JP5437672B2 - Reducing agent for serum uric acid level - Google Patents

Description

  The present invention relates to a serum uric acid level reducing agent, and in particular, serum that has a remarkable effect of reducing serum uric acid level and is excellent in safety and useful as a therapeutic / preventive measure for hyperuricemia in daily life. The present invention relates to a medium uric acid level reducing agent.

  There are two types of uric acid accumulation in the body, one in which purines are biosynthesized in the liver and metabolized to uric acid, and the other is metabolized from dietary purines by ingestion of nucleic acid, protein, fructose and alcohol. A state in which a large amount of uric acid is accumulated is called hyperuricemia, and complications such as gout develop if hyperuricemia persists for a long period of time.

As therapeutic agents for hyperuricemia, benzbromarone, brobenecid (uric acid excretion promoter), potassium citrate (alkalizing agent), allopurinol (metabolic inhibitor to uric acid) and the like are used. Since these are transient effects and are pharmaceuticals, they were not usable as preventive measures for people with borderline hyperuricemia in daily life.
Today, hyperuricemia is increasing and becoming younger due to excessive intake of nutrients and prejudice, and there is a need for safe and highly effective preventive measures that can be used in daily life against mild and borderline hyperuricemia, which is a gout reserve group. It has been.

  Patent Document 1 (Japanese Patent Laid-Open No. 2006-273762) describes a uric acid excretion enhancer containing ellagic acid as an active ingredient, such as a pomegranate extract. Patent Document 2 (Japanese Patent Laid-Open No. 2006-206474) describes a nuclease inhibitor containing alginic acid or a derivative thereof as an active ingredient. Patent Document 3 (Patent No. 3768795) describes a xanthine oxidase inhibitor and a hyperuricemia-improving agent containing lobster and / or red scenic belonging to the family Aceraceae.

JP 2006-273762 A JP 2006-206474 A Japanese Patent No. 3768795

  Although the above-described plant extracts of pomegranate and others inhibit the uric acid producing enzyme XOD (xanthine oxidase), the inhibitory effect is not sufficient. Accordingly, an object of the present invention is to provide an active ingredient that has a remarkable effect of reducing serum uric acid level and is excellent in safety and useful as a therapeutic / preventive measure for hyperuricemia in daily life.

  As a result of intensive studies, the present inventors have found that phloroglucinol and its polymer contained in the ascophyllum extract and its tamarind extract have an effect of reducing serum uric acid level, and have reached the present invention. .

The present invention provides the following [1] to [5].
[1] A serum uric acid level reducing agent comprising as an active ingredient at least one selected from the group consisting of phloroglucinol and a polymer thereof, and a tamarind extract.
[2] The serum uric acid level reducing agent according to [1], wherein the phloroglucinol and a polymer thereof are an ascophyllum extract.
[3] The serum uric acid level reducing agent according to [1] or [2], further containing anserine as an active ingredient.
[4] The serum uric acid level reducing agent according to any one of [1] to [3], wherein the tamarind extract contains one or more selected from the group consisting of epicatechin and its condensation polymer.
[5] A food or drink comprising the serum uric acid level reducing agent according to any one of [1] to [4].

  According to the present invention, serum uric acid level has a remarkable effect of reducing serum uric acid level and is excellent in safety and useful as a therapeutic / preventive measure for hyperuricemia in daily life and gout that is a complication thereof. A value reducing agent is provided. The serum uric acid level-reducing agent of the present invention is useful as various pharmaceuticals, foods and the like, and is expected to be used particularly as a health food.

FIG. 1 is a graph showing the results of xanthine oxidase (XOD) activity inhibition evaluation of various polyphenols. FIG. 2 is a diagram showing the administration period of samples and the like in the test of Example 2.

  The active ingredient of the serum uric acid level-reducing agent of the present invention is at least one component selected from the group consisting of phloroglucinol and its polymer, and tamarind extract. In addition, the said active ingredient may use only 1 type, and may be used in combination of 2 or more type.

Phloroglucinol (1,3,5-trihydroxybenzene or benzene-1,3,5-triol) is a compound represented by the following structural formula (I-1) and is a kind of polyphenol. In the present invention, phloroglucinol may take the form of a pharmacologically acceptable salt or hydrate with a metal or the like.

The phloroglucinol polymer is a kind of polyphenol obtained by dehydration condensation of two or more of the above phloroglucinol. For example, as in the polymer represented by the following structural formula (I-2), usually several tens to hundreds of phloroglucinol are bonded, and the degree of polymerization is not particularly limited, and phloroglucinol is regarded as one unit. What consists of 2 units or more should just be sufficient.

  The molecular weight of the phloroglucinol polymer is not particularly limited, but those having a number average molecular weight of around 10,000 (usually 150,000 or less, preferably 1000 to 30000) are preferred. Those having a number average molecular weight of about 10,000 correspond to polymers having about 10 to 100 phloroglucinol. In the present invention, the number average molecular weight means that measured by gel filtration chromatography. For the measurement, a column using a styrene-based filler is used, and tetrahydrofuran (THF) is used for the mobile phase. As internal standards, benzene (molecular weight 78) and polystyrene (molecular weight 4000, 25000, 50000 and 170000) are used (0.6 mg / 3 mL THF).

  Phloroglucinol and its polymer can be synthesized and used, but organisms containing these molecules and extracts thereof can be used. Examples of such organisms include algae and are included in brown algae and red algae. In particular, algae of the genus Ascophilum is preferable. A representative algae of the genus Ascophilum is Ascophyllum nodosum.

  Ascophyllum nodsum is a kind of dehydrated algae of the family Fucaceae that grows naturally in Scandinavia and Canada. In France it is allowed as food by law. There are eating habits in France, Iceland, Scandinavia and others. While being dried and drunk as tea, it is industrially used as a raw material for alginic acid, a food additive (stabilizer), and as a fertilizer and feed.

  In the present invention, it is preferable to use an ascofilum extract (ascofilum seaweed extract) as phloroglucinol and its polymer. The ascofilum extract means an extract obtained by extracting a plant body of a living organism (seaweed) belonging to the genus Ascophilum.

  The polyphenol content (corresponding to phloroglucinol) of the ascophyllum extract is not particularly limited, but since a higher effect can be obtained even if the amount used is reduced, it is preferably 75% by mass or more. More preferably, it is the range of 75-90 mass%.

  Although the extraction method of an ascophyllum extract is not particularly limited, it can be extracted using a solvent such as water, hot water, alcohol, or a mixture thereof. After extraction, dialysis, purification using various columns, lyophilization, or the like may be performed as necessary.

  Ascophyllum extract may be a commercially available product such as seaweed polyphenol (RIKEN vitamin).

  In the present invention, the tamarind extract means one obtained by extracting a plant body (for example, a seed, particularly a seed coat part) of a plant belonging to the genus Tamarind. An example of a Tamarind genus plant is tamarind (Tamarindus indica L.). Tamarind (Tamarindus indica L.) is an evergreen tree plant native to Africa, native to tropical regions such as Asia and Africa, and cultivated in India and Thailand. In India, it is used for flavoring curry and sauce. In Japan, polysaccharides contained in the endosperm portion of seeds are used as foods for thickeners as tamarind seed gum. Examples of the extraction site of the plant of the genus Tamarind include, for example, seeds, and particularly preferably seed coat portions.

  The extraction method of the tamarind extract is not particularly limited. When tamarind seed coat is used as a material, extraction can be performed using a solvent such as water, hot water, alcohol, or a mixture thereof. The extraction conditions can be appropriately determined depending on the solvent used. After extraction, dialysis, purification using various columns, lyophilization, or the like may be performed as necessary.

  A commercial item can also be used for a tamarind extract, for example, Indian Date Extract (Maruzen Pharmaceutical) can be mentioned.

  Tamarind extract contains abundant polyphenols (usually 35% by mass or more), and usually 5% by mass (sometimes 10% by mass or more) is occupied by epicatechin and its condensation polymer.

  The content of polyphenol (equicatechin equivalent amount) of the tamarind extract is not particularly limited, but a higher effect can be obtained even if the amount used is reduced, so that it is preferably 35% by mass or more. More preferably, it is the range of 35-60 mass%.

The epicatechin condensation polymer means a polymer obtained by condensing two or more epicatechins (l-epicatechin). The structural formula of the epicatechin condensation polymer is as shown in the following formula (II). N in the formula represents an integer of 0 or more.

  The degree of polymerization of the epicatechin condensation polymer in the tamarind extract (that is, the number of n in the formula (II)) is generally in the range of 2 to 100, particularly in the range of 2 to 10. Moreover, the number average molecular weight of an epicatechin condensation polymer is usually 300-30000, and many are 1000-10000. Therefore, epicatechin and polycondensates thereof among polyphenols, particularly epicatechin polycondensates having a degree of polymerization and a number average molecular weight in the above range, may be deeply involved in reducing serum uric acid levels.

  The serum uric acid level-reducing agent of the present invention contains one or more selected from the above-mentioned phloroglucinol and its polymer and tamarind extract as an active ingredient, and can further contain anserine as an active ingredient. By using in combination with anserine, the serum uric acid level can be further reduced.

Anserine is a dipeptide in which L-histidine and β-alanine are bound, and its structural formula is as shown in the following formula (III). Anserine is abundant in migratory fish and chicken muscle and brain, and increases the gene expression level of hypoxanthine phosphoribosyltransferase (HPRT), a rate-limiting enzyme in the salvage pathway that re-synthesizes nucleic acids from purines in purine metabolism. (2006, The 60th Annual Meeting of the Japan Nutrition and Food Society). Other functions include antioxidants and fatigue recovery.

  The serum uric acid level reducing agent of the present invention has an action to reduce uric acid level in serum. The effect of reducing serum uric acid level is to decrease to normal when serum uric acid level (uric acid concentration) is high due to hyperuricemia, or to normal when uric acid level is normal. It means to keep it as it is. Confirmation of the effect of reducing serum uric acid level was carried out as described in Chem. Pharm. Bull, 38 (5), (1990) 1224-1229 can be measured by measuring the xanthine oxidase inhibition rate. Moreover, it can also be confirmed by actually administering a high uric acid-inducing component and a sample to a laboratory animal as in Example 2 described later.

  The use of the high uric acid reducing agent of the present invention (that is, a serum uric acid level reducing agent) is not limited to use for prevention or improvement of hyperuricemia, but is used in any scene.

  In the serum uric acid level reducing agent of the present invention, the blending ratio when the active ingredient is phloroglucinol or a polymer thereof can be appropriately adjusted so that the uric acid level in the serum is sufficiently reduced. In the case of administration to humans, the intake of phloroglucinol and its polymer is usually 1-1000 mg per day, preferably 5-600 mg. Further, the concentration of phloroglucinol and the polymer thereof contained in the serum uric acid level reducing agent of the present invention is usually 0.001% by mass or more, preferably 0.01% by mass or more, and usually 100% by mass or less, preferably Is 99.9 mass% or less.

  Moreover, also when using an Ascophylum seaweed extract as a phloroglucinol or its polymer, it is preferable to adjust so that the mixture ratio may become the above-mentioned range in conversion to a phloroglucinol and its polymer. For example, in the case of an ascofilum extract having a polyphenol content (equivalent to phloroglucinol) of 75 to 90% by mass, the amount of human intake as an ascofilum extract is generally 1 mg or more, preferably 10 mg or more per day. is there.

In the serum uric acid level reducing agent of the present invention, when the active ingredient is a tamarind extract and the polyphenol content (equicatechin equivalent amount) of the tamarind extract is, for example, 35 to 60% by mass, The human intake as a tamarind extract is generally in the range of 1 mg or more, preferably 10 mg or more per day. Furthermore, when the polyphenol content (equicatechin equivalent amount) of the tamarind extract is, for example, 35 to 60% by mass, the concentration of the tamarind extract contained in the serum uric acid level reducing agent of the present invention is usually 0.001% by mass. As mentioned above, Preferably it is 0.01 mass% or more, and is 100 mass% or less normally, Preferably it is 99.9 mass% or less.
The concentration of epicatechin and the condensation polymer thereof contained in the serum uric acid level reducing agent of the present invention is usually 0.00035% by mass or more, preferably 0.0035% by mass or more, and usually 60% by mass or less, preferably Is 59.9 mass% or less.

  Furthermore, the human intake of anserine taken at the same time as these components is generally 1 mg or more, preferably 10 mg or more per day. The concentration of anserine contained in the serum uric acid level reducing agent of the present invention is usually 0.001% by mass or more, preferably 0.01% by mass or more, and usually 99.999% by mass or less, preferably 99.9%. It is below mass%.

  Administration forms of the serum uric acid level-reducing agent of the present invention include oral administration (oral administration, sublingual administration, etc.), parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, Oral administration is preferable, although not particularly limited. Also, the dosage form is not particularly limited, and in the case of oral administration, it takes various forms such as tablets, capsules, powders, solutions, tablets, soft capsules, beverages, soups, cookies, gums, drinks and other food forms. be able to.

  Since the serum uric acid level-reducing agent of the present invention can remarkably reduce the serum uric acid level, such as hyperuricemia and its complications such as hyperuricemia and its complications, such as foods and drinks, pharmaceuticals, and quasi-drugs. It can be used for prevention and improvement. In particular, it is useful as a functional food such as a health food.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

  In the following examples, phloroglucinol dihydrate (Wako Pure Chemical Industries, purity 98%), seaweed polyphenol as an ascophyllum extract (RIKEN vitamin, polyphenol content 85.2% by mass (equivalent to phloroglucinol)) , Number average molecular weight 10,000), tamarind extract as Indian date extract (Maruzen Pharmaceutical, polycategory of epicatechin, polyphenol content 36.2% by mass), anserine as marine active (anserine content 10 mass) %) Was used.

Example 1 Evaluation of Xanthine Oxidase (XOD) Activity Inhibition 1-1) Method XOD inhibitory activity at a polyphenol content of 3 ppm was measured for extracts containing various polyphenols in addition to ascofilum extract and tamarind extract.

[Test method of xanthine oxidase (XOD) inhibitory activity]
XOD inhibitory activity was determined according to Chem. Pharm. Bull, 38 (5), (1990) 1224-1229. After mixing a sample solution dissolved in 720 μL of 100 mmol / L phosphate buffer (pH 7.5), 352 μL of distilled water and 48 μL of dimethyl sulfoxide (DMSO) in a test tube, dissolve in 80 μL of 100 mmol / L phosphate buffer Xanthine oxidase (Wako Pure Chemical Industries, 0.04 U / mL) was added and preincubated at 37 ° C. for 10 minutes. Next, 1200 μL of a 0.1 mmol / L xanthine (Wako Pure Chemical Industries) aqueous solution was added as a substrate and reacted at 37 ° C. for 30 minutes. 200 μL of 1 mol / L hydrochloric acid was added to stop the reaction, and the produced uric acid was measured by absorbance at 295 nm.

  The inhibitory activity of xanthine oxidase indicates the ratio of the amount of uric acid due to the addition of the sample, with the amount of uric acid when DMSO is added instead of the sample as a control as 100%.

1-2) Results A very high inhibition rate was confirmed in the ascofilum extract and the tamarind extract (FIG. 1).

  In addition, ascophyllum extract (phloroglucinol and its polymer fluorotannin) and tamarind extract (epicatechin polycondensate) showed a much higher inhibition rate than other polyphenols. On the other hand, ellagic acid, which has already been known to have an XOD inhibitory activity, was inferior at 1/3 or less of the ascofilum extract regardless of the extraction material. In addition, a high inhibitory activity could not be confirmed with theobromine (cocoa extract) and other polyphenols, which were expected to be effective due to the similarity in structure with xanthine (substrate).

On the other hand, the IC ₅₀ of the ascofilum extract and tamarind extract for xanthine oxidase was as shown in Table 1 below. IC ₅₀ represents a concentration that inhibits enzyme activity by 50%.

Example 2 Efficacy Test Using Hyperuric Acid-Induced Rats 2-1) Test Method Efficacy was evaluated using Wistar 6-week-old male rats (6 animals / group). Non-treated group, control group administered with 1.0 g / Kg inosinic acid and 1.0 g / Kg oxonic acid, which are high uric acid-inducing components, Example 2- (1) administered with high uric acid-inducing component and efficacy evaluation sample ˜2- (5) group and Comparative example- (1) to (2) group were carried out.

  As an efficacy evaluation sample, phloroglucinol dihydrate, ascofilum extract, tamarind extract, ascofilum extract and anserine mixture, tamarind extract and anserine mixture, pomegranate extract and anserine were used.

  As shown in FIG. 2, the animals were divided into groups after 7 days of preliminary breeding and tested for 4 days. The efficacy samples shown in Table 2, namely phloroglucinol dihydrate, ascophyllum extract, tamarind extract, anserine, and pomegranate extract, were orally administered once a day for 4 days with a sonde. Separately, the high uric acid-inducing component shown in Table 2 was mixed with powdered feed (CE-2, Nippon Claire) and administered as shown in Table 2.

2-2) Effectiveness evaluation results for uric acid level reduction Table 2 shows the test groups and results.

Due to the induction of hyperuricemia, compared to the uric acid level of 1.0 mg / dL in the untreated group, a higher uric acid level in the control group (administration of inosinic acid 1.0 g / Kg + oxonic acid 1.0 g / Kg) was 4.5 mg / dL. dL was obtained.
On the other hand, in Example 2- (1) to Example 2- (5) to which Ascofilum extract, tamarind extract, and phloroglucinol were administered, the uric acid level was significantly reduced as compared with the control group. In particular, as shown in the results of Examples 2- (3) and 2- (4), although the effect of reducing serum uric acid level is weak with anserine alone as shown in Comparative Example- (2), the above extract is used. Serum uric acid levels were further reduced by the combination of anthrine and anserine. On the other hand, in Comparative Example (1) to which the pomegranate extract was administered, the serum uric acid level was not sufficiently improved.

Reference Example 1: Method for quantifying polyphenol The polyphenol contained in the ascophyllum extract and the tamarind extract was quantified. As standard substances, phloroglucinol dihydrate (Kanto Chemical) and (+)-catechin (SIGMA) were used and analyzed by the Folin Denis method. The analysis conditions and the like were in accordance with reference literature (Japan Food Science and Technology Journal, No. 49, 507-511, 2002). As a result, as shown at the beginning of the examples, it was revealed that the polyphenol content of the ascophyllum extract was 75% by mass or more, and the polyphenol content of the tamarind extract was 35% by mass or more.

Example 3 Composition Example Inventive products 1 to 10 used in the examples are as follows. In the following inventions, a tamarind extract can be used instead of the ascofilum extract.
Invention 1
A film was coated with shellac on tablets obtained by tableting 100 mg of Ascofilum extract, 60 mg of lactose, 80 mg of crystalline cellulose, 5 mg of carboxymethylcellulose-Ca, and 5 mg of sucrose fatty acid ester as usual.

Invention 2
A film coated with shellac on tablets obtained by compressing ascofilum extract 50 mg, marine active (anserine content 10% by mass) 50 mg, lactose 60 mg, crystalline cellulose 80 mg, carboxymethylcellulose-Ca 5 mg, sucrose fatty acid ester 5 mg as usual. .

Invention 3
It mixed so that it might become a ratio of 150g of coffee drinks with respect to 20mg of Ascophyllum extract, and it was set as the drink.

Invention 4
A curry-flavored soup was produced by a conventional method using the following ingredients.
Ascofilum extract 20 mg, butter 30 g, wheat flour 15 g, onion 30 g, pork 50 g, curry powder 3 g, salt 1.5 g, water 200 mL.

Invention 5
Cookies were produced by the usual method using the following raw materials.
The ratio is 20 mg of Ascofilum extract, 100 g of unsalted butter, 60 g of sugar, 0.3 g of salt, 2 egg yolks, and 120 g of flour.

Invention 6
A gum was produced by a conventional method using the following raw materials.
Gum base 32.8% by mass *), Ascofilum extract 2% by mass, sodium tripolyphosphate 1% by mass, xylitol 30.1% by mass, maltitol 30% by mass, aspartame 0.1% by mass, fragrance 4% by mass **) The ratio of
*) Gum base: natural resin 25% by mass, vinyl acetate (degree of polymerization 200) 20% by mass, polyisobutylene 10% by mass, ester gum 10% by mass, wax 20% by mass, fatty acid glycerin ester 5% by mass, calcium carbonate 10% by mass
**) Fragrance: Peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander Oil, mandarin oil, lime oil, lavender oil, rosemary oil, laurel oil, camomil oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil and the like. In addition, menthol, anethole, cineol, eugenol, thymol, linalool, linalyl acetate, limonene, menthone, menthyl acetate, pinene, octylaldehyde, pregon, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl Examples include cyclohexane propionate, methyl anthranilate, ethyl methyl anthranilate, vanillin, undecalactone, hexanal, ethyl alcohol, propyl alcohol, butanol, isoamyl alcohol and the like. Examples of blended fragrances including single fragrances and / or natural fragrances include strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, tropical fruit flavor, butter flavor, milk flavor, fruit mix flavor and the like.

Invention 7
The tablet was manufactured by the conventional method using the following raw materials.
Granulated product *) 108 mg, Ascofilum extract 20 mg, sorbitol 110 mg, partially pregelatinized starch 15 mg, magnesium phosphate 75 mg, calcium stearate 3 mg, menthol particles 40 mg, aspartame 5 mg.
*) 450 g of rosemary extract, 300 g of guava leaf extract, 15 g of sunflower extract, 1935 g of erythritol and 300 g of corn starch are added with 4000 g of a 6% by weight aqueous solution of hydroxypropylcellulose to produce a granulated product, and a granulated product having an average particle size of 290 μm Obtained.

Invention 8
Soft capsules were produced by the conventional method using the following raw materials.
Soft capsules were produced using pork gelatin as a mixture of 20 mg of Ascofilum extract, 110 mg of vegetable oil and fat, 10 mg of glycerin fatty acid ester, and 10 mg or more of beeswax.

Invention 9
A drink was produced by a conventional method using the following raw materials.
Ascofilum extract 20 mg, L-ascorbic acid 800 mg, aspartame 10 mg, citric acid 50 mg, white peach juice 3000 mg, flavor *), purified water balance, total volume 50 mL
*) Can be applied mutatis mutandis from Invention 6.

Invention 10
Using the following raw materials, tablets were produced by routine use.
Ascofilum extract 3 mg, sorbitol 100 mg, fine silicon dioxide 1 mg, aspartame 4 mg, calcium stearate 0.5 mg, flavor *) 15 mg
*) Can be applied mutatis mutandis from Invention 6.

Claims (2)

A serum uric acid level-reducing agent containing at least one selected from the group consisting of phloroglucinol and a polymer thereof as an active ingredient in an amount that reduces the uric acid level in serum . Furthermore, the serum uric acid level reducing agent of Claim 1 which contains anserine as an active ingredient.

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