Classifications

• • 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
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to an antioxidant that can be used as a medicine, food and drink, a food additive, a skin external preparation, and the like.
• Oxidative stress is defined as a state in which the production of reactive oxygen species (ROS) in the living body and the antioxidant defense mechanism are unbalanced and leaning toward oxidation. That is, excessive production of ROS or a decrease in antioxidant capacity leads to oxidative stress.
• ROS oxidizes low density lipoproteins (LDL) of lipids, particularly phospholipids, to produce lipid peroxides and oxidized LDL, and oxidatively denatures and inactivates proteins to cause oxidative damage to DNA. Therefore, oxidative stress is involved in the development of many diseases such as arteriosclerosis, cancer, various lifestyle-related diseases, Alzheimer's disease, and Parkinson's disease by damaging cells and tissues and impairing biological functions. Is promoted (for example, Non-Patent Document 1).
• ROS is easily produced by stimulation of environmental factors such as ultraviolet rays.
• ROS in the skin damages cells by destroying biological tissues such as collagen, and causes skin symptoms such as wrinkles, reduced elasticity, inflammation, and pigmentation.
• ROS is also known to oxidize scalp proteins and lipids and cause hair loss (for example, Patent Documents 1 and 2).
• lipid peroxide is known to cause vascular disorders, liver dysfunctions, cataracts, etc., when the concentration of lipid peroxide increases in the blood itself or its oxidative degradation products directly act on nucleic acids and proteins. Yes. Furthermore, it is considered to cause arteriosclerosis because it causes damage to vascular endothelial cells, increased platelet aggregation, and formation of foam cells. For example, it is known that early lesions of arteriosclerosis are caused by oxidized low density lipoprotein (LDL), and the simplest way to know the oxidation of LDL is known to be measuring lipid peroxides. (For example, Non-Patent Document 2).
• LDL low density lipoprotein
• vitamin E As antioxidants derived from natural products, vitamin E, vitamin C, neutral fractions of plant extracts of the genus Helichrysum (for example, Patent Document 1), extracts of Euphorbia (for example, Patent Document 2), etc. It has been known.
• Patent Document 9 discloses hyperlipidemia of ⁇ -oryzanol, which is a mixture of compounds in which ferrate esters are bonded to campesterol, ⁇ -sitosterol, cycloartol, 24-methylenecycloartanol, and cyclobranol. The use of the treatment / prevention agent is described.
• Patent Document 10 when cycloartol and 24-methylcycloartol are each administered alone, cholesterol in plasma decreases, HDL-C, which is good cholesterol, decreases, and TG, PL, and LPO Has not been shown to show significant variation.
• antioxidants such as BHT (3,5-tert-butyl-4-hydroxytoluene) and BHA (2,3-tert-butyl-hydroxyanisole) have been developed to suppress oxidation of lipids and the like.
• BHT 3,5-tert-butyl-4-hydroxytoluene
• BHA 2,3-tert-butyl-hydroxyanisole
• Cyclolanostane compounds such as 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol, and 4-methylcholest-7-en-3-ol, 4 -Hyperglycemia improving agent, pancreatic function improving agent, insulin resistance improvement containing rophenol compounds such as methyl ergost-7-en-3-ol and 4-methylstigmast 7-en-3-ol as active ingredients
• Agents and visceral fat accumulation inhibitors are known (Patent Documents 11 to 13, Patent Documents 14 to 15, Patent Documents 16 to 17, and Patent Document 18 respectively).
• An object of the present invention is to provide an antioxidant that is highly safe, suppresses oxidation of biological components, particularly lipids, and can be used as a medicine, food and drink, food additive, skin external preparation, and the like.
• an object of the present invention is to provide a medicine, food and drink, etc. for inhibiting lipid peroxide production, which effectively inhibits production of lipid peroxide in blood.
• a first invention for solving the above-described problem is an antioxidant (hereinafter referred to as “an antioxidant of the present invention”) containing a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• an antioxidant of the present invention containing a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the following (1) to (9) are preferred forms.
• a second invention for solving the above-mentioned problem is a method for producing an antioxidant, comprising a step of blending a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient. Same as one invention.
• 1st invention contains the form of the pharmaceutical for lipid-peroxide production suppression containing the compound chosen from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the following (10) to (13) are preferable modes.
• the second invention includes a form of a method for producing a medicament for inhibiting lipid peroxide production, comprising a step of blending a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the preferred form of the compound in the form is the same as described above.
• 1st invention contains the form of the food-drinks for lipid peroxide production suppression containing the compound chosen from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the following (14) to (20) are preferable modes.
• 2nd invention includes the form of the manufacturing method of the food / beverage products for lipid peroxide production suppression including the process of mix
• the preferred form of the compound in the form is the same as described above.
• 1st invention contains the form of the food additive for lipid peroxide production suppression containing the compound chosen from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the following (21) to (25) are preferable modes.
• the second invention includes a form of a method for producing a food additive for inhibiting lipid peroxide production, comprising a step of blending a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the preferred form of the compound in the form is the same as described above.
• blends an emulsifier is also preferable.
• the third invention for solving the above-mentioned problem is the use of a compound selected from a cyclolanostane compound and a rophenol compound in the production of an antioxidant, and the preferred form of the compound is the same as that of the first invention. is there.
• the third invention includes a form of use of a compound selected from a cyclolanostane compound and a rophenol compound in the manufacture of a medicament for inhibiting lipid peroxide production.
• a compound selected from a cyclolanostane compound and a rophenol compound in the manufacture of a medicament for inhibiting lipid peroxide production.
• the preferred form of the compound in this form is the same as in the first invention. Moreover, the following are also contained in this form.
• 3rd invention includes the form of use of the compound chosen from the cyclolanostane compound and the rophenol compound in manufacture of the food-drinks for lipid peroxide production
• the preferred form of the compound in this form is the same as in the first invention. Moreover, the following are also contained in this form.
• 3rd invention also includes the form of use of the compound chosen from the cyclolanostane compound and the rophenol compound in manufacture of the food additive for lipid peroxide production
• the preferred form of the compound is the same as in the first invention. Moreover, the following are also contained in this form.
• a fourth invention for solving the above problems is a compound selected from a cyclolanostane compound and a rophenol compound used for antioxidation, and a preferable form of the compound is the same as that of the first invention. .
• the said compound is used in order to suppress the oxidation of a lipid, and it is preferable to be used in order to suppress the production
• the fourth invention includes a form of a composition containing a compound selected from a cyclolanostane compound and a rophenol compound used for antioxidant purposes.
• a fifth invention for solving the above-mentioned problem is that a compound selected from a cyclolanostane compound and a rophenol compound is administered to a subject in need of antioxidant treatment of a disease or symptom contributed by oxidation or A preventive method, and the preferred form of the compound is the same as in the first invention.
• the following (37) to (39) are preferable modes.
• the sixth invention for solving the above-mentioned problem is a method for imparting antioxidant activity to a food or drink, wherein the concentration of the compound selected from the cyclolanostane compound and the rophenol compound in the food or drink is at least a total amount. It is a method including the process of mix
• the preferred form of the compound is the same as in the first invention.
• a seventh invention for solving the above-mentioned problems is a method for enhancing the antioxidant activity of a food or drink comprising a compound selected from a cyclolanostane compound and a rophenol compound, comprising: This is a method including a step of blending the compound with a food or drink so that the concentration of the compound selected from the phenol compounds is at least 0.0001% by mass in the total amount.
• the preferred form of the compound is the same as in the first invention.
• the antioxidant of the present invention can be used in various forms such as pharmaceuticals, foods and drinks, food additives, and external preparations for skin, and suppresses oxidation of biological components, particularly lipid oxidation.
• the medicament of the present invention can be safely administered and effectively suppresses the oxidation of biological components, particularly the production of lipid peroxide in the blood.
• the food / beverage products of this invention can be ingested safely, and suppress effectively the oxidation of a biological component, especially the production
• the food additive of this invention is suitable for manufacturing the said food / beverage products, or preventing the oxidation of the component of food / beverage products.
• the skin external preparation of this invention can be apply
• the cyclolanostane compound and the rophenol compound which are the active ingredients of the antioxidant of the present invention, can be produced by chemical synthesis, according to the production method of the present invention, the antioxidant of the present invention can be simplified. Can be manufactured.
• the active ingredient of the antioxidant of the present invention is easily produced from a lily family plant, for example, a plant such as Aloe barbadensis Miller, which has been confirmed to be safe from dietary experience and is easily available. Therefore, according to the production method of the present invention, the antioxidant of the present invention can be produced easily.
• the antioxidant of the present invention contains a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• cyclolanostan compound The cyclolanostan compound (compound having a cyclolanostane skeleton) is represented by the following general formula (1).
• R1 is a linear or branched alkyl group having 6 to 8 carbon atoms, an alkenyl group having one or two double bonds, or these alkyl groups and alkenyl groups.
• 1 or 2 of the hydrogen atom is a substituted alkyl group or a substituted alkenyl group substituted with a hydroxyl group and / or a carbonyl group
• R2 and R3 are each independently a hydrogen atom or a methyl group
• R1 is preferably any one of the groups represented by the following formulae.
• Preferred cyclolanostane compounds include 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol.
• Each compound has a structure represented by the following formulas (2) and (3).
• the cyclolanostane compound can be chemically produced according to a known production method.
• 24-methylene-9,19-cyclolanostane-3-ol (common name: 24-methylenecycloartanol) represented by the formula (3) is disclosed in JP-A-57-018617. It is possible to manufacture by a method. Further, the cyclolanostane compound is produced by a method disclosed in JP-A-2003-277269, using a hydrolyzate of cycloartol ferrate (formula (4)) from ⁇ -oryzanol as a starting material. Is possible.
• Cyclolanostane compounds are known to be contained in plants such as liliaceae, legumes, gramineae, solanaceae, and pepperaceae ([Phytochemistry, USA, 1977, No. 1). 16, pp. 140-141], [Handbook of phytochemical constituents of GRAS herbs and other economic plants], 1992, CRC, USA], or [Hager's Handbuch der Pharmazeutica für für für Science, Volumes 2-6, 1969-1979, Springer Fairlake Berlin, Germany ⁇ reference). Therefore, it is also possible to extract from these plants using methods such as organic solvent extraction or hot water extraction.
• the cyclolanostane compound may be biologically produced using a microorganism or the like. Or you may manufacture using the enzyme derived from microorganisms.
• the molecular weight, structure, etc. of the compound produced as described above can be determined or confirmed by, for example, a mass spectrum (MS) method and a nuclear magnetic resonance spectrum (NMR) method.
• the cyclolanostane compound may be a pharmaceutically acceptable salt.
• Pharmaceutically acceptable salts include both metal salts (inorganic salts) and organic salts, the list of which is “Remington's Pharmaceutical Sciences, 17th Edition, 1985, What is published in "page 1418" is illustrated.
• inorganic acid salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and sulfate, malate, maleate, fumarate, tartrate
• Organic salts such as succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, and stearate are included without limitation.
• solvates such as a hydrate of the said compound or its pharmaceutically acceptable salt, can also be used.
• rophenol compound The rophenol compound (compound having a rophenol skeleton) is represented by the following general formula (5).
• R1 is a linear or branched alkyl group having 5 to 16 carbon atoms or an alkenyl group containing one or two double bonds. These alkyl groups or alkenyl groups may be substituted alkyl groups or substituted alkenyl groups in which at least one hydrogen atom is substituted with a hydroxyl group and / or a carbonyl group.
• R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a substituted alkyl group, and R4 forms C ⁇ O together with the carbon atoms constituting the ring, or —OH, —OCOCH One of the three .
• the alkyl group having 1 to 3 carbon atoms is preferably a methyl group, an ethyl group or the like, and particularly preferably a methyl group.
• R1 is preferably any one of groups represented by the following formulae.
• Preferred rophenol compounds include 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstigmast-7-en-3-ol. .
• Each compound has a structure represented by the following formulas (6) to (8).
• the rophenol compound is known to be contained in a plant, like the cyclolanostane compound, and can be produced according to a known method for producing rophenol using a plant as a raw material (for example, Japanese Patent No. 3905913). No. publication). Furthermore, rophenol compounds can be synthesized according to supplement data described in, for example, Vitali Matyash et al., PLOS BIOLOGY, Volume 2, Issue 10, e280, 2004. The molecular weight, structure, etc. of the compound produced as described above can be determined or confirmed by, for example, a mass spectrum (MS) method and a nuclear magnetic resonance spectrum (NMR) method.
• MS mass spectrum
• NMR nuclear magnetic resonance spectrum
• the rophenol compound may be a pharmaceutically acceptable salt.
• examples of such salts include the same salts as in the case of cyclolanostane compounds.
• the antioxidant of the present invention contains a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the compound may be one kind or plural kinds.
• the antioxidant of the present invention preferably contains a combination of a compound selected from cyclolanostane compounds and a compound selected from rophenol compounds.
• Each of the cyclolanostane compound and the rophenol compound may be one kind or plural kinds.
• the mass ratio range between the cyclolanostane compound and the rophenol compound is preferably as follows.
• the specific mass ratio range includes cyclolanostane compounds (particularly 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostane-3-) contained in natural aloe vera. All) and rophenol compounds (especially 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstigmast-7-en-3-ol) ).
• the content of the compound selected from the cyclolanostane compound and the rophenol compound in the antioxidant of the present invention can be appropriately selected according to the target disease, the administration subject, etc., but the total amount is preferably at least 0.0001. % By weight, more preferably at least 0.001% by weight, even more preferably at least 0.005% by weight, particularly preferably at least 0.01% by weight.
• the upper limit of the amount in the medicament of the present invention is not particularly limited, but the total amount is 90% by mass or less, preferably 70% by mass or less, more preferably 50% by mass or less.
• the antioxidant of the present invention can be used in the form of pharmaceuticals, foods and drinks, food additives, skin external preparations and the like.
• the antioxidant of the present invention in the form of using the antioxidant of the present invention as a medicine (referred to as “medicament of the present invention”), it can be administered to mammals including humans orally or parenterally.
• the medicament of the present invention can be used for preventing and / or treating a disease or symptom involving the oxidation of biological components such as lipids, particularly the production of lipid peroxide.
• diseases or symptoms include arteriosclerosis, stroke, angina pectoris, myocardial infarction, liver dysfunction, cirrhosis, hepatitis, retinopathy, cataract, Alzheimer's disease, Parkinson's disease, allergic disease, cancer, rough skin
• diseases or symptoms include arteriosclerosis, stroke, angina pectoris, myocardial infarction, liver dysfunction, cirrhosis, hepatitis, retinopathy, cataract, Alzheimer's disease, Parkinson's disease, allergic disease, cancer, rough skin
• examples include aging, atopic dermatitis, pigmentation such as stains and freckles, wrinkles and decreased elasticity, hair loss, rheumatoid arthritis, tissue disorders such as Behcet's disease, stiff shoulders, coldness, and the like.
• the medicament of the present invention has a remarkable effect particularly on the prevention and / or treatment of arteriosclerosis, angina pectoris, and myocardial infarction.
• the pharmaceutical of this invention is useful with respect to the person
• the form of the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected depending on the therapeutic purpose and usage. Specific examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, syrups, suppositories, injections, ointments, patches, eye drops, nasal drops, etc. it can.
• the administration time of the medicament of the present invention is not particularly limited, and can be appropriately selected according to the target disease.
• the dosage is preferably determined according to the preparation form, usage, patient age, sex, other conditions, the degree of symptoms, and the like.
• the dosage of the medicament of the present invention is appropriately selected depending on the usage, patient age, sex, disease severity, other conditions, and the like.
• the range is preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg / kg / day.
• one of the preferable forms of the medicament of the present invention is that the total amount of the compound selected from the cyclolanostane compound and the rophenol compound is preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to It is a medicine used to be administered at 1 mg / kg / day.
• the medicament of the present invention may contain additives commonly used in medicaments for inhibiting lipid peroxide production.
• additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, surfactants, solvents for injections, and the like.
• the medicament of the present invention is an active ingredient according to the disease or symptom to be prevented or treated, for example, arteriosclerosis, stroke, liver function, as long as the antioxidant action of the cyclolanostane compound and the rophenol compound is not impaired. You may contain the other component which has the improvement of a disorder
• the medicament of the present invention can be produced by blending a compound selected from a cyclolanostane compound and a rophenol compound into a pharmaceutical carrier as an active ingredient.
• the medicament of the present invention can be produced, for example, by formulating the compound together with the aforementioned additives.
• the medicament of the present invention is prepared by extracting the extract obtained by performing extraction using hot water or various solvents, supercritical extraction, subcritical extraction from a known plant containing the above compound as a raw material. It can also be manufactured by formulating together.
• the medicament of the present invention containing a cyclolanostane compound and a rophenol compound in the range of the specific mass ratio can be produced by mixing each compound in the range of the mass ratio.
• such a medicament is produced by using a known plant or the like containing a cyclolanostane compound and a rophenol compound as a raw material by a method such as extraction using various solvents, supercritical extraction, subcritical extraction, or the like. It is also possible.
• the medicament of the present invention can be produced, for example, by supercritical extraction of powdered aloe vera mesophyll prepared by freeze-drying or hot-air drying of mesophyll (transparent gel) that does not contain aloe vera leaf bark.
• the extraction solvent supercritical propane, supercritical ethylene, supercritical 1,1,1,2-tetrafluoroethane, etc. are used from the viewpoint of improving the extraction efficiency of the cyclolanostane compound and the rophenol compound.
• carbon dioxide gas it is preferable to use carbon dioxide gas.
• the extraction temperature can be appropriately selected within a temperature range of 28 ° C. to 120 ° C., but an anthraquinone compound that improves the extraction efficiency of the cyclolanostane compound and the rophenol compound and has a laxative action.
• a range of 50 to 69 ° C is preferable, and a range of 50 to 59 ° C is more preferable.
• the pressure can be appropriately selected within the range of 5.5 to 60 MPa. From the viewpoint of improving the extraction efficiency of the cyclolanostane compound and the rophenol compound and reducing the content of the anthraquinone compound. Is preferably in the range of 15-60 MPa, more preferably in the range of 15-24 MPa.
• the entrainer such as ethanol, but from the viewpoint of reducing the extraction amount of the anthraquinone compound, the entrainer It is preferable not to use.
• the medicament of the present invention may be used alone, but can also be used in combination with a known prophylactic / therapeutic agent for the disease. By using in combination, the preventive / therapeutic effect of the disease can be enhanced.
• the prophylactic / therapeutic agent for the disease to be used in combination may be contained as a component of the pharmaceutical agent of the present invention, or formulated separately from the pharmaceutical agent of the present invention, arranged in combination with the pharmaceutical agent of the present invention, It is good as a kit.
• the medicament of the present invention exhibits an excellent lipid peroxide production inhibitory effect due to the antioxidant action of a compound selected from a cyclolanostane compound and a rophenol compound.
• the food and drink of the present invention In the form of using the antioxidant of the present invention as a food or drink (referred to as “the food or drink of the present invention”), the food or drink is a risk of a disease or symptom involving the oxidation of biological components such as lipids, particularly the production of lipid peroxide. Or can be used to prevent such diseases or symptoms.
• the food / beverage products of this invention contain the compound chosen from a cyclolanostane compound and a rophenol compound as an active ingredient. The compound may be one kind or plural kinds.
• “food and beverage” includes food and beverages consumed by humans and feeds consumed by animals other than humans.
• the food or drink of the present invention preferably contains a combination of both a compound selected from cyclolanostane compounds and a compound selected from rophenol compounds.
• Each of the cyclolanostane compound and the rophenol compound may be one kind or plural kinds.
• the amount of the compound selected from the cyclolanostane compound and the rophenol compound in the food / beverage product of the present invention is appropriately set depending on the form of the food / beverage product, but is preferably at least 0.0001% by mass, more preferably at least 0, in the total amount. 0.001% by weight, more preferably at least 0.005% by weight, particularly preferably at least 0.01% by weight.
• the upper limit of the said quantity in the food / beverage products of this invention is not restrict
• the amount of the compound in the food and drink of the present invention is a total amount of a compound selected from a cyclolanostane compound and a rophenol compound, preferably 0.001 to 50 mg / kg / day, depending on the form of the food and drink. More preferably, it can be an amount suitable for ingestion in the range of 0.01 to 1 mg / kg / day. Therefore, one of the preferred forms of the food and drink of the present invention is that the compound selected from the cyclolanostane compound and the rophenol compound is preferably in a total amount of preferably 0.001 to 50 mg / kg / day, more preferably 0.01. It is a food / beverage product used for ingestion of 1 mg / kg / day.
• the food or drink of the present invention preferably further contains an emulsifier.
• an emulsifier is not particularly limited as long as it can be used for food.
• the food / beverage products containing an emulsifier have high dispersibility of the cyclolanostane compound and the rophenol compound, they are excellent in stability of the effect.
• a compound selected from a cyclolanostane compound and a rophenol compound into a food or drink containing fats and oils, preferably a food or drink mainly containing fats and oils, it is excellent in storage stability in which deterioration due to lipid oxidation is suppressed.
• Food and drinks can also be provided.
• the content of the above compound and the mass ratio when combining the cyclolanostane compound and the rophenol compound are as described above.
• it is also preferable that such food and drink is an emulsified food.
• Food / beverage products containing fats and oils include edible oil, dressing, mayonnaise, butter, margarine, cream and the like.
• a form containing an emulsifier is preferable. Preferred emulsifiers are as described above.
• the food or drink of the present invention is preferably a functional food or drink.
• the “functional food or drink” means a food on which a disease prevention effect or a disease risk reduction effect is directly or indirectly displayed.
• foods sold in the form of specified health foods and health supplements in Japan at present are examples of the food or drink of the present invention.
• Examples of the form of the food and drink of the present invention include beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit juice drinks, lactic acid bacteria drinks (including concentrated concentrates and powders for preparation of these drinks); ice cream, ice sherbet, shaved ice, etc.
• Noodles such as buckwheat, udon, harusame, gyoza skin, cucumber skin, Chinese noodles, instant noodles, etc.
• Confectionery such as confectionery; processed fishery and livestock products such as kamaboko, ham and sausage; dairy products such as processed milk, milk drinks, fermented milk and butter; sugar beet; breads; other enteral nutrition foods, liquid foods, childcare Milk and sports drinks.
• the functional food or drink is in the form of granules, tablets, or liquid because it is easy for the intaker to grasp the intake amount of the active ingredient.
• the food / beverage products of the present invention are preferably in a form with indications of uses “for antioxidants”, “for lipid lipid inhibition”, and “for lipid peroxide production inhibition”. That is, the food / beverage product of the present invention contains, for example, a compound selected from a cyclolanostane compound and a rophenol compound, which is used for “for inhibiting lipid peroxide production”, as an active ingredient. It is preferable to sell as a food or drink for suppression.
• the “display” includes all displays having a function of informing the consumer of the use.
• any display capable of recalling / analyzing the application corresponds to the “display” regardless of the purpose of display, the content of display, the object / medium to be displayed, and the like.
• the “display is attached” means that there is a display act of associating and recognizing the display and the food or drink (product). It is preferable that the display act is one in which the consumer can directly recognize the application.
• the use of the use of the above-mentioned use on the product or the product packaging related to the food or drink of the present invention, the advertisement related to the product, the price list or transaction documents can be exemplified.
• the displayed content is a display approved by the government or the like (for example, a display that is approved based on various systems determined by the government and is performed in a mode based on such approval).
• the display of health foods, functional foods and drinks, enteral nutritional foods, special purpose foods, health functional foods, foods for specified health, nutritional functional foods, quasi drugs, and the like can be exemplified.
• a display approved by the Ministry of Health, Labor and Welfare for example, a display approved by a food system for specific health use or a system similar thereto can be exemplified.
• Examples of the latter can include a display as a food for specified health use, a display as a condition specific food for specified health use, a display that affects the structure and function of the body, a display for reducing disease risk, etc.
• a display as a food for specified health use a display as a condition specific food for specified health use
• a display that affects the structure and function of the body a display for reducing disease risk, etc.
• the display can be listed as a typical example.
• the wording indicating the use is not limited to the words “for antioxidation”, “for lipid oxidation inhibition”, “for lipid peroxide production inhibition”, and other words, Antioxidant action or effect, words expressing action or effect of inhibiting lipid peroxide production, ROS, action or effect for preventing disease or symptom involving lipid peroxide, action for reducing risk of occurrence of the disease or symptom, or Needless to say, any word including an expression relating to the effect is included in the scope of the present invention.
• the food / beverage products of this invention include the display of the said active ingredient in addition to the display of the said use, Furthermore, the display which shows the relevance of the said use and the said active ingredient.
• the food / beverage products of this invention can be manufactured by mix
• the food / beverage products of this invention can be manufactured by mixing the said compound with food-drinks raw material, and processing, for example.
• the food and drink of the present invention is prepared by using a known plant or the like containing the above compound as a raw material, an extract obtained by extraction with hot water or various solvents, supercritical extraction, or subcritical extraction. It can also be manufactured by processing together.
• the specific method for obtaining the extract is as exemplified in the section of “medicament of the present invention”.
• the compound as an active ingredient is, for example, a saccharide such as lactulose, maltitol, and lactitol, and others.
• Sugars such as dextrin and starch; proteins such as gelatin, soybean protein and corn protein; amino acids such as alanine, glutamine and isoleucine; polysaccharides such as cellulose and gum arabic; fats and oils such as soybean oil and medium chain fatty acid triglycerides It is also preferable to formulate together.
• the food additive In the form in which the antioxidant of the present invention is used as a food additive (referred to as “food additive of the present invention”), the food additive is used as a disease that involves oxidation of biological components such as lipids, particularly lipid peroxides. In order to reduce the risk of symptoms or prevent such diseases or symptoms, it can be added to food and drink.
• the food additive of the present invention can be used by adding to a food or drink in order to suppress oxidation of components in the food or drink, for example, lipids.
• the food additive of the present invention is particularly suitable for addition to foods and drinks containing fats and oils, preferably foods and drinks mainly comprising fats and oils.
• the example of the food / beverage products containing fats and oils is as having mentioned by the term of the "food / beverage products of this invention".
• the food additive of the present invention contains a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the compound may be one kind or plural kinds.
• the food additive of the present invention preferably contains a combination of a compound selected from cyclolanostane compounds and a compound selected from rophenol compounds.
• Each of the cyclolanostane compound and the rophenol compound may be one kind or plural kinds.
• the amount of the compound selected from the cyclolanostane compound and the rophenol compound in the food additive of the present invention is set as appropriate, but the total amount is preferably at least 0.001% by mass, more preferably at least 0.01% by mass, More preferably it is at least 0.05% by weight, particularly preferably at least 0.1% by weight.
• the upper limit of the amount in the food additive of the present invention is not particularly limited, but is 90% by mass or less, preferably 70% by mass or less, and more preferably 50% by mass or less in terms of the total amount.
• the food additive of the present invention preferably further contains an emulsifier.
• an emulsifier is not particularly limited as long as it can be used for food.
• the emulsifier By containing the emulsifier in the food additive of the present invention, the dispersibility of the cyclolanostane compound and the rophenol compound, which are the active ingredients of the food additive of the present invention, in water-soluble food and drink is improved.
• the normal form of food additives such as a powder, a granule, a tablet, a liquid
• the food additive of the present invention contains the above-mentioned emulsifier, it is particularly preferable that the food additive is in an emulsifier form.
• the food additive of the present invention may contain additives such as commonly used excipients in addition to the cyclolanostane compound and rophenol compound as active ingredients and an emulsifier. Moreover, the well-known other component normally used for a food additive may be included.
• the food additive of the present invention can be produced by blending a compound selected from a cyclolanostane compound and a rophenol compound as an active ingredient.
• the food additive of the present invention can be produced, for example, by formulating the active ingredient, preferably with the emulsifier, and optionally with the additive or other ingredients.
• the food additive of the present invention is preferably an extract obtained by performing extraction using hot water or various solvents, supercritical extraction, subcritical extraction, using a known plant containing the compound as a raw material, It can also manufacture by formulating with the said additive and another component with the said emulsifier if desired.
• the specific method for obtaining the extract is as exemplified in the section of “medicament of the present invention”.
• the food additive of the present invention can be used for producing the food and drink of the present invention described above.
• the amount added to the food or drink can be appropriately adjusted based on the amount of the compound selected from the cyclolanostane compound and the rophenol compound as the active ingredients in the food and drink of the present invention described above.
• the food additive of the present invention is in a form with indications of uses such as “for antioxidant”, “for inhibiting lipid oxidation”, and “for inhibiting lipid peroxide production”. “Display” and “display act” are as described in the section of “Food and Drink of the Present Invention”.
• the external preparation for skin of the present invention In the form using the antioxidant of the present invention as an external preparation for skin (referred to as “the external preparation for skin of the present invention”), treatment or improvement of skin conditions involving oxidation of biological components such as lipids, particularly formation of lipid peroxide. Can be used to prevent or prevent. For example, it can be used for pigmentation such as stains and freckles, dermatitis such as atopic dermatitis and acne, treatment or improvement or prevention of rough skin, improvement or prevention of wrinkles and decreased elasticity, hair loss and the like.
• the topical skin preparation includes those classified as pharmaceuticals, quasi drugs, and cosmetics.
• the skin external preparation can be produced by blending a compound selected from a cyclolanostane compound and a rophenol compound with a commonly known base. Preferred forms, extraction methods, and the like of the compounds are as described in “Pharmaceuticals of the Present Invention”.
• the present invention is a method for imparting antioxidant activity, preferably lipid oxidation inhibitory activity, more preferably lipid peroxide production inhibitory activity to foods and drinks, selected from cyclolanostane compounds and rophenol compounds in foods and drinks.
• the concentration of the compound is such that the total amount is at least 0.0001% by weight, preferably at least 0.001% by weight, more preferably at least 0.005% by weight, particularly preferably at least 0.01% by weight.
• blending with food and drink is included.
• the definition of “food / beverage” is the same as the definition of food / beverage in the above-mentioned “food / beverage products of the present invention”.
• the present invention also relates to a method for enhancing the antioxidant activity, preferably the lipid oxidation inhibitory activity, more preferably the lipid peroxide production inhibitory activity of foods and drinks containing a compound selected from a cyclolanostane compound and a rophenol compound.
• the concentration of the compound selected from the cyclolanostane compound and the rophenol compound in the food and drink is at least 0.0001% by mass, preferably at least 0.001% by mass, more preferably at least 0.005% by mass,
• the definition of “food / beverage product of the present invention” is also applied to the definition of “food / beverage product”.
• the description in the above-mentioned section of “Food and Drink of the Present Invention” also applies to the mixing ratio of the cyclolanostane compound and the rophenol compound and particularly preferable compounds among the compounds.
• the food and drink containing a compound selected from a cyclolanostane compound and a rophenol compound include food and drink containing an extract of a lily family plant.
• the food-drinks containing the flesh of an Aloe genus plant are mentioned.
• “compounding the compound” includes blending the purified or synthesized compound as well as blending the extract.
• the lipid peroxide production inhibitory action of various analytes containing the antioxidant of the present invention can be evaluated using, for example, the amount of thiobarbituric acid (TBA) -reactive substance (TBARS) as an index. Specifically, it can be defined that the larger the amount of TBARS, the more lipid peroxide is generated.
• TAA thiobarbituric acid
• TBARS thiobarbituric acid
• TBARS thiobarbituric acid
• TBARS thiobarbituric acid
• TBARS thiobarbituric acid
• TBARS thiobarbituric acid
• MDA malondialdehyde
• the MDA-TBA adduct can be detected by measuring the absorbance at 530 to 540 nm, whereby the MDA can be colorimetrically measured.
• the lipid peroxide production inhibitory effect of a subject can be evaluated using ApoE gene-deficient mice, which are often used as model animals that develop arteriosclerosis due to hypercholesterolemia (high LDL cholesterolemia).
• ApoE gene-deficient mice which are often used as model animals that develop arteriosclerosis due to hypercholesterolemia (high LDL cholesterolemia).
• Possible for example, Reference 1: “Cell Engineering”, separate volume “Medical Experiment Manual” series, “Arteriosclerosis + Hyperlipidemia Research Strategy”, Shujunsha, 1st edition, 1st edition, April 1996 Issued 1 day, see pages 441-443).
• This model mouse does not exhibit obesity, and is known to develop cardiovascular disease through hyper LDLemia through arteriosclerosis.
• lipid peroxide is increased in this model mouse as compared with normal mice, and formation of atherosclerotic lesions (plaque) in the artery is observed over time. Therefore, by administering a subject to a model mouse and measuring lipid peroxide in the blood of the model mouse, it is possible to evaluate the inhibitory effect of the subject on lipid peroxide production. Furthermore, since it is generally known that the initial lesion of arteriosclerosis is caused by oxidized LDL, by measuring the number of atherosclerotic plaques (plaques) in the artery of the model mouse administered the subject, It is also possible to evaluate the effect of the subject to reduce the risk of arteriosclerosis by suppressing lipid peroxide production.
• the mixture was heated with stirring, and when the temperature reached 50 ° C., the hydrogen pressure was 5 kg / cm 2, and the reaction was performed for 6 hours while maintaining the pressure by supplementing the absorbed hydrogen.
• the reaction solution was filtered to remove the catalyst, concentrated, and then purified by silica gel column chromatography (developing solvent: chloroform 100%) to obtain 275 mg of 9,19-cyclolanostan-3-ol.
• the elution fractions were collected in order of 300 ml (fraction A), 300 ml (fraction B), and 500 ml (fraction C).
• HPLC equipped with Cosmo Seal C18 manufactured by Nacalai Tesque
• rophenol compound of the present invention was concentrated in fraction A by normal phase and reverse phase thin layer chromatography, Separated with chloroform / hexane mixture (85:15), 4-methylcholest-7-en-3-ol), 4-methylergost-7-en-3-ol, 4-methylstigmast-7 -En-3-ol was obtained in an amount of 1.3 mg, 1.2 mg and 1 mg, respectively.
• the structure of each compound was confirmed by MS and NMR.
• Example 1 Using the ApoE gene-deficient mouse, which is a model animal that develops arteriosclerosis, the inhibitory action of cycloperanostane compound, rophenol compound, and a mixture of cyclolanostan compound and rophenol compound on lipid peroxide production was examined.
• mevalotin (Daiichi Sankyo), which is an HMG-CoA reductase inhibitor (hyperlipidemic drug), was used as a control sample.
• mevalotin (Daiichi Sankyo) which is an HMG-CoA reductase inhibitor (hyperlipidemic drug)
• a test solution was prepared for use in the test. Saline was used as a negative sample.
• mice Male ApoE-deficient mice (purchased from Japan SLC), 6 weeks old, were preliminarily raised for 2 weeks using a high-cholesterol diet (manufactured by Research Diet), and then divided into 15 groups per group. did. Each group of mice was orally administered once a day for 3 consecutive days with 1 ml of each test solution of test samples 1 to 6, control sample, and negative sample using a sonde. After the start of administration (14 days after the start of administration), blood is collected from each mouse's tail vein and separated into serum, and then the amount of TBARS is determined using the OxiSelect TBARS Assay Kit (manufactured by MDA Quantitation). It was measured. In addition, blood was collected from normal mice as a comparison target.
• Test result The test result of a present Example is as showing in Table 1.
• Table 1 shows the amount of lipid peroxide in blood (concentration of MDA in serum) when a sample of 30 ⁇ g per day was administered per mouse. In mice to which negative samples were administered, a tendency to increase lipid peroxide levels in blood was observed compared to normal mice. In model mice to which test samples 1 to 6 were continuously administered, blood peroxidation was clearly observed. A lipid production inhibitory effect (significantly different, “*” in the table) was confirmed.
• the cyclolanostane compound, the rophenol compound, and the mixture of the cyclolanostane compound and the rophenol compound have a lipid peroxide production inhibitory effect and are effective in preventing or treating arteriosclerosis. confirmed.
• Example 2 The present Example 2 measures the number of atherosclerotic lesions (plaques) in an artery using an ApoE-deficient mouse known as an arteriosclerosis model animal, and reduces the risk of arteriosclerosis by inhibiting lipid peroxide production.
• the cyclolanostane compound, the rophenol compound, and the mixture of the cyclolanostan compound and the rophenol compound were evaluated.
• Sample Preparation Test samples 1 to 6 a control sample, and a negative sample were prepared in the same manner as in Example 1, and each sample was used for the test.
• mice Male ApoE-deficient mice (purchased from Japan SLC), 6 weeks old, were preliminarily raised for 2 weeks using a high-cholesterol diet (manufactured by Research Diet), and then divided into 15 groups per group. did. Each group of mice was orally administered daily for 39 days using a sonde once a day for each sample solution of a test sample, a control sample, and a negative sample, each 1 ml per 25 g of mouse body weight. On the 40th day from the start of administration, the thoracic aorta was fixed in formalin, and the number of plaques was measured by oil red staining.
• Test result The test result of a present Example is as showing in Table 2.
• Table 2 shows the number of atherosclerotic lesions (plaques) in the artery of the model mouse to which each sample solution was administered.
• the number of plaques was 12.2 in the model mice administered with the negative sample, whereas the number of plaques was halved to 5.0 to 6.2 in the model mice administered with test samples 1-6.
• mevalotin a hyperlipidemic drug
• cyclolanostane compounds, rophenol compounds, and mixtures of cyclolanostane compounds and rophenol compounds have an inhibitory effect on the formation of plaque in blood vessels, reducing the risk of arteriosclerosis due to the inhibitory effect of lipid peroxide production. It became clear to do.
• the antioxidant of the present invention can be safely administered, suppresses the oxidation of biological components, and particularly effectively suppresses the production of lipid peroxide in the blood. Therefore, arteriosclerosis, stroke, angina pectoris, myocardium It is effective for treatment and / or prevention of diseases and symptoms such as infarction, liver dysfunction, cirrhosis, hepatitis, retinopathy, cataract, Alzheimer's disease, Parkinson's disease, allergic disease, cancer, rough skin, and aging. Among them, the antioxidant of the present invention is highly effective for the treatment and / or prevention of arteriosclerosis, angina pectoris, and myocardial infarction. Therefore, the medicament of the present invention is useful for the treatment and prevention of the above diseases and symptoms.
• the food and drink of the present invention can be safely ingested, and effectively suppresses the formation of lipid peroxide in the living body, particularly in blood. Useful to do.
• the food additive of this invention is useful in manufacturing such food / beverage products, or preventing the oxidation of the component in food / beverage products.
• the external preparation for skin of the present invention is useful for the treatment or improvement of pigmentation such as stains and freckles, atopic dermatitis, acne and other dermatitis, or the prevention or improvement of wrinkle reduction and hair loss. is there.

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