JP2024083632A - 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, the increase in lifestyle-related diseases such as hypertension caused by poor diet, lack of exercise, mental stress, smoking, and genetic factors has become a problem.

Drugs used to treat hypertension have a variety of mechanisms of action, including calcium (Ca) antagonists, which lower blood pressure by dilating blood vessels; angiotensin-converting enzyme (ACE) inhibitors, which lower blood pressure by suppressing the production of angiotensin II, which has a blood pressure-raising effect; and angiotensin receptor blockers (ARBs), which lower blood pressure by inhibiting the binding of angiotensin II to its receptors.

As a composition for dilating blood vessels, for example, Patent Document 1 describes a vasodilator containing as active ingredients at least one condensed tannin oligomer component of a dimer to 13-mer derived from berries, cacao beans, or persimmon fruits or leaves, and at least one organic acid component, in which 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.

International Publication No. 2010/092941

The vasodilator described in Patent Document 1 is a combination of a specific condensed tannin oligomer component and an organic acid component as an active ingredient, which synergistically improves the vasodilatory effect compared to the case of using only the components alone. Patent Document 1 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 examples in Patent Document 1, the citric acid concentration in the samples was all 100 μg/mL or less. As will be seen from the examples described later, when such a low concentration of citric acid was used in the Magnus method, no vasodilatory effect was observed, so it can be said that Patent Document 1 does not even suggest the vasodilatory effect of citric acid alone.

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

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

The above vasodilator contains at least one active ingredient selected from the group consisting of citric acid and its salts, and therefore exhibits a significant vasodilatory effect.

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

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

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

The present invention provides a novel vasodilator.

1 is a graph showing the measurement results of vasodilatory action (vasodilatory rate) in Test Example 1. 1 is a graph showing the measurement results of changes in systolic blood pressure in Test Example 2. 1 is a graph showing the measurement results of diastolic blood pressure change in Test Example 2.

The following describes in detail the embodiments of the present invention. Note that the present invention is not limited to the following embodiments.

The vasodilator of this embodiment contains at least one active ingredient selected from the group consisting of citric acid and its salts.

(Active ingredient)
The active ingredient of the vasodilator according to this 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. Citric acid may be citric acid anhydride or citric acid hydrate.

There are no particular limitations on the salt of citric acid, so long as it is acceptable as a food, quasi-drug, or pharmaceutical. Specific examples of the salt of citric acid 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 of this embodiment may contain, as an active ingredient, one type of citric acid or a salt thereof, or two or more types.

(Active ingredient content)
The vasodilator according to the present embodiment preferably contains an effective amount of the above-mentioned active ingredient. The term "effective amount" means an amount that exerts a vasodilatory effect when administered.

The content of the active ingredient in the vasodilator according to this embodiment can be set appropriately depending on the specific aspects of the vasodilator (e.g., form, method of use, dosage, etc.).

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

The above-mentioned daily oral administration (oral intake) amount 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. From the viewpoint of vasodilatory action, there is no particular upper limit to the above-mentioned daily oral administration (oral intake) amount, but from the viewpoint of reducing production costs, it may be, for example, 20,000 mg or less, 15,000 mg or less, 10,000 mg or less, 8,000 mg or less, or 6,000 mg or less. The above-mentioned daily oral administration (oral intake) amount is preferably an amount per 60 kg body weight.

The content of the active ingredient in the vasodilator according to this embodiment is appropriately set according to the specific aspect of the vasodilator (e.g., form, usage, dosage, etc.), but in one aspect, the content of the 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 possible to easily achieve the above-mentioned daily oral administration (oral intake) amount. The upper limit of the content of the active ingredient in the vasodilator according to this embodiment may be, for example, 20,000 mg or less, 15,000 mg or less, 10,000 mg or less, 8,000 mg or less, or 6,000 mg or less.

The vasodilator according to this embodiment may be administered orally (ingested orally) or parenterally, but is preferably administered orally (ingested orally). The vasodilator may be administered (ingested) once a day, or may be administered (ingested) in multiple divided doses per day.

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

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

(Form of vasodilator)
The vasodilator according to the present embodiment may be in any form, such as a solid, a liquid (including a solution and a suspension), a paste, etc. In addition, the vasodilator according to the present embodiment may be in any form, such as a tablet (orally disintegrating tablet, chewable tablet, film-coated tablet, etc.), a capsule, a powder, a granule, a liquid (syrup, jelly, etc.), an ointment, a plaster, etc.

Specific Embodiments of Vasodilators
The vasodilator according to the present embodiment can be prepared, for example, as a food composition (beverage and food), a quasi-drug, or a pharmaceutical. Examples of beverages include water, soft drinks, fruit juice drinks, carbonated drinks, milk drinks, alcoholic drinks, sports drinks, and nutritional drinks. Examples of foods include bread, noodles, rice, tofu, dairy products, soy sauce, miso, and confectionery. Examples of food compositions include health foods, functional foods, special purpose foods, nutritional supplements, supplements, and foods for specified health uses.

The vasodilator according to this embodiment is preferably a food composition (vasodilator food composition) because it can be easily taken on a daily basis. The vasodilator food composition according to this embodiment may take the form described above, and is preferably a beverage (vasodilator beverage) because it can be easily taken on a daily basis.

(Method of manufacturing vasodilators)
The vasodilator according to the present embodiment can be obtained by, for example, blending the above-mentioned active ingredients according to the specific embodiment, and can preferably be obtained by preparing the vasodilator so as to contain an effective amount of the above-mentioned active ingredients. In this case, as the active ingredients, citric acid or a salt thereof, citric acid or a salt thereof itself may be used, or a composition containing citric acid or a salt thereof (e.g., fruit juice such as lemon juice, grapefruit juice, orange juice, mandarin juice, and plum juice) may be used.

(Action and Effect)
The vasodilator according to the present embodiment contains at least one active ingredient selected from the group consisting of citric acid and its salts, and thus can dilate blood vessels by administering (ingesting) the vasodilator. As a result of dilating blood vessels, blood circulation improves, and poor circulation, stiff shoulders, headaches, hypertension, angina, constipation, and the like can be improved or prevented.

The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.

<Test Example 1: Vasodilatory Effect Test>
A vasodilator test was performed using the Magnus method. Specifically, the vasodilator test was performed according to the following method. The thoracic aorta was excised from male spontaneously hypertensive rats (SHR, Charles River Japan, Inc.) aged 14 to 16 weeks, and the connective tissue attached to the blood vessel was removed to prepare a ring specimen with a width of about 2 to 3 mm. The ring specimen was attached to a tension _measurement hook in the organ bath of an isometric tension tester (Easy _Magnus Experimental Apparatus, manufactured by Iwashiya Kishimoto Medical Industry Co., Ltd.) filled with Krebs solution (composition: 118 mM NaCl, 4.7 mM _KCl , 1.2 mM _KH2PO4 , 1.2 mM _MgSO4 , 25 mM NaHCO3, _2.5 mM CaCl2, and 11.1 mM Glucose) at 37 _° C and aerated with mixed gas (95% O2, 5% CO2). A resting tension of 1.5 g was applied to the ring specimen, and the Krebs solution was replaced at 15-minute intervals to stabilize for 60 minutes, and the contraction response 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 three times with Krebs solution, the tension was returned to the resting tension, and replaced with Krebs solution, and phenylephrine (0.3 μM) was added to contract the blood vessel. When the tension was stabilized, citric acid solution (Example 1) or lemon juice (Example 2) was added cumulatively so that the citric acid concentration in the organ bath became 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 dilation rate (%) of the ring specimen. The dilation rate (%) is the ratio (percentage) of the increase or decrease in vascular tension when a citric acid solution or lemon juice is added to the vascular tension when contracted from resting tension by phenylephrine. The results are shown in Figure 1 and Table 1.

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

<Test Example 2: Single oral administration test>
The Magnus method used in Test Example 1 is a method in which a drug (phenylephrine in Test Example 1) is applied to blood vessels extracted from a living body to forcibly contract the blood vessels, and then a test component (citric acid solution or lemon juice in Test Example 1) is applied to the contracted blood vessels to examine the state of blood vessel dilation. Since the added drug acts strongly, in order to detect the vasodilatory effect by the Magnus method, the concentration must be higher than the concentration of the test component that exerts the vasodilatory effect in the living body. In other words, the concentration of the test component that exerts the vasodilatory effect in the Magnus method is different from the concentration of the test component that exerts the vasodilatory effect in the living body, so when considering the concentration and content of the test component that exerts the desired effect in the living body, an oral administration test that can evaluate the effect in the living body is generally used. Therefore, a single oral administration test was performed in rats to evaluate the vasodilatory effect. Since it is difficult to directly evaluate the vasodilatory effect in the living body, the vasodilatory effect was indirectly evaluated using blood pressure reduction, which is one of the downstream effects caused by vasodilatory effect, as an index.

The single oral administration test was specifically conducted according to the following method. The single oral administration test was conducted using male spontaneously hypertensive rats (SHR, Charles River Japan, Inc.) aged 17 to 18 weeks. Eighteen rats were divided into three groups of six rats each (low-dose citric acid group, high-dose citric acid group, and control group). After one week of acclimation, the rats in each group were fasted for 12 hours, and then a single oral administration of a sample (citric acid solution or pure water) was administered to them. Specifically, the rats in the low-dose citric acid group were orally administered a single dose of a citric acid solution in which citric acid was dissolved in pure water at a dose of 10 mg citric acid/kg-body weight. The rats in the high-dose citric acid group were orally administered a single dose of a citric acid solution in which citric acid was dissolved in pure water at a dose of 100 mg citric acid/kg-body weight. The rats in the control group were orally administered a single dose of pure water.

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

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

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

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

As shown in Figure 3, a significant and marked decrease in diastolic blood pressure was observed in the high-dose citric acid group (100 mg/kg body weight) from 3 to 9 hours after administration compared to the control group.

From the above results, it can be seen that a significant vasodilatory effect can be obtained by orally administering (ingesting) citric acid at a dose of 600 mg or more (the value calculated by converting 10 mg/kg-body weight in the low-dose citric acid group to a human value of 60 kg-body weight). In addition, as shown in Figures 2 and 3, it can be seen that a continuous vasodilatory effect can be obtained by orally administering (ingesting) 600 mg or more per day.

Claims (1)

A vasodilator containing at least one active ingredient selected from the group consisting of citric acid and its salts.

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