WO2020004463A1 - Composition pour la prévention ou le traitement de la neuropathie périphérique diabétique - Google Patents

Composition pour la prévention ou le traitement de la neuropathie périphérique diabétique Download PDF

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WO2020004463A1
WO2020004463A1 PCT/JP2019/025391 JP2019025391W WO2020004463A1 WO 2020004463 A1 WO2020004463 A1 WO 2020004463A1 JP 2019025391 W JP2019025391 W JP 2019025391W WO 2020004463 A1 WO2020004463 A1 WO 2020004463A1
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Prior art keywords
peripheral neuropathy
preventing
diabetic peripheral
composition
treating diabetic
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PCT/JP2019/025391
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English (en)
Japanese (ja)
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升三 西田
正寛 椿
朋也 武田
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学校法人近畿大学
小林製薬株式会社
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Publication of WO2020004463A1 publication Critical patent/WO2020004463A1/fr

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    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor

Definitions

  • the present invention relates to a composition for preventing or treating diabetes-induced peripheral neuropathy (hereinafter, sometimes referred to as diabetic peripheral neuropathy).
  • diabetes-induced peripheral neuropathy hereinafter, sometimes referred to as diabetic peripheral neuropathy.
  • Diabetic peripheral neuropathy is a complication of diabetes. It is known that peripheral neuropathy such as hyperesthesia or hypoesthesia occurs as diabetes progresses. This peripheral neuropathy is a major problem because the quality of daily life of patients is reduced. However, at present, no effective treatment has been established for diabetic peripheral neuropathy. There is a need for a method for preventing and / or treating diabetic peripheral neuropathy.
  • Patent Document 1 discloses that a lactam compound is effective as a sugar transport-enhancing agent, preventing diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic macroangiopathy, impaired glucose tolerance, or preventing obesity and And / or can be used as a therapeutic agent.
  • Patent Document 1 discloses that a lactam compound has a sugar transporting ability, including Examples, but does not specifically describe peripheral neuropathy. Patent Document 1 is limited to the disclosure that it has an effect of lowering the blood sugar level.
  • tricyclic antidepressants pregabalin as an ⁇ 2 ⁇ ligand, duloxetine as a serotonin / noradrenaline reuptake inhibitor, and the like have been recommended as treatments for peripheral neuropathy, but the side effects cannot be ignored. In addition, these drugs cannot be used as a composition for preventing diabetic peripheral neuropathy.
  • An object of the present invention is to provide a composition for preventing or treating diabetic peripheral neuropathy, which is capable of preventing and treating diabetic peripheral neuropathy.
  • the present inventors searched for a material capable of preventing or treating diabetic peripheral neuropathy, and found a shiitake mycelium.
  • the present inventors have clarified that the shiitake mushroom mycelium exhibits an excellent preventive or therapeutic effect on diabetic peripheral neuropathy, and completed the present invention.
  • the first invention is a composition for preventing or treating diabetic peripheral neuropathy, comprising an extract of Shiitake mushroom mycelium.
  • the second invention is a pharmaceutical composition for preventing or treating diabetic peripheral neuropathy, comprising an extract of Shiitake mushroom mycelium.
  • the second invention is a pharmaceutical composition for preventing or treating diabetic peripheral neuropathy, wherein the daily dose of the extract of Shiitake mushroom mycelium is 4 mg / kg body weight or more as a dry powder weight. .
  • the third invention is a processed food having an effect of preventing or treating diabetic peripheral neuropathy, comprising an extract of Shiitake mushroom mycelium.
  • a fourth invention provides a method for preventing or treating diabetic peripheral neuropathy, comprising administering to a subject the pharmaceutical composition for preventing or treating diabetic peripheral neuropathy according to the second invention. Excluding methods of surgery, treatment, and diagnosis).
  • the present invention may also be referred to as prevention or treatment of diabetic peripheral neuropathy using a Shiitake mushroom mycelium extract.
  • the present invention can prevent or treat diabetic peripheral neuropathy. That is, by administering the Shiitake mushroom mycelium extract, numbness of the limbs induced by diabetes, pain in the limbs, decreased deep tendon reflex, decreased muscular strength, allodynia, hyperalgesia, elaborate dysfunction of the fingers, walking disorders, The stumbling, falling, bending disorder (difficult or impossible such as sitting straight, cross-legged, sitting sideways or sitting on a chair), or paralysis of limbs are improved.
  • the composition for preventing or treating diabetic peripheral neuropathy according to the present invention can exert its effects when taken orally. Therefore, there is no need to go to the hospital and the burden on the patient is small.
  • the improvement of diabetic peripheral neuropathy also improves the quality of life of the patient.
  • composition for preventing or treating diabetic peripheral neuropathy according to the present invention exerts a preventive effect on diabetic peripheral neuropathy, so that when taken together with daily food, it can also be used to prevent diabetic peripheral neuropathy. effective.
  • composition for preventing or treating diabetic peripheral neuropathy according to the present invention will be described with reference to the drawings and examples. Note that the following description exemplifies one embodiment and one example of the present invention, and the present invention is not limited to the following description. The following description can be modified without departing from the spirit of the present invention.
  • prevention includes the concepts of prevention, early treatment, and prevention of functional decline.
  • treatment is not necessarily limited to the improvement of the symptoms of the affected patient, but is a concept that also includes the alleviation and improvement of the symptoms of a healthy person (preliminary group).
  • “Lentinus edodes mycelium”, which is a raw material of the shiitake mushroom mycelium extract used in the composition for preventing or treating diabetic peripheral neuropathy according to the present invention, is not particularly limited as long as it is a shiitake mushroom mycelium. Not done.
  • a mycelium in a stage before the edible fruiting body can be used.
  • an extract (Lentinus edodes mycelium extract) obtained by culturing Lentinus edodes on a solid medium can be used.
  • the Shiitake mushroom mycelium extract used in the composition for preventing or treating diabetic peripheral neuropathy according to the present invention can be prepared by a method known in the art.
  • an extract obtained by extracting a shiitake mycelium after pulverization can be suitably used as a shiitake mushroom mycelium extract.
  • an extract obtained by pulverizing and decomposing a solid medium containing Shiitake mycelium in the presence of water can also be used.
  • Examples of the solvent used for the preparation of the extract include water, ethanol, methanol, butanol, isopropanol and the like. Among them, water can be suitably used.
  • the extraction can be performed under heating of the solvent (for example, about 85 to 105 ° C.). However, extraction can also be performed by sonication at lower temperatures (eg, 25-50 ° C., preferably 30-45 ° C.).
  • the “Shitake mushroom mycelium extract” is not limited, but for example, those obtained by the following method can be used. That is, shiitake mushrooms are inoculated on a solid medium based on bagasse (sugar cane pulp) and defatted rice bran. Next, the solid medium containing the shiitake mushroom mycelium obtained by growing the shiitake mushroom mycelium is loosened so that the amount of 12-mesh passage is 30% by weight or less. Water is added to the loosened solid medium, and the solid medium is crushed and ground while maintaining the temperature at 30 to 55 ° C., so that at least 70% by weight or more of the bagasse fiber passes through 12 mesh. Next, the temperature of the treated product is raised to 80 ° C., and the resulting suspension is filtered to obtain a shiitake mushroom mycelium extract.
  • the extract thus obtained may be used as it is as a Shiitake mushroom mycelium extract.
  • it may be stored as a powder by concentration, freeze drying or spray drying.
  • the powder thus prepared is useful because it can be used in various forms at the time of use.
  • the shiitake mushroom mycelium extract thus obtained contains 15 to 50%, preferably 20 to 40% (w / w) of saccharide by saccharide analysis by the phenol-sulfuric acid method. In addition, it contains 10 to 40%, preferably 13 to 30% (w / w) of the protein by the protein analysis by the Lowry method. Further, it contains 1 to 5%, preferably 2.5 to 3.5% (w / w) of polyphenols by the Folin-Denis method using gallic acid as a standard. The shiitake mushroom mycelium extract also contains about 0.1% lipid, about 0.4% fiber, about 20% ash, and the like.
  • composition % by mass
  • the composition may vary depending on the culture conditions and the like: xylose: 15.2; arabinose: 8.2; mannose: 8.4; glucose: 39.4; galactose: 5.4; amino sugar (glucosamine): 12 0.0; uronic acid: 11.3.
  • the composition for preventing or treating diabetic peripheral neuropathy according to the present invention comprises the above-mentioned Shiitake mushroom mycelium extract.
  • the content of the shiitake mushroom mycelium extract in the composition for preventing or treating diabetic peripheral neuropathy according to the present invention is not particularly limited.
  • the content of the Shiitake mushroom mycelium extract can be appropriately changed depending on the administration subject (including an animal) and the symptom (cause).
  • the composition for preventing or treating diabetic peripheral neuropathy contains the shiitake mushroom mycelium extract usually in an amount of 10% by mass or more, preferably 20% by mass or more, more preferably 30% by mass or more.
  • the content of Shiitake mushroom mycelium extract may be 100% by mass.
  • the composition for preventing or treating diabetic peripheral neuropathy according to the present invention can be provided as a therapeutic drug (pharmaceutical composition) for diabetic peripheral neuropathy.
  • the pharmaceutical composition according to the present invention can be provided as an internal preparation (oral preparation).
  • oral preparation for example, it can be provided in the form of a capsule, granule, powder, tablet, liquid, jelly or the like.
  • components such as a binder, a lubricant, a disintegrant, a colorant, a flavor, a preservative, an antioxidant, and a stabilizer.
  • antacids stomachic, digestive, intestinal, antispasmodic, mucosal repair, anti-inflammatory, astringent, antiemetic, antitussive, expectorant, anti-inflammatory enzyme, sedative-hypnotic, antihistamine, caffeine, inotropic diuresis
  • antibacterial agents vasoconstrictors, vasodilators, local anesthetics, crude drugs, herbal extract powders, vitamins, menthols, glucosamine compounds, chitin, chitosan and the like can be appropriately contained.
  • the pharmaceutical composition according to the present invention can be provided as an external preparation (transdermal preparation).
  • it can be provided in the form of a liquid, ointment, cream, gel, patch, aerosol, or the like.
  • components such as water, lower alcohol, polyhydric alcohol, solubilizer, surfactant, emulsion stabilizer, gelling agent, adhesive, stabilizer, pH adjuster, preservative, bactericide, fat, and oil can be contained.
  • an anti-inflammatory agent an analgesic, a local anesthetic, a vasodilator, a corticosteroid, a keratolytic agent, a humectant, a bactericide, an antioxidant, a refreshing agent, a fragrance, a pigment, and the like can be appropriately contained. .
  • the shiitake mushroom mycelium extract is usually contained in an amount of at least 10% by mass, preferably at least 20% by mass, more preferably at least 30% by mass, based on the total amount of the composition. Further, the pharmaceutical composition according to the present invention may have a shiitake mushroom mycelium extract content of 100% by mass.
  • composition for preventing or treating diabetic peripheral neuropathy according to the present invention can also be provided as a processed food.
  • Processed foods include, for example, candy, gum, jelly, biscuits, cookies, rice crackers, bread, noodles, fish and animal meat products, tea, soft drinks, coffee drinks, milk drinks, whey drinks, lactic acid bacteria drinks, yogurt, ice
  • General processed foods including taste foods such as creams and puddings and health foods can be exemplified.
  • the processed foods according to the present invention include functional health foods such as foods for specified health use and nutritional foods specified in the health functional food system of the Ministry of Health, Labor and Welfare. Further, it may contain dietary supplements (supplements), feeds, food additives, and the like.
  • the processed food according to the present invention can be prepared by including the shiitake mushroom mycelium extract in these processed foods.
  • the shiitake mushroom mycelium extract is generally contained in an amount of 10% by mass or more, preferably 20% by mass or more, more preferably 30% by mass or more. Further, the processed food according to the present invention may have a shiitake mushroom mycelium extract content of 100% by mass.
  • the dose of the composition for preventing or treating diabetic peripheral neuropathy according to the present invention can be appropriately selected depending on symptoms, age, body weight, elapsed time after onset, therapeutic measures used in combination, and the like.
  • the dose of the shiitake mycelium extract to a human adult as a dry powder weight is, for example, 4 mg / kg body weight or more, preferably 8 mg / kg body weight or more, more preferably 8 to 1700 mg / kg body weight per day. And more preferably 25 to 1700 mg / kg body weight.
  • the composition for preventing or treating diabetic peripheral neuropathy according to the present invention was subjected to 50 mg / kg body weight, 100 mg / kg body weight, 500 mg / kg per day by experiments using model mice. Body weight, 1000 mg / kg body weight, and 2000 mg / kg body weight are indicated. Such dosages are based on a human equivalent dose (HED) of 12.3 in mice ("Guidance for Industry ⁇ Estimating ⁇ the ⁇ Maximum ⁇ Safe ⁇ Starting ⁇ Dose ⁇ in ⁇ Initial ⁇ ClinicalTrials ⁇ for ⁇ Therapeutic.com).
  • HED human equivalent dose
  • composition for preventing or treating diabetic peripheral neuropathy according to the present invention can be used for animals such as domestic animals and companion animals in addition to humans.
  • the present invention provides a method for preventing, ameliorating, or treating the symptoms (administering a person by surgery or treatment) by administering a shiitake mushroom mycelium extract to a diabetic peripheral neuropathy patient or a subject to be administered as a preliminary group thereof. , Except for the method of diagnosis).
  • ⁇ Culture of Shiitake mycelium> As a medium for cultivating Shiitake mushroom mycelium, a solid medium comprising 80 parts by weight of bagasse and 10 parts by weight of defatted rice bran to which a suitable amount of pure water was added was used. Shiitake mushroom mycelium was inoculated into this medium, and allowed to stand in a culture room where the temperature and humidity were controlled to grow the shiitake mushroom mycelium.
  • Example 1 ⁇ Preventive effect on streptozotocin-induced diabetic mouse peripheral neuropathy>
  • the preventive effect of Shiitake mushroom mycelium extract on hyperesthesia such as allodynia due to mechanical stimuli induced by diabetes (usually severe pain caused by sensory stimuli that do not cause pain) and abnormal sensation in cold stimuli were examined.
  • a shiitake mushroom mycelium extract was orally administered to a mouse as a test substance, and the following tests (Cold plate test and von Frey test) were performed.
  • test substance administration group Using C57BL / 6J male mice of 6 to 7 weeks of age, control group, streptozotocin administration group, streptozotocin and test substance administration group (streptozotocin + test substance administration group) were divided into three groups. Configured.
  • the horizontal axis is the elapsed period (days) after administration, and the vertical axis is the escape reaction time (seconds). Those that can be judged to be significant from the control by a test with a significance level of 5% are marked with “*”. Similarly, in the following graphs, those for which the difference from the control can be determined to be significant by the test at the significance level of 5% are marked with “*”.
  • a white circle (written as “vehicle”), a vertical bar (written as “50 mg / kg LEM”), an asterisk (written as “100 mg / kg LEM”), and a white diamond. (Described as “500 mg / kg LEM”), a white triangle (described as “1000 mg / kg LEM”), and a white square (described as “2000 mg / kg LEM”) are control groups.
  • “Vehicle” is a mouse to which nothing was administered, and “50 mg / kg LEM”, “100 mg / kg LEM”, “500 mg / kg LEM”, “1000 mg / kg LEM”, and “2000 mg / kg LEM” were each treated with a test subject. It means that 50 mg / kg body weight, 100 mg / kg body weight, 500 mg / kg body weight, 1000 mg / kg body weight and 2000 mg / kg body weight were given per day. That is, these show the results when healthy mice were administered the test article.
  • Black circles (described as “200 mg / kg STZ”) are streptozotocin-administered groups. The result of giving 200 mg / kg body weight per day of streptozotocin is shown. Mice suffer from diabetes after administration of streptozotocin.
  • a black cross 50 mg / kg LEM + 200 mg / kg STZ (administered LEM from day 0)), a two-dot chain line only (100 mg / kg LEM + 200 mg / kg STZ (administered LEM from day 0)) and a black diamond (500 mg / kg LEM + 200 mg / kg STZ ( The black triangle (1000 mg / kg LEM + 200 mg / kg STZ (administered LEM from day 0)) and the black square (2000 mg / kg LEM + 200 mg / kg STZ (administered LEM from day 0)) were composed of streptozotocin and It is a test group.
  • the horizontal axis is the elapsed period (days) after administration, and the vertical axis is the avoidance response (score). If the number of avoidances is large, it is considered that the stimulation by the filament is more repelled.
  • the line types in FIG. 2 are the same as those in FIG. However, the vertical bar (shown as “50 mg / kg LEM” in FIG. 1) and the black cross (50 mg / kg LEM + 200 mg / kg STZ in FIG. 1 (administered LEM from day 0)) are not shown in FIG. In the control group, the avoidance response score was 1 or less stably.
  • test substance extract of Shiitake mushroom mycelium
  • streptozotocin has an effect of preventing diabetic peripheral neuropathy caused by streptozotocin.
  • Example 2 ⁇ Therapeutic effect on streptozotocin-induced diabetic mouse peripheral neuropathy> The therapeutic effect of Shiitake mushroom mycelium extract on hyperesthesia such as allodynia caused by mechanical stimulation induced by diabetes and paresthesia caused by low-temperature stimulation was examined. From day 21 after the administration of streptozotocin, a shiitake mushroom mycelium extract was orally administered to a mouse as a test substance, and the following tests (Cold plate test and von Frey test) were performed.
  • test substance Using C57BL / 6J male mice 6 to 7 weeks old, a control group, a streptozotocin administration group, a streptozotocin and a test substance administration group (streptozotocin + test substance administration group; (Administration started on day 3).
  • the horizontal axis is the elapsed period after administration (days), and the vertical axis is the escape reaction time (seconds).
  • the line types in the graph are the same as those in FIG. 2 for the control group and the streptozotocin-administered group.
  • “administration from day 0” in FIG. 2 was replaced with “administration from day 21” in FIG.
  • a white circle (written as “vehicle”), an asterisk (written as “100 mg / kg LEM”), a white diamond (written as “500 mg / kg LEM”), and a white triangle (Indicated as “1000 mg / kg LEM”) and a white square (indicated as “2000 mg / kg LEM”) are control groups.
  • “Vehicle” is a mouse to which nothing is administered, and “100 mg / kg LEM”, “500 mg / kg LEM”, “1000 mg / kg LEM”, and “2000 mg / kg LEM” indicate that the test substance is 100 mg / kg body weight per day. , 500 mg / kg body weight, 1000 mg / kg body weight, and 2000 mg / kg body weight. That is, they show the results when healthy mice were administered the test article.
  • the streptozotocin-administered group was designated as "STZ”.
  • STZ The streptozotocin-administered group
  • the two-dot chain line 100 mg / kg LEM + 200 mg / kg STZ (administered LEM from day 21)
  • the black diamond 500 mg / kg LEM + 200 mg / kg STZ (from day 21)).
  • the control group had an escape reaction time of about 15 to 18 seconds.
  • the escape reaction time was shorter as the administration elapsed time was longer. The escape reaction time became constant in about 14 days.
  • the horizontal axis is the elapsed period (days) after administration, and the vertical axis is the avoidance response (score). If the number of avoidances is large, it is considered that the stimulation by the filament is more repelled.
  • the line types in FIG. 4 are the same as those in FIG. Further, the same symbols in FIG. 3 were used for the symbols in the graph.
  • the avoidance response score was 1 or less stably.
  • the avoidance response score became higher as the administration elapsed time became longer, and the avoidance response score became constant at about 14 days. Thus, it was considered that the administration of streptozotocin caused diabetic peripheral neuropathy.
  • the composition for preventing or treating diabetic peripheral neuropathy according to the present invention shows that peripheral neuropathy is improved and has a therapeutic effect. Is shown.
  • composition according to the present invention can be used for preventing or treating peripheral neuropathy induced by diabetes.

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Abstract

L'invention concerne une composition pour la prévention ou le traitement de la neuropathie périphérique diabétique. Une composition pour la prévention ou le traitement de la neuropathie périphérique diabétique, ladite composition étant caractérisée en ce qu'elle comprend un extrait de mycélium de Lentinus edodes (LEM), permet de prévenir ou de traiter l'engourdissement des membres, la douleur des membres, la diminution du réflexe des tendons profonds, la faiblesse musculaire, l'allodynie, l'hyperalgie, les troubles de la fonction motrice fine des doigts, les troubles de la marche, les trébuchements, les chutes, les troubles de la flexion [difficulté ou impossibilité de s'asseoir en seiza (en position assise, avec les jambes repliées sous soi), en agura (en position assise avec les jambes croisées), en yokozuwari (en position assise avec les jambes d'un côté), sur une chaise, etc.], la paralysie des membres, etc., induits par le diabète.
PCT/JP2019/025391 2018-06-27 2019-06-26 Composition pour la prévention ou le traitement de la neuropathie périphérique diabétique WO2020004463A1 (fr)

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JP2002087981A (ja) * 2000-07-11 2002-03-27 Hitoshi Nagaoka 糖質脂質代謝異常改善剤
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