JPWO2018016455A1 - Nourishing tonic - Google Patents

Abstract

Disclosed is at least one selected from the group consisting of echinacea or an extract thereof, chicoric acid, artepillin C, kevra pedra or an extract thereof, sedro or an extract thereof, and marcella or an extract thereof Containing as active ingredients for tonic and spermatozoa, for improving sexual function, for improving menopausal symptoms, for cultivating tonics, for improving vitality, for improving erectile dysfunction, for enhancing cavernous relaxation, for improving prostatic hyperplasia, for improvement of dysuria It is a composition for improving blood flow, for improving blood pressure, for improving pulmonary hypertension, for inhibiting PDE5, for promoting cGMP elevation, or for suppressing cGMP degradation.

Description

  The present invention is intended for tonicity, sexual function improvement, men's menopausal symptom improvement, nourishment tonicity, vitality improvement, erectile dysfunction improvement, cancellous body relaxation enhancement, prostatic hypertrophy improvement, urination disorder improvement, The present invention relates to a composition for blood flow improvement, blood pressure improvement, pulmonary hypertension improvement, PDE5 inhibition, cGMP increase promotion or cGMP degradation suppression.

  One of the aging problems facing men is male menopausal manifestations. It is estimated that about 40% of men in their 40s to 60s will experience some degree of male menopause.

  When men become menopausal, various symptoms (eg depression, discouragement, analgesia, anxiety, nervousness, fatigue, loss of life, myositis, arthritis, muscle weakness, hot flashes, sweating, memory loss, sleep disorder, concentration decline , Physical exhaustion, erectile dysfunction (ED), decreased libido, loss of ejaculation, etc.) are strongly expressed. Methods for determining whether or not male menopause is present include measurement of blood testosterone concentration by blood test and methods by questionnaire. It has been pointed out that various stress at work and at homes of working men are largely involved in the onset of male menopausal disorder, and the number of middle-aged and elderly men suspected of being menopausal is increasing in recent years.

  Male menopausal disorders have a state in which autonomic ataxic symptoms and neuropsychiatric symptoms similar to female menopausal disorders appear with a background of age-related androgen decline and, in most cases, they are accompanied by male dysfunction. (Okuyama Akihiko Author Menopausal Disorders LOH Syndrome I Men's Menopausal Disorders D. From the Viewpoint of Psychosomatic Internal Medicine Page 24 (Nansandou Co., Ltd. 2007.) On the other hand, in the secretion of sex hormones including testosterone, hormone secretion including testosterone is regulated through negative feedback via hypothalamus-pituitary-testis system (Okuyama Akihiko) Male menopausal disorder LOH syndrome II. Diagnosis of male menopausal disorder C. Measurement of hormone and its evaluation page 65 (Nanzando Co., Ltd. 2007.) Therefore, it is difficult to judge male menopausal disorder only by the testosterone measurement value.

  In general, subjects who are aware of hypoactivity and have a tendency to lower free testosterone in blood are diagnosed with age-related male hypogonadism syndrome (LOH syndrome), and androgen replacement therapy to maintain QOL It can be an adaptation of However, while hormone replacement therapy in women is widespread internationally, treatment for men is not a target of medical treatment other than the spread of PDE5 (phosphodiesterase-5) inhibitors for ED.

  As a therapeutic agent for ED, PDE5 inhibitors "vardenafil", "sildenafil" and "tadalafil" are used. By inhibiting PDE5 which is a cGMP (cyclic guanosine monophosphate) specific hydrolase, the normal actions of NO and cGMP are enhanced. Inhibition of PDE5 in the corpus cavernosum increases intracellular cGMP levels, relaxes the smooth muscle system of the corpus cavernosum, and causes blood to flow into the corpus cavernosum (reference: Japanese Patent No. 4860469). Studies using such "vardenafil" and "sildenafil" are reported in Non-Patent Documents 1 and 2.

  In Non-Patent Document 1, the combination of vardenafil and resveratrol with sirtuin activation has a synergistic effect on the increase of cGMP levels in corpus cavernosum smooth muscle cells, and also a synergistic effect on ED improvement even in vivo It has been reported that it was obtained.

  Non-Patent Document 2 reports that a combination of sildenafil and resveratrol has a synergistic effect on ED improvement in rats and a synergistic effect on elevation of the cGMP level in the corpus cavernosum .

  In addition, it is known that PDE5 inhibitors suppress cGMP degradation to relax the muscles of the urethra and improve prostate hypertrophy and dysuria, and in fact, sildenafil and tadalafil exhibit the effects described in the left. It is reported by nonpatent literature 3-8.

  Furthermore, a significant negative correlation between cerebral blood flow and a sense of fatigue has been confirmed (Nichigo Shimbun, 56: 122-127, 2008), improving blood flow, stiff shoulders and tired body , Symptoms of coldness of hands, feet, tired eyes, and blurred vision are improved (Japanese Journal of Complementary and Alternative Medicine, 5 (1): 49-56, 2008). Therefore, it is expected that PDE5 inhibitors that contribute to blood flow improvement not only exhibit a strong tonic effect but also a nodular tonic effect.

  Pulmonary hypertension is a state in which the pulmonary artery that sends blood from the heart to the lungs is in high blood pressure, and the fact that blood is less likely to flow in the small arteries of the lung is the main body of the disease. Because PDE5 is also widely distributed in the smooth muscle of the pulmonary artery in vivo, the PDE5 inhibitor maintains high cGMP levels in pulmonary artery smooth muscle cells and enhances vasodilation by endogenous NO, resulting in pulmonary arterial hypertension. Improvement in pulmonary hemodynamics is expected.

  However, vardenafil, which is a PDE5 inhibitor, has been reported as a side effect of sudden visual loss, and there are strong safety concerns. Also, side effects and drug interactions have been reported, albeit transiently, for the PDE5 inhibitor sildenafil as well. For example, sildenafil acts as a promoter for the hypotensive action of nitrate drugs such as nitroglycerin, so their combination with them is contraindicated, and the action on the eye also includes bluesightedness, diplopia, Red vision and the like are recognized.

J Sex Med 2011; 8: 1061-1071 Life Sciences 2015; 135: 43-48 J Urol 2007; 177: 1071-1077 Int Urol Nephrol 2009; 41: 287-292 Eur Urol 2007; 51: 1717-1723 J Urol 2008; 180: 1228-1234 Eur Urol 2009; 56: 727-735 J Urol 2007; 177: 1401-1407

  The present invention is highly safe for strong tonicity, for improving sexual function, for improving menopausal symptoms, for improving nourishment, for improving vitality, for improving erectile dysfunction, for enhancing cavernous relaxation, which comprises a naturally derived component as an active ingredient. For the purpose of providing a composition for improving prostate hypertrophy, for treating urination disorder, for improving blood flow, for improving blood pressure, for improving pulmonary hypertension, for inhibiting PDE5, for promoting cGMP increase or for suppressing cGMP degradation Do.

  As a result of intensive studies to achieve the above object, the present inventors have found that echinacea and its components chicory acid, altepillin C, quebra pedra, sedro, and marcella have PDE5 inhibitory action, and It has been found that, in combination with gunectin C or a bee cub, significant action to elevate cGMP levels can be obtained.

  The present invention has been completed based on these findings and has been repeatedly studied, and provides the following composition and the like.

Item 1. Tonic comprising at least one member selected from the group consisting of echinacea or an extract thereof, chicoric acid, altepillin C, kevra pedra or an extract thereof, sedro or an extract thereof, and marcella or an extract thereof as an active ingredient Use for strong semen, sexual function improvement, men's menopausal symptom amelioration, nourishment tonic, vitality improvement, erectile dysfunction improvement, cancellous body relaxation enhancement, prostatic hypertrophy improvement, urination disorder improvement, blood flow improvement, A composition for improving blood pressure, for improving pulmonary hypertension, for inhibiting PDE5, for promoting cGMP elevation, or for inhibiting cGMP degradation.
Item 2. Item 2. The composition according to item 1, further comprising at least one selected from the group consisting of gnetum or an extract thereof, and gnetin C.
Item 3. Item 3. The composition according to item 1 or 2, further comprising a bee cub or an extract thereof.
Item 4. Item 4. The composition according to any one of Items 1 to 3, which is a cosmetic, a food and drink, a medicine, or a quasi-drug.
Item 5. At least one effective amount selected from the group consisting of echinacea or an extract thereof, chicoric acid, altepillin C, kebra pedra or an extract thereof, sedro or an extract thereof, and marsella or an extract thereof; Treatment process, tonic and physical activity, sexual function improvement, men's menopausal symptom improvement, nourishment tonic, vitality improvement, erectile dysfunction improvement, cavernous body relaxation enhancement, prostate hypertrophy improvement, urination disorder improvement, blood flow improvement, blood pressure improvement, lung A method for improving hypertension, inhibiting PDE5, promoting cGMP elevation or inhibiting cGMP degradation.
Item 6. 6. The method according to item 5, further comprising administering at least one effective amount selected from the group consisting of gnetum or an extract thereof and gnetin C.
Item 7. 7. The method according to item 5 or 6, further comprising administering an effective amount of a bee child or an extract thereof.
Item 8. Use for tonic strength, improvement of sexual function, improvement of men's menopausal symptoms, improvement of nourishment, energy improvement, improvement of erectile dysfunction, enhancement of cavernous relaxation, improvement of prostatic hyperplasia, improvement of urination disorder, improvement of blood flow Echinacea or an extract thereof, chicoric acid, artepilin C, kebra pedra or an extract thereof in the preparation of a composition for improving blood pressure, for improving pulmonary hypertension, for suppressing PDE5, for promoting cGMP elevation or for suppressing cGMP degradation At least one use selected from the group consisting of Sedro or an extract thereof, and Marcella or an extract thereof.
Item 9. 11. The use according to item 8, further using at least one selected from the group consisting of gnetum or an extract thereof and gnetin C.
Item 10. Item 10. The use according to Item 8 or 9, further using a bee child or an extract thereof.
Item 11. Item 11. The use according to any one of Items 8 to 10, wherein the composition is a cosmetic, a food and drink, a medicine, or a quasi-drug.

  Echinacea and its components chicoric acid, artepilin C, kebra pedra, sedro, and marsella have a PDE5 inhibitory action, so they are used for tonicity, for improving sexual function, for improving menopausal symptoms, for nourishing menstruation, For vitality improvement, erectile dysfunction improvement, cavernous body relaxation enhancement, for prostate hypertrophy improvement, for urination disorder improvement, for blood flow improvement, for blood pressure improvement, for pulmonary hypertension improvement, for PDE5 inhibition, for cGMP increase promotion or It is useful as an active ingredient of a composition for suppressing cGMP degradation. Moreover, they are highly safe because they are components of natural origin.

  In addition, it is known that a combination effect of a PDE5 inhibitor and a sirtuin activator provides a synergistic effect on the increase of cGMP levels, and therefore, it is known to use gunetin C having excellent sirtuin activation activity and gnetum containing the same. It is expected that significant synergy will be obtained by using in combination with the above components.

  Furthermore, since blood sphingosine 1-phosphate is known to elevate cGMP through NO production, significant cGMP levels can be obtained by using a bee offspring capable of increasing sphingosine 1-phosphate together with the above components. It is expected that a rising effect will be obtained.

It is a graph which shows the blood level of sphingosine monophosphate before and after administration of a bee child (subject 1). It is a graph which shows the blood level of sphingosine monophosphate before and after administration of a bee child (subject 2).

  Hereinafter, the present invention will be described in detail.

  In the present specification, the term "comprise" also includes the meaning of "essentially consist of" and the meaning of "consist of".

  The invention of the present invention for the treatment of tonicity, improvement of sexual function, improvement of menopausal symptoms, improvement of nourishment, energy improvement, improvement of erectile dysfunction, enhancement of cavernous relaxation, improvement of prostatic hyperplasia, improvement of urination disorder, blood The composition for flow improvement, blood pressure improvement, pulmonary hypertension improvement, PDE5 inhibition, cGMP elevation promotion or cGMP degradation suppression is echinacea or its extract, chicoric acid, artepilin C, kebra pedra or its extract It is characterized in that at least one selected from the group consisting of Sedro or its extract and Marcella or its extract (hereinafter sometimes referred to as “component A”) is used as an active ingredient.

  Echinacea (murasakibarengiku, scientific name: Echinacea purpurea) is a perennial plant belonging to the family Asteraceae, the genus Murasakibarengiku. Echinacea is a type of herb and is thought to have a protective effect against colds, influenza, etc. by enhancing immunity.

  Kevla pedra (Phyllanthus niruri) is a kind of herb and is considered to have therapeutic effects on stomach related pain in addition to jaundice and hepatitis in Asia.

  Sedro (scientific name: Cedrela fissilis) is a tree belonging to the family Cephalidae, and is native to tropical America.

  Marsella (Masera, Masera da Terra, Scientific name: Egletes viscosa) belongs to the family Asteraceae and is an annual herb distributed in tropical America. As a physiologically active function, anti-dermatitis, anti-inflammatory, anti-allergy etc. have been reported.

  In the present invention, a part or the whole of the above-mentioned plant (that is, Echinacea, Kevra pedra, sedro and marsella) can be used as it is, or an extract of a part or the whole of the plant can be used. . Examples of part of the plant include leaves, bark, stems, stems, fruits, seeds, flowers, roots and the like, and these can be used alone or in combination of plural sites. Moreover, as said plant, the thing of any state, such as a raw thing, a dried thing, a cut | judged or crushed thing, can be used.

  It does not restrict | limit especially as an extraction method at the time of manufacturing the extract of the said plant, For example, the method of carrying out normal temperature or heat extraction using an extraction solvent, the supercritical extraction method by carbon dioxide etc., etc. are mentioned. As such an extraction solvent, water, an organic solvent or a water-containing organic solvent can be used. As the organic solvent, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 C1-C5 lower alcohols such as -methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-pentanol, etc. ethers such as diethyl ether, methyl acetate, Examples thereof include esters such as ethyl acetate, ketones such as acetone, and organic acids such as acetic acid, glacial acetic acid and propionic acid. These organic solvents can be used singly or in combination of two or more. The extraction solvent is preferably water, hydrous ethanol and ethanol. The ethanol concentration of the hydrous ethanol is usually 20 to 90% by volume, preferably 40 to 80% by volume.

  The extraction temperature can be set appropriately, and in the case of normal temperature extraction, it is usually 10 to 50 ° C., preferably 20 to 40 ° C., and in the case of heat extraction, it is usually 40 to 100 ° C., preferably 70 to 100 ° C. is there. The extraction time in the case of using an extraction solvent can be set appropriately, and is usually 20 minutes to 5 days, preferably 1 hour to 24 hours.

  The recovered extract can be used as it is, and if necessary, ultrafiltration, molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, affinity chromatography, high performance liquid chromatography (HPLC) ), Dialysis methods, combinations thereof and the like.

  As the extract of the above-mentioned plant, the solvent of the extract is removed by the recovered extract (including those further purified as necessary), the concentrated solution obtained by concentrating the extract, lyophilization, spray drying, etc. Solids and the like. Here, concentration of the extract, lyophilization and spray drying can be carried out according to a conventional method.

  Cicholic acid (cichoric acid) may be used whether it is a home-made product or a commercially available product. Here, the method of preparing chicory acid in-house is not particularly limited, and examples thereof include a method of extracting from chicory acid-containing plants and natural products, and a method of chemical synthesis. As a plant containing chicoric acid, for example, Echinacea can be mentioned. Extraction of chicoric acid from Echinacea can be performed, for example, using the extraction method described above. It is possible to use either chicory acid which is not in the isolated or purified state (crude extract) and in isolated or purified state.

  Artepillin C (artepillin C) can be used whether it is a home-made product or a commercially available product. Here, the method for preparing altepilin C in-house is not particularly limited, and examples thereof include a method for extracting from a plant and a natural product containing altepyrin C, and a method for chemical synthesis. The plant containing artepilin C is not particularly limited, and includes, for example, plants of the family Asteraceae such as Baccaris durakuncrifolia. In addition, natural products are not particularly limited, and examples thereof include propolis containing altepyrin C. As propolis containing artepyrin C, as long as it contains artepyrin C, materials derived from any origin and plant can be used, such as Brazil, China, European countries, Oceania, America and the like. Extraction of artepillin C from the Asteraceae and propolis can be performed, for example, using the above-mentioned extraction method. Artepilin C which is not in the isolated or purified state (crude extract) and in the isolated or purified state can be used.

  Chicory acid and artepillin C can be used in free or salt form. Examples of salts include inorganic salts such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine, ornithine and arginine, and ammonium Salt is mentioned. The salt may be an acid addition salt, and specific examples of such a salt include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, Organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, etc. with acidic amino acids such as aspartic acid and glutamic acid Acid addition salts may be mentioned. In addition, chicoric acid and artepillin C also include hydrates, solvates, crystal polymorphs and the like.

  Echinacea, Kevla Pedra, Sedro, Marcella, chicoric acid and Artepillin C have PDE5 inhibitory activity, so they have strong tonicity, sexual function improvement, men's menopausal symptom improvement, nourishment tonic, vitality improvement , Ectopic dysfunction improvement action, cavernous relaxation enhancement action, prostatic hypertrophy improvement action, urination disorder improvement action, blood flow improvement action, blood pressure improvement action, pulmonary hypertension improvement action, cGMP elevation promotion action and cGMP degradation suppression action There is expected.

  The composition of the present invention is characterized by further including at least one selected from the group consisting of gnetum or an extract thereof and gnetin C (hereinafter sometimes referred to as “component B”).

  Gnetum (aka Merinjo, scientific name Gnetum gnemon L., English name Gnemon tree, Indonesian names Melinjo, Belinjo) is a plant of the family Gnetum and is grown in Southeast Asia.

  The site to be used in the present invention is not particularly limited, and examples thereof include fruits (or seeds), flowers, leaves and the like, preferably seeds. In addition, processed products can also be used as gnetum, and examples of such processing include drying, heat drying, cutting, grinding and the like.

  As used herein, Gunnetum seeds refer to those consisting of a seed coat, a thin coat, and an embryo / endosperm (endosperm). As the shape and form of the gunnetum seed, any shape and form can be used as long as the effect of the present invention can be obtained, and the major axis: about 1.3 to 2.3 cm, the minor axis: about 0.6 to 1.3 cm And peanut-like shapes are preferred. As the gnetum seed, any substance containing gnetum seed can be used in the present invention, and examples thereof include gnetum fruit which is a form having a skin of gnetum seed.

  In the present invention, the seeds of "Gnetum" also include processed ones, and examples of processed products of such Gnetsum seeds include those in a dried state (by sun-drying etc.), those in a heat-dried state, etc. Be Moreover, as a gnetum seed, the thing of the intact state which is not cut | disconnected and grind | pulverized, and the processed thing of a sliced and ground gnetum seed can be used. In the present invention, it is also possible to use embryo / endosperm (endosperm) of Gunnetum seed, or a processed product of Gunnetum seed only with seed coat.

  The method for producing the extract of gnetum in the present invention is not particularly limited, and can be carried out using, for example, the above-mentioned extraction method, the extraction method described in JP-A-2013-82701, or the like.

  Gunnetin C can be used either in-house preparation or commercially available. Here, as a method for preparing Gunetin C in-house, it is not particularly limited, and a method of extracting from a plant containing Gunetin C, a method of causing a microorganism to produce (eg, Adil E Bala et al., "Antifungal activity of resveratrol oligomers from Cyphostemma crotalarioides ", Pesticide Science, Vol. 55, Issue 2, Pages 206-208, etc.) and chemically synthesized methods.

  Examples of plants containing gunetin C include, but are not particularly limited to, preferably plants belonging to the family Gnetum (Ibrahim Iliya et al., “Stilbenoids from the stem of Gnetum latifolium (Gnetaceae)”, Phytochemistry, 2002 Dec; 61 (8): 959-61; Ibrahim Iliya et al., "Dimeric Stylenes from Stem Lianas of Gnetum Africanum", HeteroCycles, VOL. 57; NO. 6; PAGE. 1057-1062 (2002)).

  Specifically, Gnetum latifolium, Gnetum Africanum and Gnetum gnemon (Gnetum) belonging to the Gnetum family can be exemplified, with preference given to Gnetum. The site of the plant used is not limited as long as it is a site containing a large amount of gunetin C, such as fruits (or seeds), flowers, leaves, etc., preferably fruits (or seeds) and more preferably real endosperm.

  Here, when gunetin C is extracted from plants, the method is not particularly limited, and, for example, the extraction method described in Japanese Patent Application Laid-Open No. 2013-82701 can be used. Gunetin C can be used either in an isolated or purified state (crude extract), or in an isolated or purified state.

  Gunetin C can be used in free or salt form. Salts include those mentioned above. In addition, gunetin C includes its hydrate, solvation, crystal polymorph and the like.

  Activating sirtuin upregulates the NO-cGMP signaling pathway and raises cGMP levels. Then, it is known that a synergistic effect can be obtained in the increase of cGMP levels by using a PDE5 inhibitor and a sirtuin activator in combination (J Sex Med 2011; 8: 1061-1071). Therefore, it is expected that a remarkable synergy (action to elevate cGMP levels) can be exerted by using gunetum having an excellent sirtuin activating action or its extract and its component gunetin C in combination with the above component A.

  The composition of the present invention is characterized by further comprising bee cub or its extract (hereinafter sometimes referred to as “component C”).

  Here, the term "bey cub" means bee larvae and pupa. The type of bee is not particularly limited, and known bees such as Japanese honeybees, honeybees such as western honeybees, African bee honeybees, wasps (including cross hornets), green wasps and bumblebees can be widely used. It is preferably a honeybee, more preferably a honeybee from the viewpoint of easy availability. The male and the female are preferably male or female.

  The larvae and pupa are not particularly limited as long as they are hatched from eggs. Among them, preferably used are the bee larvae and pupa which are 16 to 23 days after hatching, and more preferably the bee larvae and pupa after 18 to 21 days after hatching.

  The bee cub is accumulating nutrients in the body. In particular, honeybee males have long been used as materials for traditional Chinese medicine, and contain various amino acids including essential amino acids in a well-balanced manner, and vitamins such as proteins, lipids, saccharides, vitamin Bs, folic acid, nicotinic acid, pantothenic acid, etc. And minerals such as zinc and selenium (selenium). Antibacterial action, anti-inflammatory action, antiviral action, antiprotozoal action, tinnitus elimination action and the like are known as physiological activities and pharmacological actions of bee offspring.

  The bee cubs of the present invention are used in the raw state and in the processed state of the live bee cubs. The processed product of the bee child, specifically, the crushed product of the bee child (raw or dried), the dried product of the bee child (raw or crushed), the bee child (raw or dried) The thing etc. which heat-processed the thing or a grinding | pulverization thing are mentioned. In the present invention, as the bee cub, preferably, it is a dried powder of bee cub prepared by drying the bee cub (raw) and then grinding it.

  In the present invention, the term "bee cub" means, unless otherwise stated, a processed product obtained by subjecting the bee cub to drying, grinding or heat treatment, as well as a bee cub and The processed product is treated with a proteolytic enzyme (peptidase).

  As a drying method, there can be used known methods employed in general food processing such as through-air drying, natural drying such as sun drying, forced drying in which heating and drying are performed by electricity, and lyophilization. Preferably, it is freeze-dried. The drying time is not particularly limited. For example, in the case of natural drying such as ventilation or sun drying, about 3 days, in the case of forced drying by heating with electricity, etc., 1 to 3 days at about 50 ° C. The degree can be mentioned. In general, it is preferable to dry so that the water content is 10% by mass or less, preferably 5% by mass or less. In the case where it is difficult to reduce the water content to 10% by mass or less as in the case of natural drying such as ventilation or sun drying, a process of lowering the moisture further by a freeze dryer may be performed thereafter.

  The grinding treatment (powdering treatment) may be performed using a known method such as a method of grinding using a grinder (mill), a method of grinding using a stone mill, and the like.

  The method for heating the bee is not particularly limited, and preferably includes a method of heat treatment at 70 to 120 ° C. The bee cub (including raw, dried and ground products) can be conveniently added to boiling water and heat treated, and in order to avoid elution of active ingredients such as various vitamins and amino acids as much as possible, As the heat treatment, a method of steaming bee-child is preferably used.

  The proteolytic enzyme treatment of the bee offspring can be carried out, for example, according to the description of JP-A-2009-159997. The bee offspring is treated with a proteolytic enzyme to reduce the molecular weight of the protein contained in the bee offspring, and the enzyme-treated product (allergenized enzyme-treated product) in which the allergic reaction caused by the protein is suppressed It is expected to be obtained.

  It does not restrict | limit especially as a manufacturing method of the extract of a bee-child in this invention, For example, it can carry out by the extraction method etc. which are mentioned above.

  The inventors of the present invention have found that the test of feeding the bee offspring to humans shows that the effect on men's menopausal symptoms is improved, the anti-fatigue effect, and the anti-stress effect without increasing the testosterone level in the bee offspring. In other words, it has been confirmed that it exerts a strong sexual activity. And in the test example mentioned later, it is shown that it has an action to increase sphingosine 1-phosphate in blood to bee offspring, and the action mechanism of the strong sperm action of bee offspring is blood sphingosine 1 phosphate It is presumed to be due to the increasing action of the acid.

  Blood sphingosine monophosphate is known to produce NO from vascular endothelial cells and neurons (Rikitake Y et al., Arterioscler Thromb Vasc Biol 2002; 22 (1): 108-14.), This NO Activates guanylate cyclase in the corpus cavernosum smooth muscle cells to elevate cGMP (Kimura K et al., Int J Urology 2004; 11: 321-325). Therefore, it is expected that a significant increase in cGMP levels can be exerted by using a bee cub or an extract thereof capable of increasing sphingosine 1-phosphate together with the component A.

  The composition of the present invention is a cosmetic, a food and drink (in particular, a food and drink for the purpose of health, health maintenance, improvement, etc. (eg, health food, functional food, nutritional composition, nutritional supplement, supplement) (Food for health, food for specified health, nutritive function food, or food with functional indication)), quasi-drugs and medicines (especially oral medicine). In addition, the composition of the present invention has a strong tonic effect, an action to improve sexual function, an action to improve men's menopausal symptoms, an action to improve nourishment, an action to improve vitality, an action to improve erectile dysfunction, an action to enhance cavernous relaxation, an action to improve prostate hypertrophy. It also includes the meaning of additives imparting urination disorder improvement action, blood flow improvement action, blood pressure improvement action, pulmonary hypertension improvement action, PDE inhibition action, cGMP elevation promotion action and cGMP degradation inhibition action.

  In the above cosmetic products, in addition to the components A, B and C, components usually used in cosmetics, such as skin lightening agents, moisturizers, antioxidants, oil components, ultraviolet light absorbers, surfactants, thickeners, alcohols Classes, powder components, coloring materials, aqueous components, water, various skin nutrients and the like can be appropriately blended as required.

  The content of component A in the cosmetic is usually 0.001 to 1.0% by mass, preferably 0.01 to 1.0% by mass. When the cosmetic contains component B, the content is usually 0.001 to 1.0% by mass, preferably 0.01 to 1.0% by mass. When the cosmetic contains component C, the content is usually 0.001 to 1.0% by mass, preferably 0.01 to 1.0% by mass.

  The cosmetics include all cosmetics applied to the skin of animals (including humans), mucous membranes, body hair, hair, scalp, nails, teeth, skins, lips and the like.

  The dosage form of cosmetics is a wide range such as aqueous solution type, solubilization type, emulsion type, powder type, oil liquid type, gel type, ointment type, aerosol type, water-oil two-layer system, water-oil-powder three-layer system, etc. It can take a dosage form.

  The use of cosmetics is also arbitrary, and for example, in the case of basic cosmetics, there may be mentioned face wash, lotion, milk, cream, gel, essence, essence, pack, mask etc., and in the case of makeup cosmetics, foundation, Lipsticks, blushers, eye shadows, eyeliners, mascaras, etc. may be mentioned, and in the case of nail cosmetics, manicures, base coats, top coats, light removal liquids etc. may be mentioned, others, cleansers, dentures or dentifrices , Mouthwash, Massage agent, Cleansing agent, After shave lotion, Pre shave lotion, Shaving cream, Body soap, Soap, Shampoo, Rinse, Hair treatment, Hair styling agent, Hair tonic agent, Hair restorer, Antiperspirant, Bath agent etc. Can be mentioned.

  In the above food and drink, if necessary, excipients, brighteners, minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, Disintegrants, lubricants, colorants, flavors, stabilizers, preservatives, sustained release regulators, surfactants, solubilizers, wetting agents and the like can be blended.

  Food and drink include any food and drink that animals (including humans) can consume. The type of food and drink is not particularly limited. For example, beverages (soft drinks such as coffee, juice and tea drinks, milk drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, sake such as sake, western liquor, and fruit liquor) Spreads (custard cream etc.) Pastes (fruit paste etc) Western-style confectionery (chocolate, donut, pie, cream puff, gum, jelly, candy, cookie, cake, pudding etc); Japanese confectionery (daifuku, sweet potato , Sesame head, castella, anmitsu, oat, etc .; Frozen foods (ice cream, ice candy, sherbet etc.); Foods (curry, beef bowl, risotto, miso soup, miso soup, soup, meat sauce, pasta, pickles, jam etc); Seasoning And the like (dressing, sprinkle, umami seasoning, soup ingredients, etc.).

  The dosage unit form for use as a supplement is not particularly limited and can be appropriately selected, and examples thereof include tablets, capsules, granules, solutions, powders and the like.

  The content of component A in food and drink is usually 0.5 to 70% by mass, preferably 5 to 35% by mass. When the food and drink contain the component B, the content is usually 0.5 to 70% by mass, preferably 5 to 35% by mass. When the food and drink contain the component C, the content is usually 0.5 to 70% by mass, preferably 5 to 35% by mass.

  The intake amount of the food and drink can be appropriately set according to various conditions such as the weight, age, sex and symptoms of the user.

  Only the components A, B and C can be used in the above-mentioned pharmaceutical products, or they can be used in combination with other pharmaceutical ingredients described in the Japanese Pharmacopoeia, such as vitamins and crude drugs.

  When the composition of the present invention is prepared as a pharmaceutical, the components A, B and C together with a nontoxic carrier, diluent or excipient acceptable in pharmaceuticals are used as tablets (solid tablets, sugar-coated tablets, effervescent tablets, films Prepared in the form of coated tablets, chewable tablets, troches, etc., capsules, pills, powders (powders), fine granules, granules, solutions, suspensions, emulsions, syrups, pastes, etc. It can be made into a preparation for oral use.

  The content of component A in the medicament is usually 0.5 to 70% by mass, preferably 5 to 35% by mass. When the pharmaceutical composition contains component B, the content is usually 0.5 to 70% by mass, preferably 5 to 35% by mass. When the pharmaceutical contains component C, the content is usually 0.5 to 70% by mass, preferably 5 to 35% by mass.

  The dose of the pharmaceutical can be determined appropriately according to various conditions such as the weight, age, sex and symptoms of the patient.

  The pharmaceuticals and cosmetics of the present invention also include quasi drugs.

  The composition of the present invention described above is to be applied to mammals including humans (preferably humans, particularly males).

  The cosmetics, food and drink, quasi-drugs and medicines of the present invention have strong tonicity, sexual function improving action, male menopausal symptom improving action, nourishing tonic action, vitality improving action, erectile dysfunction improving action, cancellous body relaxation enhancing action It has an action to improve prostatic hyperplasia, an action to improve urination disorder, an action to improve blood flow, an action to improve blood pressure, an action to improve pulmonary hypertension, an action to inhibit PDE5, an action to promote cGMP elevation or a cGMP degradation inhibitory action. In addition, the cosmetics, food and drink, quasi-drugs and medicines of the present invention have high safety because they use naturally-derived components as active ingredients.

  Hereinafter, the present invention will be described in detail by way of examples. However, the present invention is not limited to these examples.

Materials Chicory acid (manufactured by Extrasynthese, 4987S) was purchased from Funakoshi Co., Ltd., and artepillin C (propolis-derived, 016-19131) and gunetin C standard product (070-06141) were purchased from Wako Pure Chemical Industries, Ltd. The Echinacea purpurea extract used what was extracted with the hot water of 90 degreeC or more. The extract of Kebla pedra extract, Sedro extract, and Marcella extract was used after being stirred with hot water of 90 ° C. or more for 1 hour.

  As the bee snail powder, as described in the example of JP-A-2016-077259, a product obtained by enzymatically treating a male bee larva and a pupa that has passed 19 to 20 days after hatching was used.

  As isoflavone, Soya flavone E (manufactured by Fuji Oil Co., Ltd.) was used.

Test Example 1
Using PDE5A Assay Kit (BPS Bioscience), the inhibitory activity of PDE5 of various materials was evaluated using fluorescence polarization. Evaluation was performed according to the instruction manual attached to the kit, but customized the dose for the 384-well plate. Each measurement was performed using Sildenafil citrate (TOCRIS) as a positive control, setting the concentration of PDE 5 to about 18 ng / ml so that the IC ₅₀ would be 30 nM. The PDE5 inhibitory activities of various materials evaluated under these conditions are shown in Tables 1 and 2.

  From Table 1, it has become clear in an in vitro test that echinacea and its component chicoric acid inhibit PDE5. It is known that PDE5 inhibition contributes to strong fertility through maintenance of cGMP, suggesting that echinacea and its component chicory acid are useful as an active ingredient of the composition of the present invention.

  From Table 2, it has become clear in an in vitro test that Artepilin C, Kevra Pedra, Sedro and Marcela inhibit PDE5. Since PDE5 inhibition is known to contribute to strong fertility through maintenance of cGMP, it is suggested that Artepillin C, Quebra pedra, Sedro and Marcella are useful as active ingredients of the composition of the present invention. The

Test example 2
In two male subjects, 1,080 mg of bee-child powder was consumed daily for one week, and blood was collected before and after bee-child drinking. Serum was separated from the collected blood, and sphingosine 1-phosphate contained in the serum was measured using Sphingosine 1 phosphate ELISA kit (Wako Pure Chemical Industries, Ltd.).

  The results are shown in FIGS. 1 and 2. It has been shown in human studies that sphingosine monophosphate (S1P) in the blood increases when the bee offspring is consumed. Blood sphingosine monophosphate raises cGMP through NO production to exert a strong spermatogenic action. Therefore, it was suggested that a synergistic action can be obtained by using it in combination with the above-mentioned components that contribute to the inhibition of cGMP degradation.

Test Example 3
Using FLUOR DE LYS SIRT1 fluorometric drug discovery assay kit (Enzo life science), the improvement or inhibition of the deacetylation activity of p53 lysine 382 was measured. Kit-associated transresveratrol was evaluated as a positive control for activation and Suramin sodium as a positive control for inhibition. With regard to activation, at a high concentration (67 μg / ml), the degree of activation (how many times activity without compound) and EC ₂₀₀ (concentration that gives 200% of activity without compound) Two indicators were used to assess its strength. The measurement results of activation of the sirtuin enzyme are shown in Table 3.

Although it has been already known that gunetin C and trans resveratrol activate sirtuin enzymes, gunetin C is approximately twice as active and approximately ₂₀₀ EC 1 ₂₀₀ compared to trans resveratrol. In vitro studies have revealed that they show potent activity.

  Because it is known that cGMP is synergistically increased when a PDE5 inhibitor (Vardenafil) and a SIRT1 activator (transresveratrol) are used in combination (J Sex Med 2011; 8: 1061-1071). It was suggested that a synergistic cGMP raising effect can be obtained by using the above component having an inhibitory effect in combination with gunetin C or a gunnet containing the same.

Prescription Examples The following are formulation examples of the present invention.

Preparation Example 1
Echinacea purpura was extracted with hot water, concentrated, and 10% by mass of dextrin was added. It heat-sterilized, powdered by spray-drying, and after sieving, it filled, and it was set as the Echinacea extract.

Preparation Example 2
According to the description of the example of JP-A-2016-077259, an enzyme-treated bee-koko powder was obtained by enzymatically treating the larva and pupa of 19 to 20 days after hatching.

Preparation Example 3
According to the description in paragraph [0024] of JP-A-2009-013123, the crushed dried fruit of melinjo is immersed in water-containing ethanol at room temperature, and the obtained extract is concentrated under reduced pressure to contain 63.2% by mass of solid content I got a Merinjo extract. To 50 g of the obtained extract, 2.3 g of an aqueous solution containing 10% by mass of dextrin was added and stirred until uniform. Thereafter, lyophilization was performed to obtain a Merinjo extract powder containing 227 mM (20% by mass) of resveratrols.

Prescription example 1
According to the following formulation, a hard capsule containing 125 mg of each powder of Preparation Example 1-3 was prepared per tablet.
1 tablet 400 mg Echinacea extract 125 mg
Enzyme-treated Beetle powder 125 mg
Melinjo extract powder 125 mg
Dextrin 17 mg
Silicon dioxide 8 mg

Prescription example 2
According to the following formulation, a soft capsule containing 62.5 mg of each powder of Preparation Example 1-3 was prepared per tablet.
1 tablet 490 mg Echinacea extract 62.5 mg
Enzyme-treated honeybee powder 62.5 mg
Melinjo extract powder 62.5 mg
Edible fat 120 mg
Plant lecithin (derived from soybeans) 8 mg
Beeswax 4.5 mg
Gelatin (coating agent) 116.3 mg
Glycerin (coating agent) 46.5 mg
Caramel pigment (coating agent) 7.2 mg

Prescription example 3
According to the following formulation, tablets containing 91.0 mg of each powder of Preparation Example 1-3 were prepared per tablet.
1 tablet 355 mg Echinacea extract 91.0 mg
Enzyme-treated Beetle powder 91.0 mg
Melinjo extract powder 91.0 mg
Cellulose 71.3 mg
Silicon dioxide 7.1 mg
Calcium stearate 3.6 mg

Prescription example 4
According to the following formulation, a drink containing 1000.0 mg of each powder of Preparation Example 1-3 was prepared.
Echinacea extract 1000.0 mg in a volume of 100 ml
Enzyme-treated Beetle powder 1000.0 mg
Melinjo extract powder 1000.0 mg
Erythritol 3500.0 mg
Honey 2000.0 mg
Glucose fructose sugar 1500.0 mg
Citric acid 450.0 mg
Perfume 125.0 mg
Polysaccharide thickener 100,0 mg
Sucralose 50.0 mg
Vitamin C 10.0 mg
Water 89.3 mg

Prescription example 5
A lotion was prepared according to a conventional method using the following formulation containing each powder of Preparation Example 1-3.
Echinacea extract 0.5 mass%
Enzyme-treated Beetle powder 0.5% by mass
Melinjo extract powder 0.5 mass%
Ethanol 5.0 mass%
Glycerin 4.0 mass%
1,3-butylene glycol 4.0 mass%
Citric acid QS Sodium citrate QS Purified water balance

Prescription example 6
An emulsion was prepared according to a conventional method using the following formulation containing each powder of Preparation Example 1-3.
Echinacea extract 0.5 mass%
Enzyme-treated Beetle powder 0.5% by mass
Melinjo extract powder 0.5 mass%
Squaran 12.0 mass%
Carboxyl vinyl polymer 0.1% by mass
Xanthan gum 0.2% by mass
0.1% by mass of triethanolamine
1.3-butylene glycol 5.0 mass%
Purified water residual

Prescription example 7
An external preparation having a cream form was prepared according to a conventional method according to the following formulation containing each powder of Preparation Example 1-3.
Echinacea extract 0.5 mass%
Enzyme-treated Beetle powder 0.5% by mass
Melinjo extract powder 0.5 mass%
Stearic acid 2.0 mass%
Stearyl alcohol 7.0% by mass
Reduced lanolin 2.0% by mass
Squalane 5.0 mass%
Octyl dodecanol 6.0 mass%
Polyoxyethylene oleyl ether (25E.O.) 3.0 mass%
New oil type glycerin monostearate 2.0% by mass
Propylene glycol 5.0 mass%
Purified water residual

Prescription example 8
Hard capsules, soft capsules, tablets, drinks containing the echinacea extract in the formulation example 1-7 as the active ingredient by replacing it with chicoric acid, artepillin C, kevra pedra extract, sedro extract or marsella extract Cosmetics, emulsions, and external preparations can be prepared.

Claims (4)

  Tonic comprising at least one member selected from the group consisting of echinacea or an extract thereof, chicoric acid, altepillin C, kevra pedra or an extract thereof, sedro or an extract thereof, and marcella or an extract thereof as an active ingredient Use for strong semen, sexual function improvement, men's menopausal symptom amelioration, nourishment tonic, vitality improvement, erectile dysfunction improvement, cancellous body relaxation enhancement, prostatic hypertrophy improvement, urination disorder improvement, blood flow improvement, A composition for improving blood pressure, for improving pulmonary hypertension, for inhibiting PDE5, for promoting cGMP elevation, or for inhibiting cGMP degradation.   The composition according to claim 1, further comprising at least one member selected from the group consisting of gnetum or an extract thereof, and gnetin C.   The composition according to claim 1 or 2, further comprising a bee cub or an extract thereof.   The composition according to any one of claims 1 to 3, which is a cosmetic, food and drink, medicine, or quasi-drug.

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