WO2020262325A1 - Agent anti-vieillissement pour femelles - Google Patents

Agent anti-vieillissement pour femelles Download PDF

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Publication number
WO2020262325A1
WO2020262325A1 PCT/JP2020/024469 JP2020024469W WO2020262325A1 WO 2020262325 A1 WO2020262325 A1 WO 2020262325A1 JP 2020024469 W JP2020024469 W JP 2020024469W WO 2020262325 A1 WO2020262325 A1 WO 2020262325A1
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WIPO (PCT)
Prior art keywords
salt
pyrroloquinoline quinone
agent
extract
female
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PCT/JP2020/024469
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English (en)
Japanese (ja)
Inventor
昌之 島田
Original Assignee
国立大学法人広島大学
ロート製薬株式会社
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Application filed by 国立大学法人広島大学, ロート製薬株式会社 filed Critical 国立大学法人広島大学
Priority to CN202080045230.3A priority Critical patent/CN114007618A/zh
Priority to JP2021526988A priority patent/JPWO2020262325A1/ja
Publication of WO2020262325A1 publication Critical patent/WO2020262325A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the present invention relates to a female anti-aging agent.
  • Non-Patent Document 1 Non-Patent Document 1
  • menopause is mainly caused in women in their late 40s to 50s. In some cases, even women in their 30s to mid-40s, combined with stress and overwork, may exhibit irregular menstruation in addition to the above-mentioned symptoms of menopause. This is also called pre-menopause, and along with menopause, it significantly reduces women's quality of life. Hormone replacement therapy is mainly used in the treatment of these menopausal disorders and pre-menopausal disorders, but there are problems of side effects such as the possibility of carcinogenesis, irregular bleeding, vaginal bleeding, headache, and liver dysfunction.
  • Non-Patent Document 2 a safe and effective treatment method for pre-menopausal disorders and menopausal disorders is required.
  • aging of female reproductive tissues has become a problem not only in humans but also in domestic animals such as cattle and pigs.
  • the cycle from mating to calving of sows is 2.5 times a year, but the number of offspring of sows decreases with aging and breeding due to an increase in reproductive disorders such as miscarriage. Grades also deteriorate. Therefore, it is desired to develop a method for suppressing the progress of aging of female reproductive tissues not only in humans but also in non-human animals.
  • An object of the present invention is to provide an anti-aging agent for an ovary, a follicle or an egg (hereinafter, these may be collectively referred to as "female reproductive tissue").
  • the present inventors have found that pyrroloquinoline quinone or a salt thereof suppresses the progress of aging of female reproductive tissues and promotes the production of estradiol.
  • the present invention is based on this novel finding.
  • the present invention provides, for example, the following inventions.
  • An ameliorating or prophylactic agent for ovarian hyperstimulation syndrome containing pyrroloquinoline quinone or a salt thereof.
  • the agent according to [6] which ameliorates or prevents symptoms caused by female estrogen deficiency.
  • the agent according to [6] which improves or prevents pre-menopause or menopause in females.
  • Test Example 1 it is a graph which shows the blood AMH concentration in each female mouse.
  • A is a graph showing the estrous cycle when pyrroloquinoline quinone disodium salt is not administered to female aging model mice in Test Example 2.
  • B is a graph showing the estrous cycle when pyrroloquinoline quinone was administered to a female aging model mouse in Test Example 2.
  • M indicates the late estrous cycle
  • WE indicates the microestrous cycle
  • E indicates the estrous cycle
  • P indicates the early estrous cycle
  • D indicates the telogen effluvium.
  • (A) shows the time and blood estradiol concentration when eCG (equine chorionic gonadotropin) was administered to immature female mice to which pyrroloquinoline quinone disodium salt was administered or not administered in Test Example 4. It is a graph which shows the relationship.
  • (B) administered eCG (equine chorionic gonadotropin) and hCG (human chorionic gonadotropin) to immature female mice to which pyroloquinolinquinone disodium salt was administered or not. It is a graph which shows the relationship between time and blood progesterone concentration at time.
  • (A) is a photograph of the ovary of a female aging model mouse before administration of pyrroloquinoline quinone disodium salt in Test Example 5 taken by PSR staining (magnification 20 times).
  • (B) is a photograph of the ovary after administration of pyrroloquinoline quinone disodium salt for 2 weeks to a female aging model mouse in Test Example 5 by PSR staining (magnification 20 times).
  • (C) and (D) are traces of (A) and (B), respectively, and shaded areas indicate stained areas.
  • the ovarian, follicle or egg anti-aging agent according to the present embodiment contains pyrroloquinoline quinone or a salt thereof (also referred to as "component (A)").
  • Pyrroloquinoline quinone or a salt thereof has an effect of suppressing the disappearance or decrease of AMH (Anti-Mullerian Hormone; anti-Müllerian hormone) in females.
  • AMH is a hormone that is an index of aging of female reproductive tissues (particularly ovaries), and it is known that the blood AMH concentration decreases as the aging of female reproductive tissues progresses.
  • pyrroloquinoline quinone or a salt thereof has an effect of suppressing or improving fibrosis of female reproductive tissues (ovary, follicle, egg, etc., particularly ovary).
  • an anti-aging agent for ovary, follicle or egg, and an agent for suppressing or improving fibrosis of female reproductive tissue, which contains pyrroloquinoline quinone or a salt thereof are provided.
  • Anti-aging here means rejuvenating women, suppressing the progress of aging of women, being able to maintain a high QOL even when women are old, and being lively and young even when women are old. It refers to being able to spend time in a different way.
  • the term “elderly” as used herein refers to those in their thirties or older, preferably in their forties or older, and more preferably in their fifties or older.
  • ovarian reserve (the number of secondary follicles remaining in the ovary).
  • pyrroloquinoline quinone or a salt thereof has an effect of suppressing the disappearance or decrease of AMH in females, it also has an effect of improving ovarian reserve.
  • Pyrroloquinoline quinone or its salt has the effect of improving the quality of eggs. Therefore, as an embodiment of the present invention, an egg quality improving agent containing pyrroloquinoline quinone or a salt thereof is provided.
  • improved of egg quality refers to maintaining or improving the fertilization rate of the ovulated egg while increasing the number of ovulations
  • the fertilization rate here refers to fertilization with respect to the total number of ovulated eggs. It is the ratio of the number of ovulated eggs. Therefore, as an embodiment of the present invention, there is provided an agent containing pyrroloquinoline quinone or a salt thereof for increasing the number of ovulated eggs and maintaining or improving the fertilization rate of the ovulated eggs. ..
  • improved of egg quality refers to maintaining or improving the development rate while maintaining or improving the fertilization rate of the egg, and the development rate here means the blastocyst stage embryo of the fertilized egg. Refers to the proportion of those that became. Therefore, as an embodiment of the present invention, an agent containing pyrroloquinoline quinone or a salt thereof for maintaining or improving the fertilization rate of an egg and maintaining or improving the incidence rate is provided.
  • Pyrroloquinoline quinone or its salt has the effect of improving or preventing menstrual irregularities. Therefore, as an embodiment of the present invention, an improving agent or a preventive agent for irregular menstruation containing pyrroloquinoline quinone or a salt thereof is provided.
  • “irregular menstruation” means a state in which the cycle of menstruation (ovulation in female non-human animals without menstruation) in females is abnormal. For example, in humans, the normal menstrual cycle is 25 to 38 days, and the menstrual cycle is within 24 days or 39 days or more, or there is no menstruation for 3 months or more (in the case of amenorrhea). Menstruation is irregular.
  • Pyrroloquinoline quinone or a salt thereof has an effect of promoting the production of estrogen (estron, estradiol, estriol, preferably estradiol). Therefore, as an embodiment of the present invention, an estrogen production promoter containing pyrroloquinoline quinone or a salt thereof is provided.
  • pyroloquinolinquinone or a salt thereof promotes the production of estrogen, thereby improving or preventing the symptoms caused by estrogen deficiency in females, improving or preventing menopausal symptoms in females, and pre-menopausal disorders in females. In addition to having the effect of improving or preventing menopause or improving or preventing menopause in females, it also has the effect of supplementing female hormones.
  • a symptom ameliorating agent or a preventive agent for female estrogen deficiency a female climacteric symptom ameliorating agent or a preventive agent, or a female pre. Menopausal disorders or ameliorating or prophylactic agents for menopause are provided.
  • ovarian hyperstimulation syndrome means various symptoms caused by ascites and pleural effusion caused by swelling of the ovary due to excessive stimulation of an ovarian inducer, and in severe cases, blood is concentrated and renal failure or It also causes complications such as thrombosis.
  • Specific symptoms of ovarian hyperstimulation syndrome include bloating, nausea, rapid weight gain, decreased urine output, abdominal pain, diarrhea and the like.
  • pyrroloquinoline quinone or a salt thereof has an effect of improving or preventing ovarian hyperstimulation syndrome, thereby improving or preventing symptoms derived from ovarian hyperstimulation syndrome and complications of ovarian hyperstimulation syndrome.
  • agent containing pyrroloquinoline quinone or a salt thereof according to each of the above embodiments is also collectively referred to as "agent according to this embodiment".
  • menopause means about 10 years before and after menopause in females, and in the case of humans, the period from the late 40s to the 50s corresponds to the menopause. Further, in the present specification, the term “pre-menopause” refers to a period younger than the above-mentioned menopause, in which symptoms of pre-menopause described later may be exhibited, and in the case of humans, the period from the 30s to the mid-40s is. Corresponds to pre-menopause.
  • Symptoms of "female menopause” include, for example, suffocation, lightheadedness, dizziness, numbness in limbs, stiffness in limbs, swelling, tiredness, ringing in the ears, swelling, hot flash, sweating, palpitation, excitement, etc. Sleeplessness, irritation, anger, emotional instability, depressed mood, fragile tears, decreased motivation, anxiety, headache, stiff shoulders, chest pain, lower back pain, joint pain, cold hands and feet, itching, dry skin and eyes, nausea , Loss of appetite, abdominal pain, constipation, dizziness, frequent urination, palpitations, palpitations, etc.
  • Symptoms derived from female estrogen deficiency include, for example, menopause, autonomic imbalance, neuropsychiatric symptoms, urogenital atrophy, hyperlipidemia, arteriosclerosis, hypertension, stroke, osteoporosis, bone mass.
  • urogenital atrophy urogenital atrophy
  • hyperlipidemia urogenital atrophy
  • arteriosclerosis hypertension
  • stroke osteoporosis
  • bone mass a malignant osis
  • Expected actions / effects of HRT can be mentioned.
  • Symptoms of "female pre-menopause (female juvenile menopause)" include irregular menstruation, amenorrhea, etc., in addition to the above-mentioned “female menopause” symptoms.
  • “Female menopause” refers to the above-mentioned “female menopause” symptoms and “female pre-menopause (female juvenile menopause)” symptoms.
  • the symptom can be exhibited not only from “menopause” or “pre-menopause” but also from a younger age (for example, in the case of a human being in his teens when menstruation begins).
  • the "female menopausal symptom” among these specific symptom described above, the symptom may be mild. For example, there may be a state in which the person is aware of burning or sweating but the number of times is small, or a state in which the degree of depression or stiff shoulder is small.
  • Pyrroloquinoline quinone has the following formula: It is a known compound represented by.
  • Examples of the pyroloquinolinquinone salt include alkali metal salts, alkaline earth metal salts and ammonium salts.
  • Examples of the alkali metal salt include sodium salt, potassium salt and lithium salt.
  • Examples of the alkaline earth metal salt include calcium salt and magnesium salt.
  • pyrroloquinoline quinone or a salt thereof an alkali metal salt of pyrroloquinoline quinone is preferable, a sodium salt of pyrroloquinoline quinone is more preferable, and a disodium salt of pyrroloquinoline quinone is further preferable.
  • pyrroloquinoline quinone or a salt thereof commercially available ones can also be used. Further, as the pyrroloquinoline quinone or a salt thereof, for example, natto, soybean, cocoa powder, cacao mass, cacao, parsley, peppers and the like containing pyrroloquinoline quinone or a salt thereof may be used.
  • the content of component (A) in the agent according to this embodiment is the total amount of component (A) based on the total amount of the agent according to this embodiment from the viewpoint of the stability of the drug to be administered.
  • the content is preferably 0.01 to 30% by weight, more preferably 0.2 to 10% by weight, further preferably 1 to 5% by weight, and 1.3 to 3% by weight. Is particularly preferable.
  • the content of the component (A) in the agent according to the present embodiment is such that the total content of the component (A) is 0, based on the total amount of the agent according to the present embodiment. It is preferably 01 to 0.3% by weight, more preferably 0.02 to 0.2% by weight.
  • the daily intake of the component (A) may differ depending on the condition (body weight, age, sex, etc.) of the individual ingesting, the formulation form, etc., but when used in humans, From the viewpoint of ease of ingestion as a single dose, the viewpoint of the effectiveness of the physiological action based on the component (A), and the viewpoint of safety, preferably 7 to 100 mg, more preferably 10 to 40 mg, still more preferably 20 to 20 to It is 25 mg, and when used for non-human animals, it is preferably 1 to 30 mg / kg, more preferably 2 to 20 mg / kg.
  • the agent according to the present embodiment may further contain a polyamine (also referred to as “component (B)”) and a crude drug (also referred to as “component (C)”).
  • component (B) a polyamine
  • component (C) a crude drug
  • Polyamine is an aliphatic hydrocarbon containing two or more primary amino groups in the molecule.
  • Specific examples of polyamines include, for example, ptolessin, cadaverine, ethylenediamine, trimethylenediamine, hexamethylenediamine, spermine, kardin, homospermine, aminopropyl cadaverine, spermine, thermin, thermospermine, canabalmin, aminopentylnorspermine, aminopropyl.
  • Homo spermine canabalmin, homospermine, cardopentamine, homocardopentamine, aminopropyl canabalmin, bis (aminopropyl) homospermine, bis (aminopropyl) norspermine, aminobutyl canabalmin, aminopropyl homospermine, Examples thereof include homopentamine, cardohexamine, homocardohexamine, selmohexamine, and homoselmohexamine.
  • polyamine spermidine, spermine, and putrescine are preferable, spermidine and spermine are more preferable, and spermidine is further preferable, from the viewpoint of ease of use.
  • polyamines can also be used.
  • One type of polyamine may be used alone, or two or more types may be used in combination.
  • extracts from plants such as soybean (preferably soybean germ), wheat (preferably wheat germ) or rice (preferably rice germ), extracts from seafood (preferably shirako), and dried sake.
  • a composition containing a polyamine such as yeast can also be used.
  • yeast also referred to as a "polyamine composition”
  • the polyamine composition is an extract from a plant, water, an organic solvent such as ethanol, or a mixed solvent thereof can be used as the extraction solvent.
  • an extract from a plant is preferable, and an extract from soybean (preferably soybean germ) is more preferable from the viewpoint of ease of use.
  • Examples of commercially available polyamine compositions include “Soipolya” (manufactured by Combi Co., Ltd.), “Oryzapolyamine-P” (manufactured by Oryza Yuka Co., Ltd.), “Oryzapolyamine-LC” (manufactured by Oryza Yuka Co., Ltd.)
  • Examples thereof include “Fight Polyamine-S” (manufactured by Toyobo Co., Ltd.), “Fight Polyamine-SP” (manufactured by Toyobo Co., Ltd.), and “Elion SP” (manufactured by Mitsubishi Gas Chemicals Co., Ltd.).
  • the content of the component (B) in the agent according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (B), the type and content of other compounding components, the formulation form, and the like.
  • the content of the component (B) is determined based on, for example, the total amount of the agent according to the present embodiment from the viewpoint of the stability of the preparation and the viewpoint of reducing the influence of the odor of the component (B).
  • the total content of is preferably 0.001 to 10% by weight, more preferably 0.01 to 0.1% by weight, still more preferably 0.02 to 0.05% by weight. ..
  • the content of the polyamine composition is not particularly limited, and the type of the polyamine composition, the type and content of other compounding components, and the preparation. It is appropriately set according to the form and the like.
  • the content of the polyamine composition is determined from the viewpoint of the stability of the preparation, the viewpoint of the effectiveness of the physiological action based on the component (B), the viewpoint of safety, and the viewpoint of reducing the influence of the odor of the component (B).
  • the total content of the polyamine composition is preferably 5 to 35% by weight, more preferably 10 to 30% by weight, and 14 to 23% by weight. It is more preferably%.
  • the content ratio of the component (B) to the component (A) in the agent according to the present embodiment is not particularly limited, and the types of the components (A) and (B), the types and contents of other compounding components, and the formulation form. It is set appropriately according to the above.
  • the total content of the component (B) is preferably 0.001 to 0.1 parts by weight, more preferably 0.01 to 0.03 parts by weight, and 0.015 to 0.02. It is more preferably a part by weight.
  • the content ratio of the polyamine composition to the component (A) is not particularly limited, and the type of the component (A) and the polyamine composition, etc. It is appropriately set according to the type and content of the compounding components of the above, the formulation form, and the like.
  • the content ratio of the polyamine composition to the component (A) from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by weight of the total content of the component (A) contained in the agent according to the present embodiment.
  • the total content of the polyamine composition is preferably 5 to 15 parts by weight, more preferably 7 to 10 parts by weight.
  • the weight ratio of spermine to spermidine is not particularly limited, and the types of the components (A) and (B) and other compounding components. It is appropriately set according to the type, content, formulation form and the like.
  • the weight ratio of spermine to spermidine is preferably, for example, 0.01 to 10, more preferably 0.1 to 2, and 0.2 to 0 from the viewpoint of further enhancing the effect of the present invention. It is more preferably .5.
  • the daily intake of the component (B) may differ depending on the condition (body weight, age, sex, etc.) of the individual ingesting, the formulation form, etc., but is based on the component (B).
  • the viewpoint of the effectiveness of physiological action the viewpoint of safety, and the viewpoint of reducing the influence of the odor of the component (B)
  • it is preferably 0.001 to 20 mg, more preferably 0.01 to 2 mg, and further preferably 0. It is 1 to 0.7 mg, particularly preferably 0.3 to 0.4 mg.
  • the daily intake of the polyamine composition depends on the condition (body weight, age, sex, etc.) of the individual ingesting, the formulation form, etc. It may vary depending on the viewpoint, but from the viewpoint of ease of ingestion as a single dose, from the viewpoint of (B) effectiveness of physiological action based on the component, from the viewpoint of safety, and from the viewpoint of reducing the influence of the odor of the component (B). Therefore, it is preferably 50 to 400 mg, more preferably 100 to 300 mg, still more preferably 200 to 250 mg, and particularly preferably 201 to 220 mg.
  • Crude drugs are those that have undergone simple processing such as drying all or part of natural products such as plants, animals, and minerals, or drying them, for the purpose of medicinal purposes.
  • the form of the crude drug for example, the crude drug itself (herbal medicine); the crude drug powder obtained by drying and powdering the crude drug; the crude drug or the crude drug powder in an organic solvent such as water or ethanol, or these.
  • Examples thereof include crude drug extracts extracted with a mixed solvent of. Among these, crude drug extracts are preferable from the viewpoint of exerting the effect of the present invention more remarkably.
  • the crude drug extract may be the extract as it is (tincture, stream extract, etc.), may be a diluted or concentrated extract (soft extract, etc.), or the extract may be dried and then pulverized. Alternatively, it may be in the form of a paste (dried extract, etc.).
  • the crude drug extract include ginger extract, maca extract, kanzo extract, ougi extract, chimpi extract, shakyaku extract, otane carrot extract, corn extract, nikjuyo extract, keihi extract, elephant kogi extract, sanzashi extract, dioscorea extract, and touki extract.
  • crude drug extracts include maca extract, otane carrot extract, sawtooth palm extract, ginger extract, toncat ant extract, French coastal pine bark extract, European oak extract, wild yam extract, diosgenin-containing yam extract, and pomegranate seeds. Extracts and chest tree extracts are preferable, and maca extract and otane carrot extract are more preferable.
  • crude drug commercially available ones may be used.
  • crude drug one kind may be used alone, or two or more kinds may be used in combination.
  • the content of the component (C) in the agent according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (C), the type and content of other compounding components, the formulation form, and the like.
  • the total content of the component (C) is 0.1 to 0 based on the total amount of the agent according to the present embodiment. It is preferably 70% by weight, more preferably 1 to 10% by weight, and even more preferably 2 to 4% by weight.
  • the content ratio of the component (C) to the component (A) in the agent according to the present embodiment is not particularly limited, and the types of the components (A) and (C), the types and contents of other compounding components, and the formulation form. It is set appropriately according to the above.
  • the total content of the component (C) is preferably 0.1 to 3 parts by weight, more preferably 0.5 to 2.5 parts by weight, and 1 to 1.5 parts by weight. Is even more preferable.
  • the content ratio of the component (C) to the component (B) in the agent according to the present embodiment is not particularly limited, and the types of the component (B) and the component (C), the types and contents of other compounding components, and the formulation form. It is set appropriately according to the above.
  • the total content of the component (C) is preferably 50 to 250 parts by weight, more preferably 80 to 200 parts by weight, and even more preferably 100 to 170 parts by weight.
  • the agent according to the present embodiment may contain a pharmacologically active ingredient or a physiologically active ingredient other than the components (A), (B) and (C) as long as the effects of the present invention are not impaired.
  • pharmacologically active ingredients or physiologically active ingredients include ubiquinone (coenzyme Q10), vitamin B1, vitamin B2, vitamin B6, folic acid, vitamin B12, vitamin C, vitamin D, vitamin A, and vitamin E.
  • ubiquinone (coenzyme Q10), vitamin B12, vitamin C, vitamin E, astaxanthin, zinc, carnitine, resveratrol, isoflavone, equol from the viewpoint of further enhancing the effect of the present invention.
  • Pycnogenol (proanthocyanidin) and folic acid are preferable, and ubiquinone (coenzyme Q10), astaxanthin, zinc, resveratrol, isoflavone, equol, pycnogenol (proanthocyanidin) and folic acid are more preferable.
  • the pharmacologically active ingredient or the physiologically active ingredient one kind may be used alone, or two or more kinds may be used in combination.
  • the agent according to the present embodiment may contain various additives in addition to the above components as long as the effects of the present invention are not impaired.
  • additives include excipients, binders, disintegrants, thickeners, colorants, flavoring agents, flavoring agents, sugars, sugar alcohols / polyhydric alcohols, and high-sweetness sweetness.
  • excipients include lactose, sucrose, sodium chloride, glucose, starch, gelatin, calcium carbonate, kaolin, crystalline cellulose, and silicic acid.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dried starch, sodium alginate, canten powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like.
  • lubricant examples include talc, stearate, borax, polyethylene glycol and the like.
  • Examples of the flavoring agent include white sugar, orange peel, citric acid, tartaric acid and the like.
  • sugars include sugars such as sucrose, high fructose corn syrup, glucose, fructose, palatinose, trehalose, lactose and xylose.
  • sugar alcohols and polyhydric alcohols include sorbitol, xylitol, erythritol, lactitol, palatinit, reduced starch syrup, reduced malt sugar starch syrup, glycerin, propylene glycol and the like.
  • high-sweetness sweeteners include aspartame, stevia, acesulfame potassium, sucralose and the like.
  • fats and oils examples include safflower oil (safflower oil), grape seed oil, sunflower oil (sunflower oil), olive oil, corn oil, sesame oil, soybean oil, rapeseed oil, and perilla oil.
  • emulsifier examples include sucrose fatty acid ester, glycerin fatty acid ester, lecithin and the like.
  • thickener examples include carrageenan, xanthan gum, guar gum, pectin, locust bean gum and the like.
  • the acidulant include citric acid, lactic acid, malic acid and the like.
  • fruit juices include lemon juice, orange juice, and berry juice.
  • the additive preferably contains fats and oils from the viewpoint of stability of the component (A) and the component (B) at the time of formulation.
  • the dosage form of the agent according to the present embodiment is not particularly limited, and for example, tablets (including orally disintegrating tablets, chewable tablets, troche tablets, etc.), granules, powders, soft capsules, hard capsules, troches, and jellies.
  • Oral agents such as agents or liquids (including suspensions, emulsions, syrups, etc.); external agents such as ointments, suppositories, patches, sprays; injections, etc. may be mentioned.
  • oral preparations are preferable, and tablets, granules, soft capsules, and hard capsules are more preferable.
  • the agent according to this embodiment can be used as a component of, for example, pharmaceuticals, quasi-drugs, cosmetics, and foods and drinks (beverages, foods).
  • the agents according to the present embodiment include, for example, pharmaceutical preparations, non-pharmaceutical preparations, foods for specified health use, foods with nutritional functions, foods for the elderly, foods for special purposes, foods with functional claims, health supplements (supplements), etc. It can also be used as a dietary supplement (eg, confectionery tablets), apparently a food.
  • the agent according to this embodiment can also be used as, for example, a veterinary drug or a feed additive.
  • the food may be a general food containing the component (A) and, if necessary, other components.
  • examples of such foods include solid foods such as cookies, biscuits, snacks, jellies, gummies, chocolates, gums, candy and cheese; and liquid foods such as energy drinks, juices, tea beverages, coffee beverages and milk beverages.
  • the agent according to this embodiment is a subject (for example, human; cow, pig, horse, sheep, goat, dog, rabbit, mouse, rat, guinea pig, etc.) that requires an action of suppressing the progress of aging of female reproductive tissues. It can be suitably used for non-human animals such as gerbils, hamsters and ferrets).
  • a human is preferable from the viewpoint of further enhancing the effect of the present invention.
  • cows, pigs and horses are preferable among non-human animals, and pigs are more preferable.
  • Pyrroloquinoline quinone or a salt thereof has an action of suppressing the progress of aging of ovaries, follicles or ova. Therefore, as one embodiment of the present invention, there is provided a method of suppressing the progress of aging of an ovary, a follicle or an egg by ingesting a composition containing pyrroloquinoline quinone or a salt thereof.
  • the ovary, follicle or egg may be a human ovary, follicle or egg and is a non-human animal such as cow, pig, horse, sheep, goat, dog, rabbit, mouse, rat, guinea pig, snail, hamster, ferret. It may be an ovary, a follicle or an egg. From the viewpoint of further enhancing the effect of the present invention, it is preferably a human ovary, follicle or egg.
  • follicles or eggs of non-human animals bovine, pig or horse ovaries
  • follicles or eggs are preferable
  • pig ovaries, follicles or eggs are more preferable.
  • the type, content, daily intake, etc. of pyrroloquinoline quinone or a salt thereof in the composition the type, content, daily intake, etc. of other components, etc.
  • the formulation form of the product see [1. Anti-aging agents for ovaries, follicles or eggs].
  • AMH anti-Müllerian hormone
  • AMH ELISA kit Elabscience Biotechnology, Bethesda, MD
  • the results are shown in FIG.
  • the Leydig cell-specific NRG1-deficient female mouse has a short life span, and 6 months of age corresponds to the human 40s.
  • control female mice not administered PQQ disodium salt had a lower concentration of AMH than WT mice, whereas female mice administered PQQ disodium salt had AMH compared to WT mice. Concentration increased. That is, it was confirmed that the ovarian tissue was rejuvenated by ingestion of PQQ disodium salt.
  • control female mice not administered PQQ disodium salt always maintained a microestrus period, and no periodic change in estrus was observed, whereas PQQ disodium salt was administered.
  • PQQ disodium salt was administered in female mice.
  • the cyclical change in estrus resumed about 14 days after the start of administration. That is, it was confirmed that the administration of PQQ disodium salt improved the abnormal ovulation cycle of female mice.
  • the number of ovulations is determined by collecting the fallopian tubes from the slaughtered mice, incising the ampulla of the fallopian tubes, collecting the ovulated egg-cumulus cell complex, and observing the complex visually under a microscope. Calculated. In vitro fertilization was performed using the ovulated ovum, and the fertilization rate and the incidence rate were calculated.
  • the fertilized egg refers to a split egg 24 hours after fertilization
  • the fertilization rate refers to the ratio of the number of successfully fertilized eggs to the total number of mature eggs ovulated.
  • the incidence refers to the proportion of fertilized eggs that have become blastocyst stage embryos.
  • Table 1 shows the results of the number of ovulations and the fertilization rate expressed by the mean ⁇ standard deviation. In addition, 3 weeks of age in mice corresponds to the teens when menstruation begins in humans.
  • mice administered with PQQ disodium salt maintained in vitro fertilization rates while increasing ovulation numbers and maintained in vitro fertilization rates as compared to control female mice not administered PQQ disodium salt.
  • the incidence improved while maintaining the in vitro fertilization rate. That is, it was confirmed that the quality of the egg was improved by the administration of PQQ disodium salt.
  • Serum of each female mouse was collected over time immediately before administration of eCG, and blood estradiol (E2) concentration as a follicle development marker and progesterone (P4) concentration as a luteal marker were measured in Endocrine Technology, Inc. Measurements were made using a commercially available kit from (Newark, CA). The results are shown in FIG.
  • estradiol is one of the female hormones widely used in hormone replacement therapy, and it is widely known that it is used for the treatment of menopausal disorders and the improvement of menopausal symptoms.
  • pyrroloquinoline quinone or a salt thereof is useful as an ameliorating agent or a preventive agent for symptoms derived from estrogen deficiency in females, and as an ameliorating agent or a preventive agent for pre-menopausal disorders or climacteric disorders in females. This allows pre-menopausal or menopausal women to reach menopause without pain.
  • FIG. 3 (B) no significant difference was observed in the increase in blood progesterone concentration between the female mouse to which PQQ disodium salt was administered and the control female mouse to which PQQ disodium salt was not administered. ..
  • Progesterone is known to be involved in blood enrichment in ovarian hyperstimulation syndrome. That is, it was confirmed that pyrroloquinoline quinone or a salt thereof is useful as a preventive agent for ovarian hyperstimulation syndrome by relaxing the production of progesterone while promoting the production of estradiol.

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Abstract

La présente invention concerne un agent anti-vieillissement pour les ovaires, les follicules ovariens ou les ovules, ledit agent anti-vieillissement comprenant de la pyrroloquinoléine quinone ou un sel de celle-ci.
PCT/JP2020/024469 2019-06-28 2020-06-22 Agent anti-vieillissement pour femelles WO2020262325A1 (fr)

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CN113813261A (zh) * 2021-09-15 2021-12-21 常州市妇幼保健院 吡咯喹啉醌在预防和/或治疗女性生殖功能障碍的用途
CN114306360A (zh) * 2021-11-12 2022-04-12 温州医科大学附属第二医院（温州医科大学附属育英儿童医院） 蓝靛果花青素提取物在制备改善多囊卵巢综合征的药物和/或保健品中的应用

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