WO2022059776A1 - オートファジー活性化剤 - Google Patents
オートファジー活性化剤 Download PDFInfo
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- WO2022059776A1 WO2022059776A1 PCT/JP2021/034305 JP2021034305W WO2022059776A1 WO 2022059776 A1 WO2022059776 A1 WO 2022059776A1 JP 2021034305 W JP2021034305 W JP 2021034305W WO 2022059776 A1 WO2022059776 A1 WO 2022059776A1
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- salt
- autophagy
- inositol
- gene
- derivative
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Classifications
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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 a composition for autophagy activation.
- Autophagy responds to extracellular or intracellular stress and signals such as starvation, growth factor deficiency, and pathogen infections by breaking down aging or damaged intracellular substances and organelles to regenerate energy. 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. Therefore, by decomposing the aged substances and organelles in the cells and activating autophagy that recycles the decomposition products, it is possible to promptly remove unnecessary substances in the cells and increase the homeostasis of the cells. ..
- 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 the 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 that are markers of autophagy activity and activate autophagy, and promote autophagy flux (including fusion of autophagosomes to lysosomes). Compounds and active ingredients 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.
- a composition for autophagy activation which comprises the autophagy activator according to any one of [1] to [8] and a pharmaceutically acceptable carrier.
- the composition for autophagy activation according to [9] wherein the total content of the inositol derivative is 0.1 to 2% by mass.
- At least the vitamin derivative or a salt thereof is selected from the group consisting of ascorbyl phosphate or a salt thereof, a fatty acid ester of ascorbyl phosphate or a salt thereof, a tocopherol phosphate ester or a salt thereof, and methyl hesperidin or a salt thereof.
- the composition for activating autophagy according to [11] which is one kind of vitamin derivative or a salt thereof.
- an autophagy activator capable of effectively activating autophagy, and an autophagy activation composition containing the autophagy activator.
- the autophagy activator of the present embodiment contains an inositol derivative in which a sugar is bound to inositol 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, the ATG5 gene contained in the autophagosome, and the Beclin 1 gene, and can activate autophagy. ..
- autophagy can be activated by suppressing the expression of the mTOR gene, which acts as an inhibitor of autophagy.
- the inositol derivative in the autophagy activator of the present embodiment is a compound composed of inositol and a sugar, and specifically, is a compound in which a sugar is bound to at least one hydroxyl group of inositol.
- the inositol constituting the inositol derivative is a cyclic hexahydric alcohol represented by C 6 H 6 (OH) 6 .
- isomer There is an isomer.
- myo-inositol having physiological activity is preferable as the inositol constituting the inositol derivative.
- the structural formula of myo-inositol is shown below.
- Examples of the method for producing inositol include a method of extracting from rice bran, a chemical synthesis method, and a fermentation method.
- the sugar constituting the inositol derivative may be a monosaccharide or an oligosaccharide.
- the monosaccharide means a sugar that is not further hydrolyzed, and means a compound that is a component when forming a polysaccharide. It can also be said that a monosaccharide is the smallest unit of a sugar.
- the oligosaccharide is an oligomer of a sugar in which a plurality of monosaccharides are bound by glycosidic bonds.
- Monosaccharides include glucose (dextrose), fructose (fructose), galactose, ribose, xylose, mannitol, sorbitol, xylitol, erythritol, pentaerythritol and the like.
- oligosaccharides specifically, disaccharides such as sucrose (sucrose), lactose (lactose), maltose (malt sugar), isomaltose, trehalose, cellobiose, and martitol; Such as trisaccharides; sucrose such as stakiose; hexasaccharides such as ⁇ -cyclodextrin; seven sugars such as ⁇ -cyclodextrin; octasaccharides such as ⁇ -cyclodextrin.
- the sugar constituting the inositol derivative is preferably glucose or an oligosaccharide containing glucose as a monosaccharide unit.
- the monosaccharide unit means a chemical structure corresponding to a monosaccharide, and can also be said to be a chemical structure derived from a monosaccharide.
- the oligosaccharide containing glucose as a single sugar unit may be an oligosaccharide in which only glucose is bound by a glycosidic bond, or an oligosaccharide in which at least one molecule of glucose and a sugar other than glucose are bound by a glycosidic bond. May be.
- the molecular weight of the oligosaccharide containing glucose as a monosaccharide unit may be, for example, about 300 to 3000.
- the sugar may be bound to any one of the six hydroxyl groups present in the inositol molecule, or may be bound to any two or more. good.
- one molecule of inositol may be bound to one or more monosaccharides
- one molecule of inositol may be bound to one or more oligosaccharides
- one molecule of inositol may be bound to one or more monosaccharides.
- the sugar and one or more oligosaccharides may be bound.
- the total number of sugars (monosaccharides and / or oligosaccharides) bound to one molecule of inositol is 1 or more in terms of monosaccharide units, and may be 2 or more, for example. For example, it may be 3 or more, for example, 4 or more, and for example, 10 or more.
- the conversion to a monosaccharide unit indicates how many monosaccharide units the sugar bound to one molecule of inositol is composed of.
- a plurality of sugars are bound to one molecule of inositol, it means the total value of the monosaccharide units of the plurality of sugars.
- monosaccharides such as glucose (dextrose), fructose (fructose), galactose, ribose, xylose, mannitol, sorbitol, xylitol, erythritol, and pentaerythritol are converted into monosaccharide units.
- disaccharides such as sucrose (sucrose), lactose (lactose), maltose (maltose), isomaltose, trehalose, cellobiose, and maltose are converted into single sugar units, it is 2. Further, when trisaccharides such as raffinose, melezitose, and maltotriose are converted into monosaccharide units, it is 3.
- stachyose and other tetrasaccharides are converted into monosaccharide units, it is 4, and when hexasaccharides such as ⁇ -cyclodextrin are converted into monosaccharide units, it is 6, and ⁇ -cyclodextrin and other seven sugars are converted into monosaccharide units. It is 7 when converted, and 8 when converted into a monosaccharide unit of octasaccharide such as ⁇ -cyclodextrin.
- the inositol derivative in the present embodiment preferably uses ⁇ -cyclodextrin as a raw material sugar from the viewpoint of facilitating the acquisition of an inositol derivative having a high degree of purification.
- ⁇ -Cyclodextrin is industrially inexpensive and can be stably supplied.
- the sugar constituting the inositol derivative contains glucose as a constituent unit.
- cheaper starch or the like is used as the sugar as the raw material of the inositol derivative, various sugars are transferred to various places during the synthesis of the inositol derivative, so that the degree of purification of the obtained inositol derivative tends to be unstable. There is.
- the inositol derivative in this embodiment may be in the form of a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt means the form of a salt that does not inhibit the bioactivity of the inositol derivative.
- the pharmaceutically acceptable salt of the inositol derivative is not particularly limited, and is, for example, a salt with an alkali metal (sodium, potassium, etc.); a salt with an alkaline earth metal (magnesium, calcium, etc.); an organic base (pyridine, etc.). , Triethylamine, etc.), salt with amine, etc.
- the inositol derivative may be in the form of a solvate. Further, the inositol derivative may be in the form of a solvate of a salt of the inositol derivative.
- the solvate is not particularly limited, and examples thereof include hydrates and ethanol solvates.
- one type of inositol derivative may be used alone, or two or more types may be used in combination.
- the inositol derivative in the autophagy activator of the present embodiment is preferably a mixture of two or more kinds of inositol derivatives, more preferably a mixture of 2 to 40 kinds of inositol derivatives, and 2 to 2 to 40 kinds. It is more preferably a mixture of 30 kinds of inositol derivatives, and particularly preferably a mixture of 10 to 30 kinds of inositol derivatives.
- the inositol derivative in the autophagy activator of the present embodiment preferably contains an inositol derivative in which the total amount of sugars bound to one molecule of inositol is 10 or more in terms of monosaccharide unit.
- the inositol derivative in the autophagy activator of the present embodiment is preferably an inositol derivative in which glucose or an oligosaccharide containing glucose as a monosaccharide unit is bound to inositol, and is a mixture of two or more kinds of the inositol derivatives. It is preferably a mixture of 2 to 40 types of the inositol derivative, more preferably a mixture of 2 to 30 types of the inositol derivative, and further preferably a mixture of 10 to 30 types of the inositol derivative. It is particularly preferable to have.
- the inositol derivative in the autophagy activator of the present embodiment contains an inositol derivative in which glucose or an oligosaccharide containing glucose as a monosaccharide unit is bound to inositol, and contains glucose and glucose bound to one molecule of inositol as a monosaccharide unit. It is preferable to include an inositol derivative having a total oligosaccharide of 10 or more in terms of monosaccharide unit.
- the method for producing the inositol derivative is not particularly limited, and the inositol derivative can be appropriately produced by a conventionally known method.
- inositol and cyclodextrin which is one of oligosaccharides, may be reacted in the presence of cyclodextrin glucanotransferase to synthesize an inositol derivative (see, for example, Japanese Patent Application Laid-Open No. 63-196596). ..
- an inositol derivative may be synthesized by a method of obtaining a glucosyl compound using a glucosyl phosphite ester as a sugar donor (see, for example, JP-A-6-298783).
- 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 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 the expression of the Beclin 1 gene 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 promotes the expression of at least one gene selected from the group consisting of the LC3 gene, the ATG5 gene, and the Beclin 1 gene in the presence of amyloid ⁇ , particularly in nerve cells. Can be done.
- 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 Beclin1 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.
- 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 of the present embodiment contains an autophagy activator containing an inositol derivative in which a sugar is bound to the above-mentioned inositol, and a pharmaceutically acceptable carrier.
- composition for activating autophagy of the present embodiment follows a conventional method (for example, the method described in the Japanese Pharmacopoeia), the above-mentioned autophagy activator, a pharmaceutically acceptable carrier, and possibly other components. 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 is not substantially toxic to the subject to be administered.
- 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.
- Polymer / thickening / gelling agent solvent, propellant, antioxidant, reducing agent, oxidizing agent, chelating agent, acid, alkali, powder, inorganic salt, water, metal-containing compound, unsaturated monomer , Polyhydric alcohol, polymer additive, wetting agent, thickener, tackifier, oily raw material, liquid matrix, fat-soluble substance, polymer carboxylate and the like.
- compositions for activating autophagy of the present embodiment may be used alone or in combination of two or more.
- the other components are not particularly limited, and are not particularly limited, and are preservatives, antibacterial agents, ultraviolet absorbers, whitening agents, vitamins and their derivatives, anti-inflammatory agents, anti-inflammatory agents, hair growth agents, blood circulation promoters, and stimulants. , Hormones, anti-wrinkle agents, anti-aging agents, tightening agents, cooling sensitizers, warming agents, wound healing promoters, stimulant relievers, analgesics, cell activators, plant / animal / microbial extracts, seed oils, itching Agents, keratin exfoliating / dissolving agents, antiperspirants, cooling agents, astringents, enzymes, nucleic acids, fragrances, pigments, colorants, dyes, pigments, anti-inflammatory analgesics, antifungal agents, antihistamines, hypnotic sedatives, tranquilizers , Antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial agents,
- 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 autophagy activator may be an amount in which an inositol derivative in which a sugar is bound to inositol can activate autophagy.
- the therapeutically effective amount of the autophagy activator is that the inositol derivative in which a sugar is bound to inositol expresses at least one gene selected from the group consisting of the LC3 gene, the ATG5 gene, and the Beclin1 gene. It can be an amount that can be promoted.
- the therapeutically effective amount of the autophagy activator may be an amount in which an inositol derivative in which a sugar is bound to inositol can suppress the expression of the mTOR gene.
- the therapeutically effective amount of the autophagy activator may be an amount in which an inositol derivative in which a sugar is bound to inositol can suppress apoptosis in the presence of amyloid ⁇ .
- the therapeutically effective amount of the autophagy activator (total content of inositol derivative in which sugar is bound to inositol) in the composition for autophagy activation of the present embodiment is based on the total amount of the composition for autophagy activation. For example, it may be 0.1 to 2% by mass, for example, 0.15 to 1.5% by mass, or 0.2 to 1% by mass.
- the total content of the inositol derivative in which sugar is bound to inositol means the content of the compound when the inositol derivative in which sugar is bound to one kind of inositol is used alone, and the sugar is bound to inositol. When two or more kinds of inositol derivatives are used in combination, it means the total content of these compounds.
- the composition for autophagy activation of the present embodiment may contain other autophagy activating components in addition to the autophagy activating agent.
- other autophagy-activating components include at least one vitamin derivative selected from the group consisting of vitamin C derivatives, vitamin E derivatives, and vitamin P derivatives, or salts thereof.
- the composition for activating autophagy of the present embodiment contains at least one vitamin derivative selected from the group consisting of vitamin C derivatives, vitamin E derivatives, and vitamin P derivatives or a salt thereof, the vitamin derivative or its salt thereof.
- the total content of the salts is preferably 0.01 to 15% by mass, more preferably 0.05 to 10% by mass, and 0.1 to 0.1 to the total amount of the composition for activating autophagy. It is more preferably 5% by mass.
- composition for activating autophagy of the present embodiment preferably contains a vitamin C derivative or a salt thereof in addition to the autophagy activator.
- a vitamin C derivative or a salt thereof By containing a vitamin C derivative or a salt thereof, the activation action of autophagy is further improved.
- vitamin C derivatives examples include ascorbic acid derivatives in which at least one hydroxyl group of ascorbic acid is derivatized.
- ascorbic acid derivative more specifically, ascorbyl phosphate (also referred to as ascorbic acid phosphate ester) in which any of the hydroxyl groups of ascorbic acid is phosphorically esterified; any of the hydroxyl groups of ascorbic acid is a phosphoric acid ester.
- Ascorbyl phosphate fatty acid ester obtained by esterifying other hydroxyl groups with fatty acid; ethyl ascorbic acid ethoxylated from any of the hydroxyl groups of ascorbic acid; ascorbic acid glucoside obtained by glucosidizing any of the hydroxyl groups of ascorbic acid.
- Ascorbic acid acylated by acylating one of the hydroxyl groups of ascorbic acid Ascorbyl acylated phosphate obtained by acylating one of the hydroxyl groups of ascorbic acid and phosphorylating the other hydroxyl group; Glyceryl ascorbic acid in which either is replaced with glycerin; a phosphate diester of ascorbic acid and tocopherol (specifically, dl- ⁇ -tocopherol 2-L) in which ascorbic acid and tocopherol are bound by an ester bond via phosphoric acid, respectively. -Ascorbic acid phosphate diester, etc.) and the like.
- Examples of the salt of the ascorbic acid derivative include a salt of an ascorbic acid derivative and an inorganic base, a salt of an ascorbic acid derivative and an organic base, and the like.
- 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.
- ascorbic acid derivative or salt thereof examples include (i) ascorbyl phosphate or a salt thereof, (ii) a fatty acid ester of ascorbyl phosphate or a salt thereof, (iii) ethylascorbic acid or a salt thereof, and (iv) ascorbin.
- Acid glucoside or a salt thereof is preferable, and (i) ascorbyl phosphate or a salt thereof, and (ii) a fatty acid ester of ascorbyl phosphate or a salt thereof are more preferable.
- Ascorbic Phosphate is a compound in which a phosphate group is introduced into at least one hydroxyl group of ascorbic acid.
- Ascorbyl phosphate a compound represented by the following chemical formula (1) is preferably mentioned.
- the compound represented by the following chemical formula (1) is an ascorbic acid-2-phosphate ester in which the hydroxyl group at the 2-position of ascorbic acid is protected by a phosphoric acid ester.
- Ascorbyl phosphate has D-form and L-form stereoisomers and racemic DL-form.
- the ascorbyl phosphate in the present embodiment may be any of these stereoisomers, but from the viewpoint of availability, it is preferably L-form, and specifically, L-ascorbic acid-2- Phosphoric acid esters are preferred.
- salt of ascorbyl phosphate examples include a salt of ascorbyl phosphate and an inorganic base, a salt of ascorbyl phosphate and an organic base, and the like.
- 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.
- the salt of ascorbyl phosphate is preferably an alkali metal salt or an alkaline earth metal salt, more preferably a sodium salt or a magnesium salt, and even more preferably a magnesium salt.
- the magnesium salt of ascorbyl phosphate is preferable from the viewpoint of high stability and resistance to coloring.
- the ascorbyl phosphate or a salt thereof is preferably a salt of ascorbyl phosphate from the viewpoint of improving stability, and is an alkali metal salt of the compound represented by the above chemical formula (1) or the above chemical formula.
- the alkaline earth metal salt of the compound represented by (1) is more preferable, and the sodium salt of the compound represented by the chemical formula (1) or the magnesium salt of the compound represented by the chemical formula (1) is further preferable. ..
- the magnesium salt of the compound represented by the chemical formula (1) specifically, the magnesium salt of L-ascorbic acid-2-phosphate ester is particularly preferable.
- the sodium salt of the compound represented by the chemical formula (1) specifically, the sodium salt of L-ascorbic acid-2-phosphate ester is particularly preferable.
- composition for activating autophagy of the present embodiment ascorbyl phosphate or a salt thereof may be used alone or in combination of two or more.
- content thereof shall be 0.1 to 15% by mass with respect to the total amount of the composition for autophagy activation. Is preferable, 0.5 to 10% by mass is more preferable, and 1 to 5% by mass is further preferable.
- Ascorbyl phosphate or a salt thereof can be produced by a known production method, for example, the method described in JP-A-2-279690 and JP-A-6-345786.
- a specific method for producing ascorbic phosphate it can be obtained by reacting ascorbic acid with phosphorus oxychloride or the like to phosphorylate it.
- phosphorus is obtained by neutralizing an ascorbyl phosphate solution with a metal oxide such as magnesium oxide or a metal hydroxide such as sodium hydroxide.
- a salt of ascorbyl acid can be obtained.
- ascorbic acid PS compound name; sodium salt of L-ascorbic acid-2-phosphate ester (also referred to as L-ascorbic acid-2-sodium phosphate)) manufactured by Showa Denko Co., Ltd. , Display name; Na ascorbyl phosphate), Ascorbic acid PM manufactured by Showa Denko Co., Ltd.
- the fatty acid ester of ascorbyl phosphate is a compound in which a fatty acid is ester-bonded to at least one hydroxyl group of ascorbyl phosphate.
- the fatty acid is a linear or branched fatty acid having 6 to 22 carbon atoms (that is, a fatty acid having a linear or branched alkyl group bonded to a carboxy group having 5 to 21 carbon atoms).
- fatty acid ester of phosphoric acid ascorbyl examples include compounds represented by the following general formula (2).
- the compound represented by the following general formula (2) has ascorbic acid-2-phosphate-6-fatty acid in which phosphoric acid is ester-bonded to the hydroxyl group at the 2-position of ascorbic acid and fatty acid is ester-bonded to the hydroxyl group at the 6-position. Is.
- Rc 1 is a linear or branched-chain alkyl group having 5 to 21 carbon atoms.
- Rc 1 is a linear or branched-chain alkyl group having 5 to 21 carbon atoms. Specifically, a linear or branched pentyl group, a linear or branched hexyl group, a linear or branched heptyl group, a linear or branched octyl group, a direct chain.
- Chained or branched nonyl group linear or branched decyl group, linear or branched undecyl group, linear or branched dodecyl group, linear or branched chain Tridecyl group, linear or branched tetradecyl group, linear or branched pentadecyl group, linear or branched hexadecyl group, linear or branched heptadecyl group, straight chain Examples thereof include a linear or branched octadecyl group, a linear or branched nonadesyl group, a linear or branched icosyl group, and a linear or branched henicosyl group.
- Rc 1 is preferably a linear or branched alkyl group having 9 to 19 carbon atoms, and is a linear or branched alkyl group having 11 to 17 carbon atoms.
- a branched alkyl group is more preferable, and a linear or branched alkyl group having 13 to 15 carbon atoms is more preferable, and the carbon atom number is 15 from the viewpoint of raw material availability and the like.
- Fatty acid esters of ascorbyl phosphate include D-form and L-form stereoisomers and racemic DL-forms.
- the fatty acid ester of ascorbyl phosphate in the present embodiment may be any of these three steric isomers, but from the viewpoint of availability, it is preferably L-form, and specifically, L-ascorbic acid.
- Fatty acid esters of -2-phosphate esters are preferred.
- the salt of fatty acid ester of ascorbyl phosphate include a salt of a fatty acid ester of ascorbyl phosphate and an inorganic base, a salt of a fatty acid ester of ascorbyl phosphate and a salt of an organic base, and the like. Be done.
- 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.
- the salt of the fatty acid ester of ascorbyl phosphate is preferably an alkali metal salt or an alkaline earth metal salt, more preferably a sodium salt or a magnesium salt, and even more preferably a sodium salt.
- Sodium salts of fatty acid esters of ascorbyl phosphate are preferred from the standpoint of stability and ease of formulation.
- the fatty acid ester of ascorbyl phosphate or a salt thereof is preferably a salt of the fatty acid ester of ascorbyl phosphate from the viewpoint of stability and ease of blending into a preparation, and is represented by the above general formula (2).
- the alkali metal salt of the compound to be used or the alkaline earth metal salt of the compound represented by the general formula (2) is more preferable, and the sodium salt of the compound represented by the general formula (2) or the general formula is described above.
- the magnesium salt of the compound represented by the formula (2) is more preferable, and the sodium salt of the compound represented by the above general formula (2), specifically, L-ascorbic acid-2-phosphoric acid-6-palmitic acid.
- the sodium salt of is particularly preferred.
- the fatty acid ester of ascorbyl phosphate or a salt thereof may be used alone or in combination of two or more.
- the content thereof is preferably 0.05 to 12% by mass, preferably 0.05 to 5% by mass. %, More preferably 0.1 to 2% by mass.
- the fatty acid ester of ascorbyl phosphate or a salt thereof can be produced by a known production method, for example, the method described in Patent 6265550.
- a specific method for producing a fatty acid ester of ascorbyl phosphate after producing ascorbyl phosphate by the same method as the above-mentioned method for producing ascorbyl phosphate, the ascorbyl phosphate and the fatty acid or an ester thereof are used. It can be obtained by subjecting it to a condensation reaction.
- a fatty acid ester solution of ascorbyl phosphate is mixed with a metal oxide such as magnesium oxide or a metal hydroxide such as sodium hydroxide.
- a salt of a fatty acid ester of ascorbyl phosphate can be obtained.
- the salt of the fatty acid ester of ascorbyl phosphate in the composition for activating autophagy of the present embodiment is a commercially available example of the salt of the fatty acid ester of ascorbyl phosphate in the composition for activating autophagy of the present embodiment.
- Aprecier registered trademark
- Examples thereof include a sodium salt of phosphoric acid-6-palmitic acid (also referred to as a sodium salt of L-6-O-palmitoyle ascorbic acid-2-phosphate ester), a display name; ascorbyl phosphate 3Na of palmitate).
- Ethyl ascorbic acid is a compound in which an ethyl group is introduced into at least one hydroxyl group of ascorbic acid.
- a compound represented by the following chemical formula (3) is preferably mentioned.
- the compound represented by the following chemical formula (3) is 3-O-ethylascorbic acid in which the hydrogen atom of the hydroxyl group at the 3-position of ascorbic acid is substituted with an ethyl group.
- Ethyl ascorbic acid has D-form and L-form stereoisomers and racemic DL-form.
- Ethyl ascorbic acid may be any of these stereoisomers, but from the viewpoint of availability, it is preferably L-form, and specifically, L-3-O-ethylascorbic acid (3). -O-ethyl-L-ascorbic acid) is preferable.
- salt of ethyl ascorbic acid examples include a salt of ethyl ascorbic acid and an inorganic base, a salt of ethyl ascorbic acid and an organic base, and the like.
- 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.
- ethylascorbic acid or a salt thereof is preferably ethylascorbic acid, and more preferably L-3-O-ethylascorbic acid, from the viewpoint of availability.
- ethylascorbic acid or a salt thereof may be used alone or in combination of two or more.
- the content thereof shall be 0.01 to 15% by mass with respect to the total amount of the composition for autophagy activation. Is more preferable, 0.1 to 10% by mass is more preferable, and 0.5 to 5% by mass is further preferable.
- Ethyl ascorbic acid or a salt thereof can be produced by a known production method.
- a method for producing ethyl ascorbic acid a method of alkylating ascorbic acid in dimethyl sulfoxide (DMSO) with an alkyl halide in the presence of sodium methoxide; It can be manufactured by a method or the like.
- DMSO dimethyl sulfoxide
- a salt of ethyl ascorbic acid ethyl ascorbic acid solution is neutralized with a metal oxide such as magnesium oxide or a metal hydroxide such as sodium hydroxide to ethyl.
- a salt of ascorbic acid can be obtained.
- ethyl ascorbic acid examples include 3-O-ethyl-L-ascorbic acid (display name; 3-O-ethylascorbic acid) manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.
- Ascorbic acid glucoside is a compound in which at least one hydroxyl group of ascorbic acid is glucosided.
- the glucosidic bond is preferably an ⁇ -glucoside bond.
- Ascorbic acid glucoside is preferably a compound represented by the following chemical formula (4).
- the compound represented by the following chemical formula (4) is ascorbic acid 2-glucoside in which glucose is bound to the hydroxyl group at the 2-position of ascorbic acid.
- Ascorbic acid has D-form and L-form stereoisomers, and racemic DL-form.
- the ascorbic acid in the ascorbic acid glucoside may be any of these stereoisomers, but from the viewpoint of availability, it is preferably L-form, and the ascorbic acid glucoside is specifically L-. Ascorbic acid-2-glucoside is preferred.
- the glucose in the ascorbic acid glucoside may be D-form or L-form, but is preferably D-form from the viewpoint of availability.
- the salt of ascorbic acid glucoside examples include a salt of ascorbic acid glucoside and an inorganic base, a salt of ascorbic acid glucoside and an organic base, and the like.
- 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.
- ascorbic acid glucoside or a salt thereof is preferably ascorbic acid glucoside, and more preferably L-ascorbic acid 2-glucoside, from the viewpoint of availability.
- composition for activating autophagy of the present embodiment ascorbic acid glucoside or a salt thereof may be used alone or in combination of two or more.
- content thereof shall be 0.01 to 15% by mass with respect to the total amount of the composition for autophagy activation. Is more preferable, 0.1 to 10% by mass is more preferable, and 0.5 to 5% by mass is further preferable.
- Ascorbic acid glucoside or a salt thereof can be produced, for example, by the method described in JP-A-03-139288.
- Ascorbic acid glucoside it can be produced by binding one molecule of glucose to the hydroxyl group at the 2-position of ascorbic acid by an enzymatic reaction.
- Ascorbin is obtained by neutralizing the ascorbic acid glucoside solution with a metal oxide such as magnesium oxide or a metal hydroxide such as sodium hydroxide.
- a salt of acid glucoside can be obtained.
- ascorbic acid glucoside examples include ascorbic acid 2-glucoside (compound name; L-ascorbic acid 2-glucoside, display name; ascorbic glucoside) manufactured by Hayashibara Co., Ltd.
- the ascorbic acid derivative or a salt thereof may be used alone or in combination of two or more.
- As the ascorbic acid derivative or a salt thereof contained in the composition for activating autophagy of the present embodiment (i) ascorbyl phosphate or a salt thereof or (ii) from the viewpoint of further activating autophagy among the above. It is preferably a fatty acid ester of ascorbyl phosphate or a salt thereof, and more preferably (ii) a fatty acid ester of ascorbyl phosphate or a salt thereof.
- composition for activating autophagy of the present embodiment expresses the LC3 gene, the ATG5 gene, or the Beclin 1 gene by containing an ascorbic acid derivative or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol. Can be promoted more. Further, the composition for autophagy activation of the present embodiment can further suppress the expression of the mTOR gene by containing an ascorbic acid derivative or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol. ..
- the composition for activating autophagy of the present embodiment contains an ascorbic acid derivative or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol, so that the composition thereof contains, in particular, in nerve cells, in the presence of amyloid ⁇ .
- the expression of the LC3 gene, ATG5 gene, or Beclin1 gene can be further promoted.
- the composition for autophagy activation of the present embodiment contains an ascorbic acid derivative or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol, so that the composition contains ascorbic acid derivative or a salt thereof, particularly in nerve cells, in the presence of amyloid ⁇ . Apoptosis can be further suppressed.
- composition for activating autophagy of the present embodiment preferably contains a vitamin E derivative or a salt thereof in addition to the autophagy activator.
- a vitamin E derivative or a salt thereof By containing the vitamin E derivative or a salt thereof, the activation action of autophagy is further improved.
- vitamin E derivative examples include tocopherol phosphate ester or a salt thereof.
- tocopherol phosphate ester examples include compounds represented by the following general formula (5).
- Rd 1 , Rd 2 and Rd 3 independently represent a hydrogen atom or a methyl group.
- 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 (5) 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 (5), 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
- Sodium salt alkali metal 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.
- composition for activating autophagy of the present embodiment one kind of tocopherol phosphate ester or a salt thereof may be used alone, or two or more kinds may be used in combination.
- the content thereof is 0.01 to 10% by mass with respect to the total amount of the composition for autophagy activation. It is preferably 0.05 to 5% by mass, more preferably 0.1 to 3% by mass.
- the tocopherol phosphate ester or a salt thereof can be produced by a known production method, for example, 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.
- Ester salts can be obtained.
- composition for autophagy activation of the present embodiment expresses the LC3 gene, the ATG5 gene, or the Beclin 1 gene by containing tocopherol phosphate ester or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol. Can be further promoted. Further, the composition for autophagy activation of the present embodiment can further suppress the expression of the mTOR gene by containing tocopherol phosphate ester or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol. can.
- composition for autophagy activation of the present embodiment contains tocopherol phosphate ester or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol, whereby in the presence of amyloid ⁇ , particularly in nerve cells.
- the expression of the LC3 gene, ATG5 gene, or Beclin1 gene can be further promoted.
- the composition for activating autophagy of the present embodiment contains tocopherol phosphate ester or a salt thereof in addition to an inositol derivative in which a sugar is bound to inositol, whereby in the presence of amyloid ⁇ , particularly in nerve cells. It is possible to further suppress the apoptosis of.
- composition for activating autophagy of the present embodiment preferably contains a vitamin P derivative or a salt thereof in addition to the autophagy activator.
- a vitamin P derivative or a salt thereof By containing the vitamin P derivative or a salt thereof, the activation action of autophagy is further improved.
- Examples of the vitamin P derivative include methyl hesperidin obtained by methylating hesperidin.
- the methyl hesperidin is preferably solubilized in water.
- the methyl hesperidin mainly includes a chalcone-type compound represented by the following general formula (6) (chalcone-form methyl hesperidin) and a flavanone-type compound represented by the following general formula (7) (flavanone-form methyl hesperidin). It is known.
- R 1 to R 9 are each independently a methyl group or a hydrogen atom. However, at least one of R 1 to R 9 is a methyl group.
- R 11 to R 18 are each independently a methyl group or a hydrogen atom. However, at least one of R 11 to R 18 is a methyl group.
- the methyl hesperidin used in the composition for activating autophagy of the present embodiment comprises the chalcone methyl hesperidin represented by the general formula (6) and the flavanone methyl hesperidin represented by the general formula (7). It is preferably one or more selected from the group.
- R 1 to R 9 are independently methyl groups or hydrogen atoms, and at least one of R 1 to R 9 is a methyl group.
- any 1 to 6 is preferably a methyl group, and any 2 to 5 is more preferably a methyl group.
- R 11 to R 18 are each independently a methyl group or a hydrogen atom, and at least one of R 11 to R 18 is a methyl group. Of R 11 to R 18 , it is preferable that any 1 to 4 are methyl groups, and it is more preferable that any 1 to 3 are methyl groups.
- the compound represented by the following general formula (8) is preferable as the chalcone methyl hesperidin.
- the compound represented by the following general formula (9) is preferable as the flavanone methyl hesperidin.
- R 20 to R 23 are each independently a methyl group or a hydrogen atom.
- R 24 to R 25 are each independently a methyl group or a hydrogen atom.
- R 20 to R 23 are independently methyl groups or hydrogen atoms.
- the chalcone methyl hesperidin represented by the general formula (8) is at least one selected from the group consisting of chalcones -1 to 3 having a combination of R 20 to R 23 shown in Table 1 below. Is preferable.
- R 24 to R 25 are independently methyl groups or hydrogen atoms.
- the flavanone methyl hesperidin represented by the general formula (9) is one or more selected from the group consisting of flavanones -1 to 4 having a combination of R 24 to R 25 shown in Table 2 below. Is preferable.
- the methyl hesperidin used in the composition for activating autophagy of the present embodiment may be one kind alone or a mixture of two or more kinds.
- the methyl hesperidin is a chalcone methyl hesperidin represented by the general formula (6) or a chalcone methyl hesperidin represented by the general formula (8), and a flavanone methyl hesperidin represented by the general formula (7). It may contain both of the flavanone-form methyl hesperidin represented by the general formula (9), or may contain only one of them.
- the methyl hesperidin may contain a chalcone-form methyl hesperidin represented by the general formula (8) and a flavanone-form methyl hesperidin represented by the general formula (9). Further, the methyl hesperidin may contain any one or more of the chalcones -1 to 3 and may contain any one or more of the flavanone -1 to 4. Further, the composition for activating autophagy of the present embodiment may contain a mixture of chalcone -1 to 3 and flavanone -1 to 3 as methyl hesperidin.
- Methyl hesperidin can be produced by a known method. Methyl hesperidin is obtained by dissolving hesperidin produced from citrus peels in an aqueous solution of sodium hydroxide, allowing a corresponding amount of dimethyl sulfate to act on the alkaline solution, neutralizing the reaction solution with sulfuric acid, and extracting with n-butyl alcohol. , The solvent can be distilled off and then recrystallized from isopropyl alcohol (Sakiburo, Journal of Japanese Chemistry, (1958) Vol. 79, pp. 733-736; Japanese Patent No. 6312333). The method for producing methyl hesperidin is not limited to the above method.
- Methyl hesperidin is a commercially available product (for example, a product distributed as a pharmaceutical additive, a food additive, and a raw material for cosmetics, or "Methyl hesperidin” (Showa Denko KK), “Methyl hesperidin” (Tokyo Chemical Industry Co., Ltd.). , “Hesperidin Methyl Calcon” (Sigma), etc.) can also be purchased and used.
- the content thereof may be 0.01 to 5% by mass with respect to the total amount of the composition for autophagy activation. It is preferably 0.01 to 2% by mass, more preferably 0.05 to 1% by mass.
- composition for activating autophagy of the present embodiment further expresses the LC3 gene, the ATG5 gene, or the Beclin 1 gene by containing methyl hesperidin or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol. Can be promoted.
- composition for autophagy activation of the present embodiment can further suppress the expression of the mTOR gene by containing methyl hesperidin or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol.
- composition for autophagy activation of the present embodiment contains methyl hesperidin or a salt thereof in addition to the inositol derivative in which a sugar is bound to inositol, whereby LC3 is contained in the presence of amyloid ⁇ , especially in nerve cells.
- the expression of the gene, ATG5 gene, or Beclin1 gene can be further promoted.
- composition for autophagy activation of the present embodiment contains methyl hesperidin or a salt thereof in addition to an inositol derivative in which a sugar is bound to inositol, thereby causing apoptosis in the presence of amyloid ⁇ , particularly in nerve cells. Can be further suppressed.
- 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 Pharmaceutical Standards outside the Japanese Pharmacopoeia, 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 Excipients, 7th edition (Pharmaceutical Press, 2012) and the like can be used.
- 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 Pharmaceutical Standards outside the Japanese Pharmacopoeia, the Pharmaceutical Additive 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 the total content of the inositol derivative in which sugar is bound to inositol in the case of oral administration, and 0.01 to 500 mg in the case of an injection.
- the total content of inositol derivatives in which sugar is bound to inositol is 0.02 to 250 mg per administration unit form, and in the case of suppositories, the total content of inositol derivatives in which sugar is bound to inositol is 0. 01 to 500 mg, in the case of an external preparation for skin, the total content of the inositol derivative in which sugar is bound to inositol is 0.01 to 500 mg per administration unit form.
- 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, 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 amount effective for activating autophagy.
- the amount of the cosmetic used in the present embodiment is 0.01 to 500 mg per use as the total content of the inositol derivative in which sugar is bound to inositol, and may be, for example, 0.15 to 300 mg.
- it may be 0.15 to 200 mg, and may be, for example, 0.2 to 100 mg.
- 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 in order to prevent the onset of symptoms resulting from decreased autophagy activity.
- the present invention provides a method for activating autophagy, which comprises a step of administering an inositol derivative in which a sugar is bound to inositol to a subject.
- the present invention provides a method for promoting the expression of an LC3 gene, an ATG5 gene, or a Beclin 1 gene, which comprises a step of administering an inositol derivative in which a sugar is bound to inositol to a subject.
- the present invention provides a method for suppressing the expression of the mTOR gene, which comprises a step of administering an inositol derivative in which a sugar is bound to inositol to a subject.
- the present invention provides a method for suppressing apoptosis in the presence of amyloid ⁇ , which comprises a step of administering an inositol derivative in which a sugar is bound to inositol to a subject.
- the present invention provides an inositol derivative in which a sugar is bound to inositol for activating autophagy.
- the present invention provides an inositol derivative in which a sugar is bound to inositol for promoting the expression of the LC3 gene, the ATG5 gene, or the Beclin1 gene.
- the present invention provides an inositol derivative in which a sugar is bound to inositol for suppressing the expression of the mTOR gene.
- the present invention provides an inositol derivative in which a sugar is bound to inositol for suppressing apoptosis in the presence of amyloid ⁇ .
- the present invention provides an inositol derivative in which a sugar is bound to inositol 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 an inositol derivative in which a sugar is bound to inositol for producing an autophagy activator.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing an agent for promoting the expression of the LC3 gene, the ATG5 gene, or the Beclin1 gene.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing an agent for suppressing mTOR gene expression.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing an LC3 gene, an ATG5 gene, or a Beclin1 gene expression promoter in the presence of amyloid ⁇ .
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing an inhibitor of apoptosis in the presence of amyloid ⁇ .
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing a composition for activating autophagy.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing a composition for promoting expression of the LC3 gene, the ATG5 gene, or the Beclin1 gene.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing a composition for suppressing mTOR gene expression.
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing a composition for promoting expression of the LC3 gene, ATG5 gene, or Beclin1 gene in the presence of amyloid ⁇ . ..
- the present invention provides the use of an inositol derivative in which a sugar is bound to inositol for producing a composition for suppressing apoptosis in the presence of amyloid ⁇ .
- the inositol derivative in which a sugar is bound to inositol may be used in combination with at least one selected from the group consisting of an ascorbic acid derivative or a salt thereof, a tocopherol phosphate ester or a salt thereof, and methyl hesperidin. preferable.
- the inositol derivative A produced by the method described in International Publication No. 2019/045113 was used. Specifically, myo-inositol (manufactured by Tsukino Rice Fine Chemicals) and ⁇ -cyclodextrin (manufactured by Shiomizu Port Refinery) are reacted in the presence of cyclodextrine lucanotransferase (manufactured by Novozyme) to react with myo-inositol.
- Inositol derivative A which is a mixture of inositol derivatives to which glucose or an oligosaccharide having glucose as a monosaccharide unit is bound to glucose, was prepared.
- LC-MS liquid chromatography-mass spectrometry
- APM Magnesium salt of L-ascorbic acid-2-phosphate ester (display name; ascorbyl phosphate Mg, product name; ascorbic acid PM, manufactured by Showa Denko KK)
- APPS Sodium salt of L-ascorbic acid-2-phosphate-6-palmitic acid (display name; ascorbyl palmitate 3Na, product name; APPS, manufactured by Showa Denko)
- ⁇ -TPNa Na ⁇ -tocopheryl phosphate (product name; TPNa (registered trademark), manufactured by Showa Denko KK)
- ⁇ -TPNa Na ⁇ -tocopheryl phosphate (manufactured by Showa Denko KK)
- Methyl hesperidin Methyl hesperidin (product name: methyl hesperidin) sold by Showa Denko KK was used.
- ⁇ Preparation of aging fibroblasts Human normal fibroblasts (NB1RGB; RIKEN BRC Cellbank) were cultured in D-MEM medium (Sigma-Aldrich) supplemented with 10% fetal bovine serum (MP Biomedicals) until confluent. Then, it was treated with 250 ⁇ M hydrogen peroxide solution for 2 hours, and cultured in D-MEM medium supplemented with fresh 10% fetal bovine serum for 24 hours. This treatment with hydrogen peroxide solution and the operation of cell culture were repeated three times, and the obtained fibroblasts were designated as senescent fibroblasts.
- Example 1 the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -4 % (V / V).
- Example 2 the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V).
- Example 3 inositol derivatives A and APM dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APM was 100 ⁇ M.
- Example 4 inositol derivatives A and APPS dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APPS was 10 ⁇ M.
- Example 5 inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A is 10 -3 % (V / V) and the final concentration of ⁇ -TPNa is 10 ⁇ M are used as a medium. Added. In Example 6, inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A is 10 -3 % (V / V) and the final concentration of ⁇ -TPNa is 10 ⁇ M are used as a medium. Added.
- Example 7 the inositol derivative A dissolved in purified water so that the final concentration of the inositol derivative A is 10 -3 % (V / V) and the final concentration of methyl hesperidin is 10-2 % (V / V). And methyl hesperidin were added to the medium. Further, in Comparative Example 1, only purified water was added to the medium. In Comparative Example 2, inositol (hereinafter, also referred to as an inositol aqueous solution) dissolved in purified water so that the final concentration of inositol (myo-inositol, manufactured by Tokyo Chemical Industry Co., Ltd.) is 10-3 % (V / V). Was added to the medium. Each medium was then cultured for 24 hours at 37 ° C. under 5% CO 2 .
- inositol hereinafter, also referred to as an inositol aqueous solution
- Reference Example 1 the above-mentioned normal human fibroblasts were prepared at a seeding density of 10,000 cells / cm 2 , and 10% fetal bovine serum (manufactured by MP Biomedicals) was added to the D-MEM medium (Sigma-). The cells were cultured in Aldrich) for 24 hours, and only purified water was added to the medium. The medium was then cultured for 24 hours at 37 ° C. under 5% CO 2 .
- RNA was extracted from the aged fibroblasts or human normal fibroblasts of each example, and cDNA was synthesized from the obtained RNA.
- 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 Beclin 1 gene (manufactured by Takara Bio Inc.).
- GAPDH primary; manufactured by Takara Bio Inc.
- the expression level of GAPDH which is a housekeeping gene whose gene 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 4.
- the aged fibroblasts had the LC3 gene and the ATG5 gene, respectively. It was also confirmed that the expression level of the Beclin 1 gene was decreased. Comparing the aged fibroblasts cultured with the addition of the inositol aqueous solution of Comparative Example 2 and the aged fibroblasts cultured with the addition of only the purified water of Comparative Example 1, the aged fibroblasts of Comparative Example 2 were compared. The expression levels of the ATG5 gene and the Beclin 1 gene were higher than those of the senile fibroblasts of Example 1, but the expression levels of the LC3 gene were lower.
- the LC3 gene and ATG5 were compared with the aged fibroblasts cultured with the addition of only purified water of Comparative Example 1.
- the expression levels of both the gene and the Beclin 1 gene were increased, and in particular, the expression level of the LC3 gene was increased.
- the senile fibroblasts cultured by adding the autophagy activator of Examples 3 to 7 and the vitamin derivative or a salt thereof have the expression levels of the LC3 gene, the ATG5 gene, and the Beclin1 gene. In particular, the expression level of the LC3 gene was further increased.
- ⁇ 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 8, the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -4 % (V / V).
- Example 9 the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V).
- Example 10 inositol derivatives A and APM dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APM was 100 ⁇ M.
- Example 11 inositol derivatives A and APPS dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APPS was 10 ⁇ M.
- Example 12 inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A was 10 -3 % (V / V) and the final concentration of ⁇ -TPNa was 10 ⁇ M were used as a medium. Added. In Example 13, inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A is 10 -3 % (V / V) and the final concentration of ⁇ -TPNa is 10 ⁇ M are used as a medium. Added.
- Example 14 the inositol derivative A was dissolved in purified water so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of methyl hesperidin was 10-2 % (V / V). And methyl hesperidin were added to the medium. Further, in Comparative Example 3, only purified water was added to the medium. In Comparative Example 4, inositol (hereinafter, also referred to as an inositol aqueous solution) dissolved in purified water so that the final concentration of inositol (myo-inositol, manufactured by Tokyo Chemical Industry Co., Ltd.) is 10-3 % (V / V). Was added to the medium. Each medium was then cultured for 24 hours at 37 ° C. under 5% CO 2 .
- inositol hereinafter, also referred to as an inositol aqueous solution
- the above-mentioned normal human fibroblasts were prepared at a seeding density of 10,000 cells / cm 2 , and 10% fetal bovine serum (manufactured by MP Biomedicals) was added to the D-MEM medium (Sigma-). The cells were cultured in Aldrich) for 24 hours, and only purified water was added to the medium. The medium was then 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 3 was 1.00. The results are shown in Table 5.
- the aging fibroblasts cultured with the addition of the autophagy activator of Examples 8 to 14 express the mTOR gene as compared with the aging fibroblasts cultured with the addition of only purified water of Comparative Example 3.
- the amount was reduced and the expression of the mTOR gene was suppressed.
- the expression level of the mTOR gene was further reduced in the aged fibroblasts cultured by adding the autophagy activator of Examples 10 to 14 and the vitamin derivative or a salt thereof, and the expression of the mTOR gene was further reduced.
- the expression level of the mTOR gene was further reduced in the aged fibroblasts cultured by adding the autophagy activator of Examples 10 to 14 and the vitamin derivative or a salt thereof, and the expression of the mTOR gene was further reduced.
- SH-SY5Y cells were prepared at a seeding density of 10000 cells / cm 2 and placed in D-MEM / Ham's F-12 medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals). Was cultured for 24 hours. Then, in Example 15, the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -4 % (V / V). In Example 16, the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V).
- Example 17 inositol derivatives A and APM dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APM was 100 ⁇ M.
- Example 18 inositol derivatives A and APPS dissolved in purified water were added to the medium so that the final concentration of inositol derivative A was 10 -3 % (V / V) and the final concentration of APPS was 10 ⁇ M.
- Example 19 inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A was 10 -3 % (V / V) and the final concentration of ⁇ -TPNa was 10 ⁇ M were used as a medium. Added. In Example 20, inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A is 10 -3 % (V / V) and the final concentration of ⁇ -TPNa is 10 ⁇ M are used as a medium. Added.
- Example 21 the inositol derivative A was dissolved in purified water so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of methyl hesperidin was 10-2 % (V / V). And methyl hesperidin were added to the medium. Further, in Comparative Example 5, only purified water was added to the medium. In Comparative Example 6, inositol (hereinafter, also referred to as an inositol aqueous solution) dissolved in purified water so that the final concentration of inositol (myo-inositol, manufactured by Tokyo Chemical Industry Co., Ltd.) is 10 -3 % (V / V). Was added to the medium.
- inositol hereinafter, also referred to as an inositol aqueous solution
- 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 purified water was added, and the 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 Beclin 1 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 6.
- the SH-SY5Y cells cultured by adding the autophagy activator of Examples 15 to 21 and the amyloid ⁇ solution were added.
- the expression levels of the LC3 gene, the ATG5 gene, and the Beclin1 gene were all increased, and in particular, the expression level of the LC3 gene was increased.
- the effect of promoting the expression levels of the LC3 gene, the ATG5 gene, and the Beclin 1 gene was more remarkable than in the SH-SY5Y cells of Comparative Example 6.
- the expression levels of the LC3 gene, the ATG5 gene, and the Beclin 1 gene were all higher than those of the SH-SY5Y cells cultured by adding only the purified water of Reference Example 3. It was increasing, and in particular, the expression level of the LC3 gene was increasing.
- SH-SY5Y cells cultured with the addition of the autophagy activators and vitamin derivatives of Examples 17 to 21 or salts thereof have any expression levels of the LC3 gene, the ATG5 gene, and the Beclin 1 gene. In particular, the expression level of the LC3 gene was further increased.
- amyloid ⁇ which is known to induce a decrease in autophagy and cell death called apoptosis of nerve cells, was added to each medium for the test.
- SH-SY5Y cells were prepared at a seeding density of 50,000 cells / cm 2 and placed in D-MEM / Ham's F-12 medium (manufactured by Sigma-Aldrich) supplemented with 10% fetal bovine serum (manufactured by MP Biomedicals). Was cultured for 24 hours. Then, in Example 22, the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -4 % (V / V). In Example 23, the inositol derivative A dissolved in purified water was added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V).
- Example 24 inositol derivatives A and APM dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APM was 100 ⁇ M.
- Example 25 inositol derivatives A and APPS dissolved in purified water were added to the medium so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of APPS was 10 ⁇ M.
- Example 26 inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A was 10 -3 % (V / V) and the final concentration of ⁇ -TPNa was 10 ⁇ M were used as a medium. Added. In Example 27, inositol derivatives A and ⁇ -TPNa dissolved in purified water so that the final concentration of inositol derivative A was 10 -3 % (V / V) and the final concentration of ⁇ -TPNa was 10 ⁇ M were used as a medium. Added.
- Example 28 the inositol derivative A was dissolved in purified water so that the final concentration of the inositol derivative A was 10 -3 % (V / V) and the final concentration of methyl hesperidin was 10-2 % (V / V). And methyl hesperidin were added to the medium. Further, in Comparative Example 7, only purified water was added to the medium. In Comparative Example 8, inositol (hereinafter, also referred to as an inositol aqueous solution) dissolved in purified water so that the final concentration of inositol (myo-inositol, manufactured by Tokyo Chemical Industry Co., Ltd.) is 10-3 % (V / V). Was added to the medium.
- inositol hereinafter, also referred to as an inositol aqueous solution
- 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 purified water was added to the medium, and the 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 Fujifilm Wako Junyaku Co., 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
- SH-SY5Y cells cultured by adding the autophagy activator of Examples 22 to 28 and the amyloid ⁇ solution SH- was cultured by adding the purified water of Comparative Example 7 and the amyloid ⁇ solution. It was confirmed that the proportion of apoptotic cells was lower than that of SY5Y cells. Among them, it was confirmed that the proportion of apoptotic cells was further reduced in SH-SY5Y cells cultured with the addition of the autophagy activators of Examples 24 to 28 and vitamin derivatives or salts thereof.
- Table 8 shows Formulation Examples 1 to 5 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
Description
本願は、2020年9月17日に、日本に出願された特願2020-156460号に基づき優先権を主張し、その内容をここに援用する。
したがって、細胞内の老化した物質およびオルガネラを分解し、その分解産物をリサイクルするオートファジーを活性化することで、細胞内の不要物をすみやかに除去することで細胞の恒常性を高めることができる。
[1]イノシトールに糖が結合したイノシトール誘導体を有効成分として含有する、オートファジー活性化剤。
[2]前記糖がグルコース又はグルコースを単糖単位として含むオリゴ糖である、[1]に記載のオートファジー活性化剤。
[3]前記イノシトールがmyo-イノシトールである、[1]又は[2]に記載のオートファジー活性化剤。
[4]LC3遺伝子の発現を促進する、[1]~[3]のいずれか一項に記載のオートファジー活性化剤。
[5]ATG5遺伝子の発現を促進する、[1]~[4]のいずれか一項に記載のオートファジー活性化剤。
[6]Beclin 1遺伝子の発現を促進する、[1]~[5]のいずれか一項に記載のオートファジー活性化剤。
[7]mTOR遺伝子の発現を抑制する、[1]~[6]のいずれか一項に記載のオートファジー活性化剤。
[8]アルツハイマー病の予防または治療に用いる、[1]~[7]のいずれか一項に記載のオートファジー活性化剤。
[9][1]~[8]のいずれか一項に記載のオートファジー活性化剤及び薬学的に許容される担体を含有する、オートファジー活性化用組成物。
[10]前記イノシトール誘導体の合計含有量が0.1~2質量%である、[9]に記載のオートファジー活性化用組成物。
[11]さらに、ビタミンC誘導体、ビタミンE誘導体、およびビタミンP誘導体からなる群より選択される少なくとも1種のビタミン誘導体又はその塩を含有する、[9]又は[10]に記載のオートファジー活性化用組成物。
[12]前記ビタミン誘導体又はその塩が、リン酸アスコルビル又はその塩、リン酸アスコルビルの脂肪酸エステル又はその塩、トコフェロールリン酸エステル又はその塩、およびメチルヘスペリジン又はその塩からなる群より選択される少なくとも1種のビタミン誘導体又はその塩である、[11]に記載のオートファジー活性化用組成物。
[13]前記ビタミン誘導体又はその塩の合計含有量が、オートファジー活性化用組成物全量に対して、0.01~15質量%である、[11]又は[12]に記載のオートファジー活性化用組成物。
本実施形態のオートファジー活性化剤は、イノシトールに糖が結合したイノシトール誘導体を有効成分として含有する。
ここで「オートファジー(autophagy)」とは、老朽または損傷した細胞内物質およびオルガネラを分解することで、エネルギーの再生産および損傷物質の除去をするメカニズムである。
本実施形態のオートファジー活性化剤は、オートファジーマーカーであるLC3遺伝子、ならびにオートファゴソームに含まれるATG5遺伝子、およびBeclin 1遺伝子の発現を促進することができ、オートファジーを活性化させることができる。また、オートファジーの抑制因子として働くmTOR遺伝子の発現を抑制することで、オートファジーを活性化させることができる。
本実施形態のオートファジー活性化剤におけるイノシトール誘導体は、イノシトールと糖から構成される化合物であり、具体的には、イノシトールの少なくとも一つの水酸基に糖が結合した化合物である。
イノシトール誘導体を構成するイノシトールは、C6H6(OH)6で表される環状六価アルコールである。イノシトールには、cis-イノシトール、epi-イノシトール、allo-イノシトール、myo-イノシトール、muco-イノシトール、neo-イノシトール、chiro-イノシトール(D体及びL体が存在する)、scyllo-イノシトールの、9つの立体異性体が存在する。
イノシトール誘導体を構成する糖は、単糖であってもよく、オリゴ糖であってもよい。ここで、単糖とは、それ以上加水分解されない糖を意味し、多糖を形成する際の構成要素となる化合物を意味する。単糖は、糖類の最小単位であるということもできる。オリゴ糖とは、単糖がグリコシド結合によって複数個結合した糖のオリゴマーである。
単糖として、具体的には、グルコース(ブドウ糖)、フルクトース(果糖)、ガラクトース、リボース、キシロース、マンニトール、ソルビトール、キシリトール、エリスリトール、ペンタエリスリトール等が挙げられる。
オリゴ糖として、具体的には、スクロース(ショ糖)、ラクトース(乳糖)、マルトース(麦芽糖)、イソマルトース、トレハロース、セロビオース、マルチトール等の二糖;ラフィノース、メレジトース、マルトトリオース等の三糖;スタキオース等の四糖;α-シクロデキストリン等の六糖;β-シクロデキストリン等の七糖;γ-シクロデキストリン等の八糖が挙げられる。
ここで、単糖単位とは、単糖に相当する化学構造を意味し、単糖に由来する化学構造であるということもできる。
該グルコースを単糖単位として含むオリゴ糖の分子量は、例えば、300~3000程度であってもよい。
ここで、単糖単位に換算とは、1分子のイノシトールに結合した糖がいくつの単糖単位から構成されているかを示すものである。なお、1分子のイノシトールに複数の糖が結合している場合は、複数の糖の単糖単位をそれぞれ合計した値を意味する。
具体的には、二糖を単糖単位に換算すると2であり、三糖を単糖単位に換算すると3である。また、1分子のイノシトールに二糖および三糖が結合している場合は、単糖単位に換算すると5である。
より具体的には、グルコース(ブドウ糖)、フルクトース(果糖)、ガラクトース、リボース、キシロース、マンニトール、ソルビトール、キシリトール、エリスリトール、ペンタエリスリトール等の単糖を単糖単位に換算すると1である。
また、スクロース(ショ糖)、ラクトース(乳糖)、マルトース(麦芽糖)、イソマルトース、トレハロース、セロビオース、マルチトール等の二糖を単糖単位に換算すると2である。
また、ラフィノース、メレジトース、マルトトリオース等の三糖を単糖単位に換算すると3である。
また、スタキオース等の四糖を単糖単位に換算すると4であり、α-シクロデキストリン等の六糖を単糖単位に換算すると6であり、β-シクロデキストリン等の七糖を単糖単位に換算すると7であり、γ-シクロデキストリン等の八糖を単糖単位に換算すると8である。
この場合、イノシトール誘導体を構成する糖はグルコースを構成単位として含むことになる。
一方で、イノシトール誘導体の原料の糖として、より安価なデンプン等を用いた場合、イノシトール誘導体の合成時に様々な糖が様々な場所に転移されるため、得られるイノシトール誘導体の精製度が安定しない傾向がある。
本明細書において、「薬学的に許容可能な塩」とは、イノシトール誘導体の生理活性を阻害しない塩の形態を意味する。イノシトール誘導体の薬学的に許容可能な塩としては、特に制限されず、例えば、アルカリ金属(ナトリウム、カリウムなど)との塩;アルカリ土類金属(マグネシウム、カルシウムなど)との塩;有機塩基(ピリジン、トリエチルアミンなど)との塩、アミンとの塩等が挙げられる。
本実施形態のオートファジー活性化剤は、ATG5遺伝子の発現を促進することで、オートファジーを効果的に活性化することができる。
本実施形態のオートファジー活性化剤は、Beclin 1遺伝子の発現を促進することで、オートファジーを効果的に活性化することができる。
本実施形態のオートファジー活性化剤は、mTOR遺伝子の発現を抑制することで、オートファジーを効果的に活性化することができる。
本実施形態のオートファジー活性化剤は、オートファジーを効果的に活性化することができるので、アルツハイマー病の予防または治療に用いることができる。
本実施形態のオートファジー活性化剤は、アミロイドβ存在下でのLC3遺伝子発現を促進させることができる。
本実施形態のオートファジー活性化剤は、アミロイドβ存在下でのATG5遺伝子発現を促進させることができる。
本実施形態のオートファジー活性化剤は、アミロイドβ存在下でのBeclin 1遺伝子発現を促進させることができる。
本実施形態のオートファジー活性化剤は、アミロイドβ存在下でのアポトーシスを抑制することができる。
本実施形態のオートファジー活性化剤は、特に神経細胞において、アミロイドβ存在下でのLC3遺伝子、ATG5遺伝子、及びBeclin 1遺伝子からなる群より選択される少なくとも1種の遺伝子の発現を促進させることができる。また、本実施形態のオートファジー活性化剤は、特に神経細胞において、アミロイドβ存在下でのアポトーシスを抑制することができる。
アミロイドβ存在下でアポトーシスを抑制するとは、アミロイドβ存在下において、本実施形態のオートファジー活性化剤を投与することにより、前記オートファジー活性化剤を投与しなかった場合と比較して、アポトーシスが抑制されることを意味する。
本実施形態のオートファジー活性化用組成物は、上述したイノシトールに糖が結合したイノシトール誘導体を含有するオートファジー活性化剤と、薬学的に許容される担体とを含有する。
なお、「実質的な毒性を示さない」とは、その成分が通常使用される投与量において、投与対象に対して毒性を示さないことを意味する。
薬学的に許容される担体としては、特に制限されず、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、希釈剤、注射剤用溶剤、保湿剤、感触向上剤、界面活性剤、高分子・増粘・ゲル化剤、溶剤、噴射剤、酸化防止剤、還元剤、酸化剤、キレート剤、酸、アルカリ、粉体、無機塩、水、金属含有化合物、不飽和単量体、多価アルコール、高分子添加剤、湿潤剤、増粘剤、粘着付与物質、油性原料、液状マトリックス、脂溶性物質、高分子カルボン酸塩等を挙げることができる。
本実施形態のオートファジー活性化用組成物における薬学的に許容される担体は、1種を単独で用いてもよく、2種以上を併用してもよい。
他の成分は、1種を単独で用いてもよく、2種以上を併用してもよい。
本実施形態のオートファジー活性化用組成物において、上記オートファジー活性化剤の治療的有効量は、イノシトールに糖が結合したイノシトール誘導体が、オートファジーを活性化し得る量であり得る。また、上記オートファジー活性化剤の治療的有効量は、イノシトールに糖が結合したイノシトール誘導体が、LC3遺伝子、ATG5遺伝子、及びBeclin 1遺伝子からなる群より選択される少なくとも1種の遺伝子の発現を促進し得る量であり得る。また、上記オートファジー活性化剤の治療的有効量は、イノシトールに糖が結合したイノシトール誘導体が、mTOR遺伝子の発現を抑制し得る量であり得る。また、上記オートファジー活性化剤の治療的有効量は、イノシトールに糖が結合したイノシトール誘導体が、アミロイドβの存在下で、アポトーシスを抑制し得る量であり得る。
なお、イノシトールに糖が結合したイノシトール誘導体の合計含有量とは、1種のイノシトールに糖が結合したイノシトール誘導体を単独で使用する場合にはその化合物の含有量を意味し、イノシトールに糖が結合したイノシトール誘導体を2種以上組み合わせて用いる場合には、これらの化合物の合計の含有量を意味する。
本実施形態のオートファジー活性化用組成物が、ビタミンC誘導体、ビタミンE誘導体、およびビタミンP誘導体からなる群より選択される少なくとも1種のビタミン誘導体又はその塩を含む場合、前記ビタミン誘導体又はその塩の合計含有量は、オートファジー活性化用組成物全量に対して、0.01~15質量%であることが好ましく、0.05~10質量%であることがより好ましく、0.1~5質量%であることがさらに好ましい。
本実施形態のオートファジー活性化用組成物は、前記オートファジー活性化剤に加えて、ビタミンC誘導体又はその塩を含有することが好ましい。ビタミンC誘導体又はその塩を含有することにより、オートファジーの活性化作用がより向上する。
前記アスコルビン酸誘導体として、より具体的には、アスコルビン酸の水酸基のいずれかをリン酸エステル化させたリン酸アスコルビル(アスコルビン酸リン酸エステルともいう);アスコルビン酸の水酸基のいずれかをリン酸エステル化し、他の水酸基を脂肪酸によりエステル化させたリン酸アスコルビルの脂肪酸エステル;アスコルビン酸の水酸基のいずれかをエトキシ化させたエチルアスコルビン酸;アスコルビン酸の水酸基のいずれかをグルコシド化させたアスコルビン酸グルコシド;アスコルビン酸の水酸基のいずれかをアシル化させたアシル化アスコルビン酸;アスコルビン酸の水酸基のいずれかをアシル化し、他の水酸基をリン酸エステル化させたアシル化リン酸アスコルビル;アスコルビン酸の水酸基のいずれかをグリセリンで置換したグリセリルアスコルビン酸;リン酸を介してアスコルビン酸とトコフェロールとがそれぞれエステル結合で結合したアスコルビン酸とトコフェロールのリン酸ジエステル(具体的には、dl-α-トコフェロール2-L-アスコルビン酸リン酸ジエステルなど)等が挙げられる。
無機塩基との塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アルミニウム塩;アンモニウム塩;亜鉛塩等が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
・リン酸アスコルビル
リン酸アスコルビルは、アスコルビン酸の少なくとも1つの水酸基にリン酸基が導入された化合物である。
リン酸アスコルビルとしては、下記化学式(1)で表される化合物が好適に挙げられる。
下記化学式(1)で表される化合物は、アスコルビン酸の2位の水酸基をリン酸エステルによって保護した、アスコルビン酸-2-リン酸エステルである。
リン酸アスコルビルの塩としては、例えば、リン酸アスコルビルと無機塩基との塩、リン酸アスコルビルと有機塩基との塩等が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
リン酸アスコルビルのマグネシウム塩は、安定性が高く、かつ、着色されにくいという観点から好ましい。
上記化学式(1)で表される化合物のマグネシウム塩は、具体的には、L-アスコルビン酸-2-リン酸エステルのマグネシウム塩が特に好ましい。
上記化学式(1)で表される化合物のナトリウム塩は、具体的には、L-アスコルビン酸-2-リン酸エステルのナトリウム塩が特に好ましい。
本実施形態のオートファジー活性化用組成物がリン酸アスコルビル又はその塩を含有する場合、その含有量は、オートファジー活性化用組成物全量に対して、0.1~15質量%であることが好ましく、0.5~10質量%であることがより好ましく、1~5質量%であることがさらに好ましい。
例えば、リン酸アスコルビルの具体的な製造方法としては、アスコルビン酸と、オキシ塩化リン等とを反応させて、ホスホリル化することにより得ることができる。
また、リン酸アスコルビルの塩の具体的な製造方法としては、リン酸アスコルビル溶液を、酸化マグネシウム等の金属酸化物、または、水酸化ナトリウム等の金属水酸化物等で中和することにより、リン酸アスコルビルの塩を得ることができる。
・リン酸アスコルビルの脂肪酸エステル
リン酸アスコルビルの脂肪酸エステルは、リン酸アスコルビルの少なくとも1つの水酸基に脂肪酸がエステル結合した化合物である。該脂肪酸としては、炭素原子数6~22の直鎖状又は分岐鎖状の脂肪酸(すなわち、カルボキシ基に結合する直鎖状または分岐鎖状のアルキル基の炭素原子数が5~21の脂肪酸)であることが好ましく、炭素原子数10~20の直鎖状または分岐鎖状の脂肪酸であることがより好ましく、炭素原子数12~18の直鎖状または分岐鎖状の脂肪酸であることがさらに好ましい。
リン酸アスコルビルの脂肪酸エステルとしては、下記一般式(2)で表される化合物が挙げられる。下記一般式(2)で表される化合物は、アスコルビン酸の2位の水酸基にリン酸がエステル結合し、6位の水酸基に脂肪酸がエステル結合した、アスコルビン酸-2-リン酸-6-脂肪酸である。
すなわち、上記一般式(2)で表される化合物としては、6-O-パルミトイルアスコルビン酸-2-リン酸エステル(アスコルビン酸-2-リン酸-6-パルミチン酸ともいう)が特に好ましい。
リン酸アスコルビルの脂肪酸エステルの塩としては、例えば、リン酸アスコルビルの脂肪酸エステルと無機塩基との塩、リン酸アスコルビルの脂肪酸エステルと有機塩基との塩等が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
リン酸アスコルビルの脂肪酸エステルのナトリウム塩は、安定性及び製剤への配合容易性の観点から好ましい。
本実施形態のオートファジー活性化用組成物がリン酸アスコルビルの脂肪酸エステル又はその塩を含有する場合、その含有量は、0.05~12質量%であることが好ましく、0.05~5質量%であることがより好ましく、0.1~2質量%であることがさらに好ましい。
例えば、リン酸アスコルビルの脂肪酸エステルの具体的な製造方法としては、上述したリン酸アスコルビルの製造方法と同様の方法でリン酸アスコルビルを製造した後、該リン酸アスコルビルと、脂肪酸またはそのエステルとを縮合反応させることにより得ることができる。
また、リン酸アスコルビルの脂肪酸エステルの塩の具体的な製造方法としては、リン酸アスコルビルの脂肪酸エステル溶液を、酸化マグネシウム等の金属酸化物、または、水酸化ナトリウム等の金属水酸化物等で中和することにより、リン酸アスコルビルの脂肪酸エステルの塩を得ることができる。
・エチルアスコルビン酸
エチルアスコルビン酸は、アスコルビン酸の少なくとも1つの水酸基にエチル基が導入された化合物である。
エチルアスコルビン酸としては、下記化学式(3)で表される化合物が好適に挙げられる。
下記化学式(3)で表される化合物は、アスコルビン酸の3位の水酸基の水素原子をエチル基によって置換した、3-O-エチルアスコルビン酸である。
エチルアスコルビン酸の塩としては、例えば、エチルアスコルビン酸と無機塩基との塩、エチルアスコルビン酸と有機塩基との塩等が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
本実施形態のオートファジー活性化用組成物がエチルアスコルビン酸又はその塩を含有する場合、その含有量は、オートファジー活性化用組成物全量に対して、0.01~15質量%であることが好ましく、0.1~10質量%であることがより好ましく、0.5~5質量%であることがさらに好ましい。
例えば、エチルアスコルビン酸の製造方法としては、アスコルビン酸をジメチルスルホキシド(DMSO)中でナトリウムメトキシド存在下にハロゲン化アルキルによりアルキル化する方法;特開平8-134055、特開平1-228977に記載の方法等により製造することができる。
また、エチルアスコルビン酸の塩の具体的な製造方法としては、エチルアスコルビン酸溶液を、酸化マグネシウム等の金属酸化物、または、水酸化ナトリウム等の金属水酸化物等で中和することにより、エチルアスコルビン酸の塩を得ることができる。
・アスコルビン酸グルコシド
アスコルビン酸グルコシドは、アスコルビン酸の少なくとも1つの水酸基がグルコシド化された化合物である。グルコシド結合は、α-グルコシド結合であることが好ましい。
アスコルビン酸グルコシドとしては、下記化学式(4)で表される化合物が好適に挙げられる。
下記化学式(4)で表される化合物は、アスコルビン酸の2位の水酸基にグルコースが結合した、アスコルビン酸2-グルコシドである。
アスコルビン酸グルコシドの塩としては、例えば、アスコルビン酸グルコシドと無機塩基との塩、アスコルビン酸グルコシドと有機塩基との塩等が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
本実施形態のオートファジー活性化用組成物がアスコルビン酸グルコシド又はその塩を含有する場合、その含有量は、オートファジー活性化用組成物全量に対して、0.01~15質量%であることが好ましく、0.1~10質量%であることがより好ましく、0.5~5質量%であることがさらに好ましい。
例えば、アスコルビン酸グルコシドの具体的な製造方法としては、アスコルビン酸の2位の水酸基にグルコース1分子を酵素反応でα-グルコシド結合させることにより製造することができる。
また、アスコルビン酸グルコシドの塩の具体的な製造方法としては、アスコルビン酸グルコシド溶液を、酸化マグネシウム等の金属酸化物、または、水酸化ナトリウム等の金属水酸化物等で中和することにより、アスコルビン酸グルコシドの塩を得ることができる。
本実施形態のオートファジー活性化用組成物が含有するアスコルビン酸誘導体又はその塩としては、上記の中でも、よりオートファジーを活性化できる観点から、(i)リン酸アスコルビル若しくはその塩又は(ii)リン酸アスコルビルの脂肪酸エステル若しくはその塩であることが好ましく、(ii)リン酸アスコルビルの脂肪酸エステル又はその塩であることがより好ましい。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、アスコルビン酸誘導体又はその塩を含有することにより、mTOR遺伝子の発現をより抑制することができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、アスコルビン酸誘導体又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのLC3遺伝子、ATG5遺伝子、又はBeclin 1遺伝子の発現をより促進することができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、アスコルビン酸誘導体又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのアポトーシスをより抑制することができる。
本実施形態のオートファジー活性化用組成物は、前記オートファジー活性化剤に加えて、ビタミンE誘導体又はその塩を含有することが好ましい。ビタミンE誘導体又はその塩を含有することにより、オートファジーの活性化作用がより向上する。
トコフェロールリン酸エステルとしては、下記一般式(5)で表される化合物が挙げられる。
有機塩基との塩としては、例えば、アルキルアンモニウム塩、塩基性アミノ酸との塩等が挙げられる。
本実施形態のオートファジー活性化用組成物がトコフェロールリン酸エステル又はその塩を含有する場合、その含有量は、オートファジー活性化用組成物全量に対して、0.01~10質量%であることが好ましく、0.05~5質量%であることがより好ましく、0.1~3質量%であることがさらに好ましい。
例えば、溶媒中に溶解したトコフェロールにオキシ塩化リン等のリン酸化剤を作用させ、反応終了後に適宜精製することによりトコフェロールリン酸エステルを得ることができる。さらに、得られたトコフェロールリン酸エステルを、酸化マグネシウム等の金属酸化物、水酸化ナトリウム等の金属水酸化物、又は、水酸化アンモニウムや水酸化アルキルアンモニウム等で中和することにより、トコフェロールリン酸エステルの塩を得ることができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、トコフェロールリン酸エステル又はその塩を含有することにより、mTOR遺伝子の発現をより抑制することができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、トコフェロールリン酸エステル又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのLC3遺伝子、ATG5遺伝子、又はBeclin 1遺伝子の発現をより促進することができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、トコフェロールリン酸エステル又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのアポトーシスをより抑制することができる。
本実施形態のオートファジー活性化用組成物は、前記オートファジー活性化剤に加えて、ビタミンP誘導体又はその塩を含有することが好ましい。ビタミンP誘導体又はその塩を含有することにより、オートファジーの活性化作用がより向上する。
式(7)中、R11~R18は、それぞれ独立に、メチル基または水素原子である。ただし、R11~R18のうち、少なくとも1つはメチル基である。]
また、本実施形態のオートファジー活性化用組成物は、メチルヘスペリジンとして、カルコン体-1~3およびフラバノン体-1~3の混合物を含むものであってもよい。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、メチルヘスペリジン又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのLC3遺伝子、ATG5遺伝子、又はBeclin 1遺伝子の発現をより促進することができる。
また、本実施形態のオートファジー活性化用組成物は、イノシトールに糖が結合したイノシトール誘導体に加えて、メチルヘスペリジン又はその塩を含有することにより、特に神経細胞において、アミロイドβ存在下でのアポトーシスをより抑制することができる。
一実施形態において、本発明は、上述したオートファジー活性化剤及び薬学的に許容される担体を含有する、オートファジー活性化用医薬組成物を提供する。
薬学的に許容される担体は、1種を単独で用いてもよく、2種以上を併用してもよい。
例えば、本実施形態の医薬組成物の投与量は、経口投与の場合には、イノシトールに糖が結合したイノシトール誘導体の合計含有量として投与単位形態あたり0.01~500mg、注射剤の場合には、イノシトールに糖が結合したイノシトール誘導体の合計含有量として投与単位形態あたり0.02~250mg、坐剤の場合には、イノシトールに糖が結合したイノシトール誘導体の合計含有量として投与単位形態あたり0.01~500mg、皮膚外用剤の場合には、イノシトールに糖が結合したイノシトール誘導体の合計含有量として投与単位形態あたり0.01~500mg等が挙げられる。
本実施形態の医薬組成物は、上記の中でも、特にアルツハイマー病を治療するために好適に用いることができる。
一実施形態において、本発明は、上述したオートファジー活性化剤及び薬学的に許容される担体を含有する、オートファジー活性化のための化粧料を提供する。
薬学的に許容される担体は、1種を単独で用いてもよく、2種以上を併用してもよい。
例えば、本実施形態の化粧料の使用量は、イノシトールに糖が結合したイノシトール誘導体の合計含有量として1回の使用あたり0.01~500mgであり、例えば0.15~300mgであってもよく、例えば0.15~200mgであってもよく、例えば0.2~100mgであってもよい。
一実施形態において、本発明は、イノシトールに糖が結合したイノシトール誘導体を対象に投与する工程を含む、オートファジーを活性化する方法を提供する。
以下の実施例および処方例では、国際公開第2019/045113号に記載の方法により製造したイノシトール誘導体Aを使用した。
具体的には、myo-イノシトール(築野ライスファインケミカルズ社製)とβ-シクロデキストリン(塩水港精糖社製)とをシクロデキストリングルカノトランスフェラーゼ(ノボザイム社製)の存在下で反応させ、myo-イノシトールにグルコース又はグルコースを単糖単位とするオリゴ糖が結合したイノシトール誘導体の混合物であるイノシトール誘導体Aを作製した。
作製したイノシトール誘導体Aを液体クロマトグラフィー質量分析法(LC-MS)で分析した結果、組成は以下の通りであった。
以下の実施例および処方例では、下記のビタミン誘導体又はその塩を使用した。
APM:L-アスコルビン酸-2-リン酸エステルのマグネシウム塩(表示名称;リン酸アスコルビルMg、製品名;アスコルビン酸PM、昭和電工社製)
APPS:L-アスコルビン酸-2-リン酸-6-パルミチン酸のナトリウム塩(表示名称;パルミチン酸アスコルビルリン酸3Na、製品名;アプレシエ(APPS)、昭和電工社製)
α-TPNa:α-トコフェリルリン酸Na(製品名;TPNa(登録商標)、昭和電工社製)
γ-TPNa:γ-トコフェリルリン酸Na(昭和電工社製)
メチルヘスペリジン:昭和電工株式会社から販売されているメチルヘスペリジン(製品名:メチルヘスペリジン)を使用した。この製品は、前記カルコン体-1~3及び前記フラバノン体-1~3の合計含有量が、組成物全量中、97.5質量%以上である。
人為的に老化を誘発した細胞を作製するため、線維芽細胞を用いて試験を行った。老化線維芽細胞は、以下の手順により作製した。
10%ウシ胎児血清(MP Biomedicals社製)を添加したD-MEM培地(Sigma-Aldrich社製)で、ヒト正常線維芽細胞(NB1RGB;RIKEN BRC セルバンク製)をコンフルエントになるまで培養した。その後、250μM過酸化水素水で2時間処理し、新しい10%ウシ胎児血清を添加したD-MEM培地で24時間培養した。この過酸化水素水による処理と細胞培養の操作を3回繰り返し、得られた線維芽細胞を老化線維芽細胞とした。
作製した老化線維芽細胞を、10000個/cm2の播種密度で準備し、10%ウシ胎児血清(MP Biomedicals社製)を添加したD-MEM培地(Sigma-Aldrich社製)にて24時間培養した。次いで、実施例1では、イノシトール誘導体Aの終濃度が10-4%(V/V)となるように、精製水に溶かしたイノシトール誘導体Aを培地に添加した。実施例2では、イノシトール誘導体Aの終濃度が10-3%(V/V)となるように、精製水に溶かしたイノシトール誘導体Aを培地に添加した。実施例3では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、APMの終濃度が100μMとなるように精製水に溶かしたイノシトール誘導体AおよびAPMを培地に添加した。実施例4では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、APPSの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体AおよびAPPSを培地に添加した。実施例5では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、α-TPNaの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体Aおよびα-TPNaを培地に添加した。実施例6では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、γ-TPNaの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体Aおよびγ-TPNaを培地に添加した。実施例7では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、メチルヘスペリジンの終濃度が10-2%(V/V)となるように精製水に溶かしたイノシトール誘導体Aおよびメチルヘスペリジンを培地に添加した。
また、比較例1では、培地に精製水のみを添加した。比較例2では、イノシトール(myo-イノシトール、東京化成工業株式会社製)の終濃度が10-3%(V/V)となるように、精製水に溶かしたイノシトール(以下、イノシトール水溶液ともいう)を培地に添加した。
次いで、それぞれの培地を、24時間、37℃、5%CO2下で培養した。
比較例2のイノシトール水溶液を添加して培養した老化線維芽細胞と、比較例1の精製水のみ添加して培養した老化線維芽細胞とを比較すると、比較例2の老化線維芽細胞は、比較例1の老化線維芽細胞よりも、ATG5遺伝子、およびBeclin 1遺伝子の発現量は増加していたが、LC3遺伝子の発現量は低下していた。
また、その中でも、実施例3~7のオートファジー活性化剤およびビタミン誘導体又はその塩を添加して培養した老化線維芽細胞は、LC3遺伝子、ATG5遺伝子および、Beclin 1遺伝子の発現量がいずれもより増加しており、特にLC3遺伝子の発現量がより増加していた。
上記で作製した老化線維芽細胞を、10000個/cm2の播種密度で準備し、10%ウシ胎児血清(MP Biomedicals社製)を添加したD-MEM培地(Sigma-Aldrich社製)にて24時間培養した。次いで、実施例8では、イノシトール誘導体Aの終濃度が10-4%(V/V)となるように、精製水に溶かしたイノシトール誘導体Aを培地に添加した。実施例9では、イノシトール誘導体Aの終濃度が10-3%(V/V)となるように、精製水に溶かしたイノシトール誘導体Aを培地に添加した。実施例10では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、APMの終濃度が100μMとなるように精製水に溶かしたイノシトール誘導体AおよびAPMを培地に添加した。実施例11では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、APPSの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体AおよびAPPSを培地に添加した。実施例12では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、α-TPNaの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体Aおよびα-TPNaを培地に添加した。実施例13では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、γ-TPNaの終濃度が10μMとなるように精製水に溶かしたイノシトール誘導体Aおよびγ-TPNaを培地に添加した。実施例14では、イノシトール誘導体Aの終濃度が10-3%(V/V)となり、メチルヘスペリジンの終濃度が10-2%(V/V)となるように精製水に溶かしたイノシトール誘導体Aおよびメチルヘスペリジンを培地に添加した。
また、比較例3では、培地に精製水のみを添加した。比較例4では、イノシトール(myo-イノシトール、東京化成工業株式会社製)の終濃度が10-3%(V/V)となるように、精製水に溶かしたイノシトール(以下、イノシトール水溶液ともいう)を培地に添加した。
次いで、それぞれの培地を、24時間、37℃、5%CO2下で培養した。
比較例4のイノシトール水溶液を添加して培養した老化線維芽細胞のmTOR遺伝子の発現量は、比較例3の老化線維芽細胞とほぼ同等であった。
また、その中でも、実施例10~14のオートファジー活性化剤およびビタミン誘導体又はその塩を添加して培養した老化線維芽細胞は、mTOR遺伝子の発現量がより低下しており、mTOR遺伝子の発現がより抑制されていた。
オートファジー活性化剤存在下で、ヒト神経芽細胞腫(SH-SY5Y;ATCCから入手)におけるLC3遺伝子、ATG5遺伝子、および、Beclin 1遺伝子の発現量を以下の試験方法で測定し、オートファジー活性化剤によるLC3遺伝子、ATG5遺伝子、および、Beclin 1遺伝子の発現促進効果を評価した。
以下の実施例及び比較例では、神経細胞におけるオートファジーの低下を引き起こすことが知られているアミロイドβを各培地に添加して試験を行った。
次いで、アミロイドβ(Sigma-Aldrich社製)を0.01%(V/V)DMSO水溶液に溶かしたアミロイドβ溶液を調製し、各培地におけるアミロイドβの終濃度が20μMとなるように、該アミロイドβ溶液を各培地に添加した。
なお、参考例3では精製水のみ添加し、アミロイドβ溶液は添加しなかった。
次いで、それぞれの培地を、48時間、37℃、5%CO2下で培養した。
比較例6のイノシトール水溶液を添加して培養したSH-SY5Y細胞は、参考例3のSH-SY5Y細胞に比べて、LC3遺伝子、ATG5遺伝子、および、Beclin 1遺伝子の発現量が若干増加していた。
また、その中でも、実施例17~21のオートファジー活性化剤およびビタミン誘導体又はその塩を添加して培養したSH-SY5Y細胞は、LC3遺伝子、ATG5遺伝子、および、Beclin 1遺伝子の発現量がいずれもより増加しており、特にLC3遺伝子の発現量がより増加していた。
以下の実施例及び比較例では、オートファジーの低下とそれによる神経細胞のアポトーシスと呼ばれる細胞死を誘引することが知られているアミロイドβを各培地に添加して試験を行った。
次いで、アミロイドβ(Sigma-Aldrich社製)を0.01%(V/V)DMSO水溶液に溶かしたアミロイドβ溶液を調製し、各培地におけるアミロイドβの終濃度が30μMとなるように、該アミロイドβ溶液を各培地に添加した。
なお、参考例4では培地に精製水のみ添加し、アミロイドβ溶液は添加しなかった。
次いで、それぞれの培地を、48時間、37℃、5%CO2下で培養した。
比較例8のイノシトール水溶液を添加して培養したSH-SY5Y細胞のアポトーシス細胞の割合は、比較例7のSH-SY5Y細胞とほぼ同等であった。
また、その中でも、実施例24~28のオートファジー活性化剤およびビタミン誘導体又はその塩を添加して培養したSH-SY5Y細胞は、アポトーシス細胞の割合がより低下することが確認できた。
オートファジー活性化用組成物として、外用剤の処方例1~5を表8に示した。
Claims (13)
- イノシトールに糖が結合したイノシトール誘導体を有効成分として含有する、オートファジー活性化剤。
- 前記糖がグルコース又はグルコースを単糖単位として含むオリゴ糖である、請求項1に記載のオートファジー活性化剤。
- 前記イノシトールがmyo-イノシトールである、請求項1又は2に記載のオートファジー活性化剤。
- LC3遺伝子の発現を促進する、請求項1~3のいずれか一項に記載のオートファジー活性化剤。
- ATG5遺伝子の発現を促進する、請求項1~4のいずれか一項に記載のオートファジー活性化剤。
- Beclin 1遺伝子の発現を促進する、請求項1~5のいずれか一項に記載のオートファジー活性化剤。
- mTOR遺伝子の発現を抑制する、請求項1~6のいずれか一項に記載のオートファジー活性化剤。
- アルツハイマー病の予防または治療に用いる、請求項1~7のいずれか一項に記載のオートファジー活性化剤。
- 請求項1~8のいずれか一項に記載のオートファジー活性化剤及び薬学的に許容される担体を含有する、オートファジー活性化用組成物。
- 前記イノシトール誘導体の合計含有量が0.1~2質量%である、請求項9に記載のオートファジー活性化用組成物。
- さらに、ビタミンC誘導体、ビタミンE誘導体、およびビタミンP誘導体からなる群より選択される少なくとも1種のビタミン誘導体又はその塩を含有する、請求項9又は10に記載のオートファジー活性化用組成物。
- 前記ビタミン誘導体又はその塩が、リン酸アスコルビル又はその塩、リン酸アスコルビルの脂肪酸エステル又はその塩、トコフェロールリン酸エステル又はその塩、およびメチルヘスペリジン又はその塩からなる群より選択される少なくとも1種のビタミン誘導体又はその塩である、請求項11に記載のオートファジー活性化用組成物。
- 前記ビタミン誘導体又はその塩の合計含有量が、オートファジー活性化用組成物全量に対して、0.01~15質量%である、請求項11又は12に記載のオートファジー活性化用組成物。
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