JP6838752B2 - Blood flow improving composition - Google Patents

Description

The present invention relates to a composition having a blood flow improving effect, and more particularly to a composition containing citrulline and a specific other ingredient as active ingredients.

In modern society, blood circulation (blood flow) is often a problem due to various factors such as lack of exercise and autonomic imbalance due to stress. This disorder of blood flow (decrease in blood flow) causes various symptoms such as headache, stiff shoulders, dull skin, poor circulation, and swelling. Measures to improve the flow are required.

Examples of the composition for improving blood flow include a hisop extract (see Patent Document 1), a composition containing a cassis concentrate and an amino acid or an organic acid (see Patent Document 2), and a chamomile extract (see Patent Document 2). (See Patent Document 3) and the like have been proposed.

On the other hand, the applicant has proposed a composition for improving blood flow (see Patent Document 4) containing a pine bark extract and a black pepper extract.

Japanese Unexamined Patent Publication No. 2006-8575 Japanese Unexamined Patent Publication No. 2004-262878 Japanese Unexamined Patent Publication No. 2005-68069 Japanese Unexamined Patent Publication No. 2012-051833

An object of the present invention is to provide a composition having a high blood flow improving effect.

The present inventors have diligently investigated and studied the blood flow improving ability of citrulline, and found that a high blood flow improving effect can be obtained by combining citrulline with a specific other component, and complete the present invention. It came to. That is, it was found that the blood flow improving ability can be synergistically improved by combining citrulline with a specific other component having little or little ability to improve blood flow.

That is, the present invention relates to a composition characterized by containing citrulline and at least one component selected from the group consisting of the following (a) to (e) as an active ingredient.
(A) At least one plant material selected from terminaria, rice, makiberry, black ginger, ginger, and pepper (b) At least one selected from malt sugar, trehalose, reduced palatinose, reduced malt sugar, calcium stearate, and shelac. Functional Additives (c) At least one amino acid selected from leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine (d) gallic acid (e) vitamin A, vitamin B1, vitamin B2, At least one vitamin / mineral selected from vitamin C, sodium pantothenate, niacin, folic acid, biotin, vitamin K, inositol, calcium, zinc, iron, copper, selenium, molybdenum, magnesium, and chromium.

..
The composition of the present invention may be obtained by adding an active ingredient consisting of citrulline and at least one ingredient selected from the group consisting of (a) to (e).

In the composition of the present invention, the compounding mass ratio of citrulline and other active ingredients is preferably in the range of 0.5: 1 to 70: 1.
Further, the composition of the present invention is preferably a tablet, a capsule, a powder, a granule, or a liquid.

The present invention also relates to a method for improving blood flow (excluding medical practice), which comprises ingesting the composition of the present invention.

According to the composition of the present invention, the blood flow rate can be increased and a high blood flow improving effect can be obtained.

It is a figure which shows the result of the NO production amount at the time of applying the composition (citrulline + plant material) of this invention to a porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses Terminaria as the plant material, the upper right graph uses rice (rice bran) as the plant material, and the lower left graph uses makiberry as the plant material. , The graph on the lower right shows the use of black ginger as a plant material. It is a figure which shows the result of the NO production amount at the time of applying the composition (citrulline + plant material) of this invention to a porcine pulmonary artery vascular endothelial cell (PPAEC). The graph on the left uses ginger as the plant material, and the graph on the right uses pepper (bioperine) as the plant material. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + functional additive) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses maltose as a functional additive, the upper right graph uses trehalose as a functional additive, and the lower left graph uses reduced palatinose as a functional additive. The graph on the lower right shows the use of reduced maltose as a functional additive. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + functional additive) to porcine pulmonary artery vascular endothelial cell (PPAEC). The graph on the left shows the use of calcium stearate as the functional additive, and the graph on the right shows the use of shellac as the functional additive. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + amino acid) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses leucine as the amino acid, the upper right graph uses methionine as the amino acid, the lower left graph uses phenylalanine as the amino acid, and the lower right graph uses phenylalanine. , Proline is used as an amino acid. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + amino acid) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses serine as an amino acid, the upper right graph uses threonine as an amino acid, the lower left graph uses tryptophan as an amino acid, and the lower right graph uses tryptophan. , Tyrosine is used as an amino acid. It is a figure which shows the result of the NO production amount at the time of applying the composition (citrulline + amino acid) of this invention to a porcine pulmonary artery vascular endothelial cell (PPAEC), and is the one which used valine as an amino acid. It is a figure which shows the result of the NO production amount at the time of applying the composition (citrulline + polyphenol) of this invention to a porcine pulmonary artery vascular endothelial cell (PPAEC), and is the thing which used gallic acid as a polyphenol. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + vitamins, minerals) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses vitamin A as vitamins, the upper right graph uses vitamin B1 as vitamins, and the lower left graph uses vitamin B2 as vitamins. , The lower right graph shows the use of vitamin C as vitamins. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + vitamins, minerals) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses sodium pantothenate as vitamins, the upper right graph uses niacin as vitamins, and the lower left graph uses folic acid as vitamins. The lower right graph shows the use of biotin as a vitamin. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + vitamins, minerals) to porcine pulmonary artery vascular endothelial cell (PPAEC). The graph on the left shows the use of vitamin K as vitamins, and the graph on the right shows the use of inositol as vitamins. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + vitamins, minerals) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses calcium as minerals, the upper right graph uses zinc as minerals, and the lower left graph uses iron as minerals, lower right. The graph in is the one using copper as a mineral. It is a figure which shows the result of the NO production amount at the time of applying the composition of this invention (citrulline + vitamins, minerals) to porcine pulmonary artery vascular endothelial cell (PPAEC). The upper left graph uses selenium as a mineral, the upper right graph uses molybdenum as a mineral, and the lower left graph uses magnesium as a mineral, and the lower right graph. The graph in is the one using chromium as a mineral.

The composition of the present invention is characterized by containing citrulline and at least one component (hereinafter, may be referred to as another component) selected from the group consisting of the following (a) to (e) as an active ingredient. To do. The following components (a) to (e) used together with citrulline may be used alone (for example, component (a)) or in combination of two or more. When two or more other components are used in combination, it is preferable to combine citrulline and other components having a high synergistic effect.

The composition of the present invention (blood flow improving composition) can more effectively relax the muscles around the blood vessels, dilate the blood vessels, and increase the blood flow by the synergistic effect of the combination of the active ingredients. Symptoms such as headache, stiff shoulders, dull skin, poor circulation, and erectile dysfunction can be effectively prevented or ameliorated.

[Citrulline]
The citrulline to be the active ingredient of the blood flow improving composition of the present invention may be L-citrulline or D-citrulline, but L-citrulline is preferable. Citrulline may be produced by chemical synthesis, fermentation, etc., regardless of the production method. Further, citrulin may be in the form of a salt, and the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. You can mention salt. Citrulline is commercially available as pharmaceuticals, reagents, etc., and these commercially available products can be used.

[Other ingredients]
(A) Plant material In the blood flow improving composition of the present invention, it is preferable to use at least one plant material selected from terminaria, rice, makiberry, black ginger, ginger, and pepper as an active ingredient together with citrulline. ..

These plant materials may be any part of the plant such as leaves, stems, roots, flowers, fruits, trunks, branches, etc. In addition to the plant materials themselves (including dried products), crushed products and juices thereof. , Plant material processed products such as extracts can be used. Examples of the pulverized product include powder, granules and the like. The juice and extract may be liquid, but can also be used as a paste or a dry powder. The extract can be obtained by extracting with an appropriate solvent, and as the solvent, for example, water (hot water, hot water), ethanol, or hydrous ethanol can be used. As these plant materials, commercially available ones can be used.

Examples of Terminaria include Terminalia bellirica (belerica), Terminalia catappa, Terminalia tomentosa, Terminalia citrina, Terminalia phellocarpa, Terminalia copelandii, Terminalia brassi, Terminalia ivorensis, Terminalia superba, Terminalia arjuna, Terminalia chebula, etc. Of these, Terminalia bellirica (belerica) and Terminalia chebula are preferable. Fruits are preferable as the site used as the plant material of the present invention.

Rice is a plant of the genus Oryza in the family Gramineae. As the site used as the plant material of the present invention, the exodermis or embryo of brown rice is preferable, and specifically, rice bran obtained as a by-product when milling brown rice is preferably used. The type of rice is not particularly limited, and examples thereof include japonica rice and indica rice.

Makiberry is a plant of the family Portonoki, which originates in Patagonia, Chile, and its academic name is Aristotellia chilensis. Fruits are preferable as the site used as the plant material of the present invention.

The scientific name of Kaempferia Parviflora is Kaempferia Parviflora, and it is a plant of the genus Kaempferia of the family Zingiberaceae that grows naturally in Southeast Asia. Rhizome is preferable as the site used as the plant material of the present invention.

Ginger is a plant belonging to the genus Ginger of the family Zingiberaceae, and examples thereof include Sanshu ginger, yellow ginger, Kintoki ginger, and Tananaka ginger. In addition, red ginger (Zingiber officinale var. Rubra) cultivated in Indonesia and India can also be preferably used. Rhizome is preferable as the site used as the plant material of the present invention.

Pepper is a plant of the Piperaceae family (Piper nigurum), and fruits are preferable as the site used as the plant material of the present invention. There are various types such as black pepper, white pepper, and red pepper depending on the timing of harvesting, and any type may be used, but black pepper is preferable. Black pepper is a dried immature fruit from a pepper tree and contains the pungent ingredient piperine. The pepper of the present invention preferably contains this piperine.

(B) Functional Additives In the blood flow improving composition of the present invention, at least one functional additive selected from maltose, trehalose, reduced palatinose, reduced maltose, calcium stearate, and shellac as active ingredients together with citrulline. It is preferable to use an agent.

(C) Amino Acids In the blood flow improving composition of the present invention, at least one amino acid (salt) selected from leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine as active ingredients together with citrulin. (Including) is preferably used. Examples of the salt include sodium salts, hydrochlorides and the like.

(D) Gallic acid In the blood flow improving composition of the present invention, it is preferable to use gallic acid as an active ingredient together with citrulline.

(E) Vitamin / Minerals In the blood flow improving composition of the present invention, along with citrulin, as active ingredients, vitamin A, vitamin B1, vitamin B2, vitamin C, sodium pantothenate, niacin, folic acid, biotin, vitamin K, It is preferable to use at least one vitamin / mineral selected from inositol, calcium, zinc, iron, copper, selenium, molybdenum, magnesium, and chromium. Calcium, zinc, iron, copper, selenium, molybdenum, magnesium, and chromium as minerals of the present invention include the form of compounds containing these metals.

The blood flow improving composition of the present invention can be used as a blood flow improving agent having a blood flow improving action, and the blood flow improving agent contains citrulline and a predetermined other component and is used for improving blood flow. In the above, there is no particular limitation as long as the product can be distinguished from other products. For example, the scope of the present invention includes a product indicating that any of the main body, packaging, instruction manual, and promotional material of the product according to the present invention has a function of improving blood flow. For example, so-called health foods such as pharmaceuticals (including non-pharmaceutical products), foods for specified health use, foods with nutritional function, foods with functional claims, etc. Can be mentioned. In so-called health foods, "improve circulation", "improve coldness", "for those who are concerned about swelling", "for those who are concerned about skin color", "for those who are concerned about dark circles" For example, "toward", "enhance vascular function", "enhance suppleness of blood vessels", "to support male function", "to increase male vitality", etc. can be exemplified. The blood flow improving agent of the present invention can be ingested by a person who is concerned about the above effects regardless of gender or age, but the effect of the blood flow improving agent of the present invention can be enjoyed more effectively. Since it can be taken, it is desirable that it is taken by healthy people excluding sick people, and it is desirable that it is taken by elderly people who have the above problems. In addition, it is desirable to take it at night because it has the effect of improving coldness and improving male function.

The form of the blood flow improving composition of the present invention includes, for example, tablets, capsules, powders, granules, liquids, granules, rods, plates, blocks, solids, rounds, etc. Examples thereof include paste-like agents, cream-like agents, capsule-like agents, gel-like agents, chewable-like agents, stick-like agents and the like. Among these, the forms of tablets, capsules, powders, granules, and liquids are particularly preferable. Specifically, supplements, packaged beverages filled in PET bottles, cans, bottles, etc., instant powdered beverages for dissolving in water (hot water), milk, fruit juice, green juice, etc., and instant granule beverages. Can be exemplified. These are preferable in that they are easy to drink at the time of meals and can enhance the palatability.

The content of citrulline and other components (active ingredients) in the blood flow improving composition of the present invention may be appropriately contained within the range in which the effect is exhibited.

Generally, when the blood flow improving composition of the present invention is a drug or supplement (tablet, capsule), the active ingredient may be contained in an amount of 0.0001 to 100% by mass in terms of dry mass. It is preferable that it is contained in an amount of 0.1 to 85% by mass, more preferably 0.5 to 70% by mass.

When the blood flow improving composition of the present invention is a packaged beverage (liquid), the active ingredient is preferably contained in an amount of 0.0001 to 15% by mass in terms of dry mass, preferably 0.001 to 12%. It is more preferably contained in an amount of 5.5% by mass, and further preferably contained in an amount of 0.01 to 10% by mass.

When the blood flow improving composition of the present invention is an instant powdered beverage (powder) or an instant granule beverage (granule), the active ingredient is contained in an amount of 0.001 to 80% by mass in terms of dry mass. It is more preferable that it is contained in an amount of 0.005 to 70% by mass, and it is more preferable that it is contained in an amount of 0.1 to 60% by mass.

In order to exert the effect of the present invention more effectively, it is preferable that the active ingredient is contained in an amount of 80% or more, and 90% or more, of the entire blood flow improving composition (excluding water) of the present invention in terms of dry mass. It is more preferably contained, more preferably 95% or more, and particularly preferably 100%. Further, when the blood flow improving composition of the present invention contains any of the components (a) to (e), it is preferable that the contained component is composed of only the active ingredient in the present invention. That is, when the blood flow improving composition of the present invention contains, for example, component (a) (plant material), it is configured so as not to contain plant materials other than terminaria, rice, makiberry, black ginger, ginger, and pepper. Is preferable.

The intake amount of the blood flow improving composition of the present invention is not particularly limited, but from the viewpoint of exerting the effect of the present invention more remarkably, the intake amount of the active ingredient per day should be 200 mg / day or more. It is preferably taken, more preferably 400 mg / day or more, and even more preferably 600 mg / day or more. The upper limit is not particularly limited, but is, for example, 10 g / day, preferably 8 g / day.

The blood flow improving composition of the present invention may be contained in one container or, for example, divided into a plurality of containers of 2 to 3 and contained as one day's worth so that the daily intake becomes the above-mentioned intake. it can.

The compounding mass ratio of citrulline and other components is preferably in the range of 0.5: 1 to 70: 1, more preferably in the range of 0.75: 1 to 60: 1 in terms of dry mass. , 1: 1 to 60: 1, and more preferably 1: 1 to 50: 1. When the blending ratio of citrulline and other components is within the above range, the effects of the present invention can be more effectively exhibited.

The blood flow improving composition of the present invention can be produced by a known formulation method by adding an ingredient other than the active ingredient permitted for oral use, if necessary.

Further, as the blood flow improving composition of the present invention, in addition to the blood flow improving food containing the active ingredient, a blood flow improving food obtained by adding the active ingredient to the food can be mentioned, for example, usually. Examples thereof include foods in which the content of the active ingredient of the present invention is increased as compared with the foods of the present invention, and foods in which the active ingredient is added to foods that do not normally contain the active ingredient of the present invention. The active ingredient may be added separately, simultaneously, or together with other ingredients other than the active ingredient.

Examples of the blood flow improving food of the present invention include beverages such as carbonated beverages, nutritional beverages, fruit beverages, lactic acid beverages, smoothies, and green juices; cold confectioneries such as ice cream, ice sherbets, and shaved ice; Noodles such as noodles and instant noodles; Confectionery such as candy, candy, gum, chocolate, tablet confectionery, snack confectionery, biscuits, jelly, jam, cream, baked confectionery, bread; Dairy products such as processed milk, fermented milk, yogurt; oils and fats such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, dressing and their processed foods; seasonings such as sauces and soy sauce; curry, stew, parent and child bowl , Porridge, miscellaneous dishes, Chinese bowl, and bowl, tempura bowl, beef bowl, hayashi rice, omelet rice, oden, marbo dough, dumplings, shumai, hamburger, meat balls, various sauces, various soups and other retort pouch foods. ..

The blood flow improving method of the present invention is characterized by ingesting the blood flow improving composition of the present invention described above, but does not include medical practice. The blood flow improving composition of the present invention can be ingested by a person who is concerned about the above effects regardless of gender or age, but the effect of the blood flow improving composition of the present invention is more effectively enjoyed. Therefore, it is desirable to ingest it to healthy people excluding sick people, and it is further desirable to ingest it to elderly people having the above-mentioned problems. In addition, it is desirable to take it at night because it has the effect of improving coldness and improving male function. Examples of the method of the present invention include a method of improving blood flow by providing the blood flow improving food of the present invention in a restaurant such as a restaurant.

Hereinafter, the present invention will be described based on examples.
[Example 1]
1. 1. Cell culture
(1) Pig pulmonary artery vascular endothelial cells (PPAEC) were cultured in 10% FBS-RPMI 1640 in a 5% CO ₂ incubator at ^{37 ° C. using a 75 cm 2 flask.}
(2) Cells suspended by trypsin treatment were seeded from a ^{75 cm 2} flask into each well of a 96-well plate at ^{a cell density of 1.0 × 10 4 cells / well.}
(3) Pre-cultured at 37 ° C. in a 5% CO ₂ incubator for 48 hours.
(4) After removing the medium from each well, 100 μL of the test substance-containing medium prepared to a predetermined concentration with 4% FBS-αMEM was added, and the cells were cultured in a _{CO 2 incubator for 24 hours.}

For the combined sample of citrulline and other components, 50 μL of each of the test substance-containing mediums having a double concentration was added to obtain the desired concentration. The control was prepared using 4% FBS-αMEM containing 0.25% DMSO for the test substance dissolved in DMSO, and 4% FBS-αMEM for other test substances. Prepared.

As for citrulline, commercially available citrulline was used. As the other components used together with citrulline, the substances shown in Tables 1 to 5 were used.

2. 2. Evaluation of NO production
(1) After culturing for 24 hours, 50 μL of the culture supernatant was collected in a 1.5 mL sample tube, and a sample of N = 3 was mixed.
(2) Centrifugation was carried out at 4 ° C. and 2000 g for 3 minutes, and the supernatant was transferred to another 1.5 mL Eppen tube.
(3) Using Nitrate / Nitrite Assay Kit and Fluorometer (manufactured by Cayman), the NO concentration (μM) in the sample of (2) was measured. NO produced from vascular endothelial cells has the effect of relaxing the muscles around the blood vessels and expanding the blood vessels.
(4) “% of control” was calculated based on the calculated NO concentration.

% Of control
= NO concentration of sample (μM) / NO concentration of control (μM) × 100

The results are shown in Tables 1 to 5 and FIGS. 1 to 13. From the left, each figure shows the results of "control (without addition)", "addition of citrulline alone", "addition of other components alone", and "addition of citrulline + other components". Further, the numerical value in the explanation at the bottom of the graph indicates the sample concentration, and for example, "citrulline_31.2" in the upper left graph of FIG. 1 indicates citrulline 31.2 (μg / mL). The concentration unit of the additive component is μg / mL in all graphs. The vertical axis indicates "% of control".

For terminaria, hot water extract of fruit (dry powder) was used.
For rice bran, a commercially available product was used.
For long-lived grass, dried and crushed leaves were used.
For maki berries, commercially available dried fruit powder was used.
For black ginger, a 60% ethanol extract (dry powder) of the rhizome of black ginger was used.
For ginger, a hot water extract (dry powder) of ginger rhizome was used.
For pepper, a 100% ethanol extract of black pepper was used.
For mugwort, finely ground powder of fresh leaves was used.
As for caffeine, commercially available caffeine was used.

As shown in Tables 1 to 5 and FIGS. 1 to 13, the amount of NO produced was synergistically increased by combining citrulline with a specific other component of the present invention. Therefore, according to the blood flow improving composition of the present invention, vasodilation is promoted, and blood flow can be effectively improved.

[Example 2] (Production of tablets)

Six tablets (7200 mg) composed of the following ingredients were produced.
Reduced maltose 5% by mass
Citrulline 80% by mass
Ginger extract 4% by mass
Pepper extract 2% by mass
Vitamin C 1% by mass
Folic acid 1% by mass
Gallic acid 1% by mass
Cellulose 2% by mass
Silicon dioxide 2% by mass
Calcium stearate 1% by mass
Shellac 1% by mass

The above tablets should be taken with water in 2 to 3 divided doses a day.

[Example 3] (Manufacturing of capsules)
The following mixture was encapsulated in soft capsules to produce capsules.

Citrulline 200mg
Black ginger powder 100 mg
Maltose 50 mg
Silicon dioxide 10 mg
Niacin 5 mg
Vitamin B1 5 mg
Vitamin B2 5 mg
Leucine 2.5 mg
Tyrosine 2.5 mg
Valine 2.5 mg
Iron chloride 1 mg

The above capsules are taken in 8 capsules 2 to 4 times a day with water.

[Example 4] (Production of granules)
The following components were mixed to prepare granules (5000 mg) by a conventional method.

Citrulline 3000mg
Terminalia bellirica powder 400 mg
Reduced isomaltulose 500 mg
Silicon dioxide 200mg
Sucrose fatty acid ester 50 mg
Inositol 25 mg
Biotin 10 mg
Zinc gluconate 10 mg
Magnesium chloride 5 mg
Threonine 5 mg
Tryptophan 2.5 mg
Starch residue

[Example 5] (Production of instant powder)
The following ingredients were mixed to produce an instant powder (10 g) by a conventional method.

Trehalose 0.1g
Reduced isomaltulose 0.1g
Calcium stearate 2g
Black ginger extract (dry powder) 1 g
Citrulline 1g
Gallic acid 0.02g
Glutamine 0.01g
Zinc gluconate 0.001 g
Iron chloride 0.001g
Water-soluble cellulose balance

[Example 6] (Production of liquid preparation)
A liquid preparation (500 mL) consisting of the following components was produced.
Makiberry extract 3000mg
Trehalose 250 mg
Citrulline 300mg
Vitamin K 150mg
Calcium chloride 50 mg
Valine 25 mg
Leucine 25 mg
Isoleucine 25 mg
Phenylalanine 10 mg
Proline 10 mg
Vitamin C 500mg
Vitamin A 120 mg
Vitamin B1 60 mg
Vitamin B2 60mg
Zinc gluconate 50 mg
Remaining water

Since the composition of the present invention has an effect of improving blood flow and can be used as an oral preparation, the industrial usefulness of the present invention is high.

Claims (1)

A blood flow improving agent comprising citrulline and at least one amino acid selected from tyrosine, threonine, tryptophan, and proline.

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