extract thereof as an active ingredient. 4. An anti-inflammatory agent comprising asnaro or an extract thereof as an active ingredient. 5. A prophylactic and / or therapeutic agent for chronic arthritis comprising asnaro or an extract thereof as an active ingredient. 6. A prophylactic / therapeutic agent for arteriosclerosis comprising asunaro or an extract thereof as an active ingredient.