JP6915774B2 - Testosterone increaser - Google Patents

Description

The present invention relates to tomato-derived testosterone-increasing agents.

Testosterone, which accounts for 95% of male hormones, is secreted from the testes and has a powerful function of building bones and muscles as well as male gonad function, and even females make it in the ovaries. It also affects the brain and is involved in energy and cognitive function. Testosterone is known to decrease with aging, and a symptomatology called male menopause appears in which not only gonad function but also memory and motivation decline. Menopause tends to be too late as it progresses slowly. Androgens are reduced by stress. In a super-aging stress society, it is desired to strengthen male hormones with foods and the like to prevent the decrease of male hormones in order to solve this problem.

The main raw material for testosterone biosynthesis is "cholesterol", which is synthesized through a complicated process by various components such as vitamins, various minerals such as zinc, essential amino acids, and blood circulation promoting components such as arginine. Therefore, for testosterone biosynthesis, it is most effective to consciously supplement nutrients called "coenzymes" such as minerals and vitamins that cannot be easily taken in a normal diet.

Patent Document 1 describes a testosterone increasing agent containing vitamin K as an active ingredient, and describes that vitamin K1 is contained in tomatoes in addition to green perilla, egoma, moroheiya, parsley, and garland chrysanthemum. Has been done.

However, according to Non-Patent Document 1, the content of vitamin K per 100 g of food is 850 μg for parsley, 690 μg for shiso, 640 μg for moroheiya, and 460 μg for garland chrysanthemum (boiled), whereas it is 4 μg for tomato. When tomatoes are used, the effect of vitamin K cannot be expected unless they are purified so that the content of vitamin K is high.

Further, in Patent Document 2, 2-methyl-1,3-propanediol extract of tomato fruit increases the concentration of active TGFβ-1 in the skin and promotes the proliferation of fibroblasts, thereby exhibiting an anti-aging effect. It is described to play.
Patent Document 3 describes that foods and drinks containing a water-insoluble component derived from tomato fruit and alanine have an effect of reducing blood alcohol concentration.
Patent Document 4 describes that a tomato-derived composition containing a water-soluble component derived from tomato fruit and substantially free of lycopene is useful as an antithrombotic agent.

However, the relationship between the dry powder of tomato, the water-soluble component derived from tomato fruit, and the testosterone-increasing action has not been reported so far.

Japanese Patent No. 5110478 (Claim 1, paragraph 0019) Japanese Patent No. 5511284 (claims 1 to 3, paragraph 0001) Japanese Patent No. 5801515 (Claims 1, 8-11) Japanese Patent No. 4975902 (claims 1 to 3)

Vitamin K-rich foods and vitamin K content list of foods, Internet <URL: http://www.eiyoukeisan.com/calorie/nut_list/vitamin_k.html>

An object of the present invention is to provide a highly safe testosterone increasing agent.

In order to solve the above problems, the present inventors have found that a decrease in testosterone can be suppressed by ingesting a dry powder, an extract or a processed product thereof of tomato prepared from tomatoes whose safety has been established. , The present invention has been completed.
That is, the gist of the present invention is as follows.
(1) A testosterone increasing agent containing a dry powder of tomato, an extract or a processed product thereof.
(2) The testosterone increasing agent according to (1) above, which contains a water-soluble component derived from tomato fruit.
(3) The testosterone increasing agent according to (2) above, which does not substantially contain lycopene.
(4) The testosterone increasing agent according to (2) above, which does not substantially contain a water-insoluble component derived from tomato fruit.
(5) A testosterone-increasing agent containing a water-soluble component derived from tomato fruit and substantially free of lycopene.
(6) The testosterone increasing agent according to (5) above, which does not substantially contain a water-insoluble component derived from tomato fruit.
(7) The testosterone increasing agent according to any one of (1) to (6) above, which is used as a food.

According to the present invention, it is possible to provide a highly safe testosterone increasing agent.

FIG. 1 shows the amount of testosterone secreted from primary testis cultured cells in a testis disorder model. FIG. 2 shows the amount of testosterone secreted from primary testis cultured cells in a chronic stress model. FIG. 3 shows the measurement results of PAO activity. FIG. 4 shows the amount of testosterone secreted from primary testis cultured cells in a chronic stress model. FIG. 5 shows testicular glutathione peroxidase activity in a chronic stress model. FIG. 6 shows the amount of testosterone secreted from primary testis cultured cells in a chronic stress model.

In the present invention, as tomato (Solanum lycopersicum), a dry powder of fruit, an extract or a processed product thereof is usually used. As the tomato fruit used as a raw material, it is preferable to use one having high PAO (potential anti-oxidant) activity. Such tomatoes can be obtained by cultivating them by a method of supplying a very small amount of medium frequently and in a small amount. The amount of medium per strain in the ultra-small medium frequent small amount feeding method is usually less than 1000 ml, preferably 200 to 500 ml.

Examples of the dry powder of tomato fruit include a powder obtained by pureing the whole tomato fruit, filtering it to remove insoluble matter, and then drying the tomato fruit, and then drying the tomato fruit by a conventional method. Examples include powder obtained by crushing and dry powder of an extract.

Solvents used to obtain tomato extracts include water; alcohols such as methanol, ethanol, propanol, butanol; esters such as acetate such as ethyl acetate; ethers such as ethyl ether, dioxane; ketones such as ketones. Acetone and the like can be mentioned. When the extract is once removed from the solvent and used as a dried product, any of the above-mentioned solvents can be used alone or in combination. On the other hand, when the extract is used in a state of being dissolved in a solvent, it is necessary to use a solvent that does not have a harmful effect on the human body, and in this case, it is preferable to use water, ethanol or a mixture thereof. .. At the time of extraction, the tomato fruit can be used as it is, or it can be crushed or crushed after drying to enhance the contact with the solvent.

Extract with 2-4 L of solvent per kg of tomato fruit. The extraction temperature is within the range of room temperature or the boiling point of the solvent under normal pressure, and the extraction time varies depending on the extraction temperature and the like, but is preferably performed at room temperature for 24 to 30 hours at the boiling point of the solvent under normal pressure. The case is 0.5 to 2 hours.

The extract thus obtained may be used by filtering it with a cloth, a stainless steel filter, a filter paper, a filter for filtration sterilization or the like to remove insoluble matter, impurities and the like, if necessary. Further, the extracted extract after filtration may be subjected to a treatment such as a spray-drying treatment, a freeze-drying treatment, or a supercritical treatment.

The dry powder, extract or processed product thereof obtained as described above can be used as it is as an active ingredient of the testosterone increasing agent of the present invention. Further, the extract or the like may be treated by various purification means such as ion exchange chromatography, gel filtration chromatography, dialysis and the like to be used as a treated product having further enhanced activity.
Further, the testosterone increasing agent of the present invention containing a dry powder of tomato, an extract or a processed product thereof may contain a water-insoluble component derived from tomato fruit such as lycopene, but for reasons such as formulation. From the point of view, the water-insoluble component derived from tomato fruit such as lycopene may be removed and used as a composition substantially free of the water-insoluble component.
Here, "substantially free of water-insoluble components derived from tomato fruits such as lycopene" does not exclude the case where they are contained as impurities to the extent that the water-insoluble components do not affect them.
The method for removing the water-insoluble component derived from tomato fruit such as lycopene is not particularly limited, but for example, a composition containing a dry powder of tomato, an extract or a processed product thereof is centrifuged and solidified. The minutes may be precipitated and removed, and the supernatant may be collected.

The testosterone increasing agent of the present invention is obtained by removing a water-insoluble component derived from tomato fruit such as lycopene from a dry powder of tomato, an extract or a processed product thereof, or a composition thereof. A composition substantially free of the above can be formulated in combination with a known food carrier or pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected as needed, but generally includes tablets, capsules, granules, fine granules, powders, liquids, syrups, suspensions, emulsions, elixirs and the like. Used as an oral preparation. In addition, the testosterone increasing agent of the present invention may be used as a parenteral agent such as an injection, a drip, a suppository, an inhalant, a transdermal absorbent, a transmucosal absorbent, a patch, and an ointment. Further, the testosterone increasing agent of the present invention is added to foods, chewing gums, beverages, etc., so-called foods for specified health use or foods with functional claims (for example, foods for increasing male hormones, foods for improving stress, foods for recovery from fatigue, etc. It can also be used as a food for preventing male menopausal disorders).

The dose of the testosterone-increasing agent of the present invention varies depending on the age, body weight, degree of disease, and route of administration of the patient. The dose is ~ 500 mg, and the number of administrations is usually 1 to 3 times a day for oral administration.

Oral preparations are prepared according to conventional methods using excipients such as starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, and inorganic salts.

In the above-mentioned preparation, in addition to the above-mentioned excipient, a binder, a disintegrant, a surfactant, a lubricant, a fluidity accelerator, a flavoring agent, a coloring agent, a fragrance and the like can be appropriately used.

Specific examples of the binder include crystalline cellulose, crystalline cellulose carmellose sodium, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and carmellose sodium. , Ethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, purulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkyl Examples thereof include methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, gum arabic, rubber arabic powder, agar, gelatin, white cellac, tragant, purified sucrose, and macrogol.

Specific examples of the disintegrant include crystalline cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partial pregelatinization. Examples include starch, hydroxypropyl starch, sodium carboxymethyl starch and tragant.

Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, and sorbitan monostearate. , Polysorbate monopalmitate, sorbitan monolaurate, polysorbate, glycerin monostearate, sodium lauryl sulfate, lauromacrogol.

Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, etc. Examples thereof include magnesium aluminometasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, braces, hydrogenated vegetable oil, and polyethylene glycol.

Specific examples of the fluidity accelerator include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

In addition, the testosterone increasing agent of the present invention may contain a flavoring agent and a coloring agent when administered as a liquid agent, a syrup agent, a suspending agent, an emulsion, or an elixir agent.
The tomato, which is a raw material for producing the testosterone increasing agent of the present invention, is edible and its safety has been established.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to the following Examples.
(Production Example 1) Preparation of tomato powder The whole tomato (Solanum lycopersicum) fruit was pureed and then dried and powdered to obtain tomato powder.
The tomato fruits used here are obtained by cultivating with a very small amount of medium and a small amount of liquid feeding method (medium amount per plant: 300 ml, medium type: coconut fruit fibers and powder dried and crushed coconut husk medium). It was obtained from Uma Healthy Co., Ltd.

(Example 1) Effect of increasing testosterone secretion by tomato powder It is known that the secretion of male hormone (testosterone) from the testis (testis) decreases due to aging and stress. Therefore, in the following tests, the effect of tomato powder on increasing testosterone secretion was examined in two model experiments using a testis disorder model and a stress model mouse.

(Test method 1) Testicular disorder model mice (ddY system, male, 7 weeks old) were divided into 3 groups, the 1st group was ingested with a normal diet (MF, oriental yeast), and no treatment was performed, the 2nd group. The group ingested a normal diet and cisplatin (2.5 mg / kg) was intraperitoneally administered, and the third group ingested a test diet containing 10% tomato powder (tomato powder obtained in Production Example 1). The group was divided into a group in which cisplatin (2.5 mg / kg) was intraperitoneally administered. Each group was set to n = 3. One week after the start of breeding, the testis was taken out and the testis cells were cultured by the primary culture method. After culturing overnight, human chorionic gonadotropin (hCG) (1U) was added as a stimulant, and the amount of testosterone secreted from the testis was quantitatively measured by the EIA method.

(Test method 2) Stress model mice (ddY system, male, 7 weeks old) were divided into 3 groups, and the 1st group was ingested with a normal diet (MF, oriental yeast) and no treatment was performed, the 2nd group. Was fed a normal diet, and the third group was fed a test diet containing 10% tomato powder (tomato powder obtained in Production Example 1). The second and third groups were subjected to restraint stress treatment on the 5th to 7th days of breeding. Restraint was placed in a plastic tube (50 ml) with many vents for about 12 hours. Each group was set to n = 3. One week after the start of breeding, the testis was taken out and the testis cells were cultured by the primary culture method. After culturing overnight, human chorionic gonadotropin (hCG) (1U) was added as a stimulant, and the amount of testosterone secreted from the testis was quantitatively measured by the immunoassay (EIA) method.

(Test results)
The results of the testicular disorder model are shown in FIG. When testicular disorders were caused, the amount of testosterone secreted from the testes was significantly lower in the group to which cisplatin was administered and fed with a normal diet than in the untreated group, and cisplatin-induced testosterone disorders occurred and testosterone. There was a decrease in secretion. On the other hand, in the group to which cisplatin was administered and tomato powder was ingested, the increase was significantly higher than that in the group to which cisplatin was ingested and the normal diet was ingested, and to almost the same level as the untreated group in which cisplatin was not administered. It was shown that testicular damage can be suppressed.

The results of the chronic stress model are shown in FIG. The amount of testosterone secreted from the testes was higher in the group that received restraint stress treatment after ingesting a normal diet (chronic stress group, group 2) than in the untreated group that did not give chronic stress (group 1). The amount of secretion was significantly reduced, and testicular dysfunction was observed. On the other hand, in the group in which tomato powder was ingested together with the restraint stress load (tomato powder intake group), testosterone was compared with the group in which restraint stress treatment was performed after ingesting a normal diet (chronic stress group, second group). It was suggested that the amount of secretion was significantly increased and that the decrease in testosterone function due to stress could be suppressed.

(effect)
With aging, the amount of androgen gradually decreases, and various symptoms called male menopause such as hypogonadism, muscle weakness, and vitality appear. Ingestion of tomato powder can be expected to prevent these menopausal symptoms. In addition, since it has the same effect on the decrease in the amount of male hormone due to chronic stress, a stress-reducing effect is also recognized.

In a super-aged and stressed society, it is first necessary to prevent muscle weakness called sarcopenia as a measure to prevent bedridden, and it is considered important to prevent androgen decrease. In women, a hormone called adrenal androgen is said to have a similar effect. Furthermore, since male hormones also affect mental activities such as motivation and vitality, ingestion of tomato powder is expected to have the effect of maintaining these QOLs.

(Reference Example 1) Effect of tomato cultivation method on PAO activity In order to examine the effect of tomato cultivation method on PAO (potential antioxidant) activity, cultivation was carried out under the following two conditions.
Test group: Cultivation by the ultra-low medium frequency small amount liquid supply method (medium amount per strain: 300 ml)
Control group: Back cultivation (medium amount per strain: 4000 ml or more)
The test plot is a cultivation in which the roots are naturally stressed by extremely limiting the root area, and it is said that the quality of tomatoes can be improved relatively easily even if the person is not an expert in tomato cultivation.
It was analyzed how much the PAO activity of tomatoes cultivated in the test plot was higher than that of tomatoes cultivated by conventional cultivation (control plot cultivation).

(1) Preparation of sample Cut tomatoes (12 each in a test group and a control group) into 4 pieces, weigh a quarter of the tomatoes, put them in a poly test tube (50 ml), and homogenize them with a polytron homogenizer. The solid content was precipitated by a centrifuge (5,000 rpm, 10 minutes). The supernatant was collected and stored at −20 ° C. Before the measurement, a part thereof was taken and filtered through a 0.45 μm filter to remove a slight amount of insoluble matter, which was used as a sample for measuring PAO activity.

(2) Measurement of PAO activity PAO activity was measured by the method described in the instruction manual using the PAO antioxidant capacity measurement kit (Nikken Zile Co., Ltd. Japan Aging Control Laboratory).
The standard substance 2 mM uric acid was appropriately diluted to prepare a dilution series. To 6 test tubes, 10 μl of a standard substance having a different concentration and 390 μl of water were added and diluted. Separately, 10 μl of the tomato sample (fruit juice) and 390 μl of water were taken in a test tube and diluted. These diluted standard substances and diluted samples were added to the microplate, 50 μl of copper reagent was added to each well, and the mixture was stirred and reacted for 3 minutes. The reaction terminator was added to each well and stirred, and the absorbance at 490 nm was measured with a microplate reader. Based on the calibration curve of the standard substance, the uric acid equivalent concentration of the sample was determined, and the copper reducing power coefficient 2189 was multiplied by this, and this was expressed as the PAO activity value.

The results are shown in FIG.
The PAO antioxidant activity was significantly different between the test group and the control group. Since the sample (fruit juice) needed to be filtered for the convenience of measurement, it was almost colorless and water-soluble, and it is presumed that the contribution of fat-soluble substances such as lycopene, carotene, and vitamin K to the PAO antioxidant activity was small. Probably due to water-soluble antioxidants.

When the PAO antioxidant activity was converted to the average weight of one tomato, a significant difference was observed between the test group and the control group. Assuming that the amount of decrease in tomato weight in the test plot was water, the average weight was multiplied by the PAO activity, and the PAO activity was high even when this amount was taken into consideration.
The maximum PAO activity of the control group was 2.16 μmol / g, whereas the maximum PAO activity of the test group was 3.07 μmol / g.
Therefore, it is preferable to use tomatoes having a PAO activity of 2.3 to 3.5 μmol / g, and more preferably tomatoes having a PAO activity of 2.5 to 3.5 μmol / g.

(Example 2) Effect of increasing androgen secretion of tomatoes (test method 1) Stress model mice (ddY system, male, 7 weeks old) were divided into 3 groups, and the first group was an untreated group and the second group. The third group was subjected to restraint stress treatment on the 5th to 7th days of breeding. Restraint was placed in a plastic tube (50 ml) with many vents for about 12 hours. The third group ingested tomato juice instead of drinking water. The tomato juice was obtained by crushing tomatoes with a commercially available mixer and then centrifuging to obtain a transparent yellow juice from which insoluble matter such as pulp was removed. It should be noted that this contains almost no lycopene. Both groups were fed a normal diet (MF, oriental yeast). Each group was set to n = 4. After 1 week, the testes were removed and testis cells were prepared by the primary culture method. After culturing overnight, the cells were washed, and the medium was collected by culturing for 3 hours, and the amount of testosterone secreted in the medium was quantitatively measured by an immunoassay (EIA) method. In addition, a part of the testis was extracted with phosphate buffer, and the method of Flohe and Gunzler et al. (Flohe, L., Gunzler, WA, Schock, HH, Glutathione peroxidase: a selenoenzyme.FEBS Lett., 32: 132- Glutathione peroxidase activity (GPx) was measured by 134 (1973)).

(Test method 2) Stress model mice (ddY system, male, 7 weeks old) were divided into 3 groups, the 1st group was an untreated group, and the 2nd and 3rd groups were on the 5th to 7th day of breeding. , Restraint stress treatment was performed. Restraint was placed in a plastic tube (50 ml) with many vents for about 12 hours. The third group was fed with a 1% aqueous vitamin C solution as drinking water. Both groups were fed a normal diet (MF, Oriental yeast). Each group was set to n = 4. After 1 week, the testes were removed and testis cells were prepared by the primary culture method. After culturing overnight, the cells were washed, and the medium was collected by culturing for 3 hours, and the amount of testosterone secreted in the medium was quantitatively measured by an immunoassay (EIA) method.

(Test results)
When the effect of ingestion of tomato juice was examined by a stress model, as shown in FIG. 4, the amount of testosterone secreted from testis cells decreased due to stress load as compared with the untreated group, but during that period, tomato juice was ingested. In the group, testosterone secretion was significantly increased, suggesting that stress-induced testicular dysfunction was suppressed. When the glutathione peroxidase activity of the testis was examined, a significant increase was observed in the fruit juice intake group as compared with the chronic stress group (Fig. 5).

In addition, when the effect of vitamin C intake was investigated using a similar stress model, as shown in FIG. 6, the amount of testosterone secreted from the testosterone cells decreased due to stress loading as compared with the untreated group, but vitamin C was added. Testosterone secretion increased slightly in the ingested group.

(Discussion)
In addition to the effect of suppressing the decrease in testosterone secretion by ingesting tomato powder containing lycopene in Example 1, in this example, the same effect of suppressing (increasing) the decrease in testosterone secretion was observed in the stress model for tomato juice containing almost no lycopene. rice field. Among them, a similar test in which vitamin C contained in fruit juice was ingested showed a slight effect. Therefore, it is considered that vitamin C partially contributes to the testosterone-increasing effect of tomato juice. The contribution of water-soluble components other than C was also suggested. Under the conditions of this example, no significant increase was observed in vitamin C having antioxidant activity, but glutathione peroxidase activity among the antioxidant activity of the testis was significantly increased by ingestion of fruit juice, and thus it was contained in fruit juice. It was suggested that the water-soluble component with antioxidant activity affected testosterone secretion.

Claims (3)

A testosterone-increasing agent containing a water-soluble component derived from tomato fruit and substantially free of a water-insoluble component derived from tomato fruit. Testosterone enhancer according to claim 1, wherein the testosterone secretion is applied to the target was lowered by stress. The testosterone increasing agent according to claim 1 or 2, which is used as a food product.

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