WO2017030167A1 - Agent for reconstructing/activating neural network - Google Patents

Agent for reconstructing/activating neural network Download PDF

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Publication number
WO2017030167A1
WO2017030167A1 PCT/JP2016/074130 JP2016074130W WO2017030167A1 WO 2017030167 A1 WO2017030167 A1 WO 2017030167A1 JP 2016074130 W JP2016074130 W JP 2016074130W WO 2017030167 A1 WO2017030167 A1 WO 2017030167A1
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component
group
extract
naringenin
food
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PCT/JP2016/074130
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French (fr)
Japanese (ja)
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千尋 東田
かつ子 小松
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レジリオ株式会社
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Priority to JP2017503639A priority Critical patent/JP6165380B1/en
Publication of WO2017030167A1 publication Critical patent/WO2017030167A1/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/254—Acanthopanax or Eleutherococcus

Definitions

  • the present invention relates to agents, compositions, and foods useful for the treatment of neurological diseases, improvement of memory ability, extension of nerve axons, and the like.
  • Naringenin is a component contained in grapefruit and the like, and is considered to be a component having an antioxidant effect and the like.
  • Non-Patent Document 1 naringenin is effective in the treatment of Alzheimer's disease (Non-Patent Document 1), but its mechanism and action mechanism have not been clarified.
  • the herbal medicine bone crush (Katsusaiho) is a rhizome of the sea urchinaceae Hakamauraboshi, and is known to contain naringenin, but the traditional effects of bone crushing are as follows: Although anti-inflammation, muscular bone pain, tinnitus, toothache and the like are known (for example, Patent Document 1), the relationship between osteoclastic prosthesis and its active ingredient and the neural circuit is not known at all.
  • Ezokogi is a plant belonging to the family Uleaceae that grows naturally in Hokkaido, etc., and is considered to have a tonic effect.
  • An object of the present invention is to provide a novel agent, composition, and food and drink useful for prevention / treatment of neurological diseases, improvement / improvement of memory ability and cognitive function, and the like.
  • ⁇ ⁇ Neurodegenerative diseases such as Alzheimer's disease, senile dementia, cerebrovascular dementia, and Parkinson's disease all have different etiologies, but all indicate symptoms that impair memory and cognition due to the breakdown of the neural network.
  • these diseases for which there is no effective therapeutic method, there is a real need for a treatment that can bring the nerve function closer to normal even when the nerve network has already been impaired.
  • treatment with less burden is more desirable than nerve cell transplantation and gene therapy that require surgery. Therefore, it is desired to develop a drug that regenerates a neural network even when a nerve cell is damaged or after it has been damaged.
  • amyotrophic lateral sclerosis is an intractable disease in which the limbs of the cerebral cortex motor cortex and the motor neurons of the spinal cord and brainstem drop off, and there is no effective treatment. Furthermore, motor neurons in the cerebral cortex motor cortex are also damaged by cerebral hemorrhage, cerebral infarction, brain tumor, brain trauma, etc., leading to paralysis of the body. Traumatic spinal cord injury also results in limb paralysis due to damage to spinal motor neurons.
  • multiple cerebral infarction is a demyelinating disease of the central nervous system caused by abnormal activation of autoimmunity, but axonal loss occurs as the disease progresses, which is an irreversible malfunction of the neural network. Leads to. In either case, it is a dysfunction due to the breakdown of the neural network, but if the surviving nerve cells are activated to form a neural network again, recovery of the function can be expected.
  • the present inventor asked herbal medicines for a component exhibiting excellent activity for improving the atrophy / degeneration of nerve axons in the brain that has become degenerated and dysfunctional.
  • naringenin and herbal medicine ingredients containing such specific ingredients (such as osteoclastic components)] and sorghum ingredients are effective in repairing neurites and improving memory impairment.
  • Such functions also lead to the prevention and treatment of neurological diseases. Therefore, the specific component and the sorghum component (particularly a combination of these) are used for the prevention and treatment of neurological diseases, memory ability.
  • the present inventors have obtained knowledge that it is effective for use in improving cognitive function and for repairing and extending neurites, and have further studied based on this knowledge to complete the present invention.
  • the agent of the present invention comprises at least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof.
  • component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof.
  • Such an agent of the present invention may be an agent for use in at least one application selected from the following (1), (2) and (3).
  • (1) Neurite repair and / or extension (growth) (2) Improvement or improvement of memory and / or cognitive function (3) Prevention and / or treatment of neurological diseases
  • such an agent of the present invention usually contains only naringenin as an active ingredient and often does not contain an agent for the prevention and / or treatment of Alzheimer's disease.
  • the component (A) may contain, for example, at least one component selected from naringenin, a glycoside of naringenin (for example, naringin, naringen glucuronide), and salts thereof.
  • the agent of the present invention may contain an osteoclastic component (such as an osteoclastic extract) as a component containing the component (A).
  • an osteoclastic component such as an osteoclastic extract
  • the agent of the present invention may be used in combination of the component (A) and the component (B), and particularly may contain the component (A) and the component (B).
  • the agent of the present invention contains a bone crush extract as the component (A) and a carp extract as the component (B), and the ratio of the bone crush extract and the carp extract is the former /
  • the latter (weight ratio) 1 / 0.01 to about 1/100 may be used.
  • the agent of the present invention may further combine at least one component (C) selected from diosgenins (such as diosgenin and diosine), dihydroxyvitamin D3, and desonomin.
  • the component (C) may be a different agent from the component (A) and the component (B), or may be an agent (mixture) containing the component (A) and the component (B).
  • the present invention includes at least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof, and an elephant component A composition containing (B) is also included.
  • a composition may be a pharmaceutical composition.
  • the component (A) may contain, for example, at least one or more components selected from naringenin, glycosides of naringenin (eg, naringin, naringen glucuronide), and salts thereof. .
  • composition of the present invention may contain an osteoclastic component (such as an osteoclastic extract) as the component containing component (A).
  • an osteoclastic component such as an osteoclastic extract
  • the composition of the present invention may further combine at least one component (C) selected from diosgenins (such as diosgenin and diosine), dihydroxyvitamin D3, and desonomin.
  • the component (C) may be a composition different from the component (A) and the component (B), or may be a composition containing the component (A) and the component (B).
  • composition of the present invention may be a composition for use in at least one application selected from the following (1), (2) and (3).
  • Included in the present invention are foods and drinks containing the above-mentioned agent (particularly, an agent in which component (A) and component (B) are combined) or the composition of the present invention.
  • Such foods and drinks may be supplements, health foods, functional indication foods, nutritional functional foods, or foods for specified health use.
  • the food or drink of the present invention may be a food or drink containing 1 to 90% by weight of the osteoclast extract, or a food or drink containing 1 to 90% by weight of the elephant extract.
  • Such a food or drink may contain at least one component (C) selected from diosgenins (such as diosgenin and diosin), dihydroxyvitamin D3, and desonomin.
  • component (C) selected from diosgenins (such as diosgenin and diosin), dihydroxyvitamin D3, and desonomin.
  • the proportion of component (C) may be, for example, about 1 to 90% by weight.
  • the neural network can be reconstructed and / or activated.
  • Such reconstruction and activation are usually accompanied by repair and / or extension (extension) of neurites (axons, dendrites, etc.). Therefore, the agent or composition of the present invention is useful for preventing, treating or improving various neurological diseases caused by degeneration or atrophy of axons and dendrites, as well as improvement or improvement (enhancement) of the cognitive memory function. It is valid.
  • the improvement of the memory ability in the cognitive function is recognized in the agent and composition of the present invention, regardless of whether or not it leads to a neurological disease, the ingredients of the food and drink for the purpose of improving and improving the memory ability, etc. It is also useful.
  • FIG. 1 is a diagram showing an axonal extension action by a bone crush extract and a bone crush component on normal cerebral cortical neurons.
  • FIG. 2 is a diagram showing an axonal re-extension effect when a crushed prosthetic component is later treated against A ⁇ (25-35) -induced axonal atrophy in cerebral cortical neurons.
  • FIG. 3 is a diagram showing the area of amyloid plaques in the prefrontal cortex of 5XFAD mice administered with a bone fracture supplement for 31 days.
  • FIG. 4 is a diagram showing the area of the degenerated axon terminal area in the prefrontal cortex of 5XFAD mice administered with the osteoclastic prosthesis for 31 days.
  • FIG. 1 is a diagram showing an axonal extension action by a bone crush extract and a bone crush component on normal cerebral cortical neurons.
  • FIG. 2 is a diagram showing an axonal re-extension effect when a crushed prosthetic component is later treated against A ⁇ (25-35)
  • FIG. 5 is a diagram showing the area of amyloid plaques in the peri-olfactory cortex of 5XFAD mice to which the osteoclastic extract was administered for 31 days.
  • FIG. 6 is a diagram showing the area of the degenerated axon terminal area in the perianptic cortex of 5XFAD mice administered with the osteoclastic extract for 31 days.
  • FIG. 7 is a diagram showing the area of amyloid plaques in the hippocampal CA1 region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days.
  • FIG. 8 is a diagram showing the area of the degenerated axon terminal area in the hippocampal CA1 region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days.
  • FIG. 6 is a diagram showing the area of the degenerated axon terminal area in the hippocampal CA1 region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days.
  • FIG. 9 is a diagram showing the area of amyloid plaques in the hippocampal dentate gyrus region of 5XFAD mice to which the osteoclastic extract was administered for 31 days.
  • FIG. 10 is a diagram showing the area of the degenerated axon terminal area in the hippocampal dentate gyrus region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days.
  • FIG. 11 is a diagram showing the level of phosphorylation of threonine of the 514th amino acid of CRMP2 in the cerebral cortex of 5XFAD mice administered with the osteoclastic extract for 22 days.
  • FIG. 12 is a diagram showing an axonal re-extension effect when a fraction of the osteoclastic extract is treated later against A ⁇ (25-35) -induced axonal atrophy in cerebral cortical neurons.
  • FIG. 13 is a diagram showing an LC-MS chart of the n-butanol fraction of the osteoclastic extract.
  • FIG. 14 is a diagram showing the axonal re-extension effect when a compound contained in the osteoclastic extract is later treated against A ⁇ (25-35) -induced axonal atrophy in cerebral cortical neurons.
  • FIG. 12 is a diagram showing an axonal re-extension effect when a fraction of the osteoclastic extract is treated later against A ⁇ (25-35) -induced axonal atrophy in cerebral cortical neurons.
  • FIG. 15 is a diagram showing the results of an object recognition memory test in 5XFAD mice administered with a bone crush extract, or an extract of Ekokogi leaves, or a combination of an osteoclastic extract and an extract of Ekokogi leaves for 15 days.
  • FIG. 16 is a diagram showing the results of an object recognition memory test in normal mice administered with Ezocogi leaf extract for 27 days.
  • the agent or composition of the present invention comprises a specific component (A) or an sorghum component (B).
  • Such an agent or composition (and food or drink) of the present invention is useful for the reconstruction and / or activation of a neural network.
  • the agent or composition of the present invention often has a function of repairing or extending (extending) neurites [particularly atrophy or deficient neurites (axons or dendrites)].
  • the agent or composition of the present invention is often associated with such a function, or has an effect of improving or improving memory ability and / or cognitive function, and an effect of preventing and / or treating a neurological disease. .
  • the agent or composition of the present invention may be suitably used for at least one application selected from the following (1), (2), and (3).
  • Neurological diseases especially nerves And / or treatment of neurological diseases associated with atrophy or loss of processes (axons and dendrites)
  • the neurological disease may be a traumatic neurological disease or a neurodegenerative disease.
  • Alzheimer's disease dementia (non-Alzheimer type dementia such as senile dementia, Cerebrovascular dementia, Pick's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, etc.), Parkinson's disease, Huntington's disease, brain contusion, spinal cord injury, amyotrophic lateral sclerosis, multiple occurrences Include cerebral infarction.
  • dementia non-Alzheimer type dementia such as senile dementia, Cerebrovascular dementia, Pick's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, etc.
  • Parkinson's disease Huntington's disease
  • brain contusion spinal cord injury
  • amyotrophic lateral sclerosis multiple occurrences Include cerebral infarction.
  • agent or composition of the present invention may prevent or treat one or more neurological diseases.
  • Component (A) consists of naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof [or glycosides (O-glycosides)], and salts thereof (especially pharmaceutically acceptable) Selected salt).
  • the sugar constituting the glycoside is not particularly limited, and is a monosaccharide [eg, glucose, galactose, apiose, rhamnose, xylose, uronic acid (glucuronic acid, etc.)], disaccharide (eg, rutinose, neohesperidose, etc.) , Gentiobiose, etc.), and sugars to which these sugars are bonded.
  • a monosaccharide eg, glucose, galactose, apiose, rhamnose, xylose, uronic acid (glucuronic acid, etc.)
  • disaccharide eg, rutinose, neohesperidose, etc.
  • Gentiobiose etc.
  • the glycoside may be bound with one or more sugars.
  • glycosides include, for example, naringenin glycoside [eg, naringenin glucoside (eg, naringenin-7-glucoside, naringenin-4-glucoside, etc.), naringening glucuronide (eg, naringenin-4-glucuronide, naringenin- 4-glucuronide etc.), naringenin rutinosides (eg naringin etc.)], eriodictyol glycosides [eg eriodictyol rutinosides (eg neoeriocitrin etc.)], 5,7-dihydroxychromone Glucose [eg, 5,7-dihydroxychromone neohesperidoside (eg, 5,7-dihydroxychromone-7-neohesperidoside, etc.)], caffeic acid glycoside [eg, caffeic acid glucoside
  • the salt is not particularly limited, and examples thereof include metal salts [for example, alkali metal salts (for example, lithium salt, sodium salt, potassium salt), alkaline earth metal salts (for example, magnesium salt, calcium salt), periodic table, etc. Group 13 metal salts (for example, aluminum salts), transition metal salts (for example, salts such as zinc), etc.] ammonium salts, amine salts [for example, alkylamine salts (for example, trialkylamine salts, trialkylamine salts of triethylamine salts) ), Alkanolamine salts (for example, monoethanolamine salts, triethanolamine salts), cyclic amine salts (for example, pyridine salts)] and the like.
  • metal salts for example, alkali metal salts (for example, lithium salt, sodium salt, potassium salt), alkaline earth metal salts (for example, magnesium salt, calcium salt), periodic table, etc.
  • Group 13 metal salts for example, aluminum salts), transition metal salts (for example,
  • Component (A) may contain one or more components. When component (A) contains two or more components, it may contain two or more components that are common in the basic skeleton (for example, including naringenin and naringenin glycoside), and combinations of components having different basic skeletons 2 or more may be included (for example, having a combination of naringenin or its glycoside and eriodictyol or its glycoside).
  • component (A) may contain one or more components.
  • component (A) may contain two or more components that are common in the basic skeleton (for example, including naringenin and naringenin glycoside), and combinations of components having different basic skeletons 2 or more may be included (for example, having a combination of naringenin or its glycoside and eriodictyol or its glycoside).
  • component (A) is typically at least one component selected from naringenin, a glycoside of naringenin (naringin, naringen glucuronide, etc.), and salts thereof (collectively, naringenins) May be included) at least.
  • the component (A) may be synthesized or derived from a natural product.
  • a synthesis method a conventional method can be used.
  • Naringenin and Naringin are known to be contained in citrus plants (citrus plants such as grapefruit and hassaku), and the component (A) may be obtained from such plants.
  • osteoclasts often contain other components (A) in addition to naringenin, etc., and in combination with these, the effects of the present invention are effectively expressed.
  • A components in addition to naringenin, etc.
  • the agent of the present invention may contain a bone crush prosthetic component as a component containing the component (A).
  • osteoclastic component examples include osteoclastic prosthesis, osteoclastic extract (osteoclast extract) and the like, and these may be combined.
  • a commercially available product may be used as the osteoclastic extract, and the osteoclastic extract is extracted by a conventional method ⁇ for example, using an extraction solvent [for example, water, alcohol (methanol, ethanol, etc.), a mixture thereof, etc.]]. It can also be obtained by subjecting to extraction at ordinary temperature or under heating by a conventional method or a method according thereto.
  • an extraction solvent for example, water, alcohol (methanol, ethanol, etc.), a mixture thereof, etc.
  • a part having a high content or concentration of component (A) may be separated or fractionated.
  • an aqueous solvent extract of osteoclast for example, an extract using water, a mixed solvent of water and alcohol as an extraction solvent
  • an alcohol for example, n-butanol and the like having 3 or more carbon atoms (for example, n-butanol)
  • Processed products obtained by separation or fractionation by extraction or the like with an alcohol having about 4 to 6 carbon atoms often contain a high content of component (A) containing naringenin. You may use a processed material suitably.
  • the osteoclastic prosthesis may be used as it is or after being crushed (crushed).
  • the extract may be further subjected to concentration and drying (room temperature drying, freeze drying, etc.).
  • the form of the osteoclastic component is not particularly limited, but may be, for example, powder (or powder).
  • Ezokogi component (B) examples of the Ekokogi component (B) include Ezoukogi, Ezoukogi extract (Ezoukogi extract), and the like.
  • Ezoukogi scientific name: Eleutherococcus senticosus, Acanthopanax senticosus (Rupr. May be used, these may be used in combination, or the whole plant may be used.
  • At least the leaves of Ezokogi may be suitably used.
  • the Ekokogi extract may be a commercially available product or can be obtained by extracting Ezokogi by a conventional method.
  • the extraction solvent examples include water, alcohol [eg, alkanol (eg, C 1-4 alkanol such as methanol, ethanol, isopropanol, n-butanol), polyol (eg, ethylene glycol, propylene glycol, 1,3-butylene]. Glycol, glycerin, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, diethyl ether, etc.), esters (eg, ethyl acetate, etc.) and the like. You may use an extraction solvent individually or in combination of 2 or more types. Typical extraction solvents include water, alcohol (such as ethanol), a mixed solution thereof, and the like.
  • alkanol eg, C 1-4 alkanol such as methanol, ethanol, isopropanol, n-butanol
  • polyol eg, ethylene glycol, propylene glycol, 1,
  • Extraction temperature and extraction time are not particularly limited and can be appropriately selected according to the extraction solvent, extraction method, and the like.
  • the elephant may be subjected to an appropriate treatment (pulverization treatment, heat treatment, drying treatment, etc.) as necessary.
  • the extract may be further subjected to concentration and drying (room temperature drying, freeze drying, etc.).
  • the form of the Ekokogi component is not particularly limited, but may be powdery (or powdery).
  • component (C) In the agent or composition of the present invention, component (A) and / or component (B) may be combined with diosgenins, dihydroxyvitamin D3, desonomin and the like. By combining with these components (hereinafter, these may be referred to as component (C)), the effects of the present invention may be realized more efficiently.
  • component (C) may be composed of at least diosgenins.
  • diosgenins include diosgenin, diosgenin derivatives, and salts thereof.
  • diosgenin derivative a compound in which the hydroxyl group at the C3 position of diosgenin is substituted, a compound having a substituent at the C2 position (or a compound having a hydrogen atom at the C2 position substituted), a compound having a substituent at the C4 position (or C4) Compound having a hydrogen atom at the position), a compound having a substituent at the C6 position (or a compound having the hydrogen atom at the C6 position substituted) [for example, ester derivatives of the hydroxyl group at the C3 position (for example, amino acid derivatives, aminosulfones) Acid derivatives, carbamate derivatives), halogenated derivatives of the hydroxyl group at the C3 position, etc.], and glycosides thereof.
  • diosgenin derivative examples include a compound represented by the following formula (I-1), a glycoside of diosgenin or a compound represented by the following formula (I-1), and the like.
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a substituent. However, when R 2 , R 3 and R 4 are hydrogen atoms, R 1 is hydroxyl. Not a group.
  • the substituent includes a hydrocarbon group ⁇ eg, alkyl group [eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group].
  • alkyl group eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group.
  • alkyl group such as pentyl group (eg C 1-12 alkyl group, preferably C 1-8 alkyl group)], cycloalkyl group (eg cyclopentyl group, cyclohexyl group, cycloheptyl) Group, a C 4-10 cycloalkyl group such as a cyclooctyl group, preferably a C 5-8 cycloalkyl group), an aralkyl group (for example, a C 6-10 aryl C 1-4 alkyl group such as a benzyl group or a phenethyl group) Saturated with a polycyclic aliphatic hydrocarbon group (for example, a decalinyl group, a norbornyl group, an adamantyl group, a dimethyladamantyl group, etc.) Saturated aliphatic hydrocarbon group; an aryl group (e.g., phenyl group, a to
  • R a is a hydrocarbon group (eg, the exemplified hydrocarbon group such as an alkyl group), and R b is a hydrogen atom or a hydrocarbon group (eg, the exemplified hydrocarbon group such as an alkyl group).
  • R c is a sugar (or sugar chain or sugar residue)
  • R d is an alkylene group (eg, C 2-4 alkylene group such as ethylene group, propylene group, trimethylene group, etc.)
  • R e is a hydrogen atom, hydroxyl group A group or a hydrocarbon group (for example, the above exemplified hydrocarbon group such as an alkyl group (such as a methyl group))
  • k represents an integer of 2 or more (for example, 2 to 10)
  • R a and R b are the same Or they may be different groups, and when R b is plural, they may be the same or different.
  • the hydrocarbon group may further have a substituent.
  • the substituent is not particularly limited, but includes the above-exemplified substituents, for example, an oxygen atom-containing group (for example, a hydroxyl group, a carboxyl group, a group —OR a , a group —O—CO—R a, etc.), a nitrogen atom-containing group A group (for example, an amino group, a group —NR a R b ), a sulfur atom-containing group (for example, a mercapto group, a group —SR a , a sulfo group, a group —SO 2 —R b, etc.).
  • an oxygen atom-containing group for example, a hydroxyl group, a carboxyl group, a group —OR a , a group —O—CO—R a, etc.
  • a nitrogen atom-containing group A group for example, an amino group, a group —NR a R
  • the hydrocarbon group may have these substituents alone or in combination of two or more.
  • the number of substituents may be 1 or more, for example, 1 to 10 (eg, 1 to 8), preferably 1 to 6 (eg, 1 to 4), Preferably, it may be about 1 to 3.
  • R 1 When R 1 is a substituent, representative R 1 includes, for example, a hydrocarbon group [eg, alkyl group (eg, group — (CH 2 ) n —CH 3 ), cycloalkyl group, aralkyl group, etc.] , Heteroatom-containing groups ⁇ eg oxygen atom-containing groups [eg hydroxyl groups, groups —O— (CH 2 ) n —CH 3 , groups —O— (CH 2 ) m —NH 2 , groups —O— (CH 2 ) m —COOH, group —O— (CH 2 ) m —SO 3 H, group —O—CO— (CH 2 ) n —CH 3 , group —O—CO—NH— (CH 2 ) n —CH 3 , group —O—CO—NR— (CH 2 ) n —CH 3 , group —O—CO—NH—CH (R b ) —COOH, group
  • m is an integer of 1 or more (eg, 1 to 10, preferably 1 to 4, more preferably 1 or 2), and n is an integer of 0 or more (eg, 0 to 10, preferably 0 to 2). 7) and R b is the same as the above [that is, a hydrogen atom or a hydrocarbon group (for example, an alkyl group, etc.)].
  • examples of the substituent include the same substituents as those exemplified in the section of R 1 .
  • typical examples of the substituent include an oxygen atom-containing group, a nitrogen atom-containing group, a sulfur atom-containing group, an amino acid group, and a halogen atom.
  • R 3 is a substituent, typical substituents include a halogen atom.
  • combinations of R 1 to R 4 are not limited, and all combinations are included.
  • Typical combinations of R 1 to R 4 include, for example, the following combinations. (1) A combination in which R 1 is a substituent other than a hydroxyl group, and R 2 to R 4 are hydrogen atoms. (2) R 1 is a substituent other than a hydroxyl group, R 2 is a substituent, R 3 and R 4 are hydrogen.
  • diosgenin derivatives include, for example, the following formula (II) (3 ⁇ , 25R) -3- (2-aminoethanoyloxy) -spirost-5-ene ⁇ (3 ⁇ , 25R) -3- (2-Aminoethanoyloxy) -spirost-5-ene ⁇ , represented by the following chemical formula ( III) (3 ⁇ , 25R) -3-fluorospirost-ene ⁇ (3 ⁇ , 25R) -3-Fluorospirost-5-ene ⁇ represented by the formula (3 ⁇ , 25R) -3- (2-aminoethylsulfonyloxy) -Spirost-5-ene ⁇ (3 ⁇ , 25R) -3- (2-Aminoethylsulfonyl-oxy) -spirost-5-ene ⁇ , (3 ⁇ , 25R) -3- (2-aminopropylsulfonyloxy) -spirost-5 -Ene, (3 ⁇ , 25
  • glycoside examples include diosgenin or a compound in which R 1 is a hydroxyl group in the above formula (I-1) and a sugar (such as the sugar exemplified above) is bonded to a hydroxy group (for example, diosine).
  • salts include hydrohalides (for example, hydrofluorates, hydrochlorides, hydrobromides, hydroiodates, etc.) and inorganic acid salts.
  • hydrohalides for example, hydrofluorates, hydrochlorides, hydrobromides, hydroiodates, etc.
  • inorganic acid salts include hydrohalides (for example, hydrofluorates, hydrochlorides, hydrobromides, hydroiodates, etc.) and inorganic acid salts.
  • organic carboxylates eg acetate, oxalate, maleate, tartrate, fumarate, citric acid Acid salts
  • organic sulfonates eg methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.
  • amino acid salts eg aspartic acid) Salt, glutamate, etc.
  • diosgenins include diosgenin, compounds represented by the above formula (I-1), diosin, and salts thereof.
  • Particularly preferred diosgenins include diosgenin, a compound represented by the formula (II), a compound represented by the formula (III), diosine, and salts thereof.
  • the agent or composition of this invention should just contain any one of a component (A) and a component (B), and may combine a component (A) and a component (B). Usually, in the composition of this invention, you may combine a component (A) and a component (B). By combining the component (A) and the component (B), it is easier to obtain a memory improvement effect and the like.
  • a component (A) and a component (B) are good also as another agent or a composition, and the agent (A) containing a component (A) and a component (B) ( A mixture) or a composition may be used.
  • the said ratio is a ratio of an active ingredient (or solid content) conversion.
  • agent or composition is not particularly limited, and component (A) and / or component (B) may be used as an agent (for example, powder) or composition as it is, and other components (carrier, excipient, etc.). You may formulate with it.
  • excipients for example, excipients, binders, disintegrants, coating agents, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants,
  • a pH adjusting agent, preservative, antioxidant and the like can be used, and it can be formulated by a conventional method by incorporating components generally used as a raw material of the formulation.
  • the component (carrier) used for the formulation is not particularly limited, but for example, animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; octyldodecyl myristate, myristic acid Ester oil such as isopropyl; Higher alcohol such as cetostearyl alcohol and behenyl alcohol; Silicone resin; Silicone oil; Polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, poly Surfactants such as oxyethylene polyoxypropylene block copolymer; hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol Water-soluble polymers such as ethanol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydr
  • excipients examples include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.
  • binder examples include polyvinyl alcohol, gelatin, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, corn starch and the like.
  • disintegrant examples include corn starch, low-substituted hydroxypropylcellulose, crospovidone, crystalline cellulose, precipitated calcium carbonate, croscarmellose sodium, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium and the like.
  • lubricant examples include magnesium stearate, talc, polyethylene glycol, light anhydrous silicic acid, sucrose fatty acid ester, and the flavoring agents include cocoa powder, menthol, aroma powder, mint oil, dragonfly, For example, cinnamon powder is used.
  • agent or composition of the present invention may be further combined with another component useful for improving neurological diseases and memory as long as the effects of the present invention are not impaired.
  • another component useful for improving neurological diseases and memory as long as the effects of the present invention are not impaired.
  • the aspect used separately from an agent or a composition other than the aspect contained in an agent or a composition is mentioned.
  • Examples of the form (dosage form) of the agent or composition of the present invention include tablets, powders, fine granules, granules, dry syrups, coated tablets, orally disintegrating tablets, chewable tablets, capsules, soft capsules, and syrups.
  • Agent oral solution, troche, jelly, inhalant, suppository, injection, ointment, eye drop, eye ointment, nasal drop, ear drops, poultice, lotion, external solution, spray, External aerosols, creams, gels, tapes, buccal tablets, sublingual tablets, vaginal suppositories, vaginal tablets, rectal soft capsules and the like can be mentioned.
  • the administration (taking) form of the agent or composition of the present invention is not particularly limited, and may be oral administration or parenteral administration.
  • Parenteral administration includes, for example, rectal administration, nasal administration, pulmonary administration, injection administration (eg, intravenous administration, intrathecal administration, intraepidural administration, intramuscular administration, subcutaneous administration, intraperitoneal administration)
  • Intraarterial administration eg, intravenous administration, intrathecal administration, intraepidural administration, intramuscular administration, subcutaneous administration, intraperitoneal administration
  • a typical administration form is oral administration.
  • component (A) and / or component (B) contained in the agent or composition of the present invention is not particularly limited, and is preferably a dose sufficient to obtain a desired effect.
  • the dose varies depending on, for example, the degree of symptom, age, sex, body weight, dosage form, salt type, specific type of disease, etc., but usually per day, component (A) and / or Component (B) may be about 0.01 to 100 mg / kg, preferably about 0.1 to 10 mg / kg, more preferably about 0.5 to 5 mg / kg.
  • the dose (intake, dose) of component (A) is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, more preferably 0.5 to 5 mg / kg per day. It may be a degree.
  • the dosage (intake, dose) of the osteoclastic extract is 10 to 2000 mg / kg, preferably 20 to 1000 mg / kg, more preferably 50 to 100 per day. It may be about 800 mg / kg (for example, 100 to 700 mg / kg).
  • the dose (intake, dose) of component (B) is 10 to 2000 mg / kg, preferably 20 to 1000 mg / kg, more preferably 50 to 800 mg / kg per day ( For example, it may be about 100 to 700 mg / kg).
  • the dose (intake, dose) of the component (C) is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg per day. More preferably, it may be about 0.5 to 5 mg / kg.
  • Administration may be divided once or multiple times.
  • kit comprising a container such as a pack or a dispenser device that may contain one or more unit dosage forms containing component (A) and / or component (B). Good.
  • kits may be composed of a container containing an agent or composition containing component (A) and a container containing an agent or composition containing component (B).
  • kits typically include containers for containing separate agents or compositions, such as split bottles or split foil packets, but include the separate compositions in a single unsplit container. You can also. Kit forms are particularly useful when different components are administered in different dosage forms, when separate components are administered at different dosage intervals, or when the combined individual components need to be titrated by the prescribing physician. is there.
  • Packs can include, for example, metal or plastic foil, blister packs and the like.
  • Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.).
  • Blister packs generally consist of a sheet of relatively hard material covered by a foil of transparent plastic material.
  • recesses are formed in the plastic foil. These indentations are tailored to the size and shape of the individual tablets or capsules to be packed.
  • the tablet or capsule is then placed in the recess and the sheet of relatively hard material is sealed against the plastic foil at the foil surface opposite to the direction in which the recess was formed.
  • the strength of the sheet is preferably such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess so that an opening is formed in the sheet at the location of the recess. Tablets or capsules can be removed through the opening.
  • Package or dispenser device can be accompanied by package inserts, product inserts, etc. for administration.
  • Containers such as packs or dispensers can be adapted to the notifications of government agencies and authorities that regulate the manufacture, use or sale of medicines.
  • the present invention includes foods and drinks containing the component (A), the component (B) (and other components such as the component (C)) (that is, foods and drinks containing the agent or composition).
  • foods and drinks containing the component (A), the component (B) (and other components such as the component (C)) that is, foods and drinks containing the agent or composition).
  • preferred embodiments of the component (A) and the component (B), the ratio thereof, and the like are the same as described above.
  • foods and drinks also include health foods such as foods for specified health use and foods with nutrient function specified by the Ministry of Health, Labor and Welfare.
  • Nutritional supplements feed, food additives, and the like are also included in the food and drink of the present invention.
  • the food and drink may be food or drink for a specific subject [for example, for elderly people, patients or patients (for example, for patients having a neurological disease (such as the above-described neurological diseases)]). Good.
  • component (A) and / or the component (B) In order to use the component (A) and / or the component (B) in foods and drinks, it is necessary to produce foods and drinks as they are or together with various nutritional components and the like in raw materials for foods and drinks such as processed meat and soft drinks. it can.
  • the components (A) and / or (B) are used as health foods, dietary supplements, etc., for example, using conventional means, tablets, capsules (soft capsules, hard capsules, etc.), powders, granules, liquids (Suspensions, syrups, etc.), emulsions, jellies, sticks, etc.
  • the tablet includes a disintegrating tablet (orally disintegrating tablet).
  • the food and drink may contain a food additive (food additive) as long as it contains bone fracture supplement or an extract of bone fracture supplement.
  • a food additive for example, excipient
  • fillers for example, wheat starch, corn starch, cellulose, lactose, sucrose, mannitol, sorbitol, xylitol, pregelatinized starch, casein, magnesium aluminate silicate, Calcium silicate, etc.
  • binder eg, pregelatinized starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • disintegrant eg, cellulose, hydroxypropylcellulose, corn starch, etc.
  • fluidizing agent eg, light anhydrous silicic acid
  • oils eg, vegetable oils such as soybean oil, sesame oil, olive oil, linseed oil, sesame oil, rapeseed oil, coconut oil, corn oil, etc.
  • nutrients
  • Food additives may be used alone or in combination of two or more, and in particular, two or more may be used.
  • two or more components for example, two or more components selected from the components classified as excipients
  • the additive may be a combination of different additives.
  • At least two or more additives selected from excipients, binders, and disintegrants may be used.
  • the food or drink is not particularly well-maintained.
  • food e.g., noodles (such as soba, udon, Chinese noodles, instant noodles), Confectionery (cake, candy, gum, chocolate, snacks (potato chips, etc.), biscuits, cookies, gummy, jelly, jam, butter, cream (cream puffs, cakes, etc.), breads, marine or livestock processed foods (kamaboko) , Ham, sausage, etc.), dairy products (processed milk, fermented milk, etc.), fats and oils and processed foods (salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, dressing, etc.), seasonings (sauce, sauce, etc.) , Retort food (curry, stew, rice cake, porridge, miscellaneous food, etc.), frozen dessert (ice cream, sha Bet, etc. shaved ice), fried (cro
  • the amount of component (A) and / or component (B) in the above-mentioned food and drink varies depending on the addition form and administration form, and can be selected from a wide range, for example, 0.001 to 90% by weight, preferably 0. 001 to 80% by weight, more preferably 0.1 to 70% by weight (eg 1 to 50% by weight), usually 0.01 to 50% by weight (eg 0.1 to 30% by weight) Also good.
  • the proportion of the bone crush extract is 1 to 90% by weight, preferably 10 to 70% by weight, more preferably about 20 to 50% by weight. May be.
  • the ratio of the extract is, for example, 1 to 90% by weight, preferably 10 to 70% by weight, more preferably about 20 to 50% by weight. May be.
  • the proportion of the component (C) is, for example, 0.001 to 90% by weight, preferably 0.001 to 80% by weight, more preferably 0.1 to 70% by weight (for example, 1 to 50% by weight), usually about 0.01 to 50% by weight (for example, 0.1 to 30% by weight), or about 1 to 90% by weight It may be.
  • the dose (or intake or dose) of component (A) and / or component (B) (and component (C)) can be selected from the same range as described above.
  • the bone crushing extract (bone crushing water extraction) used what was obtained as follows.
  • the object recognition memory test was performed as follows. ⁇ Object recognition memory test>
  • the object recognition memory test is a test using a habit of showing interest in new things by animals. That is, in the test stage, it is a test for confirming whether or not the object seen in the training stage is remembered.
  • the test was performed as described in the literature (Int J Neurosci, 121, pp.181-190, 2011. and Int J Neurosci, 121, pp.641-648, 2011.). Specifically, it was performed as follows.
  • the test was conducted in a relatively well-lit room (approximately 100 lux). Appropriate time intervals between the training phase and the test phase were determined in advance by testing with different groups of mice. There are no landmarks on the inner wall of the open field box under test.
  • the training phase place two identical objects in the field and let them search for 10 minutes.
  • one of the objects is replaced with a new object, but the place is not changed, and a 10-minute exploratory action is performed.
  • the increase in the number of times the mouse performs an exploratory action with interest in the replaced new object is used as an index of the object memory ability.
  • the ratio (%) of the number of searches for a new object with respect to the total search time is calculated as a search index (Preference index).
  • Example 1 Naringenin and naringenin-7'-O-glucuronide, one of the glycosides of naringenin, were synthesized in order to investigate the activity against nerve cells. First, projections on normal cortical neurons The extension action was examined. On the third day of culture of primary cultured mouse cerebral cortical neurons, each compound was treated at a concentration of 0.01, 0.1, 1, 10 ⁇ M, and after 4 days, the cells were fixed, and then axons (pNF ⁇ The length per cell (H positive) was examined by immunostaining.
  • Example 2 In Example 1, in addition to the synthesized naringenin and naringenin-7′-O-glucuronide, naringenin-4′-O-glucuronide, which is a glycoside of naringenin, was synthesized, and axon of A ⁇ (25-35) was synthesized. The stretching action was examined as follows.
  • osteoprosthesis known to contain naringenin was examined.
  • Example 3 After the novel object recognition test, each mouse was anesthetized and transcardially perfused with chilled saline. The whole brain was carefully removed from the skull, soaked in 4% paraformaldehyde overnight, then soaked in 30% sucrose-PBS and stored at ⁇ 30 ° C. Brains were cut into 20 ⁇ m continuous coronal sections using a cryostat (CM3050S, Leica, Heidelberg, Germany).
  • Fluorescence images of axons and A ⁇ (1-40 / 42) were taken at 324 ⁇ m ⁇ 430 ⁇ m using a fluorescence microscope (BX-61).
  • the area of extracellular amyloid plaques was measured using image analysis software ImageJ (http://rsbweb.nih.gov/ij).
  • ImageJ image analysis software
  • the bone replenishment extract was dissolved in physiological saline and orally administered once daily to 5XFAD mice (6-8 months old, male and female) at a dose of 500 mg / kg / day for 31 days.
  • the amount of the drug solution to be administered orally was 10 ml / kg body weight.
  • amyloid plaques are not observed in wild-type mice in any part of the prefrontal cortex, periorbital cortex, hippocampal CA1, and hippocampal dentate gyrus, whereas 5 ⁇ FAD mice It was increasing.
  • the amyloid plaque area significantly decreased in the osteoclastic rehydration extract 500 mg / kg administration group.
  • the degenerated axon was wild in any part of the prefrontal cortex, periolfactory cortex, hippocampal CA1, and hippocampal dentate gyrus. It was not observed in type mice, but increased in 5XFAD mice. In the osteoclastic rehydration extract 500 mg / kg administration group, a tendency to decrease this was shown.
  • Example 4 The bone replenishment extract was dissolved in physiological saline and orally administered to 5XFAD mice (45 weeks old, male) once a day at a dose of 500 mg / kg / day.
  • 5XFAD mice 45 weeks old, male
  • a 5XFAD mouse group 45 weeks old, male
  • a wild type mouse group 45 weeks old, male
  • the amount of drug solution to be administered orally was 10 ml / kg body weight.
  • the administration period was 22 days.
  • An object recognition memory test was performed on these mice, and after confirming that a memory improving effect was observed in the bone-fed rehydration extract administered group, the cerebral cortex of the mice was extracted after refluxing and lysate was prepared.
  • the direct binding protein search experiment of the osteoclast rehydration extract found the involvement of Collapsin response mediator protein-2 (CRMP2, also known as dihydropyrimidinase-related protein 2, TOAD-64) protein prior to this example.
  • CRMP2 Collapsin response mediator protein-2
  • the degree of CRMP2 phosphorylation in cerebral cortical lysate was examined by Western blotting.
  • the antibody used was an antibody that detects phosphorylation of threonine of the 514th amino acid of CRMP2.
  • CRMP2 phosphorylation was enhanced in the 5XFAD mouse solvent-administered group compared to wild-type mice, whereas CRMP2 phosphorylation was significantly decreased in the 5XFAD mouse administered with the crushed water extract. did. Reduction of CRMP2 phosphorylation has already been recognized as a mechanism that leads to promotion of axonal extension. Therefore, suppression of CRMP2 phosphorylation in the mouse brain by administration of a bone replenishing water extract is associated with axonal elongation and It is clear that this is part of the mechanism of memory enhancement.
  • Example 5 The components contained in the osteoclastic prosthesis were analyzed, and which components can contribute to axonal extension was examined as follows.
  • the bone replenishing water extract was dissolved in sterilized purified water.
  • Mouse cerebral cortical neurons were prepared from embryonic day 14 ddY mice.
  • the crushed rehydration extract was further fractionated into a petroleum ether fraction, an ethyl acetate fraction, an n-butanol fraction, and a water-soluble fraction.
  • the axon density was significantly decreased in A ⁇ 25-35 cells compared to A ⁇ 25-35 untreated cells.
  • Axon extension tendency was observed in all fractions, but axons were significantly extended especially by the post-treatment of the n-butanol fraction (10 ⁇ g / mL).
  • Example 6 The n-butanol fraction obtained in Example 4 was analyzed in detail, and the components that can contribute to axonal extension at the compound level were examined as follows.
  • n-butanol fraction was subdivided with silica gel to isolate five compounds, which were naringenin (1), neoeriocitrin (2), 5,7-dihydroxychromone-7-O-neohe It was identified from the results of LC-MS mass analysis that it was spidoside (4) and protocatechuic acid (5).
  • the LC-MS chart of the n-butanol fraction is shown in FIG. 13, and the structure of each identified compound is shown in the following formula.
  • a ⁇ 10 ⁇ M A ⁇ (25-35) was treated on the 3rd day of culture of primary cultured mouse cerebral cortical neurons, and 3 days later, 5 compounds each were treated at a concentration of 1 or 10 ⁇ M. After fixing the cells one day later, the length per cell of axons (pNF-H positive) and dendrites (MAP2 positive) was examined by immunostaining.
  • the axon density was significantly decreased in the A ⁇ 25-35 cells compared to the A ⁇ 25-35 untreated cells, but the treatment with the compounds 1 to 5 extended the axons. .
  • neoeriocitrin compound 2
  • compound 4 which is a glycoside of caffeic acid
  • Example 7 Dissolve bone replenishment extract in physiological saline and administer once a day at a dose of 500 mg / kg / day, or dissolve elephant leaf water extract in physiological saline once a day as 500 mg / kg / day, Alternatively, a bone replenishing water extract (500 mg / kg / day) and an Ekogi leaf water extract (50 mg / kg / day) were orally administered to 5XFAD mice once a day at the same time.
  • a bone replenishing water extract 500 mg / kg / day
  • an Ekogi leaf water extract 50 mg / kg / day
  • Ezoukogi leaf extract was used by freeze-drying a filter obtained by infiltrating the leaves of Eleutherococcus senticosus in the family Urugiaceae into water at 85 degrees for 30 minutes and filtering.
  • mice 5XFAD mice were female, 27-56 weeks old, and wild-type mice in the control group were female, 52 weeks old.
  • the amount of the drug solution to be administered orally was 10 mL / kg body weight.
  • the administration period was 15 days.
  • An object recognition memory test was performed on these mice. The interval between the training stage and the test stage was set to two conditions of 1 hour (Test 1) and 24 hours (Test 2).
  • Ezoukogi leaf water extract was dissolved in physiological saline and administered orally to normal mice (ddY, male, 7 weeks old) once a day at a dose of 500 mg / kg / day.
  • the amount of the drug solution to be administered orally was 10 mL / kg body weight.
  • the administration period was 27 days.
  • Ezoukogi leaf water extract was used by freeze-drying a leaf of Eleutherococcus senticosus belonging to the family Urugiaceae infiltrated with water at 85 degrees for 30 minutes. An object recognition memory test was performed on these mice. Training was performed on the 24th day after administration, and the test was performed on the 27th day after administration. The training and test interval was 72 hours.
  • an agent or composition useful for improving or improving memory ability and cognitive function can be obtained.

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Abstract

Provided is an agent that is effective, inter alia, for improving memory and cognitive function. The agent is composed of: at least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof; and a Siberian ginseng component (B).

Description

神経回路網の再構築・賦活剤Neural network reconstruction / activator
　本発明は、神経疾患の治療、記憶力の向上、神経軸索の伸展などに有用な剤、組成物、及び食品に関する。 The present invention relates to agents, compositions, and foods useful for the treatment of neurological diseases, improvement of memory ability, extension of nerve axons, and the like.
　ナリンゲニンは、グレープフルーツなどに含まれる成分であり、抗酸化作用などを有する成分であると考えられている。 Naringenin is a component contained in grapefruit and the like, and is considered to be a component having an antioxidant effect and the like.
　なお、近年、ナリンゲニンが、アルツハイマー病の治療に有効であるとの報告がなされたが（非特許文献１）、そのメカニズムや作用機序については明らかになっていない。 In recent years, it has been reported that naringenin is effective in the treatment of Alzheimer's disease (Non-Patent Document 1), but its mechanism and action mechanism have not been clarified.
　また、生薬の骨砕補（コツサイホ）は、ウラボシ科ハカマウラボシの根茎であり、ナリンゲニンを含むことが知られているが、骨砕補の伝統的効能としては、接骨、止血、駆お血、消炎、筋骨の疼痛、耳鳴り、歯痛などが知られている（例えば、特許文献１）ものの、骨砕補やその有効成分と、神経回路との関係については全く知られていない。 In addition, the herbal medicine bone crush (Katsusaiho) is a rhizome of the sea urchinaceae Hakamauraboshi, and is known to contain naringenin, but the traditional effects of bone crushing are as follows: Although anti-inflammation, muscular bone pain, tinnitus, toothache and the like are known (for example, Patent Document 1), the relationship between osteoclastic prosthesis and its active ingredient and the neural circuit is not known at all.
　一方、エゾウコギは、北海道などに自生するウコギ科の植物であり、強壮作用などを有するものとして考えられている。 On the other hand, Ezokogi is a plant belonging to the family Uleaceae that grows naturally in Hokkaido, etc., and is considered to have a tonic effect.
特開２００５－３３０２９０号公報JP 2005-330290 A
　本発明の目的は、神経疾患の予防・治療、記憶力や認知機能の向上・改善などに有用な新規な剤、組成物、及び飲食品を提供することにある。 An object of the present invention is to provide a novel agent, composition, and food and drink useful for prevention / treatment of neurological diseases, improvement / improvement of memory ability and cognitive function, and the like.
　アルツハイマー病、老年性痴呆、脳血管性痴呆、パーキンソン病などの神経変性疾患は、病因は異なるがいずれも神経回路網の破綻により、記憶・認知に障害を呈する症候を指す。これら有効な治療法の無い疾患に対し、既に神経回路網の障害が進行している状態からでも、神経機能を正常に近づけることのできる治療が、真に求められている。しかも患者の立場を考えると、手術を要する神経細胞移植や遺伝子治療よりは、負担の少ない投薬による治療法がより望ましい。そこで、神経細胞が障害を受けている時、あるいは受けた後からでも神経回路網を再生する薬物の開発が望まれる。 神 経 Neurodegenerative diseases such as Alzheimer's disease, senile dementia, cerebrovascular dementia, and Parkinson's disease all have different etiologies, but all indicate symptoms that impair memory and cognition due to the breakdown of the neural network. For these diseases for which there is no effective therapeutic method, there is a real need for a treatment that can bring the nerve function closer to normal even when the nerve network has already been impaired. Moreover, considering the patient's standpoint, treatment with less burden is more desirable than nerve cell transplantation and gene therapy that require surgery. Therefore, it is desired to develop a drug that regenerates a neural network even when a nerve cell is damaged or after it has been damaged.
　また、筋萎縮性側索硬化症は、大脳皮質運動野の運動ニューロンと脊髄、脳幹の運動ニューロンが脱落することによって手足が動かなくなる難病であり、有効な治療法は存在しない。さらに、大脳皮質運動野の運動ニューロンは、脳出血、脳梗塞、脳腫瘍、脳外傷などによっても障害を受け、身体の麻痺に繋がる。また、外傷性の脊髄損傷では、脊髄の運動ニューロンが障害を受けることにより四肢麻痺が生じる。さらに、多発性脳梗塞は、自己免疫の異常活性化によっておこる中枢神経の脱髄疾患であるが、病態の進行に伴って軸索の脱落が生じ、それが神経回路網の不可逆的な機能不全につながる。いずれの場合も神経回路網の破綻による機能障害であるが、生き残った神経細胞を賦活化して再び神経回路網を形成させることが出来れば、機能の回復が期待できる。 Also, amyotrophic lateral sclerosis is an intractable disease in which the limbs of the cerebral cortex motor cortex and the motor neurons of the spinal cord and brainstem drop off, and there is no effective treatment. Furthermore, motor neurons in the cerebral cortex motor cortex are also damaged by cerebral hemorrhage, cerebral infarction, brain tumor, brain trauma, etc., leading to paralysis of the body. Traumatic spinal cord injury also results in limb paralysis due to damage to spinal motor neurons. In addition, multiple cerebral infarction is a demyelinating disease of the central nervous system caused by abnormal activation of autoimmunity, but axonal loss occurs as the disease progresses, which is an irreversible malfunction of the neural network. Leads to. In either case, it is a dysfunction due to the breakdown of the neural network, but if the surviving nerve cells are activated to form a neural network again, recovery of the function can be expected.
　本発明者は、上記のような事情に鑑み、変性して機能不全になっている脳内の神経軸索の萎縮・変性を改善させる優れた活性を示す成分を生薬等に求め、その作用機序を探ることで、従来の神経変性疾患の病態解析からでは予想できないような、新たな組成物を見出すことができるという考えの下、研究を進めてきた。 In view of the circumstances as described above, the present inventor asked herbal medicines for a component exhibiting excellent activity for improving the atrophy / degeneration of nerve axons in the brain that has become degenerated and dysfunctional. We have been conducting research based on the idea that by exploring the introduction, we can find new compositions that could not be expected from the pathological analysis of conventional neurodegenerative diseases.
　その結果、ナリンゲニン等の特定の成分［さらには、このような特定の成分を含む生薬成分（骨砕補成分など）］やエゾウコギ成分が、神経突起の修復作用や記憶障害の改善に有効であることを見出した。そして、このような機能は、神経疾患の予防・治療にもつながるため、これらのことから、前記特定の成分やエゾウコギ成分（特にこれらを組み合わせた成分）が、神経疾患の予防・治療用途、記憶力や認知機能の改善用途、神経突起の修復・伸展用途などに有効であるという知見を得、この知見をもとにさらなる検討を重ね、本発明を完成した。 As a result, specific ingredients such as naringenin [and herbal medicine ingredients containing such specific ingredients (such as osteoclastic components)] and sorghum ingredients are effective in repairing neurites and improving memory impairment. I found out. Such functions also lead to the prevention and treatment of neurological diseases. Therefore, the specific component and the sorghum component (particularly a combination of these) are used for the prevention and treatment of neurological diseases, memory ability. The present inventors have obtained knowledge that it is effective for use in improving cognitive function and for repairing and extending neurites, and have further studied based on this knowledge to complete the present invention.
　すなわち、本発明の剤は、ナリンゲニン、エリオジクチオール、５，７－ジヒドロキシクロモン、コーヒー酸、プロトカテク酸、これらの配糖体、及びこれらの塩から選択された少なくとも１種の成分（Ａ）又はエゾウコギ成分（Ｂ）を含む。 That is, the agent of the present invention comprises at least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof. Contains Ezokogi component (B).
　このような本発明の剤は、特に、下記の（１）、（２）及び（３）から選択された少なくとも１つの用途に使用するための剤であってもよい。
（１）神経突起の修復及び／又は伸展（成長）
（２）記憶力及び／又は認知機能の向上又は改善
（３）神経疾患の予防及び／又は治療 Such an agent of the present invention may be an agent for use in at least one application selected from the following (1), (2) and (3).
(1) Neurite repair and / or extension (growth)
(2) Improvement or improvement of memory and / or cognitive function (3) Prevention and / or treatment of neurological diseases
　なお、このような本発明の剤には、通常、ナリンゲニンのみを有効成分として含み、アルツハイマー病の予防及び／又は治療のための剤を含まない場合が多い。 It should be noted that such an agent of the present invention usually contains only naringenin as an active ingredient and often does not contain an agent for the prevention and / or treatment of Alzheimer's disease.
　本発明の剤において、成分（Ａ）は、例えば、ナリンゲニン、ナリンゲニンの配糖体（例えば、ナリンギン、ナリンゲニングルクロニド）、及びこれらの塩から選択された少なくとも１以上の成分を含んでいてもよい。 In the agent of the present invention, the component (A) may contain, for example, at least one component selected from naringenin, a glycoside of naringenin (for example, naringin, naringen glucuronide), and salts thereof.
　また、本発明の剤は、成分（Ａ）を含有する成分として、骨砕補成分（骨砕補エキスなど）を含んでいてもよい。 In addition, the agent of the present invention may contain an osteoclastic component (such as an osteoclastic extract) as a component containing the component (A).
　本発明の剤は、成分（Ａ）と成分（Ｂ）とを組み合わせて用いてもよく、特に、成分（Ａ）及び成分（Ｂ）を含んでいてもよい。 The agent of the present invention may be used in combination of the component (A) and the component (B), and particularly may contain the component (A) and the component (B).
　このような組み合わせる態様において、本発明の剤は、成分（Ａ）として骨砕補エキスを含み、かつ成分（Ｂ）としてエゾウコギエキスを含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００程度である剤であってもよい。 In such a combination aspect, the agent of the present invention contains a bone crush extract as the component (A) and a carp extract as the component (B), and the ratio of the bone crush extract and the carp extract is the former / The latter (weight ratio) = 1 / 0.01 to about 1/100 may be used.
　また、本発明の剤は、さらに、ジオスゲニン類（ジオスゲニン、ジオシンなど）、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）を組み合わせてもよい。このような組み合わせる態様において、成分（Ｃ）は、成分（Ａ）と成分（Ｂ）と別の剤としてもよく、成分（Ａ）と成分（Ｂ）とを含む剤（合剤）としてもよい。

　このような剤において、成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合は、前者／後者（重量比）＝１／０．０１～１／１００程度であってもよい。 In addition, the agent of the present invention may further combine at least one component (C) selected from diosgenins (such as diosgenin and diosine), dihydroxyvitamin D3, and desonomin. In such a combination mode, the component (C) may be a different agent from the component (A) and the component (B), or may be an agent (mixture) containing the component (A) and the component (B). .

In such an agent, the ratio of the component (A) and / or the component (B) to the component (C) may be about the former / the latter (weight ratio) = 1 / 0.01 to 1/100. .
　本発明には、ナリンゲニン、エリオジクチオール、５，７－ジヒドロキシクロモン、コーヒー酸、プロトカテク酸、これらの配糖体、及びこれらの塩から選択された少なくとも１種の成分（Ａ）と、エゾウコギ成分（Ｂ）とを含む組成物も含まれる。このような組成物は、医薬組成物であってもよい。 The present invention includes at least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof, and an elephant component A composition containing (B) is also included. Such a composition may be a pharmaceutical composition.
　このような組成物において、成分（Ａ）は、例えば、ナリンゲニン、ナリンゲニンの配糖体（例えば、ナリンギン、ナリンゲニングルクロニド）、及びこれらの塩から選択された少なくとも１以上の成分を含んでいてもよい。 In such a composition, the component (A) may contain, for example, at least one or more components selected from naringenin, glycosides of naringenin (eg, naringin, naringen glucuronide), and salts thereof. .
　また、本発明の組成物は、成分（Ａ）を含有する成分として、骨砕補成分（骨砕補エキスなど）を含んでいてもよい。代表的な本発明の組成物には、成分（Ａ）として骨砕補エキスを含み、かつ成分（Ｂ）としてエゾウコギエキスを含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００である組成物などが含まれる。 In addition, the composition of the present invention may contain an osteoclastic component (such as an osteoclastic extract) as the component containing component (A). A typical composition of the present invention contains a bone crush extract as the component (A) and a carp extract as the component (B), and the ratio between the bone crush extract and the carp extract is the former / the latter ( (Weight ratio) = 1 / 0.01 to 1/100.
　また、本発明の組成物は、さらに、ジオスゲニン類（ジオスゲニン、ジオシンなど）、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）を組み合わせてもよい。このような組み合わせる態様において、成分（Ｃ）は、成分（Ａ）と成分（Ｂ）と別の組成物としてもよく、成分（Ａ）と成分（Ｂ）とを含む組成物としてもよい。
　このような組成物において、成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合は、前者／後者（重量比）＝１／０．０１～１／１００程度であってもよい。 Moreover, the composition of the present invention may further combine at least one component (C) selected from diosgenins (such as diosgenin and diosine), dihydroxyvitamin D3, and desonomin. In such a combination mode, the component (C) may be a composition different from the component (A) and the component (B), or may be a composition containing the component (A) and the component (B).
In such a composition, the ratio of the component (A) and / or the component (B) to the component (C) may be about the former / the latter (weight ratio) = 1 / 0.01 to 1/100. Good.
　本発明の組成物は、特に、下記の（１）、（２）及び（３）から選択された少なくとも１つの用途に使用するための組成物であってもよい。
（１）神経突起の修復及び／又は伸展（成長）
（２）記憶力及び／又は認知機能の向上又は改善
（３）神経疾患の予防及び／又は治療 In particular, the composition of the present invention may be a composition for use in at least one application selected from the following (1), (2) and (3).
(1) Neurite repair and / or extension (growth)
(2) Improvement or improvement of memory and / or cognitive function (3) Prevention and / or treatment of neurological diseases
　本発明には、前記剤（特に、成分（Ａ）と成分（Ｂ）とを組み合わせた剤）又は本発明の組成物を含有する飲食品も含まれる。 Included in the present invention are foods and drinks containing the above-mentioned agent (particularly, an agent in which component (A) and component (B) are combined) or the composition of the present invention.
　このような飲食品は、サプリメント、健康食品、機能性表示食品、栄養機能食品又は特定保健用食品であってもよい。 Such foods and drinks may be supplements, health foods, functional indication foods, nutritional functional foods, or foods for specified health use.
　また、本発明の飲食品は、骨砕補エキスを１～９０重量％含む飲食品であってもよく、エゾウコギエキスを１～９０重量％含む飲食品であってもよい。 In addition, the food or drink of the present invention may be a food or drink containing 1 to 90% by weight of the osteoclast extract, or a food or drink containing 1 to 90% by weight of the elephant extract.
　代表的な本発明の飲食品には、骨砕補エキスを１～９０重量％、エゾウコギエキスを１～９０重量％含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００である飲食品などが含まれる。 A typical food and drink product of the present invention contains 1 to 90% by weight of a bone crush extract and 1 to 90% by weight of an elephant extract, and the ratio of the osteocrush extract to the elephant extract is the former / the latter (weight ratio). ) = 1 / 0.01 to 1/100.
　このような飲食品は、ジオスゲニン類（ジオスゲニン、ジオシンなど）、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）を含んでいてもよい。このような飲食品において、成分（Ｃ）の割合は、例えば、１～９０重量％程度であってもよい。
　また、このような飲食品において、成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合は、前者／後者（重量比）＝１／０．０１～１／１００程度であってもよい。 Such a food or drink may contain at least one component (C) selected from diosgenins (such as diosgenin and diosin), dihydroxyvitamin D3, and desonomin. In such a food or drink, the proportion of component (C) may be, for example, about 1 to 90% by weight.
In such a food or drink, the ratio of component (A) and / or component (B) to component (C) is about the former / the latter (weight ratio) = 1 / 0.01 to 1/100. May be.
　本発明によれば、神経回路網を再構築及び／又は賦活できる。このような再構築や賦活は、通常、神経突起（軸索、樹状突起など）の修復及び／又は伸長（伸展）を伴う場合が多い。そのため、本発明の剤や組成物は、認知記憶機能の向上又は改善（亢進）をはじめ、軸索や樹状突起の変性や萎縮等を要因とする種々の神経疾患の予防、治療又は改善に有効である。 According to the present invention, the neural network can be reconstructed and / or activated. Such reconstruction and activation are usually accompanied by repair and / or extension (extension) of neurites (axons, dendrites, etc.). Therefore, the agent or composition of the present invention is useful for preventing, treating or improving various neurological diseases caused by degeneration or atrophy of axons and dendrites, as well as improvement or improvement (enhancement) of the cognitive memory function. It is valid.
　また、本発明の剤や組成物は、認知機能における記憶力の向上が認められることから、神経疾患にまで至っているか否かにかかわらず、記憶力の向上や改善を目的とした飲食品の配合成分などとしても有用である。 Moreover, since the improvement of the memory ability in the cognitive function is recognized in the agent and composition of the present invention, regardless of whether or not it leads to a neurological disease, the ingredients of the food and drink for the purpose of improving and improving the memory ability, etc. It is also useful.
図１は、正常大脳皮質神経細胞に対する骨砕補エキスおよび骨砕補成分による軸索伸展作用を示す図である。FIG. 1 is a diagram showing an axonal extension action by a bone crush extract and a bone crush component on normal cerebral cortical neurons. 図２は、大脳皮質神経細胞におけるＡβ（２５－３５）誘発の軸索萎縮に対して、骨砕補成分を後から処置した場合の軸索再伸展作用を示す図である。FIG. 2 is a diagram showing an axonal re-extension effect when a crushed prosthetic component is later treated against Aβ (25-35) -induced axonal atrophy in cerebral cortical neurons. 図３は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの前頭前皮質におけるアミロイドプラークの面積を示す図である。FIG. 3 is a diagram showing the area of amyloid plaques in the prefrontal cortex of 5XFAD mice administered with a bone fracture supplement for 31 days. 図４は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの前頭前皮質における変性した軸索終末部の面積を示す図である。FIG. 4 is a diagram showing the area of the degenerated axon terminal area in the prefrontal cortex of 5XFAD mice administered with the osteoclastic prosthesis for 31 days. 図５は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの嗅周囲皮質におけるアミロイドプラークの面積を示す図である。FIG. 5 is a diagram showing the area of amyloid plaques in the peri-olfactory cortex of 5XFAD mice to which the osteoclastic extract was administered for 31 days. 図６は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの嗅周囲皮質における変性した軸索終末部の面積を示す図である。FIG. 6 is a diagram showing the area of the degenerated axon terminal area in the perianptic cortex of 5XFAD mice administered with the osteoclastic extract for 31 days. 図７は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの海馬ＣＡ１領域におけるアミロイドプラークの面積を示す図である。FIG. 7 is a diagram showing the area of amyloid plaques in the hippocampal CA1 region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days. 図８は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの海馬ＣＡ１領域における変性した軸索終末部の面積を示す図である。FIG. 8 is a diagram showing the area of the degenerated axon terminal area in the hippocampal CA1 region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days. 図９は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの海馬歯状回領域におけるアミロイドプラークの面積を示す図である。FIG. 9 is a diagram showing the area of amyloid plaques in the hippocampal dentate gyrus region of 5XFAD mice to which the osteoclastic extract was administered for 31 days. 図１０は、骨砕補エキスを３１日間投与した５ＸＦＡＤマウスの海馬歯状回領域における変性した軸索終末部の面積を示す図である。FIG. 10 is a diagram showing the area of the degenerated axon terminal area in the hippocampal dentate gyrus region of 5XFAD mice administered with the osteoclastic prosthesis for 31 days. 図１１は、骨砕補エキスを２２日間投与した５ＸＦＡＤマウスの大脳皮質におけるＣＲＭＰ２の５１４番アミノ酸のスレオニンのリン酸化のレベルを示す図である。FIG. 11 is a diagram showing the level of phosphorylation of threonine of the 514th amino acid of CRMP2 in the cerebral cortex of 5XFAD mice administered with the osteoclastic extract for 22 days. 図１２は、大脳皮質神経細胞におけるＡβ（２５－３５）誘発の軸索萎縮に対して、骨砕補エキスの分画を後から処置した場合の軸索再伸展作用を示す図である。FIG. 12 is a diagram showing an axonal re-extension effect when a fraction of the osteoclastic extract is treated later against Aβ (25-35) -induced axonal atrophy in cerebral cortical neurons. 図１３は、骨砕補エキスのｎ－ブタノール画分のＬＣ－ＭＳのチャートを示す図である。FIG. 13 is a diagram showing an LC-MS chart of the n-butanol fraction of the osteoclastic extract. 図１４は、大脳皮質神経細胞におけるＡβ（２５－３５）誘発の軸索萎縮に対して、骨砕補エキスに含まれる化合物を後から処置した場合の軸索再伸展作用を示す図である。FIG. 14 is a diagram showing the axonal re-extension effect when a compound contained in the osteoclastic extract is later treated against Aβ (25-35) -induced axonal atrophy in cerebral cortical neurons. 図１５は、骨砕補エキス、またはエゾウコギ葉エキス、または骨砕補エキスとエゾウコギ葉エキスの合剤を１５日間投与した５ＸＦＡＤマウスにおける物体認知記憶試験結果を示す図である。FIG. 15 is a diagram showing the results of an object recognition memory test in 5XFAD mice administered with a bone crush extract, or an extract of Ekokogi leaves, or a combination of an osteoclastic extract and an extract of Ekokogi leaves for 15 days. 図１６は、エゾウコギ葉エキスを２７日間投与した正常マウスにおける物体認知記憶試験結果を示す図である。FIG. 16 is a diagram showing the results of an object recognition memory test in normal mice administered with Ezocogi leaf extract for 27 days.
＜剤・組成物＞
　本発明の剤又は組成物は、特定の成分（Ａ）又はエゾウコギ成分（Ｂ）を含む。 <Agent / Composition>
The agent or composition of the present invention comprises a specific component (A) or an sorghum component (B).
　このような本発明の剤又は組成物（さらには飲食品）は、神経回路網の再構築及び／又は賦活に有用である。 Such an agent or composition (and food or drink) of the present invention is useful for the reconstruction and / or activation of a neural network.
　具体的には、本発明の剤又は組成物は、神経突起［特に萎縮又は欠損した神経突起（軸索や樹状突起）］の修復や伸展（伸長）機能を有する場合が多い。
　また、本発明の剤又は組成物は、このような機能に付随してか、記憶力及び／又は認知機能の向上又は改善効果や、神経疾患の予防及び／又は治療効果を備えている場合が多い。 Specifically, the agent or composition of the present invention often has a function of repairing or extending (extending) neurites [particularly atrophy or deficient neurites (axons or dendrites)].
In addition, the agent or composition of the present invention is often associated with such a function, or has an effect of improving or improving memory ability and / or cognitive function, and an effect of preventing and / or treating a neurological disease. .
　そのため、本発明の剤又は組成物は、下記（１）、（２）、及び（３）から選択された少なくとも１つの用途に好適に使用してもよい。
（１）神経突起の修復及び／又は伸展（成長）
（２）記憶力及び／又は認知機能［特に、神経突起（軸索や樹状突起）の萎縮又は欠損に伴って低下した記憶力及び／又は認知機能］の向上又は改善
（３）神経疾患［特に神経突起（軸索や樹状突起）の萎縮又は欠損に伴う神経疾患］の予防及び／又は治療 Therefore, the agent or composition of the present invention may be suitably used for at least one application selected from the following (1), (2), and (3).
(1) Neurite repair and / or extension (growth)
(2) Improvement or improvement of memory ability and / or cognitive function [especially memory ability and / or cognitive function reduced due to atrophy or loss of neurites (axons or dendrites)] (3) Neurological diseases [especially nerves And / or treatment of neurological diseases associated with atrophy or loss of processes (axons and dendrites)
　上記（３）において、神経疾患としては、外傷性神経疾患であっても、神経変性疾患であってもよく、例えば、アルツハイマー病、認知症（非アルツハイマー型認知症、例えば、老年性認知症、脳血管性認知症、ピック病、前頭側頭型認知症、レビー小体型認知症、血管性認知症など）、パーキンソン病、ハンチントン病、脳挫傷、脊髄損傷、筋萎縮性側索硬化症、多発性脳梗塞などが挙げられる。 In the above (3), the neurological disease may be a traumatic neurological disease or a neurodegenerative disease. For example, Alzheimer's disease, dementia (non-Alzheimer type dementia such as senile dementia, Cerebrovascular dementia, Pick's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, etc.), Parkinson's disease, Huntington's disease, brain contusion, spinal cord injury, amyotrophic lateral sclerosis, multiple occurrences Include cerebral infarction.
　本発明の剤又は組成物は、これらのうち、１又は２以上の神経疾患を予防又は治療してもよい。 Of these, the agent or composition of the present invention may prevent or treat one or more neurological diseases.
　［成分（Ａ）］
　成分（Ａ）は、ナリンゲニン、エリオジクチオール、５，７－ジヒドロキシクロモン、コーヒー酸、プロトカテク酸、これらの配糖体［又はグリコシド（Ｏ－グリコシド）］、及びこれらの塩（特に薬学的に許容される塩）から選択された少なくとも１種である。 [Component (A)]
Component (A) consists of naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof [or glycosides (O-glycosides)], and salts thereof (especially pharmaceutically acceptable) Selected salt).
　配糖体を構成する糖としては、特に限定されず、単糖類［例えば、グルコース、ガラクトース、アピオース、ラムノース、キシロース、ウロン酸（グルクロン酸など）など］、二糖類（例えば、ルチノース、ネオヘスペリドース、ゲンチオビオースなど）、これらの糖が結合した糖などが挙げられる。 The sugar constituting the glycoside is not particularly limited, and is a monosaccharide [eg, glucose, galactose, apiose, rhamnose, xylose, uronic acid (glucuronic acid, etc.)], disaccharide (eg, rutinose, neohesperidose, etc.) , Gentiobiose, etc.), and sugars to which these sugars are bonded.
　配糖体は、１又は２以上の糖が結合していてもよい。 The glycoside may be bound with one or more sugars.
　具体的な配糖体としては、例えば、ナリンゲニン配糖体［例えば、ナリンゲニングルコシド（例えば、ナリンゲニン－７－グルコシド、ナリンゲニン－４－グルコシドなど）、ナリンゲニングルクロニド（例えば、ナリンゲニン－４－グルクロニド、ナリンゲニン－４－グルクロニドなど）、ナリンゲニンルチノシド（例えば、ナリンギンなど）など］、エリオジクチオール配糖体［例えば、エリオジクチオールルチノシド（例えば、ネオエリオシトリンなど）など］、５，７－ジヒドロキシクロモン配糖体［例えば、５，７－ジヒドロキシクロモンネオヘスペリドシド（例えば、５，７－ジヒドロキシクロモン－７－ネオヘスペリドシドなど）など］、コーヒー酸配糖体［例えば、コーヒー酸グルコシド（例えば、コーヒー酸－４－グルコシドなど）など］、プロトカテク酸配糖体［例えば、プロトカテク酸グルコシド（例えば、プロトカテク酸－３－グルコシドなど）など］などが挙げられる。 Specific glycosides include, for example, naringenin glycoside [eg, naringenin glucoside (eg, naringenin-7-glucoside, naringenin-4-glucoside, etc.), naringening glucuronide (eg, naringenin-4-glucuronide, naringenin- 4-glucuronide etc.), naringenin rutinosides (eg naringin etc.)], eriodictyol glycosides [eg eriodictyol rutinosides (eg neoeriocitrin etc.)], 5,7-dihydroxychromone Glucose [eg, 5,7-dihydroxychromone neohesperidoside (eg, 5,7-dihydroxychromone-7-neohesperidoside, etc.)], caffeic acid glycoside [eg, caffeic acid glucoside (eg, Caffeic acid-4-glu Sid, etc.), etc.], protocatechuic acid glycosides [e.g., protocatechuic acid glucoside (e.g., such as protocatechuic acid 3-glucoside), etc.] and the like.
　塩としては、特に限定されず、例えば、金属塩［例えば、アルカリ金属塩（例えば、リチウム塩、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例えば、マグネシウム塩、カルシウム塩）、周期表第１３族金属塩（例えば、アルミニウム塩）、遷移金属塩（例えば、亜鉛などの塩）など］、アンモニウム塩、アミン塩［例えば、アルキルアミン塩（例えば、トリメチルアミン塩、トリエチルアミン塩のトリアルキルアミン塩）、アルカノールアミン塩（例えば、モノエタノールアミン塩、トリエタノールアミン塩）、環式アミン塩（例えば、ピリジン塩）］などが挙げられる。 The salt is not particularly limited, and examples thereof include metal salts [for example, alkali metal salts (for example, lithium salt, sodium salt, potassium salt), alkaline earth metal salts (for example, magnesium salt, calcium salt), periodic table, etc. Group 13 metal salts (for example, aluminum salts), transition metal salts (for example, salts such as zinc), etc.] ammonium salts, amine salts [for example, alkylamine salts (for example, trialkylamine salts, trialkylamine salts of triethylamine salts) ), Alkanolamine salts (for example, monoethanolamine salts, triethanolamine salts), cyclic amine salts (for example, pyridine salts)] and the like.
　成分（Ａ）は、１又は２以上の成分を含んでいてもよい。成分（Ａ）が、２以上の成分を含む場合、基本骨格において共通する成分を２以上含んでいてもよく（例えば、ナリンゲニンとナリンゲニン配糖体を含むなど）、基本骨格が異なる成分を組み合わせて２以上含んでいてもよい（例えば、ナリンゲニンやその配糖体と、エリオジクチオールやその配糖体とを組み合わせて有するなど）。 Component (A) may contain one or more components. When component (A) contains two or more components, it may contain two or more components that are common in the basic skeleton (for example, including naringenin and naringenin glycoside), and combinations of components having different basic skeletons 2 or more may be included (for example, having a combination of naringenin or its glycoside and eriodictyol or its glycoside).
　これらのうち、成分（Ａ）は、代表的には、ナリンゲニン、ナリンゲニンの配糖体（ナリンギン、ナリンゲニングルクロニドなど）、及びこれらの塩から選択された少なくとも１以上の成分（これらをまとめてナリンゲニン類ということがある）を少なくとも含んでいてもよい。 Among these, component (A) is typically at least one component selected from naringenin, a glycoside of naringenin (naringin, naringen glucuronide, etc.), and salts thereof (collectively, naringenins) May be included) at least.
　なお、成分（Ａ）は、合成したものを用いてもよく、天然物由来であってもよい。なお、合成方法は、慣用の手法を利用できる。 The component (A) may be synthesized or derived from a natural product. As a synthesis method, a conventional method can be used.
　例えば、ナリンゲニンやナリンギンは、柑橘系植物（グレープフルーツ、はっさくなどのミカン科植物）などに含まれることが知られており、このような植物から成分（Ａ）を得てもよい。 For example, Naringenin and Naringin are known to be contained in citrus plants (citrus plants such as grapefruit and hassaku), and the component (A) may be obtained from such plants.
　特に、骨砕補（コツサイホ）には、ナリンゲニンなどに加えて、その他の成分（Ａ）を含んでいる場合が多く、これらを組み合わせて有することと相まってか、本発明の効果を有効に発現しやすい。 In particular, osteoclasts often contain other components (A) in addition to naringenin, etc., and in combination with these, the effects of the present invention are effectively expressed. Cheap.
　そのため、本発明の剤は、成分（Ａ）を含有する成分として、特に、骨砕補成分を含んでいてもよい。 Therefore, the agent of the present invention may contain a bone crush prosthetic component as a component containing the component (A).
　骨砕補成分としては、骨砕補、骨砕補の抽出物（骨砕補エキス）などが挙げられ、これらを組み合わせてもよい。 Examples of the osteoclastic component include osteoclastic prosthesis, osteoclastic extract (osteoclast extract) and the like, and these may be combined.
　骨砕補エキスは、市販品を利用してもよく、骨砕補を慣用の方法で抽出処理｛例えば、抽出溶媒［例えば、水、アルコール（メタノール、エタノールなど）、これらの混合物など］を用い、常温または加熱下で常法またはそれに準じた方法で抽出処理｝することで得ることもできる。 A commercially available product may be used as the osteoclastic extract, and the osteoclastic extract is extracted by a conventional method {for example, using an extraction solvent [for example, water, alcohol (methanol, ethanol, etc.), a mixture thereof, etc.]]. It can also be obtained by subjecting to extraction at ordinary temperature or under heating by a conventional method or a method according thereto.
　抽出物の中でも、特に、成分（Ａ）の含量や濃度が高い部分を分離又は分画して用いてもよい。例えば、骨砕補の水性溶媒抽出物（例えば、水、水とアルコールとの混合溶媒を抽出溶媒とする抽出物）を、さらに、アルコール［例えば、ｎ－ブタノールなどの炭素数３以上（例えば、炭素数４～６程度）のアルコール］で抽出などにより分離又は分画処理して得られる処理物には、ナリンゲニンを含む成分（Ａ）が高含量で含まれている場合が多く、このような処理物を好適に使用してもよい。 Among the extracts, in particular, a part having a high content or concentration of component (A) may be separated or fractionated. For example, an aqueous solvent extract of osteoclast (for example, an extract using water, a mixed solvent of water and alcohol as an extraction solvent), an alcohol [for example, n-butanol and the like having 3 or more carbon atoms (for example, n-butanol) Processed products obtained by separation or fractionation by extraction or the like with an alcohol having about 4 to 6 carbon atoms] often contain a high content of component (A) containing naringenin. You may use a processed material suitably.
　抽出に際しては、骨砕補をそのまま又は粉砕（破砕）して供してもよい。また、抽出物は、さらに、濃縮や乾燥（常温乾燥、凍結乾燥など）に供してもよい。 In the extraction, the osteoclastic prosthesis may be used as it is or after being crushed (crushed). The extract may be further subjected to concentration and drying (room temperature drying, freeze drying, etc.).
　骨砕補成分の形態は、特に限定されないが、例えば、粉状（又は粉粒状）であってもよい。 The form of the osteoclastic component is not particularly limited, but may be, for example, powder (or powder).
　［エゾウコギ成分（Ｂ）］
　エゾウコギ成分（Ｂ）としては、エゾウコギ、エゾウコギの抽出物（エゾウコギエキス）などが挙げられ、これらを組み合わせてもよい。 [Ezokogi component (B)]
Examples of the Ekokogi component (B) include Ezoukogi, Ezoukogi extract (Ezoukogi extract), and the like.
　エゾウコギ［学名：Eleutherococcus senticosus，Acanthopanax senticosus (Rupr. et Maxim.) Harms］は、ウコギ科の植物で、根、茎、幹、樹皮、葉、花、果実、果皮、果穂、種子、種皮などの部分を使用してもよく、これらを組み合わせて使用してもよく、全草を使用してもよい。 Ezoukogi [scientific name: Eleutherococcus senticosus, Acanthopanax senticosus (Rupr. May be used, these may be used in combination, or the whole plant may be used.
　特に、エゾウコギは、少なくとも葉を好適に使用してもよい。 In particular, at least the leaves of Ezokogi may be suitably used.
　エゾウコギエキスは、市販品を利用してもよく、エゾウコギを慣用の方法により抽出処理することで得ることもできる。 The Ekokogi extract may be a commercially available product or can be obtained by extracting Ezokogi by a conventional method.
　抽出溶媒としては、例えば、水、アルコール［例えば、アルカノール（例えば、メタノール、エタノール、イソプロパノール、ｎ－ブタノールなどのＣ１－４アルカノール）、ポリオール（例えば、エチレングリコール、プロピレングリコール、１，３－ブチレングリコール、グリセリンなど）、ケトン類（例えば、アセトン、メチルエチルケトンなど）、エーテル類（例えば、ジエチルエーテルなど）、エステル類（例えば、酢酸エチルなど）などが挙げられる。
　抽出溶媒は、単独で又は２種以上組み合わせて用いてもよい。
　代表的な抽出溶媒は、水、アルコール（エタノールなど）、これらの混合液などが挙げられる。 Examples of the extraction solvent include water, alcohol [eg, alkanol (eg, C 1-4 alkanol such as methanol, ethanol, isopropanol, n-butanol), polyol (eg, ethylene glycol, propylene glycol, 1,3-butylene]. Glycol, glycerin, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, diethyl ether, etc.), esters (eg, ethyl acetate, etc.) and the like.
You may use an extraction solvent individually or in combination of 2 or more types.
Typical extraction solvents include water, alcohol (such as ethanol), a mixed solution thereof, and the like.
　抽出温度や抽出時間は、特に限定されず、抽出溶媒や抽出方法などに応じて適宜選択できる。 Extraction temperature and extraction time are not particularly limited and can be appropriately selected according to the extraction solvent, extraction method, and the like.
　なお、抽出に際しては、エゾウコギを、必要に応じて、適当な処理（粉砕処理、加熱処理、乾燥処理など）に供してもよい。また、抽出物は、さらに、濃縮や乾燥（常温乾燥、凍結乾燥など）に供してもよい。 In the extraction, the elephant may be subjected to an appropriate treatment (pulverization treatment, heat treatment, drying treatment, etc.) as necessary. The extract may be further subjected to concentration and drying (room temperature drying, freeze drying, etc.).
　エゾウコギ成分の形態は、特に限定されないが、粉状（又は粉粒状）であってもよい。 The form of the Ekokogi component is not particularly limited, but may be powdery (or powdery).
　［成分（Ｃ）］
　本発明の剤又は組成物において、成分（Ａ）及び／又は成分（Ｂ）は、ジオスゲニン類、ジヒドロキシビタミンＤ３、デソノミンなどと組み合わせてもよい。これらの成分（以下、これらを成分（Ｃ）ということがある）と組み合わせることで、本発明の効果をより一層効率よく実現できる場合がある。 [Component (C)]
In the agent or composition of the present invention, component (A) and / or component (B) may be combined with diosgenins, dihydroxyvitamin D3, desonomin and the like. By combining with these components (hereinafter, these may be referred to as component (C)), the effects of the present invention may be realized more efficiently.
　これらの中でも、特に、ジオスニゲン類を好適に使用してよい。そのため、成分（Ｃ）は、少なくともジオスゲニン類で構成してもよい。
　ジオスゲニン類としては、ジオスゲニン、ジオスゲニン誘導体、これらの塩などが挙げられる。 Among these, in particular, diosunigens may be preferably used. Therefore, component (C) may be composed of at least diosgenins.
Examples of diosgenins include diosgenin, diosgenin derivatives, and salts thereof.
　ジオスゲニン誘導体としては、ジオスゲニンのＣ３位の水酸基が置換された化合物、Ｃ２位に置換基を有する化合物（又はＣ２位の水素原子が置換された化合物）、Ｃ４位に置換基を有する化合物（又はＣ４位の水素原子が置換された化合物）、Ｃ６位に置換基を有する化合物（又はＣ６位の水素原子が置換された化合物）［例えば、Ｃ３位の水酸基のエステル誘導体（例えば、アミノ酸誘導体、アミノスルホン酸誘導体、カーバメイト誘導体）、Ｃ３位の水酸基のハロゲン化誘導体など］、これらの配糖体などが挙げられる。 As the diosgenin derivative, a compound in which the hydroxyl group at the C3 position of diosgenin is substituted, a compound having a substituent at the C2 position (or a compound having a hydrogen atom at the C2 position substituted), a compound having a substituent at the C4 position (or C4) Compound having a hydrogen atom at the position), a compound having a substituent at the C6 position (or a compound having the hydrogen atom at the C6 position substituted) [for example, ester derivatives of the hydroxyl group at the C3 position (for example, amino acid derivatives, aminosulfones) Acid derivatives, carbamate derivatives), halogenated derivatives of the hydroxyl group at the C3 position, etc.], and glycosides thereof.
　具体的なジオスゲニン誘導体としては、例えば、下記式（Ｉ－１）で表される化合物、ジオスゲニン又は下記式（Ｉ－１）で表される化合物の配糖体などが挙げられる。
Figure JPOXMLDOC01-appb-C000001
 （式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、同一又は異なって水素原子又は置換基を示す。ただし、Ｒ２、Ｒ３及びＲ４が水素原子であるとき、Ｒ１はヒドロキシル基でない。） Specific examples of the diosgenin derivative include a compound represented by the following formula (I-1), a glycoside of diosgenin or a compound represented by the following formula (I-1), and the like.
Figure JPOXMLDOC01-appb-C000001
 (In the formula, R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a substituent. However, when R 2 , R 3 and R 4 are hydrogen atoms, R 1 is hydroxyl. Not a group.)
　Ｒ１において、置換基としては、炭化水素基｛例えば、アルキル基[例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓ－ブチル基、ｔ－ブチル基、ペンチル基などの直鎖又は分岐鎖アルキル基（例えば、Ｃ１－１２アルキル基、好ましくはＣ１－８アルキル基）]、シクロアルキル基（例えば、シクロペンチル基、シクロへキシル基、シクロヘプチル基、シクロオクチル基などのＣ４－１０シクロアルキル基、好ましくはＣ５－８シクロアルキル基）、アラルキル基（例えば、ベンジル基、フェネチル基などのＣ６－１０アリールＣ１－４アルキル基）、多環式脂肪族炭化水素基（例えば、デカリニル基、ノルボルニル基、アダマンチル基、ジメチルアダマンチル基など）などの飽和又は不飽和脂肪族炭化水素基；アリール基（例えば、フェニル基、トリル基、キシリル基などのＣ６－１０アリール基）などの芳香族炭化水素基｝、ヘテロ原子（窒素原子、酸素原子、硫黄原子、リン原子など）含有基｛例えば、酸素原子含有基[例えば、ヒドロキシル基、オキソ基（＝Ｏ）、基－ＯＲａ、基－Ｏ－ＣＯ－Ｒａ、基－Ｏ－ＣＯ－Ｎ（Ｒｂ）２、基－Ｏ－ＣＯ－Ｏ－Ｒａ、基－Ｏ－ＣＯ－Ｓ－Ｒａ、基－ＯＲｃ、基－Ｏ－ＳＯ２－ＯＨ、基－Ｏ－ＰＯ２－ＯＨ、基－（ＯＲｄ）ｋ－Ｒｅ、カルボキシル基、基－ＣＯ－Ｏ－Ｒａ、基－ＣＯ－Ｎ（Ｒｂ）２など]、窒素原子含有基[例えば、アミノ基、基－ＮＲａＲｂ、基－ＮＲｂ－ＣＯ－Ｏ－Ｒａ、基－ＮＲｂ－ＣＯ－Ｎ（Ｒｂ）２、窒素含有環基（例えば、ピリジン、ピロリン、ピロール、インドールなどに対応する基）など]、硫黄原子含有基[例えば、メルカプト基、基－ＳＲａ、基－Ｓ－Ｓ－Ｒａ、スルホ基（－ＳＯ３Ｈ）、基－ＳＯ２－Ｒｂ、基－Ｓ－ＣＯ－Ｎ（Ｒｂ）２など]、リン原子含有基[例えば、リン酸基（Ｈ２ＰＯ４－）、基－ＰＯ３Ｈなど]、アミノ酸基[又はアミノ酸の残基、例えば、ジオスゲニンを構成する３位（上記式においてＲ１の置換位置に対応）のヒドロキシル基と、アミノ酸（グリシン、アラニンなど）のカルボキシル基とのエステル結合により形成された基]など｝、ハロゲン原子（例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子など）などが挙げられる。 In R 1 , the substituent includes a hydrocarbon group {eg, alkyl group [eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group]. Group, linear or branched alkyl group such as pentyl group (eg C 1-12 alkyl group, preferably C 1-8 alkyl group)], cycloalkyl group (eg cyclopentyl group, cyclohexyl group, cycloheptyl) Group, a C 4-10 cycloalkyl group such as a cyclooctyl group, preferably a C 5-8 cycloalkyl group), an aralkyl group (for example, a C 6-10 aryl C 1-4 alkyl group such as a benzyl group or a phenethyl group) Saturated with a polycyclic aliphatic hydrocarbon group (for example, a decalinyl group, a norbornyl group, an adamantyl group, a dimethyladamantyl group, etc.) Saturated aliphatic hydrocarbon group; an aryl group (e.g., phenyl group, a tolyl group, C 6-10 aryl group such as xylyl) aromatic hydrocarbon group}, a hetero atom (a nitrogen atom such as an oxygen atom, a sulfur atom, Phosphorus atom etc.) containing group {eg oxygen atom containing group [eg hydroxyl group, oxo group (═O), group —OR a , group —O—CO—R a , group —O—CO—N (R b ) 2 , group —O—CO—O—R a , group —O—CO—S—R a , group —OR c , group —O—SO 2 —OH, group —O—PO 2 —OH, group — (OR d ) k —R e , carboxyl group, group —CO—O—R a , group —CO—N (R b ) 2 etc.], nitrogen atom-containing group [for example, amino group, group —NR a R b A group —NR b —CO—O—R a , a group —NR b —CO—N (R b ) 2 , a nitrogen-containing ring group (eg Group corresponding to pyridine, pyrroline, pyrrole, indole, etc.)], a sulfur atom-containing group [eg, mercapto group, group —SR a , group —S—S—R a , sulfo group (—SO 3 H) , Group —SO 2 —R b , group —S—CO—N (R b ) 2 and the like], phosphorus atom-containing group [eg, phosphate group (H 2 PO 4 —), group —PO 3 H and the like], An amino acid group [or a residue of an amino acid, for example, formed by an ester bond between a hydroxyl group at position 3 constituting diosgenin (corresponding to the substitution position of R 1 in the above formula) and a carboxyl group of an amino acid (glycine, alanine, etc.) Group], a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.).
　なお、上記式において、Ｒａは炭化水素基（例えば、アルキル基などの前記例示の炭化水素基など）、Ｒｂは水素原子又は炭化水素基（例えば、アルキル基などの前記例示の炭化水素基）、Ｒｃは糖（又は糖鎖又は糖の残基）、Ｒｄはアルキレン基（例えば、エチレン基、プロピレン基、トリメチレン基などのＣ２－４アルキレン基）、Ｒｅは水素原子、ヒドロキシル基又は炭化水素基（例えば、アルキル基（メチル基など）などの前記例示の炭化水素基）、ｋは２以上の整数（例えば、２～１０）を、それぞれ示し、Ｒａ及びＲｂは同一又は異なる基であってもよく、Ｒｂが複数であるとき、同一又は異なっていてもよい。 In the above formula, R a is a hydrocarbon group (eg, the exemplified hydrocarbon group such as an alkyl group), and R b is a hydrogen atom or a hydrocarbon group (eg, the exemplified hydrocarbon group such as an alkyl group). ), R c is a sugar (or sugar chain or sugar residue), R d is an alkylene group (eg, C 2-4 alkylene group such as ethylene group, propylene group, trimethylene group, etc.), R e is a hydrogen atom, hydroxyl group A group or a hydrocarbon group (for example, the above exemplified hydrocarbon group such as an alkyl group (such as a methyl group)), k represents an integer of 2 or more (for example, 2 to 10), and R a and R b are the same Or they may be different groups, and when R b is plural, they may be the same or different.
　Ｒａ及びＲｂにおいて、炭化水素基（アルキル基など）は、さらに、置換基を有していてもよい。置換基としては、特に限定されないが、前記例示の置換基、例えば、酸素原子含有基（例えば、ヒドロキシル基、カルボキシル基、基－ＯＲａ、基－Ｏ－ＣＯ－Ｒａなど）、窒素原子含有基（例えば、アミノ基、基－ＮＲａＲｂ）、硫黄原子含有基（例えば、メルカプト基、基－ＳＲａ、スルホ基、基－ＳＯ２－Ｒｂなど）が挙げられる。
　炭化水素基は、これらの置換基を単独で又は２種以上組み合わせて有していてもよい。
　炭化水素基が置換基を有する場合、置換基の数は、１以上であればよく、例えば、１～１０（例えば、１～８）、好ましくは１～６（例えば、１～４）、さらに好ましくは１～３程度であってもよい。 In R a and R b , the hydrocarbon group (such as an alkyl group) may further have a substituent. The substituent is not particularly limited, but includes the above-exemplified substituents, for example, an oxygen atom-containing group (for example, a hydroxyl group, a carboxyl group, a group —OR a , a group —O—CO—R a, etc.), a nitrogen atom-containing group A group (for example, an amino group, a group —NR a R b ), a sulfur atom-containing group (for example, a mercapto group, a group —SR a , a sulfo group, a group —SO 2 —R b, etc.).
The hydrocarbon group may have these substituents alone or in combination of two or more.
When the hydrocarbon group has a substituent, the number of substituents may be 1 or more, for example, 1 to 10 (eg, 1 to 8), preferably 1 to 6 (eg, 1 to 4), Preferably, it may be about 1 to 3.
　Ｒ１が置換基である場合、代表的なＲ１には、例えば、炭化水素基[例えば、アルキル基（例えば、基－（ＣＨ２）ｎ－ＣＨ３）、シクロアルキル基、アラルキル基など]、ヘテロ原子含有基｛例えば、酸素原子含有基[例えば、ヒドロキシル基、基－Ｏ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－（ＣＨ２）ｍ－ＮＨ２、基－Ｏ－（ＣＨ２）ｍ－ＣＯＯＨ、基－Ｏ－（ＣＨ２）ｍ－ＳＯ３Ｈ、基－Ｏ－ＣＯ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－ＣＯ－ＮＨ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－ＣＯ－ＮＲ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－ＣＯ－ＮＨ－ＣＨ（Ｒｂ）－ＣＯＯＨ、基－Ｏ－（ＣＨ２）ｎ－ＣＯ－ＮＨ－ＡＤ（式中、ＡＤはアダマンチル基（１－アダマンチル基、２，６－ジメチルアダマンタン－１－イル基など）を示す）、基－Ｏ－ＣＯ－ＮＨ－（ＣＨ２）ｍ－ＳＯ３Ｈ、基－Ｏ－ＣＯ－ＮＨ－（ＣＨ２）ｍ－ＣＯＯＨ、基－Ｏ－ＣＯ－Ｏ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－ＣＯ－Ｓ－（ＣＨ２）ｎ－ＣＨ３、基－Ｏ－ＳＵ（式中、ＳＵは、糖鎖を示す）、基－Ｏ－ＳＯ２－ＯＨ、基－Ｏ－ＰＯ２－ＯＨ、基－（ＯＣＨ２ＣＨ２）ｍ－ＣＨ３、基－（ＯＣＨ２ＣＨ２ＣＨ２）ｍ－ＣＨ３、カルボキシル基、基－ＣＯＯ（ＣＨ２）ｎＣＨ３、基－ＣＯ－ＮＨ－（ＣＨ２）ｎ－ＣＨ３、基－ＳＯ３Ｈ、基－ＳＯ２－（ＣＨ２）ｎ－ＣＨ３、基－ＳＯ２－Ｐｈ（式中、Ｐｈはフェニル基を示す。）、基－ＣＯ－ＮＨ－ＣＨ（Ｒｂ）－ＣＯＯＨ、基－ＣＯ－ＮＨ－（ＣＨ２）ｎ－ＳＯ３Ｈなど]、窒素原子含有基[例えば、アミノ基、基－ＮＨ－（ＣＨ２）ｎ－ＣＨ３、基－ＮＨ－（ＣＨ２）ｎ－ＮＨ２、基－ＮＨ－ＣＨ（Ｒｂ）－ＣＯＯＨ、基－ＮＨ－（ＣＨ２）ｍ－ＳＯ３Ｈ、基－ＮＨ－（ＣＨ２）ｍ－ＳＯ２Ｈ、基－ＮＨ－ＣＯ－Ｏ－（ＣＨ２）ｎ－ＣＨ３、基－ＮＨ－ＣＯ－ＮＨ２、基－ＮＨ－ＣＯ－ＮＨ－ＡＤ（式中、ＡＤはアダマンチル基（１－アダマンチル基、２，６－ジメチルアダマンタン－１－イル基など）を示す）、基－ＮＨ－ＣＯ－ＮＨ－ＣＨ（Ｒｂ）－ＣＯＯＨ、基－ＮＨ－ＣＯ－ＮＨ－（ＣＨ２）ｍ－ＳＯ３Ｈ、基－ＮＨ－ＣＯ－ＮＨ－（ＣＨ２）ｍ－ＣＯＯＨなど]、硫黄原子含有基[例えば、メルカプト基、基－Ｓ－（ＣＨ２）ｎ－ＣＨ３、基－Ｓ－（ＣＨ２）ｍ－ＣＯＯＨ、基－Ｓ－（ＣＨ２）ｍ－ＣＨ（ＮＨ２）－ＣＯＯＨ、基－Ｓ－ＣＯ－ＮＨ－ＡＤ（式中、ＡＤはアダマンチル基（１－アダマンチル基、２，６－ジメチルアダマンタン－１－イル基など）を示す）、基－Ｓ－Ｓ－（ＣＨ２）ｍ－ＣＨ（ＮＨ２）－ＣＯＯＨ、基－ＳＯ３Ｈなど]、リン原子含有基[例えば、基－ＰＯ３Ｈなど]、アミノ酸基（例えば、基－Ｏ－ＣＯ－ＣＨ２－ＮＨ２など）など｝、ハロゲン原子（例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子など）などが挙げられる。 When R 1 is a substituent, representative R 1 includes, for example, a hydrocarbon group [eg, alkyl group (eg, group — (CH 2 ) n —CH 3 ), cycloalkyl group, aralkyl group, etc.] , Heteroatom-containing groups {eg oxygen atom-containing groups [eg hydroxyl groups, groups —O— (CH 2 ) n —CH 3 , groups —O— (CH 2 ) m —NH 2 , groups —O— (CH 2 ) m —COOH, group —O— (CH 2 ) m —SO 3 H, group —O—CO— (CH 2 ) n —CH 3 , group —O—CO—NH— (CH 2 ) n —CH 3 , group —O—CO—NR— (CH 2 ) n —CH 3 , group —O—CO—NH—CH (R b ) —COOH, group —O— (CH 2 ) n —CO—NH—AD (In the formula, AD is an adamantyl group (1-adamantyl group, 2,6-dimethyladamantan-1-yl A group, etc.)), groups -O-CO-NH- (CH 2 ) m -SO 3 H, group -O-CO-NH- (CH 2 ) m -COOH, group -O-CO-O- ( CH 2 ) n —CH 3 , group —O—CO—S— (CH 2 ) n —CH 3 , group —O—SU (wherein SU represents a sugar chain), group —O—SO 2 — OH, group —O—PO 2 —OH, group — (OCH 2 CH 2 ) m —CH 3 , group — (OCH 2 CH 2 CH 2 ) m —CH 3 , carboxyl group, group —COO (CH 2 ) n CH 3 , group —CO—NH— (CH 2 ) n —CH 3 , group —SO 3 H, group —SO 2 — (CH 2 ) n —CH 3 , group —SO 2 —Ph where Ph is A phenyl group)), a group —CO—NH—CH (R b ) —COOH, a group —CO—NH— (CH 2 ) n —SO 3 H, etc.], A nitrogen atom-containing group [for example, an amino group, a group —NH— (CH 2 ) n —CH 3 , a group —NH— (CH 2 ) n —NH 2, a group —NH—CH (R b ) —COOH, a group — NH— (CH 2 ) m —SO 3 H, group —NH— (CH 2 ) m —SO 2 H, group —NH—CO—O— (CH 2 ) n —CH 3 , group —NH—CO—NH 2 , a group —NH—CO—NH—AD (wherein AD represents an adamantyl group (1-adamantyl group, 2,6-dimethyladamantan-1-yl group, etc.)), a group —NH—CO—NH— CH (R b ) —COOH, groups —NH—CO—NH— (CH 2 ) m —SO 3 H, groups —NH—CO—NH— (CH 2 ) m —COOH, etc.], sulfur atom-containing groups [eg , Mercapto group, group -S- (CH 2 ) n -CH 3 , group -S- (CH 2 ) m -C OOH, group —S— (CH 2 ) m —CH (NH 2 ) —COOH, group —S—CO—NH—AD (where AD is an adamantyl group (1-adamantyl group, 2,6-dimethyladamantane— 1-yl group, etc.)), groups —SS— (CH 2 ) m —CH (NH 2 ) —COOH, groups —SO 3 H etc.], phosphorus atom-containing groups [eg group —PO 3 H Etc.], amino acid groups (eg, group —O—CO—CH 2 —NH 2 etc.)}, halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom etc.) and the like.
　なお、上記式において、ｍは１以上の整数（例えば、１～１０、好ましくは１～４、さらに好ましくは１又は２）、ｎは０以上の整数（例えば、０～１０、好ましくは０～７）を示し、Ｒｂは前記と同じ[すなわち、水素原子又は炭化水素基（例えば、アルキル基など）]である。 In the above formula, m is an integer of 1 or more (eg, 1 to 10, preferably 1 to 4, more preferably 1 or 2), and n is an integer of 0 or more (eg, 0 to 10, preferably 0 to 2). 7) and R b is the same as the above [that is, a hydrogen atom or a hydrocarbon group (for example, an alkyl group, etc.)].
　Ｒ２、Ｒ３及びＲ４において、置換基としては、Ｒ１の項で例示の置換基と同様の置換基を挙げることができる。
　Ｒ２及び／又はＲ４が置換基である場合、代表的な置換基としては、酸素原子含有基、窒素原子含有基、硫黄原子含有基、アミノ酸基、ハロゲン原子などが挙げられる。
　また、Ｒ３が置換基である場合、代表的な置換基としては、ハロゲン原子などが挙げられる。 In R 2 , R 3 and R 4 , examples of the substituent include the same substituents as those exemplified in the section of R 1 .
When R 2 and / or R 4 is a substituent, typical examples of the substituent include an oxygen atom-containing group, a nitrogen atom-containing group, a sulfur atom-containing group, an amino acid group, and a halogen atom.
In addition, when R 3 is a substituent, typical substituents include a halogen atom.
　式（Ｉ－１）において、Ｒ１～Ｒ４の組み合わせは、限定されず、すべての組み合わせが含まれる。代表的なＲ１～Ｒ４の組み合わせには、例えば、以下の組み合わせなどが挙げられる。
　（１）Ｒ１がヒドロキシル基以外の置換基、Ｒ２～Ｒ４が水素原子である組み合わせ
　（２）Ｒ１がヒドロキシル基以外の置換基、Ｒ２が置換基、Ｒ３及びＲ４が水素原子である組み合わせ
　（３）Ｒ１がヒドロキシル基以外の置換基、Ｒ３が置換基、Ｒ２及びＲ４が水素原子である組み合わせ
　（４）Ｒ１がヒドロキシル基以外の置換基、Ｒ２及びＲ３が置換基、Ｒ４が水素原子である組み合わせ
　（５）Ｒ１がヒドロキシル基以外の置換基、Ｒ２、Ｒ３及びＲ４が置換基である組み合わせ
　（６）Ｒ１がヒドロキシル基以外の置換基、Ｒ２及びＲ３が水素原子、Ｒ４が置換基である組み合わせ
　（７）Ｒ１がヒドロキシル基以外の置換基、Ｒ３が水素原子、Ｒ２及びＲ４が置換基である組み合わせ
　（８）Ｒ１がヒドロキシル基以外の置換基、Ｒ２が水素原子、Ｒ３及びＲ４が置換基である組み合わせ
　（９）Ｒ１がヒドロキシル基、Ｒ２が置換基、Ｒ３及びＲ４が水素原子である組み合わせ
　（１０）Ｒ１がヒドロキシル基、Ｒ３が置換基、Ｒ２及びＲ４が水素原子である組み合わせ
　（１１）Ｒ１がヒドロキシル基、Ｒ２及びＲ３が置換基、Ｒ４が水素原子である組み合わせ
　（１２）Ｒ１がヒドロキシル基、Ｒ２～Ｒ４が置換基である組み合わせ
　（１３）Ｒ１がヒドロキシル基、Ｒ２及びＲ３が水素原子、Ｒ４が置換基である組み合わせ
　（１４）Ｒ１がヒドロキシル基、Ｒ２が水素原子、Ｒ３及びＲ４が置換基である組み合わせ
　（１５）Ｒ１がヒドロキシル基、Ｒ３が水素原子、Ｒ２及びＲ４が置換基である組み合わせ In the formula (I-1), combinations of R 1 to R 4 are not limited, and all combinations are included. Typical combinations of R 1 to R 4 include, for example, the following combinations.
(1) A combination in which R 1 is a substituent other than a hydroxyl group, and R 2 to R 4 are hydrogen atoms. (2) R 1 is a substituent other than a hydroxyl group, R 2 is a substituent, R 3 and R 4 are hydrogen. Combinations that are atoms (3) Combinations in which R 1 is a substituent other than a hydroxyl group, R 3 is a substituent, R 2 and R 4 are hydrogen atoms (4) R 1 is a substituent other than a hydroxyl group, R 2 and A combination in which R 3 is a substituent and R 4 is a hydrogen atom (5) A combination in which R 1 is a substituent other than a hydroxyl group, and R 2 , R 3 and R 4 are substituents (6) R 1 is other than a hydroxyl group A combination in which R 2 and R 3 are hydrogen atoms and R 4 is a substituent (7) R 1 is a substituent other than a hydroxyl group, R 3 is a hydrogen atom, and R 2 and R 4 are substituents Combination (8) R 1 is hydroxyl A substituent other than a group, a combination in which R 2 is a hydrogen atom, R 3 and R 4 are substituents (9) a combination in which R 1 is a hydroxyl group, R 2 is a substituent, and R 3 and R 4 are hydrogen atoms ( 10) A combination in which R 1 is a hydroxyl group, R 3 is a substituent, R 2 and R 4 are hydrogen atoms (11) R 1 is a hydroxyl group, R 2 and R 3 are substituents, and R 4 is a hydrogen atom Combination (12) A combination in which R 1 is a hydroxyl group and R 2 to R 4 are substituents (13) A combination in which R 1 is a hydroxyl group, R 2 and R 3 are hydrogen atoms, and R 4 is a substituent (14) A combination in which R 1 is a hydroxyl group, R 2 is a hydrogen atom, R 3 and R 4 are substituents (15) A combination in which R 1 is a hydroxyl group, R 3 is a hydrogen atom, and R 2 and R 4 are substituents
　代表的なジオスゲニン誘導体には、例えば、下記式（ＩＩ）
Figure JPOXMLDOC01-appb-C000002
 で表わされる（３β，２５Ｒ）－３－（２－アミノエタノイロキシ）－スピロスト－５－エン｛(3β, 25R)-3-(2-Aminoethanoyloxy)-spirost-5-ene｝、下記化学式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000003
 で表わされる（３β，２５Ｒ）－３－フルオロスピロスト－エン｛(3β, 25R)-3-Fluorospirost-5-ene｝、並びに、（３β，２５Ｒ）－３－（２－アミノエチルスルホニルオキシ）－スピロスト－５－エン｛(3β, 25R)-3-(2-Aminoethylsulfonyl-oxy)-spirost-5-ene｝、（３β，２５Ｒ）－３－（２－アミノプロピルスルホニルオキシ）－スピロスト－５－エン、（３β，２５Ｒ）－３－[Ｎ－（２，６－ジメチルアダマンタン－１－イル）カルバモイルオキシ]－スピロスト－５－エン、（３β，２５Ｒ）－３－｛［Ｎ－（２，６－ジメチルアダマンタン－１－イル）カルバモイル］アミノ｝－スピロスト－５－エン、（３β，２５Ｒ）－３－［Ｎ－（２，６－ジメチルアダマンタン－１－イル）カルバモイルチオ］－スピロスト－５－エン、（３β，２５Ｒ）－３－｛［Ｎ－（アダマンタン－１－イル）カルバモイル］アミノ｝－スピロスト－５－エン、（３β，２５Ｒ）－３－［Ｎ－（アダマンタン－１－イル）カルバモイルチオ］－スピロスト－５－エン、及び（３β，２５Ｒ）－３－［Ｎ－（アダマンタン－１－イル）カルバモイルオキシ］－スピロスト－５－エン[又は（３β，２５Ｒ）－３－（１－アダマンチル－アミノカルボニルオキシ）－スピロスト－５－エン｛(3β, 25R)-3-(1-adamantyl-aminocarbonyloxy)-spirost-5-ene｝]などが挙げられる。 Representative diosgenin derivatives include, for example, the following formula (II)
Figure JPOXMLDOC01-appb-C000002
 (3β, 25R) -3- (2-aminoethanoyloxy) -spirost-5-ene {(3β, 25R) -3- (2-Aminoethanoyloxy) -spirost-5-ene}, represented by the following chemical formula ( III)
Figure JPOXMLDOC01-appb-C000003
 (3β, 25R) -3-fluorospirost-ene {(3β, 25R) -3-Fluorospirost-5-ene} represented by the formula (3β, 25R) -3- (2-aminoethylsulfonyloxy) -Spirost-5-ene {(3β, 25R) -3- (2-Aminoethylsulfonyl-oxy) -spirost-5-ene}, (3β, 25R) -3- (2-aminopropylsulfonyloxy) -spirost-5 -Ene, (3β, 25R) -3- [N- (2,6-dimethyladamantan-1-yl) carbamoyloxy] -spirost-5-ene, (3β, 25R) -3-{[N- (2 , 6-Dimethyladamantan-1-yl) carbamoyl] amino} -spirost-5-ene, (3β, 25R) -3- [N- (2,6-dimethyladamantan-1-yl) carbamoylthio] -spirost- 5-ene, (3β, 25R) -3-{[N- Adamantan-1-yl) carbamoyl] amino} -spirost-5-ene, (3β, 25R) -3- [N- (adamantan-1-yl) carbamoylthio] -spirost-5-ene, and (3β, 25R ) -3- [N- (adamantan-1-yl) carbamoyloxy] -spirost-5-ene [or (3β, 25R) -3- (1-adamantyl-aminocarbonyloxy) -spirost-5-ene {( 3β, 25R) -3- (1-adamantyl-aminocarbonyloxy) -spirost-5-ene}].
　配糖体としては、ジオスゲニン又は前記式（Ｉ－１）においてＲ１がヒドロキシル基である化合物において、ヒドロキシ基に糖（前記例示の糖など）が結合した化合物（例えば、ジオシン）などが挙げられる。 Examples of the glycoside include diosgenin or a compound in which R 1 is a hydroxyl group in the above formula (I-1) and a sugar (such as the sugar exemplified above) is bonded to a hydroxy group (for example, diosine). .
　なお、塩（特に薬学的に許容される塩）としては、例えばハロゲン化水素酸塩（例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等）、無機酸塩（例えば硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩等）、有機カルボン酸塩（例えば酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩等）、有機スルホン酸塩（例えばメタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩等）、アミノ酸塩（例えばアスパラギン酸塩、グルタミン酸塩等）、有機アミン塩（例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン、アルギニン及びリジンなどの有機塩基との塩）、四級アミン塩、アルカリ金属塩（例えばナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例えばマグネシウム塩、カルシウム塩等）などが挙げられる。 Examples of salts (particularly pharmaceutically acceptable salts) include hydrohalides (for example, hydrofluorates, hydrochlorides, hydrobromides, hydroiodates, etc.) and inorganic acid salts. (Eg sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citric acid Acid salts), organic sulfonates (eg methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartic acid) Salt, glutamate, etc.), organic amine salt (for example, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N′-dibenzylethylenedi) Salts with organic bases such as min, arginine and lysine), quaternary amine salts, alkali metal salts (eg sodium salts, potassium salts etc.), alkaline earth metal salts (eg magnesium salts, calcium salts etc.), etc. .
　代表的なジオスゲニン類には、ジオスゲニン、前記式（Ｉ－１）で表される化合物、ジオシン、これらの塩などが挙げられる。特に好ましいジオスゲニン類には、ジオスゲニン、前記式（ＩＩ）で表される化合物、前記式（ＩＩＩ）で表される化合物、ジオシン、これらの塩が含まれる。 Representative diosgenins include diosgenin, compounds represented by the above formula (I-1), diosin, and salts thereof. Particularly preferred diosgenins include diosgenin, a compound represented by the formula (II), a compound represented by the formula (III), diosine, and salts thereof.
　［形態・投与］
　本発明の剤又は組成物は、成分（Ａ）及び成分（Ｂ）のいずれか一方を含んでいればよく、成分（Ａ）と成分（Ｂ）とを組み合わせてもよい。通常、本発明の組成物では、成分（Ａ）及び成分（Ｂ）を組み合わせてもよい。
　成分（Ａ）と成分（Ｂ）とを組み合わせることで、より一層、記憶力改善効果などを得やすい。 [Form / Administration]
The agent or composition of this invention should just contain any one of a component (A) and a component (B), and may combine a component (A) and a component (B). Usually, in the composition of this invention, you may combine a component (A) and a component (B).
By combining the component (A) and the component (B), it is easier to obtain a memory improvement effect and the like.
　成分（Ａ）と成分（Ｂ）とを組み合わせる場合、成分（Ａ）と成分（Ｂ）とは、別の剤又は組成物としてもよく、成分（Ａ）と成分（Ｂ）とを含む剤（合剤）又は組成物としてもよい。 When combining a component (A) and a component (B), a component (A) and a component (B) are good also as another agent or a composition, and the agent (A) containing a component (A) and a component (B) ( A mixture) or a composition may be used.
　なお、成分（Ｃ）についても同様である。 The same applies to the component (C).
　成分（Ａ）と成分（Ｂ）とを組み合わせる場合、これらの割合は、所望の効果などに応じて適宜選択できるが、例えば、成分（Ａ）と成分（Ｂ）との割合は、前者／後者（重量比）＝１／０．００１～１／１０００、好ましくは１／０．０１～１／１００、さらに好ましくは１／０．０２～１／５０、特に１／０．１～１／１０程度であってもよい。 When the component (A) and the component (B) are combined, these ratios can be appropriately selected according to the desired effect. For example, the ratio between the component (A) and the component (B) is the former / the latter (Weight ratio) = 1 / 0.001 to 1/1000, preferably 1 / 0.01 to 1/100, more preferably 1 / 0.02 to 1/50, particularly 1 / 0.1 to 1/10 It may be a degree.
　特に、成分（Ａ）としての骨砕補エキスと、成分（Ｂ）としてのエゾウコギエキスとを組み合わせる場合、これらの割合は、前者／後者（重量比）＝１／０．００１～１／１０００、好ましくは１／０．０１～１／１００、さらに好ましくは１／０．０２～１／５０、特に１／０．１～１／１０程度であってもよい。 In particular, in the case of combining the osteoclastic extract as the component (A) and the sorghum extract as the component (B), the ratio of the former / the latter (weight ratio) = 1 / 0.001 to 1/1000, Preferably, it may be 1 / 0.01 to 1/100, more preferably 1 / 0.02 to 1/50, and particularly about 1 / 0.1 to 1/10.
　なお、骨砕補エキスやエゾウコギエキスが、溶媒成分などを含む場合、上記割合は、有効成分（又は固形分）換算の割合である。 In addition, when the osteoclast supplement and the sorghum extract contain a solvent component etc., the said ratio is a ratio of an active ingredient (or solid content) conversion.
　また、成分（Ｃ）を組み合わせる場合、成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合は、前者／後者（重量比）＝１／０．００１～１／１０００、好ましくは１／０．０１～１／１００、さらに好ましくは１／０．０２～１／５０、特に１／０．１～１／１０程度であってもよい。 When the component (C) is combined, the ratio of the component (A) and / or the component (B) to the component (C) is the former / the latter (weight ratio) = 1 / 0.001 to 1/1000, preferably May be 1 / 0.01 to 1/100, more preferably 1 / 0.02 to 1/50, especially about 1 / 0.1 to 1/10.
　剤又は組成物の形態としては、特に限定されず、成分（Ａ）及び／成分（Ｂ）をそのまま剤（例えば、粉剤）又は組成物としてもよく、他の成分（担体、賦形剤など）とともに製剤化してもよい。 The form of the agent or composition is not particularly limited, and component (A) and / or component (B) may be used as an agent (for example, powder) or composition as it is, and other components (carrier, excipient, etc.). You may formulate with it.
　特に、製剤化には、例えば、賦形剤、結合剤、崩壊剤、コーティング剤、滑沢剤、着色剤、矯味矯臭剤や、必要により安定化剤、乳化剤、吸収促進剤、界面活性剤、ｐＨ調製剤、防腐剤、抗酸化剤などを使用することができ、一般に製剤の原料として用いられる成分を配合して常法により製剤化可能である。 In particular, for formulation, for example, excipients, binders, disintegrants, coating agents, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, A pH adjusting agent, preservative, antioxidant and the like can be used, and it can be formulated by a conventional method by incorporating components generally used as a raw material of the formulation.
　製剤化に用いられる成分（担体）としては、特に限定されないが、例えば、大豆油、牛脂、合成グリセライドなどの動植物油；流動パラフィン、スクワラン、固形パラフィンなどの炭化水素；ミリスチン酸オクチルドデシル、ミリスチン酸イソプロピルなどのエステル油；セトステアリルアルコール、ベヘニルアルコールなどの高級アルコール；シリコン樹脂；シリコーンオイル；ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレンブロックコポリマーなどの界面活性剤；ヒドロキシエチルセルロース、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、ポリビニルピロリドン、メチルセルロースなどの水溶性高分子；エタノール、イソプロパノールなどの低級アルコール；グリセリン、プロピレングリコール、ジプロピレングリコール、ソルビトールなどの多価アルコール；グルコース、ショ糖などの糖；無水ケイ酸、ケイ酸アルミニウムマグネシウム、ケイ酸アルミニウムなどの無機粉体；精製水などが挙げられる。 The component (carrier) used for the formulation is not particularly limited, but for example, animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; octyldodecyl myristate, myristic acid Ester oil such as isopropyl; Higher alcohol such as cetostearyl alcohol and behenyl alcohol; Silicone resin; Silicone oil; Polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, poly Surfactants such as oxyethylene polyoxypropylene block copolymer; hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol Water-soluble polymers such as ethanol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; Inorganic powders such as aluminum magnesium silicate and aluminum silicate; purified water and the like.
　賦形剤としては、例えば、乳糖、コーンスターチ、白糖、ブドウ糖、マンニトール、ソルビット、結晶セルロース、二酸化ケイ素などが挙げられる。 Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.
　結合剤としては、例えば、ポリビニルアルコール、ゼラチン、メチルセルロース、エチルセルロース、アラビアゴム、トラガント、ゼラチン、シェラック、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリビニルアセタールジエチルアミノアセテート、トウモロコシデンプンなどが挙げられる。 Examples of the binder include polyvinyl alcohol, gelatin, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, corn starch and the like.
　崩壊剤としては、例えば、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース、クロスポビドン、結晶セルロース、沈降炭酸カルシウム、クロスカルメロースナトリウム、クエン酸カルシウム、デキストリン、ペクチン、カルボキシメチルセルロースカルシウムなどが挙げられる。 Examples of the disintegrant include corn starch, low-substituted hydroxypropylcellulose, crospovidone, crystalline cellulose, precipitated calcium carbonate, croscarmellose sodium, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium and the like.
　滑沢剤としては、例えば、ステアリン酸マグネシウム、タルク、ポリエチレングリコール、軽質無水ケイ酸、ショ糖脂肪酸エステルなどが挙げられ、矯味矯臭剤としては、ココア末、メントール、芳香散、ハッカ油、竜脳、桂皮末などが用いられる。 Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, light anhydrous silicic acid, sucrose fatty acid ester, and the flavoring agents include cocoa powder, menthol, aroma powder, mint oil, dragonfly, For example, cinnamon powder is used.
　なお、本発明の剤又は組成物は、本発明の効果を阻害しない範囲であれば、さらに、神経疾患や記憶力の改善に有用な別の成分と組み合わせてもよい。組み合わせる態様としては、剤又は組成物に含有させる態様の他、剤又は組成物とは別に用いる態様が挙げられる。 It should be noted that the agent or composition of the present invention may be further combined with another component useful for improving neurological diseases and memory as long as the effects of the present invention are not impaired. As an aspect combined, the aspect used separately from an agent or a composition other than the aspect contained in an agent or a composition is mentioned.
　本発明の剤又は組成物の形態（剤形）としては、例えば、錠剤、散剤、細粒剤、顆粒剤、ドライシロップ剤、被覆錠剤、口腔内崩壊錠、チュアブル錠、カプセル剤、ソフトカプセル剤、シロップ剤、経口液剤、トローチ剤、ゼリー剤、吸入剤、坐剤、注射剤、軟膏剤、点眼剤、眼軟膏剤、点鼻剤、点耳剤、パップ剤、ローション剤、外用液剤、スプレー剤、外用エアゾール剤、クリーム剤、ゲル剤、テープ剤、バッカル錠、舌下錠、膣坐剤、膣錠、直腸ソフトカプセル剤等が挙げられる。 Examples of the form (dosage form) of the agent or composition of the present invention include tablets, powders, fine granules, granules, dry syrups, coated tablets, orally disintegrating tablets, chewable tablets, capsules, soft capsules, and syrups. Agent, oral solution, troche, jelly, inhalant, suppository, injection, ointment, eye drop, eye ointment, nasal drop, ear drops, poultice, lotion, external solution, spray, External aerosols, creams, gels, tapes, buccal tablets, sublingual tablets, vaginal suppositories, vaginal tablets, rectal soft capsules and the like can be mentioned.
　本発明の剤又は組成物の投与（服用）形態は、特に限定されず、経口投与であっても、非経口投与であってもよい。非経口投与としては、例えば、直腸投与、経鼻投与、経肺投与、注射投与（例えば、静脈内投与、脊椎腔内投与、硬膜外腔内投与、筋肉内投与、皮下投与、腹腔内投与、動脈内投与、関節内投与、心臓内投与、嚢内投与、皮内投与、病巣内投与、眼内投与、胸腔内投与、くも膜下投与、子宮内投与、脳室内投与）などが挙げられる。 The administration (taking) form of the agent or composition of the present invention is not particularly limited, and may be oral administration or parenteral administration. Parenteral administration includes, for example, rectal administration, nasal administration, pulmonary administration, injection administration (eg, intravenous administration, intrathecal administration, intraepidural administration, intramuscular administration, subcutaneous administration, intraperitoneal administration) Intraarterial administration, intraarticular administration, intracardiac administration, intracapsular administration, intradermal administration, intralesional administration, intraocular administration, intrathoracic administration, subarachnoid administration, intrauterine administration, intraventricular administration) and the like.
　代表的な投与形態は経口投与である。 A typical administration form is oral administration.
　本発明の剤又は組成物に含まれる成分（Ａ）及び／又は成分（Ｂ）の量は、特に限定されず、所望の効果を得るのに十分な用量とすることが好ましい。
　例えば、投与量は、例えば症状の程度、年齢、性別、体重、投与形態、塩の種類、疾患の具体的な種類等に応じて異なるが、通常、１日あたり、成分（Ａ）及び／又は成分（Ｂ）を、０．０１～１００ｍｇ／ｋｇ、好ましくは０．１～１０ｍｇ／ｋｇ、さらに好ましくは０．５～５ｍｇ／ｋｇ程度であってもよい。 The amount of component (A) and / or component (B) contained in the agent or composition of the present invention is not particularly limited, and is preferably a dose sufficient to obtain a desired effect.
For example, the dose varies depending on, for example, the degree of symptom, age, sex, body weight, dosage form, salt type, specific type of disease, etc., but usually per day, component (A) and / or Component (B) may be about 0.01 to 100 mg / kg, preferably about 0.1 to 10 mg / kg, more preferably about 0.5 to 5 mg / kg.
　特に、成分（Ａ）の投与量（摂取量、服用量）は、１日あたり、０．０１～１００ｍｇ／ｋｇ、好ましくは０．１～１０ｍｇ／ｋｇ、さらに好ましくは０．５～５ｍｇ／ｋｇ程度であってもよい。 In particular, the dose (intake, dose) of component (A) is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, more preferably 0.5 to 5 mg / kg per day. It may be a degree.
　なお、骨砕補エキスを投与する場合、骨砕補エキスの投与量（摂取量、服用量）は、１日あたり、１０～２０００ｍｇ／ｋｇ、好ましくは２０～１０００ｍｇ／ｋｇ、さらに好ましくは５０～８００ｍｇ／ｋｇ（例えば、１００～７００ｍｇ／ｋｇ）程度であってもよい。 In the case of administering the osteoclastic extract, the dosage (intake, dose) of the osteoclastic extract is 10 to 2000 mg / kg, preferably 20 to 1000 mg / kg, more preferably 50 to 100 per day. It may be about 800 mg / kg (for example, 100 to 700 mg / kg).
　また、成分（Ｂ）（エゾウコギエキスなど）の投与量（摂取量、服用量）は、１日あたり、１０～２０００ｍｇ／ｋｇ、好ましくは２０～１０００ｍｇ／ｋｇ、さらに好ましくは５０～８００ｍｇ／ｋｇ（例えば、１００～７００ｍｇ／ｋｇ）程度であってもよい。 In addition, the dose (intake, dose) of component (B) (such as Ezokogi extract) is 10 to 2000 mg / kg, preferably 20 to 1000 mg / kg, more preferably 50 to 800 mg / kg per day ( For example, it may be about 100 to 700 mg / kg).
　さらに、成分（Ｃ）を組み合わせて投与する場合、成分（Ｃ）の投与量（摂取量、服用量）は、１日あたり、０．０１～１００ｍｇ／ｋｇ、好ましくは０．１～１０ｍｇ／ｋｇ、さらに好ましくは０．５～５ｍｇ／ｋｇ程度であってもよい。 Further, when the components (C) are administered in combination, the dose (intake, dose) of the component (C) is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg per day. More preferably, it may be about 0.5 to 5 mg / kg.
　投与は、１回又は複数回に分けてもよい。 Administration may be divided once or multiple times.
　なお、本発明の剤又は組成物は、所望により、キットの形態で提供することもできる。このようなキットは、例えば、成分（Ａ）及び／又は成分（Ｂ）を含有する１つ以上の単位剤形を含有することができるパック又はディスペンサー装置等の容器を備えたキットであってもよい。 The agent or composition of the present invention can be provided in the form of a kit if desired. Such a kit may be, for example, a kit comprising a container such as a pack or a dispenser device that may contain one or more unit dosage forms containing component (A) and / or component (B). Good.
　本発明では、別々の剤又は組成物をキット形に組み合わせることもできる。例えば、このようなキットは、成分（Ａ）を含む剤又は組成物を含む容器と、成分（Ｂ）を含む剤又は組成物とを含む容器とで構成してもよい。 In the present invention, separate agents or compositions can be combined in a kit form. For example, such a kit may be composed of a container containing an agent or composition containing component (A) and a container containing an agent or composition containing component (B).
　このようなキットは、通常、分割式ボトル又は分割式ホイルパケットのような、別々の剤又は組成物を含有するための容器を含むが、別々の組成物を単一の非分割式容器に含めることもできる。キット形は、別々の成分を異なる投与形で投与する場合や、別々の成分を異なる投与間隔で投与する場合、処方医師によって組み合わせた個々の成分を滴定する必要がある場合などに、特に有用である。 Such kits typically include containers for containing separate agents or compositions, such as split bottles or split foil packets, but include the separate compositions in a single unsplit container. You can also. Kit forms are particularly useful when different components are administered in different dosage forms, when separate components are administered at different dosage intervals, or when the combined individual components need to be titrated by the prescribing physician. is there.
　パックは、例えば、金属もしくはプラスチックホイル、ブリスターパックなどを含むことができる。ブリスターパックはパッケージング業界において周知であり、製薬的単位投与形（錠剤、カプセル等）のパッケージングに広く用いられている。ブリスターパックは一般に、透明なプラスチック材料のホイルによって覆われた比較的硬質材料のシートから成るのが好ましい。パッケージング・プロセス中に、該プラスチックホイル中に凹みが形成される。これらの凹みは、パックされる個々の錠剤又はカプセルのサイズ及び形状に合わせてある。次に、錠剤又はカプセルを凹み中に入れて、凹みが形成された方向とは逆のホイル面において、比較的硬質材料のシートをプラスチックホイルに対してシールする。その結果、錠剤又はカプセルが該プラスチックホイルと該シートとの間の凹み中にシールされる。シートの強度は、凹みの場所においてシートに開口が形成されるように手で圧力を凹みに加えることによって、錠剤又はカプセルをブリスターパックから取り出すことができるような強度が好ましい。錠剤又はカプセルを前記開口によって取り出すことができる。 Packs can include, for example, metal or plastic foil, blister packs and the like. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively hard material covered by a foil of transparent plastic material. During the packaging process, recesses are formed in the plastic foil. These indentations are tailored to the size and shape of the individual tablets or capsules to be packed. The tablet or capsule is then placed in the recess and the sheet of relatively hard material is sealed against the plastic foil at the foil surface opposite to the direction in which the recess was formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. The strength of the sheet is preferably such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess so that an opening is formed in the sheet at the location of the recess. Tablets or capsules can be removed through the opening.
　パック又はディスペンサー装置には、投与のための添付文書、プロダクトインサート等を添付することができる。パック又はディスペンサー等の容器は、医薬の製造、使用又は販売を規制する政府機関、当局の通達に適応させることができる。 * Package or dispenser device can be accompanied by package inserts, product inserts, etc. for administration. Containers such as packs or dispensers can be adapted to the notifications of government agencies and authorities that regulate the manufacture, use or sale of medicines.
　＜飲食品＞
　本発明には、成分（Ａ）と成分（Ｂ）と（さらには成分（Ｃ）などの他の成分と）含む飲食品（すなわち、前記剤又は組成物を含む飲食品）が含まれる。
　なお、このような飲食品において、成分（Ａ）や成分（Ｂ）の好ましい態様、これらの割合などは、前記と同様である。 <Food &Drink>
The present invention includes foods and drinks containing the component (A), the component (B) (and other components such as the component (C)) (that is, foods and drinks containing the agent or composition).
In such a food and drink, preferred embodiments of the component (A) and the component (B), the ratio thereof, and the like are the same as described above.
　飲食品としては、いわゆる健康食品を含む一般食品の他、厚生労働省の保健機能食品制度に規定された特定保健用食品や栄養機能食品などの保健機能食品をも含むものであり、さらに、サプリメント（栄養補助食品）、飼料、食品添加物なども本発明の飲食品に包含される。 In addition to general foods, including so-called health foods, foods and drinks also include health foods such as foods for specified health use and foods with nutrient function specified by the Ministry of Health, Labor and Welfare. Nutritional supplements), feed, food additives, and the like are also included in the food and drink of the present invention.
　また、飲食品は、特定の対象者用［例えば、高齢者用、患者又は病者用（例えば、神経疾患（前記例示の神経疾患など）を有する患者用）など］の飲食品であってもよい。 In addition, the food and drink may be food or drink for a specific subject [for example, for elderly people, patients or patients (for example, for patients having a neurological disease (such as the above-described neurological diseases)]). Good.
　成分（Ａ）及び／又は成分（Ｂ）を飲食品に使用するには、そのまま、または種々の栄養成分等とともに加工肉、清涼飲料などの飲食品の原料に混ぜて飲食品を製造することができる。 In order to use the component (A) and / or the component (B) in foods and drinks, it is necessary to produce foods and drinks as they are or together with various nutritional components and the like in raw materials for foods and drinks such as processed meat and soft drinks. it can.
　また、成分（Ａ）及び／又は（Ｂ）を、健康食品、栄養補助食品などとして使用する場合、例えば、慣用の手段を用いて、錠剤、カプセル（ソフトカプセル、ハードカプセルなど）、散剤、顆粒、液剤（懸濁剤、シロップ剤など）、乳剤、ゼリー、スティック状などの形態に調製することができる。また、錠剤には、崩壊錠（口腔内崩壊錠）も含まれる。 In addition, when the components (A) and / or (B) are used as health foods, dietary supplements, etc., for example, using conventional means, tablets, capsules (soft capsules, hard capsules, etc.), powders, granules, liquids (Suspensions, syrups, etc.), emulsions, jellies, sticks, etc. The tablet includes a disintegrating tablet (orally disintegrating tablet).
　飲食品は、骨砕補又は骨砕補の抽出物を含んでいる限り、食品添加剤（食品用添加剤）を含んでいてもよい。食品添加剤としては、特に限定されないが、例えば、賦形剤（例えば、コムギデンプン、トウモロコシデンプン、セルロース、乳糖、ショ糖、マンニトール、ソルビトール、キシリトール、アルファー化デンプン、カゼイン、ケイ酸アルミン酸マグネシウム、ケイ酸カルシウムなど）、結合剤（例えば、アルファー化デンプン、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンなど）、崩壊剤（例えば、セルロース、ヒドロキシプロピルセルロース、トウモロコシデンプンなど）、流動化剤（例えば、軽質無水ケイ酸、ショ糖脂肪酸エステルなど）、油（例えば、大豆油、ゴマ油、オリーブ油、亜麻仁油、エゴマ油、ナタネ油、ココナッツ油、トウモロコシ油などの植物油又は動物・魚由来の油）、栄養素（例えば、各種ミネラル、各種ビタミン、アミノ酸）、香料、甘味料、矯味剤、着色料、溶媒(エタノール)、塩類、界面活性剤、ｐＨ調節剤、緩衝剤、抗酸化剤、安定化剤、ゲル化剤、増粘剤、滑沢剤、カプセル化剤、懸濁剤、コーティング剤、防腐剤などが挙げられる。 The food and drink may contain a food additive (food additive) as long as it contains bone fracture supplement or an extract of bone fracture supplement. Although it does not specifically limit as a food additive, For example, excipient | fillers (for example, wheat starch, corn starch, cellulose, lactose, sucrose, mannitol, sorbitol, xylitol, pregelatinized starch, casein, magnesium aluminate silicate, Calcium silicate, etc.), binder (eg, pregelatinized starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrant (eg, cellulose, hydroxypropylcellulose, corn starch, etc.), fluidizing agent (eg, light anhydrous silicic acid) Sucrose fatty acid esters, etc.), oils (eg, vegetable oils such as soybean oil, sesame oil, olive oil, linseed oil, sesame oil, rapeseed oil, coconut oil, corn oil, etc.), nutrients (eg, various Minera , Various vitamins, amino acids), flavorings, sweeteners, flavoring agents, coloring agents, solvents (ethanol), salts, surfactants, pH regulators, buffers, antioxidants, stabilizers, gelling agents, thickening Agents, lubricants, encapsulating agents, suspending agents, coating agents, preservatives and the like.
　食品添加剤は、単独で又は２種以上組み合わせてもよく、特に２種以上用いてもよい。なお、２種以上の添加剤を用いる場合、同系統の添加剤から２以上の成分（例えば、賦形剤に分類される成分から２以上の成分）を選択してもよく、異種の添加剤を２以上組み合わせて（例えば、賦形剤と結合剤とを組み合わせて）もよく、これらの両方を選択してもよい。特に、添加剤は、異種の添加剤を組み合わせてもよい。 Food additives may be used alone or in combination of two or more, and in particular, two or more may be used. When two or more kinds of additives are used, two or more components (for example, two or more components selected from the components classified as excipients) may be selected from the same type of additives. May be combined (for example, a combination of an excipient and a binder), or both of them may be selected. In particular, the additive may be a combination of different additives.
　また、錠剤などの形態の飲食品では、上記の中でも、特に、賦形剤、結合剤、及び崩壊剤から選択された少なくとも２以上の添加剤を少なくとも使用してもよい。 In addition, in the food and drink in the form of tablets and the like, at least two or more additives selected from excipients, binders, and disintegrants may be used.
　成分（Ａ）及び／又は成分（Ｂ）を食品添加物として用いる場合、飲食品としては、特に原手入れないが、例えば、食品［例えば、麺類（そば、うどん、中華麺、即席麺など）、菓子類（飴、キャンディー、ガム、チョコレート、スナック菓子（ポテトチップなど）、ビスケット、クッキー、グミ、ゼリー、ジャム、バター、クリーム（シュークリームなど）、ケーキなど）、パン類、水産又は畜産加工食品（かまぼこ、ハム、ソーセージなど）、乳製品（加工乳、発酵乳など）、油脂および油脂加工食品（サラダ油、てんぷら油、マーガリン、マヨネーズ、ショートニング、ホイップクリーム、ドレッシングなど）、調味料（ソース、たれなど）、レトルト食品（カレー、シチュー、丼、お粥、雑炊など）、冷菓（アイスクリーム、シャーベット、かき氷など）、揚げ物（コロッケ、フライドポテト、フライドチキンなど）など］、飲料（茶飲料、清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳酸飲料など）などが挙げられる。 When the component (A) and / or the component (B) is used as a food additive, the food or drink is not particularly well-maintained. However, for example, food [e.g., noodles (such as soba, udon, Chinese noodles, instant noodles), Confectionery (cake, candy, gum, chocolate, snacks (potato chips, etc.), biscuits, cookies, gummy, jelly, jam, butter, cream (cream puffs, cakes, etc.), breads, marine or livestock processed foods (kamaboko) , Ham, sausage, etc.), dairy products (processed milk, fermented milk, etc.), fats and oils and processed foods (salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, dressing, etc.), seasonings (sauce, sauce, etc.) , Retort food (curry, stew, rice cake, porridge, miscellaneous food, etc.), frozen dessert (ice cream, sha Bet, etc. shaved ice), fried (croquettes, fries, etc. fried chicken), etc.], drinks (tea drinks, soft drinks, carbonated drinks, energy drinks, fruit drinks, such as lactic acid beverage), and the like.
　上記の飲食品における成分（Ａ）及び／又は成分（Ｂ）の配合量は、添加形態及び投与形態によっても異なり広い範囲から選択できるが、例えば、０．００１～９０重量％、好ましくは０．００１～８０重量％、さらに好ましくは０．１～７０重量％（例えば、１～５０重量％）、通常、０．０１～５０重量％（例えば、０．１～３０重量％）程度であってもよい。 The amount of component (A) and / or component (B) in the above-mentioned food and drink varies depending on the addition form and administration form, and can be selected from a wide range, for example, 0.001 to 90% by weight, preferably 0. 001 to 80% by weight, more preferably 0.1 to 70% by weight (eg 1 to 50% by weight), usually 0.01 to 50% by weight (eg 0.1 to 30% by weight) Also good.
　特に、本発明の飲食品が、骨砕補エキスを含む場合、骨砕補エキスの割合は、１～９０重量％、好ましくは１０～７０重量％、さらに好ましくは２０～５０重量％程度であってもよい。 In particular, when the food or drink of the present invention contains a bone crush supplement, the proportion of the bone crush extract is 1 to 90% by weight, preferably 10 to 70% by weight, more preferably about 20 to 50% by weight. May be.
　また、本発明の飲食品が、特に、エゾウコギエキスを含む場合、エゾウコギエキスの割合は、例えば、１～９０重量％、好ましくは１０～７０重量％、さらに好ましくは２０～５０重量％程度であってもよい。 In addition, particularly when the food or drink of the present invention contains an elephant extract, the ratio of the extract is, for example, 1 to 90% by weight, preferably 10 to 70% by weight, more preferably about 20 to 50% by weight. May be.
　さらに、本発明の飲食品が、特に、成分（Ｃ）を含む場合、成分（Ｃ）の割合は、例えば、０．００１～９０重量％、好ましくは０．００１～８０重量％、さらに好ましくは０．１～７０重量％（例えば、１～５０重量％）、通常、０．０１～５０重量％（例えば、０．１～３０重量％）程度であってもよく、１～９０重量％程度であってもよい。 Furthermore, when the food or drink of the present invention contains the component (C), the proportion of the component (C) is, for example, 0.001 to 90% by weight, preferably 0.001 to 80% by weight, more preferably 0.1 to 70% by weight (for example, 1 to 50% by weight), usually about 0.01 to 50% by weight (for example, 0.1 to 30% by weight), or about 1 to 90% by weight It may be.
　なお、飲食品において、成分（Ａ）及び／又は成分（Ｂ）（さらには成分（Ｃ））の投与量（又は摂取量又は服用量）は、前記と同様の範囲から選択できる。 In addition, in food and drink, the dose (or intake or dose) of component (A) and / or component (B) (and component (C)) can be selected from the same range as described above.
　以下に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。 EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples, and many modifications are within the technical scope of the present invention. This is possible by those with ordinary knowledge.
　なお、実施例において、骨砕補抽出物（骨砕補水エキス）は、以下のようにして得たものを用いた。 In addition, in the Example, the bone crushing extract (bone crushing water extraction) used what was obtained as follows.
　骨砕補（栃本天海堂、大阪）に２０倍量の水を加え、煎じ器（ウチダ和漢薬、東京）を用いて抽出を行った。生薬に加えた水が沸騰するまで強火で加熱し（１５～２０分）、その後とろ火での加熱を１時間続けた。ろ液を濾した後、熱時綿栓濾過し、ろ液を室温で放冷後、液体窒素で凍結させた。さらに凍結乾燥器にて乾燥させ、粉末状の骨砕補の抽出物を得た（収率７．８％）。 Twenty times the amount of water was added to osteoclast (Tochimoto Tenkaido, Osaka), and extraction was performed using a decoction device (Uchida Wakayaku, Tokyo). The mixture was heated on a strong fire until the water added to the crude drug boiled (15-20 minutes), and then the heat was continued for 1 hour. The filtrate was filtered and then filtered with a cotton plug while hot. The filtrate was allowed to cool at room temperature and then frozen with liquid nitrogen. Furthermore, it was made to dry with a freeze dryer, and the extract of the powdered osteoclastic supplement was obtained (yield 7.8%).
　また、実施例において、物体認知記憶試験は、次のようにして行った。
＜物体認知記憶試験＞
　物体認知記憶試験とは、動物が新しいものに興味を示す習性を利用した試験である。すなわち、テスト段階において、トレーニング段階で見た物体を覚えているか否かを確認する試験である。試験は、文献（Int J Neurosci, 121, pp.181-190, 2011.、およびInt J Neurosci, 121, pp.641-648, 2011.）の記載にしたがって行った。具体的には、以下のように行った。 In the examples, the object recognition memory test was performed as follows.
<Object recognition memory test>
The object recognition memory test is a test using a habit of showing interest in new things by animals. That is, in the test stage, it is a test for confirming whether or not the object seen in the training stage is remembered. The test was performed as described in the literature (Int J Neurosci, 121, pp.181-190, 2011. and Int J Neurosci, 121, pp.641-648, 2011.). Specifically, it was performed as follows.
　試験は比較的照明をおとした部屋（約100ルクス）にて行った。トレーニング段階とテスト段階の間の適切な時間間隔（インターバル）は、別のマウスのグループで予めテストして決めた。試験を行うオープンフィールドボックスの内側の壁には、一切の目印はない。トレーニング段階ではフィールド内に２つの同じ物体を置き10分間の探索行動をさせる。テストの段階では、物体の一つを新しい物体に置き換え、しかし置き場所は変えずに、10分間の探索行動をさせる。マウスが、置き換えた新しい物体に興味を示して探索行動する回数の増加を、物体記憶能力の指標とするものである。
　実施例では、総探索時間に対する新たな物体への探索回数の割合（％）を探索指向指数（Preference index）として算出した。 The test was conducted in a relatively well-lit room (approximately 100 lux). Appropriate time intervals between the training phase and the test phase were determined in advance by testing with different groups of mice. There are no landmarks on the inner wall of the open field box under test. In the training phase, place two identical objects in the field and let them search for 10 minutes. During the test phase, one of the objects is replaced with a new object, but the place is not changed, and a 10-minute exploratory action is performed. The increase in the number of times the mouse performs an exploratory action with interest in the replaced new object is used as an index of the object memory ability.
In the example, the ratio (%) of the number of searches for a new object with respect to the total search time is calculated as a search index (Preference index).
（実施例１）
　ナリンゲニン、ナリンゲニンの配糖体の一種であるナリンゲニン－７’－Ｏ－グルクロニドが神経細胞に対して活性を示すことを検討するために、これらをそれぞれ合成し、まず、正常大脳皮質神経細胞に対する突起伸展作用を検討した。初代培養したマウス大脳皮質神経細胞の培養３日目に、０．０１、０．１、１、１０μＭの濃度で各化合物を処置し、さらに４日後に細胞を固定した後、軸索（ｐＮＦ－Ｈ陽性）の細胞あたりの長さを免疫染色によって検討した。 Example 1
Naringenin and naringenin-7'-O-glucuronide, one of the glycosides of naringenin, were synthesized in order to investigate the activity against nerve cells. First, projections on normal cortical neurons The extension action was examined. On the third day of culture of primary cultured mouse cerebral cortical neurons, each compound was treated at a concentration of 0.01, 0.1, 1, 10 μM, and after 4 days, the cells were fixed, and then axons (pNF− The length per cell (H positive) was examined by immunostaining.
　なお、これら２つの化合物及び後述のナリンゲニン－４’－Ｏ－グルクロニドの構造を下記に示す。
Figure JPOXMLDOC01-appb-C000004
 The structures of these two compounds and naringenin-4′-O-glucuronide described later are shown below.
Figure JPOXMLDOC01-appb-C000004
　結果を図１に示す。なお、図１において、「Cont」はコントロール、「Naringenin」はナリンゲニン、「Naringenin-7-O」はナリンゲニン－７’－Ｏ－グルクロニドを示し、値はコントロールの値を１００とし、μｍ／ニューロンで換算したものである。 The results are shown in FIG. In FIG. 1, “Cont” indicates control, “Naringenin” indicates naringenin, and “Naringenin-7-O” indicates naringenin-7′-O-glucuronide. The value is 100 μm / neuron. It is converted.
　図１の結果から明らかなように、ナリンゲニン及びナリンゲニン－７’－Ｏ－グルクロニドのいずれについても、活性を示すことがわかった。 As is clear from the results of FIG. 1, it was found that both naringenin and naringenin-7'-O-glucuronide showed activity.
（実施例２）
　実施例１において、合成したナリンゲニン及びナリンゲニン－７’－Ｏ－グルクロニドに加えて、ナリンゲニンの配糖体であるナリンゲニン－４’－Ｏ－グルクロニドを合成し、Ａβ（２５－３５）による軸索の伸展作用を以下のようにして調べた。 (Example 2)
In Example 1, in addition to the synthesized naringenin and naringenin-7′-O-glucuronide, naringenin-4′-O-glucuronide, which is a glycoside of naringenin, was synthesized, and axon of Aβ (25-35) was synthesized. The stretching action was examined as follows.
　初代培養したマウス大脳皮質神経細胞の培養３日目に、１０μＭ　Ａβ（２５－３５）を処置し、その３日後に、０．０１、０．１、１，１０μＭの濃度でそれぞれの化合物を処置し、さらに４日後に細胞を固定した後、軸索（ｐＮＦ－Ｈ陽性）の細胞あたりの長さを免疫染色によって検討した。 On the third day of culture of primary cultured mouse cerebral cortical neurons, 10 μM Aβ (25-35) was treated, and three days later, each compound was treated at concentrations of 0.01, 0.1, 1, and 10 μM. After 4 days, the cells were fixed, and the length per cell of the axon (pNF-H positive) was examined by immunostaining.
　結果を図２に示す。なお、図２において、「Cont」はコントロール（Ａβ（２５－３５）の処置なし）、「Veh」は溶媒のみ、「Naringenin」はナリンゲニン、「Naringenin-４’-O」はナリンゲニン－４’－Ｏ－グルクロニド、「Naringenin-7-O」はナリンゲニン－７’－Ｏ－グルクロニドを示し、値はコントロールの値を１００とし、μｍ／ニューロンで換算したものである。 The results are shown in FIG. In FIG. 2, “Cont” is the control (no treatment of Aβ (25-35)), “Veh” is the solvent only, “Naringenin” is naringenin, “Naringenin-4′-O” is naringenin-4′- O-glucuronide, “Naringenin-7-O” indicates naringenin-7′-O-glucuronide, and the value is converted to μm / neuron with the control value being 100.
　図２の結果から明らかなように、Ａβ（２５－３５）による軸索萎縮に対して、ナリンゲニン、ナリンゲニン－４’－Ｏ－グルクロニド、ナリンゲニン－７’－Ｏ－グルクロニドのいずれにおいても再伸展活性が認められた。 As is apparent from the results of FIG. 2, re-extension activity of any of naringenin, naringenin-4′-O-glucuronide and naringenin-7′-O-glucuronide against axonal atrophy caused by Aβ (25-35) Was recognized.
　以下の実施例では、ナリンゲニンを含有することが知られている骨砕補について調べた。 In the following examples, osteoprosthesis known to contain naringenin was examined.
（実施例３）
　新奇物体認識試験の後、各マウスを麻酔し、冷却した生理食塩水で経心臓灌流した。全脳を慎重に頭蓋骨から外し、４％パラホルムアルデヒドに１晩浸けたのち３０％スクロース－ＰＢＳに浸し、－３０℃で保存した。脳をクライオスタット（ＣＭ３０５０Ｓ、ライカ（Ｌｅｉｃａ）社、ハイデルベルク、ドイツ）を用いて２０μｍの連続した冠状切片に切り出した。 (Example 3)
After the novel object recognition test, each mouse was anesthetized and transcardially perfused with chilled saline. The whole brain was carefully removed from the skull, soaked in 4% paraformaldehyde overnight, then soaked in 30% sucrose-PBS and stored at −30 ° C. Brains were cut into 20 μm continuous coronal sections using a cryostat (CM3050S, Leica, Heidelberg, Germany).
　スライスは４％パラホルムアルデヒドで固定し、Ａβ（１－４０／４２）（１：３００）に対するポリクローナル抗体（ケミコン（Ｃｈｅｍｉｃｏｎ）、テメキュラ（Ｔｅｍｅｃｕｌａ）、カリフォルニア州、米国）、ｐＮＦ－Ｈ（１：３００）に対するモノクローナル抗体（コバンス（Ｃｏｖａｎｃｅ）、エメリーヴィル（Ｅｍｅｒｙｖｉｌｌｅ）、カリフォルニア州、米国）を用い、４℃で２０時間染色した。二次抗体として、Ａｌｅｘａ　Ｆｌｕｏｒ　４８８標識ヤギ抗ウサギＩｇＧ抗体（１：３００）とＡｌｅｘａ　Ｆｌｕｏｒ　５６８標識ヤギ抗マウス抗体（１：３００）（モレキュラープローブス（Ｍｏｌｅｃｕｌａｒ　Ｐｒｏｂｅｓ）社、ユージーン（Ｅｕｇｅｎｅ）、オレゴン州、米国）を用いた。 Slices were fixed with 4% paraformaldehyde and polyclonal antibodies against Aβ (1-40 / 42) (1: 300) (Chemicon, Temecula, Calif., USA), pNF-H (1: 300). ) And a monoclonal antibody (Covance, Emeryville, CA, USA) for 20 hours at 4 ° C. As secondary antibodies, Alexa Fluor 488-labeled goat anti-rabbit IgG antibody (1: 300) and Alexa Fluor 568-labeled goat anti-mouse antibody (1: 300) (Molecular Probes, Eugene, Oregon) , USA).
　軸索及びＡβ（１－４０／４２）の蛍光画像は、蛍光顕微鏡（ＢＸ－６１）を使用して３２４μｍ×４３０μｍで撮影した。 Fluorescence images of axons and Aβ (1-40 / 42) were taken at 324 μm × 430 μm using a fluorescence microscope (BX-61).
　細胞外アミロイド斑の面積は、画像解析ソフトウェアＩｍａｇｅＪ（ｈｔｔｐ：／／ｒｓｂｗｅｂ．ｎｉｈ．ｇｏｖ／ｉｊ）を用いて測定した。ｐＮＦ－Ｈ陽性の肥大化して軸索終末部の面積は、すべてのアミロイド斑に対してＩｍａｇｅＪを用いて測定した。 The area of extracellular amyloid plaques was measured using image analysis software ImageJ (http://rsbweb.nih.gov/ij). The area of pNF-H positive hypertrophied and axon terminal was measured using ImageJ for all amyloid plaques.
　なお、骨砕補水エキスは生理食塩水に溶解して投与量を５００ｍｇ／ｋｇ／日として１日１回、５ＸＦＡＤマウス（６－８か月齢、雄性及び雌性）に３１日間、経口投与した。経口投与する薬液の量は、１０ｍｌ／ｋｇ体重とした。 The bone replenishment extract was dissolved in physiological saline and orally administered once daily to 5XFAD mice (6-8 months old, male and female) at a dose of 500 mg / kg / day for 31 days. The amount of the drug solution to be administered orally was 10 ml / kg body weight.
　結果を図３～１０に示す。なお、図３～１０において、「Ｗｉｌｄ」は野生型マウス、「５ＸＦＡＤ」は「５ＸＦＡＤマウス」、「Ｖｅｈ」は溶媒のみ、「Ｅｘｔ５００」は骨砕補水エキスを５００ｍｇ／ｋｇの割合で投与した群（マウス）を示す。 The results are shown in Figs. In FIGS. 3 to 10, “Wild” is a wild-type mouse, “5XFAD” is “5XFAD mouse”, “Veh” is a solvent only, “Ext500” is a group administered with a bone replenishment extract at a rate of 500 mg / kg (Mouse).
　図３～１０の結果から明らかなように、前頭前皮質、嗅周囲皮質、海馬ＣＡ１、海馬歯状回のいずれの部位においても、アミロイドプラークは野生型マウスでは見られないのに対し、５ＸＦＡＤマウスでは増加していた。 As is apparent from the results of FIGS. 3 to 10, amyloid plaques are not observed in wild-type mice in any part of the prefrontal cortex, periorbital cortex, hippocampal CA1, and hippocampal dentate gyrus, whereas 5 × FAD mice It was increasing.
　一方、骨砕補水エキス５００ｍｇ／ｋｇ投与群では、有意にアミロイドプラーク面積が減少した。またアミロイドプラーク近傍に観察される肥大化した変性軸索終末部の面積を定量したところ、前頭前皮質、嗅周囲皮質、海馬ＣＡ１、海馬歯状回のいずれの部位においても、変性軸索は野生型マウスでは見られないのに対し、５ＸＦＡＤマウスでは増加していた。骨砕補水エキス５００ｍｇ／ｋｇ投与群では、これが減少する傾向が示された。 On the other hand, the amyloid plaque area significantly decreased in the osteoclastic rehydration extract 500 mg / kg administration group. Moreover, when the area of the enlarged terminal end of the enlarged axon observed in the vicinity of the amyloid plaque was quantified, the degenerated axon was wild in any part of the prefrontal cortex, periolfactory cortex, hippocampal CA1, and hippocampal dentate gyrus. It was not observed in type mice, but increased in 5XFAD mice. In the osteoclastic rehydration extract 500 mg / kg administration group, a tendency to decrease this was shown.
（実施例４）
　骨砕補水エキスを、生理食塩水に溶解して、投与量を５００ｍｇ／ｋｇ／日として、１日１回、５ＸＦＡＤマウス（４５週齢、オス）に経口投与した。溶媒のみを投与した５ＸＦＡＤマウス群（４５週齢、オス）、および溶媒のみを投与した野生型マウス群（４５週齢、オス）も設けた。 Example 4
The bone replenishment extract was dissolved in physiological saline and orally administered to 5XFAD mice (45 weeks old, male) once a day at a dose of 500 mg / kg / day. A 5XFAD mouse group (45 weeks old, male) to which only the solvent was administered and a wild type mouse group (45 weeks old, male) to which only the solvent was administered were also provided.
　経口投与する薬液の量は、１０ｍｌ／ｋｇ体重とした。投与期間は、２２日間とした。このマウスに対し、物体認知記憶試験を実施し、骨砕補水エキス投与群において記憶改善作用が認められることを確認した後、マウスの大脳皮質を還流脱血後に摘出しライセートを作製した。 The amount of drug solution to be administered orally was 10 ml / kg body weight. The administration period was 22 days. An object recognition memory test was performed on these mice, and after confirming that a memory improving effect was observed in the bone-fed rehydration extract administered group, the cerebral cortex of the mice was extracted after refluxing and lysate was prepared.
　骨砕補水エキスの直接結合タンパク質探索実験により、Ｃｏｌｌａｐｓｉｎ　ｒｅｓｐｏｎｓｅ　ｍｅｄｉａｔｏｒ　ｐｒｏｔｅｉｎ－２　（ＣＲＭＰ２、別名；ｄｉｈｙｄｒｏｐｙｒｉｍｉｄｉｎａｓｅ－ｒｅｌａｔｅｄ　ｐｒｏｔｅｉｎ　２、ＴＯＡＤ－６４）タンパク質の関与を本実施例に先立ち見出していた。 The direct binding protein search experiment of the osteoclast rehydration extract found the involvement of Collapsin response mediator protein-2 (CRMP2, also known as dihydropyrimidinase-related protein 2, TOAD-64) protein prior to this example.
　大脳皮質ライセートにおける、ＣＲＭＰ２リン酸化の程度をウェスタンブロッティング法により検討した。用いた抗体はＣＲＭＰ２の５１４番アミノ酸のスレオニン（ｔｈｒｅｏｎｉｎｅ）のリン酸化を検出する抗体を用いた。 The degree of CRMP2 phosphorylation in cerebral cortical lysate was examined by Western blotting. The antibody used was an antibody that detects phosphorylation of threonine of the 514th amino acid of CRMP2.
　結果を図１１に示す。なお、図１１において、「Ｗｉｌｄ」は野生型マウス、「５ＸＦＡＤ」は「５ＸＦＡＤマウス」、「Ｖｅｈ」は溶媒のみ、「Ｅｘｔ」は骨砕補水エキスを５００ｍｇ／ｋｇの割合で投与した群（マウス）を示す。 The results are shown in FIG. In FIG. 11, “Wild” is a wild-type mouse, “5XFAD” is “5XFAD mouse”, “Veh” is a solvent only, and “Ext” is a group administered with a crushed rehydration extract at a rate of 500 mg / kg ).
　図１１から明らかなように、野生型マウスと比較して５ＸＦＡＤマウスの溶媒投与群では、ＣＲＭＰ２リン酸化が亢進し、一方、骨砕補水エキス投与した５ＸＦＡＤマウスではＣＲＭＰ２のリン酸化程度が有意に減少した。
　ＣＲＭＰ２のリン酸化減少は、軸索伸展の促進につながるメカニズムとして既に認識されているため、骨砕補水エキス投与によるマウス脳内のＣＲＭＰ２リン酸化抑制が、骨砕補水エキスによる軸索伸長、ならびにそれによる記憶亢進の機序の一端であることは明らかである。 As is clear from FIG. 11, CRMP2 phosphorylation was enhanced in the 5XFAD mouse solvent-administered group compared to wild-type mice, whereas CRMP2 phosphorylation was significantly decreased in the 5XFAD mouse administered with the crushed water extract. did.
Reduction of CRMP2 phosphorylation has already been recognized as a mechanism that leads to promotion of axonal extension. Therefore, suppression of CRMP2 phosphorylation in the mouse brain by administration of a bone replenishing water extract is associated with axonal elongation and It is clear that this is part of the mechanism of memory enhancement.
（実施例５）
　骨砕補に含まれる成分を分析し、どの成分が軸索伸展に寄与しうるかについて、以下のように調べた。 (Example 5)
The components contained in the osteoclastic prosthesis were analyzed, and which components can contribute to axonal extension was examined as follows.
　まず、骨砕補水エキスを滅菌精製水に溶解した。マウス大脳皮質神経細胞は胎生１４日齢のｄｄＹマウスから作製した。 First, the bone replenishing water extract was dissolved in sterilized purified water. Mouse cerebral cortical neurons were prepared from embryonic day 14 ddY mice.
　骨砕補水エキスを、さらに、石油エーテル画分、酢酸エチル画分、ｎ－ブタノール画分、水溶性画分に分画した。 The crushed rehydration extract was further fractionated into a petroleum ether fraction, an ethyl acetate fraction, an n-butanol fraction, and a water-soluble fraction.
　初代培養したマウス大脳皮質神経細胞の培養３日目に、１０μＭＡβ（２５－３５）を処置し、その３日後に、１又は１０μｇ／ｍＬの濃度でそれぞれの画分を処置し、さらに４日後に細胞を固定した後、軸索（ｐＮＦ－Ｈ陽性）と樹状突起（ＭＡＰ２陽性）の細胞あたりの長さを免疫染色によって検討した。 On day 3 of culture of primary cultured mouse cerebral cortical neurons, 10 μMAβ (25-35) was treated, 3 days later, each fraction was treated at a concentration of 1 or 10 μg / mL, and another 4 days later After fixing the cells, the length per cell of axons (pNF-H positive) and dendrites (MAP2 positive) was examined by immunostaining.
　結果を図１２に示す。図１２において、「Cont」はコントロール、「Veh」は溶媒のみ、「Ｐ．ｅ．」は石油画分、「ＥｔＯＡｃ」は酢酸エチル画分、「ＢｕＯＨ」はｎ－ブタノール画分、「Ｗａｔｅｒ」は水溶性画分を示し、値はコントロールの値を１００とし、μｍ／ニューロンで換算したものである。 The results are shown in FIG. In FIG. 12, “Cont” is the control, “Veh” is the solvent only, “Pe” is the petroleum fraction, “EtOAc” is the ethyl acetate fraction, “BuOH” is the n-butanol fraction, “Water”. Indicates a water-soluble fraction, and the value is converted to μm / neuron with a control value of 100.
　図１２から明らかなように、Ａβ２５－３５未処置細胞と比較してＡβ２５－３５細胞では、軸索の密度が有意に減少していた。いずれの画分でも軸索伸展傾向が認められたが、特にｎ－ブタノール画分（１０μｇ／ｍＬ）の後処置によって、有意に軸索が伸展した。 As is apparent from FIG. 12, the axon density was significantly decreased in Aβ25-35 cells compared to Aβ25-35 untreated cells. Axon extension tendency was observed in all fractions, but axons were significantly extended especially by the post-treatment of the n-butanol fraction (10 μg / mL).
（実施例６）
　実施例４で得られたｎ－ブタノール画分を詳細に分析し、化合物レベルでどの成分が軸索伸展に寄与しうるかについて、以下のように調べた。 (Example 6)
The n-butanol fraction obtained in Example 4 was analyzed in detail, and the components that can contribute to axonal extension at the compound level were examined as follows.
　まず、（Ａ）ｎ－ブタノール画分をシリカゲルで細分して５つの化合物を単離し、これらが、ナリンゲニン（１）、ネオエリオシトリン（２）、５，７－ジヒドロキシクロモン－７－Ｏ－ネオヘスペリドシド（４）、及びプロトカテク酸（５）であることを、ＬＣ－ＭＳ質量解析の結果から同定した。 First, (A) n-butanol fraction was subdivided with silica gel to isolate five compounds, which were naringenin (1), neoeriocitrin (2), 5,7-dihydroxychromone-7-O-neohe It was identified from the results of LC-MS mass analysis that it was spidoside (4) and protocatechuic acid (5).
　なお、ｎ－ブタノール画分のＬＣ－ＭＳのチャートを図１３に、同定した各化合物の構造を下記式に示す。
Figure JPOXMLDOC01-appb-C000005
 The LC-MS chart of the n-butanol fraction is shown in FIG. 13, and the structure of each identified compound is shown in the following formula.
Figure JPOXMLDOC01-appb-C000005
　そして、初代培養したマウス大脳皮質神経細胞の培養３日目に、１０μＭ　Ａβ（２５－３５）を処置し、その３日後に、１又は１０μＭの濃度で、それぞれ５つの化合物を処置し、さらに４日後に細胞を固定した後、軸索（ｐＮＦ－Ｈ陽性）と樹状突起（ＭＡＰ２陽性）の細胞あたりの長さを免疫染色によって検討した。 Then, 10 μM Aβ (25-35) was treated on the 3rd day of culture of primary cultured mouse cerebral cortical neurons, and 3 days later, 5 compounds each were treated at a concentration of 1 or 10 μM. After fixing the cells one day later, the length per cell of axons (pNF-H positive) and dendrites (MAP2 positive) was examined by immunostaining.
　結果を図１４に示す。なお、図１４において、「Cont」はコントロール、「Veh」は溶媒のみ、「１」などの数字は各化合物を示し、値はコントロールの値を１００とし、μｍ／ニューロンで換算したものである。 The results are shown in FIG. In FIG. 14, “Cont” is the control, “Veh” is the solvent only, numbers such as “1” indicate each compound, and the value is the value of the control, which is converted to μm / neuron.
　図１４から明らかなように、Ａβ２５－３５未処置細胞と比較してＡβ２５－３５細胞では、軸索の密度が有意に減少していたが、化合物１～５の処置によって、軸索が伸展した。特に、エリオジクチオールの配糖体であるネオエリオシトリン（化合物２）、コーヒー酸の配糖体である化合物４では、軸索伸展効果が顕著であった。 As is apparent from FIG. 14, the axon density was significantly decreased in the Aβ25-35 cells compared to the Aβ25-35 untreated cells, but the treatment with the compounds 1 to 5 extended the axons. . In particular, neoeriocitrin (compound 2), which is a glycoside of eriodictyol, and compound 4, which is a glycoside of caffeic acid, showed a remarkable axon extension effect.
（実施例７）
　骨砕補水エキスを生理食塩水に溶解して投与量を５００ｍｇ／ｋｇ／日として１日１回、あるいはエゾウコギ葉水エキスを生理食塩水に溶解して５００ｍｇ／ｋｇ／日として１日１回、あるいは骨砕補水エキス（５００ｍｇ／ｋｇ／日）とエゾウコギ葉水エキス（５０ｍｇ／ｋｇ／日）を同時に１日１回、５ＸＦＡＤマウスに経口投与した。 (Example 7)
Dissolve bone replenishment extract in physiological saline and administer once a day at a dose of 500 mg / kg / day, or dissolve elephant leaf water extract in physiological saline once a day as 500 mg / kg / day, Alternatively, a bone replenishing water extract (500 mg / kg / day) and an Ekogi leaf water extract (50 mg / kg / day) were orally administered to 5XFAD mice once a day at the same time.
　なお、エゾウコギ葉エキスは、ウコギ科のEleutherococcus senticosusの葉を８５度の水に３０分間浸潤し濾過したものを凍結乾燥して用いた。 In addition, the Ezoukogi leaf extract was used by freeze-drying a filter obtained by infiltrating the leaves of Eleutherococcus senticosus in the family Urugiaceae into water at 85 degrees for 30 minutes and filtering.
　５ＸＦＡＤマウスはメス、２７－５６週齢、対照群の野生型マウスはメス、５２週齢のものを用いた。経口投与する薬液の量は、１０ｍＬ／ｋｇ体重とした。投与期間は、１５日間とした。このマウスに対し、物体認知記憶試験を実施した。また、トレーニング段階とテスト段階のインターバルは１時間（テスト１）と２４時間（テスト２）の２条件にした。 5XFAD mice were female, 27-56 weeks old, and wild-type mice in the control group were female, 52 weeks old. The amount of the drug solution to be administered orally was 10 mL / kg body weight. The administration period was 15 days. An object recognition memory test was performed on these mice. The interval between the training stage and the test stage was set to two conditions of 1 hour (Test 1) and 24 hours (Test 2).
　結果を図１５に示す。なお、図１５において、「Ｗｉｌｄ」は野生型マウス、「５ＸＦＡＤ」は「５ＸＦＡＤマウス」、「Ｖｅｈ」は溶媒のみ、「Kotsusaiho」は骨砕補水エキスのみを投与した群、「Ezoukogi」はエゾウコギ葉水エキスのみを投与した群、「Kotsu/ Ezoukogi」は骨砕補水エキス及びエゾウコギ葉水エキスの双方を投与した群を示す。 The results are shown in FIG. In FIG. 15, “Wild” is a wild-type mouse, “5XFAD” is “5XFAD mouse”, “Veh” is a solvent alone, “Kotsusaiho” is a group to which only a bone rehydration extract is administered, “Ezoukogi” is an Ekoukogi leaf A group to which only the water extract was administered, “Kotsu / Ezoukogi” represents a group to which both the bone replenishing water extract and the Ezoukogi leaf water extract were administered.
　図１５の結果から明らかなように、野生型マウスではテスト１でもテスト２でも物体認知記憶が維持されているのに対し、５ＸＦＡＤマウスの溶媒投与群では、記憶障害が生じた。 As is clear from the results of FIG. 15, object recognition memory was maintained in both test 1 and test 2 in the wild type mouse, whereas memory impairment occurred in the solvent administration group of the 5XFAD mouse.
　一方、骨砕補水エキス単独投与群、エゾウコギ葉水エキス単独投与群ではインターバル時間が１時間と短いときには記憶障害の改善が示されたが、インターバル時間が２４時間のテスト２では記憶改善効果が見られなくなった。一方、骨砕補水エキスとエゾウコギ葉水エキス同時投与群では、テスト１でもテスト２でも記憶障害改善作用が有意に認められた。 On the other hand, in the osteoclastic rehydration extract alone administration group and the Ezoukogi leaf water extract administration group, memory impairment was improved when the interval time was as short as 1 hour, but test 2 with an interval time of 24 hours showed an improvement in memory. I can't. On the other hand, in the simultaneous administration group of the crushed water replenishing extract and the Ezoukogi leaf water extract, both the test 1 and the test 2 showed significant improvement in memory impairment.
　この結果は、骨砕補水エキス及びエゾウコギ葉水エキスは単独でも、記憶改善効果が得られるが、骨砕補水エキスとエゾウコギ葉水エキスとを併用することで、相乗的により強力な記憶改善効果が得られることを示している。 This result shows that the osteoclast replenishment extract and Ezoukogi leaf water extract alone have a memory improvement effect, but the combined use of the osteoclast rehydration extract and Ezoukogi leaf water extract has a synergistic and stronger memory improvement effect. It shows that it is obtained.
（実施例８）
　エゾウコギ葉水エキスを、生理食塩水に溶解して、投与量を５００ｍｇ／ｋｇ／日として、１日１回、正常マウス（ｄｄＹ，雄性、７週齢）に経口投与した。経口投与する薬液の量は、１０ｍＬ／ｋｇ体重とした。投与期間は、２７日間とした。
　なお、エゾウコギ葉水エキスは、ウコギ科のEleutherococcus senticosusの葉を８５度の水に３０分間浸潤し濾過したものを凍結乾燥して用いた。
　このマウスに対し、物体認知記憶試験を実施した。トレーニングは投与２４日目、テストは投与２７日目に実施した。トレーニングとテストのインターバルは７２時間とした。
　結果を図１６に示す。なお、図１６において、「Control」や溶媒のみを投与した対照群、「Extract」はエゾウコギ葉水エキス投与群、「Training」はトレーニング、「Test」はテストを示す。
　図１６の結果から明らかなように、溶媒のみを投与した対照群と比較すると、エゾウコギ葉水エキス投与群では有意に、正常マウスの物体認知記憶が亢進した。 (Example 8)
Ezoukogi leaf water extract was dissolved in physiological saline and administered orally to normal mice (ddY, male, 7 weeks old) once a day at a dose of 500 mg / kg / day. The amount of the drug solution to be administered orally was 10 mL / kg body weight. The administration period was 27 days.
In addition, Ezoukogi leaf water extract was used by freeze-drying a leaf of Eleutherococcus senticosus belonging to the family Urugiaceae infiltrated with water at 85 degrees for 30 minutes.
An object recognition memory test was performed on these mice. Training was performed on the 24th day after administration, and the test was performed on the 27th day after administration. The training and test interval was 72 hours.
The results are shown in FIG. In FIG. 16, “Control” and a control group to which only the solvent is administered, “Extract” is an Ezocogi leaf water extract administration group, “Training” is training, and “Test” is a test.
As is clear from the results in FIG. 16, the object recognition memory of normal mice was significantly enhanced in the Ezocogi leaf water extract administration group compared to the control group to which only the solvent was administered.
　本発明では、記憶力や認知機能の向上又は改善などに有用な剤や組成物を得ることができる。 In the present invention, an agent or composition useful for improving or improving memory ability and cognitive function can be obtained.

Claims (24)

  1. 　ナリンゲニン、エリオジクチオール、５，７－ジヒドロキシクロモン、コーヒー酸、プロトカテク酸、これらの配糖体、及びこれらの塩から選択された少なくとも１種の成分（Ａ）又はエゾウコギ成分（Ｂ）を含み、下記の（１）、（２）及び（３）から選択された少なくとも１つの用途に使用するための剤。
    （１）神経突起の修復及び／又は伸展
    （２）記憶力及び／又は認知機能の向上又は改善
    （３）神経疾患の予防及び／又は治療
    （ただし、ナリンゲニンのみを有効成分として含み、アルツハイマー病の予防及び／又は治療のための剤を除く）     Including at least one component (A) or sorghum component (B) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof, An agent for use in at least one application selected from the following (1), (2) and (3).
    (1) Restoration and / or extension of neurites (2) Improvement or improvement of memory and / or cognitive function (3) Prevention and / or treatment of neurological diseases (however, it contains only naringenin as an active ingredient and prevents Alzheimer's disease) And / or excluding therapeutic agents)
  2. 　成分（Ａ）が、ナリンゲニン、ナリンゲニンの配糖体、及びこれらの塩から選択された少なくとも１以上の成分を含む請求項１記載の剤。 The agent according to claim 1, wherein the component (A) comprises at least one component selected from naringenin, a glycoside of naringenin, and salts thereof.
  3. 　成分（Ａ）が、ナリンゲニン、ナリンギン、ナリンゲニングルクロニド、及びこれらの薬学的に許容される塩から選択された少なくとも１以上の成分を含む請求項１又は２記載の剤。 The agent according to claim 1 or 2, wherein the component (A) comprises at least one component selected from naringenin, naringin, naringen glucuronide, and pharmaceutically acceptable salts thereof.
  4. 　成分（Ａ）を含有する成分として、骨砕補成分を含む請求項１～３のいずれかに記載の剤。 The agent according to any one of claims 1 to 3, wherein the component containing the component (A) comprises a bone crushing auxiliary component.
  5. 　成分（Ａ）と成分（Ｂ）とを組み合わせて用いる請求項１～４のいずれかに記載の剤。 The agent according to any one of claims 1 to 4, wherein the component (A) and the component (B) are used in combination.
  6. 　成分（Ａ）及び成分（Ｂ）を含む請求項１～５のいずれかに記載の剤。 The agent according to any one of claims 1 to 5, comprising a component (A) and a component (B).
  7. 　成分（Ａ）として骨砕補エキスを含み、かつ成分（Ｂ）としてエゾウコギエキスを含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項５又は６記載の剤。 The component (A) contains a bone crush extract, and the component (B) contains a carp extract, and the ratio of the bone crush extract and the carp extract is the former / the latter (weight ratio) = 1 / 0.01-1 The agent according to claim 5 or 6, which is / 100.
  8. 　さらに、ジオスゲニン類、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）と組み合わせて用いる請求項１～７のいずれかに記載の剤。 Furthermore, the agent according to any one of claims 1 to 7, which is used in combination with at least one component (C) selected from diosgenins, dihydroxyvitamin D3 and desonomin.
  9. 　成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項８記載の剤。 The agent according to claim 8, wherein the ratio of component (A) and / or component (B) to component (C) is the former / the latter (weight ratio) = 1 / 0.01 to 1/100.
  10. 　ナリンゲニン、エリオジクチオール、５，７－ジヒドロキシクロモン、コーヒー酸、プロトカテク酸、これらの配糖体、及びこれらの塩から選択された少なくとも１種の成分（Ａ）と、エゾウコギ成分（Ｂ）とを含む組成物。 At least one component (A) selected from naringenin, eriodictyol, 5,7-dihydroxychromone, caffeic acid, protocatechuic acid, glycosides thereof, and salts thereof, and the sorghum component (B) A composition comprising.
  11. 　成分（Ａ）が、ナリンゲニン、ナリンゲニンの配糖体、及びこれらの塩から選択された少なくとも１以上の成分を含む請求項１０記載の組成物。 The composition according to claim 10, wherein the component (A) comprises at least one component selected from naringenin, a glycoside of naringenin, and salts thereof.
  12. 　成分（Ａ）が、ナリンゲニン、ナリンギン、ナリンゲニングルクロニド、及びこれらの塩から選択された少なくとも１以上の成分を含む請求項１０又は１１記載の組成物。 The composition according to claim 10 or 11, wherein the component (A) comprises at least one component selected from naringenin, naringin, naringen glucuronide, and salts thereof.
  13. 　成分（Ａ）を含有する成分として、骨砕補成分を含む請求項１０～１２のいずれかに記載の組成物。 The composition according to any one of claims 10 to 12, comprising an osteoclastic component as a component containing the component (A).
  14. 　成分（Ａ）として骨砕補エキスを含み、かつ成分（Ｂ）としてエゾウコギエキスを含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項１０～１３のいずれかに記載の組成物。 The component (A) contains a bone crush extract, and the component (B) contains a carp extract, and the ratio of the bone crush extract and the carp extract is the former / the latter (weight ratio) = 1 / 0.01-1 The composition according to any one of claims 10 to 13, which is / 100.
  15. 　さらに、ジオスゲニン類、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）と組み合わせて用いる請求項１０～１４のいずれかに記載の組成物。 Furthermore, the composition according to any one of claims 10 to 14, which is used in combination with at least one component (C) selected from diosgenins, dihydroxyvitamin D3 and desonomin.
  16. 　成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項１５記載の組成物。 16. The composition according to claim 15, wherein the ratio of component (A) and / or component (B) to component (C) is the former / the latter (weight ratio) = 1 / 0.01 to 1/100.
  17. 　下記の（１）、（２）及び（３）から選択された少なくとも１つの用途に使用するための組成物である請求項１０～１６のいずれかに記載の組成物。
    （１）神経突起の修復及び／又は伸展
    （２）記憶力及び／又は認知機能の向上又は改善
    （３）神経疾患の予防及び／又は治療     The composition according to any one of claims 10 to 16, which is a composition for use in at least one application selected from the following (1), (2) and (3).
    (1) Restoration and / or extension of neurites (2) Improvement or improvement of memory and / or cognitive function (3) Prevention and / or treatment of neurological diseases
  18. 　請求項５～１６のいずれかに記載の剤又は組成物を含有する飲食品。 A food or drink containing the agent or composition according to any one of claims 5 to 16.
  19. 　サプリメント、健康食品、機能性表示食品、栄養機能食品又は特定保健用食品である請求項１８記載の飲食品。 The food or drink according to claim 18, which is a supplement, health food, functional labeling food, nutritional functional food or food for specified health use.
  20. 　骨砕補エキスを１～９０重量％含む請求項１８又は１９記載の飲食品。 The food or drink according to claim 18 or 19, comprising 1 to 90% by weight of a bone fracture supplement.
  21. 　エゾウコギエキスを１～９０重量％含む請求項１８～２０のいずれかに記載の飲食品。 The food or drink according to any one of claims 18 to 20, comprising 1 to 90% by weight of Ezoukogi extract.
  22. 　骨砕補エキスを１～９０重量％、エゾウコギエキスを１～９０重量％含み、骨砕補エキスとエゾウコギエキスとの割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項１８～２１のいずれに記載の飲食品。 It contains 1-90% by weight of the osteoclastic extract and 1-90% by weight of the elephant extract, and the ratio of the osteoclastic extract to the elephant extract is the former / the latter (weight ratio) = 1 / 0.01 to 1/100. The food or drink according to any one of claims 18 to 21.
  23. 　さらに、ジオスゲニン類、ジヒドロキシビタミンＤ３、及びデソノミンから選択された少なくとも１つの成分（Ｃ）を含む請求項１８～２２のいずれかに記載の飲食品。 The food or drink according to any one of claims 18 to 22, further comprising at least one component (C) selected from diosgenins, dihydroxyvitamin D3, and desonomin.
  24. 　成分（Ａ）及び／又は成分（Ｂ）と成分（Ｃ）との割合が、前者／後者（重量比）＝１／０．０１～１／１００である請求項２３記載の飲食品。 The food / beverage product according to claim 23, wherein the ratio of component (A) and / or component (B) to component (C) is the former / the latter (weight ratio) = 1 / 0.01 to 1/100.
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