WO2006123550A1 - Agent prophylactique ou therapeutique pour les maladies inflammatoires - Google Patents

Agent prophylactique ou therapeutique pour les maladies inflammatoires Download PDF

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WO2006123550A1
WO2006123550A1 PCT/JP2006/309298 JP2006309298W WO2006123550A1 WO 2006123550 A1 WO2006123550 A1 WO 2006123550A1 JP 2006309298 W JP2006309298 W JP 2006309298W WO 2006123550 A1 WO2006123550 A1 WO 2006123550A1
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acid
salt
pharmaceutically acceptable
ester
inflammatory disease
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PCT/JP2006/309298
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English (en)
Japanese (ja)
Inventor
Nobushige Doisaki
Kiyomi Furihata
Kazuhiko Hata
Jiro Takeo
Hiroko Miyahara
Shinya Yamashita
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Nippon Suisan Kaisha, Ltd.
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Priority to JP2007516248A priority Critical patent/JP5046926B2/ja
Publication of WO2006123550A1 publication Critical patent/WO2006123550A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a preventive or therapeutic agent for inflammatory diseases comprising 6,9,12,15-hexadecatetetraenoic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.
  • a preventive or therapeutic agent for inflammatory diseases comprising 6,9,12,15-hexadecatetetraenoic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.
  • Their use for the manufacture of a medicament for the prevention or treatment of inflammatory diseases, or a method for the prevention or treatment of inflammatory diseases in which a pharmacologically effective amount thereof is administered to a human or non-human warm-blooded animal About.
  • Inflammation is (1) a phenomenon resulting from the body's defense reaction against pathogenic microorganisms (2) classically accompanied by redness, pain, swelling, and fever (3) loss of tissue function (4) immune system Site force-in secreted from cells mediates various reactions.
  • the collective term for diseases associated with these conditions is inflammatory disease.
  • cycloxygenase plays a central role in various cytokines.
  • cycloxygenase inhibitors and steroids are often effective.
  • drugs that can be used for problems such as side effects caused by long-term administration.
  • chronic inflammatory diseases such as rheumatism, Crohn's disease, ulcerative colitis, asthma, atopic dermatitis, psoriasis, systemic lupus erythematosus and gout are recognized as typical chronic inflammatory diseases.
  • Crohn's disease and ulcerative colitis are diseases characterized by chronic inflammation of various parts of the digestive tract.
  • sulfasalazine drugs are often effective, but no cure is known.
  • interleukin-1 blockers, antibodies against interleukin-12, and the most effective monoclonal antibody against tumor necrosis factor (THF-alpha) have been clinically applied as powerful immunoregulatory therapies.
  • TNF-alpha specific site force-in
  • IL-1 IL-1, etc.
  • general immunosuppressive agents such as cyclosporine nyazathioprine, which may have side effects.
  • TNF-alpha antibody drugs such as infliximab have been approved, and the significance of suppressing such cytodynamic ins has been recognized.
  • Polyunsaturated fatty acids are the names for unsaturated fatty acids that generally have more than one double bond.
  • Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are abundant in fish oil. This corresponds to this.
  • Polyunsaturated fatty acids are broadly classified into n-3 series such as linolenic acid, EPA, DHA, and ⁇ -6 series such as linolenolic acid, ⁇ -linolenic acid, arachidonic acid.
  • the position of the double bond is classified from the viewpoint of the one present at the third position from the end of the cation and the one present at the sixth position.
  • ⁇ -3 fatty acids ⁇ -linolenic acid, ⁇ and DHA weaken the action of arachidonic acid (specifically, it inhibits the release of arachidonic acid by cPLA2 from the cell membrane. Receptors affected by arachidonic acid metabolites) In contrast, it has been widely known that it has an action of suppressing inflammation by an action mechanism.
  • ⁇ -3 fatty acids such as hexadecatetraenoic acid, octadecatetraenoic acid, and octadecatrienoic acid have been reported to have anti-inflammatory and antiallergic effects. Thus, many of the ⁇ -3 fatty acids have anti-inflammatory and anti-allergic effects. It is known that the ⁇ -6 fatty acids have distinctly different effects.
  • polyunsaturated fatty acids having a double bond in the carbon at the methyl terminal ie, ⁇ -1
  • the family of fatty acids is a very rare fatty acid.
  • 6,9,12,15-Hexadecatetetraenoic acid (also referred to as C1 6: 4 (n-1)) is a kind of highly unsaturated fatty acid characteristically contained in sardines and the like.
  • Non-Patent Document 1 reports on the isolation and analysis method. 6,9,12,15- Not limited to hexadecatetraenoic acid, there are few reports on the study of bioactivity related to n-1 fatty acids.
  • Non-patent Document 3 A report that suppresses production of satetranoic acid (Non-patent Document 3) and a report that 4,7,10,13-hexadecatetetraenoic acid derived from seaweed has cell activity (Patent Document 1) There is.
  • Patent Document 1 JP-A-2005-23028
  • Non-Patent Document 1 Journal of the American chemists' Society, 66 (9), 1323-1325, 1989.
  • Non-Patent Document 2 Biochimica et Biophysica Acta, 1095, 187-195, 1991.
  • Non-Patent Document 3 Biosci. Biotechnol. Biochem., 62 (7), 1412-1415, 1998.
  • An object of the present invention is to provide a therapeutic agent for inflammatory diseases having anti-inflammatory action, anti-allergic action, and immunosuppressive action.
  • the gist of the present invention is a prophylactic or therapeutic agent for inflammatory diseases comprising 6,9,12,15-hexadecatetetraenoic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.
  • the gist of the present invention is a kit for the prophylaxis or treatment of inflammatory diseases comprising the above-mentioned therapeutic agent for inflammatory diseases and instructions for use.
  • the gist of the present invention is the use of 6,9,12,15-hexadecatetetranoic acid or a pharmaceutically acceptable salt or ester thereof for the manufacture of an agent for preventing or treating inflammatory diseases.
  • the present invention provides an effective amount of 6,9,12,15-hexadecatetetraenoic acid or a pharmaceutically acceptable salt or ester thereof for humans or non-humans in need of prevention or treatment of inflammatory diseases.
  • the gist is a method for preventing or treating an inflammatory disease including administration to a warm-blooded animal.
  • the gist of the present invention is a functional food for the prevention or treatment of inflammatory diseases comprising 6,9,12,15-hexadecatetetraenoic acid or a salt or ester acceptable as a food additive thereof as an active ingredient. To do.
  • the gist of the present invention is a functional food for the prevention or treatment of inflammatory diseases including the functional food for treating inflammatory diseases and instructions for use for inflammatory diseases.
  • the salt sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, pyridine salt, and triethylamine salt are preferable, and sodium salt is particularly preferable.
  • the pharmaceutically acceptable ester of 6,9,12,15-hexadecatetraenoic acid is a triglyceride containing 6,9,12,15-hexadecatetraenoic acid as a constituent fatty acid. Diglycerides, monoglycerides, or lower alcohol esters of 6,9,12,15-hexadecatetetranoic acid are preferred.
  • the present invention is effective for chronic inflammatory diseases among inflammatory diseases. The invention's effect
  • the 6,9,12,15-hexadecatetetraenoic acid of the present invention inhibits the production of various cytodynamic ins and is anti-inflammatory.
  • Agent Z Antiallergic agent Z It has an effective preventive or therapeutic effect on various inflammatory diseases involving inflammatory cells such as immunosuppressants.
  • the 6,9,12,15-hexadecatetraenoic acid used in the present invention is a straight-chain fat having 16 carbon atoms. It is an acid and has double bonds at the 6th, 9th, 12th and 15th positions. Sometimes written as C16: 4.
  • the pharmaceutically acceptable salt or ester of 6,9,12,15-hexadecatetetraenoic acid of the present invention can be produced by the following method.
  • fish oil used as a raw material for 6,9,12,15-hexadecatetraenoic acid is mostly triglyceride (TG), and 6,9,12,15-hexadecatetraenoic acid is its acyl. It exists as a residue.
  • Fish oil also contains TGs with high melting point fatty acids such as palmitic acid and stearic acid. By cooling and crystallizing and separating these high melting point components, 6,9,12, 15-hexade force Tetraenoic acid can be concentrated. This method is called low temperature fractionation and wintering.
  • the pharmaceutically acceptable salt of 6,9,12,15-hexadecatetraenoic acid is preferably a pharmaceutically or physiologically acceptable alkali addition salt.
  • a pharmaceutically or physiologically acceptable alkali addition salt for example, salts with sodium, potassium, magnesium, calcium, ammonium, pyridine, triethylamine and the like are used.
  • the pharmaceutically acceptable ester of 6,9,12,15-hexadecatetraenoic acid is 6,9,12,15-hexadecatetraenoic acid as a constituent fatty acid.
  • the tridalylide, diglyceride, or monoglyceride contained, or the lower alcohol ester of 6,9,12,15-hexadecatetraenoic acid is preferred. As long as it contains 6, 9, 12, 15-hexadecatetraenoic acid as a constituent fatty acid of triglyceride and diglyceride, it may contain other fatty acid as a constituent fatty acid.
  • the 6,9,12,15-hexadecatetetraenoic acid, or a pharmaceutically acceptable salt or ester thereof used in the present invention is administered in various forms.
  • the dosage form is determined according to various preparation forms, no particular limitation, age, sex and other conditions of the patient, degree of disease, etc.
  • tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered.
  • they are administered alone or mixed with normal replacement fluids such as glucose and amino acids and administered intravenously, and if necessary, administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Is done.
  • suppositories In the case of suppositories, it is administered rectally. Oral administration is preferred. 6,9,12,15-Hexacatecatelaenoic acid is easy to oxidize! / Since it is a liquid oil, it needs to be treated to prevent acidification, such as by filling capsules and antioxidants.
  • a carrier conventionally known in this field can be widely used.
  • a carrier conventionally known in this field can be widely used.
  • lactose sucrose, sodium chloride sodium salt, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose
  • key Excipients such as acids, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polypyrrole pyrrolidone sugar binder, dried starch, Sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cocoa butter, hydrogen Disintegration inhibitors such
  • excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc
  • binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran strength.
  • conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. Can be mentioned.
  • solutions and suspensions should be sterilized and should be isotonic with blood. Any of those commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Can do.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation.
  • Ordinary solubilizers, buffers, soothing agents, etc. May be added.
  • colorants, preservatives, fragrances, flavoring agents, sweetening agents, and other pharmaceuticals may be included.
  • the amount of the active ingredient-compound contained in the above pharmaceutical preparation is not particularly limited and is appropriately selected over a wide range.
  • liquid 6,9,12,15-hexa It is possible to fill only with decatetetranoic acid, and when other preparations are used, it is appropriate that the amount is usually 1 to 70% by weight in the total composition.
  • the dose of 6,9,12,15-hexadecatetetraenoic acid or a pharmaceutically acceptable salt or ester thereof varies depending on the symptom, age, administration method, etc. In some cases, it is desirable to administer 1 to 1200 mg / l, preferably 50 to: LOOOmg in one or several divided doses depending on the symptoms.
  • Functional foods containing 6,9,12,15-hexadecatetraenoic acid may be in the form of capsules, tablets, beverages such as milk, soy milk, soft drinks, or foods It is also possible to have an accompaniment.
  • the preventive or therapeutic agent for inflammatory diseases of the present invention has an anti-inflammatory action, an anti-allergic action, and an immunosuppressive action by mechanisms such as TNF-a production inhibition and cytoforce-in production inhibition action.
  • Effective for various inflammatory diseases include ulcerative colitis, inflammatory bowel diseases such as Crohn's disease, arthritis such as rheumatism, and the like.
  • 6,9,12,15-Hexadecatetetraenoic acid is a fatty acid contained in fishes such as sardines, dicins and menhadens that have been ingested by civilization for many years as a dietary habit (Reference; RGA ckman: Fatty Acid Composition of Fish Oils, In Nutritional Evaluation of Long—Chai n Fatty Acid in Fish Oil (Edited by SM Barlow & ME Stansby: Academic Press, London, New York, (1982) pp. 25-88).
  • C16 6,9,12,15-hexadecatetetraenoic acid (C16: 4) was evaluated using the Atsy system of cultured cells.
  • TNF- ⁇ test a comparative test was conducted using eicosapentaenoic acid ( ⁇ ), which is a fatty acid of 20 carbon atoms, 4 double bonds, and ⁇ -3.
  • Human peripheral blood mononuclear cells ( 5 X loVml) and drug are pre-cultured in AIM-V medium (pH 7.4) for 30 minutes. Stimulate cells by adding stimulant (concanavalin-8; 20 or lipopolysaccharide; 25 gZml) and incubate overnight at 37 ° C, 5% CO.
  • stimulant concanavalin-8; 20 or lipopolysaccharide; 25 gZml
  • Various site forces in the culture supernatant In levels were measured by sandwich ELISA. The drug concentration was screened at 30, 10, 3, 1, 0.3 ⁇ , and the inhibition of production of various site force ins was evaluated by IC.
  • the 6,9,12,15-hexadecatetraenoic acid used in this example is an ethyl ester (purity 96%) produced by the method of Example 3.
  • DNBS Compared to 293 g, administration of DNBS increased the colon weight to 0.784 g. This indicates that DNBS treatment caused inflammation in the large intestine.
  • Administration of 6,9,12,15-hexadedecatetraenoic acid (C16: 4 n-1) reduced the increase in colon weight to 0.656 g by oral administration of 100 mg / kg. The rate of decrease was 26%. In the case of oral administration of 300 mg / kg, the increase in the weight of the large intestine was reduced to 0.6 g. The decrease rate was 37%.
  • Sulfasalazine was examined. Sulfasalazine orally administered 300 mg / kg reduced the increase in colon weight to 0.582 g.
  • the decrease rate was 41%.
  • P ⁇ 0.05 between the 100 mg and 300 mg groups of 6,9,12,15-hexadecatetetraenoic acid and the control group administered with DNBS alone.
  • the Sulfasalazine 300 mg administration group showed a significant difference at P 0.01 compared to the control group to which DNBS alone was administered.
  • 6,9,12,15-hexadecatetetraenoic acid has almost the same effect as Sulfasalazine, a pharmaceutical agent that is currently used in clinical practice, and has similar administration.
  • Sulfasalazine a pharmaceutical agent that is currently used in clinical practice
  • has similar administration in quantity in a rat inflammatory colitis model. This result indicates that it can be a therapeutic agent for Crohn's disease and ulcerative colitis, which are human diseases similar to 6,9,12,15-hexadecatetetraenoic acid.
  • Sulfasalazine decreased the increase in colon weight to 0.574 g by oral administration of 300 mg / kg I let you. The reduction rate was 35%.
  • P 0.01 there was a significant difference of P 0.01 between the 100 mg-treated group of 6,9,12,15-hexadecatetetraenoic acid and the control group administered with DNBS alone.
  • the Sulfasalazine 300 mg group showed a significant difference at P 0.01 compared to the control group administered with DNBS alone. There was no significant difference between the EPA-treated group and the control group treated with DNBS at a 5% risk.
  • hind paw volume increased to 5.7 (X 0.01 ml) due to edema caused by carrageenan administration.
  • the volume of the hind paws was suppressed to 4.5 (X 0.01 ml).
  • the hind paw volume was pushed to 3.3 (X 0.01 ml).
  • Four types of monoclonal antibodies against type II collagen (D8, F10, DI-2G, A2) were administered intravenously at 20 mg per mouse on day 0.
  • lipopolysaccharide (LPS, 25 ⁇ g / mouse) was intravenously administered to induce inflammation.
  • the drug was orally administered once a day for 3 days from 1 hour after LPS administration on the third day.
  • hind paw edema was measured with a dedicated measuring instrument.
  • 6,9,12,15-hexadecatetraenoic acid was an ethyl ester produced by the method of Example 3 (purity 78%).
  • 6,9,12,15-Hexadecatetetraenoic acid (using the ethyl ester produced by the method of Example 3 (purity 91.5%)) (specific gravity 0.9) in a 833 mg polypropylene centrifuge tube, 3 A 25% polyglycerin ester aqueous solution was added and emulsified to prepare a test solution (30 mg / mL). The test solution was administered by the oral route. Administration was performed once a day for 7 days. The dose of 6,9,12,15-hexadecatetraenoic acid was 300 mg / kg, and the dose volume was 10 mL / kg. The control group received the same volume of vehicle as the test solution.
  • the representative value of each group was expressed by the average value and standard error of the pain threshold.
  • the equivariance was tested by the F test between the control group and the test solution group.
  • the number of animals used is 10 in each group.
  • the results are shown in Table 6.
  • the average pain threshold (mean ⁇ standard error) of the control group before the start of test solution administration, 1 hour before the last administration of the test substance and 3 hours after the inflammation (4 hours after the last administration of the test substance) is 92 ⁇ 1 mmHg , 90 ⁇ 1 mmHg &, 39 ⁇ 3 mmHg, and the average nociceptive response after 3 hours of inflammation decreased by 51 ⁇ 3 mmHg.
  • a high-performance liquid chromatograph was used. 200 ⁇ 1 of 6,9,12,15-hexadecatetraenoic acid ethyl ester (34.5%) in methanol (200 ⁇ 1) (approx. 90 mg as an oil) Cosmo Seal 5C18-AR packed column (20.0 mmI. D. X 250mm) Of the body chromatograph (solvent methanol, flow rate 5 ml / h), 95.4% of 6,9,1 2,15-hexadecatetraenoic acid ethyl ester 18.7 mg (recovery 57.3%) Obtained.
  • a prophylactic or therapeutic agent for inflammatory diseases or diseases caused by inflammatory diseases such as colitis and arthritis can be provided.
  • a functional food having a function of preventing or treating inflammatory diseases can be provided.

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Abstract

Le problème à résoudre dans le cadre de cette invention consiste à fournir un agent thérapeutique pour une maladie inflammatoire, qui possède un effet anti-inflammatoire, un effet anti-allergique et un effet immunosuppresseur. La solution proposée consiste à fournir un agent prophylactique ou thérapeutique pour une maladie inflammatoire, qui comprend l’acide 6, 9, 12, 15-hexadécatétraénoïque ou un sel ou un ester pharmaceutiquement acceptable de celui-ci en tant que principe actif. Le sel pharmaceutiquement acceptable de l’acide 6, 9, 12, 15-hexadécatétraénoïque est, par exemple, un sel de sodium, de potassium, de magnésium, de calcium, d’ammonium, de pyridine or de triéthylamine de l'acide 6,9,12,15-hexadécatétraénoïque. L’ester pharmaceutiquement acceptable de l’acide 6, 9, 12, 15-hexadécatétraénoïque est, par exemple, un triglycéride, diglycéride ou monoglycéride, dont le composant d'acide gras est l'acide 6,9,12,15-hexadécatétraénoïque ou un ester d’alcool inférieur de l’acide 6,9,12,15-hexadécatétraénoïque.
PCT/JP2006/309298 2005-05-16 2006-05-09 Agent prophylactique ou therapeutique pour les maladies inflammatoires WO2006123550A1 (fr)

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JP2007516248A JP5046926B2 (ja) 2005-05-16 2006-05-09 炎症性疾患予防又は治療剤

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JP2021020855A (ja) * 2019-07-24 2021-02-18 国立大学法人 東京大学 血中尿酸値低下剤及び血中尿酸値低下用食品組成物

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JP2021020855A (ja) * 2019-07-24 2021-02-18 国立大学法人 東京大学 血中尿酸値低下剤及び血中尿酸値低下用食品組成物
JP7500037B2 (ja) 2019-07-24 2024-06-17 国立大学法人 東京大学 血中尿酸値低下剤及び血中尿酸値低下用食品組成物

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