WO2015152311A1 - Régulateur de la sécrétion de mélatonine, et procédé de régulation de la sécrétion de la mélatonine - Google Patents

Régulateur de la sécrétion de mélatonine, et procédé de régulation de la sécrétion de la mélatonine Download PDF

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Publication number
WO2015152311A1
WO2015152311A1 PCT/JP2015/060283 JP2015060283W WO2015152311A1 WO 2015152311 A1 WO2015152311 A1 WO 2015152311A1 JP 2015060283 W JP2015060283 W JP 2015060283W WO 2015152311 A1 WO2015152311 A1 WO 2015152311A1
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Prior art keywords
ornithine
melatonin secretion
sleep
sleep disorder
salt
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PCT/JP2015/060283
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English (en)
Japanese (ja)
Inventor
しのぶ 安尾
幸宏 菱田
さおり 秋月
麻実 根橋
神村　彩子
Original Assignee
国立大学法人九州大学
協和発酵バイオ株式会社
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Application filed by 国立大学法人九州大学, 協和発酵バイオ株式会社 filed Critical 国立大学法人九州大学
Priority to CN201580018289.2A priority Critical patent/CN106163510A/zh
Priority to SG11201608082XA priority patent/SG11201608082XA/en
Priority to JP2016511972A priority patent/JP6594858B2/ja
Priority to AU2015242879A priority patent/AU2015242879A1/en
Publication of WO2015152311A1 publication Critical patent/WO2015152311A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a melatonin secretion regulator containing ornithine or a salt thereof, a melatonin secretion regulation method, ornithine or a salt thereof for use in regulating melatonin secretion, ornithine or a salt thereof for the production of a melatonin secretion regulator. Regarding use.
  • L-ornithine is used mainly in the United States as a food material that enhances muscle synthesis or increases basal metabolism and prevents obesity. In Europe, L-ornithine is used in the form of L-ornithine / L-aspartate as a medicine for improving liver damage in Europe.
  • ornithine is known to have the effect of improving sleep or waking up (Patent Document 1), cooling symptoms (Patent Document 2), and promoting eating activity and / or digestive tract activity (Patent Document 3).
  • Patent Document 1 sleep or waking up
  • Patent Document 2 cooling symptoms
  • Patent Document 3 promoting eating activity and / or digestive tract activity
  • ingestion of ornithine or a salt thereof accelerates the start of melatonin secretion.
  • Melatonin is a hormone secreted from the pineal gland of the brain and is suppressed by light during the day, but increases at night.
  • the circadian rhythm is adjusted via a receptor present in the suprachiasmatic nucleus, and natural sleep is brought about by the action of hypothermia or the regulation of neuroendocrine function.
  • ⁇ ⁇ Melatonin secretion is suppressed by nighttime lighting, which causes disturbance of circadian rhythm or sleep disorder. Moreover, the secretion of melatonin decreases with aging, and is also involved in sleep disorders in the elderly.
  • Non-Patent Documents 1 and 2 and Patent Document 4 For example, time difference syndrome, shift work sleep disorder, sleep phase regression syndrome, non-24-hour sleep-wake disorder, etc. It is expected to improve daily rhythm sleep disorders (Non-Patent Documents 1 and 2 and Patent Document 4) and, for example, sleep disorders caused by aging such as awakening and insomnia (Non-Patent Document 3).
  • melatonin or its receptor agonist preparation is used clinically for this purpose, and melatonin is sold in the United States as a dietary supplement.
  • Japanese Unexamined Patent Publication No. 2006-342148 Japanese Unexamined Patent Publication No. 2007-119348 International Publication No. 2013/129642 Japanese Unexamined Patent Publication No. 2003-335691
  • an object of the present invention is to provide a method for adjusting melatonin secretion in a living body, more specifically, a melatonin secretion regulator capable of advancing the start time of increase in melatonin secretion.
  • the present inventors have found that the above problems can be solved by an agent containing ornithine or a salt thereof as an active ingredient, and have completed the present invention. That is, the present invention relates to the following (1) to (16).
  • the melatonin secretion regulator according to (1) which is a therapeutic agent for circadian rhythm sleep disorder and / or sleep disorder due to aging.
  • the melatonin secretion regulator according to (2) wherein the sleep disorder due to aging is mid-wake awakening or insomnia.
  • a melatonin secretion regulating method comprising a step of administering to a subject in need of an effective amount of ornithine or a salt thereof.
  • the melatonin secretion regulation method according to (5) which is a method for treating circadian rhythm sleep disorder and / or sleep disorder due to aging.
  • the melatonin secretion regulation method according to (6) wherein the circadian rhythm sleep disorder is a time difference syndrome, shift work sleep disorder, sleep phase regression syndrome, or non-24-hour sleep-wake disorder.
  • a melatonin secretion regulator containing ornithine or a salt thereof can be provided.
  • the start time of the increase in melatonin secretion at night can be shortened by L-ornithine or a salt thereof contained as an active ingredient.
  • the horizontal axis represents time (hours) from the start of the light period, and the vertical axis represents plasma melatonin concentration (pg / mL).
  • a black circle ( ⁇ ) represents a group administered with distilled water (control group)
  • a white square ( ⁇ ) represents a group administered with 1000 mg / kg L-ornithine hydrochloride
  • a white triangle ( ⁇ ) represents 3000 mg / kg administered with L-ornithine hydrochloride Represents a group.
  • the present invention includes a melatonin secretion regulator containing ornithine or a salt thereof as an active ingredient.
  • Ornithine used in the present invention includes L-ornithine and D-ornithine, with L-ornithine being preferred.
  • L-ornithine is preferred because ornithine exists in L form in vivo.
  • Ornithine can be obtained by a chemical synthesis method or a fermentation production method. Ornithine can also be obtained by purchasing a commercial product.
  • L-ornithine As a method for chemically synthesizing L-ornithine, for example, Coll. Czechoslov. Chem. Commun. 24, 1993 (1959). Examples of the method for fermentative production of L-ornithine include the methods described in JP-A-53-24096 and JP-A-61-119194. L-ornithine and D-ornithine can also be purchased from Sigma-Aldrich.
  • ornithine salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, and acetate, maleate, fumarate, citrate, malate, lactate, ⁇ -ketoglutar Organic acid salts such as acid salts, gluconates and caprylates.
  • metal salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • ammonium salts include salts such as ammonium and tetramethylammonium.
  • organic amine addition salt examples include salts such as morpholine and piperidine.
  • amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid, and the like.
  • hydrochloride citrate, malate, ⁇ -ketoglutarate or aspartate is preferably used, but other salts or two or more salts may be used in appropriate combination. Good.
  • the “melatonin secretion regulator” in the present invention represents an agent that, when ingested into the body, increases the time when the daily increase in melatonin secretion starts compared to when it is not ingested.
  • the melatonin secretion regulator of the present invention can appropriately contain additives suitable for each application.
  • ornithine or a salt thereof can be administered as it is, but it is usually preferable to provide it as various preparations.
  • the preparation contains ornithine or a salt thereof as an active ingredient, but may further contain any active ingredient.
  • These preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
  • the dosage form of the preparation is preferably the most effective in adjusting melatonin secretion.
  • Oral administration or parenteral administration such as intravenous, intraperitoneal or subcutaneous administration can be mentioned, but oral administration is preferred.
  • dosage forms to be administered include tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, liquids, elixirs, extracts, tinctures, and fluid extracts. Any of these oral preparations or parenteral preparations such as injections, infusions, creams or suppositories may be used, but they are preferably used as oral preparations.
  • Liquid preparations suitable for oral administration include water, sucrose, saccharides such as sorbitol or fructose, glycols such as polyethylene glycol or propylene glycol, oils such as sesame oil, olive oil or soybean oil, Preservatives such as p-hydroxybenzoic acid esters, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, or flavors such as strawberry flavor or peppermint can be added to form a preparation. .
  • tablets, powders and granules include lactose, sucrose, glucose, sucrose, saccharides such as mannitol or sorbitol, starch such as potato, wheat or corn, calcium carbonate, calcium sulfate, sodium bicarbonate Or excipients such as inorganic substances such as sodium chloride, crystalline cellulose, plant powder such as licorice powder or gentian powder, starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium bicarbonate or Disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol or silicone oil, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose Scan, carmellose, binders such as gelatin or starch glue solution may be formulated by adding a plasticizer such as a surfactant or glycerol, such as fatty acid
  • preparations suitable for oral administration include additives generally used in foods and drinks such as sweeteners, colorants, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, Gum base, bittering agent, enzyme, brightener, sour agent, seasoning, emulsifier, strengthening agent, production agent, flavor and spice extract may be added.
  • additives generally used in foods and drinks such as sweeteners, colorants, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, Gum base, bittering agent, enzyme, brightener, sour agent, seasoning, emulsifier, strengthening agent, production agent, flavor and spice extract may be added.
  • Preparations suitable for oral administration are as they are or, for example, in the form of powdered foods, sheet foods, bottled foods, canned foods, retort foods, capsule foods, tablet foods, liquid foods, drinks, etc. It may be used as food and drink such as health food, functional food, nutritional supplement, and food for specified health use.
  • an injection preferably comprises a sterile aqueous preparation containing ornithine or a salt thereof that is isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution.
  • parenteral agents one kind selected from preservatives, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for oral agents. Or more auxiliary components can be added.
  • the concentration of ornithine or a salt thereof in the melatonin secretion regulator of the present invention is appropriately selected according to the type of preparation or the effect expected by administration of the preparation.
  • Ornithine or a salt thereof is usually preferably 0.1 to 100% by weight, more preferably 0.5 to 80% by weight, and particularly preferably 1 to 70% by weight.
  • ornithine or a salt thereof is usually preferably 50 mg to 30 g, more preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g per day per day for adults.
  • the human to be administered with the melatonin secretion regulator of the present invention may be, for example, a person who is aware of an abnormality in melatonin secretion such as a delay in the start time of melatonin secretion, or is aware of the abnormality in melatonin secretion. However, it may be a human who has a lifestyle that makes melatonin secretion abnormal, or a person who can predict the abnormality of melatonin secretion sufficiently with age.
  • the subject to be administered is preferably a human who is aware of the abnormal melatonin secretion, and specifically, a human having circadian rhythm sleep disorder and / or sleep disorder due to aging.
  • circadian rhythm sleep disorders include humans with symptoms such as time difference syndrome, shift work sleep disorder, sleep phase regression syndrome or non-24-hour sleep-wake disorder.
  • Examples of humans who have sleep disorders due to aging include humans who have awakening or insomnia. Examples of humans who have sleep disorders due to aging include humans who are preferably 51 years old or older, more preferably 61 years old or older, and even more preferably 71 years old or older.
  • the administration time of the melatonin secretion regulator of the present invention is not particularly limited, but for humans, it is from morning to daytime.
  • the administration period is not particularly limited, but usually it is preferably 1 day to 1 year, more preferably 1 week to 3 months.
  • the dose and frequency of administration vary depending on the dosage form, the age, type, etc. of the animal, but usually 1 to 5000 mg as ornithine or a salt thereof per kg body weight per day.
  • the dose is preferably once to several times a day so that the dose is preferably 2 to 4000 mg, particularly preferably 4 to 3000 mg.
  • the administration period is not particularly limited, but usually it is preferably 1 day to 1 year, more preferably 1 week to 3 months.
  • circadian rhythm sleep disorder and / or sleep disorder due to aging can be prevented or improved.
  • circadian rhythm sleep disorders include time difference syndrome, shift work sleep disorder, sleep phase regression syndrome, and non-24-hour sleep-wake disorder.
  • sleep disorder due to aging include awakening during sleep and insomnia.
  • the present invention also includes a melatonin secretion regulating method including a step of administering to a subject in need of an effective amount of ornithine or a salt thereof.
  • the “melatonin secretion regulating method” in the present invention represents a method of advancing the time when the daily increase in melatonin secretion starts.
  • the dosage and the number of administrations vary depending on the dosage form, the age or weight of the subject.
  • the effective amount of ornithine or a salt thereof required by the administration subject is usually preferably 50 mg to 30 g, more preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g as an ornithine or a salt thereof per day for an adult. Administer once or several times a day to achieve the effective dose.
  • the human to be administered ornithine or a salt thereof may be a person who is aware of an abnormality in melatonin secretion, such as a delay in the start time of melatonin secretion, or may not be aware of the abnormality in melatonin secretion. However, it may be a human who has a lifestyle that makes melatonin secretion abnormal, or a human who can sufficiently expect the abnormality of melatonin secretion in terms of age.
  • the subject to be administered is preferably a human who is aware of the abnormal melatonin secretion, and specifically, a human having circadian rhythm sleep disorder and / or sleep disorder due to aging.
  • circadian rhythm sleep disorders include humans with symptoms such as time difference syndrome, shift work sleep disorder, sleep phase regression syndrome or non-24-hour sleep-wake disorder.
  • Examples of humans who have sleep disorders due to aging include humans who have awakening or insomnia. Examples of humans who have sleep disorders due to aging include humans who are preferably 51 years old or older, more preferably 61 years old or older, and even more preferably 71 years old or older.
  • the administration time of ornithine or a salt thereof is not particularly limited, but in humans, it is from morning to daytime.
  • the administration period is not particularly limited, but usually it is preferably 1 day to 1 year, more preferably 1 week to 3 months.
  • the dose and the number of doses vary depending on the dosage form, the age, type, etc. of the animal.
  • the effective amount of ornithine or a salt thereof required by a non-human animal is preferably 1 to 5000 mg, more preferably 2 to 4000 mg, particularly preferably 4 to 3000 mg as ornithine or a salt thereof per 1 kg body weight per day. Yes, administer once or several times a day to achieve the effective dose.
  • the administration period is not particularly limited, but usually it is preferably 1 day to 1 year, more preferably 1 week to 3 months.
  • circadian rhythm sleep disorder and / or sleep disorder due to aging can be prevented or improved.
  • circadian rhythm sleep disorders include time difference syndrome, shift work sleep disorder, sleep phase regression syndrome, and non-24-hour sleep-wake disorder.
  • sleep disorder due to aging include awakening during sleep and insomnia.
  • melatonin secretion can be prepared by administering an effective amount of ornithine or a salt thereof as a “melatonin secretion regulating agent” to the subject.
  • the present invention also includes the use of ornithine or a salt thereof for the production of a melatonin secretion regulator.
  • the active ingredient When producing a melatonin secretion regulator using ornithine or a salt thereof, the active ingredient is ornithine or a salt thereof used, but may further contain any of the above active ingredients. In the case of preparing them as a preparation, the active ingredient is mixed with one or more pharmacologically acceptable carriers and manufactured by any method well known in the technical field of pharmaceutics.
  • Example 1 CBA / N mice (male, 7 weeks old, average body weight 20-30 g) were used in the study.
  • the illumination conditions were a light / dark cycle of 12 hours light period and 12 hours dark period.
  • the animals were bred under conditions of room temperature 25 ⁇ 1 ° C., free drinking / free feeding, and group breeding of 4 animals per cage.
  • the solution or distilled water to be administered to each group was prepared according to the following 1) to 3).
  • Fig. 1 shows a graph of plasma melatonin concentration. The results are shown as mean ⁇ standard error, Dunnett's multiple comparison test was used for statistical processing, and the difference was shown as a significant difference from the value at 12:00 after the start of the light period, which is the basic level of the control group. As shown in FIG. 1, in control mice administered with distilled water, a significant increase in melatonin concentration was observed from 20:00 after the start of the light period (***: p ⁇ 0.001).
  • Production of granule containing ornithine The tablets obtained in Production Example 1 are pulverized, granulated, and sieved to obtain 20-50 mesh granules.
  • the obtained mixture was compression-molded at a compression molding pressure of 10 kN using a rotary compression molding machine (VIRGO524SS1AY, manufactured by Kikusui Seisakusho Co., Ltd.) to produce a tablet having a diameter of 8 mm and 250 mg.
  • VIRGO524SS1AY manufactured by Kikusui Seisakusho Co., Ltd.

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Abstract

　La présente invention vise à fournir un régulateur de la sécrétion de mélatonine capable de réguler la sécrétion de mélatonine in vivo. La présente invention concerne par conséquent la fourniture d'un régulateur de la sécrétion de mélatonine contenant de l'ornithine ou un sel de celle-ci en tant qu'ingrédient actif.
PCT/JP2015/060283 2014-03-31 2015-03-31 Régulateur de la sécrétion de mélatonine, et procédé de régulation de la sécrétion de la mélatonine WO2015152311A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201580018289.2A CN106163510A (zh) 2014-03-31 2015-03-31 褪黑素分泌调节剂、褪黑素分泌调节方法
SG11201608082XA SG11201608082XA (en) 2014-03-31 2015-03-31 Agent for regulating melatonin secretion, and method for regulating melatonin secretion
JP2016511972A JP6594858B2 (ja) 2014-03-31 2015-03-31 メラトニン分泌調整剤、メラトニン分泌調整方法
AU2015242879A AU2015242879A1 (en) 2014-03-31 2015-03-31 Melatonin secretion regulator, and method for regulating melatonin secretion

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014-072675 2014-03-31
JP2014072675 2014-03-31

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WO2015152311A1 true WO2015152311A1 (fr) 2015-10-08

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JP (1) JP6594858B2 (fr)
CN (1) CN106163510A (fr)
AU (1) AU2015242879A1 (fr)
SG (1) SG11201608082XA (fr)
WO (1) WO2015152311A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019182775A (ja) * 2018-04-09 2019-10-24 キリンホールディングス株式会社 メラトニンの分泌開始時刻遅延促進用組成物、早期覚醒改善用組成物及び概日リズムの位相前進化の改善用組成物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006342148A (ja) * 2005-05-13 2006-12-21 Kyowa Hakko Kogyo Co Ltd 寝つきまたは寝起き改善用経口剤
JP2008050352A (ja) * 2006-07-27 2008-03-06 Ezaki Glico Co Ltd 睡眠改善剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006342148A (ja) * 2005-05-13 2006-12-21 Kyowa Hakko Kogyo Co Ltd 寝つきまたは寝起き改善用経口剤
JP2008050352A (ja) * 2006-07-27 2008-03-06 Ezaki Glico Co Ltd 睡眠改善剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARUKA MATSUO ET AL.: "L-Ornithine no Toyo Jikan Izonteki na Hormone Bunpitsu Rhythm Seigyo", AMINO ACID KENKYU, vol. 6, no. 2, February 2013 (2013-02-01), pages 179 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019182775A (ja) * 2018-04-09 2019-10-24 キリンホールディングス株式会社 メラトニンの分泌開始時刻遅延促進用組成物、早期覚醒改善用組成物及び概日リズムの位相前進化の改善用組成物

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CN106163510A (zh) 2016-11-23
AU2015242879A8 (en) 2016-11-10
SG11201608082XA (en) 2016-11-29
JP6594858B2 (ja) 2019-10-23
JPWO2015152311A1 (ja) 2017-04-13
AU2015242879A1 (en) 2016-10-20

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