JP2009126814A - Preventing or improving agent of hyperuricemia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve problems such that the patients of hyperuricemia tend to increase year by year, and on exceeding 7 mg/dl which is an upper limit of the normal value of uric acid value in blood, gout, urarthritis, nephropathy, etc., are developed, and as a therapy of the hyperuricemia, a medicine controlling the uric acid value in the blood is administered, but as such the drug, it is desired to satisfy a moderate effect, lasting property and less adverse effect, and on one hand, foodstuffs preventing or improving the hyperuricemia are also desired. <P>SOLUTION: This preventing or improving agent of the hyperuricemia contains proanthocyanidine as an active ingredient. The beverages and foods containing the above preventing or improving agent of the hyperuricemia are also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a preventive or ameliorating agent for hyperuricemia and a food or drink containing the same.

  Hyperuricemia patients show an increasing trend year by year. When it exceeds 7 mg / dl which is the upper limit of the normal value of blood uric acid level, it develops as gout, gouty arthritis, renal disorder and the like. For the treatment of hyperuricemia, drugs that control blood uric acid levels are administered, but these drugs satisfy the fact that they are mild in action, long-lasting, and have few side effects. It is desirable. On the other hand, foods that prevent or ameliorate hyperuricemia are also demanded. For example, Patent Document 1 discloses a uric acid level reducing agent containing tea polyphenol as an active ingredient.

On the other hand, proanthocyanidins are a kind of polyphenols contained in plants, and are known to have various activities such as antioxidant action (Patent Document 2) and anti-obesity action (Patent Document 3).
JP 2002-370980 A Japanese Patent Publication No. 3-7232 JP 2006-16330 A

  An object of the present invention is to provide a preventive or ameliorating agent for hyperuricemia having high safety and an excellent blood uric acid level lowering effect, and a food and drink using the same.

The invention according to claim 1 is a prophylactic or ameliorating agent for hyperuricemia characterized by containing proanthocyanidins as an active ingredient.
The invention according to claim 2 is the prophylactic or ameliorating agent for hyperuricemia according to claim 1, wherein the proanthocyanidins are pine bark-derived extracts.
The invention according to claim 3 is the prophylactic or ameliorating agent for hyperuricemia according to claim 1 or 2, characterized in that the proanthocyanidins are oligomeric proanthocyanidins.
The invention described in claim 4 is a food or drink comprising the agent for preventing or improving hyperuricemia according to any one of claims 1 to 3.

  According to the present invention, it is possible to provide an agent for preventing or improving hyperuricemia having high safety and an excellent blood uric acid level lowering effect, and a food or drink using the same.

Hereinafter, the present invention will be described in more detail.
The proanthocyanidins used as the active ingredient of the present invention have a degree of polymerization of 2 or more, preferably 2 to 10 monomers, more preferably flavan-3-ol and / or flavan-3,4-diol as a structural unit. The compound group which consists of a 2-4 mer condensation polymer, a derivative | guide_body, and those stereoisomers are designated. Among the proanthocyanidins, a polycondensation polymer having a polymerization degree of 2 to 4 having flavan-3-ol and / or flavan-3,4-diol as a structural unit is referred to as OPC (oligomeric proanthocyanidin). OPC is a powerful antioxidant and is abundant in plant leaves, bark, fruit peel or seed parts. Specifically, it is contained in grapes, pine bark, peanut skin, ginkgo, false acacia fruit, cowberry, blueberry, strawberry, avocado, barley, wheat, soybean, black soybean, cacao and the like. It is also known that OPC is contained in the roots of cola nuts in West Africa and Latania in Peru. OPC is a substance that cannot be produced in the human body.

  With regard to proanthocyanidins used as the active ingredient of the present invention, the origin of the raw material or the utilization part of the raw material, the production method, and the purification method are not limited at all, but the bark, fruit or seed pulverized product, or the extract of these extracts Such food ingredients can be used. In particular, it is preferable to use an extract of pine bark, more preferably French coast pine bark rich in OPC. French coastal pine bark is preferably used as a raw material for proanthocyanidins.

  Proanthocyanidins can be obtained by a known method [for example, the method described in Patent Document 1 or an extraction method from pine bark; RW Hemingway et al., Physochemistry, 1983, Volume 22, p. 275-281] or a method based thereon can be easily obtained from the above-mentioned various plants.

  Hereinafter, a method for preparing proanthocyanidins will be described by taking an extract of pine bark rich in OPC as an example.

  The pine bark extract is obtained by extracting pine bark with water or an organic solvent. When water is used, warm water or hot water is used. As the organic solvent used for extraction, an organic solvent that is acceptable for food or pharmaceutical production is used, for example, methanol, ethanol, propanol, butanol, butane, acetone, hexane, cyclohexane, propylene glycol, hydrous ethanol, hydrous propylene glycol, Examples include ethyl methyl ketone, glycerin, methyl acetate, ethyl acetate, diethyl ether, dichloromethane, edible oils and fats, 1,1,1,2-tetrafluoroethane, 1,2-trichloroethene and the like. These water and organic solvent may be used alone or in combination. In particular, hot water, hydrous ethanol, and hydrous propylene glycol are preferably used.

  A method for extracting proanthocyanidins from pine bark is not particularly limited, and for example, a warm extraction method, a supercritical fluid extraction method, or the like is used.

  The supercritical fluid extraction method is a method of performing extraction using a supercritical fluid that is a fluid that exceeds the critical point (critical temperature, critical pressure) of a gas-liquid substance. As the supercritical fluid, carbon dioxide, ethylene, propane, nitrous oxide (laughing gas) or the like is used, and carbon dioxide is particularly preferably used.

  The supercritical fluid extraction method includes an extraction step of extracting a target component with a supercritical fluid and a separation step of separating the target component and the supercritical fluid. In the separation step, any one of extraction separation by pressure change, extraction separation by temperature change, or extraction separation using an adsorbent and an absorbent may be performed.

  Moreover, you may perform supercritical fluid extraction by the entrainer addition method. In this method, for example, about 2 to 20% of ethanol, propanol, n-hexane, acetone, toluene, or the like is added to the supercritical fluid, and supercritical fluid extraction is performed with the obtained extraction fluid, so that OPC or the like is performed. This is a method for dramatically increasing the solubility of the extract in the extraction fluid, or for enhancing the separation selectivity, and for efficiently obtaining a pine bark extract.

  Extraction from pine bark may be performed by a liquid carbon dioxide batch method, a liquid carbon dioxide reflux method, a supercritical carbon dioxide reflux method, or the like, in addition to the above method.

  The proanthocyanidins obtained as described above can be obtained in a liquid or semi-solid form. If the extraction solvent is removed from this product by a known method such as distillation under reduced pressure, spray drying, freeze drying, or the like, it remains as it is. It can be used as a proanthocyanidin-containing concentrate or dried product. For further purification, a known purification means such as column chromatography or countercurrent distribution method can be employed to achieve the object.

  The proanthocyanidins of the present invention dissolve well in water and have high absorbability to living bodies. It is highly stable in any of acidic, neutral and alkaline conditions, and can be easily blended with food and drink while maintaining its function. In addition, the effect can be expected in a short period after the start of ingestion, and a sufficient effect can be obtained even with a small amount of ingestion, so it can be used as a food material for infants and the elderly who have limited intake allowance and intake form as food and drink High value. Therefore, the food and drink of the present invention may be, for example, health foods, health function foods (specific health foods, nutrient function foods), and the like.

  The preventive or ameliorating agent for hyperuricemia of the present invention should be appropriately prepared by a known method in the form of solids or solutions (hereinafter also referred to as preparations) such as tablets, pills, capsules, granules, powders, powders, and liquids. Can do. That is, the solid preparation or liquid preparation useful in the present invention is produced by mixing proanthocyanidins and, if desired, additives and using a well-known preparation method that has been well established. Examples of additives include excipients, pH adjusting agents, cooling agents, suspending agents, diluents, antifoaming agents, thickeners, solubilizers, disintegrating agents, binders, lubricants, antioxidants. Agents, coating agents, coloring agents, flavoring agents, surfactants, plasticizers or fragrances.

  Examples of the excipient include sugar alcohols such as D-sorbitol, D-mannitol or xylitol, sugars such as glucose, sucrose, lactose or fructose, crystalline cellulose, carmellose sodium, calcium hydrogen phosphate, wheat starch, rice Examples thereof include starch, corn starch, potato starch, dextrin, β-cyclodextrin, light anhydrous silicic acid, titanium oxide, and magnesium aluminate metasilicate.

Examples of the pH adjuster include citric acid, malic acid, sodium hydrogen phosphate, and dipotassium phosphate.
Examples of the refreshing agent include l-menthol or mint water.
Examples of the suspending agent include kaolin, carmellose sodium, xanthan gum, methylcellulose, and tragacanth.
Examples of the diluent include purified water, ethanol, vegetable oil, and emulsifier.
Examples of the antifoaming agent include dimethylpolysiloxane or silicon antifoaming agent.

Examples of the thickener include xanthan gum, tragacanth, methylcellulose, and dextrin.
Examples of the solubilizer include ethanol, sucrose fatty acid ester, and macrogol.
Examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, or partially pregelatinized starch.

  Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, or propylene glycol alginate. Can be mentioned.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax and white beeswax.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, ascorbic acid, and citric acid.

Examples of the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate. Copolymer, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, polyvinyl acetate diethylaminoacetate or shellac.
Examples of the colorant include turmeric extract, riboflavin, titanium oxide, or carotene solution.

Examples of the flavoring agents include citric acid, adipic acid, ascorbic acid, fructose, D-sorbitol, glucose, sodium saccharin, simple syrup, sucrose, honey, amacha, licorice, citric acid, adipic acid, ascorbic acid, orange oil, Spruce tincture, fennel oil, mint or menthol.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol or sucrose. Examples include fatty acid esters.
Examples of the plasticizer include triethyl citrate, polyethylene glycol, triacetin, and cetanol.
As said fragrance | flavor, synthetic fragrance | flavors, such as natural fragrance | flavors, such as an animal fragrance | flavor or a vegetable fragrance | flavor, or an isolated fragrance | flavor etc. are mentioned, for example.

In the various preparation forms, the amount of proanthocyanidins is usually about 1 to 80% by weight, preferably about 2 to 50% by weight, based on the whole preparation.
The administration method of the preparation of the present invention may be oral or parenteral. The dose of proanthocyanidins, which are the active ingredients of the present invention, varies depending on the type, dosage form, patient age, body weight, indication symptoms, and the like. Several doses may be administered at a dose of about 1 to 500 mg, preferably about 3 to 300 mg.

  The food / beverage products of this invention are manufactured by mix | blending proanthocyanidin or the said proanthocyanidin containing formulation with food / beverage-drink material at the time of food-drinks manufacture. For example, solid foods such as bread, chewing gum, cookies, chocolate, cereals, jams, ice cream, yogurt, jelly and other jams, creams or gels, juices, coffee, cocoa, green tea, oolong tea, tea and other beverages Any food form can be used. Moreover, it can also mix | blend with a seasoning, a food additive, etc. The blending amount of the proanthocyanidins or the proanthocyanidin-containing preparations in the food and drink material is not particularly limited, but is usually about 0.0001 to 80% by weight, preferably about 0.005 to 50% by weight. Moreover, especially in the case of a drink, it is 1 mg / L-20 g / L, Preferably it is 2 mg / L-10 g / L.

  In addition, the intake of proanthocyanidins when the present invention is a food or drink may be an amount equivalent to the dose of the internal medicine because there is no concern about side effects.

Moreover, in this invention, it is also a preferable form to use a kuzu flower processed material together.
The processed kuzu flower used in the present invention is not particularly limited as long as it is a processed product of the flower part of the kuzu plant belonging to the leguminous plant. Kuzuka includes flowers collected at the stage from buds to fully opened flowers. It is preferable to use soot. In the present specification, the “Kuzuka processed product” refers to a product obtained by subjecting Kuzuka to at least one of a drying process, a pulverization process, and an extraction process. The kuzu flower processed product includes a dried kuzu flower, a kuzu flower crushed product, a dried katsu flower kuzu flower powder, and a kuzu flower extract. The kuzu flower extract includes an extract obtained by performing an extraction process from kuzu flower, kuzu flower crushed material, kuzu flower dry product or kuzu flower powder. The shape of the kuzu flower extract is not limited and may be liquid, paste, or powder.

  The processed Kuzuka product used in the present invention contains saponins, tryptophan glycosides and the like in addition to flavonoids such as isoflavones, and preferably can contain isoflavones and saponins. The content of these components is not particularly limited. Preferably, the isoflavones in the processed kuzuhana product are 3% by mass or more, more preferably 5% by mass to 90% by mass in terms of dry mass. The saponin is preferably 1% by mass or more, more preferably 2% by mass to 50% by mass. As such a kuzu flower processed product containing a high content of isoflavones and saponins, a kuzu flower extract is preferably used. The kuzu flower extract has an effect of preventing and reducing the accumulation of visceral fat and subcutaneous fat, and thus has an effect of preventing and reducing the accumulation of body fat. As a result, it has an anti-obesity effect that reduces body weight. It also has an effect of improving blood lipids. These body fat accumulation preventing effect, body fat reducing effect, anti-obesity effect, and blood lipid improving effect are considered to involve components other than isoflavones contained in kuzuhana. As shown in the examples, this is superior to soy extracts containing the same amount of isoflavones or saponins.

  Hereinafter, the preparation method of the dried katsuka, kuzuka powder and kuzuka extract, which are the kuzuka processed products, will be described.

  The dried product of Kuzuka is a dried Kuzuka, preferably Kuzuka in the cocoon stage, dried by a method such as sun drying or hot air drying. Preferably, it can be carried out until the water content is 10% by mass or less.

  The kuzu flower powder is obtained by pulverizing the dried kuzu flower. The powderization is performed by a method usually used by those skilled in the art, for example, a ball mill, a hammer mill, a roller mill, or the like.

  The kuzu flower powder can also be obtained by crushing the collected kuzu flowers using a mascolloider, slicer, comitolol, etc. to obtain a kuzu flower crushed material, and drying the kuzu flower crushed material.

  For example, the Kuzuka extract can be added as necessary by adding a solvent to the Kuzuka collection, Kuzuka crushed material, dried Katsuka or Kuzuka powder (hereinafter sometimes referred to simply as “raw material”). Extraction is performed by heating, and the extract is collected by centrifugation or filtration.

  Examples of the solvent used for the extraction include water, an organic solvent, a water-containing organic solvent, and the like similar to the pine bark extract described above, and most preferably ethanol.

  The extraction temperature is not particularly limited as long as it is a temperature below the boiling point of the solvent used. The extraction temperature varies depending on the solvent to be used, but is generally 4 ° C to 130 ° C in consideration of decomposition of active ingredients. Preferably they are 50 to 130 degreeC, More preferably, it is 70 to 100 degreeC. When extracting by heating, for example, a heating extraction method such as heating under reflux, a supercritical extraction method, or the like can be employed. When heating, pressurization may be performed.

  The extraction time may be a time for sufficiently extracting soluble components from the extraction raw material, and may be set as appropriate according to the extraction temperature and the like. Preferably, it is 30 minutes to 48 hours. For example, when the extraction temperature is less than 50 ° C., it can be extracted for 6 hours to 48 hours, and when it is 50 ° C. or more, it can be extracted for 30 minutes to 24 hours.

  Moreover, the obtained extract is concentrated by a method used by those skilled in the art, such as vacuum concentration or freeze-drying, as necessary, and a kuzuhana extract is obtained by forming a liquid, a paste, or a powder. In addition, a powdery kuzu flower extract may be called an extract powder.

  Alternatively, this extract is further purified using a synthetic adsorbent (Diaion HP20, Sephabies SP825, Amberlite XAD4, MCIgelCHP20P, etc.) or dextran resin (Sephadex LH-20, etc.), and the concentration of flavonoids, saponins, etc. is high. Kuzuhana extract can be obtained.

  The intake of the processed kuzuhana product is the same as that of proanthocyanidins. That is, it is good to administer about 1 to 500 mg, preferably about 3 to 300 mg once a day for adults once to several times a day.

  Furthermore, in the present invention, for example, royal jelly, propolis, vitamins (A, C, D, E, K, folic acid, pantothenic acid, biotin, derivatives thereof, etc.), minerals (iron, magnesium, calcium, zinc, etc.), Selenium, lecithin, carotenoids (lycopene, astaxanthin, zeaxanthin, lutein, etc.), saponins (gymnemic acid, soybean saponin, ginseng saponins, etc.), fatty acids, proteins (collagen, elastin, etc.), oligosaccharides (isomalto-oligosaccharides, cyclic oligosaccharides, etc.) ), Phospholipids and derivatives thereof (phosphatidylcholine, sphingomyelin, ceramide, etc.), sulfur-containing compounds (eg, alliin, sepaene, taurine, glutathione, methylsulfonylmethane), sugar alcohols, lignans (sesamin, etc.), Contains animal and plant extracts Root vegetables (turmeric, ginger, etc.), green leaves of gramineous plants such as wheat leaves, green leaves of cruciferous plants such as kale, dried cactus leaves, terminaria berylica extract, whole potato stems and leaves, soybean It is also possible to use a ceramide-like component-extracted material extracted from the above, herbs such as Chancapiedra, and the like. Among them, green leaves of gramineous plants such as young wheat leaves, green leaves of cruciferous plants such as kale, dried cactus leaves, terminaria berylica extract, whole potato stems and leaves, ceramide-like components extracted from soybeans When using herbs such as foods and Chanca Piedra, the effect of lowering blood uric acid level is the same as that of the above-mentioned form in which proanthocyanidins and kuzuka processed products are used in combination.

  Hereinafter, the present invention will be described in detail by way of examples using a pine bark extract rich in OPC as an example, but the present invention is not limited thereto.

Example 1
To 900 g of pine bark, 7.2 L of purified water was added, crushed with a blender (Waring Blender), and then extracted by heating at 100 ° C. for 10 minutes. Then, it filtered immediately and obtained the filtrate. The residue after filtration was washed with 1.8 L of purified water, and the filtrate and the washing solution were combined to obtain 9 L of a crude hot water extract of pine bark. When 1 mL of this extract was freeze-dried, the dry weight was 8 mg.

  1 L of the above crude extract (powder dry weight 8 g) was allowed to cool to 25 ° C., sodium chloride was added to 100% saturation concentration and stirred well, and then allowed to stand at 4 ° C. for 24 hours. After standing, this solution was filtered to obtain 910 mL of filtrate. This filtrate was further purified by the steps shown below. First, the filtrate was passed through a 30 × 300 mm column packed with 100 mL of an aromatic synthetic resin swollen with water (Diaion HP-20: manufactured by Mitsubishi Chemical Corporation), and further washed with 1 L of purified water. . Next, the column was eluted with a 15% (V / V) ethanol-water mixed solvent to obtain 200 mL of a pine bark hot water extraction purified product (hereinafter referred to as pine bark hot water extract 1). The obtained purified product was freeze-dried and powdered. This operation was repeated to obtain 7.51 g of dry powder of hot water extract 1 of pine bark from 9 L of hot water extract of pine bark.

  As a result of measuring the content of proanthocyanidins and OPC in the dry powder by the method described in JP-A-2005-23032, 40% by weight of proanthocyanidins was contained in the dry powder. Further, OPC was contained as a 2 to 4 mer in 20% by weight in the dry powder.

The effect of the dry powder of the hot water extract 1 on hyperuricemia was examined.
Experimental Method As test animals, Wistar rats (female) (8 weeks old, body weight of about 180 g) were used in 6 animals per group.
Adenine was added to the test feed at a concentration of 0.75% and fed to rats to cause inhibition of uric acid excretion into the urine from the kidney, thereby giving a model animal of hyperuricemia.
The control group was the above 0.75% adenine feed alone, and the drug administration group was a feed containing 0.75% adenine and the dry powder of hot water extract 1 described above. Although the feed was freely consumed, the concentration of the dry powder of the hot water extract 1 in the test diet of the drug administration group was adjusted so that the intake amount was 1 mg / kg body weight. The uric acid level in the blood was measured on the test start day and 24th day.
As a result, the blood uric acid concentration on the test start day of the control group was 0.57 mg / ml, and it was 2.33 mg / ml on the 24th day. The uric acid concentration was 0.73 mg / ml.
As is clear from this result, the blood uric acid concentration in the control group was significantly increased, whereas in the drug administration group, the concentration was not increased. Therefore, it has been shown that a drug containing proanthocyanidins as an active ingredient is useful as an agent for preventing or improving hyperuricemia.

Example 2
20 times the amount of hot water (80 ° C.) was added to the dried product of the crushed katsuhana, and stirred for 2 hours to obtain a hot water extract 2. The hot water extract 2 was concentrated under reduced pressure and lyophilized to obtain a powder.
In the drug administration group of Example 1, in addition to the dry powder of hot water extract 1, the powder of this example was added, and the same experiment as in Example 1 was performed. The concentration of the powder of this example was adjusted so that the intake amount was 1 mg / kg body weight. As a result, the blood uric acid concentration on day 24 of the drug administration group in this example was 0.60 mg / ml.

Example 3
Six humans (normal male adult volunteers) were orally administered 500 mg of the dry powder of hot water extract 1 of Example 1 once, and then the serum uric acid level was measured over 48 hours.
The results are shown in Table 1.

  Each numerical value after administration has a significant difference at a risk rate of 5%.

Example 4
In Example 3, Example 3 was repeated except that 500 mg of the powder derived from the hot water extract 2 of Example 2 was added to 500 mg of the dry powder of the hot water extract 1 and further administered orally. As a result, the serum uric acid level at 12 hours after administration decreased to 4.67 ± 0.77 mg / dl.

Example 5
Deionized water was added so that the tea leaf usage rate was 0.8% by weight with respect to the extract of oolong tea, black tea, green tea, hoji tea and jasmine tea extracted with hot water at 85 ° C. At that time, ascorbic acid was added so that it might become 0.025 weight%, and then it adjusted to pH which was easy to drink using baking soda. Furthermore, after adding so that the dry powder of the said hot-water extract 1 might be set to 5 mg with respect to the said preparation liquid 100g, UHT sterilization was performed as usual, and it filled into the 350 ml volume PET bottle, and various drinks were obtained.

Example 6
Juice was prepared according to the following formulation.
Frozen concentrated orange juice 5.0 parts by weight Fructose glucose liquid sugar 1.0 part by weight Citric acid 0.10 parts by weight L-ascorbic acid 0.09 parts by weight Dry powder of the hot water extract 1 0.05 parts by weight

  The agent for preventing or improving hyperuricemia of the present invention is useful as a pharmaceutical, food, or feed form.

Claims (4)

  An agent for preventing or improving hyperuricemia, comprising proanthocyanidins as an active ingredient.   The agent for preventing or improving hyperuricemia according to claim 1, wherein the proanthocyanidins are pine bark-derived extracts.   The agent for preventing or improving hyperuricemia according to claim 1 or 2, wherein the proanthocyanidins are oligomeric proanthocyanidins.   A food or drink comprising the agent for preventing or improving hyperuricemia according to any one of claims 1 to 3.