Vasodilators

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

Technical Field

[0001] The present invention relates to a vasodilator.

Background Art

[0002] In recent years, the increase in lifestyle-related diseases such as hypertension due to factors such as diet, lack of exercise, mental stress, smoking, and genetic factors has become a problem.

[0003] As drugs used for the treatment of hypertension, calcium (Ca) antagonists that lower blood pressure by dilating blood vessels, angiotensin-converting enzyme (ACE) inhibitors that lower blood pressure by suppressing the production of angiotensin II that has a blood pressure-raising effect, and angiotensin receptor antagonists (ARBs) that lower blood pressure by inhibiting the binding of angiotensin II to receptors are known, and the mechanisms of action for treating hypertension are various.

[0004] As a composition for dilating blood vessels, for example, in Patent Document 1, there is described a vasodilator containing, as active ingredients, at least one condensed tannin oligomer component derived from berries or cacao beans or persimmon fruits or persimmon leaves, and at least one organic acid component, wherein the condensed tannin oligomer component is a procyanidin oligomer and / or a prodelphinidin oligomer having at least one of catechin, epicatechin, gallocatechin, epigallocatechin and / or their gallates as a constituent unit.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] The vasodilator described in Patent Document 1 combines a predetermined condensed tannin oligomer component with an organic acid component as the active ingredient, resulting in a synergistic improvement in vasodilatory effect compared to the case of a single component. Patent Document 1 also describes a comparative example in which the vasodilatory effect of citric acid (organic acid component) alone was evaluated using a vascular isometric tension test (Magnus method), and no vasodilatory effect was observed. In the comparative example in Patent Document 1, the citric acid concentration in the samples was 100 μg / mL or less in all cases. 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, so it can be said that Patent Document 1 does not even suggest the vasodilatory effect of citric acid alone.

[0007] On the other hand, the present inventors have discovered that citric acid alone exhibits a remarkable vasodilatory effect. This invention is based on this novel finding and aims to provide a novel vasodilator. [Means for solving the problem]

[0008] The present invention relates to a vasodilator containing at least one selected from the group consisting of citric acid and its salts as an active ingredient.

[0009] The above-mentioned vasodilator contains at least one active ingredient selected from the group consisting of citric acid and its salts, and therefore exhibits a remarkable vasodilatory effect.

[0010] In one embodiment, the vasodilator may be used in such a way that the active ingredient is administered orally (taken orally) at a dose of 600 mg or more per day.

[0011] In one embodiment, the amount of the active ingredient in the vasodilator may be 600 mg or more.

[0012] In one embodiment, the vasodilator may be a food composition for vasodilation. [Effects of the Invention]

[0013] According to the present invention, a novel vasodilator can be provided. [Brief explanation of the drawing]

[0014] [Figure 1] This graph shows the measurement results of vasodilatory effect (vasodilation rate) in Test Example 1. [Figure 2] This graph shows the measurement results of systolic blood pressure changes in Test Example 2. [Figure 3] This graph shows the measurement results of diastolic blood pressure changes in Test Example 2. [Modes for carrying out the invention]

[0015] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[0016] The vasodilator according to this embodiment contains at least one selected from the group consisting of citric acid and its salts as an active ingredient.

[0017] (Active ingredients) The active ingredient of the vasodilator according to this embodiment is at least one selected from the group consisting of citric acid and its salts.

[0018] Citric acid is a type of hydroxy acid, also known as 2-hydroxypropane-1,2,3-tricarboxylic acid. Citric acid may also be used as citrate anhydride or citrate hydrate.

[0019] There are no particular restrictions on the type of citric acid salt, as long as it is acceptable as a food, quasi-drug, or pharmaceutical product. Specific examples of citric acid salts 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 citric acid salt may also be a hydrate.

[0020] The vasodilator according to this embodiment may contain citric acid or its salt alone as an active ingredient, or may contain two or more of them.

[0021] (Content of active ingredient) The vasodilator according to this embodiment preferably contains the above-described active ingredient in an effective amount. The "effective amount" means an amount that exhibits a vasodilating action by administration of the vasodilator according to this embodiment.

[0022] The content of the active ingredient in the vasodilator according to this embodiment can be appropriately set according to the specific form (for example, form, usage, and dosage, etc.) of the vasodilator.

[0023] For example, when the vasodilator according to this embodiment is orally administered (orally ingested), the active ingredient may be used so that 600 mg or more is orally administered (orally ingested) per day. By orally administering (orally ingesting) 600 mg or more of the active ingredient per day, a sufficient vasodilating action can be obtained. For example, when the vasodilator according to this embodiment is used so that it is orally administered (orally ingested) three times a day, by containing 200 mg or more of the active ingredient in the vasodilator, the oral administration (oral ingestion) amount per day becomes 600 mg or more.

[0024] The above oral administration (oral ingestion) amount 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. Also, from the viewpoint of the vasodilating action, there is no particular limitation on the upper limit of the above oral administration (oral ingestion) amount per day, but from the viewpoint of reducing the manufacturing cost, it 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. Further, the above oral administration (oral ingestion) amount per day is preferably the amount per 60 kg of body weight.

[0025] The amount of active ingredient in the vasodilator according to this embodiment is set appropriately according to the specific form of the vasodilator (e.g., form, method of use, and dosage). In one embodiment, the amount of active ingredient in the vasodilator according to this embodiment may be, 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, or 1000 mg or more, based on the total amount of the vasodilator. This makes it easy to achieve the above-mentioned daily oral dose (oral intake). The upper limit of the amount of active ingredient in the vasodilator according to this 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.

[0026] The vasodilator according to this embodiment may be administered orally (by oral ingestion) or parenterally, but oral administration (by oral ingestion) is preferred. The vasodilator may be administered (ingested) once a day or divided into multiple doses per day.

[0027] The vasodilator according to this embodiment may be administered (ingested) to humans or to non-human mammals.

[0028] (Other ingredients) The vasodilator according to this embodiment may consist only of the above-mentioned active ingredient, or, depending on the specific form of the vasodilator, may contain other ingredients permitted for use in foods, quasi-drugs, or pharmaceuticals in addition to the above-mentioned active ingredient.

[0029] (Form of vasodilators) The vasodilator according to this embodiment may be in any form, such as solid, liquid (including solution and suspension), or paste. Furthermore, the vasodilator according to this embodiment may be in any dosage form, such as tablets (orally disintegrating tablets, chewable tablets, film-coated tablets, etc.), capsules, powders, granules, liquids (syrups, jellies, etc.), ointments, or hard ointments.

[0030] (Specific forms of vasodilators) The vasodilator according to this embodiment can be prepared, for example, as a food composition (beverages and food), a quasi-drug, or a pharmaceutical. Examples of beverages include water, soft drinks, fruit juices, carbonated drinks, milk beverages, alcoholic beverages, sports drinks, and nutritional drinks. Examples of food products include bread, noodles, rice, tofu, dairy products, soy sauce, miso, and confectionery. Food compositions include, for example, health foods, foods with functional claims, foods for special dietary uses, nutritional supplements, supplements, and foods for specified health uses.

[0031] The vasodilator according to this embodiment is preferably a food composition (vasodilator food composition) because it can be easily consumed on a daily basis. The forms of the vasodilator food composition according to this embodiment are those described above, and from the viewpoint of being easily consumed on a daily basis, it is preferably a beverage (vasodilator beverage).

[0032] (Method of manufacturing vasodilators) The vasodilator according to this embodiment can be obtained, for example, by incorporating the above-mentioned active ingredients, depending on its specific form, and preferably by preparing it to contain an effective amount of the above-mentioned active ingredients. In this case, as the active ingredients, citric acid and its salts may be citric acid or its salts themselves, or a composition containing citric acid or its salts (for example, fruit juices such as lemon juice, grapefruit juice, orange juice, mandarin orange juice, and plum juice) may be used.

[0033] (Effects and Benefits) The vasodilator according to this embodiment contains at least one selected from the group consisting of citric acid and its salts as an active ingredient. Therefore, by administering (ingesting) the vasodilator, blood vessels can be dilated. As a result of vasodilation, blood circulation improves, which can alleviate or prevent conditions such as cold hands and feet, stiff shoulders, headaches, hypertension, angina pectoris, and constipation. [Examples]

[0034] The present invention will be described more specifically below based on examples. However, the present invention is not limited to the following examples.

[0035] <Test Example 1: Vasodilatory Effect Test> A vasodilatory effect test was performed using the Magnus method. Specifically, the vasodilatory effect test was performed according to the following method: The thoracic aorta was excised from male 14-16 week old spontaneously hypertensive rats (SHR, manufactured by Charles River Co., Ltd. Japan), and a ring specimen approximately 2-3 mm wide was prepared by removing the connective tissue attached to the blood vessel. The prepared ring specimen was attached to a tension measuring hook in the organ bath of an isometric tension testing apparatus (Easy Magnus experimental apparatus, manufactured by Iwashiya Kishimoto Medical Industry Co., Ltd.) filled with a Krebs solution (composition: 118 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM NaHCO3, and 2.5 mM CaCl2 and 11.1 mM Glucose) at 37°C with a mixture of gases (95% O2, 5% CO2) passed through it. A resting tension of 1.5 g was applied to the ring specimen, and the Krebs solution was changed at 15-minute intervals. The specimen was stabilized for 60 minutes, and the contraction reaction was confirmed using phenylephrine (0.3 μM). Subsequently, acetylcholine (0.1 mM) was added to confirm that the vascular endothelium was normally preserved. The ring specimen was washed three times with Krebs solution, the tension was returned to resting tension, the Krebs solution was changed, and phenylephrine (0.3 μM) was added to constrict the blood vessels. Once the tension was stable, citric acid solution (Example 1) or lemon juice (Example 2) was added cumulatively so that the citric acid concentration in the organ bath reached 0.1 mM (19.2 mg / L), 0.3 mM (57.6 mg / 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 adding citric acid solution or lemon juice was evaluated by the vasodilation rate (%) of ring specimens. The vasodilation rate (%) is expressed as a ratio (percentage) of the increase or decrease in vasoconstriction when citric acid solution or lemon juice is added, with the vasoconstriction rate when phenylephrine was used as the baseline. The results are shown in Figure 1 and Table 1.

[0036] [Table 1]

[0037] As shown in Figure 1 and Table 1, a strong vasodilatory effect was observed at citrate concentrations of 3.0 mM (576 mg / L) or higher. In the comparative example in Patent Document 1, only samples with citrate concentrations of 100 μg / mL or less were used, so the vasodilatory effect of citrate could not be confirmed. On the other hand, the results in Figure 1 and Table 1 show for the first time that citrate alone exhibits a vasodilatory effect in a vasodilatory effect test using the Magnus method.

[0038] <Test Example 2: Single Oral Administration Test> The Magnus method used in Test Example 1 involves applying a drug (phenylephrine in Test Example 1) to blood vessels extracted from the body to forcibly constrict them, and then applying a test component (citric acid solution or lemon juice in Test Example 1) to the constricted blood vessels to examine the state of vasodilation. Because the added drug has a strong effect, detecting vasodilatory effects using the Magnus method requires a higher concentration than that of the test component that exerts vasodilatory effects in the body. In other words, the concentration of the test component that exerts vasodilatory effects using the Magnus method differs from the concentration of the test component that exerts vasodilatory effects in the body. Therefore, when considering the concentration and content of the test component that exerts the desired effect in the body, oral administration tests that can evaluate the effect in the body are generally used. Accordingly, a single oral administration test was conducted in rats to evaluate the vasodilatory effect. Since it is difficult to directly evaluate vasodilatory effects in the body, the vasodilatory effect was indirectly evaluated using a decrease in blood pressure, one of the downstream effects caused by vasodilation, as an indicator.

[0039] The single-dose oral administration study was conducted according to the following method. The single-dose oral administration study was conducted using male spontaneously hypertensive rats (SHR, manufactured by Charles River Co., Ltd., Japan) aged 17-18 weeks. Eighteen rats were divided into three groups of six rats each (low-dose citrate group, high-dose citrate group, and control group). After a one-week acclimatization period, each group of rats was fasted for 12 hours before being given a single oral dose of the sample (citric acid solution or purified water). Specifically, rats in the low-dose citrate group were given a single oral dose of 10 mg / kg-body weight of citrate solution, which was prepared by dissolving citrate in purified water. Rats in the high-dose citrate group were given a single oral dose of 100 mg / kg-body weight of citrate solution, which was prepared by dissolving citrate in purified water. Rats in the control group were given a single oral dose of purified water.

[0040] Using a non-invasive blood pressure monitor (Softron BP-98A, manufactured by Softron Co., Ltd.), we measured the blood pressure in the tail of rats using the tail cuff method to evaluate changes in systolic and diastolic blood pressure. Blood pressure was measured before sample administration and at 3, 6, 9, and 24 hours after administration. The results are shown in Figures 2 and 3.

[0041] Figure 2 is a graph showing the measurement results of systolic blood pressure changes. The horizontal axis of Figure 2 shows the elapsed time [h] after sample administration. Blood pressure was measured at 0 hours elapsed, and the sample was administered immediately afterward. The vertical axis of Figure 2 shows the change in systolic blood pressure [mmHg] relative to the measurement value before sample administration.

[0042] Figure 3 is a graph showing the measurement results of diastolic blood pressure changes. The horizontal axis of Figure 3 is the same as in Figure 2. The vertical axis of Figure 3 shows the change in diastolic blood pressure [mmHg] relative to the measurement value before sample administration.

[0043] As shown in Figure 2, in terms of systolic blood pressure, the low-dose citrate group (10 mg / kg-body weight) showed a significant decrease in systolic blood pressure 3 hours after administration compared with the control group. Furthermore, in the high-dose citrate group (100 mg / kg-body weight), a significant and marked decrease in systolic blood pressure was observed from 3 hours to 9 hours after administration compared with the control group.

[0044] As shown in Figure 3, in terms of diastolic blood pressure, the high-dose citrate group (100 mg / kg-body weight) showed a significant and marked decrease in diastolic blood pressure from 3 to 9 hours after administration compared to the control group.

[0045] From the above results, it can be understood that a significant vasodilatory effect can be obtained by administering 600 mg or more of citrate orally (this value is calculated by converting the low-dose citrate group's dose of 10 mg / kg-body weight to a human dose of 60 kg-body weight). Furthermore, as shown in Figures 2 and 3, it can be understood that a continuous vasodilatory effect can be obtained by administering 600 mg or more orally per day.

Claims

1. It contains at least one active ingredient selected from the group consisting of citric acid and its salts, The active ingredient is administered orally in an amount of 10 mg / kg-body weight or more and 100 mg / kg-body weight or less per dose, and is a vasodilator that significantly lowers systolic blood pressure 3 hours after administration (however, this excludes products containing condensed tannin oligomer components which are at least one dimer to thucaper derived from berry fruits or cocoa beans or persimmon fruits or leaves, and which consist of at least one of catechin, epicatechin, gallocatechin, epigallocatechin and / or their gallates as constituent units, procyanidin oligomers and / or prodelphinidins, health and beauty foods containing active ingredients which include citric acid, turmeric, alpha-lipoic acid, hyaluronic acid and collagen, health drinks which contain citric acid and seawater minerals, products which contain potassium magnesium citrate and products which contain blackcurrant concentrate).

2. The vasodilator according to claim 1, wherein the active ingredient is administered orally in an amount of 600 mg or more per day.

3. The vasodilator according to claim 1 or 2, wherein the content of the active ingredient is 600 mg or more.

4. A vasodilator according to any one of claims 1 to 3, which is a food composition for vasodilation.

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