JP2002241305A - Antihypertensive agent - Google Patents

Abstract

(57) Abstract: A prophylactic / therapeutic agent for hypertension comprising (a) γ-aminobutyric acid and (b) an angiotensin inhibitor as active ingredients. The drug of the present invention has an excellent antihypertensive effect, is highly safe, has a good feeling of taking, and is suitable for taking for a long time.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a prophylactic / therapeutic agent for hypertension which is suitable for long-term administration.

[0002]

2. Description of the Related Art The etiology of hypertension is still largely unknown, and it is estimated that various factors such as genetic background, diet and environmental factors are involved. Prevention of hypertension
Conventionally, thiazides, loop diuretics, calcium antagonists and the like have been used as therapeutic agents. But,
These drugs have a problem of side effects such as hypokalemia and erythropenia. Diet therapy, such as suppression of salt intake, is an effective method for preventing hypertension, but continuing it for a long period of time would be extremely troublesome.

[0003] In recent years, as the renin-angiotensin system has been recognized as a common factor causing hypertension, an angiotensin converting enzyme (AC
E) Inhibitors are regarded as effective agents for a wide range of hypertension. Naturally-derived ACs currently effective
Examples of the E inhibitor include peptides derived from milk, sardine, bonito and the like. However, these peptides have a bitter taste and a unique odor, so that they are not preferable in taste when taken orally. For this reason, especially for use in a form that is easy to take continuously such as food and drink,
The quantity was limited and it was difficult to obtain a satisfactory effect.

[0004] On the other hand, γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter existing in the brain and spinal cord of mammals, and its physiological effect is to increase blood flow in the brain.
Increases oxygen supply to increase brain metabolic function, acts on central and peripheral vasomotor centers to lower blood pressure,
Involves in suppressing the secretion of the antidiuretic hormone bumplessin to dilate blood vessels and lower blood pressure, increasing the hexokinase activity required for the introduction of the TCA cycle, and promoting glucose metabolism (new brain metabolic activation) , Edited by Eiichi Otomo, Pharmaceutical Journal (1987)), which is also used as a pharmaceutical for the purpose of activating brain metabolism. Also,
GABA is also used for food applications, for example,
GABA with enhanced GABA content by anaerobic treatment of rice germ
There are known enriched rice germ (Oriza Yuka Co., Ltd.) and GABARON tea (Nextage Co., Ltd.) whose tea leaves are anaerobically treated to increase the amount of GABA.

However, the ACE inhibitory peptide is also GABA
However, there is a limit to the blood pressure lowering effect even if the dose is increased by a certain amount or more alone. In addition, in essential hypertension, which accounts for the majority of hypertensive patients, there are various causes, and the effects of these ACE inhibitors or GABA alone will vary among individuals. For this reason, there is a need for a drug that is highly effective in preventing and treating hypertension in a wide range of patients, has no side effects, and is suitable for long-term administration.

[0006]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a drug which is effective for prevention and treatment of hypertension, has no side effects, has no adverse effect on flavor, and is suitable for long-term use. I do.

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies. As a result, surprisingly synergistic blood pressure lowering effect was obtained by using GABA and an angiotensin inhibitor in combination. The present invention has been found that they can be used for a long period of time, and that when both are used in combination, the flavor is good and suitable for long-term administration.

That is, the present invention provides a prophylactic / therapeutic agent for hypertension comprising (a) GABA and (b) an angiotensin inhibitor as active ingredients. The present invention also provides a food or drink containing the above agent for preventing or treating hypertension.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION GABA used in the present invention is a kind of amino acid produced by decarboxylation of glutamic acid, the production method is not particularly limited, and it is chemically synthesized or extracted from natural products including GABA. , Purification or enzymatic method can be used. For example, as an enzymatic method, glutamic acid is treated with glutamate decarboxylase to produce GABA.
Is prepared. When GABA is prepared by an enzymatic method, a food material containing glutamic acid as a starting material, for example, milk, meat, vegetables, or the like, a food material to which glutamic acid is added, or the like may be used. It may be performed using a fermentation method using microorganisms such as yeast, chlorella, and lactic acid bacteria.

[0010] Examples of natural products containing GABA include rice germ, tea leaves, pumpkins, mushrooms, and the like. GABA can be used as an extract obtained by extracting these with hot water, water, alcohol, or the like. It is.

The obtained GABA or a composition containing GABA may be used as it is, or may be used by appropriately subjecting it to processing means such as concentration and purification by a conventional method.

In the present invention, GABA is preferably used in an amount of 1 to 100 mg / day / person, particularly preferably 5 to 30 mg / day / person, since a moderate antihypertensive action is exhibited and the economy is good.

On the other hand, an angiotensin inhibitor (ACE inhibitor) used in the present invention is a substance that inhibits the activity of an enzyme (angiotensin converting enzyme) that converts angiotensin I to angiotensin II having vasoconstriction. Specifically, commercially available pralen tablets, sardine peptides, skipjack peptides, tuna peptides, and other fish-derived peptides, gelatin-derived peptides, and other meat-derived peptides, milk peptides, corn (α-zein, γ-zein ), Wheat (wheat gliadin), rice (rice protein), and peptides derived from grains such as soybean (soy protein). Among them, the use of peptides selected from fish-derived peptides and milk peptides such as sardine peptides, skipjack peptides, tuna peptides, etc. is preferred because they have a high blood pressure lowering effect when used in combination with GABA, and are preferably sardine peptides and milk peptides. Is preferred. Here, the peptide has a molecular weight of 200
~ 7000 peptides, including oligopeptides,
Particularly, an oligopeptide having 2 to 10 amino acid residues is preferable.

These ACE inhibitory peptides may be prepared by decomposing the raw protein with a protease, or may be prepared by decomposing the raw protein by a fermentation method using a microorganism. Further, those obtained by peptide synthesis may be used.

The amount of the ACE inhibitor used is not particularly limited, and is preferably 1 to 1000 mg / day / person, particularly for milk peptide and sardine peptide, since they exhibit a mild antihypertensive effect and are economically favorable. 3-10 mg / day / person is preferred.

In the present invention, a composition having a synergistically enhanced blood pressure lowering effect can be obtained by using GABA and an ACE inhibitor in combination. Prevention of these hypertension
The therapeutic agent can be used for applications such as medicine and food. As described above, when both are used as oral drugs, GABA is used in an amount of 0.01 to less in terms of flavor and hypotensive effect.
It is preferable that the content of the ACE inhibitor is 0.2 to 0.2% by weight, and the content of the ACE inhibitor is 0.01 to 0.2% by weight.

When the agent for preventing or treating hypertension of the present invention is used as a medicament, it can be made into various types of pharmaceutical compositions together with a pharmaceutically acceptable carrier according to a conventional method. For example, when an oral solid preparation is prepared, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, and the like are added to the above composition, and then the composition is treated with an ordinary drug. Tablets, coated tablets, granules, powders, capsules and the like can be produced by the method. As such additives, those generally used in the art may be used.For example, as excipients, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose , Silicic acid, etc .; water, ethanol,
Propanol, simple syrup, glucose solution, starch solution,
Gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, methylcellulose, ethylcellulose, calcium phosphate, polyvinylpyrrolidone, etc .; disintegrants are dried starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearin Acid monoglycerides, lactose, etc .; Lubricants include purified talc, stearate, borax, polyethylene glycol, etc .; Flavoring agents include sucrose, orange peel, citric acid, tartaric acid and the like.

When an oral liquid preparation is prepared, a flavoring agent, a buffer, a stabilizing agent,
Oral liquids, syrups, elixirs and the like can be produced by a conventional method by adding a deodorant and the like. In this case, those mentioned above may be used as the flavoring agent, and sodium citrate or the like may be used as the buffer, and tragacanth, gum arabic, gelatin or the like may be used as the stabilizer.

Further, the agent for preventing or treating hypertension of the present invention comprises
It can also be used as food or drink. Preferred foods and drinks here include fermented milk, processed fruit juice drinks, nutritional drinks, cookies, candies, tablet foods and the like, and particularly have various physiological effects and have long been popular as a food that contributes to health. Milk is preferred because it has a good flavor and a high antihypertensive effect. Food and drinks also include animal feed.

The method for producing the food or drink may be in accordance with a conventional method, and may be prepared by adding the above GABA and ACE inhibitor. In addition, in the case of foods and drinks accompanied by fermentation at the time of production, GA is produced by using the action of microorganisms or enzymes produced by microorganisms.
BA or peptide may be generated.

In the production of foods and drinks, other food materials, that is, various sugars, emulsifiers, thickeners, sweeteners, acidulants, fruit juices, and the like can be appropriately added. Specifically, sucrose, isomerized sugar, glucose, fructose,
Sugars such as palatinose, trehalose, lactose, and xylose; sugar alcohols such as sorbitol, xylitol, erythritol, lactitol, palatinit, reduced starch syrup, reduced maltose syrup; high-sweetness sweeteners such as aspartame, stevia, acesulfame potassium, sucralose, and sucrose Emulsifiers such as fatty acid esters, glycerin fatty acid esters, lecithin, thickening (stabilizing) agents such as carrageenan, xanthan gum, guar gum, pectin, locust bean gum, acidulants such as citric acid, lactic acid and malic acid, lemon juice, orange juice, Juices such as berry juice and the like can be mentioned. In addition, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, and vitamin E, and minerals such as calcium, iron, manganese, and zinc can be added.

[0022]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 (Synergistic antihypertensive effect of GABA and ACE inhibitor) Animal: SHR / Izm 8 weeks old (about 230 g), male, 6
Animals / group x 4 groups = 24 animals

[0024]

[Table 1]

Method: The blood pressure should not be different between the groups.
The SHRs were divided into 4 groups (n = 6), and each sample was administered at a single dose of 2 mL / kg using a gastric probe. After 1, 4, 8, and 24 hours, the systolic blood pressure was measured by the tail cuff method (cuff on the tail). Method of measuring by winding) Measurement was performed.

Statistical processing: A significance test was performed using a t-test on the physiological saline administration group used as a control. p <0.05 was considered significant.

Results: A stronger blood pressure lowering effect was observed when GABA or sardine peptide was used alone than when GABA or sardine peptide was used alone (FIG. 1). The experiment was performed by separately adding GABA or sardine peptide in a double amount.
With such an increase in the amount of addition, no difference was observed in the blood pressure lowering effect. From this, it was found that the combined effect of GABA and sardine peptide was synergistic.

Example 2 (Production of Fermented Milk) Lactococcus lactis YIT2027 and Lactobacillus casei YIT9029 were inoculated at a ratio of 10: 1 into a 20% skim milk solution heat-sterilized at 121 ° C. for 15 minutes.
After culturing at 30 ° C. for 3 days, fermented milk containing 30 mg / 100 mL of GABA was prepared. This was homogenized at 15 MPa using a homogenizer, and 0.05% of a sardine-derived antihypertensive peptide (manufactured by Senmi Extract Co., Ltd.) was added. Forty parts of fermented milk containing this peptide and GABA are mixed with 60 parts of a 15% sucrose solution, and a 0.1% final concentration of yogurt flavor (Ogawa flavor) is added to adjust the taste. A fermented milk product was obtained. When the obtained fermented milk product was ingested by 5 high blood pressure subjects at 100 mL / day for 1 month, the evaluation for taste was good and a sustained antihypertensive effect was observed. Also, sardine peptide (manufactured by Senmi Extract Co., Ltd.) was added to a final concentration of 0.3%, and fermented milk was prepared in the same manner as described above, and the flavor was evaluated. Bitterness and unpleasant odor were noticeable compared to the case of.

Example 3 (Production of Fermented Milk) Streptococcus thermophilus YIT2001 was added to a 15% skim milk solution heat-sterilized at 121 ° C. for 15 minutes.
% Inoculated to obtain fermented milk cultured at 35 ° C. for 24 hours. The amount of the peptide in the obtained fermented milk was measured using HPLC, and was found to be 0.5%. To this, GABA derived from tomato extract was added in an amount equivalent to 0.05%, and homogenized at 15 MPa with a homogenizer. To 40 parts of the fermented milk containing this peptide and GABA, 60 parts of a 15% sucrose solution and a yogurt flavor having a final concentration of 0.1% (manufactured by Ogawa Corporation).
Was added to adjust the taste to obtain a fermented milk product. The resulting fermented milk product was administered to 6 borderline hypertensive patients at 100 mL / day,
When they were taken for 8 weeks, the antihypertensive effect continued during drinking. The questionnaire after drinking was evaluated as easy to drink.

[0030]

The drug of the present invention has an excellent antihypertensive effect,
It has high safety and good feeling of taking, and is suitable for taking for a long time.

[Brief description of the drawings]

FIG. 1 is a diagram showing the antihypertensive effect of GABA, sardine peptide and their combination.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/197 A61P 9/12 38/00 A23L 2/00 F A61P 9/12 A61K 37/02 (72) Inventor Keisuke Matsumoto 1-1-19 Higashi-Shimbashi, Minato-ku, Tokyo, Japan Yakult Honsha (72) Inventor Hiroshi Misawa 1-1-19, Higashi-Shimbashi, Minato-ku, Tokyo F-term (Fukushima, Japan) Reference) 4B001 AC05 EC05 4B017 LC03 LK14 LK15 4B018 MD19 MD20 ME04 4C084 AA01 AA17 CA14 CA17 CA45 DC40 MA02 MA52 NA14 ZA422 ZC202 4C206 AA01 AA02 FA45 MA02 MA72 NA14 ZA42

Claims (5)

[Claims] 1. An agent for preventing or treating hypertension comprising (a) γ-aminobutyric acid and (b) an angiotensin inhibitor as active ingredients. 2. The preventive / therapeutic agent for hypertension according to claim 1, wherein (b) the angiotensin inhibitor is a peptide having angiotensin inhibitory activity. 3. The method according to claim 2, wherein the peptide is one or more peptides derived from fish, meat, milk or cereals. 4. A food or drink comprising the agent for preventing or treating hypertension according to claim 1. 5. The food or drink according to claim 4, wherein the food or drink is fermented milk.