WO2021261490A1 - Sécrétagogue de testostérone - Google Patents

Sécrétagogue de testostérone Download PDF

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WO2021261490A1
WO2021261490A1 PCT/JP2021/023614 JP2021023614W WO2021261490A1 WO 2021261490 A1 WO2021261490 A1 WO 2021261490A1 JP 2021023614 W JP2021023614 W JP 2021023614W WO 2021261490 A1 WO2021261490 A1 WO 2021261490A1
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testosterone
secretagogue
delphinidin
extract
structural formula
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PCT/JP2021/023614
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English (en)
Japanese (ja)
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洋介 稲垣
英介 加藤
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株式会社 日本薬業
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Priority to CN202180044211.3A priority Critical patent/CN115697087A/zh
Priority to KR1020227043153A priority patent/KR20230015368A/ko
Priority to JP2021553377A priority patent/JP7014483B1/ja
Publication of WO2021261490A1 publication Critical patent/WO2021261490A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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    • A—HUMAN NECESSITIES
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
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    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
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    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to an accelerator having a testosterone secretion promoting action. More specifically, the present invention relates to a promoter that promotes the synthesis and secretion of testosterone using a plant extract and components contained therein.
  • menopausal symptoms range from decreased libido, depression, decreased memory, decreased concentration, fatigue, hot flashes, sleep disorders, and decreased muscle mass, and the cause is thought to be a decrease in male hormones due to aging.
  • Testosterone is known as a representative of the male hormone (androgen), and in males it is synthesized in the Leydig cells of the testis and secreted into the blood. Testosterone has the strongest androgen action among male hormones, and is said to affect the development of male reproductive organs, the development of skeleton and muscles, and the enhancement of brain and mental vitality. Therefore, a decrease in blood testosterone concentration causes various systemic disorders as described above. It is also known that low testosterone levels increase the risk of metabolic syndrome, cardiovascular disease, diabetes, and respiratory diseases and are related to longevity (Non-Patent Document 1).
  • the symptom that the testosterone level decreases with aging is called so-called male climacteric (LOH syndrome, age-related hypogonadism). It is reported that the potential number of affected people is 12% in their 50s, 20% in their 60s, 30% in their 70s, and 50% in their 80s.
  • LH syndrome age-related hypogonadism
  • the present inventors searched for a new material that promotes the synthesis and secretion of testosterone in order to obtain a promoter that promotes the synthesis and secretion of testosterone without side effects.
  • the present inventors have diligently investigated whether there is a substance that promotes the synthesis and secretion of testosterone from natural materials considered to have few side effects, and as a result, newly promote testosterone secretion from Leydig cells. I found a natural material. In addition, one of the mechanisms was found to be due to increased StAR gene expression. Furthermore, regarding the three types of natural materials, the components involved in promoting the secretion of testosterone were identified, and it was found that these components have a combined effect, and the present invention was completed.
  • the present invention includes the following.
  • the testosterone secretagogue according to the present invention is characterized by containing myo-inositol represented by the following structural formula (4) as an active ingredient.
  • the testosterone secretagogue according to the present invention is Myo-inositol represented by the following structural formula (4) and Rosmarinic acid (RA) represented by the following structural formula (3) And / or Delphinidin-3-lucinoside (D3R) represented by the following structural formula (2) and Is a feature of the active ingredient.
  • RA Rosmarinic acid
  • D3R Delphinidin-3-lucinoside
  • Is a feature of the active ingredient it is preferable that the testosterone secretagogue is ingested by men.
  • myo-inositol is preferably derived from Tenyokenkoushi and / or Komenuka.
  • rosmarinic acid is preferably derived from perilla.
  • delphinidin-3-lutinoside is preferably derived from blackcurrant.
  • the testosterone secretagogue according to the present invention includes olive leaf, eyebright, echinacea, eleuthero, cassis, chicken blood wisteria, corn silk, red ginseng, ginseng, rubus suavissimus, and extracts thereof. It is preferable that one or more of them are selected from the group consisting of two or more. Further, in the testosterone secretagogue according to the present invention, it is preferable that the extract of Rubus suavissimus is an extract extracted with water or hydrous ethyl alcohol.
  • the method for producing a testosterone secretagogue according to the present invention is characterized in that it is extracted from Rubus suavissimus with water or hydrous ethyl alcohol.
  • the testosterone secretagogue according to the present invention one or more selected from the group consisting of cyanidin-3-lutinoside (C3R), delphinidin-3-lutinoside (D3R) and rosmarinic acid (RA) is effective. It is preferable to use it as an ingredient.
  • the expression of StAR is induced by delphinidin-3-lutinoside (D3R) and / or rosmarinic acid (RA).
  • the testosterone secretagogue according to the present invention is rosmarinic acid (RA) represented by the following structural formula (3). Is the active ingredient.
  • the testosterone secretagogue according to the present invention is delphinidin-3-lutinoside (D3R) represented by the following structural formula (2). Is the active ingredient.
  • the testosterone secretagogue according to the present invention increases the biosynthesis and secretion of testosterone by using a natural material derived from a plant. Furthermore, since the testosterone secretagogue according to the present invention is a plant-derived component made of a natural material, there is less concern about side effects as compared with a treatment method in which a hormone preparation is replenished from outside the body to the body, and the testosterone secretagogue can be used safely.
  • the present inventors have found a natural material that promotes testosterone secretion in Leydig cells. Then, it was found that one of the secretory promoting mechanisms is due to an increase in StAR gene expression. Details of the natural materials used in the examples of the present invention are as follows. However, the form of the natural material according to the present invention is not limited to these.
  • Eyebright is an extract powder produced by extracting the above-ground part of Euphrasia rostkoviana HAYNE and other plants of the same genus (Scrophiliaceae) with water.
  • Echinacea (Latin name of Echinacea purpurea) is an extract powder produced by extracting the dry above-ground part of Echinacea purpurea (Compositee) with water.
  • Gokasan (Ezokogi) is an extract powder produced by extracting the roots of Eleutherococcus senticosus Maxim. (Alariaceae) with water.
  • Cassis blackcurrant is an extract powder prepared by extracting the fruit of Ribes nigrum (Saxifragaceae) with water and eluting it with hydrous ethyl alcohol in a column.
  • Chicken blood wisteria is an extract powder produced by extracting the stem of Keiketo Spatholobus suberectus with hydrous ethyl alcohol.
  • Corn silk is an extract powder produced by extracting the style and stigma of corn Zea mays L. (Gramineae) with water.
  • Akajiso is perilla perilla fruitess Britton var. acta Kudo or perilla fruitess Britton var.
  • C3R cyanidin-3-lucinoside
  • D3R delphinidin-3-lucinoside
  • RA rosmarinic acid
  • myo-inositol is used for testosterone for rubus suavissimus. It was identified as a involved substance that promotes secretion. Among them, it was confirmed that delphinidin-3-lucinoside (D3R) and rosmarinic acid (RA) induce the expression of StAR.
  • D3R delphinidin-3-lucinoside
  • RA rosmarinic acid
  • Cyanidin-3-lucinoside (C3R) is one of the anthocyanin components and is a derivative of cyanidin represented by the following structural formula (1). Cyanidin-3-glucoside is contained in many red berries including berries, but cyanidin-3-lucinoside (C3R) is a component peculiar to blackcurrant and is not contained in blueberries and bilberries. It is known to have an effect of promoting blood flow in the eye and an antioxidant effect. It accounts for about 35% of the anthocyanins contained in blackcurrant. Cyanidin-3-lucinoside (C3R) has synonyms such as antirrhinin.
  • Delphinidin-3-lucinoside (D3R) is represented by the following structural formula (2), and is one of the anthocyanins contained in blackcurrant like cyanidin-3-lucinoside (C3R), and is contained in blueberries and bilberries. It is a component peculiar to cassis that has not been used. It is known to have an effect of promoting blood flow in the eye and a preventive effect of glaucoma and axial myopia, and has excellent antioxidant power. It accounts for about 46% of the anthocyanins contained in blackcurrant. Delphinidin-3-lucinoside (D3R) has synonyms such as Tulipanin.
  • Cyanidin-3-lutinoside (C3R) and delphinidin-3-lucinoside (D3R) are known to be absorbed into the body by ingestion like glucosides. Unlike glucosides, lutinosides are not conjugated or methylated and are confirmed to be rapidly transferred to the blood within 1 to 2 hours after ingestion in the state of anthocyanins and excreted in the urine. It is considered that anthocyanins function as active ingredients in the body as they are (Non-Patent Document 6).
  • Rosmarinic acid is a polyphenol represented by the following structural formula (3) and contained in plants of the Labiatae family such as perilla and rosemary. It is known to have antioxidant, antiallergic, and anti-inflammatory effects, and in recent years, its effects on Alzheimer's disease have also been reported. It has been reported that rosmarinic acid is absorbed into the body by oral administration and exhibits functionality (Non-Patent Document 7). Edible rosmarinic acid is contained in lemon balm, sage, spearmint, etc. in addition to perilla and rosemary, and is used.
  • Myo-inositol is represented by the following structural formula (4), is one of the nine isomers present in inositol, and is contained in various foods in the natural world. It is absorbed into the body through the intestinal tract by ingestion. It is known to be used as osmolyte to regulate osmotic pressure in the body, and regulates lipid and glucose metabolism. In addition, myo-inositol is known to be useful for the treatment of polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • myo-inositol is also contained in rice bran (detailed in the Journal of the Japanese Society of Food and Chemical Engineering Vol.59, No.7, 301-318 (2012)), and has a purity of 97% or higher.
  • the product has been commercialized by Tsukino Rice Fine Chemicals Co., Ltd.
  • Myo-inositol includes synonyms such as Hexahydroxyculohexane, Cyclohexanehexanol, meso-Inositol, and Myo-Inositol.
  • the above-mentioned part is preferable, but in addition, flowers, spikes, pericarp, fruits, stems, leaves, branches, branches and leaves, trunks, bark, etc.
  • One or more parts selected from rhizomes, bark, roots, seeds, whole plants and the like can be used.
  • the form of the natural material in the present application in addition to the one obtained by directly extracting from these natural materials with a solvent, the squeezed liquid and / or the residue obtained after the pressing treatment is extracted by adding a solvent. It includes a wide range of forms, such as those obtained by the above, those obtained by drying and grinding plants into powder, and the like. In addition to the above, it may be industrially synthesized.
  • the extract of the natural material in the present invention may be produced by a known method, and is extracted at room temperature or by heating using, for example, an alcohol such as water, methanol, ethanol or an extraction solution such as a mixed solvent thereof. It can be produced by the above, and if necessary, it may be extracted under reduced pressure or pressure. The obtained extract can be used as it is, but usually it is concentrated or freeze-dried to dryness.
  • the accelerator according to the present invention may be ingested alone, or may be ingested in the form of an oral composition by mixing with a pharmaceutically acceptable carrier, excipient, plasticizer, coloring agent, preservative and the like.
  • a pharmaceutically acceptable carrier e.g. mannitol
  • inorganic substances eg, calcium carbonate
  • microcrystalline cellulose eg, cellulose (eg, carboxymethyl cellulose)
  • gelatin sodium alginate, and the like.
  • sodium alginate and the like.
  • examples thereof include polyvinylpyrrolidone, agar, magnesium stearate, and talc.
  • the form of the oral composition is not particularly limited, and may be in the form of tablets, pills, capsules, granules, powders, powders, troches, solutions (beverages) and the like.
  • the accelerator according to the present invention can be suitably ingested in a state of being blended in general foods, health foods, foods with health claims (foods for specified health use, foods with functional claims, etc.).
  • the food include dairy beverages, lactic acid bacteria beverages, soft beverages, carbonated beverages, fruit juice beverages, vegetable beverages, alcoholic beverages, powdered beverages, coffee beverages, tea beverages, green tea beverages, wheat tea beverages and other beverages; pudding, jelly.
  • the intake is preferably about 50 to 1500 mg per day for a 60 kg human.
  • myo-inositol ⁇ I
  • D3R delphinidin-3-lucinoside
  • RA rosmarinic acid
  • the testosterone secretagogue according to the present invention can exert the above-mentioned effect not only on humans but also on animals other than humans. Therefore, the testosterone secretagogue according to the present invention can also be added to feeds for livestock and pets.
  • male infertility has been increasing, and some of the causes include testicular dysfunction and erectile dysfunction (ED). It is known that increasing the testosterone concentration in the supraclavicular body improves the spermatogenic process in the supraclavicular body.
  • ED erectile dysfunction
  • Testosterone secretagogue activity test The inventors conducted a testosterone secretagogue experiment on 100 natural materials. For the selection of ingredients, among the natural ingredients available in Japan and overseas, the ingredients that are judged to be "food" in Japan in the current food category were selected.
  • the sample preparation method was as follows. Each material was dissolved in a 50% aqueous solution of dimethyl sulfoxide (DMSO) at a concentration of 100 mg / mL.
  • DMSO dimethyl sulfoxide
  • the method for measuring the activity was as follows. I-10 cells (JCRB cell bank, JCRB9097) were seeded on a 48-well plate (manufactured by Thermo Scientific) at 2 ⁇ 10 4 cells / well, the medium was removed after 24 hours, and the medium to which the sample was added was added.
  • the medium was F-10 (manufactured by SIGMA-Aldrich), 10% bovine serum (manufactured by Gibco), penicillin 100unit / mL, streptomycin sulfate 100 ⁇ g / mL, and gentamicin sulfate 50 ⁇ g / mL (all manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). ) Is added.
  • the medium was collected 24 hours after the sample was added, and the amount of testosterone was quantified with a microplate reader (manufactured by Biotech) using a testosterone ELISA kit (manufactured by Cayman Chemical).
  • a 50% DMSO aqueous solution was used as a control. The results are shown in Table 1.
  • Example 2 Method for extracting components in Tenyokenkoushi
  • the inventors of the present invention have the amount of the extract extracted with water and ethyl alcohol hydrous when extracting Tenyokenkoushi, which had particularly high testosterone synthesis / secretion activity in Example 1. Was examined.
  • Extraction was performed as follows. 1. Crush the dried leaves of Tenyoukenkoushi (manufactured by Matsuura Pharmaceutical Co., Ltd.) with a mill to make a powder. 2. Place 5 g of the obtained powdered leaves in two beakers, add 100 ml of water to one and 100 ml of 40% ethyl alcohol to the other, and stir. 3. After stirring, cover with plastic wrap and let stand in the refrigerator for 5 days. 4. Extract and powdered leaves are No. Separate with 2 filter papers (manufactured by Advantech Toyo), and transfer the obtained extract to a 200 mL eggplant-shaped flask. 5.
  • Freeze-drying was carried out for 24 hours in a freeze-dryer (manufactured by Tokyo Rika), and after sufficiently drying, the total weight of the extract including the flask was measured. Let the total weight at this time be (i). The amount of the obtained extract was calculated by subtracting the flask weight (ii) from the total weight (i) obtained in 6.5. The results are shown in Table 2.
  • Table 2 showed that the amount of extract obtained was slightly higher when extracted with 40% ethyl alcohol than when extracted with water. Moreover, when the amount of testosterone was quantified by the method of Example 1, as shown in FIG. 1, the extract extracted with 40% ethyl alcohol showed higher testosterone secretion promoting activity. Therefore, it was shown that the testosterone secretagogue activity can be obtained higher by extracting with a solvent containing ethyl alcohol than with water.
  • the concentration of ethyl alcohol is 10 to 90% by mass, preferably 20 to 80% by mass, more preferably 30 to 70% by mass, and most preferably 40 to 60% by mass.
  • the inventors investigated changes in the expression level of testosterone biosynthesis-related genes.
  • the testosterone biosynthesis-related gene is a factor involved in the step that corresponds to the rate-determining step of steroid hormone synthesis, and promotes the transfer of cholesterol from the outer membrane of the mitochondria to the inner membrane of the steroid (Staro).
  • CYP11A1 P450scc
  • CYP11A1 P450scc
  • CYP11A1 which continuously hydroxylates the C22 and C20 positions using cholesterol as a substrate, catalyzes another step of the oxygenase reaction, and cleaves the covalent bond between C20 and C22 to produce pregnenolone.
  • CYP17A1 (P450c17), ⁇ -5-3-, which catalyzes two reactions, a 17 ⁇ -hydroxylation reaction and a cleavage reaction between C17 and C20, and produces androstenedione from pregnenolone to Dehydropedian steroid (DHEA) and progesterone with one enzyme.
  • DHEA Dehydropedian steroid
  • 3 ⁇ -hydroxy- ⁇ 5-steroid that catalyzes the oxidative conversion of ⁇ -hydroxysteroid precursors to ⁇ -4-ketosteroids and the interconversion of 3- ⁇ -hydrokey and 3-keto-5- ⁇ -androstenedione.
  • Examples include dehydrogenase (HSD3 ⁇ ), 17 ⁇ -hydroxy steroid dehidrogenase (HSD17 ⁇ ), which catalyzes the reduction of 17-ketosteroids and the dehydrogenation of 17 ⁇ -hydroxysteroids and produces androstendiol from DHEA and testosterone from androstenedione.
  • HSD3 ⁇ dehydrogenase
  • HSD17 ⁇ 17 ⁇ -hydroxy steroid dehidrogenase
  • StAR which is in the rate-determining step, is greatly involved in steroid hormone synthesis and is considered to be the most important step in the steroid hormone synthesis system.
  • lipoid hyperplasia Prader's disease
  • This disease presents with adrenal insufficiency from birth, and in XY solids, the external genitalia become feminized due to impaired androgen production in the testes. It has also been reported that when the expression of StAR decreases in animals, the amount of steroid hormones including testosterone decreases (Non-Patent Document 4).
  • Non-Patent Document 5 shows that when 24-month-old aged mice are used as a male menopausal animal model and oral administration of the Chinese herbal medicine Saikokaryukotsuboi-to increases the expression of StAR in male menopausal model mice, the serum testosterone level is improved, and male menopause. There is a report that the decrease in sexual activity, which is one of the symptoms, was improved. This study suggests that activating the expression of StAR can improve serum testosterone levels and may improve the symptoms caused by male menopause (Non-Patent Document 5).
  • I-10 cells (JCRB cell bank, JCRB9097) were seeded in a 6-well plate (manufactured by Nippon Genetics) at 1 ⁇ 10 5 cell / mL at 2 mL / well, and F-10 medium (10% FBS, penicillin 100 unit / mL, The cells were cultured in an incubator (manufactured by Sanyo Electric Co., Ltd.) for 3 days (under 37 ° C. and 10% CO 2 conditions) in a streptomycin sulfate 100 ⁇ g / mL and gentamicin sulfate 50 ⁇ g / mL.
  • a sample (100 mg / mL, 50% DSMO aqueous solution) diluted 100-fold with F-10 medium was added to the above cells, and the cells were cultured in an incubator (manufactured by Sanyo Electric Co., Ltd.) for 3 days (37 ° C., 10% CO 2 conditions). ..
  • the cells were washed with PBS solution, then exfoliated with Accutase (manufactured by Nacalai Tesque) and collected.
  • the collected cells were centrifuged at 300 g for 3 minutes using a desktop micro-cooled centrifuge (manufactured by Kubota Shoji), and then the supernatant was removed.
  • StAR showed significantly higher expression in 11 species as compared with the control. This suggests that StAR is involved in promoting testosterone synthetic secretion.
  • Example 4 Confirmation of intestinal epithelial permeability
  • I-10 cells which is a Leydig cell model
  • Leydig cells are not absorbed from the intestinal tract after oral ingestion.
  • the ingredients cannot reach. Therefore, in order to confirm whether the accelerator according to the present invention permeates the intestinal epithelium, the inventors investigated whether the extract of Tenyokenkoushi shows activity using Caco-2 cells, which is an intestinal epithelial cell model.
  • Caco-2 cells (RIKEN Cell Bank, RCB0988) were seeded on an insert (BioCoat Collagen I inserts, manufactured by Corning) used for the permeability test, and transepithelial resistance (manufactured by Merck Millipore) was used.
  • TEER is measured every few days and cultured until it reaches about 600 ⁇ ⁇ cm 2.
  • Add 0.2 mL of medium containing a sample concentration of 5, 10 and 20 mg / mL, respectively, of an extract of Tenyokenkoushi extracted with 40% by mass ethyl alcohol
  • the side medium (0.6 mL) was collected, added to I-10 cells, and the testosterone secretagogue activity was measured by the method of Example 1. The results are shown in FIG. 40% by mass ethyl alcohol was used as a control.
  • Example 5 Test for specifying the components involved The inventors conducted the following tests to identify the components involved in 11 kinds of natural materials that increase testosterone. The results are shown in FIG. 6, and a comparison between the peak diagram obtained for Tenyokenkoushi and the reference data is shown in FIG.
  • the test was conducted by the following method.
  • 5 g of sweet tea was extracted with a 40% ethanol aqueous solution at 4 ° C. for 4 days, ethanol was removed from the obtained extract, and then the solvent was sequentially partitioned with hexane, ethyl acetate, and 1-butanol.
  • An aqueous layer (750 mg) was obtained.
  • the entire aqueous layer was passed through DIAION HP-20 column chromatography (2.4 ⁇ 20 cm), washed with water, and a 50% aqueous methanol solution and methanol were sequentially flowed.
  • the obtained fraction was followed by HPLC using Cosmosil PBr (10 ⁇ 250 mm, Nacalai Tesque), and the mobile phase was gradient (1% aqueous methanol solution to 15% aqueous methanol solution, 0.1% trifluoroacetic acid addition, 60 minutes). Fractionated by. Finally, the obtained fraction was fractionated by Shodex Asahipak NH2P-50 4E (4.6 ⁇ 250 mm, SHOWA DENKO KK), and the mobile phase was fractionated by HPLC using an 85% acetonitrile aqueous solution, and the obtained peak was obtained. 1 H-NMR and ESI-MS were measured and compared with the reference data (Biological Magnetic Resonance Bank) to identify myo-inositol.
  • GGOH Geranylgeraniol
  • Bixaceae Achiote Annatto: Bixa orella
  • Is. It is disclosed as a testosterone enhancer (Patent Document 3), and its testosterone enhancing action has been reported (Non-Patent Document 8).
  • Example 6 Test for confirming promotion of StAR expression
  • D3R delphinidin-3-lutinoside
  • RA acid
  • FIGS. 8 and 9 The results are shown in FIGS. 8 and 9.
  • Example 7 Combined effect of the components involved The inventors further determined by the method of [Example 1] whether the effect of promoting the secretion of testosterone is increased when the components involved found in Example 5 are used in combination rather than alone. A testosterone secretagogue activity test was conducted and examined. The results are shown in FIG.
  • myo-inositol ( ⁇ I), rosmarinic acid (RA), and delphinidin-3-lucinoside (D3R) alone are more than myo-inositol ( ⁇ I), rosmarinic acid (RA), and myo-inositol ( ⁇ I), respectively.
  • delphinidin-3-lutinoside (D3R) were confirmed to increase the promotion of testosterone secretion. This suggests that more testosterone is secreted by using the ingredients together.
  • Prescription example 1 Vegetable juice [ingredients] [blending amount] (1) Tenyoukenkoushi Hydrous Ethanol Extract 0.5 (2) Vegetable juice 84.5 (3) Apple 5 times concentrated juice 5.0 (4) Lemon triple concentrated juice 2.0 (5) Sodium ascorbate 0.05 (6) Residual of purified water [Manufacturing method] (1) to (6) are mixed to obtain vegetable juice.
  • Prescription example 2 cookie [ingredient] [blending amount] (1) Tenyoukenkoushi Hydrous Ethanol Extract 10.0 (2) Shortening 40.0 (3) Milk 5.0 (4) Aspartame 7.5 (5) Egg 7.5 (6) Baking powder 0.001 (7) Residual of cake flour [Manufacturing method] After mixing (2) to (4) using a stirrer, (5) was added little by little and mixed until uniform. Premixed (6), (7) and (1) were added to the mixture and kneaded to obtain a cookie dough. After standing in the refrigerator for 30 minutes, mold and bake.
  • Prescription example 3 Gummy [ingredient] [blending amount] (1) Tenyoukenkoushi Hydrous Ethanol Extract 2.5 (2) Apple 5 times concentrated juice 45.0 (3) Honey 41.5 (4) Lemon juice 5.0 (5) Gelatin 6.0 (6) Appropriate amount of cinnamon [Manufacturing method] Heat and mix (1) to (4), add (5) and (6), and heat and mix until more uniform. The mixture was poured into a mold and cooled at 4 ° C. for 1 hour. I removed it from the mold and got a gummy candy.
  • Prescription example 4 Tablet-type supplement [ingredients] [blending amount] (1) Tenyoukenkoushi Hydrous Ethanol Extract 10.0 (2) Microcrystalline cellulose 75.0 (3) Sodium ascorbate 10.0 (4) Glycerin fatty acid ester 3.0 (5) Talc 1.8 (6) Sodium stearate 0.2 [Manufacturing method] After uniformly mixing (1) to (6), tableting was performed using a single-shot tableting machine to obtain a tablet having a diameter of 5 mm and a mass of 15 mg.
  • Prescription Example 5 Granule-type supplement [ingredients] [blending amount] (1) Tenyoukenkoushi Hydrous Ethanol Extract 15.0 (2) Ascorbic acid 25.0 (3) d- ⁇ -tocopherol acetate 1.5 (4) Powder reduced maltose starch syrup 54.0 (5) Aspartame 0.6 (6) Hydroxypropyl cellulose 1.5 (7) Ribofluorobin butyrate 0.2 (8) Sucralose 0.2 (9) Sucrose fatty acid ester 2.0 [Manufacturing method] A mixture of (1) to (6) and a solution prepared by dissolving (7) and (8) in 25 mL of ethanol are mixed, kneaded, and then granulated using an extruder. (9) is added to and mixed with the obtained granules to obtain granules.
  • Prescription example 6 Tablet-type supplement [ingredients] [blending amount] (1) Siberian ginseng dry powder 10.0 (2) Microcrystalline cellulose 75.0 (3) Sodium ascorbate 10.0 (4) Glycerin fatty acid ester 3.0 (5) Talc 1.8 (6) Sodium stearate 0.2 [Manufacturing method] After uniformly mixing (1) to (6), tableting was performed using a single-shot tableting machine to obtain a tablet having a diameter of 5 mm and a mass of 15 mg.
  • Prescription Example 7 Granule-type supplement [ingredients] [blending amount] (1) Western ginseng dry powder 15.0 (2) Ascorbic acid 25.0 (3) d- ⁇ -tocopherol acetate 1.5 (4) Powder reduced maltose starch syrup 54.0 (5) Aspartame 0.6 (6) Hydroxypropyl cellulose 1.5 (7) Ribofluorobin butyrate 0.2 (8) Sucralose 0.2 (9) Sucrose fatty acid ester 2.0 [Manufacturing method] A mixture of (1) to (6) and a solution prepared by dissolving (7) and (8) in 25 mL of ethanol are mixed, kneaded, and then granulated using an extruder. (9) is added to and mixed with the obtained granules to obtain granules.
  • Prescription Example 8 Gummies [Ingredients] [Amount] (1) Perilla water extract 2.5 (2) Apple 5 times concentrated juice 45.0 (3) Honey 41.5 (4) Lemon juice 5.0 (5) Gelatin 6.0 (6) Appropriate amount of cinnamon [Manufacturing method] Heat and mix (1) to (4), add (5) and (6), and heat and mix until more uniform. The mixture was poured into a mold and cooled at 4 ° C. for 1 hour. I removed it from the mold and got a gummy candy.
  • Prescription example 9 Tablet-type supplement [ingredients] [blending amount] (1) myo-inositol 67.0 (2) Perilla extract powder (containing rosmarinic acid) 0.6 (3) Blackcurrant extract powder (containing cassis anthocyanin) 1.2 (4) Microcrystalline Cellulose 26.2 (5) Glycerin fatty acid ester 2.5 (6) Talc 1.5 (7) Sodium stearate 0.6 (8) Acidulant 0.4 (9) Appropriate amount of fragrance [Manufacturing method] After uniformly mixing (1) to (9), tableting was performed using a single-shot tableting machine to obtain a tablet having a diameter of 11 mm and a mass of 400 mg.

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Abstract

La présente invention aborde le problème de l'obtention d'un promoteur qui favorise la synthèse et la sécrétion de testostérone sans aucun effet secondaire. Les présents inventeurs ont recherché des matériaux ayant une capacité significativement élevée à favoriser la sécrétion de testostérone parmi différents matériaux naturels et, par conséquent, ont trouvé 11 matériaux qui stimulent la sécrétion de testostérone plus fortement que les cellules de Leydig. Ensuite, les présents inventeurs ont identifié des composants pertinents dans 3 de ces matériaux.
PCT/JP2021/023614 2020-06-22 2021-06-22 Sécrétagogue de testostérone WO2021261490A1 (fr)

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