TW202114674A - Anti-aging agent for female - Google Patents

Abstract

The present invention pertains to an anti-aging agent for ovaries, ovarian follicles or ova, said anti-aging agent comprising pyrroloquinoline quinone or a salt thereof.

Description

Anti-aging agent for females

The present invention relates to an anti-aging agent for females.

As women age, reproductive tissues such as ovaries, follicles, and eggs will age, making pregnancy or childbirth difficult. In the treatment of infertility for such women with difficulty in pregnancy, hormone replacement therapy is often performed in order to induce ovulation. However, in addition to the difficulty in the development and ovulation of uniformly mature follicles, as a side effect, a symptom called hyperovarian hyperfunction (OHSS) may appear. If it worsens, there is also the risk of falling into respiratory failure or circulatory failure. Therefore, in the treatment of infertility, a safe and effective treatment method is sought (Non-Patent Document 1).

In addition, as the aging of female reproductive tissues progresses, if the concentration of female hormones such as estrogen decreases, it will mainly cause menopausal disorders in women from the second half of 40-49 to 50-59 years of age. Among them, in women aged 30-39 to mid-40-49, stress or excessive fatigue work together. In addition to the symptoms of menopausal disorders mentioned above, there are also cases of abnormal menstruation. This is also known as premenopausal (premenopausal) disorder. Together with menopausal disorder, it can significantly reduce women's QOL. In the treatment of these menopausal disorders or premenopausal disorders, hormone replacement therapy is also mainly used, but there are problems with the possibility of cancer, or irregular genital bleeding, vomiting, headache, abnormal liver function and other side effects. Pre-menopausal disorders or menopausal disorders can occur in any woman. On the other hand, especially in Japan, where aging is progressing, it is very important for women to pass premenopausal to menopause healthy. Therefore, similar to the infertility treatment, a safe and effective treatment method for premenopausal disorders or menopausal disorders is sought (Non-Patent Document 2).

However, the aging of female reproductive tissues is not only a problem in humans, but also in livestock such as cattle or pigs. For example, in the swine industry, the cycle from mating to farrowing of sows is 2.5 times a year, but as the age increases, the number of litters of sows will decrease. Due to the increase of reproductive obstacles such as abortion, reproductive performance also changes difference. Therefore, it is hoped to develop methods for inhibiting the aging progress of female reproductive tissues in non-human animals in addition to humans. Prior art literature Non-patent literature

Non-Patent Document 1: The Journal of Nissan, 1998, Volume 50, No. 6, N135-N138 Non-Patent Document 2: JIM, 1999, Volume 9, No. 8, 688-691

[The problem to be solved by the invention]

The object of the present invention is to provide an anti-aging agent for ovaries, follicles or eggs (hereinafter sometimes collectively referred to as "female reproductive tissues"). [Technical means to solve the problem]

The inventors found that pyrroloquinoline quinone or its salt inhibits the aging progress of female reproductive tissues and promotes the production of estradiol. The present invention is based on this novel insight.

The present invention provides, for example, the following inventions. [1] An anti-aging agent for ovaries, follicles or eggs, which contains pyrroloquinoline quinone or its salt. [2] A female reproductive tissue fibrosis inhibitor or ameliorant, which contains pyrroloquinoline quinone or its salt. [3] An egg quality enhancer, which contains pyrroloquinoline quinone or its salt. [4] An ameliorating or preventing agent for menstrual disorders, which contains pyrroloquinoline quinone or its salt. [5] An ameliorating or preventing agent for ovarian hyperfunction, which contains pyrroloquinoline quinone or its salt. [6] An estrogen production promoter containing pyrroloquinoline quinone or a salt thereof. [7] The estrogen production promoter described in [6] improves or prevents the symptoms caused by female estrogen deficiency. [8] The estrogen production promoter described in [6] improves or prevents premenopausal or menopausal disorders in females. [9] The estrogen production promoter described in [6] improves or prevents menopausal symptoms in females. [10] The agent described in any one of [1] to [9] is used for non-human animals. [11] A method for inhibiting the aging progress of ovaries, follicles or eggs by ingesting a composition containing pyrroloquinoline quinone or its salts, thereby inhibiting the aging progress of ovaries, follicles or eggs. [2-1] The agent described in [1] inhibits or improves the fibrosis of female reproductive tissues. [2-2] The agent described in [1] improves the quality of eggs. [2-3] The agent described in [1] improves or prevents menstrual abnormalities. [2-4] The agent described in [1] improves or prevents hyperovarian hyperfunction. [2-5] The agent described in [1] promotes the production of estrogen. [2-6] The agent described in [2-5] improves or prevents the symptoms caused by female estrogen deficiency. [2-7] The agent described in [2-5] improves or prevents premenopausal or menopausal disorders in females. [2-8] The agent described in [2-5] improves or prevents menopausal symptoms in females. [Effects of Invention]

According to the present invention, an anti-aging agent for female reproductive tissues can be provided.

The embodiments of the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[1. Anti-aging agents for ovaries, follicles or eggs] The anti-aging agent for ovaries, follicles, or eggs of this embodiment contains pyrroloquinoline quinone or its salt (also referred to as "(A) component").

Pyrroloquinoline quinone or its salt exerts the effect of inhibiting the disappearance or reduction of AMH (Anti-Mullerian Hormone; anti-Mullerian Hormone) in females. Here, AMH is a hormone that becomes an indicator of the aging of female reproductive tissues (especially the ovaries). It is known that as the aging of female reproductive tissues progresses, the blood AMH concentration will decrease. In addition, pyrroloquinoline quinone or its salt exerts the effect of inhibiting or improving the fibrosis of female reproductive tissues (ovaries, follicles, eggs, etc., especially ovaries). Therefore, as an embodiment of the present invention, there is provided an anti-aging agent for ovaries, follicles, or eggs, and an inhibitor or ameliorant for female reproductive tissue fibrosis, which contains pyrroloquinoline quinone or a salt thereof. The "anti-aging" referred to here refers to women becoming younger, inhibiting the progress of women's aging, elderly women can also maintain a higher QOL, and elderly women can also live vigorously. In addition, the "advanced age" referred to here refers to 30 years of age or older, preferably 40 years of age or older, and more preferably 50 years of age or older. Furthermore, as an example of the aging of female reproductive tissues (especially ovarian tissue), ovarian reserve function (the number of secondary follicles remaining in the ovaries) can be cited. As mentioned above, because pyrroloquinoline quinone or its salt has the effect of inhibiting the disappearance or reduction of AMH in females, it also has the effect of enhancing ovarian reserve.

Pyrroloquinoline quinone or its salt exerts the effect of improving the quality of eggs. Therefore, as an embodiment of the present invention, there is provided an egg quality enhancing agent, which contains pyrroloquinoline quinone or a salt thereof. Here, "improvement of egg quality" refers to increasing the number of ovulation and maintaining or increasing the fertilization rate of the ovulated egg. The fertilization rate referred to here refers to the ratio of the number of fertilized eggs to the total number of ovulated eggs. Therefore, as an embodiment of the present invention, an agent for increasing the number of ovulated eggs and maintaining or improving the fertilization rate of the ovulated eggs is provided, which contains pyrroloquinoline quinone or a salt thereof. In addition, "enhancement of egg quality" refers to the maintenance or improvement of the fertilization rate of the egg, and the maintenance or improvement of the occurrence rate. The occurrence rate referred to here refers to the rate of fertilized eggs that become blastocyst stage embryos. Therefore, as an embodiment of the present invention, there is provided an agent for maintaining or increasing the fertilization rate of an egg and maintaining or increasing the occurrence rate, which contains pyrroloquinoline quinone or a salt thereof.

Pyrroloquinoline quinone or its salt exerts the effect of improving or preventing menstrual abnormalities. Therefore, as an embodiment of the present invention, there is provided an ameliorating or preventing agent for menstrual disorders, which contains pyrroloquinoline quinone or a salt thereof. Here "abnormal menstruation" refers to the state of abnormal menstruation in females (or ovulation in the case of non-human animals with non-menstrual females). For example, in humans, the normal menstrual cycle is considered to be 25 to 38 days, and the menstrual cycle is within 24 days or 39 days or more, or if there is no menstruation for more than 3 months (no menstruation) as menstruation abnormal.

Pyrroloquinoline quinone or its salt exerts the effect of promoting the production of estrogen (e.g. estrone, estradiol, estriol, preferably estradiol). Therefore, as an embodiment of the present invention, there is provided an estrogen production promoter containing pyrroloquinoline quinone or a salt thereof. In addition, pyrroloquinoline quinone or its salt promotes the production of estrogen, exerts the effect of improving or preventing the symptoms caused by female estrogen deficiency, improving or preventing female menopausal symptoms, improving or preventing female premenopausal disorders In addition to the effect of improving or preventing menopausal disorders in females, it also exerts the effect of supplementing female hormones. Therefore, as an embodiment of the present invention, there is provided an ameliorating agent or preventive agent for symptoms caused by female estrogen deficiency, an ameliorating agent or preventive agent for female menopausal symptoms, or amelioration of female premenopausal disorders or menopausal disorders An agent or a preventive agent, which contains pyrroloquinoline quinone or a salt thereof.

Pyrroloquinoline quinone or its salt exerts the effect of improving or preventing ovarian hyperfunction. Therefore, as an embodiment of the present invention, there is provided an ameliorating or preventing agent for hyperovarian hyperfunction, which contains pyrroloquinoline quinone or a salt thereof. Here, "hyperovarian hyperfunction" refers to various symptoms caused by ascites or pleural fluid caused by swelling of the ovaries due to excessive stimulation of ovulation inducers. In severe cases, blood concentration can also cause renal failure Or thrombosis and other complications. Specific symptoms of ovarian hyperfunction include: abdominal distension, nausea, rapid increase in weight, decrease in urine output, abdominal pain, diarrhea, and the like. In addition, pyrroloquinoline quinone or its salt, by improving or preventing hyperovarian hyperfunction, also exerts the effect of improving or preventing the symptoms caused by hyperovarian hyperfunction and the complications of hyperovarian hyperfunction. In addition, the agent containing pyrroloquinoline quinone or its salt in each of the above-mentioned embodiments is also collectively referred to as "the agent of this embodiment".

In this manual, "menopause" refers to the period of about 10 years before and after menopause in females. In the case of humans, the period from the second half of 40-49 to 50-59 is equivalent to menopause. Furthermore, in this specification, "pre-menopausal" refers to a period younger than the above-mentioned menopause, and is a period during which the following symptoms of premenopausal disorders are exhibited. In the case of humans, between 30-39 years old and mid--40-49 years old The period is equivalent to before menopause.

Symptoms of "female menopausal disorder" include, for example, difficulty breathing, standing dizziness, dizziness, numbness of hands and feet, stiffness of hands and feet, edema, fatigue, tinnitus, fever, fever (hot flushes), sweating, palpitations, and excitement , Insomnia, restlessness, irritability, emotional instability, depression, easy tearing, decreased motivation, anxiety, headache, shoulder pain, chest pain, low back pain, joint pain, cold hands and feet, itching, dry skin or eyes, nausea , Loss of appetite, abdominal pain, constipation, diarrhea, frequent urination, dyspareunia, vulvar discomfort, etc.

As "symptoms caused by female estrogen deficiency", such as menstrual abnormalities, autonomic disorders, psychiatric nervous system symptoms, urogenital atrophy symptoms, hyperlipidemia, arteriosclerosis, hypertension, stroke, osteoporosis In addition to the symptoms of symptoms, osteopenia, skin atrophy, joint pain, dry mouth, changes in taste, sleep disorders, and the above-mentioned "menopausal disorders in females", examples include the "Hormone Replenishment Therapy Guidelines 2017 Edition" edited by the Japanese Society of Obstetrics and Gynecology. The symptoms described in "1. Expected effects and effects on HRT" in "".

As the symptoms of "female premenopausal disorder (female youth menopausal disorder)", in addition to the above-mentioned symptoms of "female menopausal disorder", include: irregular menstruation, absence of menstruation, etc.

"Female menopausal symptoms" refers to the symptoms of the above-mentioned "female menopausal disorder" and the symptoms of "female premenopausal disorder (female youth menopausal disorder)". However, it is not limited to "menopause" or "pre-menopause". This symptom may appear from adolescence (for example, in the case of humans, it is 10-19 years old at the beginning of menstruation). As a "female menopausal symptom", among the specific symptoms mentioned above, the symptoms can also be those with milder symptoms. For example, it may be a state in which there is a consciousness of fever or sweating but less frequently, a state in which depression or shoulder pain is small, and the like.

所表示之公知之化合物。Pyrroloquinoline quinone has the following formula:

Said well-known compound.

Examples of the salt of pyrroloquinoline quinone 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 alkaline earth metal salts include calcium salts and magnesium salts.

The pyrroloquinoline quinone or its salt is preferably an alkali metal salt of pyrroloquinoline quinone, more preferably the sodium salt of pyrroloquinoline quinone, and still more preferably pyrroloquinoline quinone disodium salt.

Commercial ones can be used for pyrroloquinoline quinone or its salt. Moreover, as pyrroloquinoline quinone or its salt, for example, natto, soybean, cocoa powder, cacaomas, cocoa, parsley, sweet pepper, etc. containing pyrroloquinoline quinone or its salt can be used.

When used in humans, from the viewpoint of the stability of the administered preparation, the content of component (A) in the agent of this embodiment is based on the total amount of the agent of this embodiment, and component (A) The total content is preferably 0.01 to 30% by weight, more preferably 0.2 to 10% by weight, still more preferably 1 to 5% by weight, particularly preferably 1.3 to 3% by weight. In addition, when used in non-human animals, the content of component (A) in the agent of this embodiment is based on the total content of the agent of this embodiment, and the total content of component (A) is preferably 0.01 to 0.3 % By weight, more preferably 0.02 to 0.2% by weight.

In the preparation of this embodiment, the daily intake of (A) component may vary according to the state of the individual ingested (weight, age, sex, etc.), the form of the preparation, etc., when used in humans, it is regarded as one time From the viewpoint of ease of ingestion, the viewpoint of effectiveness based on the physiological action of component (A), and the viewpoint of safety, it is preferably 7-100 mg, more preferably 10-40 mg, and even more preferably 20 ~25 mg, when used in non-human animals, preferably 1-30 mg/kg, more preferably 2-20 mg/kg.

The agent of this embodiment may further contain polyamines (also referred to as "(B) component") and crude drugs ("also referred to as (C) component"). In this way, the effect of the present invention can be more effective.

Polyamines are aliphatic hydrocarbons containing two or more primary amine groups in the molecule. Specific examples of polyamines include putrescine, cadaverine, ethylenediamine, trimethylenediamine, hexamethylenediamine, spermidine, caldine, Homospermidine, aminopropylcadaverine, spermine, thermospermine, thermospermine, canavalmine, aminopentylnorspermidine (Aminopentyl norspermidine), aminopropyl homospermine, concanavalin, homospermine, caldopentamine, homocaldopentamine, aminopropyl homospermine, Bis (aminopropyl) homospermine, bis(aminopropyl) norspermine (bis(aminopropyl) norspermine), aminobutyl concanavalin, aminopropyl homospermine, pentylamine ( homopentamine), caldohexamine, homocaldohexamine, thermohexamine, homothermohexamine. As the polyamine, from the viewpoint of ease of use, spermidine, spermine, and putrescine are preferred, spermidine and spermine are more preferred, and spermidine is still more preferred.

Commercially available polyamines can also be used. Polyamines may be used individually by 1 type, or may be used in combination of 2 or more types. In addition, as polyamines, it is also possible to use: extracts from plants such as soybeans (preferably soybean germ), wheat (preferably wheat germ) or rice (preferably rice germ), fish and shellfish (preferably Polyamine-containing composition (also known as "polyamine composition") such as the extract of milt, dried sake yeast, etc. When the polyamine composition is a plant-derived extract, as the extraction solvent, organic solvents such as water, ethanol, or mixed solvents can be used. As the polyamine composition, from the viewpoint of ease of use, it is preferably an extract from a plant, and more preferably an extract from soybeans (preferably soybean germ). Examples of commercially available polyamine compositions include "Soypolya" (manufactured by Combi Co., Ltd.), "Oryza Polyamine-P" (manufactured by Oryza Oil & Fat Chemical Co., Ltd.), and "Oryza Polyamine-LC" (Oryza Polyamine-LC). Oil & Fat Chemical Co., Ltd.), "Phytopolyamine-S" (Toyobo Co., Ltd.), "Phytopolyamine-SP" (Toyobo Co., Ltd.), "Erion SP" (Mitsubishi Gas Chemical Co., Ltd.), etc.

The content of the component (B) in the agent of this embodiment is not particularly limited, and can be appropriately set according to the type of component (B), the type and content of other blending ingredients, the form of the formulation, and the like. As for the content of component (B), from the viewpoint of the stability of the formulation and the viewpoint of reducing the influence of the odor of component (B), for example, based on the total amount of the agent of this embodiment, (B ) The total content of the components is preferably 0.001 to 10% by weight, more preferably 0.01 to 0.1% by weight, and still more preferably 0.02 to 0.05% by weight.

In the agent of this embodiment, when the polyamine composition is contained as the component (B), the content of the polyamine composition is not particularly limited, and it can be based on the type of the polyamine composition, the types of other blending ingredients, and The content, preparation form, etc. are appropriately set. As the content of the polyamine composition, from the viewpoint of the stability of the preparation, the viewpoint of the effectiveness based on the physiological action of the component (B), the viewpoint of safety, the viewpoint of reducing the influence of the odor of the component (B) For example, based on the total amount of the agent of this embodiment, the total content of the polyamine composition is preferably 5 to 35% by weight, more preferably 10 to 30% by weight, and still more preferably 14 to 23% by weight .

The content ratio of the component (B) to the component (A) in the agent of this embodiment is not particularly limited. It can be based on the types of components (A) and (B), the types and contents of other blending ingredients, and the form of the formulation Set up appropriately. As the content ratio of (B) component to (A) component, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by weight relative to the total content of (A) component contained in the agent of this embodiment The total content of (B) component is preferably 0.001 to 0.1 parts by weight, more preferably 0.01 to 0.03 parts by weight, and still more preferably 0.015 to 0.02 parts by weight.

In the agent of this embodiment, when a polyamine composition is contained as the (B) component, the content ratio of the polyamine composition to the (A) component is not particularly limited, and it can be based on the (A) component and the polyamine The type of composition, the type and content of other blending ingredients, and the form of preparations are appropriately set. As the content ratio of the polyamine composition relative to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by weight relative to the total content of the component (A) contained in the agent of this embodiment The total content of the polyamine composition is preferably 5-15 parts by weight, more preferably 7-10 parts by weight.

In the agent of this embodiment, when component (B) contains spermidine and spermine, the weight ratio of spermine to spermidine is not particularly limited, and it can be based on component (A) and component (B) The type, the type and content of other blending ingredients, and the form of preparations are appropriately set. As the weight ratio of spermine to spermidine, from the viewpoint of further enhancing the effect of the present invention, for example, it is preferably 0.01-10, more preferably 0.1-2, and still more preferably 0.2-0.5.

In the preparation of this embodiment, the daily intake of (B) component may vary according to the state of the individual ingested (weight, age, sex, etc.), formulation form, etc., based on the physiological effect of (B) component From the viewpoint of sex, safety, and the viewpoint of reducing the influence of the odor of component (B), it is preferably from 0.001 to 20 mg, more preferably from 0.01 to 2 mg, and even more preferably from 0.1 to 0.7 mg, particularly preferably 0.3 to 0.4 mg.

In the preparation of this embodiment, when the polyamine composition is contained as the component (B), the daily intake of the polyamine composition can be based on the state of the individual ingested (weight, age, sex, etc.), and the form of the preparation It is different from the viewpoint of the ease of ingestion as a single dose, the viewpoint based on the effectiveness of the physiological action of the component (B), the viewpoint of safety, and the reduction of the influence of the odor of the component (B) From a viewpoint, 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 used for medicinal purposes. They are directly made from all or part of natural products such as plants, animals, and minerals, or are made by simple processing such as drying. In the agent of this embodiment, the form of crude drug includes, for example, crude drug itself (primitive drug); crude drug powder obtained by drying and powdering the native drug; using organic solvents such as water, ethanol, or mixed solvents, etc. Extracts of crude drugs or crude drug extracts, etc. Among them, from the viewpoint of making the effects of the present invention more effective, crude drug extracts are preferred. The crude drug extract can be the direct extract (tincture, fluid extract, etc.), the extract can be diluted or concentrated (soft extract, etc.), or the extract can be dried and powdered Or made into a paste (dry extract, etc.).

Specific examples of crude drug extracts include: ginger extract, maca extract, licorice extract, astragalus extract, tangerine peel extract, peony extract, Korean ginseng extract, turmeric extract, Cistanche extract Extract, cinnamon extract, acanthopanax senticosus extract, hawthorn extract, rehmannia glutinosa extract, angelica extract, Sabah palm extract, ginkgo biloba extract, Bupleurum extract, cohosh extract, yam extract, Jujube Extract, Atractylodes Rhizome Extract, Atractylodes Rhizome Extract, Lychee Extract, Deer Antler Extract, Tongkat Ali Extract, French Maritime Pine Bark Extract, European Oak Extract, Wild Yam Extract, Diosgenin-containing Yam Extract , Cistanche Tubula Extract, Garlic Extract, Acanthopanax senticosus Extract, Tiger Claw Bean Extract, Gardenia Extract, Shilaji Extract, Cordyceps Mycelium Powder, Black Ginger Extract, Black Pepper Extract, Pomegranate seed extract, Jupiter extract, black cohosh extract, dandelion extract, etc. As a crude drug extract, from the viewpoint of the stability of the preparation, it is preferably Maca extract, Korean ginseng extract, Sabah palm extract, Ginger extract, Tongkat Ali extract, French Maritime Pine Bark Extract , European oak extract, wild yam extract, yam extract containing diosgenin, pomegranate seed extract, vitex extract, more preferably Maca extract, Korean ginseng extract.

A commercially available crude drug can be used. The crude drug can be used alone or in combination of two or more.

The content of the component (C) in the agent of this embodiment is not particularly limited, and can be appropriately set according to the type of component (C), the type and content of other blending ingredients, the form of the formulation, and the like. As for the content of component (C), from the viewpoint of making the effect of the present invention more effective, for example, based on the total amount of the agent of this embodiment, the total content of component (C) is preferably 0.1 to 70% by weight , More preferably 1 to 10% by weight, still more preferably 2 to 4% by weight.

The content ratio of the component (C) to the component (A) in the agent of this embodiment is not particularly limited. It can be based on the types of components (A) and (C), the types and contents of other blending ingredients, and the form of the formulation. Set up appropriately. As the content ratio of the component (C) to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by weight relative to the total content of the component (A) contained in the agent of this embodiment, (C) The total content of the components is preferably 0.1 to 3 parts by weight, more preferably 0.5 to 2.5 parts by weight, and still more preferably 1 to 1.5 parts by weight.

The content ratio of the component (C) to the component (B) in the agent of this embodiment is not particularly limited, and it can be based on the types of components (B) and (C), the types and contents of other blending ingredients, and the form of the formulation. Set up appropriately. As the content ratio of (C) component to (B) component, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by weight relative to the total content of (B) component contained in the agent of this embodiment, (C) The total content of the components is preferably 50 to 250 parts by weight, more preferably 80 to 200 parts by weight, and still more preferably 100 to 170 parts by weight.

As long as the agent of this embodiment does not impair the effects of the present invention, it may contain pharmacologically active ingredients or physiologically active ingredients other than the (A) component, (B) component, and (C) component. Specific examples of such 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 , Niacin, calcium pantothenate, taurine, carnosine, methcarnosine, balenine, citrulline, gamma aminobutyric acid, valine, leucine, isoleucine, glycine , Arginine, ornithine, carnitine, glutamine, glutamine, creatine, carnitine, lutein, luteolin, genistein, cyanidin, resveratrol, yam Diosgenin, isoflavone aglycone, isoflavone, lipoic acid, zinc, iron, calcium, selenium, reduced astaxanthin, zeaxanthin, beta carotene, myristic acid, palmitic acid, stearic acid, Oleic acid, linoleic acid, hypolinoleic acid, arachidic acid, placental extract, pycnogenol (procyanidin), equol, etc. As pharmacologically active ingredients or physiologically active ingredients, from the viewpoint of further enhancing the effects of the present invention, ubiquinone (coenzyme Q10), vitamin B12, vitamin C, vitamin E, reduced astaxanthin, zinc, carnitine, Resveratrol, isoflavones, equol, pycnogenol (proanthocyanidins), folic acid, more preferably ubiquinone (coenzyme Q10), reduced astaxanthin, zinc, resveratrol, isoflavones, equol, Pycnogenol (proanthocyanidins), folic acid. The pharmacologically active ingredient or the physiologically active ingredient may be used singly or in combination of two or more kinds.

The agent of this embodiment may contain various additives other than the above-mentioned components as long as it does not impair the effects of the present invention. Specific examples of such additives include, for example, excipients, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, flavoring agents, sugars, sugar alcohols/polyols, and high-intensity sweeteners. , Oils, emulsifiers, tackifiers, sour materials, fruit juices, etc. Examples of excipients include lactose, white sugar, sodium chloride, glucose, starch, gelatin, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like. Examples of the binding agent include water, ethanol, propanol, monosyrup, glucose solution, starch solution, gelatin solution, cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose. Propyl starch, methyl cellulose, ethyl cellulose, calcium phosphate, polyvinylpyrrolidone, etc. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. As a lubricant, talc, stearate, borax, polyethylene glycol, etc. are mentioned. As a corrective agent, white sugar, orange peel, citric acid, tartaric acid, etc. are mentioned. Examples of sugars include sugars such as sucrose, isomerized sugars, glucose, fructose, palatinose, trehalose, lactose, and xylose. Examples of sugar alcohols/polyols include sorbitol, xylitol, erythritol, lactitol, palatinit, reduced water starch, reduced maltose water starch, glycerin, propylene glycol, and the like. As a high-intensity sweetener, aspartame, stevia, acesulfame potassium (acesulfame potassium), sucralose, etc. are mentioned. Examples of fats and oils include safflower oil, grape seed oil, sunflower oil, olive oil, corn oil, sesame oil, soybean oil, rapeseed oil, and perilla oil. Examples of emulsifiers include sucrose fatty acid esters, glycerin fatty acid esters, lecithin, and the like. Examples of the thickener include carrageenan, sanxian gum, guar gum, pectin, locust bean gum, and the like. As an acidulant, citric acid, lactic acid, malic acid, etc. are mentioned. Examples of juices include lemon juice, orange juice, and berry juice. An additive may be used individually by 1 type, or may be used in combination of 2 or more types. As an additive, it is preferable to contain fats and oils from a viewpoint of the stability of (A) component and (B) component at the time of formulation.

The dosage form of the agent of this embodiment is not particularly limited, and examples thereof include tablets (including orally disintegrating tablets, chewable tablets, lozenges, etc.), granules, powders, soft capsules, hard capsules, Oral preparations such as oral lozenges, gels or liquids (including suspensions, emulsions, syrups, etc.); external preparations such as ointments, suppositories, patches, sprays, etc.; injections, etc. Among them, from the viewpoint of ease of use and the viewpoint of further enhancing the effects of the present invention, oral preparations are preferred, and tablets, granules, soft capsules, and hard capsules are more preferred.

The agent of this embodiment can be used as a component of pharmaceuticals, quasi-drugs, cosmetics, and food and beverages (drinks, foods), for example. In addition, the agent of this embodiment can also be used as, for example, pharmaceutical preparations, quasi-drug preparations, foods for specific health care, nutritional functional foods, foods for the elderly, foods for special purposes, functional labelled foods, health supplements (supplements), foods Use preparations (such as confectionery and desserts to make lozenges), obvious foods. Furthermore, the agent of this embodiment can also be used as an animal medicine and feed additive, for example.

When the agent of this embodiment is used as a food, the food may be a general food by blending the component (A) and other components as needed. Examples of such foods include solid foods such as cookies, biscuits, desserts, jelly, soft candy, chocolate, chewing gum, caramel, and cheese; liquid foods such as nutritious drinks, fruit juices, tea drinks, coffee drinks, and milk drinks.

The agent of this embodiment can be well used for objects that need to inhibit the aging progression of female reproductive tissues (for example, humans; cows, pigs, horses, sheep, goats, dogs, rabbits, mice, rats, guinea pigs, Gerbils, hamsters, ferrets and other non-human animals). As the target, from the viewpoint of further enhancing the effect of the present invention, humans are preferred. In addition, from the viewpoint of further enhancing the effect of the present invention, among non-human animals, cows, pigs, and horses are also preferable, and pigs are more preferable.

[2. Methods to inhibit the aging progress of ovaries, follicles or eggs] Pyrroloquinoline quinone or its salt has the effect of inhibiting the aging progress of ovaries, follicles or eggs. Therefore, as an embodiment of the present invention, there is provided a method for inhibiting the aging progress of ovaries, follicles, or eggs, which involves ingesting a composition containing pyrroloquinoline quinone or a salt thereof. Ovary, follicle or egg can be human ovary, follicle or egg, or non-human such as cow, pig, horse, sheep, goat, dog, rabbit, mouse, rat, guinea pig, gerbil, hamster, ferret, etc. The ovaries, follicles or eggs of animals. From the viewpoint of further enhancing the effect of the present invention, human ovaries, follicles or eggs are preferred. Moreover, from the viewpoint of further enhancing the effect of the present invention, among the ovaries, follicles or eggs of non-human animals, the ovaries, follicles or eggs of cows, pigs, or horses are preferred, and the ovaries of pigs, follicles, or eggs are more preferred. Follicle or egg.

Furthermore, regarding the type, content, and daily intake of pyrroloquinoline quinone or its salt in the composition in these embodiments, the types, content, and daily intake of other components, etc., the composition Formulations, etc., as described in [1. Anti-aging agents for ovaries, follicles or eggs]. Example

Hereinafter, the present invention will be described more specifically based on examples and the like. However, the present invention is not limited to the following examples. Furthermore, the following test examples were all implemented under the approval of the Animal Experiment Ethics Committee of Hiroshima University.

[Test Example 1: The effect of administration of pyrroloquinoline quinone on AMH (anti-Müllerian hormone) in the blood of female mice] PQQ disodium salt (2 mg/kg/day) was administered to 6-month-old female mice with specific NRG1 deficiency in Leybeck cells in drinking water for 2 weeks (n=5). In addition, 6-month-old male mice (KO; control) with NRG1-deficient cells specific to NRG1 and 6-month-old wild-type mice (WT mice) were administered with water only for 2 weeks. Thereafter, the blood was collected, and the AMH ELISA kit (Elabscience Biotechnology, Bethesda, MD) was used to determine the concentration of AMH (anti-Müllerian hormone) as a follicle marker according to the method of use of the kit. The results are shown in Fig. 1. Furthermore, the female mice with a specific NRG1 defect in the Lebecki cell have a shorter life span, and the age of 6 months is equivalent to that of a human being 40-49 years old.

As shown in Figure 1, the control female mice that were not administered PQQ disodium salt had a lower AMH concentration compared to WT mice. On the other hand, the female mice that were administered PQQ disodium salt were comparable to WT mice. Compared with that, the concentration of AMH rises. That is, it was confirmed that the ovarian tissue became younger by taking PQQ disodium salt.

[Test Example 2: Effect of administration of pyrroloquinoline quinone on the estrus cycle of female mice] PQQ disodium salt (2 mg/kg/day) was continuously administered to 6-month-old female mice (KO) with NRG1 cell-specific NRG1 deficiency in drinking water. In addition, female mice that were given only water were used as controls. The estrus cycle of each mouse was investigated by vaginal smear. Furthermore, the vaginal smear examination is carried out in the following manner: physiological saline is refluxed into the vagina, and the refluxed substance is smeared on a glass slide. After drying, it was fixed with methanol and stained with Giemsa. This was observed under an inverted microscope (manufactured by Keyence). The case where only white blood cells were observed was judged to be the resting period of estrus, the case where only nucleated epithelial cells were observed was judged to be the preestrus phase, and the case where only non-nucleated epithelial cells were observed The situation is judged to be an estrus period. If the anucleus epithelial cells and white blood cells are mixed, and the number of anucleus epithelial cells appears to be large, it is judged as a microestrus. If the anucleus epithelial cells and white blood cells are mixed, the number of white blood cells appears to be higher. Most cases are judged as late estrus. The results are shown in Figure 2.

As shown in Figure 2, it was confirmed that the control female mice that were not administered PQQ disodium salt always maintained the microestrus period, and no periodic changes in estrus were seen. In contrast, the female mice that were administered PQQ disodium salt were self-administered Periodic changes in estrus again starting 14 days after I started. That is, it was confirmed that the abnormality of the ovulation cycle of female mice was improved by the administration of PQQ disodium salt.

[Test Example 3: Effect of administration of pyrroloquinoline quinone on eggs] PQQ disodium salt (2 mg/kg/day) was administered to 3-week-old immature female mice in the drinking water (n=5). In addition, female mice that were given only water were used as controls. At the time point 2 days after the start of administration, 4 IU of eCG (pregnant horse serum gonadotropin) that induces follicle development was administered, and hCG (human chorionic gonadotropin) was administered 48 hours later. 5 IU. Thereafter, the number of ovulation in each female mouse was measured. The number of ovulation is obtained by collecting the fallopian tubes from the slaughtered mice, cutting the enlarged part of the fallopian tube to recover the ovulated egg and cumulus cell complex, and calculating the complex by visually observing the complex under a stereo microscope. In addition, the ovulated eggs are used for in vitro fertilization, and the fertilization rate and incidence rate are calculated. Here, the fertilized egg refers to the split egg 24 hours after fertilization, and the fertilization rate refers to the ratio of the number of successfully fertilized eggs to the total number of mature eggs that are ovulated. In addition, the incidence rate refers to the rate of fertilized eggs that become blastocyst stage embryos. Regarding the number of ovulations and the fertilization rate, the results represented by the mean ± standard deviation are shown in Table 1. Furthermore, the age of 3 weeks in mice is equivalent to the age of 10-19 years at the beginning of menstruation in humans.

[Table 1] Control PQQ disodium salt Number of ovulation (pcs) 40.41±1.12 60.21±1.77 Number of fertilized eggs (a) 26.63±1.29 41.67±1.48 Fertilization rate (%) 65.77±2.10 69.41±0.77 Generation rate (%) 80.42±2.44 88.09±1.56

As shown in Table 1, the female mice administered with PQQ disodium salt increased the number of ovulations and maintained the in vitro fertilization rate compared with the control female mice not administered with PQQ disodium salt. Rate increase. That is, it was confirmed that the egg quality was improved by the administration of PQQ disodium salt.

[Test Example 4: The effect of administration of pyrroloquinoline quinone on the concentration of female hormones in the blood] PQQ disodium salt (2 mg/kg/day) was administered to 3-week-old immature female mice in the drinking water. In addition, female mice that were given only water were used as controls. At the time point 2 days after the start of administration, 4 IU of eCG (pregnant horse serum gonadotropin) that induces follicular development was administered intraperitoneally, and hCG (human chorionic gonadotropin) was administered intraperitoneally 48 hours later. ) 5 IU. The serum of each female mouse was collected over time from immediately before the eCG was administered, and the blood estradiol (E2) as a marker of follicular development was measured using a commercially available kit from Endocrine Technology, Inc. (Newark, CA). Concentration, and the concentration of progesterone (P4) as a luteal marker. The results are shown in Figure 3.

As shown in Fig. 3(A), the female mice administered with PQQ disodium salt had a higher blood estradiol concentration over time than the control female mice not administered with PQQ disodium salt. That is, it was confirmed that the production of estradiol was promoted by the administration of PQQ disodium salt. Estradiol is one of the female hormones widely used in hormone replacement therapy. It is widely known for the treatment of menopausal disorders or the improvement of menopausal symptoms. That is, it has been confirmed that pyrroloquinoline quinone or its salt is useful as an ameliorating agent or preventive agent for symptoms caused by female estrogen deficiency, and an ameliorating agent or preventive agent for premenopausal disorders or menopausal disorders in females. In this way, pre-menopausal or menopausal women can usher in menopause without pain. Furthermore, as shown in Fig. 3(B), female mice administered with PQQ disodium salt and control female mice not administered with PQQ disodium salt showed a greater difference in the increase in blood progesterone concentration. It is known that progesterone is related to the concentration of blood in hyper-ovarian hyperfunction. That is, it was confirmed that pyrroloquinoline quinone or its salt promotes the production of estradiol, and by alleviating the production of progesterone, it is also useful as a preventive agent for ovarian hyperfunction.

[Test Example 5: Effect of administration of pyrroloquinoline quinone on ovarian fibrosis] PQQ disodium salt (2 mg/kg/day) was administered to 6-month-old female mice (KO) with specific NRG1 deficiency in Leybeck cells in drinking water for 2 weeks. After that, the removed ovaries were stained with PSR and observed with an inverted microscope (manufactured by Keyence) at a magnification of 20 times. The results are shown in Fig. 4.

As shown in Figure 4, since the entire interstitial cells of the mouse before PQQ disodium salt administration were stained red, it was confirmed that the collagen was deposited, that is, ovarian fibrosis. At the same time, the atrophy of interstitial follicles can also be seen. On the other hand, it was confirmed that the redness of the interstitial cells of mice administered with PQQ disodium salt for 2 weeks disappeared, and the fibrotic interstitial cells improved to a healthy state. It is known that interstitial cells of the ovaries undergo fibrosis due to aging. That is, it was confirmed that the ovarian tissue became younger by taking PQQ disodium salt. In addition, cell-shaped follicles can be seen, and it is confirmed that the atrophy of the follicles has also been improved, so it is confirmed that the quality of the eggs has been improved.

According to the results of Test Examples 1 to 5, the intake of pyrroloquinoline quinone or its salt can guarantee the QOL of women who are vulnerable to physical and mental abnormalities caused by the approaching menopause, and senior women can also live vigorously. vigorous.

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[Figure 1] A graph showing the AMH concentration in the blood of each female mouse in Test Example 1. [Figure 2] (A) is a diagram showing the estrus cycle when pyrroloquinoline quinone disodium salt is not administered to female age-increasing model mice in Test Example 2. (B) is a diagram showing the estrus cycle when pyrroloquinoline quinone is administered to female aging model mice in Test Example 2. In Figure 2, M represents late estrus, WE represents microestrus, E represents estrus, P represents pre-estrus, and D represents estrus rest period. [Figure 3] (A) shows the time and time when eCG (pregnant horse serum gonadotropin) was administered to immature female mice administered or not administered pyrroloquinoline quinone disodium salt in Test Example 4 A graph of the relationship between the concentration of estradiol in the blood. (B) In Test Example 4, eCG (pregnant horse serum gonadotropin) and hCG (human chorionic gonadotropin) were administered to immature female mice administered or not administered pyrroloquinoline quinone disodium salt in Test Example 4. Hormone) is a graph of the relationship between time and time and the concentration of progesterone in the blood. [Figure 4] (A) In Test Example 5, the "female aging model mice whose ovaries were stained with PSR before being administered pyrroloquinoline quinone disodium salt (20 times magnification)" were taken. photo. (B) In Test Example 5, a photograph taken of "female aging model mice whose ovaries were PSR stained 2 weeks after being administered pyrroloquinoline quinone disodium salt (20 times magnification)". (C) and (D) are drawings of (A) and (B) respectively. The area marked with slashes indicates the dyed area.

Claims (11)

An anti-aging agent for follicles or eggs, which contains pyrroloquinoline quinone or its salt. A female reproductive tissue fibrosis inhibitor or ameliorant, which contains pyrroloquinoline quinone or its salt. An egg quality enhancer, which contains pyrroloquinoline quinone or its salt. An ameliorating or preventing agent for menstrual disorders, which contains pyrroloquinoline quinone or its salt. An ameliorating or preventing agent for ovarian hyperfunction, which contains pyrroloquinoline quinone or its salt. An estrogen production promoter containing pyrroloquinoline quinone or a salt thereof. The estrogen production promoter of claim 6, which improves or prevents the symptoms caused by female estrogen deficiency. The estrogen production promoter of claim 6, which improves or prevents premenopausal or menopausal disorders in females. The estrogen production promoter of claim 6, which improves or prevents female menopausal symptoms. Such as the agent of any one of claims 1 to 9, which is used for non-human animals. A method for inhibiting the aging progress of ovaries, follicles or eggs by ingesting a composition containing pyrroloquinoline quinone or its salts, thereby inhibiting the aging progress of ovaries, follicles or eggs.

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