WO2022059767A1 - Activateur d'autophagie - Google Patents

Activateur d'autophagie Download PDF

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Publication number
WO2022059767A1
WO2022059767A1 PCT/JP2021/034243 JP2021034243W WO2022059767A1 WO 2022059767 A1 WO2022059767 A1 WO 2022059767A1 JP 2021034243 W JP2021034243 W JP 2021034243W WO 2022059767 A1 WO2022059767 A1 WO 2022059767A1
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Prior art keywords
gene
autophagy
tocopherol
salt
tocopherol phosphate
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PCT/JP2021/034243
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English (en)
Japanese (ja)
Inventor
夕子 中上
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昭和電工株式会社
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Application filed by 昭和電工株式会社 filed Critical 昭和電工株式会社
Priority to KR1020237008830A priority Critical patent/KR20230051262A/ko
Priority to CN202180075908.7A priority patent/CN116507314A/zh
Priority to JP2022550624A priority patent/JPWO2022059767A1/ja
Publication of WO2022059767A1 publication Critical patent/WO2022059767A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 an autophagy activator and an autophagy activating composition.
  • Autophagy responds to extracellular or intracellular stress and signals such as starvation, growth factor deficiency, and pathogenic infections, and regenerates energy by breaking down aging or damaged intracellular substances and organelles. It is a mechanism for production and removal of damaging substances, and is important for maintaining the homeostasis of normal cells. From past studies, it has been reported that the intracellular autophagy activity decreases sharply as aging progresses (Non-Patent Document 1). In addition, when autophagy is suppressed, aged mitochondria and accidentally folded proteins are excessively accumulated in the cells, and the oxidative stress in the cells is increased to induce cell death, resulting in cell aging. It will be.
  • Non-Patent Documents 2 and 3 Especially in Alzheimer's disease, since the function of autophagy is inhibited, aggregated protein called amyloid ⁇ is accumulated in the living body, and it is said that this is involved in the onset (Non-Patent Document 4).
  • SENDA disease SENDA: static encephalopathy of childhood with neurodegeneration in adulthood
  • SENDA a neurodegenerative disease associated with iron deposition in the melanoma and paleosphere of the brain and atrophy of the cerebral tract
  • clone disease which is an inflammatory bowel disease that causes it, and cancer
  • the process of autophagy has been studied in both yeast and mammals, with up to 36 proteins utilized. Among them, the formation of autophagosomes and the differentiation of their contents are controlled by the Atg protein encoded by the autophagy-related gene (ATG), and the Atg12-ATG5 binding system and LC3-Phosphatidyl Ethanolamine (PE) binding system are used. It can be divided into 6 groups including, each of which acts stepwise in each process.
  • ATG autophagy-related gene
  • PE LC3-Phosphatidyl Ethanolamine
  • Autophagy activators include compounds that increase LC3-related factors, which are markers of autophagy activity, to activate autophagy, and promote autophagy flux, including fusion of autophagosomes to lysosomes. Compounds have been reported (Patent Documents 1 to 4).
  • an object of the present invention is to provide an autophagy activator and an autophagy activation composition containing the autophagy activator, which can effectively activate autophagy. ..
  • the present invention includes the following aspects.
  • the tocopherol phosphate ester or a salt thereof is at least one tocopherol phosphate ester selected from the group consisting of ⁇ -tocopherol phosphate ester and ⁇ -tocopherol phosphate ester or a salt thereof, according to [1].
  • An autophagy activating composition comprising the autophagy activator according to any one of [1] to [9] and a pharmaceutically acceptable carrier.
  • an autophagy activator capable of effectively activating autophagy, and an autophagy activation composition containing the autophagy activator.
  • the present invention provides an autophagy activator containing a tocopherol phosphate ester or a salt thereof as an active ingredient.
  • autophagy is a mechanism for regenerating energy and removing damaged substances by decomposing old or damaged intracellular substances and organelles.
  • the autophagy activator of the present embodiment can promote the expression of the LC3 gene, which is an autophagy marker, and the ATG5 gene, ATG7 gene, and Beclin1 gene contained in the autophagosome, and activate autophagy. ..
  • autophagy can be activated by suppressing the expression of the mTOR gene, which acts as an inhibitor of autophagy.
  • the autophagy activator of the present embodiment is not particularly limited as long as it contains tocopherol phosphate ester or a salt thereof as an active ingredient.
  • Examples of the tocopherol phosphate ester used in the autophagy activator of the present embodiment include compounds represented by the following general formula (1).
  • R 1 , R 2 and R 3 represent a hydrogen atom or a methyl group independently of each other.
  • the tocopherol phosphate ester is not particularly limited, and may be any of these tocopherol phosphate esters. Among these, ⁇ -tocopherol phosphate ester and ⁇ -tocopherol phosphate ester are preferable, and ⁇ -tocopherol phosphate ester is more preferable.
  • the compound represented by the above general formula (1) has an asymmetric carbon atom at the 2-position of the chromane ring, d-form and l-form stereoisomers and dl-form exist.
  • the tocopherol phosphate ester may be any of these stereoisomers, but the dl form is preferable.
  • tocopherol phosphate ester dl- ⁇ -tocopherol phosphate ester and dl- ⁇ -tocopherol phosphate ester are preferable, and dl- ⁇ -tocopherol phosphate ester is more preferable.
  • the salt of tocopherol phosphate ester is not particularly limited, and examples thereof include a salt with an inorganic base and a salt with an organic base.
  • Examples of the salt with the inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt; zinc salt and the like.
  • Examples of the salt with an organic base include an alkylammonium salt and a salt with a basic amino acid.
  • alkali metal salt As the salt of tocopherol phosphate ester, an alkali metal salt is preferable, and a sodium salt is more preferable.
  • Alkali metal salts of tocopherol phosphate esters, particularly sodium salts have the advantages of being highly soluble in water and being easy to handle because they are powdery in nature.
  • Preferred embodiments of the tocopherol phosphate ester include an alkali metal salt (eg, sodium salt) of the compound represented by the above general formula (1), an alkali metal salt of ⁇ -tocopherol phosphate ester (eg, sodium salt), and ⁇ .
  • alkali metal salt of tocopherol phosphate eg, sodium salt
  • alkali metal salt of dl- ⁇ -tocopherol phosphate eg, sodium salt
  • alkali metal salt of dl- ⁇ -tocopherol phosphate eg, sodium salt
  • the alkali metal salts of tocopherol phosphate the sodium salt of ⁇ -tocopherol phosphate and the sodium salt of ⁇ -tocopherol phosphate are preferable, and the sodium salt of ⁇ -tocopherol phosphate is more preferable.
  • the sodium salt of dl- ⁇ -tocopherol phosphate is commercially available from Showa Denko under the product name of TPNa (registered trademark) (display name: Na tocopheryl phosphate).
  • TPNa registered trademark
  • the TPNa is exemplified as a preferable example of the tocopherol phosphate ester.
  • the autophagy activator of the present embodiment one selected from tocopherol phosphate ester and a salt thereof may be used alone, or two or more thereof may be used in combination.
  • the autophagy activator of the present embodiment preferably contains a salt of tocopherol phosphate ester, and more preferably an alkali metal salt of tocopherol phosphate ester (eg, sodium salt) is used alone.
  • the tocopherol phosphate ester or a salt thereof can be produced by a known production method.
  • the tocopherol phosphate ester or a salt thereof can be produced, for example, by the method described in JP-A-59-44375, International Publication No. 97/14705 and the like.
  • a tocopherol phosphate ester can be obtained by allowing a phosphorylating agent such as phosphorus oxychloride to act on tocopherol dissolved in a solvent and appropriately purifying the tocopherol after completion of the reaction.
  • the obtained tocopherol phosphoric acid ester is neutralized with a metal oxide such as magnesium oxide, a metal hydroxide such as sodium hydroxide, or ammonium hydroxide or alkylammonium hydroxide to obtain tocopherol phosphate.
  • a metal oxide such as magnesium oxide
  • a metal hydroxide such as sodium hydroxide
  • ammonium hydroxide or alkylammonium hydroxide to obtain tocopherol phosphate.
  • Ester salts can be obtained.
  • the method for producing the tocopherol phosphate ester or a salt thereof is not limited to the above method.
  • tocopherol phosphate ester and its salt may be collectively referred to as "tocopherol phosphate ester, etc.”
  • the autophagy activator of the present embodiment can be used by administering itself to a patient for the purpose of treating neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease.
  • the autophagy activator of the present embodiment can also be used by blending with pharmaceuticals and cosmetics for the purpose of activating autophagy. Further, it may be blended with the composition for activating autophagy described later and used.
  • the autophagy activator of the present embodiment can effectively activate autophagy by promoting the expression of the LC3 gene.
  • the autophagy activator of the present embodiment can effectively activate autophagy by promoting the expression of the ATG5 gene.
  • the autophagy activator of the present embodiment can effectively activate autophagy by promoting the expression of the ATG7 gene.
  • the autophagy activator of the present embodiment can effectively activate autophagy by promoting the expression of the Beclin 1 gene.
  • the autophagy activator of the present embodiment can effectively activate autophagy by suppressing the expression of the mTOR gene. Since the autophagy activator of the present embodiment can effectively activate autophagy, it can be used for the prevention or treatment of Alzheimer's disease.
  • Amyloid ⁇ is known to cause a decrease in autophagy in nerve cells.
  • amyloid ⁇ is known to induce a decrease in autophagy and cell death called apoptosis of nerve cells.
  • the autophagy activator of the present embodiment can promote LC3 gene expression in the presence of amyloid ⁇ .
  • the autophagy activator of the present embodiment can promote ATG5 gene expression in the presence of amyloid ⁇ .
  • the autophagy activator of the present embodiment can promote ATG7 gene expression in the presence of amyloid ⁇ .
  • the autophagy activator of the present embodiment can suppress apoptosis in the presence of amyloid ⁇ .
  • the autophagy activator of the present embodiment can promote the expression of at least one gene selected from the group consisting of the LC3 gene, the ATG5 gene, and the ATG7 gene in the presence of amyloid ⁇ , particularly in nerve cells. can.
  • the autophagy activator of the present embodiment can suppress apoptosis in the presence of amyloid ⁇ , especially in nerve cells.
  • Promoting LC3 gene expression in the presence of amyloid ⁇ means that the autophagy activator of the present embodiment is administered in the presence of amyloid ⁇ , as compared with the case where the autophagy activator is not administered. This means that the expression level of the LC3 gene is increased. The same applies to the ATG5 gene and the ATG7 gene.
  • Suppressing apoptosis in the presence of amyloid ⁇ means that by administering the autophagy activator of the present embodiment in the presence of amyloid ⁇ , the apoptosis is compared with the case where the autophagy activator is not administered. Means that is suppressed.
  • LC3 microtubule assisted protein 1 light chain 3 alpha: NCBI Gene ID: 84557
  • LC3-II is converted to LC3-II, which is attracted to the autophagosome membrane by adding phosphatidylethanolamine upstream of autophagy signal transduction. It binds to the membrane.
  • LC3 is used as a marker for autophagosomes. Examples of the base sequence of the human LC3 gene include NM_032514.4 and NM_181509.3 registered in the NCBI Reference Sequence database.
  • ATG5 (autophagy processed 5: NCBI Gene ID: 9474) binds to ATG12 and functions as an E1-like activating enzyme in a ubiquitin-like conjugated system.
  • Examples of the base sequence of the human ATG5 gene include NM_001286106.1, NM_001286107.1, NM_001286108.1, NM_001286111.1.
  • ATG7 (autophagy processed 7: NCBI Gene ID: 10533) functions as an E1-like activating enzyme that activates LC3 and ATG12 in an ATP-dependent manner.
  • Examples of the base sequence of the human ATG7 gene include NM_001136031.3, NM_001144912.2, NM_0013492322.2, NM_001349233.2.
  • Beclin 1 (NCBI Gene ID: 8678) forms the Cress III PI3K complex together with ATG14L and Vps34mp150 and functions as a positive regulator of autophagosome formation.
  • Examples of the base sequence of the human Beclin 1 gene include NM_00131398.2, NM_0013139991, NM_001314000.1, and NM_003766.4 registered in the NCBI Reference Sequence database.
  • MTOR (mechanistic target of rapamycin kinase: NCBI Gene ID: 2475) is a kind of phosphatidylinositol kinase-related kinase and mediates a cellular response to stress such as DNA damage and nutritional deficiency. mTOR functions as an inhibitor of autophagy. Examples of the base sequence of the human mTOR gene include NM_004958.4 registered in the NCBI Reference Sequence database.
  • the autophagy activator of the present embodiment is administered to a patient having a high risk of developing neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, and prevents neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. May be used for. Further, the autophagy activator of the present embodiment may be administered to a patient who has developed a neurodegenerative disease such as Alzheimer's disease, Huntington's disease, or Parkinson's disease, and may be used to suppress the progression or worsening of the neurodegenerative disease. good.
  • the autophagy activator of the present embodiment can be administered to a patient in the same manner as the composition for autophagy activation described later, and may be administered orally or parenterally. It may be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally or the like, or may be administered intrarectally as a suppository, or may be administered to the skin as an external preparation for skin.
  • composition for activating autophagy provides a composition for autophagy activation, which comprises the above-mentioned autophagy activator and a pharmaceutically acceptable carrier.
  • composition for activating autophagy of the present embodiment contains the above-mentioned autophagy activator, a pharmaceutically acceptable carrier, and optionally other components according to a conventional method (for example, the method described in the Japanese Pharmacopoeia). It can be produced by mixing and formulating.
  • the term "pharmaceutically acceptable carrier” means a carrier that does not inhibit the physiological activity of the active ingredient and does not show substantial toxicity to the administration subject thereof.
  • “does not show substantial toxicity” means that the component does not show toxicity to the administration subject at the dose normally used.
  • the pharmaceutically acceptable carrier is not particularly limited, and is not particularly limited, and includes excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, diluents, solvents for injections, oily bases, moisturizers, and feels.
  • Improvement agents surfactants, polymers, thickening / gelling agents, solvents, propellants, antioxidants, reducing agents, oxidizing agents, chelating agents, acids, alkalis, powders, inorganic salts, water, metal-containing compounds , Unsaturated monomers, polyhydric alcohols, polymer additives, auxiliaries, wetting agents, thickeners, tackifiers, oily raw materials, liquid matrices, fat-soluble substances, polymer carboxylates, etc. can.
  • polymer / thickening / gelling agent examples include metachlorooxyethyl phosphorylcholine, butyl methacrylate, and polymers thereof.
  • pharmaceutically acceptable carrier one type may be used alone, or two or more types may be used in combination.
  • the other components are not particularly limited, and are not particularly limited, and are preservatives, antibacterial agents, ultraviolet absorbers, whitening agents, anti-inflammatory agents, anti-inflammatory agents, hair growth agents, blood circulation promoters, stimulants, hormones, and anti-wrinkle agents.
  • Antibacterial agents tightening agents, cooling sensitizers, warming agents, wound healing promoters, stimulants, analgesics, cell activators, plant / animal / microbial extracts, seed oils, antipruritic agents, keratin exfoliating / dissolving agents , Antibacterial agents, refreshing agents, astringents, enzymes, nucleic acids, fragrances, pigments, coloring agents, dyes, pigments, anti-inflammatory analgesics, antifungal agents, antihistamines, hypnotic sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics Agents, antibiotics, anesthetics, antibacterial substances, antiepileptic agents, coronary vasodilators, crude drugs, antipruritic agents, keratin softening and stripping agents, UV blocking agents, antiseptic bactericides, antioxidants, pH adjusters, additives , Metallic screws and the like.
  • Specific examples of these components include those described in International Publication No. 2016/076310. Further, specific examples of plant / animal / microbial extracts include lapsana comnis flowers / leaves / stems, tea leaves and the like. Specific examples of seed oil include Moringa oleifera seed oil. Specific examples of fragrances include perillaldehyde. As for the other components, one type may be used alone, or two or more types may be used in combination.
  • the composition for activating autophagy of the present embodiment can contain the above-mentioned autophagy activator in a therapeutically effective amount.
  • “Therapeutically effective amount” means the amount of drug effective for the treatment or prevention of a patient's disease. The therapeutically effective amount may vary depending on the condition, age, sex, body weight, etc. of the disease to be administered.
  • the therapeutically effective amount of the above-mentioned autophagy activator may be an amount that tocopherol phosphate or the like can activate autophagy.
  • the therapeutically effective amount of the autophagy activator is the expression of at least one gene selected from the group consisting of LC3 gene, ATG5 gene, ATG7 gene, and Beclin1 gene by tocopherol phosphate or the like. It can be an amount that can be promoted. Alternatively, tocopherol phosphate or the like may be an amount capable of suppressing the expression of the mTOR gene, which is an autophagy suppressor. The therapeutically effective amount of the autophagy activator may be an amount of tocopherol phosphate or the like that can suppress apoptosis in the presence of amyloid ⁇ .
  • the therapeutically effective amount of the autophagy activator in the composition for autophagy activation of the present embodiment is such that the total content of tocopherol phosphate ester or a salt thereof is based on the total amount of the composition for autophagy activation.
  • 0.01 to 10% by mass for example, 0.1 to 10% by mass, for example, 0.1 to 5% by mass, for example, 0.1 to 3% by mass.
  • % for example, 0.1 to 2% by mass, for example, 0.3 to 2% by mass, and for example, 0.6 to 1.5% by mass. ..
  • the content of the above-mentioned tocopherol phosphate ester and the like in the composition for activating autophagy means the content of the compound when one kind of tocopherol phosphate ester and the like is used alone, and the tocopherol phosphate ester. When two or more kinds of the above are used in combination, it means the total content of these compounds.
  • composition for activating autophagy of the present embodiment may be a pharmaceutical composition or a cosmetic.
  • the present invention provides a pharmaceutical composition for autophagy activation, which comprises the above-mentioned autophagy activator and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is not particularly limited, and a carrier generally used for pharmaceutical products can be used in addition to those listed above.
  • a carrier generally used for pharmaceutical products can be used in addition to those listed above.
  • the Japanese Pharmacopoeia the Japanese Pharmacopoeia Non-Pharmaceutical Standards
  • the Pharmaceutical Additives Standard 2013 Yakuji Nippo, 2013
  • the Pharmaceutical Additives Dictionary 2016 edited by the Japan Pharmaceutical Additives Association, Yakuji Nippo, 2016
  • Handbook of General raw materials described in Pharmaceutical Expipients, 7th edition (Pharmaceutical Press, 2012) and the like
  • the pharmaceutically acceptable carrier one type may be used alone, or two or more types may be used in combination.
  • the pharmaceutical composition of the present embodiment may contain other components in addition to the autophagy activator and a pharmaceutically acceptable carrier.
  • the other ingredients are not particularly limited, and general pharmaceutical additives can be used.
  • an active ingredient other than the above-mentioned autophagy activator can also be used.
  • pharmaceutical additives and active ingredients as other ingredients include, for example, the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Pharmaceutical Standards, the Pharmaceutical Additives Standard 2013 (Yakuji Nippo Co., Ltd., 2013), and the addition of pharmaceuticals.
  • the dosage form of the pharmaceutical composition of the present embodiment is not particularly limited, and can be a dosage form generally used as a pharmaceutical preparation.
  • dosage forms for oral administration such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions; and parenteral such as injections, suppositories, external preparations for skin, etc. Examples thereof include a dosage form to be administered.
  • Pharmaceutical compositions of these dosage forms can be formulated according to a conventional method (for example, the method described in the Japanese Pharmacopoeia).
  • the method for administering the pharmaceutical composition of the present embodiment is not particularly limited, and the pharmaceutical composition can be administered by a method generally used as a method for administering the drug.
  • it may be orally administered as a tablet, a coated tablet, a pill, a powder, a granule, a capsule, a liquid, a suspending agent, an emulsion, etc.
  • It may be mixed with a general infusion solution such as, and administered intravenously, intraarterial, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc. It may be administered to the skin.
  • the dose of the pharmaceutical composition of the present embodiment can be a therapeutically effective amount.
  • the therapeutically effective amount may be appropriately determined depending on the patient's symptoms, body weight, age, sex, etc., the dosage form of the pharmaceutical composition, the administration method, and the like.
  • the dose of the pharmaceutical composition of the present embodiment is 0.01 to 500 mg per administration unit form as tocopherol phosphate or the like in the case of oral administration, and as tocopherol phosphate or the like in the case of an injection. 0.02 to 250 mg per administration unit form, and in the case of suppositories, 0.01 to 500 mg per administration unit form can be exemplified as tocopherol phosphate or the like.
  • 0.15 to 500 mg per administration unit form can be exemplified as a tocopherol phosphate ester or the like, and may be, for example, 0.15 to 300 mg, for example 0.15. It may be up to 200 mg, for example 0.2 to 100 mg.
  • the administration interval of the pharmaceutical composition of the present embodiment may be appropriately determined depending on the patient's symptoms, body weight, age, sex, etc., the dosage form of the pharmaceutical composition, the administration method, and the like. For example, it may be once a day or about 2 to 3 times.
  • the pharmaceutical composition of the present embodiment can be used for the treatment or prevention of diseases caused by a decrease in autophagy activity.
  • diseases include neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and SENDA's disease; inflammatory bowel diseases such as Crohn's disease; and cancer.
  • the pharmaceutical composition of the present embodiment is administered to a neurodegenerative disease such as Alzheimer's disease, Huntington's disease, Parkinson's disease, SENDA's disease; inflammatory bowel disease such as Crohn's disease; , Inflammatory bowel disease, or can be used to control the progression of cancer. Further, the pharmaceutical composition of the present embodiment is administered to a neurodegenerative disease such as Alzheimer's disease, Huntington's disease, Parkinson's disease, SENDA's disease; an inflammatory bowel disease such as Crohn's disease; or a cancer patient to cause a neurodegenerative disease. , Inflammatory bowel disease, or can be used to treat cancer. In addition, the pharmaceutical composition of the present embodiment can be used for treating a disease caused by amyloid ⁇ .
  • the pharmaceutical composition of the present embodiment can be used for treating a disease caused by a decrease in the expression level of the LC3 gene, the ATG5 gene, the ATG7 gene, or the Beclin1 gene.
  • the pharmaceutical composition of the present embodiment can be used for treating a disease caused by an increase in the expression level of mTOR.
  • the pharmaceutical composition of the present embodiment can be suitably used for treating Alzheimer's disease in particular.
  • the pharmaceutical composition of the present embodiment can also be administered to patients at high risk of developing neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and SENDA's disease to prevent neurodegenerative diseases. ..
  • the pharmaceutical composition of the present embodiment can be administered to a patient at high risk of developing inflammatory bowel disease such as Crohn's disease and used to prevent inflammatory bowel disease.
  • the pharmaceutical composition of the present embodiment can be administered to a patient at high risk of developing cancer and used to prevent cancer.
  • the present invention provides a cosmetic for autophagy activation, which comprises the autophagy activator described above and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is not particularly limited, and a carrier generally used for cosmetics can be used in addition to those listed above.
  • a carrier generally used for cosmetics can be used in addition to those listed above.
  • commentary on the second edition of the cosmetic raw material standard (edited by the Japan Official Regulations Association, Yakuji Nippo Co., Ltd., 1984), the cosmetic raw material non-standard ingredient standard (supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippo Co., Ltd., 1993), cosmetic raw material standard.
  • the cosmetic of this embodiment may contain other components in addition to the autophagy activator and the pharmaceutically acceptable carrier.
  • the other ingredients are not particularly limited, and general cosmetic additives can be used.
  • an active ingredient other than the above-mentioned autophagy activator can also be used.
  • cosmetic additives and active ingredients as other ingredients include, for example, commentary on the second edition of the cosmetic raw material standard (edited by the Japan Official Regulations Association, Yakuji Nippo, 1984), non-standard cosmetic raw material ingredients.
  • the form of the cosmetic of the present embodiment is not particularly limited, and can be a form generally used as a cosmetic.
  • hair cosmetics such as shampoo, rinse and hair conditioner
  • basic cosmetics such as wash pigments, cleansing agents, lotions, milky lotions, lotions, creams, gels, sunscreen agents, packs, masks and beauty liquids
  • foundations makeup base, make-up cosmetics such as lipsticks, lip gloss, cheeks; body cleansers, body powders, deodorant cosmetics and the like.
  • These cosmetics can be manufactured according to a conventional method.
  • the dosage form of the cosmetic of the present embodiment is not particularly limited, and is, for example, oil in water (O / W) type, water in oil (W / O) type, W / O / W type, O / W.
  • Emulsified type such as / O type, emulsified polymer type, oily, solid, liquid, paste, stick, volatile oil type, powder, jelly, gel, paste, cream, sheet, film , Mist-like, spray-type, aerosol-like, multi-layered, foam-like, flake-like and the like.
  • the amount of the cosmetic used in this embodiment is not particularly limited, but can be an effective amount for activating autophagy.
  • the amount of the cosmetic used in the present embodiment may be 0.15 to 500 mg per use as the amount of tocopherol phosphate or the like, and may be, for example, 0.15 to 300 mg.
  • it may be 0.15 to 200 mg, and may be 0.2 to 100 mg, for example.
  • the interval of use of the cosmetics of this embodiment is not particularly limited, but may be, for example, once a day or about 2 to 3 times a day.
  • the cosmetic of this embodiment can be used to alleviate the symptoms caused by the decrease in autophagy activity.
  • it may be used in routine skin care and makeup by subjects at high risk of developing these symptoms to prevent the development of symptoms due to decreased autophagy activity.
  • the invention provides a method of activating autophagy, comprising the step of administering tocopherol phosphate ester or a salt thereof to a subject.
  • the present invention provides a method for promoting expression of the LC3 gene, ATG5 gene, ATG7 gene, or Beclin1 gene, which comprises a step of administering a tocopherol phosphate ester or a salt thereof to a subject.
  • the present invention provides a method for suppressing the expression of the mTOR gene, which comprises a step of administering a tocopherol phosphate ester or a salt thereof to a subject.
  • the present invention provides a method for suppressing apoptosis in the presence of amyloid ⁇ , which comprises a step of administering a tocopherol phosphate ester or a salt thereof to a subject.
  • the present invention provides a tocopherol phosphate ester or a salt thereof for activating autophagy.
  • the present invention provides a tocopherol phosphate ester or a salt thereof for promoting the expression of the LC3 gene, ATG5 gene, ATG7 gene, or Beclin1 gene.
  • the present invention provides a tocopherol phosphate ester or a salt thereof for suppressing the expression of the mTOR gene.
  • the present invention provides a tocopherol phosphate ester or a salt thereof for suppressing apoptosis in the presence of amyloid ⁇ .
  • the present invention provides tocopherol phosphate ester or a salt thereof for preventing or treating Alzheimer's disease, Huntington's disease, Parkinson's disease, SENDA disease, Crohn's disease, or cancer.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing an autophagy activator.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing an LC3 gene, an ATG5 gene, an ATG7 gene, or a Beclin1 gene expression promoter.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing an agent for suppressing mTOR gene expression.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing an LC3 gene, ATG5 gene, or ATG7 gene expression promoter in the presence of amyloid ⁇ .
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing an inhibitor of apoptosis in the presence of amyloid ⁇ .
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing a composition for activating autophagy.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing a composition for promoting the expression of the LC3 gene, the ATG5 gene, the ATG7 gene, or the Beclin1 gene.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing a composition for suppressing mTOR gene expression.
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing a composition for promoting expression of the LC3 gene, ATG5 gene, or ATG7 gene in the presence of amyloid ⁇ .
  • the present invention provides the use of a tocopherol phosphate ester or a salt thereof for producing a composition for suppressing apoptosis in the presence of amyloid ⁇ .
  • Tocopherols In the following examples and formulation examples, the following sodium salts of tocopherol phosphate were used.
  • ⁇ -TPNa dl- ⁇ -sodium tocopheryl phosphate (display name: Na tocopheryl phosphate, product name; TPNa (registered trademark), manufactured by Showa Denko KK)
  • ⁇ -TPNa dl- ⁇ -sodium tocopheryl phosphate (manufactured by Showa Denko KK)
  • ⁇ -TPNa solution ⁇ -TPNa was dissolved in a 0.05% (V / V) ethanol aqueous solution.
  • ⁇ -TPNa solution ⁇ -TPNa was dissolved in a 0.05% (V / V) ethanol aqueous solution.
  • Tocopherol acetate ⁇ -tocopherol manufactured by Eisai Co., Ltd .: ⁇ -tocopherol manufactured by Sigma-Aldrich Co., Ltd.
  • ⁇ -tocopherol solution ⁇ -tocopherol was dissolved in a 0.05% (V / V) ethanol aqueous solution.
  • ⁇ -tocopherol solution ⁇ -tocopherol was dissolved in a 0.05% (V / V) ethanol aqueous solution.
  • the prepared aging fibroblasts were prepared at a seeding density of 10,000 cells / cm 2 and cultured for 24 hours in D-MEM medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals). did. Then, in Example 1, the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 1 ⁇ M. In Example 2, the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M. In Example 3, a ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • Comparative Example 2 a tocopherol acetate solution was added to the medium so that the final concentration of tocopherol acetate was 10 ⁇ M.
  • Comparative Example 3 the ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 4 a ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 1 only a 0.05% (V / V) ethanol aqueous solution was added to the medium. Each medium was then cultured for 24 hours at 37 ° C. under 5% CO 2 .
  • the above-mentioned normal human fibroblasts were prepared at a seeding density of 10,000 cells / cm 2 , and a D-MEM medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals) was added. For 24 hours, only 0.05% (V / V) aqueous ethanol solution was added to the medium. Then, the cells were cultured for 24 hours at 37 ° C. under 5% CO 2 .
  • RNA was extracted from aging fibroblasts or human normal fibroblasts of each example using a Nucleospin (registered trademark) RNA kit (manufactured by Takara Bio Inc.), and cDNA was synthesized from the obtained RNA.
  • a Nucleospin (registered trademark) RNA kit manufactured by Takara Bio Inc.
  • the expression level of each gene was quantified by quantitative real-time PCR using primers specific for the LC3 gene, ATG5 gene, ATG7 gene, and Beclin1 gene (manufactured by Takara Bio Inc.).
  • GAPDH primary; manufactured by Takara Bio Inc.
  • the expression level of GAPDH which is a housekeeping gene whose expression does not change due to the addition of a compound, was quantified, and the expression level of each gene was standardized based on the value.
  • the relative gene expression level was determined when the expression level of each gene in Comparative Example 1 was 1.00. The results are shown in Table 1.
  • the expression of the LC3 gene was decreased in the aged fibroblasts of Comparative Example 1, but the tocopherol phosphate ester salts of Examples 1 to 3 were added and cultured.
  • the expression level of the LC3 gene was increased as compared with the normal fibroblasts of Reference Example 1, and it was confirmed that the LC3 gene had an excellent expression promoting effect.
  • the aged fibroblasts cultured with the addition of tocopherol acetate or ⁇ -tocopherol of Comparative Examples 2 and 3 no effect of promoting the expression of the LC3 gene was observed, and the cells were cultured with the addition of ⁇ -tocopherol of Comparative Example 4.
  • the effect of promoting the expression of the LC3 gene was slight.
  • the expression levels of the ATG5 gene and the ATG7 gene were lower in the aged fibroblasts of Comparative Example 1 than in the human normal fibroblasts of Reference Example 1, but the tocopherol phosphate ester salts of Examples 1 to 3 were added.
  • the expression of the ATG5 gene and the ATG7 gene was promoted as compared with the aged fibroblasts of Comparative Example 1.
  • the effect of promoting the expression of the Beclin 1 gene was also confirmed.
  • ⁇ Evaluation of mTOR gene expression inhibitory effect in human aging fibroblasts The aging fibroblasts prepared above were prepared at a seeding density of 10000 cells / cm 2 and in D-MEM medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals) 24. Cultured for hours. Then, in Example 4, the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 1 ⁇ M. In Example 5, the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • Example 6 a ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • a tocopherol acetate solution was added to the medium so that the final concentration of tocopherol acetate was 10 ⁇ M.
  • the ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • a ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 5 only a 0.05% (V / V) ethanol aqueous solution was added to the medium. Each medium was then cultured for 24 hours at 37 ° C. under 5% CO 2 .
  • the above normal human fibroblasts were prepared at a seeding density of 10,000 cells / cm 2 , and a D-MEM medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals) was added. For 24 hours, only 0.05% (V / V) aqueous ethanol solution was added to the medium. Then, the cells were cultured for 24 hours at 37 ° C. under 5% CO 2 .
  • RNA was extracted from aging fibroblasts or human normal fibroblasts of each example using a Nucleospin (registered trademark) RNA kit (manufactured by Takara Bio Inc.), and cDNA was synthesized from the obtained RNA.
  • a Nucleospin (registered trademark) RNA kit manufactured by Takara Bio Inc.
  • cDNA was synthesized from the obtained RNA.
  • the expression level of the mTOR gene was quantified using a primer specific to the mTOR gene (manufactured by Takara Bio Inc.) by quantitative real-time PCR.
  • GAPDH primary; manufactured by Takara Bio Inc.
  • the expression level of GAPDH which is a housekeeping gene whose expression does not change due to the addition of a compound, was quantified, and the expression level of each gene was standardized based on the value.
  • the relative gene expression level was determined when the expression level of the mTOR gene in Comparative Example 5 was 1.00. The results are shown in Table 2.
  • aged fibroblasts cultured with the addition of tocopherol acetate of Comparative Example 6 aged fibroblasts cultured with the addition of ⁇ -tocopherol of Comparative Example 7, and ⁇ -tocopherol of Comparative Example 8 were added and cultured.
  • the expression level of the mTOR gene was equal to or higher than that of Comparative Example 5, and the effect of suppressing the expression of the mTOR gene could not be confirmed.
  • SH-SY5Y cells were prepared at a seeding density of 10,000 cells / cm 2 , and D-MEM / Ham's F-12 medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals).
  • Example 7 the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 1 ⁇ M.
  • Example 8 the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • Example 9 the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • Comparative Example 10 a tocopherol acetate solution was added to the medium so that the final concentration of tocopherol acetate was 10 ⁇ M.
  • Comparative Example 11 the ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 12 a ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 9 only a 0.05% (V / V) ethanol aqueous solution was added to the medium.
  • an amyloid ⁇ solution prepared by dissolving amyloid ⁇ (manufactured by Sigma-Aldrich) in a 0.01% (V / V) DMSO aqueous solution was prepared, and the amyloid ⁇ was prepared so that the final concentration of amyloid ⁇ in each medium was 20 ⁇ M.
  • ⁇ solution was added to each medium.
  • Reference Example 3 only a 0.05% (V / V) ethanol aqueous solution was added, and an amyloid ⁇ solution was not added.
  • Each medium was then cultured for 48 hours at 37 ° C. under 5% CO 2 .
  • RNA was extracted from the SH-SY5Y cells of each example using a Nucleospin (registered trademark) RNA kit (manufactured by Takara Bio Inc.), and cDNA was synthesized from the obtained RNA.
  • a Nucleospin (registered trademark) RNA kit manufactured by Takara Bio Inc.
  • cDNA was synthesized from the obtained RNA.
  • the expression level of each gene was quantified by quantitative real-time PCR using primers specific for the LC3 gene, ATG5 gene, and ATG7 gene (manufactured by Takara Bio Inc.).
  • GAPDH primary; manufactured by Takara Bio Inc.
  • the expression level of GAPDH which is a housekeeping gene whose expression does not change due to the addition of a compound, was quantified, and the expression level of each gene was standardized based on the value.
  • the relative gene expression level was determined when the expression level of each gene in Reference Example 3 was 1.00. The results are shown in Table 3.
  • the SH-SY5Y cells of Comparative Example 9 cultured with the addition of amyloid ⁇ showed decreased expression of the ATG5 gene and the ATG7 gene.
  • the SH-SY5Y cells cultured with the addition of the tocopherol phosphate ester salt which is the autophagy activator of Examples 7 to 9 the expression levels of the ATG5 gene and the ATG7 gene are higher than those of the SH-SY5Y cells of Comparative Example 9. Also increased, and the effect of promoting the expression of the ATG5 gene and the ATG7 gene of the tocopherol phosphate ester salt was confirmed.
  • SH-SY5Y cells were prepared at a seeding density of 50,000 cells / cm 2 , and D-MEM / Ham's F-12 medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals).
  • the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 1 ⁇ M.
  • the ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • a ⁇ -TPNa solution was added to the medium so that the final concentration of ⁇ -TPNa was 10 ⁇ M.
  • Comparative Example 14 a tocopherol acetate solution was added to the medium so that the final concentration of tocopherol acetate was 10 ⁇ M.
  • Comparative Example 15 the ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 16 the ⁇ -tocopherol solution was added to the medium so that the final concentration of ⁇ -tocopherol was 10 ⁇ M.
  • Comparative Example 13 only a 0.05% (V / V) ethanol aqueous solution was added to the medium.
  • an amyloid ⁇ solution prepared by dissolving amyloid ⁇ (manufactured by Sigma-Aldrich) in a 0.01% (V / V) DMSO aqueous solution was prepared, and the amyloid ⁇ was prepared so that the final concentration of amyloid ⁇ in each medium was 30 ⁇ M.
  • ⁇ solution was added to each medium.
  • Reference Example 4 only a 0.05% (V / V) ethanol aqueous solution was added, and an amyloid ⁇ solution was not added.
  • Each medium was then cultured for 48 hours at 37 ° C. under 5% CO 2 .
  • each SH-SY5Y cell was washed with phosphate buffer (PBS, manufactured by Wako Pure Chemical Industries, Ltd.), and the number of cells showing strong Hoechst fluorescence like apoptosis due to chromatin aggregation under a fluorescence microscope (Hoechst (+)). ) Cells) were measured.
  • PBS phosphate buffer
  • Table 5 shows Formulation Examples 1 and 2 of an external preparation as a composition for activating autophagy.
  • an autophagy activator capable of effectively activating autophagy and an autophagy activation composition containing the autophagy activator are provided.

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Abstract

L'invention concerne un activateur d'autophagie contenant, en tant que principe actif, un ester de phosphate de tocophérol ou un sel de celui-ci. L'invention concerne également une composition d'activation d'autophagie contenant l'activateur d'autophagie et un support pharmaceutiquement acceptable.
PCT/JP2021/034243 2020-09-17 2021-09-17 Activateur d'autophagie WO2022059767A1 (fr)

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WO2020090881A1 (fr) * 2018-11-02 2020-05-07 昭和電工株式会社 Agent externe pour la peau de type huile-dans-eau
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KR20180086187A (ko) 2015-10-05 2018-07-30 더 트러스티이스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 자가포식 유동의 활성체 및 포스포리파제 d 및 타우를 포함하는 단백질 응집물의 클리어런스 및 단백질질환의 치료
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WO2020090881A1 (fr) * 2018-11-02 2020-05-07 昭和電工株式会社 Agent externe pour la peau de type huile-dans-eau
JP2020141567A (ja) * 2019-03-04 2020-09-10 公立大学法人横浜市立大学 精子形成誘導用培地
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