JP2002080356A - Preventing and treating agent for hypertension - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a preventing and treating agent for hypertension capable of improving hypertension, useful as a medicine for preventing and treating hypertension, and further useful as a health food widely usable as a food material. SOLUTION: (a) A compound selected from a group consisting of coffeic acid, chlorogenic acid and ferulic acid, and pharmaceutically permissible salts of the compounds, and (b)a preventing and treating agent for hypertension containing a central nerve-stimulating component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for preventing and treating hypertension.

[0002]

2. Description of the Related Art Heart diseases such as angina pectoris, myocardial infarction, and heart failure or cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage are very closely related to hypertension. Occupies second and third place. According to the Ministry of Health and Welfare Basic Survey on Human Life (1998), the number of patients who visit the hospital for hypertension is 64 per 1,000 in Japan, which is the leading cause of the disease. As measures against hypertension, diuretics,
Antihypertensive drugs, such as sympathomimetic drugs, vasodilators, and angiotensin exchange enzyme inhibitors, are mainly applied to patients with severe hypertension. On the other hand, general therapies aimed at improving lifestyle, such as diet, exercise, and restricting drinking and smoking, are widely applied to hypertensive patients from mild to severe. Is recognized. Above all, it is important to improve eating habits, and there are many foods that are said to have a blood pressure lowering effect as a tradition. In addition, search for food-derived blood pressure lowering materials has been actively conducted, and many active ingredients having blood pressure lowering action have been separated and identified.

[0003]

However, many of the pharmaceuticals currently used for the purpose of countermeasures against hypertension are satisfactory in terms of efficacy, but because of the side effects such as tachycardia and bradycardia which are not a little present. The burden on the patient is great. In addition, foods that are said to have a blood pressure lowering action or active ingredients thereof are not always satisfactory in their effectiveness, and many require a long period of time to develop blood pressure lowering. Accordingly, an object of the present invention is to provide a prophylactic / therapeutic agent for hypertension which is excellent in safety, does not burden daily intake, and has a higher antihypertensive effect.

[0004]

The present invention relates to a compound selected from the group consisting of (a) caffeic acid, chlorogenic acid, ferulic acid and pharmaceutically acceptable salts thereof, and (b) a central nervous stimulating component. And a prophylactic / therapeutic agent for hypertension containing

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The component (a) used in the present invention may be one synthesized by chemical synthesis, but a natural product such as a plant can be used. Examples of the plant include a plant containing the component (a), for example, coffee, onion, radish, lemon, moloheiya, senkyu, eucalyptus, pine, spinach, agi, sweet potato, corn, barley, rice, and the like.

Caffeic acid and chlorogenic acid are plant extracts,
For example, it may be extracted from plants such as green coffee beans, leaves of southern sky, immature apples, and the like. The one obtained by extraction in is preferred.

Ferulic acid is a compound whose ester form is a natural product such as rice or barley, particularly a compound contained in plants, and can be obtained as a purified product from plants or a synthetic product obtained industrially. The ferulic acid ester is obtained, for example, after distributing rice bran oil obtained from rice bran with aqueous ethanol and hexane at room temperature under mild alkalinity, and then into an aqueous ethanol fraction. Ferulic acid can be obtained by hydrolyzing and purifying the ferulic acid ester obtained in the above step with sulfuric acid under pressure and heat, or by using bacteria (Pseudomonas).
, The scrophulariaceae (Syzygium aromaticum ME)
(RRILL et PERRY) from buds and leaves, and cultured in a culture solution containing clove oil obtained by steam distillation or eugenol obtained by refining clove oil, and the culture solution can be separated and purified. it can. When ferulic acid is prepared by chemical synthesis, it can be produced, for example, by a condensation reaction between vanillin and malonic acid (Journal of Japan).
American Chemical Society, 74, 5346, 1952). In addition, caffeic acid, chlorogenic acid, ferulic acid or a pharmaceutically acceptable salt thereof has a stereoisomer,
In the present invention, a pure stereoisomer or a mixture thereof can be used.

[0008] The use of caffeic, chlorogenic and ferulic acids in the form of pharmaceutically acceptable salts improves water solubility and increases physiological effectiveness. Examples of the base substance for salt formation of these pharmaceutically acceptable salts include hydroxides of alkali metals or alkaline earth metals (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, Inorganic bases such as calcium hydroxide or ammonium hydroxide), arginine, lysine,
Basic amino acids such as histidine and ornithine, or organic bases such as monoethanolamine, diethanolamine and triethanolamine are used. Particularly preferred are hydroxides of alkali metals or alkaline earth metals. After preparing these salts,
The salt thereof may be contained in the agent for preventing or treating hypertension of the present invention, or a salt-forming component may be separately contained and reacted in the system.

As the component (a), two or more compounds selected from the group consisting of caffeic acid, chlorogenic acid, ferulic acid and pharmaceutically acceptable salts thereof may be used in combination.

The component (b) used in the present invention stimulates the central nervous system and induces an excitatory effect, and is preferably selected from the group consisting of the pungent components of ginger, pepper and pepper. Ginger, pepper and pepper are known as spices. Ginger is a plant belonging to the family Zingiberaceae, pepper is a plant belonging to the family Capsicum,
Pepper is a plant belonging to the family Pepperaceae. The pungent components of these plants are ginger for cinerol,
Zingerone, gingerol, ginger, etc. 0.6 to 10% by weight in ginger (hereinafter simply referred to as%), pepper is about 20% in capsicin etc. in pepper, and about 6 to 13% in pepper is piperine etc. Is done. These pungent components may be extracts such as solvent extraction using water, an organic solvent or the like, or may be commercially available products. Also, two or more kinds may be used in combination.

The agent for preventing or treating hypertension of the present invention can be made into an oral or parenteral composition by adding a pharmaceutically acceptable carrier to the above active ingredient. Examples of the oral composition include tablets, granules, fine granules, pills, powders, capsules (including hard capsules and soft capsules), troches, chewables, and liquids (drinks). . Examples of the parenteral composition include intravenous preparations such as injections, suppositories, and external preparations for skin.

The agent for preventing or treating hypertension of the present invention can be added to foods. In this case, beverages such as juices, liquid foods such as soups, milky or pasty foods such as curry, semi-solid foods such as jelly and gummy gums, solid foods such as gum and tofu, or powdered foods, margarine, Oil-and-fat-containing foods such as mayonnaise and dressing are exemplified.

In the preventive or therapeutic agent for hypertension of the present invention, component (a) is 0.005 to 5%, more preferably 0.01 to 5%.
The content of component (b) is 1%, preferably 0.001 to 1%, more preferably 0.005 to 0.5%.

The daily dosage of the prophylactic / therapeutic agent for hypertension of the present invention per adult (body weight: 60 kg) is 0.1% as caffeic acid, chlorogenic acid, ferulic acid or a pharmaceutically acceptable salt of the component (a). It is preferably such that it consumes 001 to 10 g, especially 0.01 to 5 g. The central nervous system stimulating component of component (b) is 0.1 mg to 1 mg per day.
g, particularly preferably 1 to 500 mg, so as to be taken simultaneously.

[0015]

Example 1 Test Example 1 Evaluation of suppression of increase in blood pressure in rats i) Experimental materials and methods (a) Animal used A 6-week-old male spontaneously hypertensive rat (SHR) was prepared for 7 consecutive days in a row. By measuring blood pressure using an observational blood pressure measurement device (manufactured by Softlon),
After the rats were sufficiently familiarized with the blood pressure measurement operation, an evaluation test was started. All rats had a temperature of 25 ± 1 ° C., a relative humidity of 55 ± 10%, and an illumination time of 12 hours (7:00 am to 7 pm)
H) (bred room in the rat area).

(B) Administration method and dosage In the control group, drinking water and commercially available powdered feed were freely taken.
In Comparative Section 1, ferulic acid (Wako Pure Chemical Industries, Ltd.)
% Water was added to the water to make drinking water, and a commercially available powdered feed was freely ingested. In Test Zone 1, drinking water was prepared by adding caffeic acid (Wako Pure Chemical Co., Ltd.) at a concentration of 0.2%, and 0.1% capsaicin (Wako Pure Chemical Co., Ltd.) was added to commercially available powdered feed. ) Was freely taken. In test plot 2, chlorogenic acid (Wako Pure Chemical Industries, Ltd.) was 0.2%
Water added at a concentration of water was used as drinking water, and commercially available powdered feed supplemented with 0.1% gingerol (Matsuura Pharmaceutical Co., Ltd.) was allowed to freely ingest. In Test Zone 3, drinking water was obtained by adding ferulic acid at a concentration of 0.2% to water, and commercially available powdered feed containing 0.1% piperine (Wako Pure Chemical Industries, Ltd.) was freely taken. I let it.

(C) Test method Six SHRs were used per group, and after 4 weeks, systolic blood pressure of the tail artery was measured.

(D) Statistical processing method The obtained test results are expressed as an average value and a standard error.
A t's t-test was performed and the significance level was set to 5% or less.

Ii) Results Table 1 shows systolic blood pressure before administration and 4 weeks after administration. As is evident from Table 1, a remarkable inhibitory effect on the increase in blood pressure was recognized by using caffeic acid, chlorogenic acid, ferulic acid or a pharmaceutically acceptable salt in combination with the central nervous system stimulating component.

[0020]

[Table 1]

Test Example 2 Evaluation of blood pressure lowering in rats i) Experimental materials and methods (a) Animals used Male 14-week-old male spontaneously hypertensive rats (SHR) were preliminarily bred in the same manner as in Test Example 1.

(B) Administration Method and Dose In the control group, water was orally administered. 0.2% in Comparative Zone 1
Ferulic acid aqueous solution was orally administered. In test plot 1, 0.
A 2% caffeic acid and 0.01% capsaicin aqueous solution were orally administered. In test group 2, 0.2% chlorogenic acid and 0.01% gingerol aqueous solution were orally administered. In test group 3, 0.2% ferulic acid and 0.01% piperine aqueous solution were orally administered.

(C) Test Method Six SHRs were used per group, and the systolic blood pressure of the tail artery was measured one hour after administration.

(D) Statistical processing method The procedure was the same as in Test Example 1.

Table 2 shows the systolic blood pressure before the start of administration and one hour after administration. As is clear from Table 2, a remarkable drop in blood pressure was observed.

[0026]

[Table 2]

Example 1 Soft capsule In a soft capsule shell (oval type, weight 150 mg), 350 mg of soybean oil, 50 mg of ferulic acid and 100 capsaicin
mg was filled to produce a soft capsule.

Example 2 Beverage (health food) Skim milk powder 3.5% Ginger extract (Matsuura Pharmaceutical Co., Ltd.) 3.5 Fructose 9.0 Sodium ferulate 0.1 Citric acid 0.1 Ascorbic acid 0.1 Flavor 0.1 Water 83.6 The storage stability of the beverage having the above composition was high, and the flavor was also good.

Example 3 Cookies (health food) Rapeseed oil 15 g Corn starch 15 Piperine 1 Flour 50 Butter 5 Fructose 14 Ferulic acid 1 Salt 0.5 Baking soda 0.5 Water 10 A cookie having the above composition was baked. It was delicious.

[0030]

The present invention improves hypertension, is useful as a medicament for prevention and treatment of hypertension, and is widely used as a food material and useful as a health food.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/216 A61K 35/78 R 4C206 35/78 45/06 A61P 9/12 45/06 A23D 9/00 516 A61P 9/12 A23L 2/00 F (72) Inventor Ichiro Tokimitsu 2606 Akabane, Kaga-cho, Haga-gun, Tochigi Pref. DG05 DL02 DP10 DX01 4C084 AA22 MA02 NA14 ZA022 ZA421 4C088 AB36 AB50 AB81 BA11 MA07 NA14 ZA02 ZA42 4C206 AA01 AA02 DA21 DB20 MA03 MA04 NA14 ZA42

Claims (3)

[Claims] 1. Prevention and treatment of hypertension containing (a) a compound selected from the group consisting of caffeic acid, chlorogenic acid, ferulic acid and pharmaceutically acceptable salts thereof, and (b) a central nervous system stimulating component. Agent. 2. The prophylactic / therapeutic agent for hypertension according to claim 1, wherein the central nervous system stimulating component is selected from the group consisting of ginger, chili, and pungent component of pepper. 3. A food containing the agent for preventing or treating hypertension according to claim 1 or 2.