JP2020186205A - Vasodilator - Google Patents

Abstract

To provide a novel vasodilator.SOLUTION: A vasodilator contains at least one selected from the group consisting of citric acid and a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to a vasodilator.

In recent years, an increase in lifestyle-related diseases such as hypertension caused by eating habits, lack of exercise, mental stress, smoking, genetic factors and the like has become a problem.

Drugs used to treat hypertension include calcium (Ca) antagonists that lower blood pressure by dilating blood pressure, and angiotensin converting enzyme (ACE) inhibition that lowers blood pressure by suppressing the production of angiotensin II, which has a blood pressure-increasing effect. Drugs, angiotensin receptor blockers (ARBs) that lower blood pressure by inhibiting the binding of angiotensin II to receptors, and the like are known, and the mechanism of action for treating hypertension is various.

As a composition for dilating blood vessels, for example, Patent Document 1 describes at least one condensed tannin oligomer component of dimer to thirteen from berry fruit or cacao bean or persimmon fruit or persimmon leaf. A vasodilator containing an organic acid component as an active ingredient, and a procyanidin oligomer having a condensed tannin oligomer component as a constituent unit of catechin, epicatechin, galocatechin, epigalocatechin and / or at least one of these gallates. Alternatively, the vasodilator, which is a proanthocyanidin oligomer, is described.

International Publication No. 2010/092941

The vasodilator described in Patent Document 1 synergistically improves the vasodilatory action as compared with the case of a single component by combining a predetermined condensed tannin oligomer component and an organic acid component to form an active ingredient. That is. Patent Document 1 describes a comparative example in which a vasodilatory action was evaluated using a vascular isometric tension test (Magnus method) using only citric acid (organic acid component), and no vasodilatory action was observed. .. In the comparative example of Patent Document 1, the citric acid concentration in the sample is 100 μg / mL or less. As can be seen from the examples described later, when such a low concentration of citric acid is used in the Magnus method, no vasodilatory effect is observed. Therefore, Patent Document 1 even suggests a vasodilatory effect of citric acid alone. It can be said that it has not been done.

On the other hand, the present inventors have found that citric acid alone exhibits a remarkable vasodilatory effect. The present invention is based on this novel finding, and an object of the present invention is to provide a novel vasodilator.

The present invention relates to a vasodilator containing at least one selected from the group consisting of citric acid and salts thereof as an active ingredient.

Since the vasodilator contains at least one selected from the group consisting of citric acid and a salt thereof as an active ingredient, it exhibits a remarkable vasodilatory effect.

In one aspect, the vasodilator may be used such that the active ingredient is orally administered (orally ingested) in an amount of 600 mg or more per day.

In one aspect, the content of the active ingredient in the vasodilator may be 600 mg or more.

In one aspect, the vasodilator may be a vasodilator food composition.

According to the present invention, a novel vasodilator can be provided.

It is a graph which shows the measurement result of the vasodilator action (dilation rate) in Test Example 1. It is a graph which shows the measurement result of the systolic blood pressure change in Test Example 2. It is a graph which shows the measurement result of the diastolic blood pressure change in Test Example 2.

Hereinafter, embodiments for carrying out the present invention will be described in detail. The present invention is not limited to the following embodiments.

The vasodilator according to the present embodiment contains at least one selected from the group consisting of citric acid and a salt thereof as an active ingredient.

(Active ingredient)
The active ingredient of the vasodilator according to the present embodiment is at least one selected from the group consisting of citric acid and salts thereof.

Citric acid is a type of hydroxy acid and is also called 2-hydroxypropane-1,2,3-tricarboxylic acid. The citric acid may be citric acid anhydride or citric acid hydrate.

The citric acid salt is not particularly limited as long as it is acceptable as a food, quasi-drug or pharmaceutical product. Specific examples of the citric acid salt include alkali metal salts such as sodium salt, potassium salt and calcium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. The salt of citric acid may be a hydrate.

The vasodilator according to the present embodiment may contain citric acid or a salt thereof as an active ingredient alone, or may contain two or more of them.

(Content of active ingredient)
The vasodilator according to this embodiment preferably contains the above-mentioned active ingredient in an effective amount. The "effective amount" means an amount that exhibits a vasodilatory effect by administration of the vasodilator according to the present embodiment.

The content of the active ingredient in the vasodilator according to the present embodiment can be appropriately set according to the specific embodiment of the vasodilator (for example, form, usage and dose).

For example, when the vasodilator according to the present embodiment is orally administered (orally ingested), it may be used so that 600 mg or more of the active ingredient is orally administered (orally ingested) per day. A sufficient vasodilatory effect can be obtained by orally administering (orally ingesting) 600 mg or more of the active ingredient per day. For example, when the vasodilator according to the present embodiment is used so as to be orally administered (orally ingested) three times a day, the vasodilator contains 200 mg or more of the active ingredient. The daily oral administration (oral intake) amount is 600 mg or more.

The amount of oral administration (oral intake) per day may be, for example, 650 mg or more, 700 mg or more, 750 mg or more, 800 mg or more, 850 mg or more, 900 mg or more, 950 mg or more, or 1000 mg or more. Further, from the viewpoint of vasodilatory action, the upper limit of the above-mentioned amount of oral administration (oral intake) per day is not particularly limited, but from the viewpoint of reducing the manufacturing cost, for example, 20000 mg or less, 15000 mg or less, 10000 mg or less. , 8000 mg or less or 6000 mg or less. In addition, the amount of oral administration (oral intake) per day is preferably 60 kg-per body weight.

The content of the active ingredient in the vasodilator according to the present embodiment is appropriately set according to the specific embodiment of the vasodilator (for example, form, usage, dose, etc.), but in one embodiment, The content of the active ingredient in the vasodilator according to the present embodiment is, for example, 600 mg or more, 650 mg or more, 700 mg or more, 750 mg or more, 800 mg or more, 850 mg or more, 900 mg or more, 950 mg or more, based on the total amount of the vasodilator. , Or 1000 mg or more. Thereby, the above-mentioned daily oral administration (oral intake) amount can be easily achieved. The upper limit of the content of the active ingredient in the vasodilator according to the present embodiment may be, for example, 20000 mg or less, 15000 mg or less, 10000 mg or less, 8000 mg or less, or 6000 mg or less.

The vasodilator according to the present embodiment may be orally administered (orally ingested) or parenterally, but is preferably orally administered (orally ingested). The vasodilator may be administered (ingested) once a day or divided into a plurality of times a day.

The vasodilator according to this embodiment may be administered (ingested) to humans or may be administered to non-human mammals.

(Other ingredients)
The vasodilator according to the present embodiment may consist only of the above active ingredient, and depending on the specific embodiment of the vasodilator, in addition to the above active ingredient, it may be used as a food, quasi drug or pharmaceutical product. It may contain other acceptable components.

(Shape of vasodilator)
The vasodilator according to this embodiment may be in any form such as solid, liquid (including solutions and suspensions), and paste. The vasodilator according to the present embodiment includes, for example, tablets (orally disintegrating tablets, chewable tablets, film-coated tablets, etc.), capsules, powders, granules, liquids (syrups, jellies, etc.), ointments. , Ointment, etc. may be used.

(Specific aspects of vasodilators)
The vasodilator according to this embodiment can be prepared, for example, as a food composition (beverage and food), a quasi drug, or a pharmaceutical product. Examples of beverages include water, soft drinks, fruit juice beverages, sparkling beverages, milk beverages, alcoholic beverages, sports drinks, nutritional drinks and the like. Examples of foods include breads, noodles, rice, tofu, dairy products, soy sauce, miso, and confectionery. In addition, the food composition includes, for example, health foods, foods with functional claims, special purpose foods, dietary supplements, supplements, foods for specified health use and the like.

The vasodilator according to the present embodiment is preferably a food composition (food composition for vasodilation) because it can be easily ingested on a daily basis. Examples of the form of the food composition for vasodilation according to the present embodiment include those described above, and from the viewpoint of being easily ingested on a daily basis, a beverage (a beverage for vasodilation) is preferable.

(Manufacturing method of vasodilator)
The vasodilator according to the present embodiment can be obtained, for example, by blending the above-mentioned active ingredient according to a specific embodiment thereof, and is preferably prepared so as to contain an effective amount of the above-mentioned active ingredient. Can be obtained at. At this time, citric acid or a salt thereof may be used as the active ingredient citric acid and a salt thereof, or a composition containing citric acid or a salt thereof (for example, lemon juice, grapefruit juice, orange juice, etc.). Fruit juice such as tangerine juice and plum juice) may be used.

(Action effect)
Since the vasodilator according to the present embodiment contains at least one selected from the group consisting of citric acid and a salt thereof as an active ingredient, by administering (ingesting) the vasodilator, the vasodilator is administered. Can dilate blood vessels. In addition, as a result of dilating blood vessels, circulation of blood flow is improved, and cold sensitivity, stiff shoulders, headache, hypertension, angina, constipation and the like can be improved or prevented.

Hereinafter, the present invention will be described in more detail based on Examples. However, the present invention is not limited to the following examples.

<Test Example 1: Vasodilator test>
A vasodilatory effect test was performed using the Magnus method. The vasodilatory effect test was specifically performed according to the following method. A ring specimen with a width of about 2 to 3 mm is obtained by removing the thoracic aorta from a male 14 to 16 week old spontaneously hypertensive rat (SHR, manufactured by Charles River Co., Ltd.) and removing the connective tissue attached to the blood vessel. Made. The prepared ring specimen was subjected to a 37 ° C. Krebs solution (composition: 118 mM NaCl, 4.7 mM KCl, 1.2 mM KH ₂ PO ₄ , 1.2 mM trimethyl) in which a mixed gas (95% O ₂ , 5% CO ₂ ) was aerated. _For tension measurement in an organ bath of an isometric tension tester (Easy Magnus Experimental Device, manufactured by Iwashiya Kishimoto Medical Industry Co., Ltd.) filled with ₄ , 25 mM NaCl ₃ , 2.5 mM CaCl ₂ and 11.1 mM Glucose). Attached to the hook. A 1.5 g resting tension was applied to the ring specimen, the Krebs solution was changed at 15 minute intervals and stabilized for 60 minutes, and the contraction reaction was confirmed using phenylephrine (0.3 μM). Then, acetylcholine (0.1 mM) was added to confirm that the vascular endothelium was normally preserved. The ring specimen was washed 3 times with Krebs solution, the tension was returned to rest tension, replaced with Krebs solution, and phenylephrine (0.3 μM) was added to constrict the vessel. When the tension is stable, use citric acid solution (Example 1) or lemon juice (Example 2), and the citric acid concentration in the organ bath is 0.1 mM (19.2 mg / L), 0.3 mM (57.6 mg / L). Cumulative addition was made to L), 0.5 mM (96 mg / L), 1.0 mM (192 mg / L), 3.0 mM (576 mg / L), and 5.0 mM (960 mg / L). The vasodilatory effect of the addition of citric acid solution or lemon juice was evaluated by the dilation rate (%) of the ring specimen. The expansion rate (%) is expressed as a ratio (percentage) of the increase or decrease in the vascular tension when a citric acid solution or lemon juice is added, based on the vascular tension when contracted by phenilefurin from the resting tension. The results are shown in FIG. 1 and Table 1.

As shown in FIGS. 1 and 1, a strong vasodilatory effect was observed when the citric acid concentration was 3.0 mM (576 mg / L) or higher. In the comparative example of Patent Document 1, since only a sample having a citric acid concentration of 100 μg / mL or less is used, the vasodilatory effect of citric acid has not been confirmed. On the other hand, from the results of FIGS. 1 and 1, it was found for the first time that citric acid alone exerts a vasodilatory action in a vasodilatory action test using the Magnus method.

<Test Example 2: Single oral administration test>
In the Magnus method used in Test Example 1, a drug (phenyleffrin in Test Example 1) was applied to a blood vessel extracted from the living body to forcibly constrict the blood vessel, and then the test component was applied to the constricted blood vessel. (In Test Example 1, a citric acid solution or lemon juice) is allowed to act to examine the dilated state of blood vessels. Since the added drug has a strong action, in order to detect the vasodilatory action by the Magnus method, it is necessary that the concentration is higher than the concentration of the test component that exerts the vasodilatory action in vivo. That is, since the concentration of the test component that exerts the vasodilatory action by the Magnus method and the concentration of the test component that exerts the vasodilatory action in vivo are different, the concentration of the test component that exerts the desired action in vivo and In examining the content, an oral administration test that can evaluate the action in vivo is generally used. Therefore, a single oral administration test was conducted in rats to evaluate the vasodilatory effect. Since it is difficult to directly evaluate the vasodilatory effect in vivo, the vasodilatory effect was indirectly evaluated using the decrease in blood pressure, which is one of the downstream effects caused by vasodilation, as an index.

The single oral administration test was specifically performed according to the following method. The single oral administration test was performed using male 17-18 week old hypertensive spontaneously occurring rats (SHR, manufactured by Charles River Laboratories, Inc.). The 18 rats were divided into 3 groups (low dose citric acid group, high dose citric acid group and control group) with 6 animals in each group. Rats in each group were acclimated for 1 week, fasted for 12 hours, and then a single oral dose of a sample (citric acid solution or pure water) was administered. Specifically, rats in the low-dose citric acid group were orally administered a single dose of 10 mg / kg-body weight of citric acid in a citric acid solution in which citric acid was dissolved in pure water. Rats in the high dose group of citric acid were orally administered a single dose of 100 mg / kg-body weight of citric acid in a citric acid solution in which citric acid was dissolved in pure water. Rats in the control group received a single oral dose of pure water.

Evaluate changes in systolic and diastolic blood pressure in rats by measuring the blood pressure in the tail of the rat by the tail cuff method using a non-invasive blood pressure measuring device (Softron BP-98A, manufactured by Softron Co., Ltd.). did. Blood pressure was measured before and at 3, 6, 9 and 24 hours after administration of the sample. The results are shown in FIGS. 2 and 3.

FIG. 2 is a graph showing the measurement results of changes in systolic blood pressure. The horizontal axis of FIG. 2 indicates the elapsed time [h] after administration of the sample. The blood pressure was measured before the sample was administered at the elapsed time of 0 hours, and the sample was immediately administered. The vertical axis of FIG. 2 shows the fluctuation value [mmHg] of systolic blood pressure based on the measured value before sample administration.

FIG. 3 is a graph showing the measurement results of changes in diastolic blood pressure. The horizontal axis of FIG. 3 is the same as that of FIG. The vertical axis of FIG. 3 shows the fluctuation value [mmHg] of diastolic blood pressure based on the measured value before sample administration.

As shown in FIG. 2, regarding systolic blood pressure, a significant decrease in systolic blood pressure was observed in the citric acid low dose group (10 mg / kg-body weight) as compared with the control group 3 hours after administration. In addition, in the citric acid high dose group (100 mg / kg-body weight), a significant and significant decrease in systolic blood pressure was observed from 3 hours to 9 hours after administration as compared with the control group.

As shown in FIG. 3, the diastolic blood pressure was significantly and remarkable in the high-dose citric acid group (100 mg / kg-body weight) from 3 hours to 9 hours after administration as compared with the control group. A decrease was observed.

Based on the above results, the amount of oral administration (oral intake) of citric acid is set to 600 mg or more (10 mg / kg-body weight in the low-dose citric acid group is converted to human (60 kg-body weight)). It can be understood that a significant vasodilatory effect can be obtained. Further, as shown in FIGS. 2 and 3, it can be understood that a continuous vasodilatory effect can be obtained by oral administration (oral ingestion) of 600 mg or more per day.

Claims (4)

A vasodilator containing at least one selected from the group consisting of citric acid and a salt thereof as an active ingredient. The vasodilator according to claim 1, wherein the active ingredient is used so as to be orally administered in an amount of 600 mg or more per day. The vasodilator according to claim 1 or 2, wherein the content of the active ingredient is 600 mg or more. The vasodilator according to any one of claims 1 to 3, which is a food composition for vasodilation.

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