JPH09255570A - Medicine and edible composition for lowering concentration of lipid in blood - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a highly safe medicine capable of improving the metabolism of lipid in vivo to lower the concentration of the lipid in blood and useful for treating and preventing hyperlipemia, arteriosclerosis, etc. SOLUTION: This medicine contains an isoflavone derivative of the formula [R<1> is H, OH; R<2> is OH, O-glucoside, O-(6"-O-succinyl)glucoside, O-(6"-O-malonyl) glucoside, O-(6"-O-acetyl)glucoside] in an amount of >=0.5wt.%, prefrably 2-25wt.%, as an active iugredient. This edible composition contains the compound of the formula in an amount of >=0.001wt.%, preferably 0.01-10wt.%. The compound of the formula is e.g. 7-O-glucopyranosy1-4'-hydroxy-isoflavone. The compound of the formula is administered at a daily dose of 0.1-4mg/kg, and is useful for preventing and treating ischemic cardiac diseases, cerebrovascular disorders, mammary cancer, colon cancer, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug and an edible composition useful for treating and preventing hyperlipidemia, arteriosclerosis and the like. More specifically, the present invention relates to a drug and an edible composition which are characterized by containing an isoflavone derivative as an active ingredient and which can improve lipid metabolism in vivo and reduce the lipid concentration in blood with high safety.

[0002]

2. Description of the Related Art In recent years,
BACKGROUND ART Hyperlipidemia, which is considered to be caused by lack of exercise, overnutrition, hormonal imbalance (menopause, etc.), has become a major problem with changes in lifestyle and aging.

At present, the causal relationship between hyperlipidemia including hypercholesterolemia and atherosclerosis is known as a common sense, and such atherosclerosis is a major adult disease of the present day. It has a significant significance in that it forms the basis of bloody heart disease and cerebrovascular accident (Hidenori Arai, "Total cholesterol and arteriosclerosis", Clinical adult disease, 25
Vol. 10, p. 1200-1204 (1995)).

Further, recent studies have pointed out a causal relationship between the onset of breast cancer, colon cancer, etc. and cholesterol, and have been proved based on various experiments.

By the way, as therapeutic or preventive methods for hyperlipidemia, exercise therapy, diet therapy and drug therapy have been proposed. The basic treatment of hyperlipidemia that is currently adopted is diet therapy, but when it is performed at home, nutritionally correct knowledge is required, and sometimes undernutrition, especially protein, vitamins or minerals. In practice, it is difficult to carry out the administration in the most suitable manner for the patient, because it is likely to cause a shortage of time. Also, according to exercise therapy,
Although it is possible to effectively reduce blood triglyceride, it has been reported that it has almost no effect on blood cholesterol levels (Atsushi Sasaki, "Serum lipid control by exercise, prevention of arteriosclerosis") ], Clinical Adult Diseases, Volume 25
10, pp. 1260 to 1263 (1995)). Regarding drug therapy, various drugs have been developed and are being used for treatment. However, some active ingredients may have side effects or exert a strong effect rapidly, so it may It is necessary to administer the drug while performing detailed monitoring.

[0006] Therefore, a drug having an action of gently lowering lipids in the blood without causing side effects and an edible composition exhibiting an effect by ingestion in meals are
It is extremely important from the perspective of preventing adult diseases such as arteriosclerosis,
These developments are being sought after.

[0007] To provide such drugs and compositions, EPA
And n-3 polyunsaturated fatty acids such as DHA have been studied. However, although these unsaturated fatty acids have been shown to effectively reduce triglyceride, long-term administration of 4 years is required to reduce total cholesterol levels, and short-term administration of 4 years or less is required. In the case of, it has been reported that the total cholesterol level can be significantly increased (Tomohito Hamasaki, "Functions and therapeutic effects of DHA / EPA", Clinical Adult Disease, 25, No. 10, pp. 1265-1269. (199
Five)).

[0008]

In view of the above-mentioned problems in the technical field of the present invention, the present inventors have conducted extensive and extensive research on various food ingredients, and as a result, the isoflavone derivative contained in soybean and the like in a large amount. Of the general formula (I)
The compound represented by has the effect of significantly lowering the serum cholesterol level, and was invented to discover that it is also highly safe for living organisms,
The following agents and edible compositions are provided.

That is, the present invention has the features described in (1) to (4) below.

(1) General formula (I)

[0011]

Embedded image

[In the formula, R ¹ represents H or OH, and R ²
Is OH, O-glucoside group, O- (6 "-O-succinyl) glucoside group, O- (6" -O-malonyl) glucoside group or O-
(Representing a 6 "-O-acetyl) glucoside group] is contained in the isoflavone derivative as an active ingredient, and a drug for reducing blood lipid concentration.

(2) The isoflavone derivative is daidzein, soybean in, 6 "-O-succinyl soybean in, 6" -O-
The agent according to (1) above, which is malonyl soybean in or 6 "-O-acetyl soybean.

(3) General formula (I)

[0015]

Embedded image

[In the formula, R ¹ represents H or OH, and R ²
Is OH, O-glucoside group, O- (6 "-O-succinyl) glucoside group, O- (6" -O-malonyl) glucoside group or O-
(Representing (6 "-O-acetyl) glucoside group] is contained as an active ingredient, the edible composition used for reducing the blood lipid concentration.

(4) The isoflavone derivative is daidzein, soybean in, 6 "-O-succinyl soybean in, 6" -O-
The edible composition according to (3) above, which is malonyl soybean in or 6 "-O-acetyl soybean in.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The isoflavone derivative contained as an active ingredient in the drug and edible composition for reducing blood lipid of the present invention has the general formula (I).

[0019]

Embedded image

[In the formula, R ¹ represents H or OH, and R ²
Is OH, O-glucoside group, O- (6 "-O-succinyl) glucoside group, O- (6" -O-malonyl) glucoside group or O-
Represents a (6 "-O-acetyl) glucoside group].

Among the isoflavone derivatives represented by the above general formula (I), daidzein, soybean in, 6 "-O-succinyl soybean, 6" -O-malonyl soybean or 6 "-O-
Acetyl soybean in is particularly preferred as the active ingredient.

The above isoflavone derivative can be obtained, for example, by extracting and purifying soybean seed or a part thereof, or a soybean fermented product, particularly preferably soybean hypocotyl or natto. Specifically, it is obtained by applying a raw material soybean hypocotyl or an alcoholic extract of natto to an adsorption column chromatography, a gel column chromatography, and a reversed phase column chromatography for purification.

Of the isoflavone derivatives, soybean in and daidzein can be obtained from Fujicco Co., Ltd.

Since the drug and the edible composition of the present invention can reduce the blood lipid level, especially the serum cholesterol level, hyperlipidemia, arteriosclerosis, and eventually ischemic heart disease, cerebrovascular disorder. Etc. and, for example, in the prevention and treatment of some cancers such as breast cancer and colon cancer.

As shown in the results of the acute toxicity test described below, the isoflavone derivative represented by the general formula (I) is orally or subcutaneously administered to mice or rats at a technical limit of 5,000 to 10,000 mg / kg. When administered in parallel, no deaths or poisoning symptoms attributable to these compounds were observed. Therefore, these compounds have low toxicity, are extremely safe, and are suitable as substances used to obtain desired effects.

The administration or intake amount of the isoflavone derivative represented by the general formula (I) varies depending on the condition or age of the subject of administration or intake, administration route, etc., but is usually 0.1 to 4 m.
g / kg body weight / day, preferably 0.2-1 mg / kg body weight / day is used. Administration or ingestion may be carried out once a day, or may be divided into a plurality of doses as needed and used in a predetermined amount.

The drug of the present invention is preferably orally administered for the purpose of preventing or treating the various disease states mentioned above.

When the pharmaceutical agent of the present invention is administered, it is a pharmacological agent which is commonly used in the art as a pharmaceutical agent and which does not show reactivity or deactivate the isoflavone derivative which is an active ingredient when mixed. It is advisable to prepare a unit dosage form composition suitable for administration, by admixing a pharmaceutically acceptable carrier.

For example, in order to prepare solid preparations such as tablets, pills, capsules, powders or granules as a dosage form suitable for oral administration, carboxymethylcellulose calcium, lactose, glucose, sucrose, etc. Agents, starch, disintegrators such as sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. It is used and formulated according to a conventional method.
These tablets, granules, capsules and the like can be appropriately coated to control disintegration and absorption in the body, such as enteric coated preparations.

For oral administration, for example, an emulsion,
Liquid preparations such as solutions, suspensions, syrups or elixirs may be manufactured according to a conventional method. Liquid formulations may also be presented in a form that dissolves or suspends in water or other suitable vehicle before use.

These preparations may contain the isoflavone derivative of the present invention in an amount of 0.5% by weight or more, preferably 2 to 25% by weight.

Further, the drug of the present invention may contain other active ingredients which are considered to be effective for treatment or prevention.

The edible composition containing the isoflavone derivative represented by the general formula (I) as an active ingredient of the present invention, which is used for reducing the lipid level in blood, contains 0.001% by weight or more of the active ingredient. , Preferably 0.01 to 10% by weight.

The form of the edible composition can be, for example, various forms suitable for beverages, confectionery, processed foods, seasonings and the like, and is not particularly limited.
Excipients, fillers, stabilizers, stabilizers, emulsifiers, sweeteners, flavors, colorants, colorants, etc., which are commonly used to form an edible composition, are used, as appropriate, against the active ingredients. As long as it does not exceed the range, it may be compounded and manufactured. The present invention will be described in more detail in the following examples, but it goes without saying that the present invention is not limited by the disclosure of these examples.

[0035]

EXAMPLES In the following examples, typical isoflavone derivatives represented by the general formula (I),
7-O-glucopyranosyl-4'-hydroxy-isoflavone (that is, soybean (purity 99% or more, manufactured by Fujicco Co., Ltd.)) and 7,4'-dihydroxy-isoflavone (that is, daidzein (purity 97% or more, manufactured by Fujicco Co., Ltd.) ))
Was used to examine its action and effect.

(Example 1) 7-O- in ovariectomized rats
Glucopyranosyl-4'-hydroxy-isoflavone serum
Cholesterol level lowering action Five 11-week-old female Sprague-Dawley rats 7 days after ovariectomy were treated as one group, and soybean in suspended in a 1% hydroxypropylcellulose aqueous solution was added at various doses shown in Table 1, Oral administration was carried out daily using a sonde for 4 weeks with normal water supply. After fasting overnight, blood was collected from the inferior vena cava of each rat, and each concentration of serum neutral fat, total cholesterol, HDL-cholesterol and LDL-cholesterol was quantified. In the control group, only 1% hydroxypropylcellulose aqueous solution was forcibly orally administered. The measurement results of each lipid concentration are shown in Table 1.

[0037]

[Table 1]

As is clear from Table 1, 25 mg of soybean in
/ Kg / day to 75 mg / kg / day dose-dependently decreases serum total cholesterol, HDL and LDL cholesterol levels, and soyin has the effect of reducing serum cholesterol It has been shown.

Example 2 Various in Ovariectomized Rats
Of serum cholesterol levels by isoflavone derivatives
Action On the 7th day after oophorectomy, 5 islets of 11-week-old female Sprague-Dawley rats were treated as a group, and each isoflavone derivative shown in Table 2 was orally administered at each dose for 4 weeks as in Example 1. After that, fasting and blood sampling were performed to quantify each lipid concentration. Table 2 shows the obtained results.

[0040]

[Table 2]

As is clearly shown in Table 2, all of the isoflavone derivatives used had a lowering effect on serum total cholesterol, HDL and LDL cholesterol levels, similar to the above-mentioned soyin.

From Examples 1 and 2 above, 7-O-glucopyranosyl-4'-hydroxyisoflavone (soybean in) and 7,4'-dihydroxy, which are typical compounds among the compounds represented by the general formula (I), are shown. Isoflavone (Daidzein), 6 "-O-succinyl soybean in, 6" -O-malonyl soybean in and 6 "-O-acetyl soybean in were observed to have a serum cholesterol lowering effect, and hyperlipidemia It was confirmed to be effective for the treatment and prevention of arteries and arteriosclerosis.

The acute toxicity test and formulation examples of the isoflavone derivative contained in the drug of the present invention are shown below.

Acute toxicity test 5-week-old ICR mice and 5-week-old Sprague-Dawley
Each group consisting of 10 male and 10 female rats was treated with 2, 2, and soybean or daidzein suspended in olive oil.
Orally in doses of 500, 5,000 and 10,000 mg / kg or
The doses of 1,250, 2,000 and 5,000 mg / kg were subcutaneously administered, and the observation was continued for 14 days after the administration. There were no deaths attributed to soybean or daidzein in any group, and no toxic symptoms were observed. Therefore,
The LD ₅₀ could not be calculated.

Formulation Example 1: Isoflavone derivative of the present invention
Tablets Contained Each of the components listed in Table 3 below was prepared in predetermined amounts.

[0046]

[Table 3]

Each component was classified with a sieve of 60 to 120 mesh and then mixed together by a V-type mixer. This is a direct compression machine (TG2S: manufactured by El Aka Co.)
To form a tablet with a plain surface plain tablet with a diameter of 8.5 mm 100
0 were produced.

Formulation Example 2: The isoflavone derivative of the present invention
Capsules contained Each of the components shown in Table 4 below was prepared in predetermined amounts.

[0049]

[Table 4]

Each component was classified with a 60-mesh sieve, and then mixed together by a V-type mixer. This was filled in 1000 capsules of No. 1 capsule to prepare a capsule.

Next, a preparation example of an edible composition containing the isoflavone derivative of the present invention is shown.

Preparation Example 1: The isoflavone derivative of the present invention
Preparation of Beverage Containing Each of the ingredients shown in Table 5 below was prepared in predetermined amounts.

[0053]

[Table 5]

Next, soybean in was added to water and suspended,
Then, after mixing the remaining ingredients with the obtained liquid,
It was instantly sterilized at 2 to 138 ° C. for 1 second and filled in a 180 ml glass bottle.

The beverage prepared in this manner has no astringency or astringent taste and is very delicious without impairing the original flavor of the fruit juice. It was satisfying.

Preparation Example 2: Isoflavone derivative of the present invention
Preparation of Containing Jelly First, the materials shown in Table 6 below were prepared in predetermined amounts.

[0057]

[Table 6]

Next, daidzein was added to water and dispersed,
To the obtained liquid, fruit juice, starch syrup and fragrance were added and mixed, and agar and granulated sugar were separately mixed and added to the mixed liquid.

While stirring well, these were heated to about 90 ° C. to melt the agar. After this melt was dispensed into a plastic cup for 50 ml, the upper surface of the cup was sealed with a plastic film and cooled at 5 to 10 ° C. to solidify to obtain a jelly.

The jelly thus prepared was very delicious and had an excellent quality as a "dessert".

[0061]

INDUSTRIAL APPLICABILITY According to the present invention, a drug and an edible composition effective for the prevention and treatment of hyperlipidemia, particularly hypercholesterolemia, arteriosclerosis, etc. by reducing blood lipid concentration Will be provided.

Further, the isoflavone derivative represented by the general formula (I), which is an active ingredient of the medicine and the edible composition of the present invention, is required for food ingredients such as taste and odor also in terms of safety. Since it is also excellent in palatability, it has an advantage that it can be ingested / administered in various modes.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location // C07D 311/36 C07H 17/07 C07H 17/07 A23L 2/26 2/00 F (72) Inventor Hitoshi Ishida 3107-2 Sena, Shizuoka City, Shizuoka Prefecture (72) Inventor Kunio Tsuji 1375-11 Ikeda, Shizuoka City, Shizuoka Prefecture

Claims (4)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ represents H or OH, and R ² represents OH, O-
Glucoside group, O- (6 "-O-succinyl) glucoside group, O-
(6 "-O-malonyl) glucoside group or O- (6" -O-acetyl) glucoside group] is included as an active ingredient to reduce blood lipid concentration. Drugs that make you. 2. The drug according to claim 1, wherein the isoflavone derivative is daidzein, soybean in, 6 "-O-succinyl soybean, 6" -O-malonyl soybean or 6 "-O-acetyl soybean. 3. A compound of the general formula (I) [In the formula, R ¹ represents H or OH, and R ² represents OH, O-
Glucoside group, O- (6 "-O-succinyl) glucoside group, O-
(6 "-O-malonyl) glucoside group or O- (6" -O-acetyl) glucoside group] is included as an active ingredient to reduce blood lipid concentration. An edible composition used for producing. 4. The edible food according to claim 3, wherein the isoflavone derivative is daidzein, soybean in, 6 "-O-succinyl soybean, 6" -O-malonyl soybean or 6 "-O-acetyl soybean. Composition.