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WO1999053937A1 - Agents immunostimulants et antitumoraux - Google Patents

Agents immunostimulants et antitumoraux Download PDF

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Publication number
WO1999053937A1
WO1999053937A1 PCT/JP1999/002074 JP9902074W WO9953937A1 WO 1999053937 A1 WO1999053937 A1 WO 1999053937A1 JP 9902074 W JP9902074 W JP 9902074W WO 9953937 A1 WO9953937 A1 WO 9953937A1
Authority
WO
WIPO (PCT)
Prior art keywords
extract
hatakeshimeji
hatake
active ingredient
mushroom
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1999/002074
Other languages
English (en)
Japanese (ja)
Inventor
Masaru Shibata
Yasushi Kojima
Yuuichi Ukawa
Hiroshi Hara
Hitoshi Ito
Makoto Hisamatsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eishogen Co Ltd
New Oji Paper Co Ltd
Original Assignee
Eishogen Co Ltd
Oji Paper Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eishogen Co Ltd, Oji Paper Co Ltd filed Critical Eishogen Co Ltd
Publication of WO1999053937A1 publication Critical patent/WO1999053937A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/04—Immunostimulants

Definitions

  • the present invention relates to an immunostimulant and an antitumor agent containing a Hatakeshimeji extract or a purified product thereof as a main component. Related technology
  • BRM biological response modifiers
  • an object of the present invention is to provide an immunostimulant and an antitumor agent which have a short cultivation period, can be artificially cultivated in large quantities, and have high immunostimulatory activity and antitumor activity, for BRM derived from basidiomycete. . Disclosure of the invention
  • the first aspect of the present invention is an immunostimulant comprising a hatake shimeji extract containing a high molecular weight polysaccharide or a purified product thereof as an active ingredient.
  • the present invention provides an immunostimulant, wherein the Hatake shimeji is an artificially cultivated product using “Kameyama No. 1” as a seed fungus.
  • the active ingredient has the following properties:
  • the present invention provides an immunostimulant which is an extract having the following.
  • the present invention provides, in another aspect, the active ingredient has the following properties:
  • An immunostimulator which is a purified product of an extract having
  • the extract of Hatake shimeji is obtained by extracting the fruit body of Hatake shimeji with hot water and, if desired, the extract is further purified.
  • the second aspect of the present invention provides an antitumor agent comprising a hatake mushroom extract containing a high molecular weight polysaccharide or a purified product thereof as an active ingredient.
  • the present invention is an antitumor agent, wherein the Hatake shimeji is an artificially cultivated product using “Kameyama No. 1” as a seed fungus.
  • the present invention provides, in another aspect, the active ingredient has the following properties:
  • the invention provides, in another aspect, the active ingredient has the following properties:
  • An antitumor agent which is a purified product of an extract having the following formula:
  • the extract of Hatake shimeji is obtained by extracting the fruit body of Hatake shimeji with hot water and, if desired, the extract is further purified.
  • Haphyshimeji mushroom (Yophyl lum decastes (Fr.) Sing.) Is a mushroom belonging to the genus Shimeji, belonging to the genus Shimeji, and is the closest mushroom to Hon-shimeji, which is said to be better than Matsutake mushrooms. .
  • Natural products occur in the form of plants in relatively familiar places such as gardens and fields (Rokuya Imaseki, Tsuguo Hongo: Japanese Fungus Encyclopedia of Primary Colors (1), Nursery, 1987).
  • Hatake shimeji used in the present invention is an artificially cultivable Hatake shimeji
  • No. 1 Seed and Seed Method Variety Registration Application No. 6 811, Type of Agriculture, Forestry and Fisheries Plant: Hatake Mushroom, Name of Applied Variety: Kameyama No. 1
  • chitin force husk
  • brewer's yeast cake etc.
  • Hatakeshimeji is a cultivation method established by Oji Paper Co., Ltd. Mori Forest Resources Research Institute (Japanese Patent Publication No. 5-154404, Patent No. 19)
  • the extract of Hatake mushroom used in the present invention can be obtained by extracting the fruit body of Hatake mushroom with hot water.
  • the fruiting body may be extracted with hot water as it is, or may be dried and extracted with hot water. Further, the fruiting body may be extracted with hot water as it is, or may be extracted with hot water by pulverizing in advance.
  • the heating method may be any of decompression, normal pressure, and pressurization, but high-temperature treatment under pressure provides better extraction efficiency.
  • the heating temperature can be carried out in the range of 7 Q to 26 D ° C. You.
  • the extraction time is 2 to 4 hours at normal pressure, and 15 minutes to 2 hours if performed under high temperature and pressure.
  • the fruit body of Hatake mushroom subjected to the hot water extraction treatment is an extract having a solid content of about 5.5% to 10%.
  • the extract is concentrated and dried to obtain a Hatake mushroom extract used in the present invention.
  • the extraction extract may be concentrated by any of a heating concentration method, a reduced pressure heating concentration method, and a concentration method by ethanol precipitation.
  • the concentrated extract extract may be dried by air drying, heat drying, spray drying, or freeze drying.
  • the Hatake mushroom extract may also be a purified product thereof.
  • This purified product can be obtained by purifying according to an ordinary method for purifying a high molecular polysaccharide.
  • a Hatake shimeji extract is dissolved in pure water and adsorbed on an ion-exchange column (such as Q-Sepharose). Then, the Hatake shimeji extract is adsorbed on the ion-exchange column, and a gradient elution is performed with a different chloride concentration. By doing so, it can be purified.
  • the purified product of the fractionated Hatake shimeji extract can be further purified by fractionation by a gel filtration method using a difference in molecular weight.
  • the Hatakeshimeji extract thus purified is concentrated and dried by removing salts and buffers used in the purification method by dialysis or ethanol precipitation.
  • the Hatake mushroom extract and its purified product used in the present invention can be used in a form convenient for obtaining a medicinal effect according to the symptoms of the disease, and used alone or as a mixture with a pharmaceutically acceptable diluent and other drugs. it can.
  • Hatakeshimeji extract and its purified product can be provided in the form of a dosage unit.
  • oral forms such as powders, granules, tablets, dragees, capsules, syrups, pills, suspensions, solutions, emulsions, or injections containing an effective amount of the active ingredient, or injection solutions
  • Parenteral dosage forms such as ampules and vials. It can also be used as a suppository.
  • the diluent may be solid, liquid, or semi-solid, and examples thereof include the following.
  • excipients that is, excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, fragrances, preservatives, solubilizers, solvents, etc. Lactose, sucrose, sorbite, mannite, starch, sedimentable carbonate calcium, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or its derivatives, miromibectin, polyvinyl alcohol , Gelatin, surfactants, water, physiological saline, ethanol, dariserin, propylene glycol, cocoa butter, laurin butter, cellulose, paraffin, higher alcohols and the like.
  • the immunostimulant and the antitumor agent of the present invention may be used in these compositions.
  • the ratio of the extract of Hatake mushroom and its purified product is 1 to 100 ⁇ 1%, preferably 5 to 100%. 80 wt%.
  • the above-described extract of Hatake mushroom and its purified product are orally or parenterally administered to humans and animals, but preferably are administered by hand.
  • Oral administration includes sublingual administration, and is performed by parenteral administration (eg, subcutaneous, intramuscular, intravenous injection, infusion), or rectal administration.
  • the dose of Hatake-shimeji extract and its purified product depends on the animal or human, and depends on the age, individual difference, medical condition, etc.Therefore, the dose outside the following range may be administered.
  • 1 mg to 10 g, preferably 10 111 to 100 111, of body weight lkg per day is administered in 1 to 4 divided doses.
  • the extract of Hatake mushroom and its purified product used in the present invention have no acute toxicity, no mutagenicity, and have immunostimulatory activity and antitumor activity, so that they are useful as pharmaceuticals thereof.
  • the extract of Hatake-shimeji mushroom and its purified product may be used as they are, or may be mixed with excipients or other pharmaceuticals. When mixing, it is preferable to mix at a rate of 3 Q to 8 Q wt% c Example
  • Bark compost manufactured by Chu Nippon Agricultural Products Co., Ltd.
  • Rice bran Force husks mixed at an absolute dry weight ratio of 100: 20: 4, and then a 850 ml 1 volume culture medium with a water content of 62%.
  • a cultivation bottle made of polypropylene was filled with 62 g.
  • the cells were cultured for 50 days in a room adjusted to a room temperature of 23 ° C and a humidity of 70% (RH), and the mycelium was sufficiently spread on the culture medium. After the bacteria were removed and water was supplied, the opening was covered with the above-mentioned bark compost so as to have a thickness of 1 to 2 cm. Further, the coated culture bin was cultured for 7 days in a room at room temperature of 23: and humidity of 95% (RH). Next, the covering part of the surface layer where the hypha did not penetrate was removed, and cultivation was continued in a room adjusted to a room temperature of 17 ° (: 95% humidity (RH) and an illuminance of 150 lux). After cultivation for 85 days after inoculation, 120 g of fruiting bodies were harvested per bottle.
  • RH room temperature of 23 ° C and a humidity of 70%
  • the harvested artificially cultivated Hatakeshimeji mushroom fruit body 1QQg was placed in a hot pot, in a pot, 1 L of water was added, and the mixture was heated and extracted for 3 hours to remove a Hatakeshimeji mushroom extract, thereby obtaining a brown Hatakeshimeji extract extract.
  • An equal amount of ethanol was added to the Hatakeshimeji extract, the precipitate was collected, and distilled water was added to the precipitate to dissolve again.
  • the mixture was concentrated by heating under reduced pressure to obtain a concentrated extract having a solid content of 15%.
  • the concentrated extract was freeze-dried to obtain 2 g of a tan extract powder.
  • the physicochemical properties of the extracted extract varied slightly depending on the state of the mushroom, but were generally as follows.
  • the Hatake mushroom extract of Example 1 was dissolved in pure water and adsorbed on an ion exchange column (Q-Sepharose, etc.). Next, the Hatakeshimeji mushroom extract adsorbed on the ion exchange column was purified by eluting it with stepwise changing the concentration of chlorinated lime from 5 mM to 35 OmM.
  • the purified fraction of Hatake Shimeji extract was fractionated by a gel filtration method using a difference in molecular weight to further purify into 11 fractions.
  • the purified Hatake Shimeji extract was dialyzed, the salts and buffers used in the above purification method were removed, and the mixture was concentrated by heating under reduced pressure and freeze-dried. Table 1 shows the physicochemical properties of the purified product purified into 11 fractions.
  • Example 2 Using the Hatake-shimeji extract extract (EX) of Example 1 and the purified product of the Hatake-shimeji extract (F-5) of Example 2 as samples, 0.2% dextrose in physiological saline was used. A solution of Strand was used as a control.
  • EX 0.5%).
  • F-5 0.1%) was dissolved in physiological saline, and 0.3 ml was administered intraperitoneally to each mouse.
  • the mice used were 15-week-old mice (IC RZSLC system, early). Two hours later, blood was collected under anesthesia. Thereafter, PBS (3 ml) was injected into the abdominal cavity of the mouse, rubbed well, and partially ablated to collect peritoneal exudate cells (mainly macrophages). Then, the peritoneal exudate cells of the mouse were washed and suspended in a serum medium, and the number of cells was counted.
  • peritoneal exudate cells mainly macrophages
  • the Hatakeshimeji extract extract (EX) of Example 1 and the purified product of the Hatakeshimeji extract (F-1 to 11) of Example 2 were used as samples, and physiological saline was used as a control group.
  • 6 to 11 5-week-old mice (ICR / SLC system, early) were used as a group. After transplanting to this?
  • the size of the cancer was measured on the first and second transplants, and the cancer suppression rate (%) was measured in comparison with the control group. On the 28th day after transplantation, the complete disappearance rate of the cancer and the survival rate of the mice were compared with those of the control group. Table 3 shows the results.
  • Hatakeshimeji extract and its purified product are concentrated and dried to form a powder composed mainly of a permanent soluble polysaccharide, but have a very high hygroscopicity and absorb moisture when left indoors, and become sticky.
  • a problem that the surface is solidified Therefore, after adding 33% of dextrin (Pinedettas manufactured by Matsutani Chemical Co., Ltd.) as a shaping agent to the above purified product and concentrating and drying by spray drying, the Hatakeshimeji extract extract which suppressed deterioration due to moisture absorption and the powdered product of the purified product could be manufactured.
  • the immunity 2 activator and antitumor agent of the present invention have strong antitumor activity against Sarcomal80 transplanted cancer and are useful as antitumor agents.
  • this antitumor activity is due to the immunostimulatory effect (activation of macula phage) and is also effective against various diseases caused by reduced immune activity.
  • Hatakeshimeji mushroom extract which is commonly used as food, and its purified product are safer without toxicity as compared with conventional anticancer drugs.
  • the artificially cultivated product can be used as an inexpensive and stable quality raw material for producing Hatake shimeji extract and its purified product.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Medicinal Chemistry (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des agents immunostimulants et antitumoraux non toxiques et présentant un coût réduit. On peut préparer ces agents immunostimulants et antitumoraux en utilisant comme ingrédient actif un extrait éventuellement purifié de Lyophyllum decastes (Fr. Sing.), qui est riche en polysaccharides de poids moléculaire élevé. On utilise en particulier le champignon cultivé artificiellement à partir de 'Kameyama No. 1'.
PCT/JP1999/002074 1998-04-20 1999-04-19 Agents immunostimulants et antitumoraux Ceased WO1999053937A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10109812A JPH11302191A (ja) 1998-04-20 1998-04-20 ハタケシメジ抽出物を活性成分とする免疫賦活剤及び抗腫瘍剤
JP10/109812 1998-04-20

Publications (1)

Publication Number Publication Date
WO1999053937A1 true WO1999053937A1 (fr) 1999-10-28

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Application Number Title Priority Date Filing Date
PCT/JP1999/002074 Ceased WO1999053937A1 (fr) 1998-04-20 1999-04-19 Agents immunostimulants et antitumoraux

Country Status (2)

Country Link
JP (1) JPH11302191A (fr)
WO (1) WO1999053937A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051070A1 (fr) * 2000-01-12 2001-07-19 Life Science Laboratories Co., Ltd. Substance eem-s physiologiquement active issue de champignons, methode de production de ladite substance et medicaments

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003073298A (ja) * 2001-09-04 2003-03-12 Fumiharu Eguchi 免疫調整剤
WO2005040179A1 (fr) * 2003-10-23 2005-05-06 Takara Bio Inc. Composition extraite du corps d'un fruit de l'espece lophyllum decastes
JP2006273835A (ja) * 2005-03-04 2006-10-12 Michishi Tani 悪性腫瘍治療剤及びそれを含む飲食品
JP2007277164A (ja) * 2006-04-07 2007-10-25 Oji Paper Co Ltd 内服用アレルギー性鼻炎改善剤
JP2008208093A (ja) * 2007-02-28 2008-09-11 Oji Paper Co Ltd 抗腫瘍剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5244632B1 (fr) * 1976-12-27 1977-11-09
JPS53109919A (en) * 1977-01-29 1978-09-26 Kureha Chem Ind Co Ltd Preparation of anti-tumor polysaccharides
JPS63287728A (ja) * 1987-05-18 1988-11-24 Noda Shiyokukin Kogyo Kk 菌糸体培養物から薬効成分を抽出する方法
JPH05306233A (ja) * 1991-01-11 1993-11-19 Nagano Pref Gov Keizai Jigiyou Nogyo Kyodo Kumiai Rengokai やまびこほんしめじ熱水抽出物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5244632B1 (fr) * 1976-12-27 1977-11-09
JPS53109919A (en) * 1977-01-29 1978-09-26 Kureha Chem Ind Co Ltd Preparation of anti-tumor polysaccharides
JPS63287728A (ja) * 1987-05-18 1988-11-24 Noda Shiyokukin Kogyo Kk 菌糸体培養物から薬効成分を抽出する方法
JPH05306233A (ja) * 1991-01-11 1993-11-19 Nagano Pref Gov Keizai Jigiyou Nogyo Kyodo Kumiai Rengokai やまびこほんしめじ熱水抽出物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051070A1 (fr) * 2000-01-12 2001-07-19 Life Science Laboratories Co., Ltd. Substance eem-s physiologiquement active issue de champignons, methode de production de ladite substance et medicaments
US6783771B2 (en) 2000-01-12 2004-08-31 Life Science Laboratories Co., Ltd. Physiologically active substance EEM-S originating in mushrooms, process for producing the same and drugs
CN100346796C (zh) * 2000-01-12 2007-11-07 有限会社生命科学研究所 来自菌类的生理活性物质eem－s、其制造方法和药物
JP4728551B2 (ja) * 2000-01-12 2011-07-20 有限会社生命科学研究所 茸からの生理活性物質ｅｅｍ−ｓ、その製造方法および医薬

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