WO2005051405A1 - Il-8産生促進剤とその用途 - Google Patents
Il-8産生促進剤とその用途 Download PDFInfo
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- WO2005051405A1 WO2005051405A1 PCT/JP2004/017443 JP2004017443W WO2005051405A1 WO 2005051405 A1 WO2005051405 A1 WO 2005051405A1 JP 2004017443 W JP2004017443 W JP 2004017443W WO 2005051405 A1 WO2005051405 A1 WO 2005051405A1
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A61K36/18—Magnoliophyta (angiosperms)
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
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Definitions
- the present invention relates to an interleukin-18 production promoter, and an immunostimulatory agent containing the same, or an agent for preventing or treating infectious diseases.
- the intestinal tract Since the intestinal tract comes into direct contact with a variety of foods, etc., entered through the mouth, it has both functions of eliminating harmful substances and absorbing useful components. Physiological functions of foods are mainly exerted by the absorption of substances in the intestinal tract and by the signal transduction and site force-in caused by the components absorbed by the cells. Among these intestinal functions, intestinal immunity is Has an important role as the forefront of the immune system.
- the intestinal tract contains gut associated lymphoreticular tissue (GALT), which elicits an immune response to antigens taken orally, and intestinal epithelial cells, which absorb nutrients and other useful components from food. Food components directly or indirectly act on these cells to regulate, ie, promote or suppress immunity.
- GALT gut associated lymphoreticular tissue
- Intestinal epithelial cells produce cytokins such as TGF- / 3, IL-11, IL-10, and TNF- ⁇ , and chemokines such as IL-8, and are affected by various pathogenic bacterial infections. It is known that chemokines increase. Intestinal epithelial cells and immunocompetent cells interact with the cytokine ⁇ chemokine, and IL-8 is particularly involved in biological defense, immune mechanisms, and inflammatory responses. Neutrophil migration and activator interleukin-18 (hereinafter abbreviated as IL-18) was purified and cloned from LPS-stimulated human peripheral blood mononuclear cells in 1998 (Proc. Natl. Acad. Sci. USA, 84, 9233-9237, 1987).
- IL-18 Neutrophil migration and activator interleukin-18
- IL_8 is produced by monocytes, macrophages, fibroblasts, vascular endothelial cells, mast cells, epidermal cells, etc., and targets neutrophils, CD8 + T cells, natural killer cells, monocytes, etc. I have.
- Functions of IL_8 include neutrophil chemotaxis, basophil and T cell migration activity, recruitment of neutrophils from bone marrow to peripheral blood, release of intracellular lysosomal enzymes in neutrophils '' Induction of leukotriene B 4 (LTB 4 ) production, activation of neutrophils such as induction of active oxygen, enhancement of neutrophil adhesion to vascular endothelial cells, Neutrophil migration activity on umbilical vein vascular endothelial cells (HU VEC) and its involvement in angiogenesis are known. (Cell Engineering Supplement, Chemokine Handbook, 1st Edition, pp. 32-34, Shujun Company, 2000).
- neutrophils are leukocyte cells that play a central role in host defense and possess the ability to phagocytose bacteria, viruses, and fungi such as Escherichia coli, staphylococci, streptococci, and pneumococci, which enter from the outside.
- IL-8 is known to promote its activation and enhance neutrophil capacity.
- Peppermint or an extract thereof, Mokutomi or its extract, Kanzo or its extract are useful for promoting IL-8 production, or for immunostimulation due to IL-8, or for preventing or treating infectious diseases It is not known.
- an object of the present invention is to provide an IL-8 production promoter derived from a safe food material, and an immunostimulatory agent containing the same, or an agent for preventing or treating infectious diseases.
- compositions containing at least one plant extract consisting of peppermint, dokudami, and kanzo as an active ingredient is an IL.
- a composition comprising at least one compound selected from the group consisting of ⁇ -humulene, ⁇ -binene, J3-binene, and L-menthol as an active ingredient, which promotes IL-8 production. 8 It was found that the production was promoted, and the present invention was completed.
- the present invention relates to an IL_8 production promoter containing a peppermint extract and an extract of Pterodactyl or Pterodactyl as an effective component.
- the present invention relates to an IL-18 production promoter containing a Kanzo extract as an active ingredient.
- the present invention relates to an interleukin-18 production promoter containing at least one compound selected from the group consisting of or a pharmaceutically acceptable salt thereof as an active ingredient.
- the IL-18 production promoter of the present invention contains, as an active ingredient, at least one plant extract consisting of peppermint, dokudami, and kanzo.
- IL-18 refers to a leukocyte chemotactic factor having a molecular weight of about 8,000 produced from various cells such as fibroblasts and endothelial cells.
- the peppermint used in the present invention is a whole plant belonging to the genus Lamiaceae (Mentha piperita L .; Seiyouhatsu force or Mentha arvensis), and the dokudami used in the present invention is The above-ground part (leaves, stems, flowers, etc.) of Houttuynia cordata Thunb.
- Kanzo is the rhizome of Gfycyrrhiza uralensis Fish. Of the genus Leguminosae, all of which are foods or food ingredients, have sufficient eating experience, and have no adverse effects or safety issues.
- Each extract of peppermint, dokudami, and kanji used in the present invention can be obtained from the above plants by solvent extraction or the like.
- the method for obtaining the extract is not limited to the solvent extraction, but may be an extraction operation such as steam distillation or extraction with carbon dioxide using a supercritical extraction technique.
- the extract can be used in the present invention as an extract, or as a crude extract or a semi-purified extract, as long as it does not contain impurities unsuitable for foods and drinks and pharmaceuticals.
- the production method may be carried out using an extraction solvent at normal temperature and normal pressure.
- the extract may be concentrated to dryness, or may be made into a solution, paste, gel, or powder by fat or the like.
- the extraction temperature is not particularly limited, and is generally in the range of 20 ° C to 100 ° C, preferably 1 ° to 80 ° C, more preferably 20 ° to 60 ° C, and the extraction time. There is no particular limitation, either, and the mixture is generally stirred or left for 0.1 to 1 month, preferably 0.5 hour to 7 days. Extraction under supercritical conditions with carbon dioxide is also possible. If necessary, it can be further purified by an optional operation using activated carbon treatment or ion exchange resin.
- the original form of each of the above-mentioned plants, crushed material or powder is immersed in 1 to 20 times the amount of the following solvent, stirred or left, and the extract is filtered or centrifuged. Obtainable. Next, the extract can be obtained by concentrating the obtained extract and removing the solvent.
- the solvent used for the extraction is not particularly limited.
- a hydrophilic solvent or a hydrophobic solvent is used. it can.
- the hydrophilic solvent referred to herein is a highly polar solvent, and includes water, lower alcohols such as ethanol / methanol, polyhydric alcohols such as propylene glycol, and ketones such as acetone.
- the hydrophobic solvent referred to herein is a non-polar solvent having a low polarity, and includes esters such as ethyl acetate, oils and fats such as rape oil, and hydrocarbons such as hexane.
- the solvent is preferably a safe solvent that can be used in the production and processing of foods, food additives, pharmaceuticals, and the like.
- Examples thereof include water, ethanol, acetone, glycerin, ethyl acetate, propylene glycol, hexane, and edible oils and fats.
- Solvents such as ethanol, acetone, ethyl acetate, and hexane are more preferred from the viewpoint of extraction efficiency and easy removal of the solvent after extraction.
- the peppermint extract obtained by steam distillation or solvent extraction from whole peppermint plants is a kind of spice extract and is an existing additive for applications such as bittering agents.
- the dokudami extract obtained by extracting and purifying dokudami leaves with ethanol is an existing additive for antioxidants.
- the extract of licorice obtained from ethanol extract of licorice root is an existing additive for antioxidants.
- peppermint extract, dokudami extract and kanzo extract which are recognized as these food additives can also be used. '
- the present invention provides a component compound of peppermint, ⁇ -humulene represented by the following formula (1), ⁇ -pinene represented by the following formula (2), i3 represented by the following formula (3) —Providing an IL-18 production promoter containing at least one compound selected from the group consisting of pinene and L-menthol represented by the following formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient: I do.
- ⁇ - represented by the following formula (1) was obtained.
- the method for obtaining the ⁇ -humulene, ⁇ _binene, i3_pinene and L-menthol represented by the formulas (1) to (4) is not particularly limited, and the obtained compound may be a single compound. Alternatively, it can be used as a mixture of two or more of the IL-8 production promoters of the present invention.
- the extraction can be carried out in the same manner as described above. After extraction, it can also be obtained by filtration, partitioning with a solvent, concentration, distillation, steam distillation, separation and purification such as chromatography, etc., but the extraction solvent, purification resin, equipment, equipment, etc. used in the process are food Or those which can be used for the production of food additives are preferred.
- Plants to be used for isolating hoehmulene, ⁇ -pinene, 1-binene, and L-menthol are not particularly limited to plants to be extracted, such as Leucaena cypress and hops.
- Salts of the above compounds may also be suitably used in the present invention.
- a salt thereof is converted into a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid. Salts may be formed by mixing with a solution of, citric, tartaric, carbonic, or phosphoric acid.
- pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; And salts formed with, for example, quaternary ammonium salts.
- the IL-18 production promoter can activate mammals or prevent or treat infectious diseases in mammals.
- the immunostimulation referred to in this specification is a foreign substance from outside Activates immune cells such as white blood cells that control the immune function to eliminate non-self, such as (bacteria and viruses) and cancer cells.
- immune cells such as white blood cells that control the immune function to eliminate non-self, such as (bacteria and viruses) and cancer cells.
- infectious diseases include respiratory tract infections, urinary tract infections, sepsis, etc., and further include viral diseases, bacterial diseases, AIDS, and the like.
- the present invention provides a composition comprising the above-mentioned IL-18 production promoter as an active ingredient and a known carrier or auxiliary agent, a food or drink material, another pharmaceutically acceptable formulation material, or the like.
- the at least one plant extract comprising peppermint, prickle, and licorice of the present invention promotes IL-18 production in mammals including humans.
- the composition for promoting IL-18 production of the present invention promotes IL-18 production
- the composition for promoting an immunostimulant caused by IL-18, or the composition for preventing or treating infectious diseases can be used. Can be used as a composition.
- the composition according to the present invention comprises, as active ingredients, a peppermint extract, a Dokudami extract and a Kanzo extract, a compound represented by the formula (1), a compound represented by the formula (2), and a compound represented by the formula (3). Containing 0.1 to 100% by weight of at least one compound selected from the group consisting of a compound represented by the formula (4) and a pharmaceutically acceptable salt thereof. And more preferably 1 to 100% by weight. More preferably, the composition contains from 10 to 100% by weight of the active ingredient, even more preferably from 20 to 100% by weight, and most preferably from 30 to 100% by weight.
- IL-18 was produced. It can be evaluated by adding or administering the above extract to the experimental system used.
- human colon cancer-derived cell lines such as HT-29 cells and Caco-12 cells, secrete IL-18 into the medium, and the above extract is added thereto. It can be evaluated by an experimental system that determines the amount of IL-18 in the medium after culturing.
- Exposure can be evaluated by a similar experimental system used with increased production of L-18 (Chowers, Y., et al., Gastroenterology, 120, 449-459, 2001; Lahav, ⁇ ⁇ , et al., Clin. Exp. Im munol., 127, 226-233, 2002). Specifically, the test is conducted as in this example, and a component that is significant at a significant level: P ⁇ 0.01 is evaluated as having an IL-8 production promoting action.
- the IL-18 production promoter, the immunostimulant, the infectious disease preventive or ameliorating agent of the present invention, and a composition containing them as an active ingredient are: It can be used for food and drink and for medical use, and its form is not limited.
- food and drink such as health foods (specified health foods and nutritional foods), health foods, nutritional supplement foods, etc.
- It can be used as easily available drugs such as general drugs or quasi-drugs.
- the prophylactic agent and the composition of the present invention may contain components other than the extract of peppermint, dokudami and kanzo.
- the extract or compound of the present invention is highly safe for living organisms because it contains, as an active ingredient, each extract or extract contained in peppermint, dokudami, and kanzo, which have been conventionally used for food. For this reason, the IL_8 production promoter of the present invention can be contained in a wide range of products such as pharmaceuticals, functional foods, foods and drinks, and quasi-drugs.
- the amount of the active ingredient is not particularly limited, but can be appropriately selected within a range in which a desired effect is exhibited.
- the dosage is preferably 0.
- the prophylactic agent and the composition of the present invention can be directly ingested as they are, and capsules, tablets, and granules can be prepared using known carriers and additives such as auxiliaries. It can be formulated and taken into a form that is easy to take.
- the content of the active ingredient (extract) in these preparations is preferably 0.01 to 10%.
- the type of food to be targeted is not particularly limited as long as the extract does not inhibit the IL-8 production promoting effect.
- confectionery such as chewing gum, chocolate, candy, jelly, biscuits, and crackers mixed with food and drink ingredients; cold desserts such as ice cream and ice confectionery; beverages such as tea, soft drinks, nutritional drinks, and beauty drinks ; Udon, Chinese food, spaghetti, instant foods, etc .; kneaded products such as scallops, bamboo rings, halves, etc .; seasonings, such as dressings, mayonnaise, sauces, etc .; It can be used for all foods and drinks, such as soups, retort foods, and frozen foods.
- the amount of the active ingredient to be consumed is preferably 0.001 to 100 mg / kg body weight, more preferably 0 to 100 mg / kg body weight per adult per day. 0 1 to 10 OmgZkg The body weight.
- the dosage form is not particularly limited, and tablets, capsules, injections, instillations, powders, suppositories, suppositories, granules, ointments, Suspensions, emulsions, syrups, creams and the like can be made.
- the composition may contain additives such as a binder, an excipient, a lubricant, a disintegrant, a stabilizer, an emulsifier, and a buffer generally used in pharmaceutical preparations.
- Suitable examples of binders include starch, trehalose, dextrin, gum arabic, and the like.
- Preferred examples of the excipient include sucrose, lactose, glucose, corn starch, mannitol, crystalline cellulose, calcium phosphate, calcium sulfate, and the like.
- Preferable examples of the lubricant include stearic acid, talc, wax, polyethylene lendalicol and the like.
- Preferred examples of the disintegrant include starch, carboxymethylcellulose, corn starch and the like.
- Preferable examples of the stabilizer include fats and oils, propylene glycol and the like.
- Preferable examples of the emulsifier include an anionic surfactant, a nonionic surfactant, and polybutyl alcohol.
- Preferred examples of the buffer include buffer solutions such as phosphate, carbonate, and citrate. The dosage of these preparations is preferably 0.001 to 100 mg Zkg body weight, more preferably 0.1 to 100 mg Zkg body weight per adult per day in terms of the extract, once to several times. Administer separately.
- additives when formulated and used as quasi-drugs, add other additives as necessary, for example, ointments, liniments, aerosols, creams, stones, face wash It can be used for body wash, lotion, lotion, bath salt, etc. and can be used topically.
- the present invention provides a mammal in need thereof comprising an effective amount of a peppermint extract, a dokudami extract, a Kanzo extract, a compound of formula (1), a compound of formula (2), a compound of formula (3)
- a method of promoting interleukin production in a mammal comprising administering at least one selected from the group consisting of a compound of the formula (4) and a pharmaceutically acceptable salt thereof;
- Methods for stimulating immunity or preventing or treating infectious diseases in mammals are provided.
- Administration includes enteral, eg, oral, and parenteral, eg, transdermal. Oral administration is preferred. Mammals include humans.
- Caco-2 cells human colon cancer-derived cell line: American Type Culture Collection, Rockville, MD, USA
- Caco-2 cells human colon cancer-derived cell line: American Type Culture Collection, Rockville, MD, USA
- the cells were cultured under O 2 conditions for 14 days to differentiate into small intestinal epithelium.
- the medium used was a DMEM medium (SIGMA) containing 10% fetal calf serum, 1% non-essential amino acid solution, 2% glutamine, 100 OU / ml pernicillin and 100 ⁇ g nom1 streptomycin.
- SIGMA DMEM medium
- the peppermint extract obtained in Example 1, the Dokudami extract obtained in Example 2, and the Kanzoku extract obtained in Example 3 were added to the medium to a final concentration of 100 ⁇ g / m 1. And cultured.
- FIG. 1 shows the relative concentration of IL-8 relative to the control.
- Caco-2 cells human colon cancer-derived cell line: American Type Culture Collection, Rockville, MD, USA
- ⁇ -humulene small intestinal epithelial cells
- ⁇ -binene small intestinal epithelial cells
- the effects of l-binen and l-menthol were evaluated.
- FIG. 1 shows the relative concentration of IL-8 relative to the control.
- the cytotoxicity of the peppermint, dokudami, and kanzo extract on Caco-2 cells was evaluated.
- Caco-2 cells differentiated like small intestinal epithelium were cultured for 24 hours in a medium containing a final concentration of 100 g_m1 of peppermint, Dokudami extract and Kanzo extract. Then, remove the medium, wash the cells twice with PBS (Phosphate buffered saline) (1) (Nissi), add 700 ⁇ l of PBS (—), and incubate at 37 ° C for 2 hours. Was placed. Thereafter, PBS (-) was recovered, and the cells were dissolved in 500 ⁇ l of 0.1% Triton X-100 (Nacalai Tester).
- PBS Phosphate buffered saline
- Free LD11 rate (%) (free LDH content) Z (free LDH content + intracellular LDHi) X 100
- the peppermint, dokudami and kanzo ⁇ extracts have no difference from the control. It was shown that there is no cytotoxicity. Furthermore, it was shown that the IL_8 production promoting effect of each of the peppermint, dokudami and Kanzoi extracts was not due to cytotoxicity.
- __humulene The cytotoxicity of __humulene on C aco -2 cells was evaluated.
- Caco-2 cells differentiated like small intestinal epithelium were cultured in a medium containing 100 g / ml of ⁇ -humulene for 24 hours. Then, remove the medium, wash the cells twice with PBS (-) (Nissy), add 7001 PBS (-), and
- Free LDH ratio (%) (free LDH amount) no (free LDH amount + intracellular LDH amount) X 100
- ⁇ -humulene is not different from the control and has no cytotoxicity. It has been shown. Furthermore, it was shown that the IL-8 production promoting action of ⁇ -humulene was not due to cytotoxicity.
- a capsule for eating and drinking containing a dokudami extract was prepared in the same manner as in Example 8, except that the dokudami extract described in Example 2 was used instead of the peppermint extract. '
- a capsule for eating and drinking containing a kanzo extract was prepared in the same manner as in Example 8, except that the kanzo extract was used in place of the peppermint extract in Example 3.
- an IL-18 production promoter derived from a safe food material, an immunostimulant containing the same, or an agent for preventing or treating infectious diseases can be obtained.
- These are useful for stimulating the immune response, preventing or treating infectious diseases, and are foods and drinks such as health foods (specified health foods, nutritional foods), health foods, dietary supplements, or pharmaceuticals. Or it can be used as a quasi-drug.
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US10/579,323 US20070082068A1 (en) | 2003-11-25 | 2004-11-17 | Il-8 production promoters and use thereof |
JP2005515779A JPWO2005051405A1 (ja) | 2003-11-25 | 2004-11-17 | Il−8産生促進剤とその用途 |
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WO2008114536A1 (ja) * | 2007-03-20 | 2008-09-25 | Arkray, Inc. | デヒドロエピアンドロステロン産生促進剤およびその用途 |
CN102670727A (zh) * | 2011-03-18 | 2012-09-19 | 山西振东开元制药有限公司 | 一种连翘子软胶囊及其制备方法和应用 |
CN103484524A (zh) * | 2013-09-26 | 2014-01-01 | 邱思锋 | 金银花萃菊免疫增强剂的药效学和毒理学试验方法 |
CN105301231A (zh) * | 2015-10-10 | 2016-02-03 | 南京中医药大学 | 一种鱼腥草注射液中抗原性物质检测方法 |
WO2019106967A1 (ja) * | 2017-11-30 | 2019-06-06 | 佳人 鳥居 | 免疫活性化剤の製造方法および免疫活性化用飲食品の製造方法 |
TWI728324B (zh) * | 2019-03-12 | 2021-05-21 | 鳥居佳人 | 免疫活性化劑的製造方法、免疫活性化用飲食品的製造方法及醫藥品 |
WO2023135949A1 (ja) * | 2022-01-11 | 2023-07-20 | 一丸ファルコス株式会社 | プロテオグリカンを含む免疫応答調節剤 |
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US9138393B2 (en) | 2013-02-08 | 2015-09-22 | The Procter & Gamble Company | Cosmetic compositions containing substituted azole and methods for improving the appearance of aging skin |
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WO2008114536A1 (ja) * | 2007-03-20 | 2008-09-25 | Arkray, Inc. | デヒドロエピアンドロステロン産生促進剤およびその用途 |
JP2008231031A (ja) * | 2007-03-20 | 2008-10-02 | Arkray Inc | デヒドロエピアンドロステロン産生促進剤およびその用途 |
CN102670727A (zh) * | 2011-03-18 | 2012-09-19 | 山西振东开元制药有限公司 | 一种连翘子软胶囊及其制备方法和应用 |
CN103484524A (zh) * | 2013-09-26 | 2014-01-01 | 邱思锋 | 金银花萃菊免疫增强剂的药效学和毒理学试验方法 |
CN105301231A (zh) * | 2015-10-10 | 2016-02-03 | 南京中医药大学 | 一种鱼腥草注射液中抗原性物质检测方法 |
CN105301231B (zh) * | 2015-10-10 | 2017-06-16 | 南京中医药大学 | 一种鱼腥草注射液中抗原性物质检测方法 |
WO2019106967A1 (ja) * | 2017-11-30 | 2019-06-06 | 佳人 鳥居 | 免疫活性化剤の製造方法および免疫活性化用飲食品の製造方法 |
JP2019099477A (ja) * | 2017-11-30 | 2019-06-24 | 佳人 鳥居 | 免疫活性化剤の製造方法および免疫活性化用飲食品の製造方法 |
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TWI728324B (zh) * | 2019-03-12 | 2021-05-21 | 鳥居佳人 | 免疫活性化劑的製造方法、免疫活性化用飲食品的製造方法及醫藥品 |
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US20070082068A1 (en) | 2007-04-12 |
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