JP2007084559A - Blood testosterone level-lowering inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine or a food with high safety which inhibits a decrease in the blood testosterone level and thus prevents or ameliorates symptoms associating male climacteric disorder. <P>SOLUTION: The blood testosterone level-lowering inhibitor contains a plant belonging to the genus Codonopsis or its extract. Blood testosterone level lowering-inhibiting effect and male climacteric disorder-ameliorating effect can further effectively be exhibited by adding extract(s) of plant(s) selected from plants having antidepressive effect, plants having anxiolytic effect and plants having blood DHEA-S lowering-inhibiting action to the inhibitor. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a medicament or food having a blood testosterone lowering inhibitory action and a male menopausal disorder improving action.

  Testosterone is said to have an effect on male genital development, skeletal and muscular development, increased libido and sexual impulses, and increased vitality of the brain and mental aspects. It is known that the concentration of testosterone in blood decreases when subjected to strong stress. Decrease in blood testosterone causes diseases such as male menopause and delayed onset of puberty.

  Men with menopause have a variety of symptoms (for example, discouragement, depression, irritation, anxiety, irritability, loss of vitality, fatigue, arthritis, myositis, weakness, sweating, hot flashes, sleep disorders, memory loss, and poor concentration. , Physical exhaustion, decreased libido, erectile dysfunction, loss of ejaculation, etc.) are strongly expressed. As a method for confirming whether or not male climacteric disorder is present, there are a method of measuring blood testosterone concentration by blood test and a method of questionnaire. The age at which male climacteric disorder develops is mainly observed for men in their 40s to 50s, but the symptoms may also appear in men in their 20s or 60s as early as possible. It has been pointed out that the development of male climacteric disorder is greatly influenced by various stresses at work and homes of active men, and the number of middle-aged and older men suspected of having climacteric disorder has been increasing recently.

  For such a decrease in blood testosterone and menopausal disorders, hormone replacement therapy using an androgen preparation containing testosterone is becoming widespread in clinical practice, and its effectiveness against various symptoms has been reported (for example, non-patent literature) 1). However, this method of treatment is limited to those who do not have prostate disease, as testosterone is clearly low in blood tests. The reason is that there is a possibility of prostatic hypertrophy and manifestation of prostate cancer as a side effect. Therefore, there has been a demand for the development of pharmaceuticals or health foods that have fewer side effects and can be prevented and alleviated with safe materials for various symptoms associated with decreased blood testosterone and menopause.

The genus Crunopins ( Codonopsis lanceolata .) Has been used as a folk medicine for anti-inflammatory, expectorant, nourishing tonic, strong, etc. for a long time, especially in Korea as a medicinal dish. It has also been reported to be used in powdered foods and beverages (see, for example, Patent Documents 1 and 2). As pharmacological research and component research of tunnin, spermatogenesis promoting action and sexual behavior disorder improving action have been reported (for example, see Non-Patent Document 2).
However, it has not been reported that tunnin and its components have a blood testosterone lowering inhibitory effect and a male menopausal disorder improving action.
JP 2001-299273 A JP 2002-218941 A Naoki Ito, Shinichi Kusue, Taiji Tsukamoto, Male hormone replacement therapy for male menopause, Geriat. Med. 42 (9): 1151-1156, 2004 Research Report on Human Science Research, Drug Discovery, etc., from 1998 to 2000, 5th Research on Development of Health Maintenance Promotion / Prevention Drugs, 86-99, 2001

  An object of the present invention is to provide a highly safe pharmaceutical or food product that suppresses a decrease in blood testosterone and prevents or ameliorates various symptoms associated with male menopause.

  As a result of various searches for highly safe natural materials, the present inventors have found that the plant of the genus Turnin or its extract remarkably suppresses the decrease in blood testosterone and is excellent in improving various symptoms of male climacteric disorder. The present invention was completed by finding out that the effect was exhibited.

  That is, the present invention relates to a blood testosterone lowering inhibitor containing a plant of the genus Cultivation or an extract thereof.

  In addition, the present invention relates to a food containing a genus plant of the genus Cervus or an extract thereof and labeled as being used for suppressing a decrease in blood testosterone.

  According to the blood testosterone decrease inhibitor of the present invention, the decrease in blood testosterone can be suppressed without causing side effects such as prostatic hypertrophy and manifestation of prostate cancer, and various symptoms associated with male climacteric disorder and delayed puberty. The onset can be prevented, treated, improved or reduced.

  In the present invention, suppression of decrease in blood testosterone means suppression of decrease in blood testosterone concentration below a normal value due to stress, aging, or the like. Therefore, the blood testosterone decrease inhibitor is useful for the prevention and improvement of diseases and symptoms caused by the decrease in blood testosterone, such as male climacteric disorder and delayed onset of puberty.

  In the present invention, improvement of male climacteric disorder refers to various symptoms caused by male climacteric disorder, such as discouragement, depression, irritation, anxiety, nervousness, loss of vitality, fatigue, arthritis, myositis, muscle weakness, sweating, hot flashes It means preventing, treating, improving or reducing sleep disorder, memory loss, concentration loss, physical exhaustion, decreased libido, erectile dysfunction, loss of ejaculation, aging and the like. The male climacteric disorder includes all disorders in which the above symptoms are observed regardless of age.

The codonopsis plants in the present invention, for example, Codonopsis lanceolata (Codonopsis lanceolata Trautv.), Shade Codonopsis (C. Pilosula Nannf.), Mountain Codonopsis (C. Sylvestris), and the like. Of these, tunnin ( C. lanceolata Tratv .) Is preferable.

  The above genus plant can use all or part of the elements constituting the plant, for example, roots, rhizomes, leaves, stems, flowers, fruits, seeds, buds, etc. Or it is preferable to use a rhizome.

  As an extract of the genus genus plant, various solvent extracts obtained by extracting the genus genus plant at room temperature or under heating or using an extractor such as a Soxhlet extractor, or a diluted solution thereof , Concentrates, extracts, and dried products obtained by drying them.

  As the extraction solvent for obtaining the extract of the present invention, either a polar solvent or a nonpolar solvent can be used, and these can also be mixed and used. For example, water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol; linear and cyclic ethers such as 1,4-dioxane, tetrahydrofuran, and diethyl ether; ketones such as acetone and methyl ethyl ketone Nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; polyethers such as polyethylene glycol; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; hydrocarbons such as hexane, cyclohexane and petroleum ether Aromatic hydrocarbons such as benzene and toluene; pyridines; supercritical carbon dioxide; fats and oils, waxes, and other oils. Among these, polar solvents, particularly water, ethanol, and mixtures thereof are used. preferable.

  The extraction varies depending on the solvent used, but can be performed by a conventional method. For example, a polar solvent is added to a pulverized, crushed or cut plant body or dried product thereof, and the temperature is 0 ° C. to 100 ° C., preferably 70 ° C. to 100 ° C. for 5 minutes to 24 hours, preferably 5 minutes to 1 hour. This can be done by leaving it alone.

The above extract can be used as it is, but the extract is diluted, appropriately filtered or centrifuged to remove insolubles, the solvent is removed, concentrated or lyophilized, and then powdered as necessary. Alternatively, it can be prepared in the form of a paste and used.
In addition, it is inactive from the above extract using a liquid-liquid partitioning technique (for example, washing with a nonpolar solvent such as ethyl acetate, diethyl ether, hexane, and extraction with water) or purification techniques such as various chromatography. It can also be used after removing impurities, and it is preferable to use such a material in the present invention. These may be used after performing treatments such as deodorization and decolorization by a known method if necessary.

  Plants of the genus Cultivation include Tangsenosides, Lanceside-A and Syringin. The chemical structures of Tangshenosides, Lancemaside-A, and Syringin are as follows, and Tangshenosides include Tangshenoside I and Tangshenoside II.

As shown in Examples 2 and 3 to be described later, tunnin ( Codonopsis lanceolata ) is extracted with alcohols such as methanol, the extract is subjected to various column chromatography, and then separated and purified by high performance liquid chromatography. Can be obtained.
In the present invention, the above-mentioned compound is not limited to such a method, and may be obtained by extraction from other natural products or chemical synthesis.

  The genus plant of the present invention or an extract thereof (hereinafter also referred to as “plant of the genus genus”) has an excellent blood testosterone decrease inhibitory effect as shown in the examples below, and has an effect of improving male climacteric disorder. In addition to having high safety, it can be used as a blood testosterone lowering inhibitor and a male menopausal amelioration agent that can be used as foods and pharmaceuticals.

  When using the genus plant of the present invention as a food, various symptoms associated with menopause (for example, discouragement, depression, irritation, anxiety, nervousness, loss of vitality, fatigue, arthritis, myositis, muscle weakness, Foods with the concept of prevention, improvement or reduction of sweating, hot flashes, sleep disorders, decreased memory, reduced concentration, physical exhaustion, decreased libido, erectile dysfunction, loss of ejaculation, aging, etc., eg products, packaging containers Foods for the sick, foods for specified health use, etc. that are marked on the catalogs, materials, etc.

  The food form can be any form such as a solid food, a creamy or jammed semi-fluid food, a gel food, a beverage, a tea leaf, such as a powder, capsule, granule, tablet, drink, tea bag, etc. A form is mentioned. Such food and drink can be processed according to conventional methods.

  Examples of the above-mentioned food include medicinal plants conventionally used for the improvement of male climacteric disorder, such as plants having antidepressant action, plants having anxiolytic action, blood DHEA-S (Dehydroepiandrosterone sulfate, dehydroepiandrosterone sulfate) ) A plant having an inhibitory action or an extract thereof can be added. In addition, these plants may be a single substance, and may have any two or more actions of antidepressant action, anti-anxiety action, and blood DHEA-S lowering inhibitory action.

  Examples of plants having an antidepressant action include, for example, Korean carrot, Ezocogi, St. John's wort, Damiana, Ginkgo biloba, Valerian, Green tea, Passiflora, Hop, Chamomile, Skull cap, Jujube, Lotus fruit, Kava kava, Pomegranate, Orange flower, Lemon verbena, linden, marjoram, passion flower, lemon balm, jasmine, lavender, mint, saffron, kola, yellowfin, honoki, seri, perilla, and luffa are preferred, and luffa is preferred.

  Examples of plants having an anxiolytic action include river, rose, hippopotamus, bacoba, clary sage, geranium, valerian, chamomile, Korean carrot, sorghum, lavender, ginkgo leaf, lemon verbena, saffron, passion flower, and cavacava.

  Examples of the plant having a blood DHEA-S decrease inhibitory action include yam, ginseng, guarana, ginseng, damiana, gotsukora, and sophon, and is preferably sophon.

When using the genus plant of the present invention as a pharmaceutical product, a pharmaceutically acceptable carrier may be added to the genus genus plant or its extract, Tangsenosides, Lanceside-A or Syringin to form a pharmaceutical composition. .
The administration form of the pharmaceutical agent of the present invention is not particularly limited, and general administration routes such as oral administration, rectal administration, transdermal administration, and administration by injection can be mentioned, and oral administration is preferred.
The drug can be formulated into a suitable solid preparation or liquid preparation using a pharmaceutically acceptable carrier according to the administration route.

  Examples of solid preparations for oral administration include capsules, tablets, pills, troches, powders and granules. Solid formulations can generally be prepared by admixing the compositions described herein with at least one additive (eg, crystalline cellulose, lactose, or starch). This formulation may be prepared using a lubricant such as magnesium stearate in addition to the additives. In the case of capsules, tablets and pills, a buffering agent may be further used. Tablets and pills can also have an enteric coating.

  Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the preparation of liquid formulations, such as water. The liquid preparation can be prepared by adding an additive to the plant body and / or extract according to the present invention and further blending an auxiliary agent such as a wetting agent, an emulsifying agent, a suspending agent, a flavoring agent, or a flavoring agent.

  The above pharmaceutical products include medicinal plants conventionally used for the improvement of male climacteric disorder and the like, drugs used for the treatment of male climacteric disorder, etc., for example, drugs having antidepressant action, drugs having anxiolytic action, A drug having a blood DHEA-S lowering inhibitory action can be added, whereby the blood testosterone lowering suppressing effect and the male climacteric disorder improving effect can be more effectively exhibited.

  Examples of the drug having an antidepressant action include tricyclic antidepressants such as amitriptyline hydrochloride, tetracyclic antidepressants such as maprotiline hydrochloride, SSRI such as fluvoxamine maleate, SNRI such as milnacipran hydrochloride, safradine hydrochloride MAO inhibitors such as trazodone hydrochloride and sulpiride.

  Examples of drugs having an anxiolytic action include benzodiazepine derivatives such as alprazolam, etizolam, oxazolam, cloxazolam, and tandospirone.

  Examples of the drug having a blood DHEA-S lowering inhibitory action include DHEA (dehydroepiandrosterone sulfate).

As a preferable embodiment of the present invention, for example, an extract obtained by a method in which roots of tunnin ( Codonopsis lanceolata ) are heated in hot water for 30 minutes to 120 minutes, insoluble components are removed, and the solvent is concentrated and dried. In addition, a composition having an anti-depressive effect such as rafuma and sophon having a blood DHEA-S lowering suppression effect, and an excipient or carrier generally used for pharmaceuticals and foods is added.

The dosage when using the genus plant of the present invention as a pharmaceutical agent varies depending on the administration method and purpose of use, but when it is a solid agent, the genus plant of the genus genus or its extract is converted into a crude drug, Usually, the dose is 0.01 to 5 g, the daily dose is 0.01 to 15 g, preferably 0.1 to 1 g, and the daily dose is 0.1 to 3 g, preferably 0.5 to 2 g. -A, Tangsenosides, and Syringin are usually 0.01 to 0.5 g at a time, 0.01 to 1.5 g as a daily dose, preferably 0.1 to 1 g as a daily dose, and 0 as a daily dose. 0.1 to 0.3 g, preferably 0.1 to 0.2 g.
Moreover, when using it as a liquid agent, as a plant of the genus Cultivation or an extract thereof, in terms of a crude drug, as a 0.02 to 10 w / v% solution, 1 to 50 mL at a time, 1 to 3 times a day, Lancemaside- As A, Tangsenosides, and Syringin, a 0.01 to 0.5 w / v% solution may be administered 1 to 50 mL at a time, 1 to 3 times a day.
Hereinafter, the present invention will be described by way of examples, but these examples do not limit the present invention.

Example 1 Preparation of tun carrot extract 13 L of purified water was added to 1.4 kg of dried root of tun carrot ( Codonopsis lanceolata ), heated in hot water at 90 ° C. or higher for 1 hour, and insoluble components were filtered. The obtained hot water extract was freeze-dried to obtain 476 g of a vine carrot extract.

Example 2 Extraction of Tangsenosides and Syringin 476 g of tunnin ginseng extract obtained in Example 1 was passed through a polystyrene porous resin (Diaion HP-20), washed with water, and then eluted with methanol. The methanol-eluted fraction was separated by silica gel chromatography using a mixed solution of chloroform and methanol as an elution solvent to obtain fraction 1 (including Tangsenoside II and Syringin) and fraction 2 (including Tangsenoside I). Fraction 1 was separated by high performance liquid chromatography (preparative condition 1) and concentrated to obtain Tangsenoside II (50 mg) and Syringin (70 mg). Fraction 2 was separated by high performance liquid chromatography (preparative condition 2) and concentrated to give Tangsenoside I (24 mg).

Preparative condition 1 (Tanshenoside II, Syringin high-performance liquid chromatography preparative condition)
Mobile phase: 25% acetonitrile Flow rate: 8 mL / min
Detection wavelength: 210 nm
Column: YMC-Pack ODS-AQ (inner diameter 20 mm, length 250 mm, particle diameter 5 μm, manufactured by YMC Co., Ltd.)
Column temperature; room temperature

Preparative condition 2 (Tanshenoside I high performance liquid chromatography preparative condition)
Mobile phase: 18% acetonitrile Flow rate: 8 mL / min
Detection wavelength: 210 nm
Column; Mightysil RP-18 GP (inner diameter 20 mm, length 250 mm, particle diameter 5 μm, Kanto Science Co., Ltd.)
Column temperature; room temperature

Example 3 Extraction of Lanceside-A Purified water (15 L) was added to 1 kg of dried roots of tunnin ( Codonopsis lanceolata ), heated in hot water at 90 ° C. or higher for 1 hour, and insoluble components were filtered. The obtained hot water extract was dried to obtain 0.4 kg of a tun carrot extract. 0.4 kg of the tun carrot extract was passed through a polystyrene porous resin (Diaion HP-20), washed with water and 30% methanol, and then eluted with methanol. The methanol-eluted fraction was separated by silica gel chromatography using a mixed solution of chloroform, methanol and water as an elution solvent, and the fraction containing Lancemaside-A was separated by high performance liquid chromatography (preparation condition 3), and Lancemaside- The eluate containing A was passed through a Diaion HP-20 column, washed with water, then eluted with methanol, concentrated, and lyophilized to obtain Lanceside-A (110 mg). The physical properties of Lancemaside-A are shown below.

Preparative condition 3 (Lancemasside-A high-performance liquid chromatography preparative condition)
Mobile phase; water: acetonitrile mixture (72:28) containing 0.1% trifluoroacetic acid
Flow rate: 9.99 mL / min
Detection wavelength: 210 nm
Column; TSK gel ODS-80TS (inner diameter 20 mm, length 250 mm, particle diameter 5 μm, Tosoh Corporation)
Column temperature: 25 ° C

Physical Properties 1) Property: White powder 2) MS: Electrospray ionization method Positive ion: m / z 1213, [M + Na] ⁺ , m / z 1229, [M + K] ⁺ , Negative ion: m / z 1189, [M−H ] ^-
3) ¹³ C-NMR (pyridine-d ₅ ):

Example 4 Blood Testosterone Level Reduction Suppression Test Using the tunnin carrot extract obtained in Example 1, the effect of suppressing blood testosterone level decrease due to aging and stress was examined by the following method. A test substance of 1 g / kg was orally administered to 7-month-old ddY male mice (10 mice per group) once a day for 2 weeks. On the final administration day, one hour after administration of the test substance, stress was imposed by restraint. For restraint stress, the body of a mouse was wrapped with a soft wire mesh, loaded for 16 hours (17:00 to 9:00) under fasting water, and blood testosterone concentration was measured immediately after the end of loading. Student's test was used for the significant difference test. The results are shown in FIG. 1, but the blood testosterone concentration in the stress-loaded group is lower than that in the group not subjected to the stress load, but the decrease in the blood testosterone concentration is clearly suppressed in the tunnin carrot extract administration group. The effect was recognized. This result was significantly different from the stress load group at a risk rate of 5%. Similarly, Lancemaside-A and Tangsenoside I also showed an inhibitory effect.

Example 5 Safety Test In order to confirm the safety of the vine carrot extract of the present invention obtained in Example 1, 5 gm old ddY mice (4 males and 4 females) were given 10 g / kg of tun carrot extract. And 20 g / kg was orally administered at a dose of 30 ml / kg, and then the body weight transition and general condition were observed for 6 days. Two males and two females from each group were necropsied on the next day and the 6th day after administration, and the thoracoabdominal organs were visually observed. There were no confirmed deaths due to administration of the tunnin carrot extract, and no abnormal findings were observed in any of the general conditions, body weight changes, and anatomical findings.

Example 6 Male Climacteric Disorder Improvement Test For 3 males in their 40s, the onset of male climacteric disorder, twice daily after breakfast and dinner, the test substance (0.5 g of carrot extract (concentration of drug substance: 1.47 g) and 0.2 g) of excipients such as dextrin and starch were taken for 14 days, and the feeling of taking was measured. As a result, the early morning erection, which was one of the symptoms of male climacteric disorder in the clinical setting, was occasionally observed in all three patients. Early morning erection was observed until the dose was completed.

Example 7 Formulation Formulation Example (1) Granule

(2) Liquid agent

It is the figure which showed the change of the blood testosterone density | concentration of the restraint stress load mouse | mouth in this invention administration group and a control group (mean +/- standard error).

Claims (3)

  A blood testosterone lowering inhibitor containing a plant of the genus Cultivation or an extract thereof.   A food that contains a plant of the genus Cultivin or an extract thereof and is labeled as being used for suppressing a decrease in blood testosterone.   Furthermore, it contains any one or two or more kinds of plants selected from plants having an antidepressant action, plants having an anxiolytic action and plants having a blood DHEA-S lowering inhibitory action, or extracts thereof. Food listed.

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