WO2018070545A1 - 経口摂取用コリンエステル含有組成物 - Google Patents

経口摂取用コリンエステル含有組成物 Download PDF

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WO2018070545A1
WO2018070545A1 PCT/JP2017/037389 JP2017037389W WO2018070545A1 WO 2018070545 A1 WO2018070545 A1 WO 2018070545A1 JP 2017037389 W JP2017037389 W JP 2017037389W WO 2018070545 A1 WO2018070545 A1 WO 2018070545A1
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Prior art keywords
choline ester
eggplant
composition
blood pressure
edible plant
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English (en)
French (fr)
Japanese (ja)
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浩蔵 中村
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Shinshu University NUC
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Shinshu University NUC
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Priority to CN201780063705.XA priority Critical patent/CN109890382A/zh
Priority to JP2018545093A priority patent/JP7362098B2/ja
Priority to US16/341,748 priority patent/US20220030896A2/en
Publication of WO2018070545A1 publication Critical patent/WO2018070545A1/ja
Anticipated expiration legal-status Critical
Priority to JP2022105480A priority patent/JP7515907B2/ja
Priority to JP2024103012A priority patent/JP7726553B2/ja
Priority to JP2025128018A priority patent/JP2025148617A/ja
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition having an antihypertensive action and / or an anti-stress action, comprising a choline ester, which is a compound in which choline and an organic acid are ester-bonded, as an active ingredient, and a method for producing the same.
  • acetylcholine is known to be an essential substance for life activity as a mammalian neurotransmitter.
  • a blood pressure-lowering substance different from histamine was isolated from the spleen of horses, and the active substance was chemically identified as acetylcholine (Non-patent Document 1).
  • the hypotensive substance of ergot is acetylcholine, and it has been confirmed that fungi produce acetylcholine (Non-patent Document 2).
  • Acetylcholine is contained in edible plants, edible fungi, royal jelly, milk, etc., acetylcholine is also present in Bacillus subtilis and yeast, and edible plants have been reported to have high acetylcholine content in eggplant and bamboo shoots (non-) Patent Documents 3 to 7).
  • Non-patent Documents 8 and 9 Propionylcholine having a propionyl group having one carbon chain longer than the acetyl group was discovered from the spleen of cattle in 1953 (Non-patent Documents 8 and 9). After that, in bull semen, European crayfish, American horseshoe crab, European cockle, Onagi, Murasaki mussel, Honbugai, in the hemolymph and smooth muscle in apple maimai, in the electro-generated tissue culture of millet ray, Propionylcholine production has been confirmed in poplar and birch (Non-Patent Documents 10 to 13).
  • Butyrylcholine was discovered from a brain extract in 1954 (Non-Patent Document 14), and it has been shown that it exists in arthropods and mollusks together with acetylcholine and propionylcholine (Non-Patent Document 11). . In addition to propionylcholine and butyrylcholine, several choline esters have been confirmed from mollusks.
  • the structure of uronoylcholine is determined from a species of mussel, ⁇ -dimethylacroylcholine (Senesi oil choline) from a species of mussel, acroylcholine from a species of oyster, and imidazolepropionylcholine from a species of mussel. (Non-patent documents 15 to 18).
  • the present inventor has studied a blood pressure lowering action and vasodilatory active ingredient contained in fermented duckweed (a fermented lactic acid product of buckwheat plant), and has a fourth main component composed of a plurality of choline esters containing at least acetylcholine and propionylcholine.
  • An extraction composition containing a quaternary alkylammonium compound is provided, and it has been shown that purified acetylcholine, propionylcholine, and butyrylcholine have a blood pressure lowering effect when administered orally to a spontaneously hypertensive rat (SHR) ( Patent Documents 1 and 2).
  • Non-patent Document 19 an interview form of a medicine containing acetylcholine chloride as an active ingredient
  • Yoshie Momogi Acetylcholine in acupuncture plants, Chemical regulation of acupuncture plants, 30 (1), 49-61 (1995) Kawashima Shinichiro, Roots of acetylcholine and non-neural acetylcholine, Basic aging research, 34 (4), 12-24 (2010) Masato Shinoda et al., About the blood flow increase factor in royal jelly, Pharmaceutical Journal, 98 (2), 139-145 (1978) Whittaker VP. Acetylcholine in Milk. Nature 181: 856-857, 1958. Horiuchi Y, Kimura R, Kato N, Fujii T, Seki M, Endo T, Kato T, Kawashima, K.
  • an object of the present invention is to provide a novel composition for oral consumption that can be easily orally ingested by humans and has a blood pressure lowering action and a vasodilatory action, using a choline ester such as acetylcholine as an active ingredient. Is to provide food as a good source.
  • the present inventor has intensively studied to solve the above-mentioned problems, surprisingly, despite the conventional theory that acetylcholine cannot be administered orally to humans, the choline ester is surprisingly administered by oral administration.
  • the present invention has been completed.
  • the present invention relates to the following.
  • a composition having a blood pressure lowering action and / or an anti-stress action comprising a choline ester as an active ingredient and having a choline ester content of 5 ⁇ g to 50 mg and for oral consumption.
  • the composition according to [1] which is a food composition.
  • composition according to any one of [1] to [4] which is an extract obtained by extracting an edible plant with ethanol or hydrous ethanol.
  • the choline ester does not contain lactoylcholine.
  • a method for producing a composition having a blood pressure lowering action and / or an anti-stress action for oral consumption containing a choline ester as an active ingredient wherein an edible plant is made into a freeze-dried powder and / or a hot-air dried powder Distributing said freeze-dried powder and / or hot-air dried powder to a choline ester content of 5 ⁇ g to 50 mg.
  • the edible plant is a fruit of Solanum melongena and / or a young shoot of Poaceae, Bambusoideae, Bambuseae.
  • the method according to [14] or [15] further comprising heating the edible plant.
  • the present invention provides a composition that has a blood pressure lowering effect and can be easily ingested over a long period of time even when it is orally ingested without using choline ester as an active ingredient as an injection. it can.
  • a composition comprising a lyophilized powder of an edible plant, it can be processed at a very low cost because it does not require extraction or purification steps.
  • a composition comprising a lyophilized powder of an edible plant, it can be processed at a very low cost because it does not require extraction or purification steps.
  • it can be heated under certain conditions before lyophilization, and acid can be added before or after lyophilization to increase the stability of the choline ester.
  • the composition of the present invention has high safety and can be used as a food composition or a pharmaceutical composition for lowering blood pressure. Further, according to the composition of the present invention, an edible plant (fresh product) carved so as to contain a predetermined amount of choline ester, a edible plant heated or frozen, an edible plant dry powder ( Freeze-dried powder, hot-air dry powder), suspension of the dry powder, extract obtained by extracting choline ester from fresh food, concentrated extract obtained by concentrating the extract, etc. be able to.
  • Choline esters act on cholinergic receptors (muscarinic acetylcholine receptor and nicotinic acetylcholine receptor).
  • cholinergic receptors muscarinic acetylcholine receptor and nicotinic acetylcholine receptor.
  • higher concentrations of acetylcholine than stimulating muscarinic acetylcholine receptors Is required (Non-patent Document 20).
  • the blood pressure decreases due to the action of the muscarinic acetylcholine receptor, but this action is thought to predominate the sympathetic nerve activity due to the action of the nicotinic acetylcholine receptor and counteract the action of the muscarinic acetylcholine receptor. .
  • the present invention is based on the knowledge that when a choline ester is orally ingested in a very small amount, it exhibits an action different from that ingested in a large amount. That is, although the choline ester in the composition of the present invention is a very small amount compared to 0.1 g / dose for obisort (registered trademark) injection, it sufficiently acts on the muscarinic acetylcholine receptor and exerts a blood pressure lowering effect, Moreover, it is contained in an amount that does not act on the nicotinic acetylcholine receptor and does not counteract such blood pressure lowering action. Since the composition of the present invention has a choline ester content according to the balance of the action of the two receptors, acetylcholine has a blood pressure lowering action by ingestion contrary to the conventional technical common sense that oral administration is impossible.
  • an edible plant having a high choline ester content such as eggplant or bamboo shoot
  • it is preferable for oral use because the amount of the plant used is small. This means that, for example, if a choline ester content such as lettuce is low, it is necessary to ingest about 7.5 kg or more of fresh weight per day, which is not realistic as a daily intake. Even when lettuce is freeze-dried, the yield is about 3.60%, and it is desirable to take about 270 g per day.
  • the daily intake standard amount obtained from the results of animal tests using SHR was only 0.41 g in fresh weight, so that it has a blood pressure lowering effect in an amount that can be continuously ingested every day. Can do.
  • the daily intake standard amount can be further reduced. Therefore, even when this is used as a processed food, it can be an extremely rational and economical oral food.
  • FIG. 1 is a graph showing the yield of each fresh produce after lyophilization.
  • FIG. 2 is a graph showing each choline ester and choline content of each fresh produce. The vertical axis is a logarithmic scale.
  • AcCh Acetylcholine, BuCh: Butyrylcholine, PrCh: Propionylcholine, Ch: Choline.
  • FIG. 3 is a graph showing changes over time in each choline ester and choline content in fresh eggplant fruits 1 to 5 days after storage at room temperature (first day after p ** ⁇ 0.05, p ** ⁇ 0.01 vs. ).
  • AcCh Acetylcholine, BuCh: Butyrylcholine, PrCh: Propionylcholine, Ch: Choline.
  • FIG. 1 is a graph showing the yield of each fresh produce after lyophilization.
  • FIG. 2 is a graph showing each choline ester and choline content of each fresh produce. The vertical axis is a logarithmic scale.
  • FIG. 4 is a graph showing the choline ester content in fresh eggplant fruits at room temperature and on the sixth day of refrigerated storage. (P ** ⁇ 0.05, p ** ⁇ 0.01). The vertical axis is a logarithmic scale.
  • AcCh acetylcholine
  • BuCh butyrylcholine
  • PrCh propionylcholine.
  • FIG. 5 is a graph showing the change over time in the amount of acetylcholine due to pH when a sample is used.
  • AcCh Acetylcholine.
  • FIG. 6 is a graph showing the change over time in the amount of acetylcholine due to pH when eggplant extract is used.
  • AcCh Acetylcholine.
  • FIG. 7 is a graph showing changes in the amount of acetylcholine in eggplant by heating.
  • AcCh Acetylcholine.
  • FIG. 8 is a graph showing the results of single oral administration test (systolic blood pressure) of eggplant lyophilized powder containing 1.00 ⁇ 10 ⁇ 9 mol / kg equivalent of acetylcholine to SHR (p * ⁇ 0.05 vs. Pure water administration).
  • FIG. 9 is a graph showing the results of a single oral administration test (diastolic blood pressure) of eggplant lyophilized powder containing 1.00 ⁇ 10 ⁇ 9 mol / kg equivalent of acetylcholine to SHR.
  • FIG. 10 is a graph showing the results of single oral administration test (heart rate) of eggplant lyophilized powder containing 1.00 ⁇ 10 ⁇ 9 mol / kg equivalent of acetylcholine to SHR.
  • FIG. 11 is a graph showing the results of single oral administration test (systolic blood pressure) of eggplant lyophilized powder to WKY rats (p ** ⁇ 0.05, p ** ⁇ 0.01 vs pure water administration).
  • FIG. 12 is a graph showing the vascular isometric tension test results of eggplant lyophilizates (p * ⁇ 0.05, p ** ⁇ 0.01 vs lyophilized 20 mesh pass; p # ⁇ 0.05, p ## ⁇ 0.01 vs. hot air drying 20 mesh pass).
  • FIG. 13 is a graph showing the results of repeated oral administration tests (systolic blood pressure) of eggplant lyophilized powder to SHR (p ** ⁇ 0.05, p ** ⁇ 0.01 vs. pure water administration).
  • FIG. 14 is a graph showing the results of repeated oral administration test (diastolic blood pressure) of eggplant lyophilized powder to SHR (p * ⁇ 0.05 vs pure water administration).
  • FIG. 15 is a graph showing the results of repeated oral administration test (change in urinary adrenaline amount) of eggplant lyophilized powder to SHR (p ** ⁇ 0.05, p ** ⁇ 0.01 vs pure water administration).
  • FIG. 16 is a graph showing the results of repeated oral administration test (change in urinary noradrenaline amount) of eggplant lyophilized powder to SHR (p * ⁇ 0.05, p ** ⁇ 0.01 vs pure water administration).
  • the present invention relates to a composition having an antihypertensive action comprising a choline ester as an active ingredient, and a composition further having an antistress action.
  • the composition of the present invention is for oral consumption and may have a choline ester content of 5 ⁇ g to 50 mg.
  • the choline ester content is 5 to 500 ⁇ g, preferably 5 to 250 ⁇ g, more preferably 10 to 50 ⁇ g, and particularly preferably 25 ⁇ g.
  • Such choline ester content is preferable, for example, when used for a subject with hypertension.
  • the choline ester content may be 5 ⁇ g to 50 mg, preferably 500 ⁇ g to 50 mg, more preferably 500 ⁇ g to 5 mg.
  • Such choline ester content is preferable, for example, when used for a subject who is healthy (not hypertensive) but has high blood pressure.
  • the composition of the present invention may be a food composition or a pharmaceutical composition.
  • the composition of the present invention may be a pharmaceutical composition for lowering blood pressure and / or antistress.
  • the choline ester which is an active ingredient of the composition of the present invention any of those derived from animals, those derived from plants, and those derived from microorganisms can be used. It is preferable to use edible plants.
  • the edible plant is not particularly limited as long as it contains a choline ester.
  • Examples of edible plants include cucumbers, tomatoes, paprika, peppers, eggplant, asparagus, yam potatoes, cabbage, lettuce, carrots, apples, fermented rice, Japanese none, grapes, squid radishes, broccoli, alfalfa, beans seedlings, buckwheat And bamboo shoots.
  • Solanum ⁇ ⁇ melongena, Solanum melongena, Poaceae, Bambusoideae, Bambuseae are preferred, especially the fruits of Solanum melongena Young shoots of Poaceae, Bambusoideae, Bambuseae are preferred.
  • the fountains such as Senshu Mizusu, Bantensu, Goryo Salad Yuzu (also known as Bijin), Higurashi Saki, Ocho Choshi, Chikuyo are preferred and can be eaten raw.
  • Water eggplant, batten eggplant, giraffe salad eggplant, and rubber gourd are preferred. Particularly preferred is Higarasaki.
  • choline ester examples include acetylcholine, butyrylcholine, propionylcholine, lactoylcholine, and the like, and a composition containing one or more of these may be used.
  • the composition of the present invention contains one or more selected from the group consisting of acetylcholine, butyrylcholine and propionylcholine, and does not contain lactoylcholine.
  • the daily intake of choline ester is adjusted to a predetermined range.
  • the content of choline ester is adjusted to 5 to 125 ⁇ g, preferably 10 to 75 ⁇ g, particularly preferably 15 to 50 ⁇ g in one package, and it is once to several times a day (preferably about three times). ) Can be taken orally.
  • the total of choline esters may be adjusted to the above range by a plurality of packages. In this case, the choline ester concentration is 5 to 2500 ⁇ g / g.
  • the daily intake of choline ester is adjusted to be larger than the above numerical range, for example, 5 ⁇ g to 50 mg, preferably 500 ⁇ g to 12.5 mg, more preferably 500 ⁇ g to 1.25 mg.
  • the choline ester concentration may be 500 to 250 mg / g.
  • the composition of the present invention is adjusted to a predetermined choline ester content.
  • a product obtained by adjusting the choline ester content and cutting a fresh produce, a frozen product, a freeze-dried product, or an extract can be used.
  • the composition of the present invention is preferably a composition comprising a lyophilized powder and / or extract of an edible plant.
  • the composition of the present invention is divided into one-day portions so as to have a choline ester content to be ingested in a day, vacuum packs, etc. in order to prevent deterioration of quality and browning of pulp. It may be individually wrapped. Moreover, it is preferable that the composition of this invention is frozen processing.
  • the composition of the present invention is preferably part or all of the frozen processed Solanum melongena fruit.
  • the present invention relates to a method for producing a composition having a blood pressure lowering action and / or an anti-stress action for ingestion, comprising a choline ester as an active ingredient.
  • the edible plant is made into lyophilized powder and / or hot air dried powder or extract, and the lyophilized powder and / or hot air dried powder or extract is distributed so that the choline ester content becomes a predetermined amount.
  • the predetermined amount may be 5 ⁇ g to 250 mg, preferably 5 ⁇ g to 50 mg, more preferably 10 ⁇ g to 50 mg.
  • the predetermined amount may be, for example, 5 to 500 ⁇ g, 5 to 250 ⁇ g, 10 to 50 ⁇ g, or 25 ⁇ g.
  • the method of the present invention can further comprise heating the edible plant. Heating can be performed by boiling in a microwave oven or hot water. For example, when heating in a microwave oven of 550 W, heating is performed for 1 to 15 minutes, preferably 2 to 10 minutes, more preferably 4 to 6 minutes per 100 g of edible plants. In addition, when boiling in hot water, it is preferable to heat in hot water of 90 to 100 ° C. Thus, by heating an edible plant, it can sterilize and can increase the choline ester in an edible plant.
  • the method of the present invention is characterized in that, in one aspect, the edible plant is further subjected to heat treatment (bactericidal action and choline ester increasing action), usually by freeze-drying or hot-air drying to avoid spoilage by microorganisms. To do.
  • the method of the present invention may further include suspending lyophilized powder and / or hot-air dried powder of edible plants in water and adding an acid to the resulting suspension.
  • the pH of the suspension to which the acid has been added is adjusted to, for example, 5.5 to 4.5, preferably 5.4 to 4.6.
  • the choline ester is stabilized and a composition (suspension) excellent in long-term storage can be obtained.
  • the present invention also relates to a method for producing an extract having a blood pressure lowering action and / or an anti-stress action for oral consumption, comprising a choline ester as an active ingredient.
  • the method of the present invention comprises extracting an edible plant or lyophilized powder and / or hot air dried powder of an edible plant with ethanol or hydrous ethanol. More specifically, in the method of the present invention, ethanol or water-containing ethanol is added to lyophilized powder and / or hot-air dried powder of edible plants, or ethanol is added to fresh edible plants and ground to remove residues.
  • the resulting extract enriched in choline ester can be included.
  • the ethanol concentration of the hydrous ethanol is not particularly limited, but can be appropriately selected from the viewpoint of the extraction rate and concentration rate of the choline ester.
  • the ethanol concentration of the hydrous ethanol may be, for example, 10% (w / w) or more, preferably 10 to 99% (w / w), more preferably 25 to 60% (w / w). Or 95% (w / w) or more, particularly preferably 30 to 60% (w / w) or 99% (w / w) or more.
  • L-ascorbic acid may be added to ethanol or water-containing ethanol used for extraction, for example, 1 to 5 wt%, preferably 3 wt%.
  • the method of the present invention may comprise adjusting the choline ester content of the extract to 5 ⁇ g to 50 mg.
  • the present invention also relates to a composition having a blood pressure lowering action and / or an anti-stress action for oral intake, comprising a choline ester produced by the above method as an active ingredient.
  • the dry powder according to the composition of the present invention is preferably a powder that has passed through an appropriate mesh sieve.
  • the composition of the present invention is preferably composed of, for example, a freeze-dried powder and / or a hot-air dried powder that can pass through a 20-mesh sieve.
  • the hot-air dry powder can be prepared by, for example, drying an edible plant by exposing it to hot air at about 90 ° C. for about 1 to 2 hours, and pulverizing it into a powder.
  • composition of the present invention can be used as an active ingredient of various functional health foods or pharmaceutical compositions.
  • food it can be used as a food composition in combination with an appropriate food additive.
  • it is not limited to such a composition for food, but it can be ingested on a daily basis as a beverage by blending with green tea, black tea, oolong tea, miscellaneous tea, etc. Can also be provided.
  • it can also be used as a so-called supplement as an appropriate dosage form according to the following pharmaceutical preparation.
  • a pharmaceutical product it can be used in various dosage forms in accordance with a normal dispensing method in combination with an appropriate pharmaceutical additive.
  • dosage forms include oral preparations such as solid preparations such as powders, granules, capsules, pills and tablets, liquids such as liquids, suspensions and emulsions.
  • composition of the present invention When used as a food, it can be used not only as a general food and drink, but also as a functional health food that exhibits a specific function to promote health.
  • Specific forms in this case include capsules, tablets, powders, granules and the like containing the composition of the present invention as an active ingredient, bakery foods such as bread, cakes and cookies, sauces, Seasonings such as soup, dressing, mayonnaise, dairy products such as milk, yogurt, cream, confectionery such as chocolate, candy, or green tea, tea, oolong tea, barley tea, millet tea, fruit juice, vegetable drink, milk drink And various beverages such as soft drinks and carbonated drinks.
  • the dose varies depending on the ratio of each component, and also varies depending on various factors such as the age, weight, sex, symptom, and administration method of the patient.
  • the choline ester content can generally be selected in the range of 5 ⁇ g to 50 mg, and in one embodiment in the range of 5 ⁇ g to 500 ⁇ g.
  • the administration frequency can be divided into once to several times a day.
  • the amount of intake when the composition of the present invention is used as a food can be selected according to the case of oral administration of the pharmaceutical product.
  • the dose and frequency of administration are not particularly limited, so the purpose of maintaining health, taste, and palatability should be considered unless particularly serious symptoms occur. And you may select intake, without being limited to said range.
  • Extraction method Sample preparation Fresh agricultural products (analytical samples) were washed with tap water immediately after they were obtained. After wiping off the moisture, only the edible portion was sliced with a knife to a width of 1 to 3 cm as necessary. The edible portion was lyophilized with a freeze dryer (FDU-2000, Tokyo Rika Kikai Co., Ltd.). The freeze-dried product was pulverized with a mill mixer (MASTER, Tokyo Unicom Co., Ltd.) to form a powder.
  • FDU-2000 Tokyo Rika Kikai Co., Ltd.
  • the freeze-dried product was pulverized with a mill mixer (MASTER, Tokyo Unicom Co., Ltd.) to form a powder.
  • the weak acid cation exchange cartridge Inert Sep CBA 100 mg / 1 mL (GL Sciences Inc.) was used for the solid phase extraction cartridge.
  • the solid phase extraction cartridge activated with methanol (1 mL) and pure water (1 mL) was equilibrated with 10 mM phosphate buffer (8 mL), and then the extraction sample prepared in (3) (about 600 ⁇ L) was added. Stabilized with 10 mM phosphate buffer (600 ⁇ L), washed with pure water (2.5 mL), and eluted with hydrochloric acid (500 ⁇ L).
  • the choline compound mixed solution was prepared as shown in Table 3, and the addition concentration of each choline compound stock solution was determined based on the analysis result of the sample without addition of the choline compound mixed solution (Table 2-A).
  • the choline compound stock solution was diluted with LC / MS / MS analysis solvent to prepare each concentration. When there was a choline compound that was not detected, only an equivalent amount of LC / MS / MS analysis solvent not containing the compound was added.
  • LC / MS / MS analysis (1) LC / MS / MS analysis conditions The column used was YMC-Triart PFP (4.6 mm ⁇ 250 mm, 5 ⁇ m, YMC). Water containing 0.01% formic acid-33% methanol was used as the analysis solvent, the flow rates were 0.5 mL / min (LC), 0.3 mL / min (MS), the injection volume was 50 ⁇ L, the separation temperature was 40 ° C., and the analysis time.
  • AcCh in the eggplant extract was unstable under neutral conditions, and more than half of it was degraded in 3 days, and almost all of AcCh was degraded in 12 days. It is relatively stable under acidic conditions, and at pH 5.4 to 4.6, 88% or more of AcCh remained even after 12 days, but in a solution adjusted to pH 3.5 with acetic acid, 24.6% AcCh after 12 days. Was disassembled.
  • AcCh in eggplant was stably present at room temperature under acidic conditions of pH 5.4 to 4.6. From the above results, the choline ester in agricultural products such as eggplant can be further stabilized by adjusting the pH to 5.5 to 4.5 by adding an organic acid or the like. If the pH is within this range when the suspension is formed, the acid may be added at an appropriate time.
  • acetylcholinesterase (EC number 3.1.1.7), which is a cholinesterase, affects the cholineester content.
  • acetylcholinesterase is widely present in plants.
  • the decrease in AcCh shown in Table 8 is thought to be mainly due to degradation by acetylcholinesterase. It was considered that more AcCh was decomposed at neutral pH close to the optimum pH 8.0 to 8.5 of acetylcholinesterase, and degradation of AcCh was suppressed at a low pH at which the enzyme activity decreased.
  • Eggplant extract preparation test Eggplant extract was prepared using eggplant freeze-dried powder and fresh eggplant.
  • An extract preparation method using eggplant freeze-dried powder is as follows. Weigh eggplant freeze-dried powder (1 g) into a centrifuge tube (50 mL capacity), add 10-fold weight (10 g) of a 10% to 100% solvent with varying EtOH concentration by 10%, and shake at room temperature at 3000 rpm for 30 minutes. After stirring, the mixture was filtered to obtain a supernatant. The supernatant was transferred to an eggplant flask (200 mL), pure water (10 g) was added, and the mixture was concentrated using an evaporator.
  • the eggplant extract is a water-soluble semi-solid material in which choline ester is concentrated more than freeze-dried powder and / or hot-air dried powder.
  • L-ascorbic acid is added to make the solution acidic and the oxidation is suppressed, it is possible to stabilize the choline ester and prevent color change during the extraction process.
  • the choline esters in the eggplant lyophilized powder is AcCh, and the AcCh content is 2.25 mg / gD. W. Met.
  • the dosage was 0.065 mg / kg of eggplant lyophilized powder corresponding to AcCh1.00 ⁇ 10 ⁇ 9 mol (0.146 ⁇ g) / kg, and it was orally administered once to 6 SHRs.
  • the administration test of AcCh preparation 1.00 ⁇ 10 ⁇ 9 mol / kg was conducted in the same manner to measure the systolic blood pressure.
  • the control group received water only under the same conditions.
  • the eggplant lyophilized powder administration group caused a significant systolic blood pressure lowering effect (p ⁇ 0.05) 3 to 9 hours after administration, and the maximum blood pressure decrease was ⁇ 17 after 9 hours administration. .8 mmHg, -10.0 mmHg compared with the control group, and showed a blood pressure lowering effect almost the same as the administration of acetylcholine 1.00 ⁇ 10 ⁇ 9 mol / kg.
  • the diastolic blood pressure also tended to decrease, and the maximum blood pressure decrease was ⁇ 11.3 mmHg 9 hours after administration, and ⁇ 8.3 mmHg compared with the control group.
  • the heart rate tended to be lower than that of the control group 3 hours after administration, but thereafter showed an upward trend until 9 hours after administration.
  • the blood pressure lowering effect by oral administration of eggplant was confirmed.
  • the effective daily AcCh dose to SHR after 12 hours fast is 1.00 ⁇ 10 ⁇ 9 mol (0.146 ⁇ g) / kg, but the effective daily AcCh dose to non-fasted SHR is a repeated oral study Was a 1.00 ⁇ 10 ⁇ 8 mol (1.46 ⁇ g) / kg in which a significant blood pressure increase inhibitory effect was observed (Non-patent Document 21).
  • the AcCh dose that causes SHR in this normal state to cause a blood pressure lowering effect when taken orally was extrapolated to humans using Kreber's law (Non-patent Document 22).
  • the metabolic rate of mammals is proportional to the third power of the body weight, and assuming that the body weight of SHR is 370 g and the body weight of human is 60 kg, 45.4 times the effective dose of SHR is estimated as the human effective dose. It is. That is, the AcHR intake of SHR causing blood pressure lowering action is 3.70 ⁇ 10 ⁇ 9 mol (0.540 ⁇ g) per day, and the effective human dose per day is 1.68 ⁇ 10 ⁇ 7 mol (24.5 ⁇ g). )
  • the present inventor has already found a blood pressure lowering action and a vasodilating action of fermented duckweed (a fermented lactic acid product of buckwheat plant), and contains and purified choline esters of AcCh, BuCh, LaCh, PrCh as active ingredients. It has been clarified that when AcCh, BuCh, PrCh is orally administered to SHR once, it exhibits a blood pressure lowering effect (Patent Documents 1 and 2). Further studies were conducted to examine the hypotensive effect of oral administration of choline esters in humans.
  • a normal high blood pressure person and a person with hypertensive I (6 males, 6 females, 33-63 years old) drink fermented duck-containing beverage (containing 25 ⁇ g choline ester per bottle) daily for 4 weeks I let you.
  • the blood pressure lowering effect was confirmed at a dose very close to the effective dose obtained by extrapolating the effective dose of AcCh causing blood pressure lowering effect by SHR to humans according to Kreber's law.
  • the blood pressure lowering effect was greatly attenuated at 2.00 ⁇ 10 ⁇ 9 mol (0.292 ⁇ g) / kg.
  • This AcCh dose is extrapolated to humans using Kleber's law (Non-patent Document 22), and the lower limit of the effective human dose per day is 3.36 ⁇ 10 ⁇ 8 mol (4.91 ⁇ g).
  • the blood pressure lowering effect was greatly attenuated at 2.00 ⁇ 10 ⁇ 7 mol (29.2 ⁇ g) / kg.
  • the upper limit of the effective human dose per day is 3.36 ⁇ 10 ⁇ 6 mol (491 ⁇ g). Therefore, the effective human dose per day for hypertensives having genetic characteristics such as SHR was estimated to be in the range of 5 to 500 ⁇ g.
  • the choline ester dose causing the blood pressure lowering effect can be finally determined in consideration of the human effective dose estimated as described above and the amount of choline ester derived from a diet other than the composition of the present invention.
  • the dosage was 0.065 mg / kg of eggplant lyophilized powder (corresponding to AcCh1.00 ⁇ 10 ⁇ 9 mol (0.146 ⁇ g) / kg) and 6.5 mg / kg (AcCh1.00 ⁇ 10 ⁇ 7 mol (14 Equivalent to 6 ⁇ g) / kg).
  • the results of a single oral administration test of eggplant lyophilized powder to WKY rats are shown in FIG.
  • eggplant fruit lyophilized product obtained by freeze-drying eggplant fruit sliced to a width of 1 to 3 cm and sterilized by heating (about 90 ° C., about 5 minutes), or hot-air dried (about 90 ° C., about 1-2)
  • the dried eggplant fruit hot-air product obtained by (hour) was pulverized with a mill mixer (MASTER, Tokyo Unicom Co., Ltd.) to form a powder.
  • Each crushed sample was passed through a stainless steel sieve (JIS standard, 20 mesh), passed through 20 mesh pass, and passed through 20 mesh on, fresh eggplant fruit crushed 20 mesh pass (sample 1), fresh Eggplant fruit pulverized product 20 mesh on (sample 2), freeze dried powder 20 mesh pass (sample 3), freeze dried powder 20 mesh on (sample 4), hot air dried powder 20 mesh pass (sample 5), hot air dried powder 20 mesh On (sample 6) was prepared.
  • Blood vessel isometric tension measurement was performed as follows. Male 14-week-old SHR (body weight: 320 to 346 g) was subjected to laparotomy and exsanguination under ether anesthesia, and the thoracic aorta was rapidly removed. The excised aorta was immersed in physiological saline, and the blood was thoroughly washed out. Then, connective tissue and adipose tissue attached to blood vessels were removed in a Krebs-Henseleit solution, and a ring specimen having a width of about 2 to 3 mm was prepared.
  • an isometric tension testing device UFER UC-05A, Iwashiya Kishimoto Medical Industry Co., Ltd., Kyoto
  • a static tension of 1.0 g Loaded and allowed the ring specimen to stabilize for 60 minutes.
  • phenylephrine PE, 0.3 ⁇ M
  • AcCh final concentration 100 ⁇ M
  • the blood vessels were contracted again with the contracting agent PE (0.3 ⁇ M) to confirm that the contraction reached the maximum, and the final concentration of AcCh was 10 ⁇ 9 , 10 ⁇ 8 , 10 ⁇ 7 , 10 ⁇ 6.
  • Each eggplant pulverized sample suspended in Krebs-Henseleit solution was added so as to be 5 , 10 ⁇ 6 , 10 ⁇ 5.5 , and 10 ⁇ 5 M.
  • Expansion rate (%) ⁇ maximum tension (g) ⁇ tension when adding sample (g) ⁇ / maximum tension (g)
  • Table 14 shows the eggplant crushed sample concentrations added so that the final AcCh concentrations are 10 ⁇ 9 , 10 ⁇ 8 , 10 ⁇ 7 , 10 ⁇ 6.5 , 10 ⁇ 6 , 10 ⁇ 5.5 , and 10 ⁇ 5 M.
  • the freeze-dried yield of the fresh eggplant fruit pulverized product used in this test was 6.0%.
  • the highest concentration was 19 mg / mL.
  • the contents of chlorogenic acids and ⁇ -aminobutyric acid (GABA) that may affect vasodilation other than choline esters are 0.56 mg / g FW and 0.24 mg / g FW, respectively.
  • the maximum expansion rate was 80% when an eggplant ground sample (6.2 ⁇ 10 ⁇ 2 mg / mL) with an AcCh concentration of 10 ⁇ 6 M was added.
  • the hot-air dry powder 20 mesh pass that showed the strongest vasodilatory effect was obtained by adding eggplant ground sample (7.2 ⁇ 10 ⁇ 4 mg / mL) so that the AcCh concentration in the chamber was 10 ⁇ 8 M.
  • Dose-dependent significant vasodilation was shown, and at higher concentrations it was slightly vasodilated, although slightly contracted.
  • the maximum expansion rate was 78% when an eggplant ground sample (7.2 ⁇ 10 ⁇ 2 mg / mL) with an AcCh concentration of 10 ⁇ 6 M was added. From these results, the strong vasodilatory effect of the dried eggplant powder was
  • samples 4 and 6 showed significant vasodilation (AcCh concentration of 10 ⁇ 7 M (freeze-dried powder 8.9 ⁇ 10 ⁇ 3 mg / mL, hot-air dry powder 9.8 ⁇ 10 ⁇ 3 mg / mL)). p ⁇ 0.05), and the maximum expansion rate was 57% freeze-dried powder and 50% hot-air dry powder when the eggplant crushed sample with an AcCh concentration of 10 ⁇ 5 M was added. Comparing the vasodilatory effects of sample 3 and sample 4, when sample 3 was added, a significantly strong vasodilatory effect was confirmed from an AcCh concentration of 10 ⁇ 8 M, and a vasodilatory effect of 10 ⁇ 8 M was 6.5. It was twice.
  • Samples 1 and 2 showed significant vasodilation (p ⁇ 0.05) from 10 ⁇ 6 M (1.4 mg / mL) and 10 ⁇ 6.5 M (0.59 mg / mL), respectively, in the AcCh concentration. Although shown, the vasodilator action was weaker than that of the dry powder, and it became clear that the 20 mesh pass dry powder exerted a high effect in the living body.
  • EC 50 is an index representing the strength of the biological action of the test sample.
  • the vasodilatory EC 50 in the main test of Sample 3 is 0.015 mg / mL, and a significantly stronger activity is recognized than the eggplant pulverized product other than Sample 5, the activity intensity is 467 times that of Sample 1, and Sample 2 660 times, 16 times that of Sample 4, and 26 times that of Sample 6.
  • the EC 50 of Sample 5 that exhibited the next strong vasodilatory action was 0.027 mg / mL, and a significantly stronger activity was observed than the ground eggplant other than Sample 3, and the strength of the activity was that of Sample 1. They were 259 times, 367 times of sample 2, 9 times of sample 4, and 14 times of sample 6. From the above results, it was concluded that dried eggplant powder finer than 20 mesh has a strong vasodilatory action.
  • the blood pressure (systolic phase, diastolic phase) was measured in the same manner as in [Experiment 9] above, on the 7th, 14th, 21st and 28th days before the start of the test and after the start of the test. Each measurement was repeated three times, and an average value ⁇ standard error (Mean ⁇ SE) was determined.
  • Urinary catecholamine was quantified using a urine sample the day before blood pressure measurement. From the day before the start of repeated oral administration, collection of urine samples for 24 hours was started. Urine was collected once a day using a urine collection container to which 5N hydrochloric acid (1 mL) was added and the amount of urination was measured. The obtained urine was stored frozen at ⁇ 80 ° C. until measurement.
  • Urinary catecholamines consist of an HPLC system (Prominence HPLC system, Shimadzu Corporation, Kyoto: System controller: CBM-20A, liquid feeding unit: LC-20AD, column oven: CTO-10A) and an electrochemical detector (ECD, Using GL Sciences Inc., ED723 diamond electrode), quantification was repeated three times under the following conditions, and an average value ⁇ standard error (Mean ⁇ SE) was determined.
  • HPLC system Prominence HPLC system, Shimadzu Corporation, Kyoto: System controller: CBM-20A, liquid feeding unit: LC-20AD, column oven: CTO-10A
  • ECD electrochemical detector
  • the test group showed significantly lower systolic blood pressure on the 14th, 21st, and 28th days of the test, and the diastolic blood pressure on the 28th day than the control group.
  • Noradrenaline is a neurotransmitter released from the sympathetic nerve endings, and adrenaline is produced by converting noradrenaline in the adrenal glands.
  • These catecholamines act on adrenergic receptors and are involved in the control of various organs and metabolic systems. The released catecholamine acts on the effector that the nerve reaches, and partly moves into the blood to affect the whole body. Blood catecholamines are metabolized and inactivated, but some are excreted in the urine as they are. Therefore, the amount of urinary catecholamine is an index of sympathetic nerve activity in the living body. In other words, as a result of increased sympathetic nerve activity and active activity, the amount of urinary catecholamine increases. Sympathetic nerves promote arousal, attack, defense and escape behavior.
  • Catecholamines released by increased sympathetic nerve activity act on vascular adrenergic alpha receptors, causing blood vessels to contract and increase blood pressure. Therefore, it is considered that the catecholamine decrease due to suppression of sympathetic nerve activity is deeply involved in the blood pressure lowering mechanism of orally ingested choline esters.
  • catecholamine is known as a stress index.
  • Catecholamine (adrenaline, noradrenaline, dopamine) is adopted as an index of the antistress action in the body of the antistress composition containing ⁇ -carotene as an active ingredient, and the antistress action is shown by a significant decrease in catecholamine by the intake of the composition (Patent Document 3).
  • the urinary catecholamine amount was significantly reduced by ingestion of eggplant lyophilized powder, and it can be said that the ingestion of eggplant lyophilized powder suppressed sympathetic nerve activity and exerted an anti-stress effect. That is, an anti-stress effect by ingesting eggplant freeze-dried powder was observed.
  • the vasodilatory effect of Experiment 11 is caused by the action of choline esters contained in eggplant on muscarinic acetylcholine receptors (Non-patent Document 25). This anti-stress effect is also thought to be the result of choline esters contained in eggplant acting on muscarinic acetylcholine receptors, suppressing sympathetic nerve activity and inhibiting catecholamine release from nerve depletion.
  • Extracts and processed foods made from eggplant containing ester are considered to have anti-stress action.
  • the hypotensive and anti-stress effects caused by the suppression of sympathetic nerve activity by orally ingested choline esters are closely related to each other. Therefore, the difference in choline ester dosage between SHR and WKY rats, where blood pressure lowering action was observed, is also applied to anti-stress action.
  • composition of the present invention has a remarkable blood pressure lowering action, and by containing this as an active ingredient, a functional indication food or a therapeutic drug for hypertension or the like can be produced.

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JPWO2020166494A1 (ja) * 2019-02-15 2021-12-16 国立大学法人信州大学 血圧低下作用を有するナス由来組成物
JP7691693B2 (ja) 2019-02-15 2025-06-12 国立大学法人信州大学 血圧低下作用を有するナス由来組成物
JP7337363B2 (ja) 2019-02-28 2023-09-04 株式会社ウェルナス 睡眠を改善するための経口摂取用組成物
JP2020137462A (ja) * 2019-02-28 2020-09-03 株式会社ウェルナス 睡眠を改善するための経口摂取用組成物
WO2020175605A1 (ja) * 2019-02-28 2020-09-03 株式会社ウェルナス 睡眠を改善するための経口摂取用組成物
JP7795802B2 (ja) 2019-02-28 2026-01-08 株式会社ウェルナス 睡眠を改善するための経口摂取用組成物
JP2023169145A (ja) * 2019-02-28 2023-11-29 株式会社ウェルナス 睡眠を改善するための経口摂取用組成物
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US20220401509A1 (en) * 2019-11-15 2022-12-22 Shinshu University Composition For Improving Mental State, Production Method For Composition For Improving Mental State, And Use Of Fruit Of Eggplant For Improving Mental State
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